Next-generation modulators of stimulator of interferon genes (STING)

Abstract

The present invention relates to compounds of formula (I) and their salts, stereoisomers, tautomers or N-oxides, which can be used as modulators of STING (stimulator of interferon genes). The present invention also relates to compounds of formula (I) for use as medicaments and pharmaceutical compositions comprising said compounds.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to compounds of formula (I), and salts, stereoisomers, tautomers or N-oxides thereof, which can be used as modulators of STING (stimulator of interferon genes). The present invention also relates to compounds of formula (I) for use as medicaments and pharmaceutical compositions comprising said compounds. BACKGROUND OF THE INVENTION

[0003] The innate immune system of cells is crucial for recognizing pathogen infections and establishing effective host defenses. The adaptor protein STING (stimulator of interferon genes), also known as TMEM 173, MPYS, MITA and ERIS, has been identified as a central signaling molecule in the innate immune response against cytosolic nucleic acids (H. Ishikawa, GN Barber, Nature, 2008, Vol. 455, pp. 674-678). STING particularly induces the production of type I interferons (IFNs) when cells are infected with intracellular pathogens such as viruses, mycobacteria and intracellular parasites.

[0004] Activation of STING promotes IRF3- and NFkB-dependent signaling and thus leads to the production of pro-inflammatory cytokines and interferons, including type I and type III interferons and TNFα, which are particularly important in cancer immunotherapy. STING is responsible for sensing cytosolic nucleic acids and their derivatives (called cyclic dinucleotides (CDNs)) of pathogen or host origin (e.g., double-stranded DNA from bacteria or viruses and cytosolic self-DNA).

[0005] The endogenous STING direct agonist 2′,3′-cGAMP (2′,3′-cyclic guanosine monophosphate-adenosine monophosphate) and its derivatives are produced in mammalian cells by the enzyme cGAS (cyclic GMP-AMP synthase, MB21D1 or C6orfl50) (P. Gao et al., Cell, 2013, 153, pp. 1094-1107, Wu et al. Science, 2013, 339, pp. 786-791) and have been shown to be active in modulating STING-dependent pathways (L. Corrales et al., J Immunother Cancer, 2013, 1 (Suppl 1): O15, L. Corrales et al., Cell Rep., May 19, 2015; 11(7), pp. 1018-30, SR. Woo et al Trends Immunol., 2015, 36(4), 250, J. Fu et al., Sci. Trans. Med., Vol. 7, No. 283, 283ra52).

[0006] Recent evidence supports the finding that once STING is activated by CDNs preferably in tumor-resident dendritic cells in the tumor microenvironment, it promotes the release of type I IFN and TNFα, leading to an immune-mediated anti-tumor response. STING-dependent activation of antigen-presenting cells (APCs) effectively drives the priming of highly specific T cells against neoantigens (L. Corrales and TF Gajewski, Clin Cancer Res, 2015, 21(21), pp. 4774-9). STING activation not only provides the generation of tumor-specific cytotoxic T cells, which directly eradicate tumors, but also generates a vaccine-like long-lasting immunity that prevents cancer recurrence.

[0007] Therefore, synthetic STING agonists are of particular interest as potential anti-cancer agents. Activation or inhibition of type I interferon production is an important strategy for treating or preventing human diseases, including viral infections and autoimmune diseases. It has been found that compounds that activate or inhibit type I interferon production can be used not only for innate immunity against infectious diseases but also for cancer (L. Zitvogel et al., Nature Reviews Immunology, 2015, vol. 15(7), pp. 405-414), allergic diseases (J. Moisan et al., Am. J. Physiol. Lung Cell Mol. Physiol., 2006, vol. 290, L987-995), neurodegenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis (H. Lemos et al., J. Immunol, 2014, vol. 192(12), pp. 5571-8; E. Cirulli et al., Science, 2015, vol. 347(6229), pp. 1436-41; A. Freischmidt et al., Nat. Neurosci., vol. 18(5), 631-6), other inflammatory disorders such as irritable bowel disease (S. Rakoff-Nahoum, Cell, 2004, 23, 118(2), pp. 229-41), and as vaccine adjuvants (Persing et al., Trends Microbi0l. 2002, 10(10 Suppl.), S32-7; Dubensky et al., Advances in Vaccines, published online on September 5, 2013).

[0008] STING is critical for antibacterial host defense, including protection against a range of DNA and RNA viruses and bacteria (reviewed in Barber et al., Nat. Rev. Immunol., 2015, Vol. 15(2), pp. 87-103, Ma and Damania, Cell Host & Microbe, 2016, Vol. 19(2), pp. 150-158). Herpesviridae, Flaviviridae, Coronaviridae, Papillomaviridae, Adenoviridae, Hepadnaviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae have evolved mechanisms to inhibit STING-mediated type I interferon production and evade host immune control (Holm et al., Nat Comm., 2016, Vol. 7, p. 10680; Ma et al., PNAS 2015, Vol. 112(31), E4306-E4315; Wu et al., Cell Host Microbe, 2015, Vol. 18(3), pp. 333-44; Liu et al., J Virol, 2016, Vol. 90(20), pp. 9406-19; Chen et al., Protein Cell 2014, Vol. 5(5), pp. 369-81; Lau et al., Science, 2013, Vol. 350(6260), pp. 568-71; Ding et al., J Hepatol, 2013, Vol. 59(1), pp. 52-8; Nitta et al., Hepatology, 2013, Vol. 57(1), pp. 46-58; Sun et al., PloS One, 2012, Vol. 7(2), e30802; Aguirre et al., PloS Pathog, 2012, Vol. 8(10), e1002934; Ishikawa et al., Nature, 2009, Vol. 461(7265), pp. 788-92). Thus, small molecule activation of STING is thought to be beneficial for treating these infectious diseases.

[0009] In contrast, increased and prolonged type I IFN production has been associated with a variety of chronic infections, including Mycobacterium (Collins et al., Cell Host Microbe, 2015, Vol. 17(6), pp. 820-8; Wassermann et al., Cell Host Microbe, 2015, Vol. 17(6), pp. 799-810; Watson et al., Cell Host Microbe, 2015, Vol. 17(6), pp. 811-9), Francisella (Storek et al., J Immunol., 2015, Vol. 194(7), pp. 3236-45; Jin et al., J Immunol., 2011, Vol. 187(5), pp. 2595-601), Chlamydia (Prantner et al., J Immunol, 2010, Vol. 184(5), pp. 2551-60), Plasmodium (Sharma et al., Immunity, 2011, Vol. 35(2), pp. 194-207), and HIV (Herzner et al., Nat Immunol, 2015, Vol. 16(10), pp. 1025-33; Gao et al., Science, 2013, Vol. 341(6148), pp. 903-6). Similarly, excessive type I interferon production has been found in patients with complex forms of autoimmune disease. Human genetic evidence and studies in animal models support the hypothesis that inhibition of STING results in reduced type I interferon that drives autoimmune disease (YJ Crow et al., Nat. Genet., 2006, Vol. 38(8), pp. 38917-920, DB Stetson et al., Cell, 2008, Vol. 134587-598). Thus, STING inhibitors provide a treatment for patients with chronic type I interferon and pro-inflammatory cytokine production associated with infection or complex autoimmune disease. Allergic diseases are associated with Th2-based immune responses to allergens. Th2 responses are associated with increased IgE levels, which promote hypersensitivity reactions to allergens through their effects on mast cells, resulting in symptoms such as those seen in allergic rhinitis and asthma. In healthy individuals, the immune response to allergens is more balanced in the context of a mixed Th2 / Th1 and regulatory T cell response. Induction of type 1 interferon has been shown to result in a reduction of Th2-type cytokines in the local environment and to promote Th1 / Treg responses. In this context, induction of type 1 interferon, for example by activating STING, may contribute to the treatment of allergic diseases such as asthma and allergic rhinitis (JP Huber et al., J Immunol, 2010, Vol. 185, pp. 813-817).

[0010] In view of the above, compounds that modulate STING can be used to treat one or more diseases selected from inflammatory diseases, allergic diseases, and autoimmune diseases, infectious diseases, cancer, and pre-cancerous syndromes, and / or as immunogenic compositions or vaccine adjuvants. Particularly relevant is the immunotherapy of cancer and viral infections, especially the immunotherapy of prostate cancer, renal cancer, melanoma, pancreatic cancer, cervical cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, fibrosarcoma, breast cancer, and hepatitis B. In addition, the activation of a local immune response against a lesion is considered to be a preferred intratumoral or systemic treatment method.

[0011] Accordingly, there is a need for compounds that modulate STING activity and thus provide a therapeutic effect in the treatment of diseases where modulation of STING is beneficial.

[0012] Objectives and Overview of the Invention

[0013] Accordingly, an object of the present invention is to provide compounds that modulate STING, particularly compounds that act as STING agonists to activate STING. In particular, there is interest in providing compounds that have high activity as STING agonists.

[0014] Another object of the present invention is to provide compounds suitable for use as drugs. Another object of the present invention is to provide compounds suitable for treating one or more diseases related to STING modulation. Yet another object is to provide compounds suitable for treating one or more diseases selected from inflammatory diseases, allergic diseases, autoimmune diseases, infectious diseases, cancer, and pre-cancerous syndromes. In particular, an object is to provide compounds suitable for treating cancer, particularly prostate cancer, lung cancer, breast cancer, head and neck cancer, bladder cancer, and / or melanoma. Yet another object is to provide compounds suitable for use in immunogenic compositions and as vaccine adjuvants.

[0015] The above objects can be achieved by the compounds of formula (I) as defined herein, and pharmaceutical compositions containing the same and their medical uses.

[0016] The inventors of the present invention have particularly unexpectedly found that the compounds of formula (I) as defined herein modulate STING, particularly acting as STING agonists. Accordingly, the compounds of formula (I) can be used as drugs, particularly for treating one or more diseases selected from inflammatory diseases, allergic diseases, autoimmune diseases, infectious diseases, cancer, and pre-cancerous syndromes. In particular, the compounds of formula (I) are suitable for treating cancer, particularly prostate cancer, lung cancer, breast cancer, head and neck cancer, bladder cancer, and / or melanoma. In addition, the compounds of formula (I) are suitable for use in immunogenic compositions and as vaccine adjuvants.

[0017] In a first aspect, the invention thus relates to a compound of formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof,

[0018]

[0019] wherein,

[0020] X 1 is CR 1 or N;

[0021] X 2 is CR 3 or N;

[0022] R 1 、R 2 and R 3 are independently H, OH, CN, halogen, C1-C4-alkyl, C1-C4-alkoxy, aryloxy, benzyloxy, C(=O)R E 、NR F C(=O)R E 、NR F -(C1-C4-alkylene)-C(=O)R E 、or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group, heterocyclic group-oxy or heterocyclic group-C1-C2-alkyl, wherein the above-mentioned heterocyclic group contains one or more identical or different heteroatoms selected from O, N or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned groups is independently unsubstituted or substituted by one or more identical or different substituents R X ;

[0023] R 4 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9- or 10-membered aromatic carbocyclic or heterocyclic bicyclic ring, wherein the heterocyclic or heterocyclic bicyclic ring contains at least one nitrogen atom and optionally one or more identical or different additional heteroatoms selected from O, N or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned rings is independently unsubstituted or substituted by one or more identical or different substituents R X ;

[0024] R 5 is a 5- or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted by one or more identical or different substituents R YSubstituted;

[0025] and wherein

[0026] R N is H, C1-C4-alkyl, HO(C=O)-C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclic or heterocyclic group, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R X Substituted;

[0027] R A is H, halogen, CN, OH, C1-C3-alkyl, C1-C3-alkoxy or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R X Substituted;

[0028] R C and R D are independently H or C1-C2-alkyl; or

[0029] R C and R D together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocycle, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said heterocycle is independently unsubstituted or substituted with one or more identical or different substituents R X Substituted;

[0030] R E is H, C1-C2-alkyl, phenyl, benzyl, OR G or NR H R I ; or a 5- or 6-membered saturated, partially or fully unsaturated heterocyclic group, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R F Substituted;

[0031] R F is H, C1-C2-alkyl, C3-C6-cycloalkyl, phenyl, benzyl or C(=O)NR H R I ;

[0032] R G is H, C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group or heterocyclic-C1-C2-alkyl, wherein said heterocyclic group contains one or more identical or different heteroatoms selected from O, N or S, and wherein said N-atoms are independently oxidized or unoxidized;

[0033] R H and R I are independently H, C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group or heterocyclic-C1-C2-alkyl, wherein said heterocyclic group contains one or more identical or different heteroatoms selected from O, N or S, and wherein said N-atoms are independently oxidized or unoxidized; or

[0034] R H and R I together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, and wherein said N-atoms and / or S-atoms are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said heterocyclic ring is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0035] R X is halogen, CN, NO2, C1-C2-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, C(=O)R E , or two R X form =O, or two R X together with the carbon atom to which they are attached form a 3- to 5-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring;

[0036] R Y is halogen, CN, OH, C1-C2-alkyl, C1-C2-alkyl-OH, C3-C6-cycloalkyl, C1-C2-alkoxy, NR C R D 、S(=O)2NR C R D 、C(=O)R E, or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group or heterocyclic group-C1-C2-alkyl, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said groups is independently unsubstituted or substituted with one or more identical or different substituents R X are substituted; or two R Y form =O; or two R Y attached to the same or adjacent carbon atoms can form a 3-membered carbocycle.

[0037] In another aspect, the present invention relates to a compound of formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof,

[0038]

[0039] wherein,

[0040] X 1 is CR 1 or N;

[0041] X 2 is CR 3 or N;

[0042] R 1 、R 2 and R 3 are independently H, OH, CN, halogen, C1-C4-alkyl, C1-C4-alkoxy, aryloxy, benzyloxy, C(=O)R E 、NR F C(=O)R E 、NR F -(C1-C4-alkylene)-C(=O)R E 、or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group, heterocyclic group-oxy or heterocyclic group-C1-C2-alkyl, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0043] R 4is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9- or 10-membered aromatic carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring contains at least one nitrogen atom and optionally one or more additional identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said ring is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0044] R 5 is a 5- or 6-membered saturated heterocyclic ring, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R Y substituted;

[0045] and wherein

[0046] R N is H, CH3, HO(C=O)-C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclic or heterocyclic group, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said group is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0047] R A is H, halogen, CN, OH, C1-C3-alkyl, C1-C3-alkoxy or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said group is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0048] R C and R D are independently H or C1-C2-alkyl; or

[0049] R C and R DTogether with the nitrogen atoms to which they are bonded, form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocycle, wherein the heterocycle contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the heterocycle is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0050] R E is H, C1-C2-alkyl, phenyl, benzyl, OR G or NR H R I ; or a 5- or 6-membered saturated, partially or fully unsaturated heterocyclic group, wherein the heterocycle contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above group is independently unsubstituted or substituted with one or more identical or different substituents R F substituted;

[0051] R F is H, C1-C2-alkyl, C3-C6-cycloalkyl, phenyl, benzyl or C(=O)NR H R I ;

[0052] R G is H, C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group or heterocyclic-C1-C2-alkyl, wherein the above heterocycle contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N-atom is independently oxidized or unoxidized;

[0053] R H and R I are independently H, C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group or heterocyclic-C1-C2-alkyl, wherein the above heterocycle contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N-atom is independently oxidized or unoxidized; or

[0054] R H and R ITogether with the nitrogen atom to which they are bonded, form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocycle, wherein the heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein the N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the heterocycle is independently unsubstituted or substituted with one or more identical or different substituents R X Substituted;

[0055] R X Is halogen, CN, NO2, C1-C2-alkyl, C1-C2-alkoxy, C(=O)R E Or two R X Form =O;

[0056] R Y Is halogen, CN, OH, C1-C2-alkyl, C1-C2-alkyl-OH, C3-C6-cycloalkyl, C1-C2-alkoxy, NR C R D 、S(=O)2NR C R D 、C(=O)R E Or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group, and heterocyclic group-C1-C2-alkyl, wherein the above heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein the N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above group is independently unsubstituted or substituted with one or more identical or different substituents R X Substituted; or two R Y Form =O; or two R Y Attached to the same or adjacent carbon atoms can form a 3-membered carbocycle.

[0057] The following embodiments are related to the above aspects.

[0058] In a preferred embodiment,

[0059] R A Is H.

[0060] In a preferred embodiment,

[0061] R N Is H, CH3 or cyclopropyl, preferably CH3.

[0062] In another preferred embodiment,

[0063] R N Is cyclopropyl.

[0064] In another preferred embodiment,

[0065] R 1 、R 2 and R 3 is H.

[0066] In another preferred embodiment,

[0067] R 5 is a 6-membered saturated heterocycle, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted by one or more identical or different substituents R Y substituted.

[0068] In a more preferred embodiment,

[0069] R 5 is piperidine, wherein each substitutable carbon or heteroatom in the piperidine ring is independently unsubstituted or substituted by one or more identical or different substituents R Y substituted.

[0070] In another more preferred embodiment,

[0071] R 5 is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted by one or more identical or different substituents R Y substituted; and wherein the nitrogen atom in the piperidine ring is preferably substituted by R Y which is pyridyl.

[0072] In another more preferred embodiment,

[0073] R 5 is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted by one or more identical or different substituents R Y substituted; and wherein the nitrogen atom in the piperidine ring is substituted by R Y substituted, R Y is pyridyl, which is unsubstituted or substituted by one or more identical or different substituents R X substituted, wherein R X is preferably methyl.

[0074] In a preferred embodiment,

[0075] R 4 is pyridyl, wherein each substitutable carbon atom in the ring is independently unsubstituted or substituted by one or more identical or different substituents RX substituted.

[0076] In another preferred embodiment,

[0077] X 1 is CR 1 ; and

[0078] X 2 is CR 3 ;

[0079] and wherein

[0080] R 1 and R 3 are preferably H.

[0081] In a preferred embodiment,

[0082] R X is halogen, CN, C1-C2-alkyl or C1-C2-alkoxy.

[0083] In another preferred embodiment,

[0084] R X is NO2, C(=O)R E , or two Rs X form =O.

[0085] In a preferred embodiment,

[0086] R Y is halogen, CN, OH, C1-C2-alkyl, or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group and heterocyclic-C1-C2-alkyl, wherein said heterocyclic contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0087] In a more preferred embodiment, the compound according to formula (I) is selected from: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyrazin-2-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyrimidin-5-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(3-bromopyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-ethylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3R,4R)-4-hydroxy-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S,{(5R)-5-methyl-1-(pyridin-3-yl)piperidin-3-yl}[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, methyl 1-[1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylate / ester, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 3-({[(3S)-1-(5-bromopyrimidin-2-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[5,5-difluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2,6-dimethylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl][(pyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-7-[4-(2,2-difluoroethyl)piperazin-1-yl]-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(2-oxopiperazin-1-yl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(oxetan-3-yl)-1,4-dihydroquinolin-4-one, 2-[3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-1-yl]acetic acid, and 1-cyclopropyl-7-{4,7-diazaspiro[2.5]octan-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one.,

[0088] In another more preferred embodiment, the compound according to formula (I) is a compound selected from the following: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyrazin-2-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyrimidin-5-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(3-bromopyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-ethylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3R,4R)-4-hydroxy-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S,{(5R)-5-methyl-1-(pyridin-3-yl)piperidin-3-yl}[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, methyl 1-[1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylate, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one.,

[0089] In another more preferred embodiment, the compound according to formula (I) is a compound selected from the following: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyrazin-2-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyrimidin-5-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(3-bromopyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-ethylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3R,4R)-4-hydroxy-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S,{(5R)-5-methyl-1-(pyridin-3-yl)piperidin-3-yl}[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-{[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, methyl 1-[1-methyl-3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylate, 1-methyl-3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-6,7-difluoro-3-{[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one.,

[0090] In an even more preferred embodiment, the compound according to formula (I) is selected from: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-7-{4,7-diazaspiro[2.5]octan-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one.,

[0091] In another even more preferred embodiment, the compound according to formula (I) is selected from: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one.,

[0092] In another even more preferred embodiment, the compound according to formula (I) is selected from: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-6,7-Difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one.,

[0093] In yet another more preferred embodiment, the compound according to formula (I) is selected from: 1-methyl-3-({[(3S)-1-(5-methyl-1,3,4- {(3S)-1-(1,3-diazol-2-yl)piperidin-3-yl}[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl][(1,2-thiazol-5-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,6-naphthyridin-4-one, 7-(cyclohex-1-en-1-yl)-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 8-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, 6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, 3-({[(1,3-dimethyl-1H-pyrazol-5-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one;

[0094] and preferably a compound selected from: 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, and 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one.

[0095] In another aspect, the present invention relates to a compound of formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof,

[0096]

[0097] wherein,

[0098] X 1 is CR 1 ;

[0099] X 2 is CR 3 ;

[0100] R 1 , R 2 and R 3 are independently H, OH, CN, halogen, C1-C4-alkyl, C1-C4-alkoxy, aryloxy, benzyloxy, C(=O)R E , NR F C(=O)R E or a 5- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group or heterocyclic group-C1-C2-alkyl, wherein the above heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each replaceable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R X ;

[0101] R 4is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9- or 10-membered aromatic carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring contains at least one nitrogen atom and optionally one or more additional identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said ring is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0102] R 5 is a 5- or 6-membered saturated heterocyclic ring, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R Y substituted;

[0103] and wherein

[0104] R N is H, CH3 or cyclopropyl;

[0105] R A is H, halogen, CN, OH, C1-C3-alkyl, C1-C3-alkoxy or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said group is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0106] R C and R D are independently H or C1-C2-alkyl; or

[0107] R C and R D together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said heterocyclic ring is independently unsubstituted or substituted with one or more identical or different substituents R X substituted;

[0108] R E is H, C1-C2-alkyl, phenyl, benzyl, OR G or NRH R I ;

[0109] R F is H, C1-C2-alkyl, C3-C6-cycloalkyl, phenyl or benzyl;

[0110] R G is H, C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group or heterocyclic-C1-C2-alkyl, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or unoxidized;

[0111] R H and R I are independently H, C1-C2-alkyl, or a 5- or 6-membered aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group or heterocyclic-C1-C2-alkyl, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atoms are independently oxidized or unoxidized; or

[0112] R H and R I together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atoms and / or S-atoms are independently oxidized or unoxidized, and wherein each replaceable carbon or heteroatom in said heterocyclic ring is independently unsubstituted or substituted by one or more identical or different substituents R X substituted;

[0113] R X is halogen, CN, C1-C2-alkyl or C1-C2-alkoxy;

[0114] R Y is halogen, CN, OH, C1-C2-alkyl, C3-C6-cycloalkyl, C1-C2-alkoxy, NR C R D , S(=O)2NR C R D , C(=O)R E, or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group, and heterocyclic group-C1-C2-alkyl, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N, or S, wherein said N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said groups is independently unsubstituted or substituted with one or more identical or different substituents R X Substituted.

[0115] In a preferred embodiment,

[0116] R A is H.

[0117] In another preferred embodiment,

[0118] R N is H, CH3, or cyclopropyl, preferably CH3.

[0119] In another preferred embodiment,

[0120] R 1 R 2 and R 3 are H.

[0121] In another preferred embodiment,

[0122] R 5 is a 6-membered saturated heterocycle, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N, or S, wherein said N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R Y Substituted.

[0123] In a more preferred embodiment,

[0124] R 5 is piperidine, wherein each substitutable carbon or heteroatom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R Y Substituted.

[0125] In another more preferred embodiment,

[0126] R 5 is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R Y Substituted; and wherein the nitrogen atom in the piperidine ring is preferably substituted with R Y which is pyridyl.

[0127] In another more preferred embodiment,

[0128] R 5 is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R Y ; and wherein the nitrogen atom in the piperidine ring is substituted with R Y , R Y is pyridyl, which is unsubstituted or substituted with one or more identical or different substituents R X , wherein R X is preferably methyl.

[0129] In a preferred embodiment,

[0130] R 4 is pyridyl, wherein each substitutable carbon atom in the ring is independently unsubstituted or substituted with one or more identical or different substituents R X .

[0131] In another aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) as defined herein and optionally a pharmaceutically acceptable carrier, diluent or excipient.

[0132] In yet another aspect, the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising a compound of formula (I) as defined herein for use in medicine. In particular, the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising a compound of formula (I) as defined herein for modulating STING, particularly for activating STING.

[0133] In yet another aspect, the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising a compound of formula (I) as defined herein for use in a method of treating a disease, wherein modulating STING, particularly activating STING, is beneficial.

[0134] In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising them are used for treating diseases selected from cancer, pre-cancerous syndromes and infectious diseases; or for use in immunogenic compositions or as vaccine adjuvants.

[0135] In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising them are used for treating diseases selected from inflammatory diseases, allergic diseases and autoimmune diseases.

[0136] In yet another aspect, the present invention relates to a method of treatment comprising administering a compound of formula (I) as defined herein or a pharmaceutical composition comprising a compound of formula (I) as defined herein to a human or animal body. Brief Description of the Drawings

[0138] Figure 1 (i) to (iii) show the in vivo anti-tumor efficacy of the compound according to Example 1 in a CT26 murine colon carcinoma allograft in Balb / C female mice by depicting the tumor volume over time at different doses of the compound according to Example 1 compared to the vehicle.

[0139] Figure 2 The in vivo anti-tumor efficacy of the compound according to Example 1 in a CT26 murine colon carcinoma allograft in Balb / C female mice is shown by a dot plot depicting the individual tumor volume and %TGI (tumor growth inhibition) at day 11 for different doses of the compound according to Example 1 compared to the vehicle.

[0140] Figure 3 (i) to (iii) show the in vivo anti-tumor immune memory of a CT26 murine colon carcinoma allograft in Balb / C female mice in a re-challenge study by depicting the tumor volume over time in mice previously treated with different doses of the compound according to Example 1 compared to naïve mice. Detailed Description of the Invention

[0142] Some preferred embodiments of the substituents in formula (I) are described in more detail below. It is understood that each preferred embodiment by itself and in combination with other preferred embodiments is relevant. In addition, it is understood that the preferences in each case also apply to the salts, stereoisomers, tautomers and N-oxides of the compounds of the present invention.

[0143] As described above, the present invention relates to compounds of formula (I)

[0144]

[0145] wherein,

[0146] X 1 is CR 1 or N, and

[0147] X 2 is CR 3 or N.

[0148] Thus, the compounds of formula (I) can thus be compounds of formula (Ia), (Ib), (Ic) or (Id) as shown below:

[0149]

[0150] Regarding the compounds according to formulae (Ia), (Ib), (Ic) and (Id), it is to be understood that the substituents R 1 and R 2 and R 3 and R 4 and R 5 and R A and R N are as defined above in formula (I). Further preferred embodiments regarding these substituents are provided below.

[0151] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ia), (Ib) or (Ic). In a particularly preferred embodiment, the compound of formula (I) is a compound of formula (Ia), wherein the six-membered ring fused to the six-membered ring containing the ═O substituent is a six-membered aromatic carbocyclic ring. Thus, the compound of formula (I) is preferably a compound of formula (Ia)

[0152]

[0153] wherein the substituents R 1 and R 2 and R 3 and R 4 and R 5 and R A and R N are as defined in formula (I) above, in particular wherein the substituents R 1 and R 2 and R 3 are independently H, OH, CN, halogen, C1-C4-alkyl, C1-C4-alkoxy, aryloxy, benzyloxy, C(═O)R E , NR F C(═O)R E , NR F -(C1-C4-alkylene)-C(═O)R E , or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, a carbocyclic group-C1-C2-alkyl, a heterocyclic group, a heterocyclic group-oxy or a heterocyclic group-C1-C2-alkyl, wherein the above-mentioned heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein the N-atoms and / or S-atoms are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned groups is independently unsubstituted or substituted by one or more identical or different substituents R X .

[0154] Regarding the substituents R 1 and R 2 and R 3 , it is to be understood that R E and R Fand R X Preferably has the meaning as defined for the compounds of formula (I) above.

[0155] Regarding the compounds of formula (I), and regarding the compounds of formulae (Ia), (Ib), (Ic) and (Id), in particular regarding the compounds of formulae (Ia), (Ib) and (Ic), especially regarding the compounds according to formula (Ia), regarding the remaining substituent R 1 、R 2 、R 3 、R 4 、R 5 、R A and R N the following preferred embodiments are relevant.

[0156] As mentioned above, regarding the compounds of the present invention,

[0157] R A is H, halogen, CN, OH, C1-C3-alkyl, C1-C3-alkoxy or a 3- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein the above-mentioned heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein the N-atoms and / or S-atoms are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned groups is independently unsubstituted or substituted by one or more identical or different substituents R X substituted;

[0158] In a preferred embodiment,

[0159] R A is H, halogen, CN or C1-C3-alkyl.

[0160] In another preferred embodiment,

[0161] R A is H, F, Cl, Br or C1-C3-alkyl.

[0162] In a more preferred embodiment,

[0163] R A is H.

[0164] In a particularly preferred embodiment, the compound according to formula (I) refers to the compound according to formula (Ia), wherein X 1 and X 2 are CR 1 and CR 3 , and wherein R A is H. Such compounds can be represented by the following general formula (Ia*)

[0165]

[0166] Regarding the compounds according to formula (Ia*), it is to be understood that R 1 , R 2 , R 3 , R 4 , R 5 and R N are preferably as defined above.

[0167] Furthermore, regarding the compounds of the present invention, it is preferred that

[0168] R N is H, C1-C4-alkyl, HO(C=O)-C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic group contains one or more identical or different heteroatoms selected from O, N or S, wherein the N atom and / or S atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0169] In particular,

[0170] R N is H, CH3, HO(C=O)-C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic group contains one or more identical or different heteroatoms selected from O, N or S, wherein the N atom and / or S atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0171] If R N is HO(C=O)-C1-C4-alkyl, or a 3- or 4-membered saturated carbocyclic or heterocyclic group, then R N is preferably any one of the following groups

[0172]

[0173] In a preferred embodiment,

[0174] R N is H, CH3, or a 3- or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic group contains one or more identical or different heteroatoms selected from O, N or S, wherein the N atom and / or S atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R XSubstituted.

[0175] If R N is a 3- or 4-membered saturated carbocyclic or heterocyclic group, then R N is preferably any one of the following groups

[0176]

[0177] In a more preferred embodiment,

[0178] R N is H, CH3, or a 3-membered saturated carbocyclic or heterocyclic group, wherein the heterocycle contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N atom and / or S-atom is independently oxidized or unoxidized, and wherein each replaceable carbon or heteroatom in the above groups is independently unsubstituted or substituted by one or more identical or different substituents R X Substituted.

[0179] In another more preferred embodiment

[0180] R N is H, CH3 or a three-membered saturated carbocyclic group, especially cyclopropyl according to formula R N -2.

[0181] In a more preferred embodiment,

[0182] R N is H, CH3 or cyclopropyl.

[0183] In a particularly preferred embodiment,

[0184] R N is CH3.

[0185] In another particularly preferred embodiment,

[0186] R N is cyclopropyl.

[0187] Furthermore, with respect to the compounds of the present invention, especially with respect to the compounds according to formula (Ia) or (Ic), it is preferred that

[0188] R 1 is H, OH, CN, halogen, C1-C4-alkyl, C1-C4-alkoxy, aryloxy, benzyloxy, C(=O)R E 、NR F C(=O)R E 、NR F -(C1-C4-alkylene)-C(=O)R E、or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group, heterocyclic group-oxy or heterocyclic group-C1-C2-alkyl, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0189] In a preferred embodiment,

[0190] R 1 is H, halogen, C1-C4-alkyl, or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group, heterocyclic group-oxy or heterocyclic group-C1-C2-alkyl, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0191] In a more preferred embodiment,

[0192] R 1 is H, F, Cl, Br or C1-C2-alkyl.

[0193] In a particularly preferred embodiment,

[0194] R 1 is H or F.

[0195] Regarding the above embodiments, it should be understood that the remaining substituents R E 、R F and R X are preferably defined as above.

[0196] Furthermore, regarding the compounds of the present invention, it is preferred that

[0197] R 2 is H, OH, CN, halogen, C1-C4-alkyl, C1-C4-alkoxy, aryloxy, benzyloxy, C(=O)R E 、NR F C(=O)R E 、NR F -(C1-C4-alkylene)-C(=O)R E, or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, a carbocyclic group-C1-C2-alkyl group, a heterocyclic group, a heterocyclic oxy group, or a heterocyclic group-C1-C2-alkyl group, wherein the above-mentioned heterocyclic ring contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0198] In a preferred embodiment,

[0199] R 2 is H, a halogen, a C1-C4-alkyl group, a C1-C4-alkoxy group, NR F -(C1-C4-alkylene)-C(=O)R E , or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, a carbocyclic group-C1-C2-alkyl group, a heterocyclic group, a heterocyclic oxy group, or a heterocyclic group-C1-C2-alkyl group, wherein the above-mentioned heterocyclic ring contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0200] In a more preferred embodiment,

[0201] R 2 is H, F, Br, Cl, a C1-C2-alkoxy group, NR F -(C1-C4-alkylene)-C(=O)R E , or a 4- to 6-membered saturated heterocyclic group, or a heterocyclic oxy group, wherein the above-mentioned heterocyclic ring contains one or more identical or different heteroatoms selected from O, N, or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0202] If R 2 is NR F -(C1-C4-alkylene)-C(=O)R E , or a 4- to 6-membered saturated heterocyclic group, or a heterocyclic oxy group, then R 2 is preferably any one of the following groups

[0203]

[0204] or any one of the following groups

[0205]

[0206] as can be seen from formula (R 2 -1) to (R 2 -8), with respect to R 2 the preferred R X groups include CH3 or C(=O)R E . In addition, it should be understood that the remaining substituents R E and R F are preferably as defined above. With respect to the above formulas (R 2 -1) to (R 2 -8), it should be understood that R 2 may optionally bear one or more additional substituents R X which are the same or different.

[0207] As can be seen from formula (R 2 -1) to (R 2 -12), with respect to R 2 the preferred R X groups include CH3, C1-C2-haloalkyl, C(=O)CH3, or the option that two R X together with the carbon atom to which they are attached form a three-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring. With respect to the above formulas (R 2 -1) to (R 2 -12), it should be understood that R 2 may optionally bear one or more additional substituents R X which are the same or different.

[0208] In a more preferred embodiment,

[0209] R 2 is H, F, Br, Cl or a 6-membered saturated heterocyclic group, wherein the heterocyclic ring contains one or more nitrogen atoms as heteroatoms and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more substituents R X which are the same or different.

[0210] If R 2 is a 6-membered saturated heterocyclic group, then R2 is preferably any one of the following groups

[0211]

[0212] or any one of the following groups

[0213]

[0214] As can be seen from formulas (R 2 -1) to (R 2 -6), the preferred R 2 groups with respect to R X include CH3 or C(=O)R E , where R E is as defined above. As can be seen from formulas (R 2 -1) to (R 2 -12), the preferred R 2 groups with respect to R X include CH3, C1-C2 haloalkyl, C(=O)CH3, or the option that two R X together with the carbon atom to which they are attached form a three-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring. With respect to the above formulas (R 2 -1) to (R 2 -12) or formulas (R 2 -1) to (R 2 -6), it should be understood that R 2 can optionally bear one or more additional substituents R X that are the same or different.

[0215] In a particularly preferred embodiment,

[0216] R 2 is H, F, Cl, Br, or any one of the following 6-membered saturated heterocyclic groups

[0217]

[0218]

[0219] As can be seen from formulas (R 2 -1), (R 2 -4) and (R 2 -9) to (R 2 -12), the preferred R 2 groups with respect to R X include CH3, C1-C2 haloalkyl, C(=O)CH3, or the option that two R X together with the carbon atom to which they are attached form a three-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring. With respect to the above formulas (R 2 -1), (R 2 -4) and (R 2 -7) to (R 2 -10), it should be understood that R 2 can optionally bear one or more additional substituents RX .

[0220] In another particularly preferred embodiment,

[0221] R 2 is H, F, Cl, Br, or any one of the following 6 - membered saturated heterocyclic groups

[0222]

[0223] As can be seen from formulas (R 2 -1) and (R 2 -4), with respect to R 2 the preferred R X groups include CH3 or C(=O)CH3. With respect to the above formulas (R 2 -1) and (R 2 -4), it should be understood that R 2 can optionally bear one or more additional substituents R X which are the same or different.

[0224] Furthermore, with respect to the compounds of the present invention, particularly with respect to the compounds according to formula (Ia) or (Ib),

[0225] R 3 is H, OH, CN, halogen, C1 - C4 - alkyl, C1 - C4 - alkoxy, aryloxy, benzyloxy, C(=O)R E , NR F C(=O)R E , NR F -(C1 - C4 - alkylene)-C(=O)R E , or a 4 - to 6 - membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic - C1 - C2 - alkyl, heterocyclic group, heterocyclic oxy group or heterocyclic - C1 - C2 - alkyl, wherein the above - mentioned heterocyclic contains one or more identical or different heteroatoms selected from O, N or S, wherein the N - atom and / or S - atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above - mentioned groups is independently unsubstituted or substituted by one or more identical or different substituents R X .

[0226] In a preferred embodiment,

[0227] R 3is H, halogen, C1-C4-alkyl, or a 4- to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic-C1-C2-alkyl, heterocyclic group, heterocyclic oxy group or heterocyclic-C1-C2-alkyl, wherein said heterocyclic ring contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0228] In a more preferred embodiment,

[0229] R 3 is H, halogen or C1-C4 alkyl.

[0230] In another more preferred embodiment,

[0231] R 3 is H, F, Cl, Br or CH3.

[0232] In a particularly preferred embodiment,

[0233] R 3 is H.

[0234] In addition, with respect to the compounds of the present invention

[0235] R 4 is a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9- or 10-membered aromatic carbobicyclic or heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring contains at least one nitrogen atom and optionally one or more identical or different additional heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said rings is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0236] In a preferred embodiment,

[0237] R 4 is a 6-membered aromatic carbocyclic or heterocyclic ring, wherein said heterocyclic ring contains at least one nitrogen atom and optionally one or more identical or different additional heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said ring is independently unsubstituted or substituted with one or more identical or different substituents R X substituted.

[0238] In a more preferred embodiment,

[0239] R 4 is a 6-membered aromatic heterocycle, wherein the heterocycle contains at least one nitrogen atom and optionally one or more additional identical or different heteroatoms selected from O, N or S, wherein the N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above ring is independently unsubstituted or substituted by one or more identical or different substituents R X substituted.

[0240] Preferably, the 6-membered aromatic heterocycle contains one or more nitrogen atoms as heteroatoms.

[0241] In a particularly preferred embodiment,

[0242] R 4 is pyridyl, wherein each substitutable carbon or heteroatom in the ring is independently unsubstituted or substituted by one or more identical or different substituents R X substituted.

[0243] Preferably, R 4 is any of the following substituted pyridine rings

[0244]

[0245] Thus, with respect to R 4 the preferred R X groups include CH3, CH2CH3 or C1-alkoxy.

[0246] In a particularly preferred embodiment,

[0247] R 4 is methylpyridyl.

[0248] Particularly preferably,

[0249] R 4 is:

[0250]

[0251] Furthermore, with respect to the compounds of the present invention,

[0252] R 5 is a 5-membered or 6-membered saturated heterocycle, wherein the heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein the N atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted by one or more identical or different substituents R Y substituted.

[0253] In a preferred embodiment,

[0254] R 5 is a 5- or 6-membered saturated heterocycle, wherein said heterocycle contains one or more nitrogen atoms, wherein said N-atoms are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R Y substituted.

[0255] In another preferred embodiment, R 5 refers to any of the following unsubstituted or substituted rings

[0256]

[0257] Regarding the above formulas (R 5 -1) to (R 5 -4), it should be understood that the curly lines represent the connection to the remainder of the molecule, and $ represents the connection to the substituent R Y . Particularly preferably, R 5 is R 5 -1.

[0258] Furthermore, it should be understood that each substitutable carbon or heteroatom in the above-shown formulas (R 5 -1) to (R 5 -4) can optionally bear one or more identical or different (additional) substituents R Y .

[0259] Preferably,

[0260] R Y is halogen, CN, OH, C1-C2-alkyl, C1-C2-alkyl-OH, C3-C6-cycloalkyl, C1-C2-alkoxy, NR C R D , S(=O)2R F , C(=O)R E , or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C1-C2-alkyl, heterocyclic group, and heterocyclic group-C1-C2-alkyl, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted with one or more identical or different substituents R X substituted; or two R Y form =O; or two R Y attached to the same or adjacent carbon atoms can form a 3-membered carbocycle.

[0261] If R Yis C(=O)R E 、or a 5- or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic group, then R Y is preferably any one of the following unsubstituted or substituted groups

[0262]

[0263] Regarding the above substituted groups (R Y -1) to (R Y -15), it should be understood that each substitutable carbon or heteroatom may optionally bear one or more identical or different (additional) substituents R X .

[0264] In addition, it should be understood that the remaining substituents R C 、R D 、R E and R X are preferably as defined above.

[0265] In a preferred embodiment,

[0266] R 5 is a 6-membered saturated heterocycle, wherein the heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein the N atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted by one or more identical or different substituents R Y .

[0267] In this regard, it should be understood that R Y is preferably as defined above.

[0268] In another preferred embodiment, R 5 is any one of (R 5 -1) to (R 5 -4).

[0269] Regarding the above embodiments, it should be understood that each substitutable carbon or heteroatom in the above rings is independently unsubstituted or substituted by one or more identical or different substituents R Y , as defined above.

[0270] In addition, it should be understood that, preferably

[0271] R Y is OH, halogen, C1-C2-alkyl, C1-C2-alkyl-OH, C(=O)R E, a 5- or 6-membered partially unsaturated or aromatic heterocyclic group, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said group is independently unsubstituted or substituted with one or more identical or different substituents R X substituted; or two R Y form =O; or two R Y attached to the same or adjacent carbon atoms may form a 3-membered carbocyclic ring.

[0272] Preferably, said heterocycle contains one or more nitrogen atoms as heteroatoms.

[0273] In addition, it should be understood that the remaining substituents R E and R X are preferably as defined above.

[0274] In a particularly preferred embodiment,

[0275] R 5 is piperidine, wherein each substitutable carbon or heteroatom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R Y substituted.

[0276] Regarding the above particularly preferred embodiment, it should be understood that preferably

[0277] R Y is OH, halogen, C1-C2-alkyl, C1-C2-alkyl-OH, C(=O)R E , or a 5- or 6-membered partially unsaturated or aromatic heterocyclic group, wherein said heterocycle contains one or more identical or different heteroatoms selected from O, N or S, wherein said N-atom and / or S-atom is independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in said group is independently unsubstituted or substituted with one or more identical or different substituents R X substituted; or two R Y form =O; or two R Y attached to the same or adjacent carbon atoms may form a 3-membered carbocyclic ring.

[0278] Preferably, the heterocycle contains one or more nitrogen atoms as heteroatoms.

[0279] In addition, it should be understood that the remaining substituents R E and R X are as defined above.

[0280] In particular, further substituted with one or more identical or different substituents R YSubstituted R 5 is any one of the following structural formulas

[0281]

[0282] or any one of the following structural formulas

[0283]

[0284] In this regard, it is obvious that R Y can optionally bear one or more identical or different substituents R X . In this regard, preferred R X groups include CH3, F, Cl, Br, NO2, C1-alkoxy, or two R X form =O.

[0285] In another particularly preferred embodiment,

[0286] R 5 is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted by one or more identical or different substituents R Y ; and wherein the nitrogen atom in the piperidine ring is preferably substituted by R Y substituted, which is pyridyl.

[0287] In this regard, it should be understood that if there is one or more substituents R Y on each substitutable carbon atom of the piperidine ring, then R Y is preferably defined as above.

[0288] In another particularly preferred embodiment,

[0289] R 5 is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted by one or more identical or different substituents R Y ; and wherein the nitrogen atom in the piperidine ring is preferably substituted by R Y substituted, R Y is pyridyl, which is unsubstituted or substituted by one or more identical or different substituents R X substituted, wherein R X is preferably methyl.

[0290] In another particularly preferred embodiment, the R 5 group is any one of the following groups:

[0291]

[0292] Particularly preferably, the R 5 group is

[0293]

[0294] Therefore, particularly preferred compounds of the present invention are the compounds of formula (Ia*) compiled in the following table.

[0295] Table 1

[0296] Compounds of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -1, R N is H, R 2 and R 5 each corresponds to a row of Table A in each case.

[0297] Table 2

[0298] Compounds of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -1, R N is H, R 2 and R 5 each corresponds to a row of Table A in each case.

[0299] Table 3

[0300] Compounds of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -2, R N is H, R 2 and R 5 each corresponds to a row of Table A in each case.

[0301] Table 4

[0302] Compounds of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -2, R N is H, R 2 and R 5 each corresponds to a row of Table A in each case.

[0303] Table 5

[0304] Compounds of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4-3, R N is H, R 2 and R 5 corresponds to a row of Table A in each case.

[0305] Table 6

[0306] A compound of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -3, R N is H, R 2 and R 5 corresponds to a row of Table A in each case.

[0307] Table 7

[0308] A compound of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -1, R N is CH3, R 2 and R 5 corresponds to a row of Table A in each case.

[0309] Table 8

[0310] A compound of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -1, R N is CH3, R 2 and R 5 corresponds to a row of Table A in each case.

[0311] Table 9

[0312] A compound of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -2, R N is CH3, R 2 and R 5 corresponds to a row of Table A in each case.

[0313] Table 10

[0314] A compound of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -2, R N is CH3, R2 and R 5 corresponds to a row of Table A in each case.

[0315] Table 11

[0316] Compounds of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -3, R N is CH3, R 2 and R 5 corresponds to a row of Table A in each case.

[0317] Table 12

[0318] Compounds of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -3, R N is CH3, R 2 and R 5 corresponds to a row of Table A in each case.

[0319] Table 13

[0320] Compounds of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -1, R N is cyclopropyl, R 2 and R 5 corresponds to a row of Table A in each case.

[0321] Table 14

[0322] Compounds of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -1, R N is cyclopropyl, R 2 and R 5 corresponds to a row of Table A in each case.

[0323] Table 15

[0324] Compounds of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -2, R N is cyclopropyl, R 2 and R5 Corresponding to a row of Table A in each case.

[0325] Table 16

[0326] A compound of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -2, R N is cyclopropyl, R 2 and R 5 Corresponding to a row of Table A in each case.

[0327] Table 17

[0328] A compound of formula (Ia*), wherein R 3 is H, R 1 is H, R 4 is R 4 -3, R N is cyclopropyl, R 2 and R 5 Corresponding to a row of Table A in each case.

[0329] Table 18

[0330] A compound of formula (Ia*), wherein R 3 is H, R 1 is F, R 4 is R 4 -3, R N is cyclopropyl, R 2 and R 5 Corresponding to a row of Table A in each case.

[0331] Table A

[0332]

[0333]

[0334]

[0335] It has been found that the compounds defined in the above tables are particularly advantageous as STING agonists and can therefore be particularly advantageously used in the pharmaceutical compositions of the present invention and the medical uses as defined herein. Accordingly, the compounds of formula (I) of the present invention are preferably the compounds according to any one of Tables 1 to 18, and the present invention preferably relates to pharmaceutical compositions containing the same and their medical uses.

[0336] In certain particularly preferred embodiments, the compounds according to formula (I) are selected from: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyrazin-2-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyrimidin-5-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(3-bromopyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-ethylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3R,4R)-4-hydroxy-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl))piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S,((5R)-5-Methyl-1-(pyridin-3-yl)piperidin-3-yl)[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, methyl 1-[1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylate / ester, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl))piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 3-({[(3S)-1-(5-bromopyrimidin-2-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[5,5-difluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2,6-dimethylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl][(pyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-7-[4-(2,2-difluoroethyl)piperazin-1-yl]-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(2-oxopiperazin-1-yl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(oxetan-3-yl)-1,4-dihydroquinolin-4-one, 2-[3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-1-yl]acetic acid, 1-cyclopropyl-7-{4,7-diazaspiro[2.5]oct-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(5-methyl-1,3,4-, {(2-Methylpyridin-4-yl)methyl}amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-Chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl][(1,2-thiazol-5-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,6-naphthyridin-4-one, 7-(Cyclohex-1-en-1-yl)-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 8-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, 6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, 3-({[(1,3-dimethyl-1H-pyrazol-5-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one.

[0337] In some further particularly preferred embodiments, the compound according to formula (I) is a compound selected from the following: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyrazin-2-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyrimidin-5-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(3-bromopyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-ethylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3R,4R)-4-hydroxy-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S,{(5R)-5-methyl-1-(pyridin-3-yl)piperidin-3-yl}[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-{[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, methyl 1-[1-methyl-3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylate / ester, 1-methyl-3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-{[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-{[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-{[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-{[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-6-fluoro-7-methoxy-3-{[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one.,

[0338] In some other particularly preferred embodiments, the compound of formula (I) is a compound selected from the following: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyrazin-2-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyrimidin-5-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(3-bromopyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-ethylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3R,4R)-4-hydroxy-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S,{(5R)-5-methyl-1-(pyridin-3-yl)piperidin-3-yl}[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-{[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, methyl 1-[1-methyl-3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylate, 1-methyl-3-{[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and 1-cyclopropyl-6,7-difluoro-3-{[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one.,

[0339] In certain even more particularly preferred embodiments, the compounds according to formula (I) are selected from: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S′)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-7-{4,7-diazaspiro[2.5]oct-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, and 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one.,

[0340] In addition, in certain even more particularly preferred embodiments, the compound of formula (I) is a compound selected from the following: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one.,

[0341] In addition, in certain even more particularly preferred embodiments, the compounds of formula (I) are compounds selected from: 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one.,

[0342] In addition, in certain even more particularly preferred embodiments, the compound of formula (I) is a compound selected from: 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl))piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-7-{4,7-diazaspiro[2.5]oct-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one.

[0343] In addition, in certain even more particularly preferred embodiments, the compounds of formula (I) are compounds selected from: 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, and 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one.

[0344] Definitions

[0345] The term "compounds of the invention" should be understood as equivalent to the term "compounds according to the invention" and also encompasses their salts, stereoisomers, tautomers or N-oxides.

[0346] The compounds according to the invention can be amorphous or can exist in one or more different crystalline forms (polymorphs), which can have different macroscopic properties such as stability or can display different biological properties such as activity. The invention relates to amorphous and crystalline forms of the compounds of formula (I), mixtures of the compounds of formula (I) in different crystalline forms, and their amorphous or crystalline salts.

[0347] The salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those comprising counterions present in drug products listed in the US FDA Orange Book database. They can be formed in a conventional manner, for example, if the compound according to the invention has a basic functional group, by reacting the compound with an acid of the anion in question, or by reacting an acidic compound according to the invention with a suitable base.

[0348] Suitable cationic counterions are in particular ions of alkali metals preferably lithium, sodium and potassium, ions of alkaline earth metals preferably calcium, magnesium and barium, and ions of transition metals preferably manganese, copper, silver, zinc and iron, and ammonium (NH4 +) and substituted ammonium in which 1 to 4 hydrogen atoms are substituted by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl. Examples of substituted ammonium ions include methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, in addition to the cations of 1,4-piperazine, meglumine, benzathine and lysine.

[0349] Suitable anionic counterions are in particular chloride, bromide, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, hydrogen carbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate, in addition lactate, gluconate, and the anions of polybasic acids, such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, in addition sulfonate anions, such as besylate (benzenesulfonate), tosylate (p-toluenesulfonate), naphthalenesulfonate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate) and ethanedisulfonate. They can be formed by reacting a compound according to the invention having a basic functional group with an acid of the corresponding anion.

[0350] Depending on the substitution pattern, the compounds according to the invention can have one or more chiral (including axial chirality) centers. The invention provides both the pure enantiomers or pure diastereomers of the compounds according to the invention and their mixtures, including racemic mixtures. Suitable compounds according to the invention also include all possible geometric stereoisomers (cis / trans isomers or E / Z isomers) and their mixtures. With respect to, for example, olefins, carbon-nitrogen double bonds or amide groups, E / Z isomers can exist.

[0351] If substituents are present in the compounds of formula (I), tautomers can be formed, which allows the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers, etc. In addition, the core structure containing a 6-membered ring with an =O substituent mainly allows keto-enol tautomerization.

[0352] The term "N-oxide" includes any compound of the invention having at least one tertiary nitrogen atom oxidized to an N-oxide moiety.

[0353] As used herein, the term "substituted" means that a hydrogen atom bonded to a specified atom is replaced by a specified substituent, provided that the substitution results in a stable or chemically viable compound. Unless otherwise specified, a substituted atom can have one or more substituents and each substituent is independently selected.

[0354] The term "substitutable", when used with respect to a specified atom, means that a hydrogen is attached to that atom and can be replaced by a suitable substituent.

[0355] When referring to certain atoms or moieties being "one or more" substituents, the term "one or more" is intended to cover at least one substituent, such as from 1 to 10 substituents, preferably 1, 2, 3, 4 or 5 substituents, more preferably 1, 2 or 3 substituents, and most preferably 1 or 2 substituents. When the term "unsubstituted" is not explicitly mentioned nor the term "substituted" with respect to a moiety, the moiety should be considered unsubstituted.

[0356] The organic moieties mentioned in the above definitions of variables - such as the term halogen - are collective terms for single lists of individual group members. The prefix Cn-Cm in each case indicates the possible number of carbon atoms in the group.

[0357] The term "halogen" in each case means fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine.

[0358] As used herein, the term "alkyl" in each case means a straight-chain or branched alkyl having generally from 1 to 6 carbon atoms, preferably from 1 to 5 or from 1 to 4 carbon atoms, more preferably from 1 to 3 or 1 or 2 carbon atoms. Examples of alkyls are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

[0359] As used herein, the term "haloalkyl" in each case denotes a straight-chain or branched alkyl group which generally has from 1 to 6 carbon atoms, often from 1 to 5 or from 1 to 4 carbon atoms, preferably from 1 to 3 or 1 or 2 carbon atoms, where some or all of the hydrogen atoms of the group are replaced by halogen atoms. Preferred haloalkyl moieties are selected from C1-C4-haloalkyl, more preferably from C1-C3-haloalkyl or C1-C2-haloalkyl, and in particular from C1-C2-fluoroalkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like.

[0360] As used herein, the term "alkenyl" in each case denotes an unsaturated hydrocarbon group which generally has from 2 to 6, preferably from 2 to 4 carbon atoms and which contains at least one carbon-carbon double bond at any position, for example, vinyl (ethenyl), allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethylprop-2-en-1-yl and the like. If geometric isomers are possible with respect to the double bond, the invention relates to both the E isomer and the Z isomer. Preferred alkenyl groups according to the invention are terminal alkenyl groups. The bonding of vinyl is illustrated by the following examples:

[0361] As used herein, the term "haloalkenyl" means an alkenyl group as defined above, where some or all of the hydrogen atoms are replaced by halogen atoms.

[0362] As used herein, the term "alkynyl" in each case denotes an unsaturated hydrocarbon group which generally has from 2 to 6, preferably from 2 to 5 or from 2 to 4 carbon atoms, more preferably from 2 to 3 carbon atoms and which contains at least one carbon-carbon triple bond at any position, for example ethynyl, propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and the like.

[0363] As used herein, the term "haloalkynyl" means an alkynyl group as defined above, where some or all of the hydrogen atoms are replaced by halogen atoms.

[0364] As used herein, the term "alkoxy" in each case denotes a straight-chain or branched alkyl group bonded via an oxygen atom and generally having from 1 to 6 carbon atoms, preferably from 1 to 2 carbon atoms, more preferably 1 carbon atom. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, isobutoxy, tert-butoxy and the like.

[0365] As used herein, the term "haloalkoxy" in each case denotes a straight-chain or branched alkoxy group having from 1 to 6 carbon atoms, preferably from 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydrogen atoms of the group are partially or completely replaced by halogen atoms, especially fluorine atoms. Preferred haloalkoxy moieties include C1-haloalkoxy, especially C1-fluoroalkoxy, such as trifluoromethoxy and the like.

[0366] As used herein, the term "HO(C=O)-C1-C4-alkyl" refers to a carboxyalkyl group, i.e., a carboxy C(=O)OH bonded via an alkyl group, preferably a C1-C4-alkyl group, more preferably a C1-C2-alkyl group, to the remainder of the molecule. Preferred examples include carboxymethyl and carboxyethyl.

[0367] As used herein, the term "cycloalkyl" in each case denotes a monocyclic cycloaliphatic group generally having from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0368] Unless otherwise indicated, the term "carbocyclic" or "carbocyclic group" generally includes a 3- to 9-membered, preferably 4- to 8-membered or 3- to 6-membered or 5- to 7-membered, more preferably 5- or 6-membered monocyclic ring containing from 3 to 9, preferably from 4 to 8 or from 3 to 6 or from 5 to 7, more preferably 5 or 6 carbon atoms. The carbocycle can be saturated, partially or completely unsaturated, or aromatic, where saturated means that only single bonds are present, partially or completely unsaturated means that one or more double bonds can be present in suitable positions while not fulfilling the Hückel rule for aromaticity, and aromatic means fulfilling the Hückel (4n+2) rule. Unless otherwise indicated, the term "carbocycle" or "carbocyclic group" can thus in particular encompass cycloalkyl, cycloalkenyl and phenyl. Preferably, the term "carbocycle" encompasses cycloalkyl and cycloalkenyl, such as cyclopropane ring, cyclobutane ring, cyclopentane ring and cyclohexane ring.

[0369] The term "carbocyclic bicyclic" or "carbocyclic bicyclic group" generally includes a bicyclic ring having 6 to 14 members, preferably 7 to 12 members or 8 to 10 members, more preferably 9 or 10 members, and the bicyclic ring contains 6 to 14 carbon atoms, preferably 7 to 12 carbon atoms or 8 to 10 carbon atoms, more preferably 9 or 10 carbon atoms. The carbocyclic bicyclic ring can be saturated, partially or fully unsaturated, or aromatic, where saturated means that only single bonds are present, partially or fully unsaturated means that one or more double bonds can be present at appropriate positions while not satisfying the Hückel's rule of aromaticity, and aromatic means satisfying the Hückel's (4n + 2) rule. Preferably, the term "aromatic" related to the carbocyclic bicyclic ring means that both rings of the bicyclic moiety are aromatic, so that, for example, there are 8 π electrons in the case of a 10-membered aromatic carbocyclic bicyclic ring. Unless otherwise specified, the term "carbocyclic bicyclic" or "carbocyclic bicyclic group" can thus particularly cover bicyclic alkyl groups, bicyclic alkenyl groups, and bicyclic aryl groups, such as bicyclohexane (decahydronaphthalene), bicycloheptane (e.g., norbornane), bicyclooctane (e.g., bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicyclononane (e.g., bicyclo[3.3.1]nonane or bicyclo[4.3.0]nonane), bicyclodecane (e.g., bicyclo[4.4.0]decane), bicycloundecane (e.g., bicyclo[3.3.3]undecane), norbornene, naphthalene, etc. Preferably, the carbocyclic bicyclic ring is a fused carbocyclic bicyclic ring, which is preferably aromatic, such as naphthalene.

[0370] The term "carbocyclic epoxy" includes a carbocyclic ring or carbocyclic group bonded to the remainder of the molecule via an oxygen atom.

[0371] Unless otherwise specified, the term "heterocyclic" or "heterocyclic group" generally includes 3- to 9-membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered, especially 6-membered monocyclic rings. The heterocycle can be saturated, partially or fully unsaturated, or aromatic, where saturated means that only single bonds are present, partially or fully unsaturated means that one or more double bonds can be present at appropriate positions while not fulfilling the Hückel's rule of aromaticity, and aromatic means fulfilling the Hückel's (4n + 2) rule. The heterocycle generally contains one or more, such as 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, where the S-atom as a ring member can exist as S, SO, or SO2. The remaining ring members are carbon atoms. In a preferred embodiment, the heterocycle is an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle containing one or more, such as 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, where the S-atom as a ring member can exist as S, SO, or SO2. The following definition of "heteroaryl" provides examples of aromatic heterocycles. The term "heterocycle" encompasses "heteroaryl (hetaryl or heteroaryl)". The saturated or partially or fully unsaturated heterocycle generally contains 1, 2, 3, 4, or 5, preferably 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, where the S-atom as a ring member can exist as S, SO, or SO2. Those skilled in the art understand S, SO, or SO2 as follows:

[0372] In addition, those skilled in the art know that resonance structures of the oxidized forms are possible. Unless otherwise specified, the saturated heterocycle generally includes a 3- to 9-membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered monocyclic ring containing at least one heteroatom and having 3 to 9, preferably 4 to 8, or 5 to 7, more preferably 5 or 6 atoms, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine, or piperazine. Alkane, morpholine, or piperazine.

[0373] The term "heterocyloxy" includes a heterocycle or heterocyclic group bonded to the remainder of the molecule via an oxygen atom.

[0374] Unless otherwise specified, the term "heterobicyclic" or "heterobicyclic group" generally includes bicyclics having 6 to 14 members, preferably 7 to 12 members or 8 to 10 members, more preferably 9 or 10 members. The heterobicyclic can be saturated, partially or fully unsaturated, or aromatic, where saturated means only single bonds are present, partially or fully unsaturated means one or more double bonds can be present at appropriate positions without fulfilling the Hückel's rule of aromaticity, and aromatic means fulfilling the Hückel's (4n + 2) rule. In principle, for being "aromatic", it is sufficient if one of the two rings of the bicyclic moiety is aromatic and the other is non-aromatic. However, with respect to the term "aromatic", it is preferred that both rings of the bicyclic moiety are aromatic, such that, for example, there are 8 π electrons in the case of a 9- or 10-membered aromatic heterobicyclic. The heterobicyclic generally contains one or more, for example 1, 2, 3 or 4, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where the S-atom as a ring member can exist as S, SO or SO2. The remaining ring members are carbon atoms. Examples of heterobicyclics include benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, benz thiazolyl, benz diazolyl, benzothiadiazolyl, benz azinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridinyl, pteridinyl, pyrido[3,2-d]pyrimidinyl, pyridoimidazolyl, triethylenediamine or quinuclidine, etc. Preferred heterobicyclics according to the present invention are aromatic heterobicyclics, such as benzodiazole, benzothiazole, quinoline and isoquinoline.

[0375] The term "heteroaryl" or "aromatic heterocycle" includes monocyclic 5- or 6-membered aromatic heterocycles containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members, where the S-atom as a ring member can exist as S, SO or SO2. Examples of 5- or 6-membered aromatic heterocycles include: pyridyl (also known as pyridinyl), i.e., 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrimidinyl, i.e., 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl; pyrazinyl; pyridazinyl, i.e., 3-pyridazinyl or 4-pyridazinyl; thienyl, i.e., 2-thienyl or 3-thienyl; furyl, i.e., 2-furyl or 3-furyl; pyrrolyl, i.e., 2-pyrrolyl or 3-pyrrolyl; azolyl, i.e., 2- azolyl, 3- azolyl or 5- azolyl; iso azolyl, i.e., 3-iso azolyl, 4-iso azolyl or 5-iso azolyl; thiazolyl, i.e., 2-thiazolyl, 3-thiazolyl or 5-thiazolyl; isothiazolyl, i.e., 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl; pyrazolyl, i.e., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl; i.e., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; diazolyl, for example 2-[1,3,4] diazolyl or 5-[1,3,4] diazolyl, 4-(1,2,3- diazolyl) or 5-(1,2,3- diazolyl) or 3-(1,2,4- diazolyl) or 5-(1,2,4- diazolyl); 2-(1,3,4-thiadiazolyl) or 5-(1,3,4-thiadiazolyl), thiadiazolyl, for example 2-(1,3,4-thiadiazolyl) or 5-(1,3,4-thiadiazolyl), 4-(1,2,3-thiadiazolyl) or 5-(1,2,3-thiadiazolyl), 3-(1,2,4-thiadiazolyl) or 5-(1,2,4-thiadiazolyl); triazolyl, for example 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-4-yl or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-1,2,4-triazolyl, 2H-1,2,4-triazolyl or 4H-1,2,4-triazolyl and tetrazolyl, i.e., 1H-tetrazolyl or 2H-tetrazolyl. Unless otherwise specified, the term "heteroaryl" also encompasses "aromatic heterobicyclic" as defined above.

[0376] The term "aryl" or "aromatic carbocycle" preferably includes a 6-membered aromatic carbocycle based on carbon atoms as ring members. Preferred examples are phenyl. Unless otherwise specified, the term "aryl" also encompasses "aromatic carbobicyclic" as defined above.

[0377] As used herein, the terms "carbocyclic alkyl", "heterocyclic alkyl" and the terms "arylalkyl", "cycloalkylalkyl", "heteroarylalkyl", etc. refer to the corresponding groups bonded to the remainder of the molecule via an alkyl group, preferably via a C1-C2-alkyl group. Preferred examples include benzyl (i.e., phenylmethyl), cyclohexylmethyl, pyridylmethyl and piperidinylmethyl.

[0378] As used herein, the terms "aryloxy" and "benzyloxy" refer to the corresponding groups bonded to the remainder of the molecule via an oxygen atom. Preferred examples include phenoxy and benzyloxy (i.e., phenylmethoxy).

[0379] As used herein, the term "alkylene" refers to a linking straight-chain or branched alkylene typically having from 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. The alkylene bridges a certain group to the remainder of the molecule. Preferred alkylenes include methylene (CH2), ethylene (CH2CH2), propylene (CH2CH2CH2), and the like. One skilled in the art understands that if, for example, CH2 is mentioned, the tetravalent carbon atom leaves two valence states for forming a bridge (-CH2-). Similarly, when, for example, CH2CH2 is mentioned, each carbon atom leaves one valence state for forming a bridge (-CH2CH2-). Further, when, for example, CH2CH2CH2 is mentioned, each terminal carbon atom leaves one valence state for forming a bridge (-CH2CH2CH2-).

[0380] If with respect to, for example, NR F -(C1-C4-alkylene)-C(=O)R E the term "alkylene" is used, it should be understood that the alkylene chain bridges the C(=O)R E group to the NR F group, and the NR F group is bonded to the remainder of the molecule.

[0381] The term "ring" moiety may refer to any cyclic group present in the compounds of formula (I) and defined above, such as cycloalkyl, cycloalkenyl, carbocyclic.

[0382] Unless the context clearly dictates otherwise, the singular forms "a / an" as used in the specification and claims also include the corresponding plural forms. This also applies to the plural forms used herein, and unless the context clearly dictates otherwise, the plural forms also include the singular form.

[0383] The terms "about" and "approximately" in the context of the present invention denote an interval of accuracy that will be understood by those skilled in the art and that still ensures the technical effect of the feature under discussion. The term generally means a deviation of ±10% and preferably ±5% from the indicated value.

[0384] It is to be understood that the term "comprising" is not restrictive. For the purposes of the present invention, the term "consisting of" is considered a preferred embodiment of the term "comprising". If a group is defined hereinafter as including at least a certain number of embodiments, this is also intended to include a group consisting preferably only of these embodiments.

[0385] The term "pharmaceutically acceptable excipient" as used herein refers to compounds that are known to those skilled in the art and that are typically included in pharmaceutical compositions. Examples of suitable excipients are exemplarily listed below. Generally, a pharmaceutically acceptable excipient can be defined as pharmaceutically inactive.

[0386] The term "treatment" should be understood to also include the option of "prevention". Thus, whenever the term "treatment" and its variations are mentioned herein, they should be understood to mean "treatment and / or prevention" and its variations.

[0387] Description of the pharmaceutical composition according to the invention

[0388] The pharmaceutical composition according to the invention can be formulated for oral administration, buccal administration, nasal administration, rectal administration, topical administration, transdermal administration or parenteral administration. Preferred non-parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, where oral administration can be preferred. Preferred parenteral routes include, but are not limited to, one or more of subcutaneous administration, intravenous administration, intramuscular administration, intra-arterial administration, intradermal administration, intrathecal administration and epidural administration. Administration via subcutaneous, intratumoral or peritumoral routes is preferred. Intratumoral administration is particularly preferred. The compound according to formula (I) should be administered in a pharmaceutically effective amount, for example, in the amounts stated hereinafter.

[0389] The pharmaceutical composition of the present invention can also be referred to as a formulation or dosage form. The compound of formula (I) can also be referred to hereinafter as an (pharmaceutically) active agent or active compound.

[0390] The pharmaceutical composition can be in solid or liquid dosage form or can have intermediate (e.g., gel-like) characteristics, depending especially on the route of administration.

[0391] Generally, the dosage forms of the present invention can contain various pharmaceutically acceptable excipients, which will be selected according to the functions to be achieved by the dosage form. "Pharmaceutically acceptable excipients" in the context of the present invention can be any substances used for preparing pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrants, release-regulating materials, carrier materials, diluents, binders and other auxiliary materials. Typical pharmaceutically acceptable excipients include substances such as sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricants such as magnesium stearate, disintegrants and buffering agents.

[0392] The term "carrier" denotes a pharmaceutically acceptable organic or inorganic carrier substance with which the active ingredient is combined to facilitate administration. Suitable pharmaceutically acceptable carriers include, for example, water; saline solutions; alcohols; oils, preferably vegetable oils; propylene glycol; polyoxyethylene sorbitan; polyethylene-polypropylene block copolymers such as poloxamer 188 or poloxamer 407; polyethylene glycols such as polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, etc.; gelatin; lactose; amylose; magnesium stearate; surfactants; aromatic oils; fatty acid monoglycerides; diglycerides and triglycerides; polyoxyethylated medium-chain or long-chain fatty acids such as ricinoleic acid; and polyoxyethylated fatty acid monoglycerides, polyoxyethylated fatty acid diglycerides, and polyoxyethylated fatty acid triglycerides such as caprylic or capric acid, petroethral fatty acid esters; hydroxymethylcellulose such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl acetate succinate; polyvinylpyrrolidone; cross-linked polyvinylpyrrolidone, etc. Preferably, the compounds of the present invention are administered as pharmaceutical compositions comprising lipids, multilamellar vesicles cross-linked between bilayers, biodegradable nanoparticles or microparticles based on poly(D,L-lactic-co-glycolic acid) ([PLGA]) or based on polyanhydrides, lipid bilayers loaded on nanoporous particles, and as conjugates with antibodies.

[0393] The pharmaceutical composition can be sterile and, if desired, can be mixed with the following adjuvants that do not react detrimentally with the active compound: such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts affecting osmotic pressure, buffers, colorants, flavoring agents, and / or aromatic substances, etc. It should be understood that the term "carrier" also encompasses antibodies for delivering the compound of formula (I).

[0394] If liquid dosage forms are contemplated for the present invention, these can include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups containing inert diluents commonly used in the art (such as water). These dosage forms can contain, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetening / flavoring agents.

[0395] For parenteral administration, particularly suitable carriers consist of solutions, preferably oily solutions or aqueous solutions, as well as suspensions, emulsions, or implants. Pharmaceutical preparations for parenteral administration are particularly preferred and include aqueous solutions of the compound of formula (I) in water-soluble form. In addition, suspensions of the compound of formula (I) can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.

[0396] A particularly preferred dosage form is an injectable preparation of the compound of formula (I). Thus, sterile injectable aqueous or oily suspensions can be formulated, for example, according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Acceptable carriers and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also commonly used as solvents or suspending media. Preferred administrations of the injectable preparation containing the compound of the present invention are intravenous administration, intratumoral administration, and peritumoral administration.

[0397] Suppositories for rectal administration of the compound of formula (I) can be prepared, for example, by mixing the compound with suitable non-irritating excipients such as cocoa butter, synthetic triglycerides, and polyethylene glycols, which are solid at room temperature but liquid at rectal temperature, so that they will melt in the rectum and release the compound according to formula (I) from the suppository.

[0398] For administration by inhalation, with the aid of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases, the compounds according to the present invention can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin, for example, for inhalers or insufflators can be formulated to contain a powder mixture of the compound and a suitable powder base component such as lactose or starch.

[0399] Oral dosage forms can be liquid or solid and include, for example, tablets, lozenges, pills, capsules, powders, effervescent preparations, dragees, and granules. Pharmaceutical preparations for oral use can be obtained as a solid excipient, and if desired, after adding suitable auxiliaries, the resulting mixture is optionally ground and the granular mixture is processed to obtain tablets or dragee cores. In particular, suitable excipients are fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added. Oral dosage forms can be formulated to ensure immediate release or sustained release of the compound of formula (I).

[0400] Solid dosage forms may include a film coating. For example, the dosage forms of the present invention may be in the form of so-called film tablets. The capsules of the present invention may be two-piece hard gelatin capsules, two-piece hydroxypropyl methyl cellulose capsules, two-piece capsules made of plants or plant-based cellulose, or two-piece capsules made of polysaccharides.

[0401] The dosage forms according to the present invention may be formulated for topical administration. Suitable pharmaceutical administration forms for such administration may be topical nasal sprays, sublingual administration forms, and controlled and / or sustained release skin patches. For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

[0402] The composition may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The method may include the step of bringing the compound into association with a carrier which constitutes one or more accessory ingredients. Usually, the composition is prepared by uniformly and intimately bringing the compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. Liquid dosage units are vials or ampoules. Solid dosage units are tablets, capsules, and suppositories.

[0403] In respect of human patients, the compounds of formula (I) may be administered to the patient in an amount of about 0.001 mg to about 5000 mg per day, preferably about 0.01 mg to about 1000 mg per day, more preferably about 0.05 mg to about 250 mg per day, as an effective amount. The phrase "effective amount" means an amount of the compound that is sufficient to treat or prevent a particular disease or disorder when administered to a mammal in need of such treatment.

[0404] In addition, the pharmaceutical composition may further contain a compound of formula (I) as a prodrug, such as its ester or amide. A prodrug is any compound that is converted under physiological conditions or by solvolysis into any compound of the present invention. The prodrug may be inactive before administration, but may be converted in vivo into the active compound of the present invention.

[0405] Indications for which the compounds of the present invention may be used

[0406] The compounds according to the present invention are suitable for use in medicine. In particular, the compounds according to the present invention are suitable for the treatment of diseases selected from inflammatory diseases, allergic diseases, autoimmune diseases, infectious diseases, cancers, and pre-cancerous syndromes. In addition, the compounds of formula (I) are suitable for use in immunogenic compositions and as vaccine adjuvants.

[0407] In one embodiment, the compounds of the present invention or pharmaceutical compositions containing them are used for the treatment of diseases selected from cancers, pre-cancerous syndromes, and infectious diseases; or for use in immunogenic compositions or as vaccine adjuvants.

[0408] In another embodiment, the compounds of the invention or pharmaceutical compositions comprising them are used for the treatment of diseases selected from inflammatory diseases, allergic diseases and autoimmune diseases.

[0409] In a preferred embodiment, the compounds of the invention or pharmaceutical compositions comprising them are used for the treatment of diseases selected from cancer or pre-cancerous syndromes.

[0410] In another preferred embodiment, the compounds of the invention or pharmaceutical compositions comprising them are used for the treatment of diseases selected from infectious diseases or in immunogenic compositions or as vaccine adjuvants.

[0411] In another preferred embodiment, the compounds of the invention or pharmaceutical compositions comprising them are used for the treatment of inflammatory diseases, allergic diseases, infectious diseases.

[0412] Particularly relevant to the present invention is the treatment of cancer. Preferably, the cancer is selected from breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulinoma, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, brain (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm’s tumor, Ewing′s sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T cell leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryocytic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), neuroendocrine cancer, and testicular cancer.

[0413] More preferably, the cancer is selected from prostate cancer, kidney cancer, melanoma, pancreatic cancer, cervical cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, fibrosarcoma, and breast cancer.

[0414] In a particularly preferred embodiment, the compounds of the present invention or pharmaceutical compositions comprising the same are used for the treatment of colon cancer.

[0415] Preferably, the autoimmune disease is selected from systemic lupus erythematosus, Addison's disease, autoimmune polyendocrinopathy (also known as autoimmune polyendocrine syndrome), glomerulonephritis, rheumatoid arthritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, glomerulonephritis, rheumatoid arthritis autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, asthma, bronchitis, acute pancreatitis, chronic pancreatitis, and various types of allergy.

[0416] It should be understood that, with respect to the medical use of the present invention, the compounds according to the present invention can preferably be administered in combination with an antibody, radiotherapy, surgical treatment, immunotherapy, chemotherapy, toxin therapy, gene therapy or any other treatment known to those of ordinary skill in the art for treating a specific disease. This is particularly relevant for cancer treatment. Preferably, the compounds of the present invention are administered in combination with an antibody. Preferred antibodies include anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-IDO, anti-KIR, anti-TIM-3, anti-Vista, anti-TIGIT, anti-BTLA and anti-LAG3 antibodies. Some non-limiting examples are BMS-936559, MPDL3280A and MEDI4736 or avelumab (an anti-PD-L1 antibody), MK-3475, pembrolizumab or pidilizumab (anti-PD-1 antibodies) and ipilimumab (an anti-CTLA-4 antibody). Preferably, the compounds of the present invention are administered in a pharmaceutical composition comprising one or more of the following: an adjuvant, inactivated or attenuated bacteria (e.g., inactivated or attenuated Listeria monocytogenes), an innate immune activation modulator, preferably a Toll-like Receptor (TLR) agonist (preferably a TLR7 or TLR9 agonist, such as SM360320, AZD8848), a (NOD)-like receptor (NLR) agonist (preferably a NOD2 agonist), a retinoic acid inducible gene (RIG)-I-like receptor (RLR) agonist, a C-type lectin receptor (CLR) agonist, or a pathogen-associated molecular pattern (PAMP), a cytokine (non-limiting examples, such as IL-2, IL-12, IL-6), an interferon (including but not limited to IFNα, IFNβ, IFNγ, IFNλ) or a chemotherapeutic agent. The medical use can further compromise the administration of at least one HBV vaccine, a nucleoside HBV inhibitor or any combination thereof (e.g., RECOMBIVAX HB, ENGERIX-B, GENEVAC-B).

[0417] Combination therapy can be achieved by using a single pharmaceutical composition containing two agents or by co-administering two different compositions, one of which contains the compound of the present invention and the other contains the second agent.

[0418] These two treatments can be given in either order and can be spaced from minutes to weeks before or after other treatments. In some embodiments where other agents are administered separately, it is generally ensured that there is a fairly long period of time between each delivery without expiration so that the agents will still be able to exert a beneficial combined effect on the patient. In such cases, it is expected that the two modalities can be administered within about 12 to 24 hours of each other, and more preferably within about 6 to 12 hours of each other. In some cases, it may be desirable to significantly extend the treatment time, however, where the separate administrations are spaced days (2, 3, 4, 5, 6, or 7 days) to weeks (1, 2, 3, 4, 5, 6, 7, or 8 weeks) apart. In some embodiments, the compounds of the invention are administered before different cancer treatments. In other embodiments, different cancer treatments are administered before the compounds of the invention.

[0419] The invention is further illustrated by the following examples. Examples

[0420] The following abbreviations are used herein:

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429] The compounds of the invention are prepared using suitable materials according to the procedures of the following schemes and examples and are further illustrated by the following specific examples.

[0430] Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise stated, all temperatures are in °C and all reactions were carried out at room temperature.

[0431] Methods and analytical data:

[0432] General:

[0433] Microwave heating was carried out using a Biotage Emrys Initiator microwave. Column chromatography was performed using an Isco Rf200d or an Interchim Puriflash 450. Solvent removal was carried out using a Büchi rotary evaporator or a Genevac centrifugal evaporator. Preparative LC / MS was carried out using a Waters mass-directed automated purification system and a Waters 19×100mm XBridge 5 micron C18 column under basic mobile phase conditions or an equivalent Waters CSH C18 column under acidic conditions. NMR spectra were recorded using a Bruker 300 MHz or 400 MHz spectrometer. Chemical shifts (δ) were reported in ppm relative to the residual solvent signal (measurement range -6.4 kHz). 1H NMR data were reported as follows: chemical shift (multiplicity, coupling constant, and number of hydrogens). Multiplicity abbreviations were as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doubledoublet), dt (doubletriplet). ESI-MS: desolvation gas flow rate 993 l / hour; desolvation temperature 500 °C; cone gas: 50 l / min; 500 - 1000 m / z; polarity: positive and / or negative.

[0434] Photochemical reactions were carried out using a Penn PhDM2 photoreactor (100% LED). Integrated photoreactor - RoyalBlue (450 nm) LED lamp, where the fan rate: 5200 rpm, stirring rate: 600 rpm, LED light intensity: 100%.

[0435] Preparative HPLC conditions for purifying the target compound:

[0436] Chromatographic condition 1:

[0437] Preparative HPLC instrument: Shimadzu

[0438] Column: Gemini-NX 5μm C18 21.2*250mm

[0439] Detector: SPD-20A / 20AV UV-VIS

[0440] Flow rate: 20 mL / min

[0441] Representative mobile phase: (1)

[0443] Mobile phase: A: 0.01% formic acid or TFA in water

[0444] Mobile phase: B: 0.01% formic acid or TFA in ACN (2)

[0446] Mobile phase: A: 0.01% NH4OH in water

[0447] Mobile phase: B: 0.01% NH4OH in ACN

[0448] Chromatographic condition 2:

[0449] Preparative HPLC instrument: Shimadzu

[0450] Column: Chiralpak AD-H, 5μm, 20*250mm

[0451] Detector: SPD-20A / 20AV UV-VIS

[0452] Flow rate: 20 mL / min

[0453] Representative mobile phase:

[0454] Mobile phase: A: EtOH

[0455] Mobile phase: B: hexane

[0456] The UPLC, HPLC, and MS data provided in the following examples are registered in:

[0457] LC-MS analysis by Shimadzu:

[0458] Method name: lc-ms1-2-ba

[0459] Equipment:

[0460] - Shimadzu LC-MS 2020

[0461] - HPLC with UV-Vis or DAD detector

[0462] - Column: Waters Acquity UPLC HSS C18, 50mm×2.1mm×1.8μm

[0463] Eluent:

[0464] (A) 0.1% formic acid in ACN

[0465] (B) 0.1% formic acid in water

[0466] Analysis method:

[0467] - Autosampler: Injection volume: 1 μL

[0468] - Pump:

[0469] Time [min] Flow rate [ml / min] %B

[0470]

[0471] -Column chamber: Column temperature: 25 °C; Analysis time: 6 minutes

[0472] -Detector: Wavelengths: 254 nm, 230 nm, 270 nm, 280 nm

[0473] LC-MS analysis on Bruker Amazon SL

[0474] Method name: lc-ms1-2-ba

[0475] Equipment:

[0476] -MS Bruker Amazon SL

[0477] -LC Dionex Ultimate 3000

[0478] -HPLC with UV-Vis or DAD detector

[0479] -Column: Waters Acquity UPLC HSS C18, 50 mm × 2.1 mm × 1.8 μm

[0480] Eluent:

[0481] (A) 0.1% formic acid in ACN

[0482] (B) 0.1% formic acid in water

[0483] Analysis method:

[0484] -Autosampler: Injection volume: 1 μL

[0485] -Pump:

[0486]

[0487] -Column chamber: Column temperature: 25 °C; Analysis time: 6 minutes

[0488] -Detector: Wavelengths: 254 nm, 230 nm, 270 nm, 280 nm

[0489] LC-MS analysis on Bruker Amazon SL

[0490] Method name: BCM-30

[0491] Equipment:

[0492] -MS Bruker Amazon SL

[0493] - LC Dionex Ultimate 3000

[0494] - HPLC with UV-Vis or DAD detector

[0495] - Column: Waters Symmetry C18 3.9×150mm 5μm

[0496] Eluent:

[0497] (A) 0.1% formic acid aqueous solution

[0498] (B) 0.1% formic acid ACN solution

[0499] Analysis method:

[0500] - Autosampler: Injection volume: 3 μL

[0501] - Pump:

[0502] Flow rate: 1.2 ml / min

[0503] Time [min] [%] B

[0504]

[0505] - Column oven: Column temperature: 25 °C; Analysis time: 30 min

[0506] - Detector: Wavelength: 254 nm

[0507] LC-MS analysis on Corona ultra

[0508] Method name: BCM-30

[0509] Equipment:

[0510] - Corona ultra

[0511] - LC Dionex Ultimate 3000

[0512] - Column: Waters Symmetry C18 3.9×150mm 5μm

[0513] Eluent:

[0514] (A) 0.1% formic acid aqueous solution

[0515] (B) 0.1% formic acid ACN solution

[0516] Analysis method:

[0517] - Autosampler: Injection volume: 3 μL

[0518] - Pump:

[0519] Flow rate: 1.2 ml / minute

[0520] Time [minutes] [%] B

[0521]

[0522]

[0523] Synthesis steps:

[0524] The following compounds are commercially available and / or can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. More specifically, the disclosed compounds can be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it should be understood that unless otherwise specified, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up steps, can be selected as standard conditions for the reaction. Those skilled in the art of organic synthesis understand that the functional groups present on different parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods are therefore indicated. The starting materials for the examples are commercially available or can be readily prepared from known materials by standard methods.

[0525] Step 1. Preparation of (3S)-1-(pyridin-3-yl)piperidin-3-amine

[0526]

[0527] a. tert-Butyl N-[(3S)-1-(pyridin-3-yl)piperidin-3-yl]carbamate

[0528]

[0529] To 3-bromopyridine (3.00 g, 18.99 mmol, 1 equiv) in anhydrous dichloro- To a stirred solution in 1,4-dioxane (80 mL) was added tert-butyl N-[(3S)-piperidin-3-yl]carbamate (4.94 g, 24.68 mmol, 1.3 equiv), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 869 mg, 0.949 mmol, 0.05 equiv), Cs2CO3 (8.35 g, 25.63 mmol, 1.3 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 659 mg, 1.14 mmol, 0.06 equiv). The resulting mixture was stirred for 4 days while heating at 100° C. under an inert atmosphere. Subsequently, the mixture was cooled to ambient temperature and heated by The residue was purified by FCC (SiHP; AcOEt 100%) to give the product as a pale yellow oil (3.2 g, 11.54 mmol, yield 61%). ESI-MS: 278.4 [M+H] +

[0530] b. (3S)-1-(Pyridin-3-yl)piperidin-3-amine

[0531]

[0532] Tert-butyl N-[(3S)1-(pyridin-3-yl)piperidin-3-yl]carbamate (3.2 g, 11.54 mmol, 1 equiv) was added to distilled water. The stirred solution in oxane (20 mL) was used in dioxane The product was treated with 4M HCl (20 mL, 80.80 mmol, 7 eq) in oxane. The reaction was carried out at 55 °C for 1 hour. The reaction mixture was concentrated in vacuo and then extracted between 5M NaOH and DCM. The organic layer was dried, filtered off and concentrated to provide the product as a yellow oil (2.00 g, 11.28 mmol, 98% yield). ESI-MS: 178.1 [M+H] +

[0533] Step 2. Preparation of 1-(pyridin-3-yl)piperidin-3-amine

[0534]

[0535] a. tert-Butyl N-[1-(pyridin-3-yl)piperidin-3-yl]carbamate

[0536]

[0537] To a stirred solution of 3-bromopyridine (394 mg, 2.497 mmol, 1 equiv) in anhydrous toluene (15 mL) was added tert-butyl N-(piperidin-3-yl)carbamate (500 mg, 2.497 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 114 mg, 0.125 mmol, 0.05 equiv), sodium tert-butoxide (288 mg, 2.966 mmol, 1.2 equiv) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (rac-BINAP, 155 mg, 0.250 mmol, 0.1 equiv). The resulting mixture was stirred for 24 h while heating at 100 °C under an inert atmosphere. Subsequently, the mixture was cooled to ambient temperature, filtered through a pad and partitioned between water and AcOEt. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by FCC (SiHP; DCM∶MeOH 95∶5) to afford the product as a yellow oil (359 mg, 1.2 mmol, 47% yield). ESI-MS: 278.5 [M+H] +

[0538] b. 1-(Pyridin-3-yl)piperidin-3-amine

[0539]

[0540] A stirred solution of tert-butyl N-[1-(pyridin-3-yl)piperidin-3-yl]carbamate (315 mg, 1.136 mmol, 1 equiv) in MeOH (5 mL) was treated with 3 M HCl in MeOH (1.5 mL, 4.543 mmol, 4 equiv). The mixture was stirred at 40 °C overnight. The reaction mixture was concentrated in vacuo, then dissolved in water and lyophilized to afford the product as the hydrochloride salt as a yellow powder (111 mg, 0.500 mmol, 43% yield). ESI-MS: 178.15 [M+H] +

[0541] Step 3. Preparation of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0542]

[0543] To 3-bromopyridine (190 mg, 1.206 mmol, 1.2 equiv) in anhydrous dichloro To a stirred solution in alkane (5 mL) was added 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one (378 mg, 1.005 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 46 mg, 0.050 mmol, 0.05 equiv), cesium carbonate (442 mg, 1.356 mmol, 1.35 equiv), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 35 mg, 0.060 mmol, 0.06 equiv). The reaction was carried out at 95 °C for 24 h under an inert atmosphere. Subsequently, the mixture was cooled to ambient temperature, filtered through a pad and concentrated under reduced pressure. The residue was purified by RP-FCC (SiC18; H2O∶MeCN 100%) to afford the product as a yellow oil (48 mg, 0.106 mmol, 10% yield). The product was converted to the hydrochloride salt. ESI-MS: 454.3 [M+H] +

[0544] 1 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J = 5.9 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H), 8.22 - 8.11 (m, 3H), 8.06 - 7.93 (m, 2H), 7.89 - 7.73 (m, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.44 (ddd, J = 8.0, 6.8, 1.0 Hz, 1H), 4.49 (d, J = 12.6 Hz, 1H), 4.40 (s, 2H), 4.04 (s, 2H), 3.94 (d, J = 13,1 Hz, 1H), 3.85 (s, 3H), 3.37 - 3.25 (m, 1H), 3.23 - 3.08 (m, 1H), 3.03 - 2.85 (m, 1H), 2.57 (s, 3H), 2.25 - 2.18 (m, 1H), 1.96 - 1.82 (m, 2H), 1.65 - 1.43 (m, 1H).

[0545] Step 4. Preparation of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0546]

[0547] a. 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0548]

[0549] A mixture of 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (2.90 g, 15.50 mmol, 1 equiv), (3S)-1-(pyridin-3-yl)piperidin-3-amine (3.02 g, 17.00 mmol, 1.1 equiv), and sodium acetate (1.27 g, 15.55 mmol, 1 equiv) in MeOH (100 mL) was stirred with activated molecular sieves at room temperature for 16 h. Then, the mixture was cooled to 0 °C and sodium borohydride (0.64 g, 17.00 mmol, 1.1 equiv) was added portionwise over 30 min. The reaction was allowed to reach room temperature over 1 h. When the reaction was complete, the mixture was filtered through a pad, washed with MeOH, and the solvent was removed in vacuo. The residue was partitioned between DCM and aqueous NaOH solution (10%, 2N or 5N). The layers were separated. The organic layer was dried, filtered, and concentrated in vacuo. The crude product was used without further purification in the next step. The product was obtained as a yellow oil. ESI-MS: 349 [M+H] +

[0550] b. 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0551]

[0552] A mixture of 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one (0.95 g, 2.70 mmol, 1 equiv) and 2-methylpyridine-4-carbaldehyde (0.33 g, 2.70 mmol, 1 equiv) in DCE (20 mL) was stirred with activated molecular sieves at room temperature for 2 h. Then, the mixture was cooled to 0 °C and sodium triacetoxyborohydride (0.87 g, 4.1 mmol, 1.5 equiv) was added portionwise. The reaction was allowed to reach room temperature over 16 h. The reaction mixture was filtered through a pad and washed with DCM. The filtrate was extracted with water. The organic layer was dried, filtered, and concentrated in vacuo. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to afford the title compound as a white solid (500 mg, 1.1 mmol, 40% yield). ESI-MS: 454 [M+H] +

[0553] 1 1H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.27 (m, 2H), 8.20 (dd, J = 8.0, 1.6 Hz, 1H), 8.04 (s, 1H), 7.92 (dd, J = 4.5, 1.3 Hz, 1H), 7.72 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.38 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.32 - 7.23 (m, 3H), 7.15 (dd, J = 8.5, 4.5 Hz, 1H), 4.00 - 3.92 (m, 1H), 3.79 - 3.56 (m, 5H), 2.90 - 2.82 (m, 1H), 2.79 - 2.60 (m, 3H), 2.38 (s, 3H), 2.04 - 1.97 (m, 1H), 1.80 - 1.73 (m, 1H), 1.61 - 1.43 (m, 2H).

[0554] Some aliphatic Hs overlap with the solvent peaks.

[0555] Step 5. Preparation of 3 - ( { [(2 - methoxypyridin - 4 - yl)methyl][1 - (pyridazin - 3 - yl)piperidin - 3 - yl]amino} methyl) - 1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0556]

[0557] To a degassed solution of 3 - bromopyridazine (29 mg, 0.18 mmol, 0.9 equiv) in anhydrous hexane (2 mL) was added 3 - ( { [(2 - methoxypyridin - 4 - yl)methyl](piperidin - 3 - yl)amino} methyl) - 1 - methyl - 1,4 - dihydroquinolin - 4 - one (80 mg, 0.20 mmol, 1 equiv), sodium tert - butoxide (39 mg, 0.41 mmol, 2 equiv) and (2 - dicyclohexylphosphino - 2′,6′ - diisopropoxy - 1,1′ - biphenyl)[2 - (2′ - amino - 1,1′ - biphenyl)]palladium(II) methanesulfonate (RuPhos Pd 3G, 18 mg, 0.020 mmol, 0.1 equiv). The reaction was carried out at 100 °C for 1 day under an inert atmosphere. Subsequently, the mixture was cooled to ambient temperature, filtered through a pad and concentrated under reduced pressure. The residue was purified by FCC (SiHP; DCM∶MeOH 9∶1) to give the product as a yellow solid (31 mg, 0.06 mmol, 30% yield). ESI - MS: 471 [M + H] +

[0558] 11H NMR (300 MHz, DMSO-d6) δ 8.49 - 8.46 (m, 1H), 8.21 - 8.16 (m, 1H), 8.06 (s, 1H), 8.03 - 7.99 (m, 1H), 7.76 - 7.69 (m, 1H), 7.66 - 7.60 (m, 1H), 7.41 - 7.23 (m, 3H), 7.06 - 7.01 (m, 1H), 6.85 (s, 1H), 4.66 - 4.56 (m, 1H), 4.34 - 4.23 (m, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.74 - 3.54 (m, 2H), 3.06 - 2.95 (m, 1H), 2.87 - 2.75 (m, 1H), 2.05 - 1.92 (m, 1H), 1.80 - 1.61 (m, 2H), 1.43 - 1.29 (m, 1H).

[0559] Some aliphatic Hs overlap with the solvent peaks.

[0560] Step 6. Preparation of 3 - ({[(2 - methoxypyridin - 4 - yl)methyl][1 - (pyrazin - 2 - yl)piperidin - 3 - yl]amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0561]

[0562] Dissolve 3 - ({[(2 - methoxypyridin - 4 - yl)methyl](piperidin - 3 - yl)amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one (80 mg, 0.20 mmol, 1 equiv), 3 - chloropyrazine (20 μL, 0.22 mmol, 1.10 equiv) and potassium carbonate (56 mg, 0.41 mmol, 2 equiv) in DMF (2 mL). The reaction is carried out at 100 °C for 24 h. Cool the resulting mixture to room temperature and partition between saturated NaHCO3 and AcOEt. Wash the organic layer with water and brine (30 mL). Dry the organic layer, filter it off and concentrate in vacuo. Purify the residue by preparative HPLC to afford the title compound as a yellow solid (28 mg, 0.059 mmol, 29% yield). ESI - MS: 471 [M + H] +

[0563] 11H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.21 - 8.15 (m, 1H), 8.07 - 7.98 (m, 3H), 7.78 - 7.68 (m, 2H), 7.66 - 7.60 (m, 1H), 7.43 - 7.33 (m, 1H), 7.07 - 7.00 (m, 1H), 6.85 (s, 1H), 4.59 - 4.48 (m, 1H), 4.34 - 4.22 (m, 1H), 3.86 (s, 3H), 3.81 - 3.74 (m, 4H), 3.73 - 3.52 (m, 2H), 3.05 - 2.93 (m, 1H), 2.84 - 2.71 (m, 1H), 2.07 - 1.95 (m, 1H), 1.83 - 1.58 (m, 2H), 1.45 - 1.30 (m, 1H).

[0564] Some aliphatic H's overlap with solvent peaks.

[0565] The product was converted to the hydrochloride salt. The product was obtained as a yellow solid. ESI-MS: 471 [M + H] +

[0566] 1 1H NMR (400 MHz, deuterium oxide) δ 8.07 (s, 1H), 7.99 - 7.93 (m, 1H), 7.93 - 7.87 (m, 1H), 7.85 - 7.79 (m, 1H), 7.79 - 7.72 (m, 1H), 7.71 - 7.59 (m, 2H), 7.56 - 7.49 (m, 1H), 7.49 - 7.42 (m, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 4.41 - 4.17 (m, 4H), 3.79 - 3.74 (m, 1H), 3.73 - 3.70 (m, 3H), 3.67 - 3.57 (m, 2H), 3.41 (s, 3H), 3.31 - 3.18 (m, 1H), 2.31 - 2.22 (m, 1H), 2.22 - 2.08 (m, 1H), 2.05 - 1.94 (m, 1H), 1.75 - 1.62 (m, 1H).

[0567] Aliphatic H's overlap with solvent peaks.

[0568] Step 7. Preparation of 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one

[0569]

[0570] a. Ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0571]

[0572] At 22 °C, thionyl chloride (2.47 mL, 33.93 mmol, 30 eq) was added dropwise to a stirred solution of ethanol (16.5 mL). After 30 minutes, the mixture became a pale yellow solution; then 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.30 g, 1.13 mmol, 1 eq) was added and the mixture was stirred for 16 h. After completion of the reaction, the solvent was removed in vacuo and the residue was partitioned between DCM and water. Extraction was carried out with DCM. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by FCC (SiHP; Hex∶AcOEt 4∶1) to afford the product as a white solid (0.33 g, 0.88 mmol, 78% yield). ESI-MS: 294 [M+H] +

[0573] b. Ethyl 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0574]

[0575] A solution of ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.26 g, 0.88 mmol, 1 eq), 1-methylpiperazine (0.293 mL, 2.64 mmol, 3 eq) and triethylamine (0.368 mL, 2.64 mmol, 3 eq) in MeCN (5 mL) was refluxed for 16 h under an inert atmosphere. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was dried, filtered and evaporated. The residue was purified by FCC (SiHP; DCM∶MeOH 9∶1) to afford the product as a yellow solid (0.14 g, 0.27 mmol, 48% yield). ESI-MS; 374 [M+H] +

[0576] c. 1-Cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0577]

[0578] A solution of ethyl 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.14 g, 0.39 mmol, 1 equiv) in concentrated HCl (1 mL), H2O (3 mL) and dichloromethane (9 mL) was stirred under reflux for 5 h. The solvent was evaporated and the crude product was partitioned between water and DCM. The organic layers were combined, dried and concentrated in vacuo. The product as a white solid (0.12 g, 0.34 mmol, 89% yield). ESI-MS: 346 [M+H] H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.91 (d, J = 13.4 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 3.83 (s, 1H), 3.74 - 3.64 (m, 1H), 3.53 - 3.44 (m, 1H), 2.26 (s, 3H), 1.37 - 1.14 (m, 4H). +

[0579] 1 Some aliphatic H overlap with the solvent peaks.

[0580] d. 1-Cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-one

[0581]

[0582]

[0583] To a cooled solution of 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.19 g, 0.34 mmol, 1 equiv) in anhydrous MeOH (5 mL) was slowly added sodium borohydride (0.059 g, 1.55 mmol, 4.5 equiv) over 30 min. The mixture was warmed to room temperature, p-toluenesulfonic acid (0.007 g, 0.034 mmol, 0.10 equiv) was added and the reaction mixture was heated under reflux for 16 h. Subsequently, the mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between chloroform and water. The organic layer was dried, filtered and concentrated under reduced pressure. FCC (SiHP; Hex∶AcOEt 4∶1) gave the product as a yellow solid (0.081 g, 0.27 mmol, 77% yield). ESI-MS: 304 [M+H] +

[0584] 1 ​1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 13.8 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 3.44 (dd, J = 7.5, 6.2 Hz, 2H), 3.19 - 3.16 (m, 4H), 2.42 - 2.35 (m, 1H), 2.24 (s, 3H), 0.91 - 0.86 (m, 2H), 0.70 - 0.64 (m, 2H).

[0585] Aliphatic H overlaps with the solvent peak.

[0586] e. 1-Cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0587]

[0588] To a mixture of sodium methoxide (0.056 g, 1.04 mmol, 3.9 eq) and ethyl formate (0.085 mL, 1.05 mmol, 3.94 eq) in anhydrous DCM (5 mL) was added a solution of 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-one (0.081 g, 0.27 mmol, 1 eq) and the mixture was stirred at room temperature for 18 h. Subsequently, the reaction mixture was poured into ice-cold water. The phases were separated. The organic layer was washed with 3M sodium hydroxide. The combined aqueous phases were acidified to pH 6 and extracted with DCM. The organic layers were combined, dried, filtered and concentrated under reduced pressure. The residue was redissolved in anhydrous MeOH (5 mL) and manganese dioxide (0.088 g, 1.01 mmol, 5 eq) was added. After stirring at room temperature for 18 h, the mixture was filtered and washed with MeOH and DCM. The filtrate was concentrated in vacuo. The residue was purified by FCC (SiHP, hexane∶AcOEt 1∶1) to afford the product as a white solid (0.048 g, 0.15 mmol, 72% yield). ESI-MS: 330 [M+H] filtered and washed with MeOH and DCM. The filtrate was concentrated in vacuo. The residue was purified by FCC (SiHP, hexane∶AcOEt 1∶1) to afford the product as a white solid (0.048 g, 0.15 mmol, 72% yield). ESI-MS: 330 [M+H] +

[0589] 1 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.32 (s, 1H), 7.81 (d, J = 13.5 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 3.75 - 3.68 (m, 1H), 3.27 (dd, J = 6.1, 3.8 Hz, 4H), 2.26 (s, 3H), 1.28 - 1.22 (m, 2H), 1.16 - 1.10 (m, 2H).

[0590] Some aliphatic H overlaps with the solvent peak.

[0591] Step 8. Preparation of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0592]

[0593] To a solution of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one (116 mg, 0.31 mmol, 1.2 equiv) in anhydrous MeCN (2 mL) was added 2-fluoropyridine (22 μL, 0.26 mmol, 1 equiv) and Na2CO3 (55 mg, 0.51 mmol, 2 equiv). The reaction was carried out at 150 °C for 90 minutes under microwave irradiation. The reaction was cooled to room temperature and partitioned between DCM and water. The organic layer was washed with brine, dried, filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to afford the title compound as a yellow solid (10 mg, 0.02 mmol, 9% yield). ESI-MS: 454 [M+H] +

[0594] 1 H NMR (300 MHz, DMSO-d6) δ 8.31 - 8.25 (m, 1H), 8.22 - 8.16 (m, 1H), 8.09 - 8.04 (m, 1H), 8.01 (s, 1H), 7.76 - 7.68 (m, 1H), 7.66 - 7.59 (m, 1H), 7.50 - 7.41 (m, 1H), 7.41 - 7.33 (m, 1H), 7.25 (s, 1H), 7.24 - 7.20 (m, 1H), 6.84 - 6.77 (m, 1H), 6.57 - 6.50 (m, 1H), 4.55 - 4.42 (m, 1H), 4.28 - 4.17 (m, 1H), 3.85 (s, 3H), 3.79 - 3.73 (m, 2H), 3.71 - 3.54 (m, 2H), 2.96 - 2.84 (m, 1H), 2.76 - 2.68 (m, 1H), 2.67 - 2.58 (m, 1H), 2.37 (s, 3H), 2.05 - 1.94 (m, 1H), 1.79 - 1.68 (m, 1H), 1.68 - 1.54 (m, 1H), 1.42 - 1.21 (m, 1H).

[0595] Step 9. Preparation of 1-methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0596]

[0597] a. 7-Bromo-1-methyl-1,4-dihydroquinolin-4-one

[0598]

[0599] Suspend 7-bromoquinolin-4-ol (3.00 g, 13.39 mmol, 1 equiv) in anhydrous THF (10 mL). Then, add dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.99 mL, 7.00 mmol, 1.5 equiv), followed by dropwise addition of methyl iodide (0.55 mL, 8.00 mmol, 2 equiv) and stir the resulting mixture overnight at room temperature. Quench the reaction with water and extract with DCM. Combine the organic layers, wash with brine, dry over anhydrous sodium sulfate and concentrate. Purify the residue by FCC (SiHP, DCM∶MeOH, 95∶5) to afford the product as a yellow solid (0.72 g, 4.40 mmol, 67% yield). ESI-MS: 239 [M+H] +

[0600] b. 1-Methyl-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one

[0601]

[0602] To a solution of 7-bromo-1-methyl-1,4-dihydroquinolin-4-one (700 mg, 2.94 mmol, 1 equiv) in anhydrous dioxane (15 mL) add 1-methylpiperazine (330 μL, 2.94 mmol, 1 equiv), sodium tert-butoxide (339 mg, 3.53 mmol, 1.2 equiv) and [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (Sphos Pd 3G, (229 mg, 0.29 mmol, 0.1 equiv). Carry out the reaction under an inert atmosphere at 100 °C for 24 h. Subsequently, cool the mixture to ambient temperature, filter through a pad and concentrate under reduced pressure. Purify the residue by FCC (SiHP, DCM∶MeOH, 8∶2) to obtain the product as a yellow solid (722 mg, 2.81 mmol, 93% yield). ESI-MS: 258 [M+H] c. 1-Methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde +

[0603]

[0604] ​​

[0605] 1-Methyl-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one (300 mg, 1.17 mmol, 1 equiv), 1,3,5,7-tetraazatricyclo[3.3.1.13,7]decane (HMT) (327 mg, 2.33 mmol, 2 equiv), and TFA (2 mL) were irradiated with microwave at 120 °C for 15 min. The reaction mixture was diluted with water (5 mL) and stirred for 10 min. Then, the mixture was neutralized with saturated Na2CO3 solution and extracted with DCM. The organic layers were combined, dried, and concentrated in vacuo. The residue was triturated with ethyl acetate to give the product as a yellow solid (270 mg, 0.95 mmol, 65% yield).

[0606] Step 10. Preparation of (2-Ethylpyridin-4-yl)methanamine

[0607]

[0608] 2-Ethylisonicotinitrile (400 mg, 3.03 mmol, 1 equiv) was dissolved in THF and cooled to -78 °C. Then, a solution of LiAlH4 (1 M in THF, 3.63 mL, 3.63 mmol, 1.2 equiv) was added dropwise. The reaction was carried out at -78 °C for 30 min, quenched with saturated Na2SO4 solution, and extracted with DCM. The organic layers were combined, washed with brine, dried, filtered, and concentrated in vacuo. The crude product was used in the next reaction without further purification. The product as a yellow oil (360 mg, 2.64 mmol, 87% yield). ESI-MS: 137 [M+H] +

[0609] 1 1H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.34 (m, 1H), 7.22 (s, 1H), 7.16 - 7.13 (m, 1H), 3.71 (s, 2H), 2.75 - 2.68 (m, 2H), 1.25 - 1.18 (m, 3H).

[0610] Step 11. Preparation of 1-Methyl-3-({[(2-Methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0611]

[0612] Dissolve 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one in a mixture of dichloro methane and 2N NaOH (v / v 1:10), and heat at 100 °C for 2 days. Dilute the mixture with 15% aqueous NaOH and extract with CHCl3:iPrOH (v / v 3:1). Dry the organic layer, filter and concentrate in vacuo. Purify the residue by preparative HPLC to afford the title compound as a beige solid (3 mg, 0.006 mmol, 6% yield). ESI-MS: 471 [M+H] +

[0613] 1 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.29 - 8.25 (m, 1H), 8.19 (dd, J = 8.1, 1.6 Hz, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.72 (ddd, J = 8.6, 6.9, 1.6 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.37 (ddd, J = 8.1, 6.9, 1.0 Hz, 1H), 7.24 (s, 1H), 7.23 - 7.19 (m, 1H), 5.30 (s, 1H), 4.42 - 4.30 (m, 1H), 4.22 - 4.12 (m, 1H), 3.85 (s, 3H), 3.80 - 3.70 (m, 2H), 3.70 - 3.51 (m, 2H), 3.01 - 2.92 (m, 1H), 2.77 - 2.70 (m, 1H), 2.60 - 2.54 (m, 1H), 2.37 (s, 3H), 2.04 - 1.96 (m, 1H), 1.76 - 1.68 (m, 1H), 1.68 - 1.57 (m, 1H), 1.35 - 1.25 (m, 1H).

[0614] Step 12. Preparation of ethyl 7-chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0615]

[0616] a. 1,3-diethyl 2-{[(3-chloro-4-fluorophenyl)amino]methylene}malonate

[0617]

[0618] 3-Chloro-4-fluoroaniline (2.5 g, 17.17 mmol, 1 equiv) and diethyl ethoxymethylenemalonate (3.47 mL, 17.17 mmol, 1 equiv) were heated at 115 °C to 120 °C for 90 min. The reaction mixture was cooled to room temperature and diluted with 70% aqueous methanol. The precipitated crystals were collected, washed with 70% aqueous methanol and dried. The product as a white solid (5.10 g, 16.17 mmol, 94% yield). ESI-MS: 316 [M+H] +

[0619] b. Ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0620]

[0621] Dowtherm A (100 mL) was preheated at 250 °C and 1,3-diethyl 2-{[(3-chloro-4-fluorophenyl)amino]methylene}malonate (5.10 g, 16.17 mmol, 1 equiv) was added. The mixture was stirred at 250 °C under reflux for 3 h. The reaction mixture was cooled to room temperature. The precipitated crystals were collected, washed with diethyl ether and dried. The product was suspended in EtOH. The mixture was stirred under reflux for 30 min, cooled to room temperature, the crystals were collected and dried. The product (3.50 g, 13.13 mmol, 81% yield) was used for the next step without further purification. ESI-MS: 268 [M+H] +

[0622] c. Ethyl 7-chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0623]

[0624] Trimethyl phosphate (1.736 mL, 14.83 mmol, 4 equiv) and anhydrous potassium carbonate (0.54 g, 3.89 mmol, 1.05 equiv) were added to ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.00 g, 3.71 mmol, 1 equiv). The mixture was stirred at 190 °C for 2 h, then cooled to 100 °C and poured into ice-cold water. The precipitated crystals were collected, washed with water and ethanol and dried. The residue was purified by FCC (Si - diol; Hex∶AcOEt 1∶1). The product as a white solid (0.70 g, 2.48 mmol, 67% yield). ESI-MS: 284 [M+H] +

[0625] 11H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.06 (d, J = 6.1 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0626] Step 13. Preparation of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0627]

[0628] a. 1-Cyclopropyl-6,7-difluoro-1,2,3,4-tetrahydroquinolin-4-one

[0629]

[0630] According to the method outlined in Step 7d, the title compound was synthesized using 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid instead of 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. The mixture was stirred overnight at room temperature. After adding p-toluenesulfonic acid, the reaction mixture was heated under reflux for 3 h. The product was obtained as a yellow solid (6.82 g, 30.55 mmol, yield 81%). ESI-MS: 224 [M+H] +

[0631] 1 1H NMR (400 MHz, chloroform-d) δ 7.69 (dd, J = 10.6, 9.2 Hz, 1H), 7.07 (dd, J = 13.0, 6.5 Hz, 1H), 3.56 - 3.50 (m, 2H), 2.67 - 2.62 (m, 2H), 2.36 - 2.30 (m, 1H), 0.96 - 0.91 (m, 2H), 0.75 - 0.70 (m, 2H).

[0632] b. 1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0633]

[0634] According to the method outlined in Step 7e, the title compound was synthesized by replacing 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinolin-4-one with 1-cyclopropyl-6,7-difluoro-1,2,3,4-tetrahydroquinolin-4-one. The product after FCC was triturated with Et2O and hexane to afford the title compound as a beige solid (1.17 g, 4.69 mmol, 15% yield). ESI-MS: 250 [M+H] +

[0635] 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.41 (s, 1H), 8.23 (dd, J = 12.1, 6.7 Hz, 1H), 8.15 (dd, J = 10.5, 8.8 Hz, 1H), 3.69 (tt, J = 7.3, 4.0 Hz, 1H), 1.32 - 1.23 (m, 2H), 1.18 - 1.11 (m, 2H).

[0636] Step 14. Preparation of 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0637]

[0638] a. 4-Chloroquinoline-3-carbaldehyde

[0639]

[0640] POCl3 (8.27 mL, 88.8 mmol, 6 equiv) was added dropwise to anhydrous DMF (20 mL) at 0 °C. Then 1-(2-aminophenyl)ethan-1-one (2.00 g, 14.8 mmol, 1 equiv) in anhydrous DMF (5 mL) was added dropwise, and the reaction was heated at 60 °C for 4 h. After that, the reaction was cooled to 0 °C and quenched with water. Then the solution was neutralized with saturated aqueous NaHCO3, diluted in water and extracted with DCM. The layers were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an orange solid (1.43 g, 7.49 mmol, 51% yield), which was sent to the next step without further purification. ESI-MS: 192 [M+H] +

[0641] b. 4-Oxo-1,4-dihydroquinoline-3-carbaldehyde

[0642]

[0643] 4-Chloroquinoline-3-carbaldehyde (1.10 g, 5.74 mmol, 1 equiv) was suspended in 54% aqueous HCOOH (13.41 mL). The reaction was carried out at 50 °C for 2 h. The resulting mixture was frozen in a refrigerator for 16 h. The precipitate was filtered off and washed with water to give the product as an orange solid (0.75 g, 4.33 mmol, 75% yield). ESI-MS: 174 [M+H] +

[0644] 1 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.20 (s, 1H), 8.49 (s, 1H), 8.22 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (m, 1H), 7.67 (dd, J = 8.3, 1.1 Hz, 1H), 7.48 (m, 1H).

[0645] c. 1-Methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0646]

[0647] 4-Oxo-1,4-dihydroquinoline-3-carbaldehyde (0.50 g, 2.89 mmol, 1 equiv) was suspended in THF (13 mL). DBU (1.01 g, 7.22, 2.5 equiv) was added, then methyl iodide (4.10 g, 28.8 mmol, 10 equiv). The reaction was carried out at 40 °C for 2 h. After that, the reaction was quenched with water and extracted with DCM. The layers were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by crystallization from hot EtOH to afford the title compound as a beige solid (0.36 g, 1.94 mmol, 67% yield). ESI-MS: 188 [M+H] +

[0648] 1 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.63 (s, 1H), 8.31 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (m, 1H), 7.80 (dd, J = 8.6, 1.1 Hz, 1H), 7.57 (m, 1H), 3.98 (s, 3H).

[0649] Step 15. Preparation of 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0650]

[0651] Under an oxygen atmosphere, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (0.124 g, 0.467 mmol, 1.1 eq) was added to (3S)-N-[(2-methylpyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine (0.12 g, 0.425 mmol, 1 eq) in DCE (10 mL), and the mixture was stirred for 1 h. Then, NaBH(OAc)3 (0.126 g, 0.595 mmol, 1.4 eq) was added portionwise. The reaction was stirred at room temperature for 16 h. Subsequently, the reaction mixture was diluted with DCM, filtered and concentrated. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) and further purified by preparative HPLC to give the product as a yellow solid (0.080 g, 0.043 mmol, 35% yield). ESI-MS: 533.3 [M+H] filtered and concentrated. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) and further purified by preparative HPLC to give the product as a yellow solid (0.080 g, 0.043 mmol, 35% yield). ESI-MS: 533.3 [M+H] +

[0652] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.22 (m, 2H), 8.16 (d, J = 6.1 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.92 (s, 2H), 7.38 - 7.24 (m, 1H), 7.21 (s, 1H), 7.18 - 7.07 (m, 2H), 3.90 (d, J = 11.8 Hz, 1H), 3.83 - 3.61 (m, 5H), 3.57 - 3.48 (m, 1H), 2.84 (t, J = 11.3 Hz, 1H), 2.78 - 2.61 (m, 2H), 2.36 (s, 3H), 2.06 - 1.89 (m, 1H), 1.86 - 1.69 (m, 1H), 1.68 - 1.39 (m, 2H), 1.36 - 1.09 (m, 2H), 1.03 - 0.77 (m, 2H).

[0653] Step 16. Preparation of 3-({[5,5-difluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one

[0654]

[0655] A mixture of 3-({[5,5-difluoro-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one (0.130 g, 0.338 mmol, 1 equiv), 2-methylpyridine-4-carbaldehyde (0.053 g, 0.440 mmol, 1.3 equiv), Na2SO4 (0.2 g) and DCE (5 mL) was stirred overnight at room temperature. Then, the mixture was cooled to 0 °C and NaBH(OAc)3 (0.108 g, 0.508 mmol, 1.5 equiv) was added portionwise over 5 minutes. Then, the reaction was carried out at 45 °C for 3 h. Subsequently, the crude mixture was filtered through a pad, the pad was washed with DCM and the filtrate was partitioned between DCM and aqueous NaOH solution (10%). The organic layers were combined, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by FCC (SiHP; DCM∶MeOH 9∶1) and further purified by RP-FCC (SiC18; H2O∶MeCN) to give the product as a yellow solid (0.050 g, 0.102 mmol, 30% yield). ESI-MS: 490.4 [M+H] +

[0656] Step 17. Preparation of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0657]

[0658] To a solution of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one (0.080 g, 0.212 mmol, 1 equiv) in 1,4-d iane (1.5 mL) was added 3-fluoro-2-nitropyridine (0.030 g, 0.212 mmol, 1 equiv) and triethylamine (0.022 g, 0.212 mmol, 1 equiv), and the resulting mixture was heated at 100 °C overnight. Subsequently, the mixture was evaporated, the residue was combined with the residue from a similar reaction (0.133 mmol of starting material) and purified by RP-FCC (SiC18; H2O∶MeCN) to afford the product as an orange solid (0.117 g, 0.345 mmol, 68% yield). ESI-MS: 499.3 [M+H] +

[0659] 11H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 5.0 Hz, 1H), 8.19 (dd, J = 8.1, 1.6 Hz, 1H), 8.09 (dd, J = 4.4, 1.3 Hz, 1H), 7.98 - 7.89 (m, 2H), 7.77 - 7.59 (m, 3H), 7.38 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.21 - 7.13 (m, 2H), 3.83 (s, 3H), 3.72 (s, 2H), 3.68 - 3.51 (m, 2H), 3.44 - 3.35 (m, 1H), 3.11 - 3.02 (m, 1H), 2.95 (t, J = 11.1 Hz, 1H), 2.82 - 2.70 (m, 2H), 2.36 (s, 3H), 2.05 - 1.95 (m, 1H), 1.83 - 1.73 (m, 1H), 1.61 - 1.38 (m, 2H).

[0660] Step 18. Preparation of 3 - ( { [ (2,6 - dimethylpyridin - 4 - yl)methyl ] [ (3S) - 1 - (pyridin - 3 - yl)piperidin - 3 - yl ] amino} methyl ) - 1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0661]

[0662] A mixture of 1 - methyl - 3 - ( { [ (3S) - 1 - (pyridin - 3 - yl)piperidin - 3 - yl ] amino} methyl ) - 1,4 - dihydroquinolin - 4 - one (0.05 g, 0.143 mmol, 1 equiv), 2,6 - dimethylpyridine - 4 - carbaldehyde (0.024 g, 0.179 mmol, 1.3 equiv) and DCM (3 mL) was stirred at room temperature for 15 minutes. Then, the reaction mixture was cooled to 0 °C and NaBH(OAc)3 (0.076 g, 0.359 mmol, 2.5 equiv) was added in portions. Thereafter, the reaction was carried out overnight at room temperature. Subsequently, the mixture was partitioned between DCM and water. The organic layer was passed through a silica gel pad and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product as a beige solid (0.031 g, 0.065 mmol, 45% yield). ESI - MS: 468.3 [M + H] +

[0663] 11H NMR (300 MHz, methanol-d4) δ 8.34 (dd, J = 8.3, 1.5 Hz, 1H), 8.24 (d, J = 2.9 Hz, 1H), 7.95 (s, 1H), 7.90 (dd, J = 4.7, 1.3 Hz, 1H), 7.76 (ddd, J = 8.6, 6.9, 1.6 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.24 (dd, J = 8.6, 4.8 Hz, 1H), 7.01 (s, 2H), 4.05 - 3.94 (m, 1H), 3.84 (s, 3H), 3.81 (d, J = 9.0 Hz, 4H), 3.77 - 3.65 (m, 1H), 3.03 - 2.84 (m, 2H), 2.82 - 2.61 (m, 1H), 2.28 (s, 6H), 2.21 - 2.10 (m, 1H), 1.97 - 1.83 (m, 1H), 1.77 - 1.56 (m, 2H).

[0664] Step 19. Preparation of 1-methyl-3-({[(3S)-1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0665]

[0666] To a degassed mixture of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one (0.100 g, 0.266 mmol, 1 equiv), 4-bromo-1-methyl-1,2-dihydropyridin-2-one (0.060 g, 0.319 mmol, 1.2 equiv), Cs2CO3 (0.173 g, 0.531 mmol, 2 equiv) and 1,4-d ane (3 mL) was added Pd2(dba)3 (0.012 g, 0.013 mmol, 0.1 equiv) and Xantphos (0.014 g, 0.024 mmol, 0.1 equiv). The reaction was carried out at 100 °C overnight. Then, the mixture was passed through Pad filtration, stirred with MPA scavenger for 30 minutes, filtered and concentrated. The residue was partitioned between DCM and water. The aqueous layer was further basified with NaOH solution (15%) and extracted with CHCl3 / iPrOH (3:1). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by FCC (SiHP; DCM:MeOH) and repurified by FCC (SiHP; DCM:MeOH) to give the product as a yellow solid (0.077 g, 0.159 mmol, 60% yield). ESI-MS: 484.7 [M+H]+

[0667] 1 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.83 - 7.57 (m, 2H), 7.45 - 7.30 (m, 2H), 7.30 - 7.19 (m, 2H), 6.06 (dd, J = 7.6, 2.6 Hz, 1H), 5.50 (d, J = 2.7 Hz, 1H), 4.05 - 3.92 (m, 1H), 3.88 (s, 3H), 3.85 - 3.46 (m, 5H), 3.23 (s, 4H), 2.98 (t, J = 12.1 Hz, 1H), 2.81 - 2.67 (m, 1H), 2.38 (s, 4H), 2.10 - 1.88 (m, 2H), 1.79 - 1.51 (m, 3H), 1.43 - 1.25 (m, 2H).

[0668] Step 20. 1-Cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one

[0669]

[0670] A mixture of 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one (0.061 g, 0.112 mmol, 1 equiv) and 2N NaOH (4 mL) was heated at 100 °C for 16 h. After that, the reaction was cooled and acidified with ice-cold acid to pH 5. Then, sodium bicarbonate was added and the resulting mixture was evaporated. The residue was dissolved in DCM, passed through Filtered and purified by RP-FCC (SiC18; H2O∶MeCN) to give the product as a white powder (0.026 g, 0.049 mmol, 44% yield). ESI-MS: 529.7 [M+H] +

[0671] 1 1H NMR (400 MHz, methanol-d4) δ 8.21 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.33 (dd, J = 8.6, 3.0 Hz, 1H), 7.28 (s, 1H), 7.26 - 7.22 (m, 1H), 7.11 (d, J = 8.6 Hz, 1H), 3.91 - 3.80 (m, 3H), 3.75 (s, 2H), 3.64 - 3.56 (m, 1H), 3.56 - 3.47 (m, 1H), 2.99 - 2.88 (m, 1H), 2.87 - 2.78 (m, 1H), 2.73 - 2.62 (m, 1H), 2.41 (s, 3H), 2.40 (s, 3H), 2.18 - 2.05 (m, 1H), 1.96 - 1.83 (m, 1H), 1.73 - 1.57 (m, 2H), 1.17 - 1.10 (m, 2H), 0.81 - 0.75 (m, 2H).

[0672] Step 21. Preparation of 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one

[0673]

[0674] To a solution of 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one (0.061 g, 0.112 mmol, 1 equiv) in MeOH (4 mL) was added MeONa (0.03 g, 0.558 mmol, 5 equiv). The suspension was stirred at 80 °C for 16 h. After that, the reaction was cooled and acidified to pH 5 with ice-cold acid. Then, sodium bicarbonate was added and the resulting mixture was evaporated. The residue was dissolved in DCM and purified by filtered and purified by RP-FCC (SiC18; H2O∶MeCN) to give the product as a white powder (0.037 g, 0.066 mmol, 60% yield). ESI-MS: 543.2 [M+H]+

[0675] 1 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 9.9 Hz, 1H), 8.08 (d, J = 2.9 Hz, 1H), 7.96 (s, 1H), 7.35 (dd, J = 8.6, 3.0 Hz, 1H), 7.26 (s, 1H), 7.24 - 7.20 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.17 (s, 3H), 3.91 - 3.81 (m, 3H), 3.79 (s, 2H), 3.63 - 3.52 (m, 2H), 3.01 - 2.92 (m, 1H), 2.90 - 2.82 (m, 1H), 2.74 - 2.66 (m, 1H), 2.40 (s, 3H), 2.38 (s, 3H), 2.17 - 2.09 (m, 1H), 1.96 - 1.89 (m, 1H), 1.75 - 1.60 (m, 2H), 1.27 - 1.21 (m, 2H), 0.94 - 0.88 (m, 2H).

[0676] Step 22. Preparation of 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0677]

[0678] Under an inert atmosphere, a mixture of tBuBrettPhos (0.007 g, 0.015 mmol, 0.08 equivalent) and Pd2(dba)3 (0.003 g, 0.004 mmol, 0.02 equivalent) was added to a solution of 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one (0.1 g, 0.183 mmol, 1 equivalent), MeOH (0.074 mL, 1.831 mmol, 10 equivalents), and tBuONa (0.025 g, 0.256 mmol, 1.4 equivalents) in 1,4-d ane (1 mL). The reaction was carried out at 70 °C for 16 h. Subsequently, the mixture was diluted with AcOEt and passed through Filtered through a pad and concentrated under reduced pressure. The residue was purified by FCC (SiHP; DCM∶MeOH 9∶1), and further purified by RP-FCC (SiC18, H2O∶CH3CN) and preparative HPLC. The title compound was isolated as the free base (0.036 g, 0.066 mmol, 36% yield). The product was obtained as a white powder. ESI-MS: 542.4 [M+H] +

[0679] 1 1H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 5.3 Hz, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 11.6 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.35 (dd, J = 8.6, 3.0 Hz, 1H), 7.25 (s, 1H), 7.24 - 7.20 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.05 (s, 3H), 3.92 - 3.83 (m, 3H), 3.79 (s, 2H), 3.64 - 3.58 (m, 1H), 3.54 - 3.47 (m, 1H), 3.01 - 2.91 (m, 1H), 2.89 - 2.82 (m, 1H), 2.75 - 2.65 (m, 1H), 2.41 (s, 3H), 2.35 (s, 3H), 2.19 - 2.11 (m, 1H), 1.97 - 1.89 (m, 1H), 1.75 - 1.59 (m, 2H), 1.37 - 1.29 (m, 2H), 0.98 - 0.92 (m, 2H).

[0680] Step 23. Preparation of tert-butyl (2R)-4-[1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazine-1-carboxylate

[0681]

[0682] To 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one (0.1 g, 0.183 mmol, 1 equiv), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (0.055 g, 0.275 mmol, 1.5 equiv), Cs2CO3 (0.119 g, 0.366 mmol, 2 equiv) in 1,4-di To the degassed solution in alkane (2.6 mL) was added Pd2(dba)3 (0.034 g, 0.037 mmol, 0.2 equiv) and Xantphos (0.032 g, 0.055 mmol, 0.3 equiv). The resulting mixture was degassed and the reaction was heated overnight at 115 °C under an inert atmosphere. Subsequently, the reaction mixture was passed through filtration, washed with DCM and purified by FCC (SiHP deactivated with NH3:DCM, DCM:MeOH 9:1) to afford the product as a yellow solid (0.055 g, 0.077 mmol, 42% yield). ESI-MS: 710.9 [M+H] +

[0683] Step 24. Preparation of 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one

[0684]

[0685] To a degassed solution of 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl]methyl]amino}methyl)-1,4-dihydroquinolin-4-one (0.100 g, 0.183 mmol, 1 equiv), piperazine (0.032 g, 0.366 mmol, 2 equiv), Cs2CO3 (0.125 g, 0.385 mmol, 2.1 equiv) in DMF (3 mL) were added BINAP (0.034 g, 0.055 mmol, 0.3 equiv) and Pd2(dba)3·CHCl3 (0.038 g, 0.037 mmol, 0.2 equiv). The reaction mixture was stirred overnight at 115 °C. Subsequently, the mixture was cooled to ambient temperature, passed through a pad filtration and the pad was washed with DCM. The filtrate was stirred with an MPA scavenger for 15 minutes, filtered and evaporated. The residue was purified by FCC (SiHP, DCM:MeOH 9:1) and further purified by preparative HPLC. The product as a free base was obtained after extraction with DCM / aqueous NaHCO3 solution, drying the organic layer with anhydrous Na2SO4 and evaporation. The title compound as a light yellow solid was isolated (0.019 g, 0.032 mmol, 17% yield). ESI-MS: 596.8 [M+H] + 。

[0686] Preparation of 1-Methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(2-oxopiperazin-1-yl)-1,4-dihydroquinolin-4-one

[0687]

[0688] a. tert-Butyl 4-[1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]-3-oxopiperazine-1-carboxylate

[0689]

[0690] To a degassed and dried mixture of 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one (0.050 g, 0.091 mmol, 1 equiv), tert-butyl 3-oxopiperazine-1-carboxylate (0.018 g, 0.091 mmol, 1 equiv), Xantphos (0.003 g, 0.005 mmol, 0.06 equiv), Cs2CO3 (0.045 g, 0.137 mmol, 1.5 equiv), Pd(OAc)2 (0.001 g, 0.005 mmol, 0.05 equiv) placed in a reaction vessel was added 1,4-d ane (3 mL) and the resulting mixture was stirred at 90 °C for 16 h under an inert atmosphere. Subsequently, the mixture was combined with another from a similar reaction (same amounts, heated for 2 h), diluted with AcOEt and washed with aqueous Na2CO3 solution. The combined organic fractions were dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by FCC (SiHP; DCM∶MeOH 9∶1). The obtained sample was dissolved in DCM and stirred with MPA scavenger for 10 min. The scavenger was filtered off and the filtrate was evaporated under reduced pressure to give the product as a beige powder (0.047 g, 0.068 mmol, yield 37%). ESI-MS: 666.8 [M+H] +

[0691] 1H NMR (400MHz, DMSO-d6) δ8.31-8.28 (m, 1H), 8.18 (d, J=8.7Hz, 1H), 8.15 (d, J=3.0Hz, 1H), 8.02 (s, 1H), 7.62 (d, J =2.0Hz, 1H), 7.38 (dd, J=8.7, 1.8Hz, 1H), 7.27-7.19 (m, 3H), 7.02 (d, J=8.5Hz, 1H), 4.17-4.10 (m, 2H), 3.88-3. 79(m, 6H), 3.78-3.69(m, 4H), 3.68-3.56(m, 2H), 3.44-3.35(m, 1H), 3.34-3.25(m, 1H), 2.83-2.70(m, 2H), 2.64 -2.54(m, 1H), 2.39(s, 3H), 2.33(s, 3H), 2.03-1.96(m, 1H), 1.79-1.72(m, 1H), 1.56-1.48(m, 1H), 1.46(s, 9H).

[0692] b. 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(2-oxopiperazin-1-yl)-1,4-dihydroquinolin-4-one

[0693]

[0694] To tert-butyl 4-[1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]-3-oxopiperazine-1-carboxylate (0.045 g, 0.068 mmol, 1 equiv) was added to 1,4-dihydroquinolin-7-yl. The stirred solution in oxane (3 mL) was added to 4M HCl in oxane (0.169 mL, 0.676 mmol, 10 equiv) was added and the resulting mixture was stirred at room temperature for 10 minutes. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was purified by FCC (SiHP; DCM: MeOH 95: 5) to give the product as an off-white powder (0.023 g, 0.038 mmol, yield 56%). ESI-MS: 566.3 [M+H] +

[0695] 11H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.27 (m, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 3.1 Hz, 1H), 8.01 (s, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.7, 1.8 Hz, 1H), 7.26 - 7.19 (m, 3H), 7.01 (d, J = 8.5 Hz, 1H), 3.88 - 3.80 (m, 4H), 3.79 - 3.68 (m, 4H), 3.67 - 3.54 (m, 3H), 3.43 (s, 2H), 3.09 - 3.01 (m, 2H), 2.85 - 2.69 (m, 3H), 2.62 - 2.54 (m, 1H), 2.38 (s, 3H), 2.32 (s, 3H), 2.03 - 1.93 (m, 1H), 1.79 - 1.70 (m, 1H), 1.60 - 1.38 (m, 2H).

[0696] Step 26. Preparation of 3 - ({[(3S)-1-(6 - methylpyridin - 3 - yl)piperidin - 3 - yl][(2 - methylpyridin - 4 - yl)methyl]amino}methyl)-1-(oxetan - 3 - yl)-1,4 - dihydroquinolin - 4 - one

[0697]

[0698] f. 1-(oxetan - 3 - yl)-4 - oxo - 1,4 - dihydroquinoline - 3 - carbaldehyde

[0699]

[0700] To a solution of 3 - iodoxetane (0.728 g, 3.955 mmol, 1.37 equiv) in DMF (13.3 mL) was added 4 - oxo - 1,4 - dihydroquinoline - 3 - carbaldehyde (0.500 g, 2.887 mmol, 1 equiv) and K2CO3 (1.596 g, 11.549 mmol, 4 equiv) and the resulting mixture was stirred at 120 °C for 1 day. Then, 3 - iodoxetane (0.500 g, 2.717 mmol, 0.94 equiv) was added and the reaction mixture was heated at 120 °C for an additional 27 h. Subsequently, the mixture was filtered through a pad and concentrated under reduced pressure. The residue was purified by FCC (SiHP; DCM∶MeOH 9∶1) and repurified by RP - FCC (SiC18; H2O∶MeCN) to afford the product as a beige solid (0.037 g, 0.139 mmol, 21% yield). ESI - MS: 230.1 [M + H] +

[0701] 1 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.47 (s, 1H), 8.34 (dd, J = 8.0, 1.6 Hz, 1H), 7.83 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.51 (d, J = 8.5 Hz, 1H), 5.82 (p, J = 6.9 Hz, 1H), 5.13 - 5.06 (m, 2H), 5.00 - 4.94 (m, 2H).

[0702] g. 3 - ({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(oxetan-3-yl)-1,4-dihydroquinolin-4-one

[0703]

[0704] A mixture of (3S)-1-(6-methylpyridin-3-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine (0.060 g, 0.202 mmol, 1 equiv), 1-(oxetan-3-yl)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (0.051 g, 0.223 mmol, 1.1 equiv) and DCE (3 mL) was stirred at 60 °C for 1.5 h. Then, NaBH(OAc)3 (0.107 g, 0.506 mmol, 2.5 equiv) was added and the reaction mixture was stirred at 60 °C for an additional 3 h. After that, the mixture was partitioned between DCM and NaOH solution. The organic layers were combined, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC to give the product as a white solid (0.037 g, 0.073 mmol, yield 36%). ESI-MS: 510.3 [M + H] +

[0705] 11H NMR (400 MHz, methanol-d4) δ 8.38 (dd, J = 8.2, 1.5 Hz, 1H), 8.21 (s, 1H), 8.20 - 8.18 (m, 1H), 8.10 (d, J = 3.0 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.47 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.36 (dd, J = 8.6, 3.0 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.29 - 7.25 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 5.80 - 5.72 (m, 1H), 5.20 (td, J = 7.2, 2.5 Hz, 2H), 4.86 (t, J = 6.7 Hz, 2H), 3.96 - 3.87 (m, 5H), 3.66 - 3.56 (m, 1H), 3.08 - 2.95 (m, 1H), 2.89 (t, J = 11.1 Hz, 1H), 2.77 - 2.66 (m, 1H), 2.41 (s, 3H), 2.34 (s, 3H), 2.23 - 2.13 (m, 1H), 2.03 - 1.89 (m, 1H), 1.78 - 1.63 (m, 2H).

[0706] Step 27. Preparation of 2-[3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-1-yl]acetic acid

[0707]

[0708] a. Methyl 2-(3-formyl-4-oxo-1,4-dihydroquinolin-1-yl)acetate

[0709]

[0710] A mixture of 4-oxo-1,4-dihydroquinoline-3-carbaldehyde (0.200 g, 1.155 mmol, 1.0 equiv) and methanol (10 mL) was heated at 70 °C overnight. PTSA monohydrate (0.044 g, 0.231 mmol, 0.2 equiv) was added and the resulting mixture was heated at 80 °C overnight and evaporated under reduced pressure. A portion of the crude material (0.100 g) was dissolved in DMF (1 mL) and potassium carbonate (0.113 g, 0.821 mmol) was added. The resulting mixture was stirred at room temperature for 5 minutes, then methyl bromoacetate (0.075 mL, 0.794 mmol) was added and the mixture was stirred at 60 °C for 1 hour. Thereafter, the mixture was partitioned between water and DCM and the aqueous layer was additionally extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by FCC (SiHP; hexane∶DCM∶EtOAc) to afford the product (0.073 g, 0.294 mmol) as a white solid. ESI-MS: 246.3 [M+H] +

[0711] 1 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.66 (s, 1H), 8.31 (dd, J = 8.0, 1.6 Hz, 1H), 7.81 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.55 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 5.43 (s, 2H), 3.72 (s, 3H).

[0712] b. Methyl 2-[3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-1-yl]acetate

[0713]

[0714] A mixture of methyl 2-(3-formyl-4-oxo-1,4-dihydroquinolin-1-yl)acetate (0.073 g, 73 mg, 0.298 mmol, 1.0 equiv), (3S)-1-(6-methylpyridin-3-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine (0.106 g, 0.357 mmol, 1.2 equiv) and anhydrous DCE (5 mL) was stirred overnight at room temperature. Subsequently, the reaction was cooled to 0 °C, NaBH(OAc)3 (0.076 g, 0.357 mmol, 1.2 equiv) was added and the mixture was stirred at room temperature for 100 minutes. Then NaBH(OAc)3 (0.076 g, 0.357 mmol, 1.2 equiv) was added and the reaction mixture was heated at 40 °C to 50 °C for about 220 minutes, during which time another portion of NaBH(OAc)3 (0.038 g, 0.179 mmol, 0.6 equiv) was added. Then the reaction mixture was stirred at room temperature over the weekend. DCE was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by FCC (SiHP; DCM∶MeOH) to afford the product as a pale yellow glass (0.043 g, 43 mg, 0.076 mmol, 26% yield). ESI-MS: 526.7 [M+H] + 。

[0715] c. 2-[3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-1-yl]acetic acid

[0716]

[0717] A mixture of methyl 2-[3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-1-yl]acetate (0.043 g, 0.082 mmol, 1.0 equiv), lithium hydroxide monohydrate (0.020 g, 0.466 mmol, 5.7 equiv), methanol (5 mL) and water (1 mL) was heated at 45 °C to 50 °C for 3 hours and then stirred overnight at room temperature. 2M aqueous HCl (0.147 mL, 3.6 equiv) was added and the mixture was evaporated in vacuo. The residue was purified by FCC (C18HP; H2O∶MeCN) to afford the product as an off-white solid (0.030 g, 0.058 mmol, 71% yield). ESI-MS: 512.3 [M+H] +

[0718] 1 1H NMR (400 MHz, methanol-d4) δ 8.33 (dd, J = 8.2, 1.6 Hz, 1H), 8.21 (dd, J = 5.1, 0.9 Hz, 1H), 8.10 - 8.01 (m, 2H), 7.70 (ddd, J = 8.6, 6.9, 1.6 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.33 - 7.27 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 4.78 (s, 2H), 3.94 - 3.76 (m, 5H), 3.65 - 3.55 (m, 1H), 2.99 - 2.80 (m, 2H), 2.75 - 2.62 (m, 1H), 2.40 (s, 6H), 2.20 - 2.09 (m, 1H), 1.94 - 1.83 (m, 1H), 1.71 - 1.55 (m, 2H).

[0719] Step 28. Preparation of 1-cyclopropyl-7-{4,7-diazaspiro[2.5]oct-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0720]

[0721] To a solution of tert-butyl 7-[1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate (0.087 g, 0.121 mmol, 1 equiv) in 1,4-dioxane (5 mL) was added 4M HCl in dioxane (0.9 mL, 3.615 mmol, 30 equiv) and the resulting mixture was stirred overnight at room temperature. Subsequently, the reaction mixture was poured into water, basified with aqueous NaOH (2M) and extracted into DCM. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to afford the product as a white solid (0.034 g, 0.055 mmol, 45% yield). ESI-MS: 622.7 [M+H] dioxane dioxane +

[0722] 11H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.27 (m, 1H), 8.13 (d, J = 3.0 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J = 13.7 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.20 - 7.15 (m, 1H), 7.04 - 7.00 (m, 1H), 3.83 - 3.56 (m, 6H), 3.54 - 3.45 (m, 1H), 3.16 - 3.11 (m, 2H), 2.98 (d, J = 24.0 Hz, 4H), 2.75 (d, J = 7.8 Hz, 2H), 2.63 - 2.54 (m, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.01 - 1.93 (m, 1H), 1.81 - 1.72 (m, 1H), 1.59 - 1.44 (m, 2H), 1.27 - 1.16 (m, 3H), 0.94 - 0.82 (m, 2H), 0.54 - 0.50 (m, 4H).

[0723] Step 29. Preparation of 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0724]

[0725] a) tert-Butyl (3S)-3-{[(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl]amino}piperidine-1-carboxylate

[0726]

[0727] Following the method outlined in Step 4a, the title compound was synthesized using tert-butyl (3S)-3-aminopiperidine-1-carboxylate (1.5 equiv) in place of (3S)-1-(pyridin-3-yl)piperidin-3-amine. After the addition of NaBH4, the mixture was stirred for 3 h. The residue was purified by FCC (Al2O3; DCM∶MeOH = 9∶1) to afford the product as a yellow solid (5.6 g, 15.1 mmol, 94% yield). AP-MS: 372.4 [M+H] +

[0728] b) 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0729]

[0730] The A mixture of MS, tert-butyl (3S) -3- { [(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl) methyl] amino} piperidine -1- carboxylate (3.0 g, 8.1 mmol, 1 eq.), 2-methylpyridine-4-carboxaldehyde (0.9 g, 8.1 mmol, 1 eq.) and DCE (30 mL) was stirred at room temperature overnight. The reaction mixture was then cooled to 0 ° C and NaBH (OAc) 3 (2.6 g, 12.1 mmol, 1.5 eq.) was added. Afterwards, the reaction was carried out at 45 ° C for 3 hours. The mixture was then filtered through a celite pad, washed with DCM and the filtrate was concentrated in vacuo. The residue was distributed between DCM and a 10% NaOH aqueous solution. The water layer was additionally washed with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by FCC (SiHP, DCM / MeOH) to give the product as a yellow oil (2.4 g, 5.0 mmol, yield 62%). ESI-MS: 477.6 [M+H] +

[0731] c) 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0732]

[0733] Tert-butyl (3S)-3-{[(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl][(2-methylpyridin-4-yl)methyl]amino}piperidine-1-carboxylate (2.4 g, 5.0 mmol, 1 equiv) was added to 1,4-dihydroquinolin-3-yl A solution in oxane (20 mL) was used in di The product was treated with 4M HCl (6.5 mL, 25.2 mmol, 5 eq) in oxane. The resulting slurry was stirred over the weekend. The volatiles in the reaction mixture were then evaporated and the residue was partitioned between DCM and 15% aqueous NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the product as a yellow oil (1.6 g, 4.2 mmol, 83% yield). ESI-MS: 377.5 [M+H] +

[0734] 11H NMR (400 MHz, DMSO-d6) δ 8.29 - 8.23 (m, 1H), 8.18 (dd, J = 8.1, 1.6 Hz, 1H), 7.93 (s, 1H), 7.71 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.36 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.24 - 7.15 (m, 2H), 3.82 (s, 3H), 3.66 (s, 2H), 3.63 - 3.49 (m, 5H), 3.11 - 3.00 (m, 1H), 2.80 - 2.72 (m, 1H), 2.35 (s, 3H), 2.34 - 2.24 (m, 1H), 2.01 - 1.88 (m, 1H), 1.63 (d, J = 12.3 Hz, 1H), 1.51 - 1.36 (m, 1H), 1.33 - 1.18 (m, 1H).

[0735] Step 30. Preparation of 3 - ( { [(3S)-1-(2 - chloropyrimidin - 4 - yl)piperidin - 3 - yl][(2 - methylpyridin - 4 - yl)methyl]amino} methyl ) - 1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0736]

[0737] A mixture of 1 - methyl - 3 - ( { [(2 - methylpyridin - 4 - yl)methyl][(3S)-piperidin - 3 - yl]amino} methyl ) - 1,4 - dihydroquinolin - 4 - one (0.12 g, 0.3 mmol, 1 equiv), 2,4 - dichloropyrimidine (0.052 g, 0.4 mmol, 1.1 equiv), K2CO3 (0.066 g, 0.5 mmol, 1.5 equiv) and acetonitrile (2.5 mL) was heated at 80 °C for 1.5 h. Then 2M aqueous NaOH was added and the reaction mixture was washed with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiHP: DCM / MeOH) to give the product as a pale yellow solid (0.076 g, 0.2 mmol, 49% yield). 0.026 g of the sample was further purified by preparative HPLC to give the formate of the compound as a pale yellow solid (0.013 g, 0.03 mmol, 8% yield). ESI - MS: 489.2 [M + H] +

[0738] 11H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 5.0 Hz, 1H), 8.19 (dd, J = 8.1, 1.6 Hz, 1H), 8.15 (s, 1H), 8.03 - 7.97 (m, 2H), 7.71 (ddd, J = 8, 6, 6.9, 1.7 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.37 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.25 - 7.19 (m, 2H), 6.89 - 6.83 (m, 1H), 4.63 - 4.11 (m, 2H), 3.84 (s, 3H), 3.82 - 3.71 (m, 2H), 3.69 - 3.57 (m, 2H), 3.14 - 3.03 (m, 1H), 2.91 - 2.80 (m, 1H), 2.61 - 2.54 (m, 1H), 2.36 (s, 3H), 2.02 - 1.95 (m, 1H), 1.80 - 1.65 (m, 2H), 1.37 - 1.22 (m, 1H).

[0739] Step 31. Preparation of 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carbaldehyde

[0740]

[0741] a) 4,6-Dichloropyridine-3-carbonyl chloride

[0742]

[0743] 4,6-Dichloropyridine-3-carboxylic acid (1.0 g, 5.2 mmol, 1 equiv) and SOCl2 (4.0 mL, 54.7 mmol, 10.5 equiv) were heated at 80 °C for 2 h. Then, the mixture was cooled to room temperature and co-evaporated with DCM to give the product as a yellow oil (1.1 g, 5.2 mmol, 99% yield), which was used in the next step without further purification.

[0744] b) Ethyl 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0745]

[0746] TEA (2.9 mL, 20.8 mmol, 4 eq) was added to acetonitrile (5 mL), followed by ethyl 3-(dimethylamino)prop-2-enoate (1.1 g, 7.8 mmol, 1.5 eq) and 4,6-dichloropyridine-3-carbonyl chloride (1.1 g, 5.2 mmol, 1 eq). The reaction mixture was stirred at 65 °C overnight, then cooled to room temperature and cyclopropylamine (0.4 g, 7.9 mmol, 1 eq) was added. The resulting mixture was heated at reflux for 3 h and then heated overnight. Subsequently, the reaction mixture was concentrated, diluted with EtOAc, washed sequentially with aqueous NaHCO3, water, brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by FCC (SiHP; Hex / AcOEt 0 to 100%) to give the product as a yellow solid (0.4 g, 1.3 mmol, 25% yield).

[0747] ESI-MS: 293.8 [M+H] +

[0748] 1 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.50 (s, 1H), 8.01 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.62 (tt, J = 7.2, 3.9 Hz, 1H), 1.32 - 1.21 (m, 5H), 1.15 - 1.08 (m, 2H).

[0749] c) 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0750]

[0751] Ethyl 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylate (0.15 g, 0.5 mmol, 1 eq) was suspended in water (2 mL) and concentrated HCl (2 mL). The reaction mixture was stirred at 60 °C for 1 h and then concentrated to give the product as a white solid (0.14 g, 0.5 mmol, 99% yield).

[0752] ESI-MS: 265.8 [M+H] +

[0753] d) 7-chloro-1-cyclopropyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-one

[0754]

[0755] The title compound was synthesized by replacing 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to the method outlined in Step 7d. The first stage of the reaction was extended to stir overnight with NaBH4, while the second stage with PTSA was shortened to 3 h. In addition, during the work-up, washing was carried out using DCM and aqueous NaHCO3 solution. The residue after evaporation of the volatiles was purified by FCC (SiHP; Hex∶AcOEt 4∶1) to give the product as a white solid (0.05 g, 0.2 mmol, 42% yield).

[0756] ESI-MS: 223.0 [M+H] +

[0757] e) 7-Chloro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbaldehyde

[0758]

[0759] A mixture of MeONa (0.05 g, 0.8 mmol, 3.9 equiv) and ethyl formate (0.07 mL 0.9 mmol, 3.9 equiv) was treated with a solution of 7-chloro-1-cyclopropyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-one (0.05 g, 0.2 mmol, 1 equiv) in anhydrous DCM (5 mL) under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 h and ice-water was added. The organic layer was washed with 2M aqueous NaOH solution, the aqueous phase was acidified to pH 6 with concentrated HCl and then washed with DCM. The combined organic extracts were dried over MgSO4, filtered and concentrated to give the crude product as a yellow solid (0.053 g, 0.2 mmol, 94% yield), which was used directly in the next step.

[0760] ESI-MS: 250.9 [M+H] +

[0761] f) 7-Chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carbaldehyde

[0762]

[0763] 7-Chloro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbaldehyde (0.053 g, 0.2 mmol, 1 equiv) was dissolved in anhydrous MeOH (5 mL) and MnO2 (0.09 g, 1.1 mmol, 5 equiv) was added. The reaction mixture was stirred overnight at room temperature. The volatiles in the mixture were then evaporated, the residue was diluted with DCM and passed through a pad of Celite. The filtrate was concentrated and the residue was purified by FCC (SiHP; DCM∶MeOH 95∶5) to give the product as a pale yellow solid (0.036 g, 0.1 mmol, 68% yield).

[0764] AP-MS: 249.0 [M+H] +

[0765] Step 32. Preparation of 7-(cyclohex-1-en-1-yl)-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0766]

[0767] A mixture of 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one (0.06 g, 0.1 mmol, 1 equiv), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.046 g, 0.2 mmol, 2 equiv), Na2CO3 (0.072 g, 0.2 mmol, 2 equiv), dioxane (3 mL) and water (0.3 mL) was purged with argon for 10 min. Then Pd(PPh3)4 (0.006 g, 0.005 mmol, 0.05 equiv) was added and the mixture was irradiated with microwave at 140 °C for 1 h. Subsequently, the reaction mixture was filtered through a pad of Celite. The residue was adsorbed on silica and purified by FCC (SiHP deactivated with NH3∶DCM; DCM∶MeOH 8∶2) and further purified by preparative HPLC to give the product as a white solid (0.031 g, 0.05 mmol, 47% yield). ESI-MS: 592.7 [M+H]

[0768] ESI-MS: 592.7 [M+H] +

[0769] Preparation of 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0770]

[0771] Charge a dry reactor vessel with (3S)-1-(6-methylpyridin-3-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine (0.342 g, 1.2 mmol, 1 equiv), 4-oxo-1,4-dihydroquinoline-3-carbaldehyde (0.2 g, 1.2 mmol, 1 equiv) and anhydrous DCE (10 mL). The reaction is carried out at 60 °C for 2 h and then cooled to 0 °C. Add NaBH(OAc)3 (0.34 g, 1.6 mmol, 1.4 equiv) and the reaction mixture is stirred at room temperature overnight. Then add additional NaBH(OAc)3 (0.122 g, 0.6 mmol, 0.5 equiv), heat the reaction while stirring at 50 °C for an additional 12 h. Subsequently add H2O, then add NaHCO3, and wash the resulting mixture with DCM. Wash the organic layer with brine, dry over Na2SO4 and concentrate in vacuo. Purify the residue by FCC (SiHP; DCM∶MeOH 9∶1) and additionally by RP-FCC (SiC18; H2O∶MeCN) to afford the product as a pale yellow powder (0.29 g, 0.6 mmol, 51% yield). Repurify a 0.12 g sample by preparative HPLC. Neutralize the collected fractions with 1N aqueous NaOH, extract with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Suspend the residue in water and lyophilize to afford the product as a beige powder (0.08 g, 0.2 mmol, 14% yield).

[0772] ESI-MS: 454.2 [M+H] +

[0773] 11H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 3.1 Hz, 1H), 8.11 - 8.09 (m, 1H), 7.94 (s, 1H), 7.60 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.32 - 7.17 (m, 4H), 7.01 (d, J = 8.5 Hz, 1H), 3.84 - 3.70 (m, 3H), 3.66 - 3.54 (m, 3H), 2.79 - 2.69 (m, 2H), 2.60 - 2.55 (m, 1H), 2.39 (s, 3H), 2.32 (s, 3H), 2.00 - 1.92 (m, 1H), 1.80 - 1.71 (m, 1H), 1.59 - 1.39 (m, 2H).

[0774] Step 34. 1-Cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0775]

[0776] 7-Chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one (0.1 g, 0.2 mmol, 1 equivalent), 1,4-di A mixture of alkane (1 mL) and H2O (1 mL) was purged with argon, and then KOH (0.013 g, 0.2 mmol, 1.3 equiv), tBuXPhos (0.006 g, 0.015 mmol, 0.08 equiv), and Pd2(dba)3 (0.003 g, 0.004 mmol, 0.02 equiv) were added. The reaction vial was capped and the reaction mixture was heated at 100 °C for 75 minutes. Then the mixture was purged with argon again and additional KOH (0.006 g, 0.1 mmol, 0.6 equiv), tBuXPhos (0.006 g, 0.015 mmol, 0.08 equiv), and Pd2(dba)3 (0.003 g, 0.004 mmol, 0.02 equiv) were added, and the reaction was continued at 100 °C for 2 hours. Then H2O was added and the reaction mixture was partitioned between DCM and aqueous NH4Cl solution. The aqueous layer was washed with DCM (3 times). The combined organic layers were evaporated in vacuo and the residue was purified by FCC (SiHP; DCM∶MeOH 9∶1) to give 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one (0.055 g, 0.1 mmol, 57% yield) as a beige solid.

[0777] ESI-MS: 528.3 [M+H] +

[0778] 1 H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.28 (d, J = 5.0 Hz, 1H), 8.13 (d, J = 2.9 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 11.5 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.28 - 7.12 (m, 3H), 7.02 (d, J = 8.5 Hz, 1H), 3.89 - 3.50 (m, 6H), 3.47 - 3.37 (m, 1H), 2.83 - 2.65 (m, 2H), 2.64 - 2.54 (m, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 2.04 - 1.90 (m, 1H), 1.83 - 1.67 (m, 1H), 1.60 - 1.38 (m, 2H), 1.23 - 1.08 (m, 2H), 0.95 - 0.81 (m, 2H).

[0779] Step 35. Preparation of 8-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0780]

[0781] a) 3-[(2-bromophenyl)amino]propanoic acid

[0782]

[0783] 2-Bromoaniline (2 g, 11.6 mmol, 1 equiv) and acrylic acid (1.5 mL, 37.2 mmol, 3.2 equiv) were added to H2O (40 mL). The resulting mixture was heated at 100 °C overnight. The mixture was then cooled to room temperature. The precipitate was filtered off and washed with cold water. The solid was mixed with 20 mL of toluene and the solvent was evaporated to give the crude product as a yellow solid (2.7 g, 11.1 mmol, 95% yield), which was used without further purification for the next step.

[0784] b) 8-Bromo-1,2,3,4-tetrahydroquinolin-4-one

[0785]

[0786] 3-[(2-Bromophenyl)amino]propanoic acid (2.7 g, 12.0 mmol, 1 equiv) was added in one portion to polyphosphoric acid (14.46 mL, 78.4 mmol, 7.1 equiv) at 60 °C. The resulting mixture was heated at 110 °C for 12 h with stirring. The reaction mixture was slowly poured into ice water. The solution was washed with EtOAc (4 × 100 mL). The organic layer was washed sequentially with saturated NaHCO3 solution, water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC (SiHP; Hex∶AcOEt 8∶2) to give the product as a yellow viscous solid (0.518 g, 2.3 mmol, 21% yield).

[0787] ESI-MS: 225.9 [M+H] +

[0788] 1 1H NMR (300 MHz, chloroform-d) δ 7.82 (dd, J = 7.9, 1.5 Hz, 1H), 7.56 (dd, J = 7.9, 1.5 Hz, 1H), 6.62 (t, J = 7.9 Hz, 1H), 4.99 (s, 1H), 3.66 (td, J = 7.1, 2.2 Hz, 2H), 2.79 - 2.64 (m, 2H).

[0789] c) 8-Bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-one

[0790]

[0791] Potassium carbonate (0.7 g, 5.2 mmol, 3 eq) was added to a solution of 8-bromo-1,2,3,4-tetrahydroquinolin-4-one (0.46 g, 1.7 mmol, 1 eq) in anhydrous DMF (10 mL) and the resulting mixture was stirred at room temperature for 20 minutes. Subsequently, methyl iodide (0.22 mL, 3.5 mmol, 2 eq) was added and the mixture was heated at 120 °C overnight. Then the reaction mixture was cooled to room temperature and additional potassium carbonate (0.7 g, 5.2 mmol, 3 eq) and methyl iodide (0.22 mL, 3.5 mmol, 2 eq) were added. The mixture was heated at 120 °C overnight. Then the reaction mixture was cooled to room temperature again and an additional amount of potassium carbonate (0.7 g, 5.2 mmol, 3 eq) and methyl iodide (0.215 mL, 3.5 mmol, 2 eq) were added. The mixture was heated at 120 °C over the weekend. Then DMF was evaporated under reduced pressure and the residue was purified by FCC (SiHP; Hex∶AcOEt 50% to 80%) to give the product as a yellow oil (0.105 g, 0.4 mmol, 25% yield).

[0792] ESI-MS: 239.9 [M+H] +

[0793] d) 8-Bromo-1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0794]

[0795] In a dry round-bottom flask, 8-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-one (0.105 g, 0.4 mmol, 1 equiv) and ethyl formate (0.106 mL, 1.3 mmol, 3 equiv) were mixed in anhydrous THF (4 mL) under an inert atmosphere. Then, 1 M NaHMDS in THF (1.2 mL, 0.7 mmol, 1.7 equiv) was added dropwise and the resulting mixture was stirred at room temperature overnight. The organics were concentrated to dryness and the residue was dissolved in anhydrous MeOH (1 mL). MnO2 (0.013 g, 0.2 mmol, 0.5 equiv) was added to the above methanol solution and stirred at room temperature for 3 h, then stirred for an additional 20 h. Subsequently, the reaction mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by FCC (SiHP; DCM∶MeOH 95∶5) to give the product as a brown solid (0.03 g, 0.1 mmol, 23% yield).

[0796] ESI-MS: 265.9 [M+H] +

[0797] e) Bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0798]

[0799] 8-Bromo-1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (0.063 g, 0.2 mmol, 1 equiv), dissolved in anhydrous DCE (1.5 mL), and (3S)-1-(6-methylpyridin-3-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine (0.084 g, 0.3 mmol, 1.2 equiv), dissolved in anhydrous DCE (1.5 mL), were added dropwise to each other into a reaction vial. The solution was purged with argon for 10 min. Drops of AcOH were added via syringe needle, followed by a pinch of dry MgSO4, and the resulting mixture was purged with argon again. The reaction vial was capped and the reaction mixture was stirred at room temperature for 3.5 h. Then the mixture was cooled in an ice-NaCl bath and NaBH(OAc)3 (0.09 g, 0.4 mmol, 1.8 equiv) was added in portions. The reaction mixture was heated at 55 °C for 3 h. Then anhydrous DCE (1 mL) was added and the reaction was stirred at room temperature overnight. Subsequently, the reaction mixture was filtered through a pad of celite and the pad was washed with a mixture of DCM:MeOH (9:1, 100 mL). The organic layer was concentrated in vacuo and the residue was purified by FCC (SiHP; DCM:MeOH 93:7), followed by purification by RP-FCC (Si-C18; H2O / ACN) to afford the product as a colorless oil (0.012 g, 0.02 mmol, 9% yield).

[0800] ESI-MS: 546.3 [M+H] +

[0801] Step 36. Preparation of 7-chloro-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one

[0802]

[0803] a) Ethyl 2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)-3-(dimethylamino)prop-2-enoate

[0804]

[0805] Suspend 2,6-dichloro-5-fluoropyridine-3-carboxylic acid (5.4 g, 25.8 mmol, 1 equiv) in SOCl2 (9.4 mL, 129.2 mmol, 5.0 equiv), and stir the reaction mixture at 80 °C for 2 h, during which time the mixture becomes a clear solution. Co-concentrate the reaction mixture with DCM. Add the residue to a mixture of ethyl 3-(dimethylamino)prop-2-enoate (3.7 mL, 25.8 mmol, 1 equiv), DIPEA (9.5 mL, 54.3 mmol, 2.1 equiv), and toluene (20 mL) within 5 min at room temperature. Stir the resulting solution at room temperature for 15 min, then heat at 90 °C for 3.5 h after that time. Subsequently, partition the reaction mixture between DCM and H2O. Dry the washed organic layer over anhydrous Na2SO4, filter, and evaporate. Purify the residue by FCC (SiHP; Hex / AcOEt) to afford the product as an orange oil (2.8 g, 8.4 mmol, 32% yield).

[0806] ESI-MS: 335.0 [M+H] +

[0807] 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 7.9 Hz, 1H), 7.95 (s, 1H), 3.91 (q, J = 7.1 Hz, 2H), 3.39 (s, 3H), 2.93 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H).

[0808] b) Ethyl 2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)-3-[(propan-2-yl)amino]prop-2-enoate

[0809]

[0810] Treat a solution of 2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)-3-(dimethylamino)prop-2-enoate (1.05 g, 3.1 mmol, 1 equiv) in a mixture of EtOH (16 mL) and Et2O (6 mL) with propan-2-amine (0.3 mL, 3.4 mmol, 1.1 equiv). Stir the reaction mixture at room temperature for 15 min. Then evaporate the solvent to afford the crude product as an orange oil (1.2 g, 3.4 mmol, 99% yield), which is used without further purification for the next step.

[0811] ESI-MS: 349.0 [M+H] +

[0812] c) Ethyl 7-chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate

[0813]

[0814] A solution of 2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)-3-[(propan-2-yl)amino]prop-2-enoate (0.85 g, 2.6 mmol, 1 equiv) in ACN (8 mL) was treated with K2CO3 (0.5 g, 3.8 mmol, 1.6 equiv), and the reaction mixture was stirred at 80 °C for 2 h. The reaction was then quenched by the addition of H2O. Then, the reaction mixture was combined with three other crude mixtures from test reactions set up using the same conditions but starting with a smaller amount of 2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)-3-[(propan-2-yl)amino]prop-2-enoate (0.1 g, 0.3 mmol) using different solvents (ACN, NMP, and DMAc). The resulting mixture was washed with DCM. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The residue was dissolved in 5 mL of DCM and heptane was added. The precipitate was filtered off and dried in vacuo to afford ethyl 7-chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate (0.81 g, 2.6 mmol, 85% yield) as an off-white solid.

[0815] ESI-MS: 313.9 [M+H] +

[0816] 1 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H), 5.53 - 5.43 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.50 (s, 3H), 1.49 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0817] d) 7-Chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0818]

[0819] Ethyl 7-chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate (0.81 g, 2.6 mmol, 1 equiv), concentrated aqueous HCl (2 mL), H2O (6 mL), and 1,4-di A mixture of alkane (12 mL) was stirred at 100 °C for 4 h. Subsequently, the reaction mixture was cooled to room temperature, and the precipitate was filtered off and dried to give the product (0.67 g, 0.2 mmol, 90% yield) as an off-white solid, which was used for the next step without further purification.

[0820] 1 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.01 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 5.61 (septet, J = 6.4 Hz, 1H), 1.56 (d, J = 6.7 Hz, 6H).

[0821] e) 7-Chloro-6-fluoro-1-(propan-2-yl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4-one and 6-fluoro-7-methoxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4-one

[0822]

[0823] Following the method outlined in Step 7d, 7-chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was used instead of 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, and the second stage was shortened to heating under reflux for 1.5 h to synthesize the title compounds. The residue after concentration of the reaction mixture was purified by FCC (SiHP; Hex∶AcOEt 1∶1) to give two compounds, 7-chloro-6-fluoro-1-(propan-2-yl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4-one (0.46 g, 0.1 mmol, 81% yield) as a yellow solid,

[0824] ESI-MS: 243.1 [M+H] +

[0825] 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.0 Hz, 1H), 4.88 (septet, J = 6.7 Hz, 1H), 3.52 - 3.44 (m, 2H), 2.67 - 2.59 (m, 2H), 1.17 (d, J = 6.8 Hz, 7H).

[0826] and 6-fluoro-7-methoxy-1-(propan-2-yl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4-one (0.074 g, 0.02 mmol, 13% yield) as a yellow solid.

[0827] ESI-MS: 239.3 [M+H] +

[0828] 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 10.3 Hz, 1H), 4.93 (septet, J = 6.8 Hz, 1H), 3.96 (s, 3H), 3.46 - 3.39 (m, 2H), 2.55 - 2.51 (m, 2H), 1.18 (d, J = 6.8 Hz, 6H).

[0829] f) 7-chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carbaldehyde

[0830]

[0831] At 0 °C, 7-chloro-6-fluoro-1-(propan-2-yl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4-one (0.46 g, 1.9 mmol, 1 equiv), dissolved in anhydrous THF (2 mL), was added to a solution of NaHMDS (2 M in THF, 1.1 mL, 2.3 mmol, 1.2 equiv) in anhydrous THF (2 mL). The reaction mixture was stirred at the same temperature for 30 minutes and a solution of ethyl formate (0.2 mL, 2.5 mmol, 1.3 equiv) in THF (2 mL) was added. The reaction mixture was stirred for 1 h and then the reaction was quenched by adding saturated aqueous NH4Cl solution. The mixture was washed with AcOEt. The aqueous layer was further washed with AcOEt (×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and dried under reduced pressure. The residue was dissolved in anhydrous 1,4-di ane (10 mL) and MnO2 (0.82 g, 9.5 mmol, 4.2 equiv) was added. The resulting mixture was heated to 50 °C and stirred for 16 h. Subsequently, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the pad was washed with a mixture of DCM:MeOH (7:3). The filtrate was concentrated and the residue was purified by FCC (SiHP; DCM:AcOEt 9:1) to give 7-chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carbaldehyde (0.29 g, 1.1 mmol, 57% yield) as a yellow solid.

[0832] AP-MS: 269.0 [M+H] +

[0833] 11H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.68 (s, 1H), 8.58 (d, J = 7.7 Hz, 1H), 5.51 (septet, J = 6.7 Hz, 1H), 1.52 (d, J = 6.8 Hz, 6H).

[0834] g) 7-chloro-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one

[0835]

[0836] Charge the dry reactor vessel with (3S)-1-(6-methylpyridin-3-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine (0.31 g, 1.0 mmol, 1.0 equiv) and 7-chloro-6-fluoro-4-oxo-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carbaldehyde (0.29 g, 1.0 mmol, 1.0 equiv) in DCE (10 mL). Heat the mixture at 50 °C for 4 h, then cool to 0 °C. Add NaBH(OAc)3 (0.43 g, 2.0 mmol, 2.0 equiv) and stir the resulting mixture at room temperature for 16 h. Subsequently, quench the reaction mixture with H2O and aqueous NaHCO3 and wash with DCM. Wash the combined organic layers with brine, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify the residue by FCC (SiHP; DCM∶MeOH 9∶1). Repurify the product by FCC (SiHP; DCM / MeOH / NH3) and RP-FCC (Si-C18; H2O / ACN) to afford the product as a white solid (0.40 g, 0.7 mmol, 70% yield).

[0837] ESI-MS: 549.4 [M+H] +

[0838] 11H NMR (400 MHz, methanol-d4) δ 8.42 - 8.34 (m, 1H), 8.24 - 8.15 (m, 2H), 8.06 (d, J = 3.0 Hz, 1H), 7.34 (dd, J = 8.6, 3.0 Hz, 1H), 7.30 (s, 1H), 7.27 - 7.22 (m, 1H), 7.11 (d, J = 8.6 Hz, 1H), 5.75 - 5.59 (m, 1H), 3.96 - 3.76 (m, 5H), 3.64 - 3.53 (m, 1H), 3.02 - 2.92 (m, 1H), 2.90 - 2.82 (m, 1H), 2.77 - 2.64 (m, 1H), 2.48 - 2.35 (m, 6H), 2.22 - 2.07 (m, 1H), 2.00 - 1.85 (m, 1H), 1.77 - 1.57 (m, 2H), 1.53 - 1.36 (m, 6H).

[0839] Step 37. 3 - ( { [(1,3 - Dimethyl - 1H - pyrazol - 5 - yl)methyl][(3S) - 1 - (pyridin - 3 - yl)piperidin - 3 - yl]amino} methyl) - 1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0840]

[0841] A solution of 1,3 - dimethyl - 1H - pyrazole - 5 - carbaldehyde (0.076 g, 0.6 mmol, 1.1 equiv) and 1 - methyl - 3 - ( { [(3S) - 1 - (pyridin - 3 - yl)piperidin - 3 - yl]amino} methyl) - 1,4 - dihydroquinolin - 4 - one in DCE (5.0 mL) was stirred at 60 °C for 1 h. Then NaBH(OAc)3 (0.3 g, 1.4 mmol, 2.5 equiv) was added and the reaction mixture was stirred at 60 °C for 24 h. After that, the reaction was quenched by adding 1 M NaOH (50 mL). Then the resulting mixture was washed with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by FCC (SiHP; DCM∶MeOH 9∶1). The final compound was suspended in water and lyophilized to give the product as a pale yellow powder (0.14 g, 0.3 mmol, 53% yield).

[0842] ESI - MS: 457.5 [M + H] +

[0843] 11H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 3.0 Hz, 1H), 8.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.92 (dd, J = 4.5, 1.3 Hz, 1H), 7.87 (s, 1H), 7.72 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.38 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.29 (ddd, J = 8.6, 3.1, 1.4 Hz, 1H), 7.21 - 7.10 (m, 1H), 5.97 (s, 1H), 4.03 - 3.49 (m, 12H), 2.93 - 2.80 (m, 1H), 2.80 - 2.68 (m, 1H), 2.68 - 2.56 (m, 1H), 2.07 - 1.91 (m, 4H), 1.83 - 1.69 (m, 1H), 1.68 - 1.35 (m, 2H).

[0844] Step 38. Preparation of 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one

[0845]

[0846] a) Ethyl 2-[4-bromo-2-fluorobenzoyl]-3-(dimethylamino)prop-2-enoate

[0847]

[0848] A mixture of ethyl 3-(dimethylamino)prop-2-enoate (0.6 mL, 4.2 mmol, 1 equiv) and DIPEA (1.5 mL, 8.8 mmol, 2.1 equiv) was stirred at room temperature and a solution of 4-bromo-2-fluorobenzoyl chloride (0.57 mL, 4.2 mmol, 1 equiv) in toluene (5 mL) was added within 5 minutes. The yellow solution was placed in an oil bath at 85 °C to 90 °C. After heating for 3 hours, the mixture was diluted with DCM and H2O. The separated organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by FCC (SiHP; Hex∶AcOEt 2∶3) to afford the title product as a yellow oil (1.24 g, 3.6 mmol, 81% yield).

[0849] ESI-MS: 344.0 [M+H] +

[0850] b) Ethyl 7-bromo-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0851]

[0852] Ethyl 2-[4-bromo-2-fluorobenzoyl]-3-(dimethylamino)prop-2-enoate (1.24 g, 3.6 mmol, 1 equiv) and cyclopropylamine (0.4 mL, 4.7 mmol, 1.3 equiv) were heated in toluene (10 mL) at 110 °C for 2 h. The reaction mixture was concentrated and the residue was diluted in DMF (8 mL). Then, K2CO3 (1.2 g, 9.0 mmol, 2.5 equiv) was added and the resulting mixture was heated at 100 °C overnight. After cooling, the reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by FCC (SiHP; Hex∶AcOEt 1∶4) to afford the title product as a yellow solid (0.97 g, 3.3 mmol, 88% yield).

[0853] AP-MS: 336.0 [M+H] +

[0854] c) 7-Bromo-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0855]

[0856] A suspension of ethyl 7-bromo-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.95 g, 3.7 mmol, 1 equiv) in 1 M aqueous HCl (8 mL) was stirred at 95 °C overnight. The reaction mixture was concentrated and the residue was co-concentrated with toluene to afford the title product as a yellow solid (0.8 g, 3.5 mmol, 92% yield).

[0857] ESI-MS: 308.0 [M+H] +

[0858] d) 7-Bromo-1-cyclopropyl-1,2,3,4-tetrahydroquinolin-4-one

[0859]

[0860] The title compound was synthesized by replacing 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 7-bromo-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid according to the method outlined in Step 7d. The first stage of the reaction was extended to stir overnight with NaBH4, and the second stage with PTSA was shortened to stir for 3 h at room temperature. In addition, DCM was used for washing. The crude product was purified by FCC (SiHP; Hex∶AcOEt 1∶1) to afford the title product as a yellow solid (0.52 g, 2.0 mmol, 65% yield).

[0861] ESI-MS: 266.0 [M+H]+

[0862] e) 7-Bromo-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydroquinoline-3-carbaldehyde

[0863]

[0864] The title compound was synthesized by replacing 7-chloro-1-cyclopropyl-1,2,3,4-tetrahydro-1,6-naphthyridin-4-one with 7-bromo-1-cyclopropyl-1,2,3,4-tetrahydroquinolin-4-one and using 4.0 equiv of MeONa and ethyl formate according to the method outlined in Step 31e. The reaction time was shortened to 3 h and MgSO4 was used as the drying agent. The title compound was obtained as an orange solid (0.44 g, 1.4 mmol, 91% yield).

[0865] AP-MS: 294.0 [M+H] +

[0866] f) 7-Bromo-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde

[0867]

[0868] The title compound was synthesized by replacing 7-chloro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbaldehyde with 7-bromo-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydroquinoline-3-carbaldehyde according to the method outlined in Step 31f. The reaction time was extended to stir throughout the weekend. The reaction mixture was passed directly through a Celite pad and the pad was washed thoroughly with a DCM / MeOH mixture. FCC purification (SiHP; DCM∶MeOH 95∶5) afforded the title compound as a yellow solid (0.17 g, 0.6 mmol, 98% yield).

[0869] AP-MS: 292.0 [M+H] +

[0870] g) tert-Butyl 3-(1-cyclopropyl-3-formyl-4-oxo-1,4-dihydroquinolin-7-yl)morpholine-4-carboxylate

[0871]

[0872] A mixture of 7-bromo-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (0.03 g, 0.1 mmol, 1 equiv), 4-[(tert-butoxy)carbonyl]morpholine-3-carboxylic acid (0.07 g, 0.3 mmol, 3.0 equiv), iridium(III) bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C][4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′] hexafluorophosphate (0.001 g, 0.001 mmol, 0.01 equiv), 4,4′-di-tert-butyl-2,2′-bipyridine (0.004 g, 0.015 mmol, 0.148 equiv) and nickel(II) dimethoxyethane adduct (0.002 g, 0.009 mmol, 0.09 equiv) was stirred at room temperature under argon in a Penn PhDM2 photoreactor (100% LED) for 1 h. The reaction mixture was evaporated in vacuo. The residue was suspended in DCM, washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by FCC (SiHP; Hex∶AcOEt 1∶1) to afford the title product as a white solid (0.024 g, 0.06 mmol, 56% yield).

[0873] ESI-MS: 399.6 [M+H] +

[0874] h) tert-Butyl 3-[1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]morpholine-4-carboxylate

[0875]

[0876] Suspend tert-butyl 3-(1-cyclopropyl-3-formyl-4-oxo-1,4-dihydroquinolin-7-yl)morpholine-4-carboxylate (0.024 g, 0.06 mmol, 1 equiv) and (3S)-1-(6-methylpyridin-3-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine (0.027 g, 0.08 mmol, 1.5 equiv) in DCE (5 mL). After 30 minutes, add NaBH(OAc)3 (0.034 g, 0.2 mmol, 2.8 equiv) and stir the resulting mixture at room temperature overnight. Purify the residue by FCC (RF-C18 column, ACN / H2O) to afford the title product as a white solid: (0.017 g, 0.02 mmol, 42% yield).

[0877] ESI-MS: 679.6 [M+H] +

[0878] i) 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one

[0879]

[0880] Dissolve tert-butyl 3-[1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]morpholine-4-carboxylate (0.017 g, 0.02 mmol, 1 equiv) in anhydrous 1,4-d ane (2 mL). Cool the solution in an ice bath and add dropwise 4 M HCl (1 mL) in d ane. Concentrate the reaction mixture. Then, dilute the residue with DCM, wash with NaHCO3 and evaporate the organic layer. Lyophilize the residue to afford the title product 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)-methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one as a white solid (0.009 g, 0.02 mmol, 62% yield).

[0881] ESI-MS: 579.5 [M+H] +

[0882] 11H NMR (400 MHz, methanol-d4) δ 8.28 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 5.1 Hz, 1H), 8.11 - 8.08 (m, 2H), 8.01 (s, 1H), 7.52 - 7.45 (m, 1H), 7.36 (dd, J = 8.6, 3.0 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.12 (d, J = 8.6 Hz, 1H), 4.11 (dd, J = 10.1, 3.3 Hz, 1H), 3.98 - 3.84 (m, 5H), 3.83 (s, 2H), 3.72 - 3.64 (m, 1H), 3.64 - 3.58 (m, 1H), 3.53 - 3.43 (m, 2H), 3.17 - 2.92 (m, 3H), 2.90 - 2.83 (m, 1H), 2.75 - 2.64 (m, 1H), 2.41 (s, 3H), 2.32 (s, 3H), 2.18 - 2.12 (m, 1H), 1.95 - 1.90 (m, 1H), 1.74 - 1.61 (m, 2H), 1.39 - 1.28 (m, 2H), 0.97 - 0.89 (m, 2H).

[0883] Preparation Example:

[0884] Example 1. 3 - ({[(2 - Methoxypyridin - 4 - yl)methyl][(3S)-1-(pyridin - 3 - yl)piperidin - 3 - yl]amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0885]

[0886] Preparation of tert - butyl N - [(3S)-1-(pyridin - 3 - yl)piperidin - 3 - yl]carbamate

[0887] The title compound was synthesized according to Step 1a. The residue was purified by FCC (SiHP, 100% AcOEt) to afford the product as a pale yellow oil (3.2 g, 11.54 mmol, yield 61%).

[0888] ESI - MS: 278.4 [M + H] +

[0889] (3S)-1-(Pyridin - 3 - yl)piperidin - 3 - amine Preparation

[0890] The title compound was synthesized according to Step 1b to afford the product as a yellow oil (2.00 g, 11.28 mmol, yield 98%). ESI - MS: 178.1 [M + H] +

[0891] (3S)-N-[(2-Methoxypyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine Preparation

[0892] The title compound was synthesized according to Step 4a by using 2-methoxypyridine-4-carbaldehyde instead of 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde. The residue was purified by FCC (SiHP, DCM∶MeOH 94∶6) to afford the product as a yellow oil (942 mg, 3.2 mmol, 62% yield). ESI-MS: 299.3 [M+H] +

[0893] 3-({[(2-Methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one Preparation

[0894] The title compound was synthesized according to Step 4b by using (3S)-N-[(2-methoxypyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine instead of 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and using 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde instead of 3-methylpyridine-4-carbaldehyde. The residue was purified by RP-FCC (SiC18; H2O∶MeCN) to afford the product as a yellow powder (1.15 g, 2.0 mmol, 65% yield). ESI-MS: 470.2 [M+H] +

[0895] 1 H NMR (400 MHz, DMSO-d6) δ8.31 - 8.29 (m, 1H), 8.22 - 8.16 (m, 1H), 8.08 (s, 1H), 8.05 - 8.01 (m, 1H), 7.94 - 7.88 (m, 1H), 7.77 - 7.69 (m, 1H), 7.68 - 7.58 (m, 1H), 7.42 - 7.34 (m, 1H), 7.32 - 7.27 (m, 1H), 7.18 - 7.11 (m, 1H), 7.07 - 7.03 (m, 1H), 6.87 (s, 1H), 3.99 - 3.92 (m, 1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.83 - 3.71 (m, 2H), 3.71 - 3.68 (m, 1H), 3.68 - 3.54 (m, 2H), 2.89 - 2.77 (m, 1H), 2.77 - 2.58 (m, 2H), 2.05 - 1.93 (m, 1H), 1.85 - 1.69 (m, 1H), 1.64 - 1.36 (m, 2H).

[0896] Example 2. 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0897]

[0898] Preparation of tert-butyl N-[1-(pyridin-3-yl)piperidin-3-yl]carbamate

[0899] The title compound was synthesized by substituting tert-butyl N-(piperidin-3-yl)carbamate for tert-butyl N-[(3S)-piperidin-3-yl]carbamate according to Step 1a. The residue was purified by FCC (SiHP, DCM∶MeOH 95∶5) to give the product as a yellow oil (359 mg, 1.2 mmol, 47% yield). ESI-MS: 278.5 [M+H] +

[0900] Preparation of 1-(pyridin-3-yl)piperidin-3-amine

[0901] The title compound was synthesized by substituting tert-butyl N-[1-(pyridin-3-yl)piperidin-3-yl]carbamate for tert-butyl N-[(3S)1-(pyridin-3-yl)piperidin-3-yl]carbamate according to Step 1b. The product was obtained as the hydrochloride salt (111 mg, 0.500 mmol, 43% yield). ESI-MS: 178.15 [M+H] +

[0902] Preparation of N-[(2-methylpyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine

[0903] The title compound was synthesized by the method outlined in Step 4a, substituting 2-methylpyridine-4-carbaldehyde for 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and 1-(pyridin-3-yl)piperidin-3-amine for (3S)-1-(pyridin-3-yl)piperidin-3-amine. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to afford the product as a colorless oil (50 mg, 0.17 mmol, 41% yield). ESI-MS: 283 [M+H] +

[0904] 11H NMR (300 MHz, DMSO-d6) δ 8.36 - 8.31 (m, 1H), 8.29 - 8.24 (m, 1H), 7.96 - 7.90 (m, 1H), 7.30 - 7.21 (m, 2H), 7.21 - 7.14 (m, 2H), 3.79 (s, 2H), 3.63 - 3.53 (m, 1H), 2.79 - 2.68 (m, 1H), 2.58 - 2.53 (m, 2H), 2.44 (s, 3H), 1.96 - 1.87 (m, 1H), 1.79 - 1.68 (m, 1H), 1.56 - 1.42 (m, 1H), 1.32 - 1.16 (m, 1H).

[0905] Aliphatic H overlaps with solvent peaks.

[0906] Preparation of 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0907] Following the method outlined in Step 4b, using DCM as the solvent, N-[(2-methylpyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine was used in place of 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was used in place of 2-methylpyridin-4-carbaldehyde to synthesize the title compound. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to afford the product as a colorless oil (28 mg, 0.06 mmol, yield 33%). ESI-MS: 454 [M+H] +

[0908] 1 1H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.28 (m, 2H), 8.22 - 8.18 (m, 1H), 8.05 (s, 1H), 7.93 - 7.90 (m, 1H), 7.75 - 7.69 (m, 1H), 7.66 - 7.61 (m, 1H), 7.41 - 7.35 (m, 1H), 7.32 - 7.23 (m, 3H), 7.18 - 7.13 (m, 1H), 4.00 - 3.93 (m, 1H), 3.87 (s, 3H), 3.81 - 3.69 (m, 2H), 3.68 - 3.56 (m, 2H), 2.90 - 2.82 (m, 1H), 2.75 - 2.61 (m, 2H), 2.38 (s, 3H), 2.04 - 1.97 (m, 1H), 1.80 - 1.72 (m, 1H), 1.62 - 1.41 (m, 2H).

[0909] The aliphatic H overlaps with the solvent peak.

[0910] Example 3. 3-({[(2-Methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one

[0911]

[0912] Preparation of tert-butyl 3-{[(2-methoxypyridin-4-yl)methyl]amino}piperidine-1-carboxylate

[0913] Following the method outlined in Step 4a, 2-methoxypyridine-4-carbaldehyde was used in place of 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and tert-butyl 3-aminopiperidine-1-carboxylate was used in place of (3S)-1-(pyridin-3-yl)piperidin-3-amine to synthesize the title compound. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to afford the product as a yellow oil (3795 g, 7.556 mmol, 26% yield). ESI-MS: 322.3 [M+H] +

[0914] Preparation of tert-butyl 3-{[(2-methoxypyridin-4-yl)methyl][(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl]amino}piperidine-1-carboxylate

[0915] Following the method outlined in Step 4b, tert-butyl 3-{[(2-methoxypyridin-4-yl)methyl]amino}piperidine-1-carboxylate was used in place of 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was used in place of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was purified by RP-FCC (SiC18, H2O∶MeCN) to afford the product as a pale yellow powder (363 mg, 0.722 mmol, 25% yield). ESI-MS: 493.80 [M+H] +

[0916] 11H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.17 (m, 1H), 8.02 - 7.98 (m, 1H), 7.97 (s, 1H), 7.72 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.38 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 6.98 - 6.95 (m, 1H), 6.78 (s, 1H), 4.13 - 3.93 (m, 1H), 3.83 (s, 3H), 3.82 - 3.78 (m, 1H), 3.77 (s, 3H), 3.71 (s, 2H), 3.58 (s, 2H), 2.83 (s, 1H), 2.02 - 1.90 (m, 1H), 1.72 - 1.61 (m, 1H), 1.59 - 1.46 (m, 1H), 1.41 - 1.20 (m, 12H).

[0917] Preparation of 3 - ({[(2 - methoxypyridin - 4 - yl)methyl](piperidin - 3 - yl)amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0918] According to the method outlined in Step 2b, tert - butyl 3 - {[(2 - methoxypyridin - 4 - yl)methyl][(1 - methyl - 4 - oxo - 1,4 - dihydroquinolin - 3 - yl)methyl]amino}piperidine - 1 - carboxylate was used instead of tert - butyl N - [(3S)1 - (pyridin - 3 - yl)piperidin - 3 - yl]carbamate to synthesize the title compound. The product was the free base. The product as a yellow oil (650 mg, 1.656 mmol, yield 22%). ESI - MS: 393.3 [M + H] +

[0919] Preparation of 3 - ({[(2 - methoxypyridin - 4 - yl)methyl][1 - (pyridazin - 3 - yl)piperidin - 3 - yl]amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0920] The title compound was synthesized according to Step 5. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to give the product as a yellow oil (30 mg, 0.06 mmol, yield 31%). ESI - MS: 471 [M + H] +

[0921] 11H NMR (300 MHz, DMSO-d6) δ 8.49 - 8.46 (m, 1H), 8.21 - 8.16 (m, 1H), 8.06 (s, 1H), 8.03 - 7.99 (m, 1H), 7.76 - 7.69 (m, 1H), 7.66 - 7.60 (m, 1H), 7.41 - 7.23 (m, 3H), 7.06 - 7.01 (m, 1H), 6.85 (s, 1H), 4.66 - 4.56 (m, 1H), 4.34 - 4.23 (m, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.74 - 3.54 (m, 2H), 3.06 - 2.95 (m, 1H), 2.87 - 2.75 (m, 1H), 2.05 - 1.92 (m, 1H), 1.80 - 1.61 (m, 2H), 1.43 - 1.29 (m, 1H).

[0922] Some aliphatic H overlaps with the solvent peak.

[0923] The product was converted to the hydrochloride salt. The product as a yellow solid. ESI-MS: 471 [M + H] +

[0924] 1 1H NMR (400 MHz, deuterium oxide) δ 8.40 - 8.36 (m, 1H), 7.95 - 7.90 (m, 1H), 7.77 (s, 1H), 7.76 - 7.72 (m, 1H), 7.66 - 7.59 (m, 1H), 7.52 - 7.48 (m, 1H), 7.47 - 7.42 (m, 1H), 7.38 - 7.32 (m, 1H), 7.27 - 7.22 (m, 1H), 6.84 - 6.79 (m, 1H), 6.61 - 6.57 (m, 1H), 4.51 - 4.25 (m, 6H), 3.82 - 3.71 (m, 1H), 3.67 (s, 3H), 3.39 (s, 3H), 3.30 - 3.21 (m, 1H), 2.32 - 2.15 (m, 2H), 2.05 - 1.95 (m, 1H), 1.75 - 1.63 (m, 1H).

[0925] Aliphatic H overlaps with the solvent peak.

[0926] Example 4. 3 - ({[(2 - Methoxypyridin - 4 - yl)methyl][1 - (pyrazin - 2 - yl)piperidin - 3 - yl]amino}methyl) - 1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0927]

[0928] The title compound was synthesized according to Step 6. The residue was purified by preparative HPLC to afford the title compound as a yellow solid (28 mg, 0.059 mmol, 29% yield). ESI-MS: 471 [M+H] +

[0929] 1 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.21 - 8.15 (m, 1H), 8.07 - 7.98 (m, 3H), 7.78 - 7.68 (m, 2H), 7.66 - 7.60 (m, 1H), 7.43 - 7.33 (m, 1H), 7.07 - 7.00 (m, 1H), 6.85 (s, 1H), 4.59 - 4.48 (m, 1H), 4.34 - 4.22 (m, 1H), 3.86 (s, 3H), 3.81 - 3.74 (m, 4H), 3.73 - 3.52 (m, 2H), 3.05 - 2.93 (m, 1H), 2.84 - 2.71 (m, 1H), 2.07 - 1.95 (m, 1H), 1.83 - 1.58 (m, 2H), 1.45 - 1.30 (m, 1H).

[0930] Some aliphatic H overlaps with the solvent peak.

[0931] The product was converted to the hydrochloride salt. The product as a yellow solid. ESI-MS: 471 [M+H] +

[0932] 1 1H NMR (400 MHz, deuterium oxide) δ 8.07 (s, 1H), 7.99 - 7.93 (m, 1H), 7.93 - 7.87 (m, 1H), 7.85 - 7.79 (m, 1H), 7.79 - 7.72 (m, 1H), 7.71 - 7.59 (m, 2H), 7.56 - 7.49 (m, 1H), 7.49 - 7.42 (m, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 4.41 - 4.17 (m, 4H), 3.79 - 3.74 (m, 1H), 3.73 - 3.70 (m, 3H), 3.67 - 3.57 (m, 2H), 3.41 (s, 3H), 3.31 - 3.18 (m, 1H), 2.31 - 2.22 (m, 1H), 2.22 - 2.08 (m, 1H), 2.05 - 1.94 (m, 1H), 1.75 - 1.62 (m, 1H).

[0933] Aliphatic H overlaps with the solvent peak.

[0934] Example 5. 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0935]

[0936] Preparation of tert-butyl (3S)-3-{[(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl]amino}piperidine-1-carboxylate

[0937] Following the method outlined in Step 4a, the title compound was synthesized using tert-butyl (3S)-3-aminopiperidine-1-carboxylate in place of (3S)-1-(pyridin-3-yl)piperidin-3-amine. The residue was purified by FCC (neutral Al2O3, DCM∶MeOH 9∶1) to afford the product as a yellow solid (5.600 g, 15.07 mmol, 94% yield). ESI-MS: 372.2 [M+H] +

[0938] 1 1H NMR (300 MHz, DMSO-d6) δ 8.23 (dd, J = 8.1, 1.6 Hz, 1H), 8.11 (s, 1H), 7.78 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.73 - 7.64 (m, 1H), 7.43 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 3.86 (s, 3H), 3.73 (s, 2H), 3.71 - 3.53 (m, 1H), 2.96 - 2.75 (m, 2H), 2.70 - 2.55 (m, 2H), 2.05 - 1.81 (m, 2H), 1.78 - 1.50 (m, 1H), 1.38 (s, 9H).

[0939] Some aliphatic Hs overlap with the solvent signals.

[0940] Preparation of tert-butyl (3S)-3-{[(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl][(2-methylpyridin-4-yl)methyl]amino}piperidine-1-carboxylate

[0941] The title compound was synthesized by replacing 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one with tert-butyl (3S)-3-{[(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl]amino}piperidine-1-carboxylate according to the method outlined in Step 4b. After adding the reducing agent, the reaction was continued at 45 °C for 3 h. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to afford the title compound as a light yellow solid (610 mg, 1.280 mmol, 86% yield). ESI-MS: 477.5 [M+H] +

[0942] 1 H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 5.0 Hz, 1H), 8.19 (dd, J = 8.1, 1.6 Hz, 1H), 7.95 (s, 1H), 7.72 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.38 (ddd, J = 7.9, 6.8, 1.1 Hz, 1H), 7.22 - 7.08 (m, 2H), 4.05 (br s, 1H), 3.82 (s, 3H), 3.70 (s, 2H), 3.59 (d, J = 2.8 Hz, 2H), 2.36 (s, 3H), 1.97 (d, J = 12.6 Hz, 1H), 1.67 (d, J = 12.6 Hz, 1H), 1.53 (br s, 1H), 1.33 (brs, 11H).

[0943] Some aliphatic H signals overlap with the solvent signals.

[0944] Preparation of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0945] The title compound was synthesized by replacing tert-butyl N-[(3S)1-(pyridin-3-yl)piperidin-3-yl]carbamate with tert-butyl (3S)-3-{[(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl][(2-methylpyridin-4-yl)methyl]amino}piperidine-1-carboxylate according to the method outlined in Step 1b. The title compound was obtained as the free base. The product as a white powder (375 mg, 1.000 mmol, 79% yield). ESI-MS: 377.5 [M+H] +

[0946] 11H NMR (300 MHz, DMSO-d6) δ 8.26 (dd, J = 4.9, 0.9 Hz, 1H), 8.18 (dd, J = 8.1, 1.6 Hz, 1H), 7.94 (s, 1H), 7.72 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.62 (dd, J = 8.8, 1.0 Hz, 1H), 7.37 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.18 (dd, J = 6.9, 1.6 Hz, 2H), 3.83 (s, 3H), 3.67 (s, 2H), 3.61 (s, 1H), 3.54 (s, 1H), 3.14 - 2.99 (m, 1H), 2.87 - 2.70 (m, 1H), 2.36 (s, 3H), 2.35 - 2.23 (m, 2H), 2.00 - 1.90 (m, 1H), 1.68 - 1.58 (m, 1H), 1.50 - 1.18 (m, 2H).

[0947] Some aliphatic H signals overlap with the solvent signals.

[0948] Preparation of 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0949] The title compound was synthesized according to Step 3. The product (48 mg, 0.106 mmol, yield 10%) was converted to the hydrochloride salt. ESI-MS: 454.3 [M + H] + .

[0950] 1 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J = 5.9 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H), 8.22 - 8.11 (m, 3H), 8.06 - 7.93 (m, 2H), 7.89 - 7.73 (m, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.44 (ddd, J = 8.0, 6.8, 1.0 Hz, 1H), 4.49 (d, J = 12.6 Hz, 1H), 4.40 (s, 2H), 4.04 (s, 2H), 3.94 (d, J = 13.1 Hz, 1H), 3.85 (s, 3H), 3.37 - 3.25 (m, 1H), 3.23 - 3.08 (m, 1H), 3.03 - 2.85 (m, 1H), 2.57 (s, 3H), 2.25 - 2.18 (m, 1H), 1.96 - 1.82 (m, 2H), 1.65 - 1.43 (m, 1H).

[0951] Example 6. 3-({[(2-Methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0952]

[0953] Preparation of tert-Butyl N-[(3S)-1-(pyridin-3-yl)piperidin-3-yl]carbamate

[0954] The title compound was synthesized by the method outlined in Step 2a, using tert-butyl N-[(3S)-piperidin-3-yl]carbamate in place of tert-butyl N-(piperidin-3-yl)carbamate. The residue was purified by FCC (SiHP, Hex∶AcOEt 1∶9) to afford the product as a yellow oil (575 mg, 1.90 mmol, 7% yield). ESI-MS: 278 [M+H] +

[0955] Preparation of (3S)-1-(pyridin-3-yl)piperidin-3-amine hydrochloride

[0956] The title compound was synthesized according to the protocol described in Step 1b. The product was obtained as the hydrochloride salt (490 mg, 2.20 mmol, 99% yield). ESI-MS: 178 [M+H] +

[0957] Preparation of (3S)-N-[(2-Methoxypyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine

[0958] The title compound was synthesized by the method outlined in Step 4a, using TEA as the base, 2-methoxypyridine-4-carbaldehyde in place of 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and (3S)-1-(pyridin-3-yl)piperidin-3-amine hydrochloride in place of (3S)-1-(pyridin-3-yl)piperidin-3-amine. The residue was purified by FCC (SiHP, DCM∶MeOH 94∶6) to afford the product as a yellow oil (0.94 g, 3.20 mmol, 62% yield). ESI-MS: 299 [M+H] +

[0959] 11H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.22 (m, 1H), 8.12 - 8.05 (m, 1H), 7.95 - 7.92 (m, 1H), 7.31 - 7.22 (m, 1H), 7.22 - 7.13 (m, 1H), 7.02 - 6.96 (m, 1H), 6.85 - 6.78 (m, 1H), 3.83 (s, 3H), 3.79 (s, 2H), 3.78 - 3.73 (m, 1H), 3.63 - 3.52 (m, 1H), 2.78 - 2.69 (m, 1H), 2.56 - 2.52 (m, 2H), 2.38 - 2.28 (m, 1H), 1.98 - 1.84 (m, 1H), 1.79 - 1.67 (m, 1H), 1.58 - 1.42 (m, 1H), 1.30 - 1.16 (m, 1H).

[0960] Aliphatic H overlaps with solvent peaks.

[0961] Preparation of 3 - ( { [ (2 - methoxypyridin - 4 - yl)methyl ][ (3S)-1 - (pyridin - 3 - yl)piperidin - 3 - yl ] amino} methyl ) - 1,4 - dihydroquinolin - 4 - one

[0962] Following the method outlined in Step 4b, using a mixture of DCE:DMF (v / v 5:7) as the solvent, replacing 1 - methyl - 3 - ( { [ (3S)-1 - (pyridin - 3 - yl)piperidin - 3 - yl ] amino} methyl ) - 1,4 - dihydroquinolin - 4 - one with (3S)-N - [ (2 - methoxypyridin - 4 - yl)methyl ] - 1 - (pyridin - 3 - yl)piperidin - 3 - amine and 4 - oxo - 1,4 - dihydroquinoline - 3 - carbaldehyde with 2 - methoxypyridin - 4 - carbaldehyde to synthesize the title compound. The residue was purified by preparative HPLC to afford the product as a yellow solid (85 mg, 0.20 mmol, 48% yield). ESI - MS: 456 [M + H] +

[0963] 11H NMR (400 MHz, DMSO-d6) δ 11.77 - 11.65 (m, 1H), 8.30 - 8.26 (m, 1H), 8.15 (s, 1H), 8.13 - 8.08 (m, 1H), 8.05 - 8.01 (m, 1H), 7.99 - 7.95 (m, 1H), 7.95 - 7.90 (m, 1H), 7.65 - 7.58 (m, 1H), 7.54 - 7.48 (m, 1H), 7.33 - 7.26 (m, 2H), 7.18 - 7.12 (m, 1H), 7.04 - 6.99 (m, 1H), 6.86 (s, 1H), 3.93 - 3.84 (m, 1H), 3.83 - 3.74 (m, 5H), 3.71 - 3.61 (m, 3H), 2.86 - 2.77 (m, 1H), 2.76 - 2.59 (m, 2H), 2.04 - 1.92 (m, 1H), 1.82 - 1.71 (m, 1H), 1.63 - 1.38 (m, 2H).

[0964] Example 7. 1-Methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one

[0965]

[0966] Following the method outlined in step 9b, 5-bromo-2-methylpyridine was used in place of 7-bromo-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one was used in place of 1-methylpiperazine, and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (Sphos) and tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) were used in place of [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (Sphos Pd 3G) to synthesize the title compound.

[0967] The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to afford the product as a yellow solid (24 mg, 0.05 mmol, 48% yield). ESI-MS: 471 [M+H] +

[0968] 11H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.27 (m, 1H), 8.22 - 8.17 (m, 1H), 8.17 - 8.13 (m, 1H), 8.03 (s, 1H), 7.75 - 7.69 (m, 1H), 7.65 - 7.60 (m, 1H), 7.41 - 7.35 (m, 1H), 7.27 - 7.20 (m, 3H), 7.04 - 7.00 (m, 1H), 3.86 (s, 3H), 3.81 - 3.72 (m, 2H), 3.72 - 3.55 (m, 3H), 2.83 - 2.66 (m, 2H), 2.64 - 2.56 (m, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.04 - 1.97 (m, 1H), 1.80 - 1.72 (m, 1H), 1.56 - 1.42 (m, 2H).

[0969] Aliphatic H overlaps with the solvent peak.

[0970] Example 8. 3 - ({[(3S)-1-(2 - methoxypyrimidin - 5 - yl)piperidin - 3 - yl][(2 - methylpyridin - 4 - yl)methyl]amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[0971]

[0972] Following the method outlined in Step 5, 5 - bromo - 2 - methoxypyrimidine was used instead of 3 - bromopyridazine and 1 - methyl - 3 - ({[(2 - methylpyridin - 4 - yl)methyl][(3S)-piperidin - 3 - yl]amino}methyl)-1,4 - dihydroquinolin - 4 - one was used instead of 3 - ({[(2 - methoxypyridin - 4 - yl)methyl](piperidin - 3 - yl)amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one to synthesize the title compound. The residue was purified by FCC (SiHP, DCM∶MeOH 9∶1) to give the product as a yellow solid (31 mg, 0.06 mmol, yield 30%). ESI - MS: 485 [M + H] +

[0973] 11H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 2H), 8.30 - 8.28 (m, 1H), 8.21 - 8.18 (m, 1H), 8.02 (s, 1H), 7.75 - 7.70 (m, 1H), 7.65 - 7.61 (m, 1H), 7.40 - 7.35 (m, 1H), 7.27 - 7.22 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.81 - 3.73 (m, 2H), 3.71 - 3.63 (m, 1H), 3.61 - 3.55 (m, 1H), 3.55 - 3.48 (m, 1H), 2.79 - 2.74 (m, 2H), 2.61 - 2.53 (m, 1H), 2.38 (s, 3H), 2.02 - 1.97 (m, 1H), 1.81 - 1.75 (m, 1H), 1.53 - 1.46 (m, 2H).

[0974] Aliphatic H overlaps with the solvent peak.

[0975] Example 9. 1-Cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one

[0976]

[0977] Preparation of 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0978] According to the method outlined in Step 4b, replace 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one with (3S)-1-(pyridin-3-yl)piperidin-3-amine and replace 2-methylpyridin-4-carbaldehyde with 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde to synthesize the title compound. The product as a yellow solid (55 mg, 0.11 mmol, yield 77%). ESI-MS: 491 [M + H] +

[0979] Preparation of 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one

[0980] Following the method outlined in Step 4b, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one was used in place of 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and 2-methoxypyridine-4-carbaldehyde was used in place of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was purified by preparative HPLC to afford the product as a yellow solid (17 mg, 0.03 mmol, 39% yield). ESI-MS: 612 [M+H] +

[0981] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 3.0 Hz, 1H), 8.01 (d, J = 5.2 Hz, 1H), 7.92 (dd, J = 4.6, 1.3 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 13.6 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.28 (ddd, J = 8.5, 3.0, 1.3 Hz, 1H), 7.15 (dd, J = 8.5, 4.5 Hz, 1H), 6.97 (dd, J = 5.3, 1.3 Hz, 1H), 6.79 (s, 1H), 3.90 - 3.83 (m, 1H), 3.77 (s, 3H), 3.76 - 3.74 (m, 2H), 3.72 - 3.65 (m, 1H), 3.61 (s, 2H), 3.54 - 3.47 (m, 1H), 3.24 - 3.16 (m, 4H), 2.84 - 2.58 (m, 3H), 2.25 (s, 3H), 1.99 - 1.92 (m, 1H), 1.81 - 1.73 (m, 1H), 1.61 - 1.43 (m, 2H), 1.26 - 1.18 (m, 2H).

[0982] Some aliphatic H signals overlap with the solvent signals.

[0983] Example 10. 1-Cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0984]

[0985] According to the method outlined in step 4b, the title compound was synthesized by replacing 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one with 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one. The residue was purified by preparative HPLC to afford the product as a yellow solid (13 mg, 0.02 mmol, 31% yield). ESI-MS: 596 [M+H] +

[0986] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.25 (m, 2H), 7.92 (dd, J = 4.5, 1.3 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J = 13.6 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.28 (ddd, J = 8.6, 3.1, 1.3 Hz, 1H), 7.22 (s, 1H), 7.19 - 7.12 (m, 2H), 3.92 - 3.86 (m, 1H), 3.77 - 3.72 (m, 2H), 3.72 - 3.65 (m, 1H), 3.61 (s, 2H), 3.54 - 3.46 (m, 1H), 3.23 - 3.17 (m, 4H), 2.86 - 2.60 (m, 3H), 2.37 (s, 3H), 2.25 (s, 3H), 2.00 - 1.93 (m, 1H), 1.80 - 1.74 (m, 1H), 1.62 - 1.43 (m, 2H), 1.25 - 1.16 (m, 2H), 0.94 - 0.83 (m, 2H).

[0987] Some aliphatic H signals overlap with the solvent signals.

[0988] Example 11. 1-Cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0989]

[0990] According to the method outlined in Step 4b, replace 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one with (3S)-N-[(2-methoxypyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine and replace 2-methylpyridine-4-carbaldehyde with 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde to synthesize the title compound. Purify the residue by preparative HPLC to afford the product as a white solid (0.60 g, 1.14 mmol, 58% yield). Convert the product to the hydrochloride salt. ESI-MS: 532 [M+H] +

[0991] 1 H NMR (400 MHz, methanol-d4) δ 8.43 (d, J = 3.1 Hz, 1H), 8.11 - 7.96 (m, 5H), 7.89 (d, J = 5.3 Hz, 1H), 7.70 (dd, J = 8.9, 5.3 Hz, 1H), 6.96 (d, J = 5.3 Hz, 1H), 6.81 (s, 1H), 4.32 - 4.24 (m, 1H), 4.22 - 3.96 (m, 6H), 3.90 - 3.81 (m, 1H), 3.76 (s, 3H), 3.54 - 3.45 (m, 1H), 3.04 - 2.95 (m, 1H), 2.34 - 2.22 (m, 1H), 2.08 - 1.98 (m, 1H), 1.97 - 1.86 (m, 1H), 1.79 - 1.65 (m, 1H), 1.35 - 1.29 (m, 2H), 1.06 - 0.98 (m, 2H).

[0992] Example 12. 1-Cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[0993]

[0994] (3S)-N-[(2-Methylpyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine Preparation

[0995] The title compound was synthesized by using (3S)-1-(pyridin-3-yl)piperidin-3-amine instead of 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one according to the method outlined in Step 4b. The reaction was allowed to proceed overnight without using molecular sieves before adding sodium triacetoxyborohydride. The residue was purified by FCC (SiHP, DCM∶MeOH 0 to 25%) to afford the crude product as a yellow oil (1.7 g, 6.02 mmol, yield 66%, purity 84%). ESI-MS: 283 [M+H] +

[0996] The title compound was synthesized by using (3S)-N-[(2-methylpyridin-4-yl)methyl]-1-(pyridin-3-yl)piperidin-3-amine instead of 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde instead of 2-methylpyridin-4-carbaldehyde according to the method outlined in Step 4b. The residue was purified by preparative HPLC to afford the product as a yellow solid (0.34 g, 0.65 mmol, yield 28%). ESI-MS: 516 [M+H] +

[0997] 1 H NMR (400 MHz, methanol-d4) δ 8.29 (d, J = 3.0 Hz, 1H), 8.22 (d, 1H), 8.07 (dd, J = 10.8, 8.7 Hz, 1H), 8.01 (s, 1H), 7.99 - 7.93 (m, 2H), 7.64 (ddd, J = 8.7, 3.0, 1.2 Hz, 1H), 7.46 - 7.37 (m, 3H), 4.09 - 4.01 (m, 1H), 3.97 (s, 2H), 3.91 - 3.73 (m, 3H), 3.52 - 3.44 (m, 1H), 3.06 - 2.96 (m, 2H), 2.88 - 2.79 (m, 1H), 2.20 - 2.13 (m, 1H), 1.99 - 1.91 (m, 1H), 1.78 - 1.61 (m, 2H), 1.34 - 1.26 (m, 2H), 1.00 - 0.93 (m, 2H).

[0998] Some aliphatic H overlap with solvent signals.

[0999] Example 13. 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[1000]

[1001] The title compound was synthesized according to the method outlined in Step 8. The residue was purified by preparative HPLC to afford the title compound as a yellow solid (10 mg, 0.02 mmol, 9% yield). ESI-MS: 454 [M+H] +

[1002] 1 1H NMR (300 MHz, DMSO-d6) δ 8.31 - 8.25 (m, 1H), 8.22 - 8.16 (m, 1H), 8.09 - 8.04 (m, 1H), 8.01 (s, 1H), 7.76 - 7.68 (m, 1H), 7.66 - 7.59 (m, 1H), 7.50 - 7.41 (m, 1H), 7.41 - 7.33 (m, 1H), 7.25 (s, 1H), 7.24 - 7.20 (m, 1H), 6.84 - 6.77 (m, 1H), 6.57 - 6.50 (m, 1H), 4.55 - 4.42 (m, 1H), 4.28 - 4.17 (m, 1H), 3.85 (s, 3H), 3.79 - 3.73 (m, 2H), 3.71 - 3.54 (m, 2H), 2.96 - 2.84 (m, 1H), 2.76 - 2.68 (m, 1H), 2.67 - 2.58 (m, 1H), 2.37 (s, 3H), 2.05 - 1.94 (m, 1H), 1.79 - 1.68 (m, 1H), 1.68 - 1.54 (m, 1H), 1.42 - 1.21 (m, 1H).

[1003] Example 14. 1-Methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[1004]

[1005] The title compound was synthesized according to the method outlined in Step 5, using 5-bromo-2-nitropyridine in place of 3-bromopyridazine and 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one in place of 3-({[(2-methoxypyridin-4-yl)methyl](piperidin-3-yl)amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one. The residue was purified by FCC (SiC18, H2O∶MeCN) to afford the title compound as a yellow solid (0.08 g, 0.27 mmol, 60% yield). ESI-MS: 499 [M+H]+

[1006] 1 1H NMR (300 MHz, DMSO-d6) δ 8.30 (dd, J = 4.9, 0.9 Hz, 1H), 8.26 (d, J = 3.0 Hz, 1H), 8.19 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 (d, J = 9.3 Hz, 1H), 8.03 (s, 1H), 7.72 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 9.3, 3.1 Hz, 1H), 7.37 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.30 - 7.22 (m, 2H), 4.35 - 4.23 (m, 1H), 4.11 - 3.97 (m, 1H), 3.86 (s, 3H), 3.82 - 3.55 (m, 4H), 3.25 - 3.13 (m, 1H), 3.06 - 2.90 (m, 1H), 2.71 - 2.60 (m, 1H), 2.38 (s, 3H), 2.07 - 1.96 (m, 1H), 1.84 - 1.65 (m, 2H), 1.52 - 1.34 (m, 1H).

[1007] Example 15. 3 - ({[(3S)-1-(3 - bromopyridin - 4 - yl)piperidin - 3 - yl][(2 - methylpyridin - 4 - yl)methyl]amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[1008]

[1009] Following the method outlined in Step 6, using sodium tert - butoxide as the base and using di ane as the solvent, 1 - methyl - 3 - ({[(2 - methylpyridin - 4 - yl)methyl][(3S)-piperidin - 3 - yl]amino}methyl)-1,4 - dihydroquinolin - 4 - one was used in place of 3 - ({[(2 - methoxypyridin - 4 - yl)methyl](piperidin - 3 - yl)amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one and 3 - bromo - 4 - fluoropyridine was used in place of 3 - chloropyrazine to synthesize the title compound. The residue was purified by FCC (SiC18, H2O∶MeCN) to afford the title compound as a yellow solid (21 mg, 0.03 mmol, yield 16%). The product was converted to the hydrochloride salt. ESI - MS: 532 and 534 [M + H] +

[1010] 11H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.60 (d, J = 6.0 Hz, 1H), 8.48 (d, J = 6.7 Hz, 1H), 8.26 (s, 1H), 8.16 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 - 7.91 (m, 2H), 7.78 (ddd, J = 8.6, 6.8, 1.6 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.54 - 7.32 (m, 2H), 4.47 - 4.38 (m, 2H), 4.06 - 3.99 (m, 2H), 3.83 (s, 3H), 3.51 - 3.37 (m, 1H), 3.30 - 3.21 (m, 1H), 3.13 - 3.01 (m, 1H), 2.58 (s, 3H), 2.34 - 2.24 (m, 1H), 2.01 - 1.80 (m, 2H), 1.73 - 1.53 (m, 1H). Some aliphatic Hs overlap with the solvent signals.

[1011] Example 16. 3 - ( { [(3S)-1-(6-Fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino} methyl ) - 1-methyl-1,4-dihydroquinolin-4-one

[1012]

[1013] Following the method outlined in Step 5, 5-bromo-2-fluoropyridine was used in place of 3-bromopyridazine and 1-methyl-3 - ( { [(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino} methyl ) - 1,4-dihydroquinolin-4-one was used in place of 3 - ( { [(2-methoxypyridin-4-yl)methyl](piperidin-3-yl)amino} methyl ) - 1-methyl-1,4-dihydroquinolin-4-one to synthesize the title compound. The residue was purified by FCC (SiC18, H2O∶MeCN) to afford the title compound as a yellow solid (6 mg, 0.013 mmol, 55% yield). ESI-MS: 472 [M + H] +

[1014] 11H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J = 5.1 Hz, 1H), 8.20 (dd, J = 8.1, 1.5 Hz, 1H), 8.02 (s, 1H), 7.84 - 7.81 (m, 1H), 7.72 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.41 - 7.34 (m, 1H), 7.26 - 7.21 (m, 2H), 6.98 (dd, J = 8.9, 3.5 Hz, 1H), 3.92 - 3.81 (m, 4H), 3.80 - 3.68 (m, 2H), 3.68 - 3.54 (m, 3H), 2.86 - 2.55 (m, 3H), 2.38 (s, 3H), 2.04 - 1.94 (m, 1H), 1.79 - 1.72 (m, 1H), 1.61 - 1.43 (m, 2H).

[1015] Example 17. 3 - ( { [(3S)-1-(6 - chloropyrimidin - 4 - yl)piperidin - 3 - yl][(2 - methylpyridin - 4 - yl)methyl]amino} methyl ) - 1 - methyl - 1,4 - dihydroquinolin - 4 - one

[1016]

[1017] Following the method outlined in Step 6, using MeCN as the solvent, 4,6 - dichloropyrimidine was used instead of 3 - chloropyrazine to synthesize the title compound. The residue was purified by preparative HPLC to afford the title compound as a yellow solid (120 mg, 0.25 mmol, 62% yield).

[1018] 1 1H NMR (400 MHz, DMSO - d6) δ 8.30 - 8.26 (m, 2H), 8.19 (dd, J = 8.0, 1.6 Hz, 1H), 8.00 (s, 1H), 7.71 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.37 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.26 - 7.21 (m, 2H), 6.98 (s, 1H), 3.84 (s, 3H), 3.82 - 3.71 (m, 2H), 3.70 - 3.54 (m, 2H), 3.13 - 3.02 (m, 1H), 2.90 - 2.79 (m, 1H), 2.61 - 2.55 (m, 1H), 2.37 (s, 3H), 2.05 - 1.95 (m, 1H), 1.79 - 1.64 (m, 2H), 1.37 - 1.22 (m, 1H). Some aliphatic H signals overlap with the solvent signals.

[1019] Convert the product to its hydrochloride salt. ESI-MS: 490 [M+H] +

[1020] 1 H NMR (400 MHz, deuterium oxide) δ 8.14 (s, 1H), 8.10 (dd, J = 8.2, 1.5 Hz, 1H), 8.01 (d, J = 5.8 Hz, 1H), 7.91 (s, 1H), 7.85 - 7.79 (m, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.40 - 7.35 (m, 1H), 7.32 (s, 1H), 6.82 (s, 1H), 4.48 - 4.39 (m, 1H), 4.09 - 3.89 (m, 5H), 3.81 (s, 3H), 3.18 - 3.06 (m, 2H), 2.19 (s, 3H), 2.03 - 1.88 (m, 3H), 1.67 - 1.54 (m, 2H).

[1021] Example 18. 1-Methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[1022]

[1023] Preparation of 1-Methyl-7-(4-methylpiperazin-1-yl)-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[1024] Following the method outlined in Step 4a, synthesize the title compound using 1-methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde in place of 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde. The crude product is used in the next step without further purification. ESI-MS: 428 [M+H] +

[1025] Preparation of 1-Methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one

[1026] According to the method outlined in step 4b, the title compound was synthesized by replacing 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one with 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one. The residue was purified by preparative HPLC to afford the product as a yellow solid (35 mg, 0.06 mmol, 22% yield). ESI-MS: 552 [M+H] +

[1027] 1 H NMR (300 MHz, DMSO-d6) δ 8.31 - 8.27 (m, 2H), 7.99 - 7.95 (m, 1H), 7.92 - 7.89 (m, 1H), 7.86 (s, 1H), 7.31 - 7.22 (m, 3H), 7.17 - 7.11 (m, 1H), 7.09 - 7.04 (m, 1H), 6.68 (s, 1H), 3.97 - 3.89 (m, 1H), 3.77 (s, 3H), 3.75 - 3.65 (m, 3H), 3.64 - 3.49 (m, 2H), 3.37 - 3.34 (m, 4H), 2.88 - 2.79 (m, 1H), 2.70 - 2.58 (m, 2H), 2.50 - 2.42 (m, 4H), 2.39 (s, 3H), 2.23 (s, 3H), 2.02 - 1.94 (m, 1H), 1.79 - 1.72 (m, 1H), 1.61 - 1.36 (m, 2H).

[1028] Example 19. 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one

[1029]

[1030] According to the method outlined in step 6, the title compound was synthesized by replacing 3-({[(2-methoxypyridin-4-yl)methyl](piperidin-3-yl)amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one with 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one and using 2,4-dichloropyrimidine instead of 3-chloropyrazine. The residue was purified by FCC (SiHP, AcOEt 100%) to afford the product as a yellow solid (89 mg, 0.17 mmol, 52% yield). ESI-MS: 489 [M+H] +

[1031] 1 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 5.0 Hz, 1H), 8.19 (dd, J = 8.1, 1.6 Hz, 1H), 8.03 - 7.97 (m, 2H), 7.71 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.37 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.25 - 7.19 (m, 2H), 6.89 - 6.83 (m, 1H), 4.63 - 4.11 (m, 2H), 3.84 (s, 3H), 3.82 - 3.71 (m, 2H), 3.69 - 3.57 (m, 2H), 3.14 - 3.03 (m, 1H), 2.91 - 2.80 (m, 1H), 2.61 - 2.54 (m, 1H), 2.36 (s, 3H), 2.02 - 1.95 (m, 1H), 1.80 - 1.65 (m, 2H), 1.37 - 1.22 (m, 1H).

[1032] Example 20. 3 - ({[(3S)-1-(2 - methoxypyridin - 4 - yl)piperidin - 3 - yl][(2 - methylpyridin - 4 - yl)methyl]amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[1033]

[1034] Following the method outlined in Step 5, 4 - bromo - 2 - methoxypyridine was used instead of 3 - bromopyridazine and 1 - methyl - 3 - ({[(2 - methylpyridin - 4 - yl)methyl][(3S)-piperidin - 3 - yl]amino}methyl)-1,4 - dihydroquinolin - 4 - one was used instead of 3 - ({[(2 - methoxypyridin - 4 - yl)methyl](piperidin - 3 - yl)amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one to synthesize the title compound. The residue was purified by preparative HPLC to afford the product as a yellow oil (40 mg, 0.08 mmol, yield 62%). ESI - MS: 484 [M + H] +

[1035] 11H NMR (300 MHz, DMSO-d6) δ 8.61 - 8.56 (m, 1H), 8.21 - 8.15 (m, 1H), 8.04 (s, 1H), 7.91 - 7.87 (m, 1H), 7.87 (s, 1H), 7.84 - 7.80 (m, 1H), 7.79 - 7.72 (m, 1H), 7.68 - 7.62 (m, 1H), 7.45 - 7.37 (m, 1H), 6.96 - 6.89 (m, 1H), 6.52 - 6.47 (m, 1H), 4.50 - 4.38 (m, 1H), 4.23 - 4.17 (m, 1H), 4.17 - 4.09 (m, 2H), 4.05 (s, 3H), 3.83 (s, 3H), 3.81 - 3.68 (m, 2H), 3.42 - 3.30 (m, 1H), 3.16 - 3.01 (m, 1H), 2.88 - 2.76 (m, 1H), 2.57 (s, 3H), 2.09 - 1.99 (m, 1H), 1.91 - 1.71 (m, 2H), 1.54 - 1.35 (m, 1H).

[1036] Example 21. 3 - ({[(2 - ethylpyridin - 4 - yl)methyl][1 - (pyridin - 3 - yl)piperidin - 3 - yl]amino}methyl)-1 - methyl - 1,4 - dihydroquinolin - 4 - one

[1037]

[1038] Preparation of tert - butyl 3 - {[(2 - ethylpyridin - 4 - yl)methyl]amino}piperidine - 1 - carboxylate

[1039] Following the method outlined in Step 4b, using DCM as the solvent, (2 - ethylpyridin - 4 - yl)methylamine was used instead of 1 - methyl - 3 - ({[(3S)-1 - (pyridin - 3 - yl)piperidin - 3 - yl]amino}methyl)-1,4 - dihydroquinolin - 4 - one and tert - butyl 3 - oxopiperidine - 1 - carboxylate was used instead of 2 - methylpyridine - 4 - carbaldehyde to synthesize the title compound. The crude product was used without further purification for the next step. The product as a golden oil (723 mg, 2.26 mmol, 98% yield). ESI - MS: 320 [M + H] +

[1040] 11H NMR (300 MHz, DMSO-d6) δ 8.39 - 8.35 (m, 1H), 7.21 (s, 1H), 7.18 - 7.13 (m, 1H), 3.73 (s, 2H), 3.68 - 3.56 (m, 1H), 2.88 - 2.77 (m, 1H), 2.76 - 2.66 (m, 2H), 2.41 - 2.31 (m, 2H), 1.92 - 1.80 (m, 1H), 1.69 - 1.55 (m, 1H), 1.52 - 1.43 (m, 1H), 1.36 (s, 9H), 1.25 - 1.18 (m, 3H). Some aliphatic Hs overlap with the solvent signals.

[1041] Preparation of tert-butyl 3-{[(2-ethylpyridin-4-yl)methyl][(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl]amino}piperidine-1-carboxylate

[1042] According to the method outlined in Step 4b, using DCM as the solvent, replace 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one with tert-butyl 3-{[(2-ethylpyridin-4-yl)methyl]amino}piperidine-1-carboxylate and replace 2-methylpyridine-4-carboxaldehyde with 1-methyl-4-oxo-1,4-dihydroquinolin-3-carboxaldehyde to synthesize the title compound. Purify the residue by FCC (SiHP, DCM∶MeOH 95∶5) to obtain the product as a golden oil (50 mg, 0.10 mmol, yield 39%). ESI-MS: 491 [M+H] +

[1043] 1 1H NMR (300 MHz, methanol-d4) δ 8.42 - 8.32 (m, 1H), 8.21 (d, J = 5.1 Hz, 1H), 8.05 (d, J = 33.4 Hz, 1H), 7.86 - 7.74 (m, 2H), 7.67 (d, J = 8.6 Hz, 1H), 7.53 - 7.43 (m, 1H), 7.28 - 7.23 (m, 1H), 4.65 (s, 1H), 4.37 - 4.16 (m, 1H), 4.00 (s, 2H), 3.89 (s, 3H), 3.86 - 3.73 (m, 2H), 2.97 - 2.68 (m, 2H), 2.62 (q, J = 7.7 Hz, 2H), 2.21 - 2.09 (m, 1H), 1.83 - 1.61 (m, 2H), 1,43 (s, 9H), 1.34 - 1.26 (m, 1H), 1.14 (t, J = 7.6 Hz, 3H). Aliphatic Hs overlap with the solve...

Claims

1. A compound of formula (I), or a salt or stereoisomer thereof, wherein, X 1 is CR 1 ; X 2 is CR 3 ; R 1 is H or F; R 3 is H; R 2 is H, F, Br, Cl, a C1-C2 alkoxy group, or any one of the following groups: R 4 is any one of the following substituted pyridine rings: R 5 is any one of the following groups: and wherein R N is H, CH3 or cyclopropyl; and R A is H.

2. The compound according to claim 1, wherein R N is CH3.

3. The compound according to claim 1, wherein: R 1 、R 2 and R 3 are H.

4. The compound according to claim 1, wherein: X 1 is CH; and X 2 is CH.

5. The compound according to claim 1, wherein the compound according to formula (I) is selected from 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyridazin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][1-(pyrazin-2-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyrimidin-5-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-2-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(3-bromopyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-fluoropyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-methoxypyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[(2-ethylpyridin-4-yl)methyl][1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(6-oxo-1,6-dihydropyrimidin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3R,4R)-4-hydroxy-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S,((5R)-5-Methyl-1-(pyridin-3-yl)piperidin-3-yl)[(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, methyl 1-[1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylate / ester, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 3-({[(3S)-1-(5-bromopyrimidin-2-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 3-({[5,5-difluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(2-nitropyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2,6-dimethylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl][(pyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-7-[4-(2,2-difluoroethyl)piperazin-1-yl]-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(2-oxopiperazin-1-yl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(oxetan-3-yl)-1,4-dihydroquinolin-4-one, 2-[3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-1-yl]acetic acid, and 1-cyclopropyl-7-{4,7-diazaspiro[2.5]octan-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one., 6. The compound according to claim 1, wherein the compound according to formula (I) is selected from 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-7-(4-methylpiperazin-1-yl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-methyl-7-(4-methylpiperazin-1-yl)-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-1-methyl-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S,5S)-5-fluoro-1-(pyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6,7-difluoro-3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methoxypyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(2-methylpyridin-4-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,8-naphthyridin-4-one, 1-cyclopropyl-6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(piperazin-1-yl)-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-7-{4,7-diazaspiro[2.5]octan-7-yl}-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one., 7. The compound according to claim 1, wherein the compound according to formula (I) is selected from 1-methyl-3-({[(3S)-1-(5-methyl-1,3,4- {(2-Methylpyridin-4-yl)methyl}amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(2-Chloropyrimidin-4-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, 1-methyl-3-({[(3S)-1-(pyridin-3-yl)piperidin-3-yl][(1,2-thiazol-5-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydro-1,6-naphthyridin-4-one, 7-(Cyclohex-1-en-1-yl)-1-cyclopropyl-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 8-bromo-1-methyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 7-chloro-6-fluoro-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, 6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, 3-({[(1,3-dimethyl-1H-pyrazol-5-yl)methyl][(3S)-1-(pyridin-3-yl)piperidin-3-yl]amino}methyl)-1-methyl-1,4-dihydroquinolin-4-one, and 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one.

8. The compound according to claim 1, wherein the compound according to formula (I) is selected from: 3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 1-cyclopropyl-6-fluoro-7-hydroxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one, 6-fluoro-7-methoxy-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1-(propan-2-yl)-1,4-dihydro-1,8-naphthyridin-4-one, and 1-cyclopropyl-3-({[(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-7-(morpholin-3-yl)-1,4-dihydroquinolin-4-one.

9. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 8 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

10. Use of the compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of a disease selected from cancer, pre-cancerous syndromes and infectious diseases; or for the preparation of an immunogenic composition or a vaccine adjuvant.

11. Use of the compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of an inflammatory disease.

12. Use of the compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of an allergic disease.

13. Use of the compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of an autoimmune disease.

14. Use of a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 8 and optionally a pharmaceutically acceptable carrier, diluent or excipient for the preparation of a medicament for the treatment of a disease selected from cancer, pre-cancerous syndromes and infectious diseases; or for the preparation of an immunogenic composition or a vaccine adjuvant.

15. Use of a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 8 and optionally a pharmaceutically acceptable carrier, diluent or excipient for the preparation of a medicament for the treatment of an inflammatory disease.

16. Use of a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 8 and optionally a pharmaceutically acceptable carrier, diluent or excipient for the preparation of a medicament for the treatment of an allergic disease.

17. Use of a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 8 and optionally a pharmaceutically acceptable carrier, diluent or excipient for the preparation of a medicament for the treatment of autoimmune diseases.

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