CN113950473A - Next generation modulators of interferon gene Stimulators (STING) - Google Patents

Abstract

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

Description

Next generation modulators of interferon gene Stimulators (STING)

Technical Field

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

Background

The cellular innate immune system is essential for the recognition of pathogen infection and for the establishment of effective host defenses. The adaptor protein STING (stimulator of interferon genes), also known as TMEM 173, MPYS, MITA and ERIS, has been identified as the central signaling molecule in the innate immune response to cytoplasmic nucleic acids (h. ishikawa, GN Barber, Nature, 2008, volume 455, p. 674-678). STING induces, inter alia, type I Interferon (IFN) production when cells are infected with intracellular pathogens, such as viruses, mycobacteria (mycobacteria) and intracellular parasites.

Activation of STING promotes IRF3 and NFkB-dependent signaling, thus leading to the production of proinflammatory cytokines and interferons, including type I and III interferons and TNF α, which are particularly important in cancer immunotherapy. STING is responsible for sensing pathogen or host derived cytosolic nucleic acids and derivatives thereof (known as Cyclic Dinucleotides (CDNs)) (e.g., double-stranded DNA from bacteria or viruses and cytosolic self-DNA).

Endogenous STING direct agonists 2 ', 3' -cGAMP (2 ', 3' -cyclic guanosine monophosphate-adenosine monophosphate) and derivatives thereof 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-.

Recent evidence supports the following findings: once STING is activated by CDN in the tumor microenvironment, preferably in tumor-resident dendritic cells, it promotes type I IFN and TNF α release, resulting in an immune-mediated anti-tumor response. STING-dependent activation of antigen-presenting cells (APCs) effectively drives highly specific T cell priming against neoantigens (l.corales and tf.gajewski, Clin Cancer Res, 2015, 21(21), pages 4774-9). STING activation not only provides for the generation of tumor-specific killer T cells, which directly eradicate the tumor, but also produces a vaccine-like long-lasting immunity, preventing cancer recurrence.

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 the treatment or prevention of human diseases, including viral infections and autoimmune diseases. It has been found that compounds which activate or inhibit the production of type I interferons can be used not only for innate immunity in infectious diseases, but also for cancer (l.zitvogel et al, Nature Reviews Immunology 2015, vol 15(7), p. 405- & ltp.414), allergic diseases (j.moisan et al, am.j.physiol.lung Cell mol. physiol.2006, vol 290, L. 987-995), neurodegenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis (h.lemos et al, j.immunol, 2014, vol 192(12), p. 5571-8; e.ciruli et al, Science 2015, p. 347(6229), p. 2004 6-41; midt et al, nat. neurosci 631, p. 18-6, p. 347 (23), other inflammatory diseases such as t. 20-12), Cell proliferation vaccine 3523, p. 2004-41; trekk et al, trekk, p. 23, t. 12, p. 2004-8; e.c., advances in Vaccines, published online 2013, 9.5.4).

STING is crucial for the protection of the antibacterial Host, 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-. The Herpesviridae (Herpesviridae), Flaviviridae (Flaviviridae), Coronaviridae (Coronaviridae), Papilomaviridae (Papilomoviridae), Adenoviridae (Adenoviridae), Hepadoviridae (Hepadnaviridae), Orthomyxoviridae (Orthomyxoviridae) and Paramyxoviridae (paramyxoviridae) and Rhabdoviridae (Rhabdoviridae) have evolved mechanisms that inhibit STING-mediated production of type I interferons and escape from Host immune control (Holm et al, Nat Comm. 2016, Vol.7, Vol.80; Maas 2015, Vol.112 (31) E4306-E4315; Wu et al, Cell Host be, Microbe 18 (Din. sup. 3, Vol.333-44; Livstrel et al, Virol, pp.90, 20119, pp.11-2015.70, 2015.52; Leu.70-20145; Leu.83, Vol.5; Leuvieridae; Leu.31; Leu.3, Vol.5, Vol.369.),369, (3, Vol.5; No. (Nittu et al.),369; pp.7; Leu.,369.,07; Leu.,369; pp.7; Leu.,07; Leu.,369; pp.7; Leu.,07; Leu; pp.7; Leu; pp.7; Leu; pp.7; Leu.,369.,07; Leu.,369; pp.7; Leu; pp.7; pp.23; Leu.,369.,07; Leu.,07; pp.7; Leu.; Leu.;.; et al; Leu; pp.7; pp.3; pp.7; pp.10; pp.7; pp.42; pp.7; pp.3, pp.7; pp.3; pp.42; pp.7; pp.25; pp, hepatology, 2013, volume 57(1), pages 46-58; sun et al, PloS One, 2012, volume 7(2), e 30802; aguirre et al, PloS Patholog, 2012, Vol.8 (10), e 1002934; ishikawa et al, Nature, 2009, Vol.461 (7265), pp.788-92). Therefore, small molecule activation of STING is considered beneficial for the treatment of these infectious diseases.

In contrast, increased and prolonged production of type I IFN is associated with a variety of chronic infections, including mycobacteria (Collins et al, Cell Host Microbe, 2015, volume 17(6), pages 820-8; Wassermann et al, Cell Host Microbe, 2015, volume 17(6), pages 799-, 2013, volume 341(6148), pages 903-6). Similarly, excessive type I interferon production is found in patients with complex forms of autoimmune disease. The following assumptions are supported by human genetic evidence and animal model studies: inhibition of STING results in a reduction in type I interferons that drive autoimmune diseases (YJ Crow et al, nat. gene., 2006, vol. 38(8), p. 38917-. Therefore, STING inhibitors provide treatment for patients with chronic type I interferon and pro-inflammatory cytokine production associated with infection or complex autoimmune diseases. Allergic diseases are associated with a Th 2-based immune response to allergens. Th2 responses are associated with elevated levels of IgE which, through its action on mast cells, promotes hypersensitivity reactions to allergens, resulting in symptoms such as those seen in allergic rhinitis and asthma. In healthy individuals, the immune response to allergens is more balanced with a mixed Th2/Th1 and regulatory T cell response. Induction of type 1 interferon has been shown to lead to a reduction of Th2 type cytokines in the local environment and to promote Th1/Treg responses. In this case, the induction of type 1 interferons by, for example, activating STING may be helpful in the treatment of allergic diseases such as asthma and allergic rhinitis (JP Huber et al, J Immunol, 2010, vol. 185, p. 813-817).

In view of the above, the compounds that modulate STING may be useful in the treatment of one or more diseases selected from inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes, and/or as immunogenic compositions or vaccine adjuvants. Of particular interest are immunotherapy of cancer and viral infections, in particular 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. Furthermore, activation of local immune responses to lesions is considered to be a preferred intratumoral or systemic treatment method.

Thus, there is a need for compounds that modulate STING activity and thus provide therapeutic impact in the treatment of disease where modulation of STING is beneficial.

Objects and summary of the invention

It is therefore an object of the present invention to provide compounds that modulate STING, in particular compounds that act as STING agonists, thereby activating STING. In particular, there is interest in providing compounds with high activity as STING agonists.

It is another object of the present invention to provide compounds suitable for use as medicaments. It is another object of the present invention to provide compounds suitable for use in the treatment of one or more diseases associated with STING modulation. It is a further object to provide compounds suitable for use in the treatment of one or more diseases selected from inflammatory diseases, allergic diseases, autoimmune diseases, infectious diseases, cancer and pre-cancerous syndromes. In particular, it is an object to provide compounds suitable for the treatment of cancer, in particular prostate cancer, lung cancer, breast cancer, head and neck cancer, bladder cancer and/or melanoma. It is a further object to provide compounds suitable for use in immunogenic compositions and as vaccine adjuvants.

The above objects may be achieved by the compounds of formula (I) as defined herein as well as pharmaceutical compositions comprising them and their medical use.

The inventors of the present invention have particularly unexpectedly found that compounds of formula (I) as defined herein modulate STING, in particular act as STING agonists. Accordingly, the compounds of formula (I) may be used as medicaments, in particular for the treatment of one or more diseases selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, infectious diseases, cancer and pre-cancerous syndromes. In particular, the compounds of formula (I) are useful for the treatment of cancer, in particular prostate cancer, lung cancer, breast cancer, head and neck cancer, bladder cancer and/or melanoma. Furthermore, the compounds of formula (I) are suitable for use in immunogenic compositions and as vaccine adjuvants.

In a first aspect, the present invention therefore relates to a compound of formula (I) or a salt, stereoisomer, tautomer or N-oxide thereof,

wherein the content of the first and second substances,

X¹is CR¹Or N;

X²is CR³Or N;

R¹、R²and R³Independently H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, aryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^E、NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C ₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XSubstitution;

R⁴is a 5-or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9-or 10-membered aromatic carbocyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least oneA nitrogen atom and optionally one or more identical or different further heteroatoms selected from O, N or S, wherein the N-atom and/or S-atom is independently oxidized or not oxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned ring is independently unsubstituted or substituted with one or more identical or different substituents R^XSubstitution;

R⁵is a 5-or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R ^YSubstitution;

and wherein

R^NIs H, C₁-C₄-alkyl, HO (C ═ O) -C₁-C₄-alkyl, or a 3-or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic ring comprises 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^XSubstitution;

R^Ais H, halogen, CN, OH, C₁-C₃Alkyl radical, C₁-C₃-alkoxy or a 3-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein the above-mentioned heterocyclic group comprises 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 not oxidized, 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^XSubstitution;

R^Cand R^DIndependently is H or C₁-C₂-an alkyl group; or

R^CAnd R^DTogether 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 comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom in the heterocycle is independently unsubstituted or substituted with one or more identical or different substituents R ^XSubstitution;

R^Eis H, C₁-C₂Alkyl, phenyl, benzyl, OR^GOr NR^HR^I(ii) a Or a 5-or 6-membered saturated, partially or fully unsaturated heterocyclyl, wherein the heterocyclyl 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 groups is independently unsubstituted or substituted with one or more identical or different substituents R^FSubstitution;

R^Fis H, C₁-C₂Alkyl radical, C₃-C₆-cycloalkyl, phenyl, benzyl or C (═ O) NR^HR^I；

R^GIs H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-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 are independently oxidized or not oxidized;

R^Hand R^IIndependently H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-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 are independently oxidized or not oxidized; or

R^HAnd R^ITogether with the nitrogen atom to which they are bonded form a 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring in which The heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or substituted with one or more identical or different substituents R^XSubstitution;

R^Xis halogen, CN, NO₂、C₁-C₂Alkyl radical, C₁-C₂-haloalkyl group, C₁-C₂-alkoxy, C (═ O) R^EOr two R^XForm ═ O, or two R^XTogether with the carbon atom to which they are bonded form a 3-to 5-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring;

R^Yis halogen, CN, OH, C₁-C₂Alkyl radical, C₁-C₂alkyl-OH, C₃-C₆-cycloalkyl, C₁-C₂Alkoxy, NR^CR^D、S(＝O)₂NR^CR^D、C(＝O)R^EOr 5-or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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 ^XSubstitution; or two R^YTo form ═ O; or two R attached to the same or adjacent carbon atoms^YA 3-membered carbocyclic ring may be formed.

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

wherein the content of the first and second substances,

X¹is CR¹Or N;

X²is CR³Or N;

R¹、R²and R³Independently H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, aryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^E、NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XSubstitution;

R⁴is a 5-or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9-or 10-membered aromatic carbocyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least one nitrogen atom and optionally one or more identical or different further heteroatoms selected from O, N or S, wherein the N-atom and/or S-atom are independently oxidized or not oxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned rings is independently unsubstituted or is substituted by one or more identical or different substituents R ^XSubstitution;

R⁵is a 5-or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R^YSubstitution;

and wherein

R^NIs H, CH₃、HO(C＝O)-C₁-C₄-alkyl, or a 3-or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic ring comprises 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^XSubstitution;

R^Ais H, halogen, CN, OH, C₁-C₃Alkyl radical, C₁-C₃-alkoxy or a 3-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein the above-mentioned heterocyclic group comprises 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 not oxidized, 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 ^XSubstitution;

R^Cand R^DIndependently is H or C₁-C₂-an alkyl group; or

R^CAnd R^DTogether with the nitrogen atom to which they are bound, form a 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or is substituted with one or more identical or different substituents R^XSubstitution;

R^Eis H, C₁-C₂Alkyl, phenyl, benzyl, OR^GOr NR^HR^I(ii) a Or a 5-or 6-membered saturated, partially or fully unsaturated heterocyclyl, wherein the heterocyclyl 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 groups is independently unsubstituted or substituted with one or more identical or different heteroatomsSubstituent R of^FSubstitution;

R^Fis H, C₁-C₂Alkyl radical, C₃-C₆-cycloalkyl, phenyl, benzyl or C (═ O) NR^HR^I；

R^GIs H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-C ₁-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 are independently oxidized or not oxidized;

R^Hand R^IIndependently H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-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 are independently oxidized or not oxidized; or

R^HAnd R^ITogether with the nitrogen atom to which they are bound, form a 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or is substituted with one or more identical or different substituents R^XSubstitution;

R^Xis halogen, CN, NO₂、C₁-C₂Alkyl radical, C₁-C₂-alkoxy, C (═ O) R^EOr two R^XTo form ═ O;

R^Yis halogen, CN, OH, C₁-C₂Alkyl radical, C₁-C₂alkyl-OH, C₃-C₆-cycloalkyl, C₁-C₂Alkoxy, NR^CR^D、S(＝O)₂NR^CR^D、C(＝O)R^EOr 5-or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C ₁-C₂-alkyl, heterocyclyl, and heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XSubstitution; or two R^YTo form ═ O; or two R attached to the same or adjacent carbon atoms^YA 3-membered carbocyclic ring may be formed.

The following embodiments are related to the above aspects.

In a preferred embodiment of the process according to the invention,

R^Ais H.

In a preferred embodiment of the process according to the invention,

R^Nis H, CH₃Or cyclopropyl, preferably CH₃。

In a further preferred embodiment of the process according to the invention,

R^Nis cyclopropyl.

In a further preferred embodiment of the process according to the invention,

R¹、R²and R³Is H.

In a further preferred embodiment of the process according to the invention,

R⁵is a 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R ^YAnd (4) substitution.

In a more preferred embodiment of the process according to the invention,

R⁵is 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^YAnd (4) substitution.

In another more preferred embodiment of the process according to the invention,

R⁵is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R^YSubstitution; and R in which the nitrogen atom of the piperidine ring is preferably pyridyl^YAnd (4) substitution.

In another more preferred embodiment of the process according to the invention,

R⁵is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R^YSubstitution; and wherein the nitrogen atom of the piperidine ring is via R^YSubstituted, R^YIs pyridyl, which is unsubstituted or substituted by one or more identical or different substituents R^XIs substituted in which R^XPreferably methyl.

In a preferred embodiment of the process according to the invention,

R⁴is pyridyl, wherein each substitutable carbon atom in the ring is independently unsubstituted or substituted by one or more identical or different substituents R^XAnd (4) substitution.

In a further preferred embodiment of the process according to the invention,

X¹Is CR¹(ii) a And

X²is CR³；

And wherein

R¹And R³Preferably H.

In a preferred embodiment of the process according to the invention,

R^Xis halogen, CN, C₁-C₂-alkyl or C₁-C₂-alkoxy groups.

In a further preferred embodiment of the process according to the invention,

R^Xis NO₂、C(＝O)R^EOr two R^XO is formed.

In a preferred embodiment of the process according to the invention,

R^Yis halogen, CN, OH, C₁-C₂-alkyl, or 5-or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl and heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XAnd (4) substitution.

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) piperidine- 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, and, 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, 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, and mixtures thereof, 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 -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- -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.

In another more preferred embodiment, the compound according to formula (I) is a compound selected from the group consisting of: 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) piperidine- 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, and, 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, 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.

In another more preferred embodiment, the compound according to formula (I) is a compound selected from the group consisting of: 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) piperidine- 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, and, 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.

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-methylpiperazin-1-yl) Pyrid-4-yl) methyl ] [ (3S) -1- (pyrid-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one, 7-bromo-1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyrid-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- (pyrid-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 ] quino-line -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) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one -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) -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- (piperazino- 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.

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-methylpiperazin-1-yl) Pyrid-4-yl) methyl ] [ (3S) -1- (pyrid-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one, 7-bromo-1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyrid-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- (pyrid-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-hydroquinolin-4-one, 3- ({ [ (2-methoxypyridin-4-yl) methyl ] [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] amino ] quino-l-4-one 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) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one -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.

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-methylpiperazin-1-yl) Pyrid-4-yl) methyl ] [ (3S) -1- (pyrid-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one, 7-bromo-1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyrid-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- (pyrid-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.

In yet a more preferred embodiment, the compound according to formula (I) is selected from: 1-methyl-3- ({ [ (3S) -1- (5-methyl-1, 3, 4-)

Oxadiazol-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;

and is 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.

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

wherein the content of the first and second substances,

X¹is CR¹；

X²Is CR³；

R¹、R²And R³Independently H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, aryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^EOr 5-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocycle comprises 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 notIs oxidized 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^XSubstitution;

R⁴is a 5-or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9-or 10-membered aromatic carbocyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least one nitrogen atom and optionally one or more identical or different further heteroatoms selected from O, N or S, wherein the N-atom and/or S-atom are independently oxidized or not oxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned rings is independently unsubstituted or is substituted by one or more identical or different substituents R ^XSubstitution;

R⁵is a 5-or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R^YSubstitution;

and wherein

R^NIs H, CH₃Or cyclopropyl;

R^Ais H, halogen, CN, OH, C₁-C₃Alkyl radical, C₁-C₃-alkoxy or a 3-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein the above-mentioned heterocyclic group comprises 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 not oxidized, 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^XSubstitution;

R^Cand R^DIndependently is H or C₁-C₂-an alkyl group; or

R^CAnd R^DTogether with the nitrogen atom to which they are bonded form a 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the heterocyclic ringComprising 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 not oxidized, and wherein each substitutable carbon or heteroatom in the heterocycle is independently unsubstituted or substituted with one or more identical or different substituents R ^XSubstitution;

R^Eis H, C₁-C₂Alkyl, phenyl, benzyl, OR^GOr NR^HR^I；

R^FIs H, C₁-C₂Alkyl radical, C₃-C₆-cycloalkyl, phenyl or benzyl;

R^Gis H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-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 are independently oxidized or not oxidized;

R^Hand R^IIndependently H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-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 are independently oxidized or not oxidized; or

R^HAnd R^ITogether with the nitrogen atom to which they are bound, form a 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or is substituted with one or more identical or different substituents R ^XSubstitution;

R^Xis halogen, CN, C₁-C₂-alkyl or C₁-C₂-an alkoxy group;

R^Yis halogen, CN, OH, C₁-C₂Alkyl radical, C₃-C₆-cycloalkyl, C₁-C₂Alkoxy, NR^CR^D、S(＝O)₂NR^CR^D、C(＝O)R^EOr 5-or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl and heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XAnd (4) substitution.

In a preferred embodiment of the process according to the invention,

R^Ais H.

In a further preferred embodiment of the process according to the invention,

R^Nis H, CH₃Or cyclopropyl, preferably CH₃。

In a further preferred embodiment of the process according to the invention,

R¹、R²and R³Is H.

In a further preferred embodiment of the process according to the invention,

R⁵is a 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R ^YAnd (4) substitution.

In a more preferred embodiment of the process according to the invention,

R⁵is 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^YAnd (4) substitution.

In another more preferred embodiment of the process according to the invention,

R⁵is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R^YSubstitution; and R in which the nitrogen atom of the piperidine ring is preferably pyridyl^YAnd (4) substitution.

In another more preferred embodiment of the process according to the invention,

R⁵is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R^YSubstitution; and wherein the nitrogen atom of the piperidine ring is via R^YSubstituted, R^YIs pyridyl, which is unsubstituted or substituted by one or more identical or different substituents R^XIs substituted in which R^XPreferably methyl.

In a preferred embodiment of the process according to the invention,

R⁴is pyridyl, wherein each substitutable carbon atom in the ring is independently unsubstituted or substituted by one or more identical or different substituents R^XAnd (4) substitution.

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.

In a further 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 use in modulating STING, in particular activating STING.

In a further 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, in particular activating STING, is beneficial.

In one embodiment, the compounds of the invention or pharmaceutical compositions comprising the same are used for the treatment of a disease selected from cancer, pre-cancerous syndrome and infectious disease; or in immunogenic compositions or as vaccine adjuvants.

In another embodiment, the compound of the present invention or the pharmaceutical composition comprising the same is used for the treatment of a disease selected from the group consisting of inflammatory diseases, allergic diseases, and autoimmune diseases.

In a further aspect, the invention relates to a method of treatment comprising administering to the human or animal body a compound of formula (I) as defined herein or a pharmaceutical composition comprising a compound of formula (I) as defined herein.

Brief Description of Drawings

Figures 1(i) to (iii) show the in vivo anti-tumor efficacy of the compound according to example 1 in CT26 mouse colon cancer allografts in Balb/C female mice by plotting tumor volume over time at different doses of the compound according to example 1 compared to vehicle.

Figure 2 shows the in vivo anti-tumor efficacy of the compound according to example 1 in CT26 mouse colon cancer allografts in Balb/C female mice by depicting a dot plot representing tumor volume and% TGI (tumor growth inhibition) alone for 11 days for different doses of the compound according to example 1 compared to vehicle.

FIGS. 3(i) to (iii) are by way of depiction and comparison

The in vivo anti-tumor immunological memory of CT26 mouse colon cancer allografts to Balb/C female mice in a re-challenge study is shown compared to tumor volume over time in mice previously treated with different doses of the compound according to example 1.

Detailed Description

Some preferred embodiments of the substituents in formula (I) above are described in more detail below. It is to be understood that each of the preferred embodiments is related by itself and in combination with other preferred embodiments. Furthermore, it is to be understood that the preferences in each case also apply to the salts, stereoisomers, tautomers and N-oxides of the compounds of the invention.

As mentioned above, the present invention relates to compounds of formula (I)

Wherein the content of the first and second substances,

X¹is CR¹Or N, and

X²is CR³Or N.

Thus, the compound of formula (I) may thus be a compound of formula (Ia), (Ib), (Ic) or (Id) as shown below:

with regard to the compounds according to formulae (Ia), (Ib), (Ic) and (Id), the substituent R is to be understood¹、R²、R³、R⁴、R⁵、R^AAnd R^NAs defined above in formula (I). Further preferred embodiments regarding these substituents are provided further below.

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 6-membered ring fused to the 6-membered ring containing the ═ O substituent is a 6-membered aromatic carbocyclic ring. Thus, the compound of formula (I) is preferably a compound of formula (Ia)

Wherein the substituent R¹、R²、R³、R⁴、R⁵、R^AAnd R^NAs defined above for formula (I), in particular wherein the substituent R¹、R²And R³Independently H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy radicalAryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^E、NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C ₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XAnd (4) substitution.

With respect to the substituent R¹、R²And R³It is understood that R^E、R^FAnd R^XPreferably have the meaning as defined above for the compounds of formula (I).

With regard to the compounds of the formula (I) and with regard to the compounds of the formulae (Ia), (Ib), (Ic) and (Id), in particular with regard to the compounds of the formulae (Ia), (Ib) and (Ic), in particular with regard to the compounds according to the formula (Ia), with regard to the remaining substituents R¹、R²、R³、R⁴、R⁵、R^AAnd R^NThe following preferred embodiments of (1) are relevant.

As described above, with respect to the compounds of the present invention,

R^Ais H, halogen, CN, OH, C₁-C₃Alkyl radical, C₁-C₃-alkoxy or a 3-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein the above-mentioned heterocyclic group comprises 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 not oxidized, 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 ^XSubstitution;

in a preferred embodiment of the process according to the invention,

R^Ais H, halogen, CNOr C₁-C₃-an alkyl group.

In a further preferred embodiment of the process according to the invention,

R^Ais H, F, Cl, Br or C₁-C₃-an alkyl group.

In a more preferred embodiment of the process according to the invention,

R^Ais H.

In a particularly preferred embodiment, the compounds according to formula (I) are those according to formula (Ia), wherein X¹And X²Is CR¹And CR³And wherein R is^AIs H. Such compounds may be represented by the following general formula (Ia)

With regard to the compound according to formula (Ia), it is understood that R is¹、R²、R³、R⁴、R⁵And R^NPreferably as defined above.

Further, as for the compound of the present invention, it is preferable that

R^NIs H, C₁-C₄-alkyl, HO (C ═ O) -C₁-C₄-alkyl, or a 3-or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic ring comprises 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^XAnd (4) substitution.

In particular, it is possible to use, for example,

R^Nis H, CH₃、HO(C＝O)-C₁-C₄-alkyl, or a 3-or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic ring comprises 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 each of the aforementioned groups The hetero atoms being independently unsubstituted or substituted by one or more identical or different substituents R^XAnd (4) substitution.

If R is^NIs HO (C ═ O) -C₁-C₄-alkyl, or a 3-or 4-membered saturated carbocyclic or heterocyclic group, then R^NPreferably any one of the following groups

In a preferred embodiment of the process according to the invention,

R^Nis H, CH₃Or a 3-or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic ring comprises 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 not, 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^XAnd (4) substitution.

If R is^NIs a 3-or 4-membered saturated carbocyclic or heterocyclic group, then R^NPreferably any one of the following groups

In a more preferred embodiment of the process according to the invention,

R^Nis H, CH₃Or a 3-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic group comprises 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 not oxidized, 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 ^XAnd (4) substitution.

In another more preferred embodiment

R^NIs H, CH₃Or a ternary saturated carbocyclic radical, in particular according to formula R^N-2 cyclopropyl.

In a more preferred embodiment of the process according to the invention,

R^Nis H, CH₃Or a cyclopropyl group.

In a particularly preferred embodiment of the process according to the invention,

R^Nis CH₃。

In another particularly preferred embodiment of the process according to the invention,

R^Nis cyclopropyl.

Furthermore, with regard to the compounds of the invention, in particular with regard to the compounds according to formula (Ia) or (Ic), preference is given to

R¹Is H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, aryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^E、NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XAnd (4) substitution.

In a preferred embodiment of the process according to the invention,

R¹is H, halogen, C₁-C₄-alkyl, or 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C ₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned group is independently not oxidizedSubstituted or by one or more identical or different substituents R^XAnd (4) substitution.

In a more preferred embodiment of the process according to the invention,

R¹is H, F, Cl, Br or C₁-C₂-an alkyl group.

In a particularly preferred embodiment of the process according to the invention,

R¹is H or F.

With respect to the above embodiments, it is understood that the remaining substituents R^E、R^FAnd R^XPreferably as defined above.

Further, as for the compound of the present invention, it is preferable that

R²Is H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, aryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^E、NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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 ^XAnd (4) substitution.

In a preferred embodiment of the process according to the invention,

R²is H, halogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocycle comprises one or more identical or different heteroatoms selected from O, N or SWherein the N-atom and/or S-atom is independently oxidized or not oxidized, 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^XAnd (4) substitution.

In a more preferred embodiment of the process according to the invention,

R²is H, F, Br, Cl, C₁-C₂Alkoxy, NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr a 4-to 6-membered saturated heterocyclyl group, or heterocyclyloxy group, wherein the above-mentioned heterocyclyl ring comprises 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 not oxidized, 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 ^XAnd (4) substitution.

If R is²Is NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated heterocyclyl, or heterocyclyloxy, then R²Preferably any one of the following groups

Or any of the following groups

Such as from formula (R)²-1) to (R)²-8) it can be seen that with respect to R²Preferred R of^XThe radical comprising CH₃Or C (═ O) R^E. Furthermore, the remaining substituents R are to be understood^EAnd R^FPreferably as defined above. With respect to the above formula (R)²-1) to (R)²-8), R is to be understood²May optionally bear one or more additional substituents R, which may be the same or different^X。

Such as from formula (R)²-1) to (R)²12) it can be seen that with respect to R²Preferred R of^XThe radical comprising CH₃、C₁-C₂-haloalkyl, C (═ O) CH₃Or two R^XTogether with the carbon atom to which they are bonded, form a ternary saturated, partially or fully unsaturated, or aromatic carbocyclic ring. With respect to the above formula (R)²-1) to (R)²-12), R is to be understood²May optionally bear one or more additional substituents R, which may be the same or different^X。

In a more preferred embodiment of the process according to the invention,

R²is H, F, Br, Cl or a 6-membered saturated heterocyclic group, wherein the heterocyclic ring comprises one or more nitrogen atoms as heteroatoms and wherein each substitutable carbon or heteroatom in the above groups is independently unsubstituted or substituted by one or more identical or different substituents R ^XAnd (4) substitution.

If R is²In the case of a 6-membered saturated heterocyclic group, R2 is preferably any one of the following groups

Or any of the following groups

Such as from formula (R)²-1) to (R)²-6) it can be seen that with respect to R²Preferred R of^XThe radical comprising CH₃Or C (═ O) R^EWherein R is^EAs defined above. Such as from formula (R)²-1) to (R)²12) it can be seen that with respect to R²Preferred R of^XThe radical comprising CH₃、C₁-C₂-haloalkyl, C (═ O) CH₃Or two R^XTogether with the carbon atom to which they are bonded, form a ternary saturated, partially or fully unsaturated, or aromatic carbocyclic ring. About inThe above formula (R)²-1) to (R)²-12) or formula (R)²-1) to (R)²-6) with the understanding that R is understood to be²May optionally bear one or more additional substituents R, which may be the same or different^X。

In a particularly preferred embodiment of the process according to the invention,

R²is H, F, Cl, Br, or any of the following 6-membered saturated heterocyclic groups

Such as from formula (R)²-1)、(R²-4) and (R)²-9) to (R)²12) it can be seen that with respect to R²Preferred R of^XThe radical comprising CH₃、C₁-C₂-haloalkyl, C (═ O) CH₃Or two R^XTogether with the carbon atom to which they are bonded, form a ternary saturated, partially or fully unsaturated, or aromatic carbocyclic ring. With respect to the above formula (R)²-1)、(R²-4) and (R)²-7) to (R)²-10), R is to be understood²May optionally bear one or more additional substituents R, which may be the same or different ^X。

In another particularly preferred embodiment of the process according to the invention,

R²is H, F, Cl, Br, or any of the following 6-membered saturated heterocyclic groups

Such as from formula (R)²-1) and (R)²-4) it can be seen that with respect to R²Preferred R of^XThe radical comprising CH₃Or C (═ O) CH₃. With respect to the above formula (R)²-1) and (R)²-4) It is understood that R²May optionally bear one or more additional substituents R, which may be the same or different^X。

Furthermore, with regard to the compounds of the invention, in particular with regard to the compounds according to formula (Ia) or (Ib),

R³is H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, aryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^E、NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XAnd (4) substitution.

In a preferred embodiment of the process according to the invention,

R³is H, halogen, C ₁-C₄-alkyl, or 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XAnd (4) substitution.

In a more preferred embodiment of the process according to the invention,

R³is H, halogen or C₁-C₄An alkyl group.

In another more preferred embodiment of the process according to the invention,

R³is H, F, Cl, Br or CH₃。

In a particularly preferred embodiment of the process according to the invention,

R³is H.

Furthermore, the compounds according to the invention

R⁴Is a 5-or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9-or 10-membered aromatic carbocyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least one nitrogen atom and optionally one or more identical or different further heteroatoms selected from O, N or S, wherein the N-atom and/or S-atom are independently oxidized or not oxidized, and wherein each substitutable carbon or heteroatom in the above-mentioned rings is independently unsubstituted or is substituted by one or more identical or different substituents R ^XAnd (4) substitution.

In a preferred embodiment of the process according to the invention,

R⁴is a 6-membered aromatic carbocyclic or heterocyclic ring, wherein the heterocyclic ring comprises at least one nitrogen atom and optionally one or more identical or different further 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-mentioned ring is independently unsubstituted or substituted with one or more identical or different substituents R^XAnd (4) substitution.

In a more preferred embodiment of the process according to the invention,

R⁴is a 6-membered aromatic heterocyclic ring, wherein the heterocyclic ring comprises at least one nitrogen atom and optionally one or more identical or different further 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-mentioned ring is independently unsubstituted or substituted with one or more identical or different substituents R^XAnd (4) substitution.

Preferably, the 6-membered aromatic heterocyclic ring comprises one or more nitrogen atoms as heteroatoms.

In a particularly preferred embodiment of the process according to the invention,

R⁴is pyridyl, wherein each of the ringsThe substitutable carbon or hetero atoms being independently unsubstituted or substituted by one or more identical or different substituents R ^XAnd (4) substitution.

Preferably, R⁴Is any one of the following substituted pyridine rings

Thus, with respect to R⁴Preferred R of^XThe radical comprising CH₃、CH₂CH₃Or C₁-alkoxy groups.

In a particularly preferred embodiment of the process according to the invention,

R⁴is a methylpyridyl group.

It is particularly preferred that,

R⁴comprises the following steps:

furthermore, with respect to the compounds of the present invention,

R⁵is a 5-or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R^YAnd (4) substitution.

In a preferred embodiment of the process according to the invention,

R⁵is a 5-or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises one or more nitrogen atoms, wherein the N-atoms are independently oxidized or not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R^YAnd (4) substitution.

In another preferred embodiment, R⁵Refers to any of the following unsubstituted or substituted rings

With respect to the above formula (R)⁵-1) to (R)⁵-4), it being understood that the coiled line represents the link to the remainder of the molecule and the substituent R ^YThe connection of (2). Particularly preferably, R⁵Is R⁵-1。

Further, it is understood that the formula (R) shown above⁵-1) to (R)⁵Each substitutable carbon or heteroatom in-4) may optionally bear one or more identical or different (further) substituents R^Y。

Preferably, the first and second electrodes are formed of a metal,

R^Yis halogen, CN, OH, C₁-C₂Alkyl radical, C₁-C₂alkyl-OH, C₃-C₆-cycloalkyl, C₁-C₂Alkoxy, NR^CR^D、S(＝O)₂R^F、C(＝O)R^EOr 5-or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, and heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XSubstitution; or two R^YTo form ═ O; or two R attached to the same or adjacent carbon atoms^YA 3-membered carbocyclic ring may be formed.

If R is^YIs C (═ O) R^EOr a 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic group, then R^YPreferably any of the following unsubstituted or substituted groups

With respect to the above substituted group (R) ^Y-1) to (R)^Y-15), it being understood that each substitutable carbon or heteroatom may optionally bear one or more identical or different (further) substituents R^X。

Furthermore, the remaining substituents R are to be understood^C、R^D、R^EAnd R^XPreferably as defined above.

In a preferred embodiment of the process according to the invention,

R⁵is a 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R^YAnd (4) substitution.

In this regard, it is understood that R^YPreferably as defined above.

In another preferred embodiment, R⁵Is (R)⁵-1) to (R)⁵-4).

With respect to the above embodiments, it is understood that each substitutable carbon or heteroatom in the above rings is independently unsubstituted or substituted with one or more of the same or different substituents R^YSubstitution, as defined above.

Furthermore, it should be understood that it is preferable

R^YIs OH, halogen, C₁-C₂Alkyl radical, C₁-C₂-alkyl-OH, C (═ O) R^EA 5-or 6-membered partially unsaturated, or aromatic heterocyclic group, wherein the above-mentioned heterocyclic group comprises 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 not oxidized, 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 ^XSubstitution; or two R^YTo form ═ O; or to the same or adjacent carbonsTwo R of an atom^YA 3-membered carbocyclic ring may be formed.

Preferably, the above-mentioned heterocyclic ring contains one or more nitrogen atoms as heteroatoms.

Furthermore, the remaining substituents R are to be understood^EAnd R^XPreferably as defined above.

In a particularly preferred embodiment of the process according to the invention,

R⁵is 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^YAnd (4) substitution.

With respect to the particularly preferred embodiments described above, it will be appreciated that preference is given to

R^YIs OH, halogen, C₁-C₂Alkyl radical, C₁-C₂-alkyl-OH, C (═ O) R^EOr a 5-or 6-membered partially unsaturated, or aromatic heterocyclic group, wherein the above-mentioned heterocyclic group comprises 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 not oxidized, 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^XSubstitution; or two R^YTo form ═ O; or two R attached to the same or adjacent carbon atoms^YA 3-membered carbocyclic ring may be formed.

Preferably, the heterocyclic ring contains one or more nitrogen atoms as heteroatoms.

Furthermore, the remaining substituents R are to be understood^EAnd R^XAs defined above.

In particular, further via one or more identical or different substituents R as defined above^YSubstituted R⁵Is any one of the following structural formulas

Or any one of the following structural formulas

In this connection, it is clear that R^YMay optionally bear one or more identical or different substituents R^X. In this connection, R is preferably^XThe radical comprising CH₃、F、Cl、Br、NO₂、C₁-alkoxy, or two R^XO is formed.

In another particularly preferred embodiment of the process according to the invention,

R⁵is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R^YSubstitution; and R in which the nitrogen atom of the piperidine ring is preferably pyridyl^YAnd (4) substitution.

In this connection, it is understood that if one or more substituents R are present on each substitutable carbon atom of the piperidine ring^YThen R is^YPreferably as defined above.

In another particularly preferred embodiment of the process according to the invention,

R⁵is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R ^YSubstitution; and wherein the nitrogen atom of the piperidine ring is preferably via R^YSubstituted, R^YIs pyridyl, which is unsubstituted or substituted by one or more identical or different substituents R^XIs substituted in which R^XPreferably methyl.

In another particularly preferred embodiment, R⁵The group is any one of the following groups:

particularly preferred is R⁵The radical is

Thus, particularly preferred compounds of the invention are compounds of formula (Ia) as compiled in the following table.

TABLE 1

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-1，R^NIs H, R²And R⁵In each case corresponding to a row of table a.

TABLE 2

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-1，R^NIs H, R²And R⁵In each case corresponding to a row of table a.

TABLE 3

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-2，R^NIs H, R²And R⁵In each case corresponding to a row of table a.

TABLE 4

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-2，R^NIs H, R²And R⁵In each case corresponding to a row of table a.

TABLE 5

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-3，R^NIs H, R²And R⁵In each case corresponding to a row of table a.

TABLE 6

A compound of formula (Ia), wherein R³Is H, R¹Is F, R ⁴Is R⁴-3，R^NIs H, R²And R⁵In each case corresponding to a row of table a.

TABLE 7

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-1，R^NIs CH₃，R²And R⁵In each case corresponding to a row of table a.

TABLE 8

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-1，R^NIs CH₃，R²And R⁵In each case corresponding to a row of table a.

TABLE 9

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-2，R^NIs CH₃，R²And R⁵In each case corresponding to a row of table a.

Watch 10

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-2，R^NIs CH₃，R²And R⁵In each case corresponding to a row of table a.

TABLE 11

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-3，R^NIs CH₃，R²And R⁵In each case corresponding to a row of table a.

TABLE 12

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-3，R^NIs CH₃，R²And R⁵In each case corresponding to a row of table a.

Watch 13

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-1，R^NIs cyclopropyl, R²And R⁵In each case corresponding to a row of table a.

TABLE 14

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-1，R^NIs cyclopropyl, R²And R⁵In each case corresponding to a row of table a.

Watch 15

A compound of formula (Ia), wherein R ³Is H, R¹Is H, R⁴Is R⁴-2，R^NIs cyclopropyl, R²And R⁵In each case corresponding to a row of table a.

TABLE 16

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-2，R^NIs cyclopropyl, R²And R⁵In each case corresponding to a row of table a.

TABLE 17

A compound of formula (Ia), wherein R³Is H, R¹Is H, R⁴Is R⁴-3，R^NIs cyclopropyl, R²And R⁵In each case corresponding to a row of table a.

Watch 18

A compound of formula (Ia), wherein R³Is H, R¹Is F, R⁴Is R⁴-3，R^NIs cyclopropyl, R²And R⁵In each case corresponding to a row of table a.

TABLE A

It has been found that the compounds as defined in the above table are particularly advantageous as STING agonists and may therefore be particularly advantageously used in the pharmaceutical compositions of the invention and the medical uses as defined herein. Accordingly, the compound of formula (I) of the present invention is preferably a compound according to any one of tables 1 to 18, and the present invention preferably relates to a pharmaceutical composition comprising the same and medical use thereof.

In certain particularly preferred embodiments, 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 group]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 group]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 group]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-carboxylic acid salt, 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-

Oxadiazol-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-radical][ (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- (prop-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- (prop-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.

In other particularly preferred embodiments, the compound according to formula (I) is a compound 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) piperidine- 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, and, 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, 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.

In other particularly preferred embodiments, the compound of formula (I) is a compound 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) piperidine- 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, and, 3- ({ [ (3S) -1- (6-Chloropyrimidin-4-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1-methyl-l, 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.

In certain even more particularly preferred embodiments, 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 ] quino-line -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) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one -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) -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- (piperazino- 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, and mixtures thereof, 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 pharmaceutically acceptable salts thereof, 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.

Furthermore, in certain even more particularly preferred embodiments, the compound of formula (I) is a compound 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-methylpiperazin-1-yl) Pyrid-4-yl) methyl ] [ (3S) -1- (pyrid-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one, 7-bromo-1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyrid-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- (pyrid-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 ] quino-line -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) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one -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.

Furthermore, in certain even more particularly preferred embodiments, the compound of formula (I) is a compound 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-methylpiperazin-1-yl) Pyrid-4-yl) methyl ] [ (3S) -1- (pyrid-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one, 7-bromo-1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyrid-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- (pyrid-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.

Furthermore, 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- ({ [ solution ], [ 2-methylpyridin-4-yl) (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-methyl - (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.

Furthermore, in certain even more particularly preferred embodiments, the compound of formula (I) is 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- (prop-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.

Definition of

The term "compound of the invention" is to be understood as being equivalent to the term "compound according to the invention" and also covers salts, stereoisomers, tautomers or N-oxides thereof.

The compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties such as stability or show different biological properties such as activity. The present invention relates to a compound of formula (I) in amorphous and crystalline form, a mixture of compounds of formula (I) in different crystalline states, and amorphous or crystalline salts thereof.

Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, such as those comprising the counter-ions present in the pharmaceutical products listed in the FDA orange book database in the united states. They may be formed in a conventional manner, for example by reacting a compound according to the invention with an acid of the anion in question if the compound has a basic functional group, or by reacting an acidic compound according to the invention with a suitable base.

Suitable cationic counterions are, in particular, ions of alkali metals, preferably lithium, sodium and potassium, of alkaline earth metals, preferably calcium, magnesium and barium, and of transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH)₄ ⁺) And wherein 1 to 4 hydrogen atoms are replaced by C₁-C₄Alkyl radical, C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkoxy-C₁-C₄-alkyl-, phenyl-or benzyl-substituted ammonium. 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.

Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, hydrogencarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and C₁-C₄Anions of alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and also anions of polybasic acids, such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions, such as benzenesulfonate (besylate), tosylate (p-toluenesulfonate), naphthalenesulfonate (naphthalene-2-sulfonate), methanesulfonate (methanesulfonate), ethanesulfonate (ethanesulfonate) and ethanedisulfonate. They can be formed by reacting the compounds according to the invention having basic functional groups with the acids of the corresponding anions.

Depending on the substitution pattern, the compounds according to the invention may have one or more chiral (including axial chiral) 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 mixtures thereof. The E/Z isomers may be present with respect to, for example, an olefin, a carbon-nitrogen double bond, or an amide group.

If substituents are present in the compounds of formula (I), tautomers may be formed which allow for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imide tautomers, and the like. Furthermore, the core structure comprising a 6-membered ring containing the ═ O substituent allows mainly keto-enol-tautomerization.

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

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

The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen, which may be replaced by a suitable substituent.

When it is mentioned that certain atoms or moieties are substituted by "one or more" substituents, the term "one or more" is intended to cover at least one substituent, e.g. 1 to 10 substituents, preferably 1, 2, 3, 4 or 5 substituents, more preferably 1, 2 or 3 substituents, most preferably 1 or 2 substituents. When the term "unsubstituted" or "substituted" is not specifically mentioned with respect to a moiety, the moiety shall be considered unsubstituted.

The organic moieties mentioned in the above definitions of variables, such as the term halogen, are collective terms for a single list of individual group members. The prefix Cn-Cm denotes in each case the number of possible carbon atoms in the radical.

The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

The term "alkyl" as used herein denotes in each case a straight-chain or branched alkyl group having typically 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon atoms. Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkyl group having typically 1 to 6 carbon atoms, frequently 1 to 5 or 1 to 4 carbon atoms, preferably 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of the group are partly or completely replaced by halogen atoms. Preferred haloalkyl moieties are selected from C₁-C₄-haloalkyl, more preferably selected from C₁-C₃-haloalkyl or C₁-C₂Haloalkyl, in particular selected from C₁-C₂Fluoroalkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl and the like.

The term "alkenyl" as used herein denotes in each case an unsaturated hydrocarbon radical having usually 2 to 6, preferably 2 to 4, carbon atoms which contains at least one carbon-carbon double bond in any position, e.g. 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, with respect to the double bond, geometric isomers are possible, the invention relates to both the E and Z isomers. Preferred alkenyl groups according to the present invention are terminal alkenyl groups. The bonding of the vinyl groups is illustrated below:

The term "haloalkenyl" as used herein refers to an alkenyl group as defined above wherein the hydrogen atoms are partially or fully replaced by halogen atoms.

The term "alkynyl" as used herein denotes in each case an unsaturated hydrocarbon radical having usually from 2 to 6, preferably from 2 to 5 or from 2 to 4, more preferably from 2 to 3, carbon atoms which contains at least one carbon-carbon triple bond in any position, for example, ethynyl, propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylpropan-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.

The term "haloalkynyl" as used herein refers to an alkynyl group as defined above in which hydrogen atoms are partially or fully replaced by halogen atoms.

The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl radical which is bonded via an oxygen atom and generally has 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.

The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the hydrogen atoms of the group are partly or completely replaced by halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C₁Haloalkoxy, especially C₁Fluoroalkoxy radicals, such as the trifluoromethoxy radical, and the like.

The term "HO (C ═ O) -C as used herein₁-C₄By alkyl is meant carboxyalkyl, i.e. via alkyl, preferably C₁-C₄-alkyl, more preferably C₁-C₂-a carboxyl group C (═ O) OH in which the alkyl group is bonded to the remainder of the molecule. Preference is given toExamples of (b) include carboxymethyl and carboxyethyl.

The term "cycloalkyl" as used herein denotes in each case a monocyclic cycloaliphatic radical having typically 3 to 10 or 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Unless otherwise indicated, the term "carbocyclic" or "carbocyclyl" generally includes 3-to 9-membered, preferably 4-to 8-or 3-to 6-or 5-to 7-membered, more preferably 5-or 6-membered, monocyclic rings containing 3 to 9, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 5 or 6 carbon atoms. Carbocycles may 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 may be present at the appropriate position while not meeting the Huckel rule for aromaticity, and aromatic means that the Houckel (4n +2) rule is met. The term "carbocycle" or "carbocyclyl" may thus encompass, inter alia, cycloalkyl, cycloalkenyl, and phenyl, unless otherwise indicated. Preferably, the term "carbocycle" encompasses cycloalkyl and cycloalkenyl groups, such as cyclopropane, cyclobutane, cyclopentane and cyclohexane rings.

The term "carbobicyclic" or "carbobicyclic group" generally includes 6-to 14-membered, preferably 7-to 12-or 8-to 10-membered, more preferably 9-or 10-membered bicyclic rings comprising 6 to 14, preferably 7 to 12 or 8 to 10, more preferably 9 or 10 carbon atoms. The carbocyclic ring may 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 may be present at the appropriate position while not meeting the huckel rule for aromaticity, and aromatic means that the houcker (4n +2) rule is met. Preferably, the term "aromatic" in relation to a carbon bicyclic ring means that both rings of the bicyclic moiety are aromatic such that, for example, in the case of a 10-membered aromatic carbon bicyclic ring, 8 pi electrons are present. Unless otherwise indicated, the term "carbobicyclic" or "carbobicyclyl" may thus encompass, inter alia, bicycloalkyl, bicycloalkenyl and bicycloaryl, such as bicyclohexane (decalin), 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 and the like. Preferably, the carbon bicyclic ring is a fused carbon bicyclic ring, which is preferably aromatic, such as naphthalene.

The term "carbocyclic oxy" includes carbocyclic rings or carbocyclic groups bonded to the remainder of the molecule via an oxygen atom.

Unless otherwise indicated, the term "heterocyclic" or "heterocyclyl" generally includes 3-to 9-membered, preferably 4-to 8-or 5-to 7-membered, more preferably 5-or 6-membered, especially 6-membered monocyclic rings. The heterocyclic ring may 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 may be present at the appropriate position while not meeting the huckel rule for aromaticity, and aromatic means that the huckel (4n +2) rule is met. Heterocycles typically comprise one or more, e.g. 1, 2, 3 or 4, preferably 1, 2 or 3, heteroatoms selected from N, O and S as ring members, wherein the S-atom as ring member may be S, SO or SO₂Are present. The remaining ring members are carbon atoms. In a preferred embodiment, the heterocyclic ring is an aromatic heterocyclic ring, preferably a 5-or 6-membered aromatic heterocyclic ring comprising one or more, e.g. 1, 2, 3 or 4, preferably 1, 2 or 3, heteroatoms selected from N, O and S as ring members, wherein the S-atom as ring member may be S, SO or SO ₂Are present. The following definitions for "heteroaryl" provide examples of aromatic heterocycles. The term "heterocycle" encompasses "heteroaryl (or heteroryl)". The saturated or partially or fully unsaturated heterocyclic ring 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 ring member may be S, SO or SO₂Are present. The skilled person is aware of S, SO or SO₂It should be understood as follows:

furthermore, the skilled person knows that resonant structures in the form of oxidation are possible. Unless otherwise indicated, a saturated heterocyclic ring generally includes a 3-to 9-membered, preferably 4-to 8-or 5-to 7-membered, more preferably 5-or 6-membered, 3-to 9-membered, preferably 4-to 8-or 5-to 7-membered, more preferably 5-or 6-membered monocyclic ring containing at least one heteroatom, such as pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, bis-heterocyclic rings

Alkane, morpholine or piperazine.

The term "heterocyclyloxy" includes a heterocycle or heterocyclyl group bonded to the remainder of the molecule via an oxygen atom.

Unless otherwise indicated, the term "heterobicyclic" or "heterobicyclic group" generally includes 6-to 14-membered, preferably 7-to 12-or 8-to 10-membered, more preferably 9-or 10-membered bicyclic rings. The heterobicyclic ring may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, partially or fully unsaturated means that one or more double bonds may be present at the appropriate position while not meeting the huckel rule for aromaticity, and aromatic means that the huckel (4n +2) rule is met. 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, in the case of a 9-or 10-membered aromatic heterobicyclic ring, 8 pi electrons are present. The heterobicyclic ring generally comprises 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, wherein the S-atom as ring member may be S, SO or S0 ₂Are present. The remaining ring members are carbon atoms. Examples of heterobicyclics include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzofuranyl

Thiazolyl, benzo

Oxadiazolyl, benzothiadiazolyl, benzo

Azinyl, quinolyl, isoquinolyl, purinyl, 1, 8-naphthyridinyl, pteridinyl, pyrido [3, 2-d ]]Pyrimidinyl, pyridoimidazolyl, triethylenediamine, quinuclidine, and the like. Preferred heterobicycles according to the present invention are aromatic heterobicycles, such as e.g. benzodiazoles, benzothiazoles, quinolines and isoquinolines.

The term "heteroaryl" or "aromatic heterocycle" includes monocyclic 5-or 6-membered aromatic heterocycles comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members, wherein the S-atom as ring member may be S, SO or SO₂Are present. Examples of the 5-or 6-membered aromatic heterocyclic ring include: pyridyl (pyridyl), also known as pyridyl (pyridyl), i.e. 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrimidinyl, i.e. 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl; a pyrazinyl group; 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 radicals, i.e. 2-

Azolyl, 3-

Azolyl or 5-

An azole group; different from each other

Azolyl radicals, i.e.3-iso

Azolyl, 4-iso

Azolyl or 5-iso

An azole group; 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;

oxadiazolyl, e.g. 2- [1, 3, 4]

Oxadiazolyl or 5- [1, 3, 4 ] azolyl]

Oxadiazolyl, 4- (1, 2, 3-)

Diazole) yl or 5- (1, 2, 3-)

Diazole) yl, 3- (1, 2, 4-)

Diazole) yl or 5- (1, 2, 4-)

Diazole) group; 2- (1, 3, 4-thiadiazole) or 5- (1, 3, 4-thiadiazole) group, thiadiazolyl, e.g. 2- (1, 3, 4-thiadiazole) or 5- (1, 3, 4-thiadiazole) group, 4- (1, 2, 3-thiadiazole) group or 5- (1, 2, 3-thiadiazole) group, 3- (1, 2, 4-thiadiazole)Diazolyl) or 5- (1, 2, 4-thiadiazole) group; 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. The term "heteroaryl" also encompasses "aromatic heterobicyclic" as defined above, unless otherwise indicated.

The term "aryl" or "aromatic carbocyclic ring" preferably includes 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl. The term "aryl" also encompasses "aromatic carbocyclic ring" as defined above, unless otherwise specified.

As used herein, the terms "carbocyclylalkyl" and "heterocyclylalkyl" as well as the terms "arylalkyl", "cycloalkylalkyl", "heteroarylalkyl" and the like refer to a radical via an alkyl group, preferably via C₁-C₂The corresponding group in which the alkyl group is bonded to the remainder of the molecule. Preferred examples include benzyl (i.e., benzyl), cyclohexylmethyl, pyridylmethyl and piperidinylmethyl.

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., benzyloxy).

As used herein, the term "alkylene" refers to a linking straight or branched alkylene group typically having 1 to 4 carbon atoms, for example 1, 2, 3, or 4 carbon atoms. Alkylene groups bridge a group to the rest of the molecule. Preferred alkylene groups include methylene (CH)₂) Ethylene (CH) ₂CH₂) Propylene (CH)₂CH₂CH₂) And the like. The skilled person understands if mention is made of, for example, CH₂The tetravalent carbon atom then leaves two valencies for the formation of a bridge (-CH)₂-). Similarly, when referring to, for example, CH₂CH₂When each carbon atom is left with a valence for the formation of a bridge (-CH)₂CH₂-). In addition, when referring to, for example, CH₂CH₂CH₂At each end of the carbon atomAll leaving a valence state for the formation of a bridge (-CH)₂CH₂CH₂-)。

If with respect to, for example, NR^F-(C₁-C₄-alkylene) -C (═ O) R^EUsing the term "alkylene" it is understood that the alkylene chain will be C (═ O) R^EThe radicals being bridged to NR^FGroup, NR^FThe group is bonded to the remainder of the molecule.

The term "cyclic" moiety may refer to any cyclic group present in a compound of formula (I) and defined above, e.g., cycloalkyl, cycloalkenyl, carbocycle.

As used in the specification and in the claims, the singular form of "a", "an", and "the" include the corresponding plural forms as well, unless the context clearly dictates otherwise. The same applies to the plural forms used herein, and the plural forms also include the singular forms unless the context clearly dictates otherwise.

The terms "about" and "approximately" in the context of the present invention denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term generally denotes a deviation of ± 10% and preferably of ± 5% from the indicated value.

It is to be understood that the term "comprises/comprising" is not limiting. For the purposes of the present invention, the term "consisting of …" is considered to be a preferred embodiment of the term "comprising". If in the following a group is defined comprising at least a certain number of embodiments, this is also intended to comprise groups preferably consisting of only these embodiments.

The term "pharmaceutically acceptable excipient" as used herein refers to compounds known to the skilled person to be normally included in pharmaceutical compositions. Examples of suitable excipients are exemplarily listed below. In general, a pharmaceutically acceptable excipient may be defined as pharmaceutically inactive.

The term "treatment" is to be understood as also including the option of "prevention". Thus, whenever reference is made herein to "treatment" and variations thereof, this is to be understood as reference to "treatment and/or prevention" and variations thereof.

Description of the pharmaceutical compositions according to the invention

The pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal or parenteral application. Preferred non-parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, where oral administration may be preferred. Preferred parenteral routes include, but are not limited to, one or more of subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intradermal administration, intrathecal administration and epidural administration. Administration by subcutaneous, intratumoral or peritumoral route is preferred. Intratumoral administration is particularly preferred. The compound according to formula (I) should be applied in a pharmaceutically effective amount, for example in the amounts as set out below.

The pharmaceutical compositions of the present invention may also be referred to as formulations or dosage forms. The compounds of formula (I) may also be referred to below as (pharmaceutically) active agents or active compounds.

The pharmaceutical composition may be in solid or liquid dosage form or may have intermediate (e.g. gel-like) characteristics, depending inter alia on the route of administration.

In general, the dosage form of the present invention may comprise a variety of pharmaceutically acceptable excipients, which will be selected according to the function to be performed by the dosage form. "pharmaceutically acceptable excipients" within the meaning of the present invention may be any substances used for the preparation of 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 buffers.

The term "carrier" denotes a pharmaceutically acceptable organic or inorganic carrier material with which the active ingredient is associated to facilitate application. Suitable pharmaceutically acceptable carriers include, for example, water; a saline solution; an alcohol; an oil, preferably a vegetable oil; propylene glycol; polyoxyethylene sorbitan; a polyethylene-polypropylene block copolymer such as poloxamer 188 or poloxamer 407; polyethylene glycols such as polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and the like; gelatin; lactose; amylose starch; magnesium stearate; a surfactant; an aromatic oil; a fatty acid monoglyceride; diglycerides and triglycerides; polyoxyethylated medium 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 capric or caprylic acid, petroleum ether (petroethral) fatty acid esters; hydroxymethyl cellulose such as hydroxymethyl, hydroxyethyl, hydroxypropyl acetate succinate; polyvinylpyrrolidone; crospovidone, and the like. Preferably, the compounds of the invention are administered as pharmaceutical compositions comprising lipids, multilamellar vesicles crosslinked between bilayers, biodegradable poly (D, L-lactic-co-glycolic acid) ([ PLGA ]) or polyanhydride based nanoparticles or microparticles, nanoporous particle loaded lipid bilayers and as conjugates with antibodies.

The pharmaceutical compositions may be sterile and, if desired, may be mixed with the following adjuvants which do not deleteriously react with the active compound: such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavors and/or aromatic substances, etc. It is to be understood that the term "carrier" also encompasses antibodies that deliver the compounds of formula (I).

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

For parenteral administration, particularly suitable carriers consist of solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants. Pharmaceutical preparations for parenteral administration are particularly preferred and comprise aqueous solutions of the compounds of the formula (I) in water-soluble form. In addition, suspensions of the compounds of formula (I) may be formulated 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 may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.

Particularly preferred dosage forms are injectable formulations of the compounds of formula (I). Thus, sterile injectable aqueous or oleaginous suspensions may be formulated, for example, according to the known art using suitable dispersing, wetting and/or suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Acceptable carriers and solvents that may be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally employed as a solvent or suspending medium. Preferred applications of the injectable formulations comprising the compounds of the invention are intravenous, intratumoral and peritumoral administration.

Suppositories for rectal administration of the compounds 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 the rectal temperature so that they will melt in the rectum and release the compound according to formula (I) from the suppository.

For administration by inhalation, the compounds according to the invention may conveniently be delivered in the form of an aerosol spray from a pressurised pack or nebuliser, with the aid of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

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 solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, 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, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Oral dosage forms may be formulated to ensure immediate release of the compound of formula (I) or sustained release of the compound of formula (I).

The solid dosage form may comprise a film coating. For example, the dosage form of the present invention may be in the form of a so-called film tablet. The capsules of the present invention may be two-piece hard gelatin capsules, two-piece hydroxypropyl methylcellulose capsules, two-piece capsules made of plant or plant-based cellulose (tow-piece capsules), or two-piece capsules made of polysaccharides.

The dosage form according to the invention may be formulated for surface application. Suitable drug application forms for such application may be topical nasal sprays, sublingual administration forms and controlled and/or sustained release skin patches. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The method may comprise the step of bringing the compound into association with a carrier which constitutes one or more accessory ingredients. Generally, the compositions are 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. The liquid dosage unit is a vial or ampoule. Solid dosage units are tablets, capsules and suppositories.

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

Furthermore, the pharmaceutical compositions may also comprise compounds of formula (I) as prodrugs, for example esters or amides thereof. A prodrug is any compound that is converted to any compound of the present invention under physiological conditions or by solvolysis. Prodrugs may be inactive prior to administration, but may be converted in vivo to the active compounds of the invention.

Indications for which the compounds of the invention may be used

The compounds according to the invention are suitable for use in medicine. In particular, the compounds according to the invention are suitable for the treatment of diseases selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, infectious diseases, cancer, and pre-cancerous syndromes. Furthermore, the compounds of formula (I) are suitable for use in immunogenic compositions and as vaccine adjuvants.

In one embodiment, the compounds of the invention or pharmaceutical compositions comprising the same are used for the treatment of a disease selected from cancer, pre-cancerous syndrome and infectious disease; or in immunogenic compositions or as vaccine adjuvants.

In another embodiment, the compound of the present invention or the pharmaceutical composition comprising the same is used for the treatment of a disease selected from the group consisting of inflammatory diseases, allergic diseases, and autoimmune diseases.

In a preferred embodiment, the compounds of the invention or the pharmaceutical compositions comprising them are used for the treatment of a disease selected from cancer or pre-cancerous syndrome.

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

In another preferred embodiment, the compound of the present invention or the pharmaceutical composition comprising the same is used for the treatment of inflammatory diseases, allergic diseases, infectious diseases.

Of particular relevance 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, lehermite-ducklopal disease (lhemitte-Duclos disease), Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, liver cancer, melanoma, ovarian cancer, pancreatic cancer, head and neck adenocarcinoma, ductal adenocarcinoma, adenocarcinomas, squamous carcinoma, head and neck cancer, adenocarcinomas, Acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous 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's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, Vulvar cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer (buccal cancer), oral cancer, GIST (gastrointestinal stromal tumor), neuroendocrine cancer, and testicular cancer.

More preferably, the cancer is selected from the group consisting of prostate cancer, renal cancer, melanoma, pancreatic cancer, cervical cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, fibrosarcoma and breast cancer.

In a particularly preferred embodiment, the compounds of the invention or the pharmaceutical compositions comprising them are used for the treatment of colon cancer.

Preferably, the autoimmune disease is selected from systemic lupus erythematosus, Addison's disease, autoimmune polyendocrine adenosis (also known as autoimmune polyendocrine gland 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 allergies.

It will be appreciated that, in relation to the medical use of the invention, it may be preferred to administer a compound according to the invention in combination with an antibody, radiotherapy, surgical treatment, immunotherapy, chemotherapy, toxin therapy, gene therapy or any other therapy known to a person of ordinary skill in the art for the treatment of a particular disease. This is particularly relevant for cancer treatment. Preferably, the compounds of the 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-LAG 3 antibodies. Some non-limiting examples are BMS-936559, MPDL3280A and MEDI4736 or avilumab (avelumab) (anti-PD-L1 antibody), MK-3475, pembrolizumab (pembrolizumab) or pidilizumab (pidilizumab) (anti-PD-1 antibody) and ipilimumab (ipilimumab) (anti-CTLA-4 antibody). Preferably, the compounds of the invention are administered in a pharmaceutical composition comprising one or more of: adjuvants, inactivated or attenuated bacteria (e.g., inactivated or attenuated Listeria monocytogenes), innate immune activation modulators, preferably Toll-like Receptor (TLR) agonists (preferably TLR7 or TLR9 agonists, such as SM360320, AZD8848), (NOD) -like Receptor (NLR) agonists (preferably NOD2 agonists), retinoic acid inducible gene (RIG) -based-I-like Receptor (RLR) agonists, C-type lectin Receptor (CLR) agonists, or pathogen-associated molecular patterns ("PAMPs"), cytokines (non-limiting examples such as IL-2, IL-12, IL-6), interferons (including but not limited to IFN α, IFN β, IFN γ, IFN λ), or chemotherapeutic agents. Medical use may further compromise the administration of at least one HBV vaccine, nucleoside HBV inhibitor, or any combination thereof (e.g., RECOMBIVAX HB, ENGERIX-B, GENEVAC-B).

Combination therapy may be achieved by using a single pharmaceutical composition comprising two agents or by administering two different compositions simultaneously, wherein one composition comprises a compound of the invention and the other comprises a second agent.

The two treatments may be given in either order and may be separated by minutes to weeks before or after the other treatment. In some embodiments where other agents are administered alone, it is generally ensured that a significant period of time will not fail between the time of each delivery, such that the agents will still be able to exert a favorable combined effect on the patient. In such cases, it is contemplated that the two modes may 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 period, however, with several days (2, 3, 4, 5, 6, or 7 days) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8 weeks) between individual administrations. In some embodiments, the compounds of the invention are administered prior to administration of a different cancer treatment. In other embodiments, a different cancer treatment is administered prior to administration of a compound of the invention.

The invention is further illustrated by the following examples.

Examples

The following abbreviations are used herein:

the compounds of the present invention are prepared according to the procedures of the following schemes and examples using suitable materials and are further exemplified by the following specific examples.

Unless otherwise indicated, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all temperatures are expressed in ° c and all reactions are performed at room temperature.

Methods and analytical data:

in general:

microwave heating was performed using a Biotage emerys Initiator microwave. Column chromatography was performed using Isco Rf200d or interchem Puriflash 450. Solvent removal was carried out using a Buchi rotary evaporator or a Genevac centrifugal evaporator. Preparative LC/MS was performed under alkaline mobile phase conditions using a Waters mass-directed automated purification system and a Waters 19 x 100mm XBridge 5 micron C18 column or under acidic conditions using an equivalent Waters CSH C18 column. NMR spectra were recorded using a Bruker 300MHz or 400MHz spectrometer. Chemical shifts (. delta.) are reported in ppm relative to the residual solvent signal (measurement range-6.4 kHz). The 1H NMR data are reported below: chemical shifts (multiplicity, coupling constants and hydrogen number). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets). ESI-MS: the flow rate of desolvated gas is 993 l/h; desolvation temperature is 500 ℃; cone gas (cone gas): 50 l/min; 500-1000 m/z; polarity: positive and/or negative.

Photochemical reactions were performed using a Penn PhDM2 photoreactor (100% LED). Integrated photoreactor-Royal Blue (450nm) LED lamp, where fan speed: 5200rpm, stirring rate: 600rpm, LED light intensity: 100 percent.

Preparative HPLC conditions for purification of the target compound:

chromatographic conditions 1:

preparative HPLC instrument: shimadzu

Column: Gemini-NX 5 mu m C18

21.2*250mm

A detector: SPD-20A/20AV UV-VIS

Flow rate: 20 mL/min

Representative mobile phases:

(1)

mobile phase: a: 0.01% formic acid or TFA in Water

Mobile phase: b: 0.01% formic acid or TFA in ACN

(2)

Mobile phase: a: 0.01% NH4OH in water

Mobile phase: b: 0.01% NH4OH in ACN

Chromatographic conditions 2:

preparative HPLC instrument: shimadzu

Column: chiralpak AD-H, 5 μm, 20X 250mm

A detector: SPD-20A/20AV UV-VIS

Flow rate: 20 mL/min

Representative mobile phases:

mobile phase: a: EtOH

Mobile phase: b: hexane (C)

The UPLC, HPLC and MS data provided in the following examples are registered to:

LC-MS analysis of Shimadzu:

the method comprises the following steps: lc-ms1-2-ba

Equipment:

-Shimadzu LC-MS 2020

HPLC with UV-Vis or DAD detectors

-a column: waters Acquity UPLC HSS C18, 50mm × 2.1mm × 1.8 μm

Eluent:

(A) 0.1% formic acid in ACN

(B) 0.1% formic acid in water

The analysis method comprises the following steps:

-an autosampler: injection volume: 1 μ L

-a pump:

time [ min ] flow [ ml/min ]% B

-a column chamber: column temperature: 25 ℃; analysis time: 6 minutes

-a detector: wavelength: 254nm, 230nm, 270nm, 280nm

LC-MS analysis on Bruker Amazon SL

The method comprises the following steps: lc-ms1-2-ba

Equipment:

-MS Bruker Amazon SL

-LC Dionex Ultimate 3000

HPLC with UV-Vis or DAD detectors

-a column: waters Acquity UPLC HSS C18, 50mm × 2.1mm × 1.8 μm

Eluent:

(A) 0.1% formic acid in ACN

(B) 0.1% formic acid in water

The analysis method comprises the following steps:

-an autosampler: injection volume: 1 μ L

-a pump:

-a column chamber: column temperature: 25 ℃; analysis time: 6 minutes

-a detector: wavelength: 254nm, 230nm, 270nm, 280nm

LC-MS analysis on Bruker Amazon SL

The method comprises the following steps: BCM-30

Equipment:

-MS Bruker Amazon SL

-LC Dionex Ultimate 3000

HPLC with UV-Vis or DAD detectors

-a column: waters Symmetry C183.9X 150mm 5 μm

Eluent:

(A) 0.1% aqueous formic acid solution

(B) 0.1% formic acid ACN solution

The analysis method comprises the following steps:

-an autosampler: injection volume: 3 μ L

-a pump:

flow rate: 1.2 ml/min

Time [ min ] [% ] B

-a column chamber: column temperature: 25 ℃; analysis time: 30 minutes

-a detector: wavelength: 254nm

LC-MS analysis on Corona ultra

The method comprises the following steps: BCM-30

Equipment:

-Corona ultra

-LC Dionex Ultimate 3000

-a column: waters Symmetry C183.9X 150mm 5 μm

Eluent:

(A) 0.1% aqueous formic acid solution

(B) 0.1% formic acid ACN solution

The analysis method comprises the following steps:

-an autosampler: injection volume: 3 μ L

-a pump:

flow rate: 1.2 ml/min

Time [ min ] [% ] B

Synthesizing mule:

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 is to be understood that, unless otherwise indicated, all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experimental duration and work-up steps, may be selected as conditions standard 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 reagents and reactions proposed. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art and alternative methods are indicated. Starting materials for the examples are either commercially available or readily prepared from known materials by standard methods.

Step 1 preparation of (3S) -1- (pyridin-3-yl) piperidin-3-amine

a. Tert-butyl N- [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] carbamate

To a solution of 3-bromopyridine (3.00g, 18.99mmol, 1 eq.) in anhydrous bis

To a stirred solution in an alkane (80mL) was added tert-butyl N- [ (3S) -piperidin-3-yl group]Carbamate (4.94g, 24.68mmol, 1.3 equiv.), tris (dibenzylideneacetone) dipalladium (0) (Pd₂(dba)₃869mg, 0.949mmol, 0.05 equiv.), Cs₂CO₃(8.35g, 25.63mmol, 1.3 equivalents) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 659mg, 1.14mmol, 0.06 equivalents). The resulting mixture was stirred for 4 days while heating at 100 ℃ under an inert atmosphere. Subsequently, the mixture was cooled to ambient temperature by

The pad was filtered and concentrated under reduced pressure. The residue was purified by FCC (SiHP; AcOEt 100%) to give the product as a pale yellow oil (3.2g, 11.54mmol, 61% yield). ESI-MS: 278.4[ M + H]⁺

(3S) -1- (pyridin-3-yl) piperidin-3-amine

Tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl group]Carbamate (3.2g, 11.54mmol, 1 eq) in bis

A stirred solution in alkane (20mL) was used in Di

4M HCl in alkane (20mL, 80.80mmol, 7 equiv.). The reaction was carried out at 55 ℃ 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 afford the product as a yellow oil (2.00g, 11.28mmol, 98% yield). ESI-MS: 178.1[ M + H ]⁺

Step 2.1 preparation of- (pyridin-3-yl) piperidin-3-amine

a. Tert-butyl N- [1- (pyridin-3-yl) piperidin-3-yl ] carbamate

To a stirred solution of 3-bromopyridine (394mg, 2.497mmol, 1 eq) in dry toluene (15mL) was added tert-butyl N- (piperidin-3-yl) carbamate (500mg, 2.497mmol, 1 eq), tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃114mg, 0.125mmol, 0.05 equiv.), sodium tert-butoxide (288mg, 2.966mmol, 1.2 equiv.) and (. + -.) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (rac-BINAP, 155mg, 0.250mmol, 0.1 equiv.). The resulting mixture was stirred for 24 hours while being heated at 100 ℃ under an inert atmosphere. Subsequently, the mixture was cooled to ambient temperature by

The pad was filtered 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 give the product as a yellow oil (359mg, 1.2mmol, 47% yield). ESI-MS: 278.5[ M + H]⁺

1- (pyridin-3-yl) piperidin-3-amines

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

Step 3.1 preparation of methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

To a solution of 3-bromopyridine (190mg, 1.206mmol, 1.2 equivalents) in anhydrous dioxane

To a stirred solution in an alkane (5mL) was added 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl group][ (3S) -piperidin-3-yl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one (378mg, 1.005mmol, 1 eq.), tris (dibenzylideneacetone) dipalladium (0) (Pd₂(dba)₃46mg, 0.050mmol, 0.05 equiv.), cesium carbonate (442mg, 1.356mmol, 1.35 equiv.), and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 35mg, 0.060mmol, 0.06 equiv.). The reaction was carried out at 95 ℃ for 24 hours under an inert atmosphere. Subsequently, the mixture was cooled to ambient temperature by

The pad was filtered and concentrated under reduced pressure. The residue was passed through RP-FCC (SiC 18; H)₂O∶MeCN 100％)Purification to give the product as a yellow oil (48mg, 0.106mmol, 10% yield). The product was converted to the hydrochloride salt. ESI-MS: 454.3[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.61(d，J＝5.9Hz，1H)，8.58(d，J＝2.7Hz，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＝8.6Hz，1H)，7.44(ddd，J＝8.0，6.8，1.0Hz，1H)，4.49(d，J＝12.6Hz，1H)，4.40(s，2H)，4.04(s，2H)，3.94(d，J＝13，1Hz，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).

Step 4.1 preparation of 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- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

A mixture of 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (2.90g, 15.50mmol, 1 eq), (3S) -1- (pyridin-3-yl) piperidin-3-amine (3.02g, 17.00mmol, 1.1 eq), sodium acetate (1.27g, 15.55mmol, 1 eq) in MeOH (100mL) was activated at room temperature with

The molecular sieve was stirred for 16 hours. The mixture was then cooled to 0 ℃ and sodium borohydride (0.64g, 17.00mmol, 1.1 equiv) was added portionwise over 30 minutes. The reaction was allowed to reach room temperature over 1 hour. When the reaction is complete, the mixture is passed through

The pad was filtered, washed with MeOH and the solvent removed in vacuo. The residue was partitioned between DCM and aqueous NaOH (10%, 2N or 5N). The layers were separated. The organic layer was dried, filtered off and concentrated in vacuo. The crude product was used in the next step without further purification. As a product of a yellow oil. ESI-MS: 349[ M + H]⁺

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- (pyridin-3-yl) piperidin-3-yl]A mixture of amino } methyl) -1, 4-dihydroquinolin-4-one (0.95g, 2.70mmol, 1 eq.) and 2-methylpyridine-4-carbaldehyde (0.33g, 2.70mmol, 1 eq.) in DCE (20mL) at room temperature was treated with activated

The molecular sieve was stirred for 2 hours. The mixture was then cooled to 0 ℃ and sodium triacetoxyborohydride (0.87g, 4.1mmol, 1.5 equiv.) was added in portions. The reaction was allowed to reach room temperature over 16 hours. Passing the reaction mixture through

The pad was filtered and washed with DCM. The filtrate was extracted with water. The organic layer was dried, filtered off and concentrated in vacuo. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to provide the title compound as a white solid (500mg, 1.1mmol, 40% yield). ESI-MS: 454[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.32-8.27(m，2H)，8.20(dd，J＝8.0，1.6Hz，1H)，8.04(s，1H)，7.92(dd，J＝4.5，1.3Hz，1H)，7.72(ddd，J＝8.6，6.9，1.7Hz，1H)，7.63(d，J＝8.2Hz，1H)，7.38(ddd，J＝8.0，6.9，1.0Hz，1H)，7.32-7.23(m，3H)，7.15(dd，J＝8.5，4.5Hz，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).

Some aliphatic H overlaps with the solvent peak.

Step 5.3 preparation of- ({ [ (2-methoxypyridin-4-yl) methyl ] [1- (pyridazin-3-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

To a solution of 3-bromopyridazine (29mg, 0.18mmol, 0.9 eq) in anhydrous di

To a degassed solution in an alkane (2mL) was added 3- ({ [ (2-methoxypyridin-4-yl) methyl](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one (80mg, 0.20mmol, 1 eq.), sodium tert-butoxide (39mg, 0.41mmol, 2 eq.) and (2-dicyclohexylphosphine-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl) [2- (2 ' -amino-1, 1 ' -biphenyl)]Palladium (II) methanesulfonate (RuPhos Pd 3G, 18mg, 0.020mmol, 0.1 equiv.). The reaction was carried out under an inert atmosphere at 100 ℃ for 1 day. Subsequently, the mixture was cooled to ambient temperature by

The pad was filtered and concentrated under reduced pressure. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) to give the product as a yellow solid (31mg, 0.06mmol, 30% yield). ESI-MS: 471[ M + H]⁺

¹H NMR(300MHz，DMSO-d6)δ8.49-8.46(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).

Some aliphatic H overlaps with the solvent peak.

Step 6.3 preparation of- ({ [ (2-methoxypyridin-4-yl) methyl ] [1- (pyrazin-2-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

3- ({ [ (2-methoxypyridin-4-yl) methyl](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one (80mg, 0.20mmol, 1 eq.), 3-chloropyrazine (20. mu.L, 0.22mmol, 1.10 eq.) and potassium carbonate (56mg, 0.41mmol, 2 eq.) were dissolved in DMF (2 mL). The reaction was carried out at 100 ℃ for 24 hours. The resulting mixture was cooled to room temperature and saturated NaHCO₃And AcOEt. The organic layer was washed with water and brine (30 mL). The organic layer was dried, filtered off and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound as a yellow solid (28mg, 0.059mmol, 29% yield). ESI-MS: 471[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.33(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).

Some aliphatic H overlaps with the solvent peak.

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

¹H NMR (400MHz, 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 (m, 1H)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).

Aliphatic H overlaps with the solvent peak.

Step 7.1 preparation of 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

a. Ethyl 1-cyclopropyl-6, 7-difluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester

Thionyl chloride (2.47mL, 33.93mmol, 30 equiv.) was added dropwise to a stirred solution of ethanol (16.5mL) at 22 ℃. After 30 minutes, the mixture became a pale yellow solution; 1-cyclopropyl-6, 7-difluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (0.30g, 1.13mmol, 1 eq) was then added and 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 performed 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 provide the product as a white solid (0.33g, 0.88mmol, 78% yield). ESI-MS: 294[ M + H ]⁺

b. Ethyl 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester

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

1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

Ethyl 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylate (0.14g, 0.39mmol, 1 eq) in concentrated HCl (1mL), H₂O (3mL) and two

The solution in alkane (9mL) was stirred at reflux for 5 hours. The solvent was evaporated and the crude was partitioned between water and DCM. The organic layers were combined, dried and concentrated in vacuo. Product as a white solid (0.12g, 0.34mmol, 89% yield). ESI-MS: 346[ M + H ] ]⁺

¹H NMR(400MHz，DMSO-d6)δ8.67(s，1H)，7.91(d，J＝13.4Hz，1H)，7.56(d，J＝7.5Hz，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).

Some aliphatic H overlaps with the solvent peak.

1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -1, 2, 3, 4-tetrahydroquinolin-4-one

To a cooled solution of 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (0.19g, 0.34mmol, 1 eq) in anhydrous MeOH (5mL) was slowly added boron over 30 minSodium hydride (0.059g, 1.55mmol, 4.5 equiv.). The mixture was allowed to warm to room temperature, p-toluenesulfonic acid (0.007g, 0.034mmol, 0.10 eq) was added and the reaction mixture was heated at 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) provided the product as a yellow solid (0.081g, 0.27mmol, 77% yield). ESI-MS: 304[ M + H]⁺

¹H NMR(400MHz，DMSO-d6)δ7.29(d，J＝13.8Hz，1H)，6.74(d，J＝7.6Hz，1H)，3.44(dd，J＝7.5，6.2Hz，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).

Aliphatic H overlaps with the solvent peak.

1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

To a mixture of sodium methoxide (0.056g, 1.04mmol, 3.9 equiv.) and ethyl formate (0.085mL, 1.05mmol, 3.94 equiv.) in anhydrous DCM (5mL) was added a solution of 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -1, 2, 3, 4-tetrahydroquinolin-4-one (0.081g, 0.27mmol, 1 equiv.) 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 (5mL) and manganese dioxide (0.088g, 1.01mmol, 5 equivalents) was added. After stirring at room temperature for 18 hours, the mixture was passed

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 obtainThe product was provided as a white solid (0.048g, 0.15mmol, 72% yield). ESI-MS: 330[ M + H]⁺

¹H NMR(400MHz，DMSO-d6)δ10.11(s，1H)，8.32(s，1H)，7.81(d，J＝13.5Hz，1H)，7.49(d，J＝7.4Hz，1H)，3.75-3.68(m，1H)，3.27(dd，J＝6.1，3.8Hz，4H)，2.26(s，3H)，1.28-1.22(m，2H)，1.16-1.10(m，2H).

Some aliphatic H overlaps with the solvent peak.

Step 8.1 preparation of methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyridin-2-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

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

¹H NMR(300MHz，DMSO-d6)δ8.31-8.25(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).

Step 9.1 preparation of methyl-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

a.7-bromo-1-methyl-1, 4-dihydroquinolin-4-one

7-Bromoquinolin-4-ol (3.00g, 13.39mmol, 1 eq.) is suspended in anhydrous THF (10 mL). Then, 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU) (0.99mL, 7.00mmol, 1.5 equivalents) was added dropwise, followed by methyl iodide (0.55mL, 8.00mmol, 2 equivalents) and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by FCC (SiHP, DCM: MeOH, 95: 5) to give the product as a yellow solid (0.72g, 4.40mmol, 67% yield). ESI-MS: 239[ M + H]⁺

1-methyl-7- (4-methylpiperazin-1-yl) -1, 4-dihydroquinolin-4-one

To a solution of 7-bromo-1-methyl-1, 4-dihydroquinolin-4-one (700mg, 2.94mmol, 1 eq.) in anhydrous dioxane

To a solution in an alkane (15mL) were added 1-methylpiperazine (330. mu.L, 2.94mmol, 1 eq), sodium tert-butoxide (339mg, 3.53mmol, 1.2 eq) and 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl) [2- (2 '-amino-1, 1' -biphenyl ]]Palladium (II) methanesulfonate (Sphos Pd 3G, (229mg, 0.29mmol, 0.1 equiv.) the reaction was carried out at 100 ℃ for 24 h under an inert atmosphere, after which the mixture was cooled to ambient temperature by passing

The pad was filtered and concentrated under reduced pressure. The residue was purified by FCC (SiHP, DCM: MeOH, 8: 2) to obtain the product as a yellow solid (722mg, 2.81mmol, 93% yield). ESI-MS: 258[ M + H ]]⁺

1-methyl-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

1-methyl-7- (4-methylpiperazin-1-yl) -1, 4-dihydroquinolin-4-one (300mg, 1.17mmol, 1 eq.) and 1, 3, 5, 7-tetraazatricyclo [3.3.1.13, 7]Decane (HMT) (327mg, 2.33mmol, 2 equiv.) and TFA (2mL) were microwaved at 120 ℃ for 15 min. The reaction mixture was diluted with water (5mL) and stirred for 10 minutes. Then, saturated Na was used₂CO₃The mixture was neutralized with DCM and extracted. 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 (270mg, 0.95mmol, 65% yield).

Step 10 preparation of (2-ethylpyridin-4-yl) methylamine

2-Ethylisonicotinitrile (2-ethylisonitinitrile) (400mg, 3.03mmol, 1 eq.) was dissolved in THF and cooled to-78 ℃. Then, LiAlH was added dropwise₄Solution of (1M in THF, 3.63mL, 3.63mmol, 1.2 equiv.). The reaction was carried out at-78 ℃ for 30 minutes with saturated Na ₂SO₄The solution was quenched and extracted with DCM. The organic layers were combined, washed with brine, dried, filtered off and concentrated in vacuo. The crude product was used without further purification for the next reaction. The product was obtained as a yellow oil (360mg, 2.64mmol, 87% yield). ESI-MS: 137[ M + H ]]⁺

¹H NMR(400MHz，DMSO-d6)δ8.37-8.34(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).

Step 11.1 preparation of 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

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 bis

Alkane and 2N NaOH (v/v 1: 10) and heated at 100 ℃ for 2 days. The mixture was diluted with 15% aqueous NaOH and CHCl₃iPrOH (v/v 3: 1). The organic layer was dried, filtered off and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound as an off-white solid (3mg, 0.006mmol, 6% yield). ESI-MS: 471[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ11.51(s，1H)，8.29-8.25(m，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.02(s，1H)，7.85(s，1H)，7.72(ddd，J＝8.6，6.9，1.6Hz，1H)，7.62(d，J＝8.5Hz，1H)，7.37(ddd，J＝8.1，6.9，1.0Hz，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).

Step 12 preparation of Ethyl 7-chloro-6-fluoro-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylate

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

3-chloro-4-fluoroaniline (2.5g, 17.17mmol, 1 equiv.) and diethylethoxymethylene malonate (3.47mL, 17.17mmol, 1 equiv.) were heated at 115 ℃ to 120 ℃ for 90 minutes. 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. Product as a white solid (5.10g, 16.17mmol, 94% yield). ESI-MS: 316[ M + H ] ]⁺

b. Ethyl 7-chloro-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester

Dowtherm A (100mL) was preheated at 250 ℃ and 1, 3-diethyl 2- { [ (3-chloro-4-fluorophenyl) amino]Methylene malonate (5.10g, 16.17mmol, 1 eq). The mixture was stirred at 250 ℃ for 3 hours under reflux. 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 at reflux for 30 minutes, cooled to room temperature, and the crystals were collected and dried. The product (3.50g, 13.13mmol, 81% yield) was used in the next step without further purification. ESI-MS: 268[ M + H]⁺

c. Ethyl 7-chloro-6-fluoro-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester

To ethyl 7-chloro-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acidTo the ester (1.00g, 3.71mmol, 1 eq) was added trimethyl phosphate (1.736mL, 14.83mmol, 4 eq) and anhydrous potassium carbonate (0.54g, 3.89mmol, 1.05 eq). The mixture was stirred at 190 ℃ for 2 hours, then cooled to 100 ℃ 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). Product as a white solid (0.70g, 2.48mmol, 67% yield). ESI-MS: 284[ M + H ] ]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.66(s，1H)，8.06(d，J＝6.1Hz，1H)，7.98(d，J＝9.4Hz，1H)，4.22(q，J＝7.1Hz，2H)，3.91(s，3H)，1.28(t，J＝7.1Hz，3H).

Step 13.1-cyclopropyl-6, 7-difluoro-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde preparation

1-cyclopropyl-6, 7-difluoro-1, 2, 3, 4-tetrahydroquinolin-4-one

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

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

1-cyclopropyl-6, 7-difluoro-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized following the procedure outlined in step 7e, substituting 1-cyclopropyl-6, 7-difluoro-1, 2, 3, 4-tetrahydroquinolin-4-one for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -1, 2, 3, 4-tetrahydroquinolin-4-one. The product after FCC was reacted with Et ₂Trituration of O with hexanes afforded the title compound as an off-white solid (1.17g, 4.69mmol, 15% yield). ESI-MS: 250[ M + H ]]⁺

¹H NMR(400MHz，DMSO-d₆)δ10.12(s，1H)，8.41(s，1H)，8.23(dd，J＝12.1，6.7Hz，1H)，8.15(dd，J＝10.5，8.8Hz，1H)，3.69(tt，J＝7.3，4.0Hz，1H)，1.32-1.23(m，2H)，1.18-1.11(m，2H).

Step 14.1 preparation of 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

a.4-chloroquinoline-3-carbaldehyde

POCl was added dropwise to anhydrous DMF (20mL) at 0 deg.C₃(8.27mL, 88.8mmol, 6 equiv.). 1- (2-aminophenyl) ethan-1-one (2.00g, 14.8mmol, 1 eq.) in anhydrous DMF (5mL) was then added dropwise and the reaction was heated at 60 ℃ for 4 h. After this time, the reaction was cooled to 0 ℃ and quenched with water. Then saturated NaHCO₃The solution was neutralized with aqueous solution, diluted in water and extracted with DCM. The layers were separated. The organic layer was washed with MgSO₄Dried, filtered off and concentrated in vacuo to afford the title compound as an orange solid (1.43g, 7.49mmol, 51% yield), which was sent to the next step without additional purificationAnd (5) carrying out a step. ESI-MS: 192[ M + H ]]⁺

4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

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

¹H NMR(400MHz，DMSO-d₆)δ12.69(s，1H)，10.20(s，1H)，8.49(s，1H)，8.22(dd，J＝8.0，1.5Hz，1H)，7.77(m，1H)，7.67(dd，J＝8.3，1.1Hz，1H)，7.48(m，1H).

1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.50g, 2.89mmol, 1 eq.) was suspended in THF (13 mL). DBU (1.01g, 7.22, 2.5 equivalents) was added followed by methyl iodide (4.10g, 28.8mmol, 10 equivalents). The reaction was carried out at 40 ℃ for 2 hours. After this time, the reaction was quenched with water and extracted with DCM. The layers were separated. The organic layer was dried over MgSO4, filtered off and concentrated in vacuo. The residue was purified by crystallization from hot EtOH to provide the title compound as an off-white solid (0.36g, 1.94mmol, 67% yield). ESI-MS: 188[ M + H ]]⁺

¹H NMR(400MHz，DMSO-d₆)δ10.19(s，1H)，8.63(s，1H)，8.31(dd，J＝8.0，1.6Hz，1H)，7.87(m，1H)，7.80(dd，J＝8.6，1.1Hz，1H)，7.57(m，1H)，3.98(s，3H).

Step 15.7-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 preparation

To (3S) -N- [ (2-methylpyridin-4-yl) methyl group in DCE (10mL) under an oxygen atmosphere]To (0.12g, 0.425mmol, 1 eq) of-1- (pyridin-3-yl) piperidin-3-amine was added 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.124g, 0.467mmol, 1.1 eq) and it was stirred for 1 hour. Next, NaBH (OAc) is added in portions₃(0.126g, 0.595mmol, 1.4 equiv.). The reaction was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was diluted with DCM and passed

Filtered and concentrated. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) and repurified by preparative HPLC to give the product as a yellow solid (0.080g, 0.043mmol, 35% yield). ESI-MS: 533.3[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.36-8.22(m，2H)，8.16(d，J＝6.1Hz，1H)，7.97(d，J＝9.4Hz，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＝11.8Hz，1H)，3.83-3.61(m，5H)，3.57-3.48(m，1H)，2.84(t，J＝11.3Hz，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).

Step 16.3 preparation of- ({ [5, 5-difluoro-1- (pyridin-3-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]Amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one (0.130g, 0.338mmol, 1 eq) 2-methylpyridine-4-carbaldehyde (0.053g, 0.440mmol, 1.3 equivalents), Na₂SO₄A mixture of (0.2g) and DCE (5mL) was stirred at room temperature overnight. Then, the mixture was cooled to 0 ℃ and NaBH (OAc) was added in 5 minutes₃(0.108g, 0.508mmol, 1.5 eq.) was portioned. Then, the reaction was carried out at 45 ℃ for 3 hours. Subsequently, the crude mixture is passed through

The pad was filtered, the pad was washed with DCM and the filtrate was partitioned between DCM and aqueous NaOH (10%). The organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and passed through RP-FCC (SiC 18; H)₂MeCN) to give the product as a yellow solid (0.050g, 0.102mmol, 30% yield). ESI-MS: 490.4[ M + H ]⁺

Step 17.1 preparation of methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (2-nitropyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

To 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3S) -piperidin-3-yl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one (0.080g, 0.212mmol, 1 eq.) in 1, 4-bis

To a solution in an alkane (1.5mL) was added 3-fluoro-2-nitropyridine (0.030g, 0.212mmol, 1 equiv.) and triethylamine (0.022g, 0.212mmol, 1 equiv.), and the resulting mixture was heated at 100 ℃ overnight. Subsequently, the mixture was evaporated, the residue was combined with the residue from a similar reaction (0.133mmol of starting material) and passed through RP-FCC (SiC 18; H)₂MeCN) to afford the product as an orange solid (0.117g, 0.345mmol, 68% yield). ESI-MS: 499.3[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.27(d，J＝5.0Hz，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.09(dd，J＝4.4，1.3Hz，1H)，7.98-7.89(m，2H)，7.77-7.59(m，3H)，7.38(ddd，J＝8.0，6.9，1.1Hz，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＝11.1Hz，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).

Step 18.3 preparation of- ({ [ (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]A mixture of amino } methyl) -1, 4-dihydroquinolin-4-one (0.05g, 0.143mmol, 1 eq.), 2, 6-dimethylpyridine-4-carbaldehyde (0.024g, 0.179mmol, 1.3 eq.), and DCM (3mL) was stirred at room temperature for 15 minutes. The reaction mixture was then cooled to 0 ℃ and NaBH (OAc) was added in portions ₃(0.076g, 0.359mmol, 2.5 equiv.). Thereafter, the reaction was carried out at room temperature overnight. Subsequently, the mixture was partitioned between DCM and water. The organic layer was passed through a pad of silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product as a beige solid (0.031g, 0.065mmol, 45% yield). ESI-MS: 468.3[ M + H]⁺

¹H NMR (300MHz, methanol-d₄)δ8.34(dd，J＝8.3，1.5Hz，1H)，8.24(d，J＝2.9Hz，1H)，7.95(s，1H)，7.90(dd，J＝4.7，1.3Hz，1H)，7.76(ddd，J＝8.6，6.9，1.6Hz，1H)，7.64(d，J＝8.5Hz，1H)，7.49-7.38(m，2H)，7.24(dd，J＝8.6，4.8Hz，1H)，7.01(s，2H)，4.05-3.94(m，1H)，3.84(s，3H)，3.81(d，J＝9.0Hz，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).

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

To 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3S) -piperidin-3-yl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one (0.100g, 0.266mmol, 1 eq.), 4-bromo-1-methyl-1, 2-dihydropyridin-2-one (0.060g, 0.319mmol, 1.2 eq.), Cs₂CO₃(0.173g, 0.531mmol, 2 equiv.) and 1, 4-bis

Pd was added to a degassed mixture of alkanes (3mL)₂(dba)₃(0.012g, 0.013mmol, 0.1 equiv.) and Xantphos (0.014g, 0.024mmol, 0.1 equiv.). The reaction was carried out at 100 ℃ overnight. Then, the mixture is passed through

Pad filtered, stirred with MPA scavenger for 30 minutes, filtered and concentrated. The residue was partitioned between DCM and water. The aqueous layer was additionally basified with NaOH solution (15%) and made up with CHCl ₃iPrOH (3: 1) extraction. The organic layer was washed with anhydrous Na₂SO₄Dried, 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 (0.077g, 0.159mmol, 60% yield). ESI-MS: 484.7[ M + H]+

¹H NMR(300MHz，DMSO-d₆)δ8.28(d，J＝5.0Hz，1H)，8.18(d，J＝8.0Hz，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＝7.6，2.6Hz，1H)，5.50(d，J＝2.7Hz，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＝12.1Hz，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).

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

Reacting 7-chloro-1-cyclopropyl-6-fluoro-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl][ (2-methylpyridin-4-yl) methyl]A mixture of amino } methyl) -1, 4-dihydro-1, 8-naphthyridin-4-one (0.061g, 0.112mmol, 1 equiv.) and 2N NaOH (4mL) was heated at 100 ℃ for 16 hours. After this time, 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, washed with water

Filtered and passed through RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a white powder (0.026g, 0.049mmol, 44% yield). ESI-MS: 529.7[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.21(d，J＝5.2Hz，1H)，8.07(d，J＝2.9Hz，1H)，7.75-7.71(m，2H)，7.33(dd，J＝8.6，3.0Hz，1H)，7.28(s，1H)，7.26-7.22(m，1H)，7.11(d，J＝8.6Hz，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).

Step 21.1 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

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-dihydro-1, 8-naphthyridin-4-one (0.061g, 0.112mmol, 1 equiv.) to a solution in MeOH (4mL) was added MeONa (0.03g, 0.558mmol, 5 equiv.). The suspension was stirred at 80 ℃ for 16 hours. After this time, 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, washed with water

Filtered and passed through RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a white powder (0.037g, 0.066mmol, 60% yield). ESI-MS: 543.2[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.17(d，J＝5.2Hz，1H)，8.10(d，J＝9.9Hz，1H)，8.08(d，J＝2.9Hz，1H)，7.96(s，1H)，7.35(dd，J＝8.6，3.0Hz，1H)，7.26(s，1H)，7.24-7.20(m，1H)，7.12(d，J＝8.6Hz，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).

Step 22.1 preparation of 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

To 7-chloro-1-cyclopropyl-6-fluoro-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl under an inert atmosphere][ (2-methylpyridin-4-yl) methyl]Amino } methyl) -1, 4-dihydroquinolin-4-one (0.1g, 0.183mmol, 1 eq), MeOH (0.074mL, 1.831mmol, 10 eq), and tBuONa (0).025g, 0.256mmol, 1.4 equiv.) in the presence of 1, 4-bis

To a solution in an alkane (1mL) were added tBuBrettPhos (0.007g, 0.015mmol, 0.08 eq.) and Pd₂(dba)₃(0.003g, 0.004mmol, 0.02 equiv.) of the mixture. The reaction was carried out at 70 ℃ for 16 hours. Subsequently, the mixture was diluted with AcOEt by

The pad was filtered and concentrated under reduced pressure. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and by RP-FCC (SiC18, H)₂O∶CH₃CN) and preparative HPLC. The title compound was isolated as the free base (0.036g, 0.066mmol, 36% yield). As a white powder product. ESI-MS: 542.4[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.16(d，J＝5.3Hz，1H)，8.09(d，J＝2.9Hz，1H)，7.95(s，1H)，7.89(d，J＝11.6Hz，1H)，7.51(d，J＝7.2Hz，1H)，7.35(dd，J＝8.6，3.0Hz，1H)，7.25(s，1H)，7.24-7.20(m，1H)，7.12(d，J＝8.6Hz，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).

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

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-bisHydroquinolin-4-one (0.1g, 0.183mmol, 1 equiv.), tert-butyl (2R) -2-methylpiperazine-1-carboxylate (0.055g, 0.275mmol, 1.5 equiv.), Cs₂CO₃(0.119g, 0.366mmol, 2 equiv.) in the presence of 1, 4-bis

Pd was added to a degassed solution in alkane (2.6mL) ₂(dba)₃(0.034g, 0.037mmol, 0.2 equiv.) and Xantphos (0.032g, 0.055mmol, 0.3 equiv.). The resulting mixture was degassed and the reaction was heated at 115 ℃ overnight under an inert atmosphere. Subsequently, the reaction mixture is passed through

Filtered, washed with DCM and passed through FCC (with NH)₃DCM-deactivated SiHP, DCM: MeOH 9: 1) to give the product as a yellow solid (0.055g, 0.077mmol, 42% yield). ESI-MS: 710.9[ M + H]⁺

Step 24.1 preparation of 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

To 7-chloro-1-cyclopropyl-6-fluoro-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl][ (2-methylpyridin-4-yl)]Methyl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one (0.100g, 0.183mmol, 1 eq), piperazine (0.032g, 0.366mmol, 2 eq), Cs₂CO₃(0.125g, 0.385mmol, 2.1 equiv.) in degassed solution of BINAP (0.034g, 0.055mmol, 0.3 equiv.) and Pd in DMF (3mL)₂(dba)₃*CHCl₃(0.038g, 0.037mmol, 0.2 equiv.). The reaction mixture was stirred at 115 ℃ overnight. Subsequently, the mixture was cooled to ambient temperature by

Pad filtered and applied DCM washing the pad. The filtrate was stirred with MPA scavenger for 15 minutes, filtered and evaporated. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) and repurified by preparative HPLC. Using DCM/NaHCO ₃Extracting with water solution, and extracting with anhydrous Na₂SO₄The product was obtained as the free base after drying the organic layer and evaporation. The title compound was isolated as a pale yellow solid (0.019g, 0.032mmol, 17% yield). ESI-MS: 596.8[ M + H]⁺。

Step 25.1 preparation of 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

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

To the 7-bromo-1-methyl-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl group placed in the reaction vessel][ (2-methylpyridin-4-yl) methyl]Amino } methyl) -1, 4-dihydroquinolin-4-one (0.050g, 0.091mmol, 1 eq.), tert-butyl 3-oxopiperazine-1-carboxylate (0.018g, 0.091mmol, 1 eq.), Xantphos (0.003g, 0.005mmol, 0.06 eq.), Cs₂CO₃(0.045g, 0.137mmol, 1.5 equiv.), Pd (OAc)₂(0.001g, 0.005mmol, 0.05 equiv.) of the degassed and dried mixture 1, 4-bis

Alkane (3mL) and the resulting mixture was stirred under an inert atmosphere at 90 ℃ for 16 hours. Subsequently, the mixture was combined with another from a similar reaction (same amount, heated for 2 hours) and Ac was used OEt dilution and Na addition₂CO₃And (4) washing with an aqueous solution. The combined organic fractions were washed with anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1). The sample obtained was dissolved in DCM and stirred with MPA scavenger for 10 minutes. The scavenger was filtered off and the filtrate was evaporated under reduced pressure to give the product as a beige powder (0.047g, 0.068mmol, 37% yield). ESI-MS: 666.8[ M + H]⁺

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).

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

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 (0.045g, 0.068mmol, 1 equiv.) in 1, 4-bis

To a stirred solution in an alkane (3mL) was added a bis

4M HCl in alkane (0.169mL, 0.676mmol, 10 equiv.) and the resulting mixture stirred at room temperature for 10 min. Subsequently, the reaction is carried outThe 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 (0.023g, 0.038mmol, 56% yield). ESI-MS: 566.3[ M + H ]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.31-8.27(m，1H)，8.16(d，J＝8.7Hz，1H)，8.14(d，J＝3.1Hz，1H)，8.01(s，1H)，7.56(d，J＝1.9Hz，1H)，7.36(dd，J＝8.7，1.8Hz，1H)，7.26-7.19(m，3H)，7.01(d，J＝8.5Hz，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).

Step 26.3 preparation of- ({ [ (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

1- (Oxetan-3-yl) -4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

To a solution of 3-iodooxetane (0.728g, 3.955mmol, 1.37 equiv.) in DMF (13.3mL) was added 4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.500g, 2.887mmol, 1 equiv.) and K₂CO₃(1.596g, 11.549mmol, 4 equiv.) and the resulting mixture was stirred at 120 ℃ for 1 day. Then, 3-iodooxetane (3-iodoxetan) (0.500g, 2.717mmol, 0.94 eq.) was added and the reaction mixture was heated at 120 ℃ for an additional 27 hours. Subsequently, the mixture is passed through

The pad was filtered and concentrated under reduced pressure. Passing the residue throughFCC (SiHP; DCM: MeOH 9: 1) and by RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a beige solid (0.037g, 0.139mmol, 21% yield). ESI-MS: 230.1[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ10.20(s，1H)，8.47(s，1H)，8.34(dd，J＝8.0，1.6Hz，1H)，7.83(ddd，J＝8.7，7.1，1.7Hz，1H)，7.60-7.55(m，1H)，7.51(d，J＝8.5Hz，1H)，5.82(p，J＝6.9Hz，1H)，5.13-5.06(m，2H)，5.00-4.94(m，2H).

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

Reacting (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl ]A mixture of piperidin-3-amine (0.060g, 0.202mmol, 1 eq), 1- (oxetan-3-yl) -4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.051g, 0.223mmol, 1.1 eq) and DCE (3mL) was stirred at 60 ℃ for 1.5 h. Then, add NaBH (OAc)₃(0.107g, 0.506mmol, 2.5 equiv.) and the reaction mixture was stirred at 60 ℃ for an additional 3 hours. After that, the mixture was partitioned between DCM and NaOH solution. The organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by preparative HPLC to give the product as a white solid (0.037g, 0.073mmol, 36% yield). ESI-MS: 510.3[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.38(dd，J＝8.2，1.5Hz，1H)，8.21(s，1H)，8.20-8.18(m，1H)，8.10(d，J＝3.0Hz，1H)，7.77-7.71(m，1H)，7.47(ddd，J＝8.0，7.0，1.0Hz，1H)，7.39(d，J＝8.9Hz，1H)，7.36(dd，J＝8.6，3.0Hz，1H)，7.32-7.29(m，1H)，7.29-7.25(m，1H)，7.12(d，J＝8.6Hz，1H)，5.80-5.72(m，1H)，5.20(td，J＝7.2，2.5Hz，2H)，4.86(t，J＝6.7Hz，2H)，3.96-3.87(m，5H)，3.66-3.56(m，1H)，3.08-2.95(m，1H)，2.89(t，J＝11.1Hz，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).

Step 27.2 preparation of- [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

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

A mixture of 4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.200g, 1.155mmol, 1.0 eq.) and methanol (10mL) was heated at 70 ℃ overnight. PTSA monohydrate (0.044g, 0.231mmol, 0.2 equiv.) was added and the resulting mixture was heated at 80 ℃ overnight and evaporated under reduced pressure. A portion of the crude material (0.100g) was dissolved in DMF (1mL) and potassium carbonate (0.113g, 0.821mmol) was added. The resulting mixture was stirred at room temperature for 5 minutes, then methyl bromoacetate (0.075mL, 0.794mmol) was added and the mixture was stirred at 60 ℃ for 1 hour. After that, the mixture was partitioned between water and DCM and the aqueous layer was extracted further with DCM. The combined organic layers were washed with brine, over anhydrous Na ₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by FCC (SiHP; hexane: DCM: EtOAc) to provide the product as a white solid (0.073g, 0.294 mmol). ESI-MS: 246.3[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ10.21(s，1H)，8.66(s，1H)，8.31(dd，J＝8.0，1.6Hz，1H)，7.81(ddd，J＝8.6，7.1，1.7Hz，1H)，7.63(d，J＝8.5Hz，1H)，7.55(ddd，J＝8.0，7.1，0.9Hz，1H)，5.43(s，2H)，3.72(s，3H).

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

Methyl 2- (3-formyl-4-oxo-1, 4-dihydroquinolin-1-yl) acetate (0.073g, 73mg, 0.298mmol, 1.0 eq), (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl ] acetate]A mixture of piperidin-3-amine (0.106g, 0.357mmol, 1.2 equiv.) and anhydrous DCE (5mL) was stirred at room temperature overnight. The reaction was then cooled to 0 ℃ and NaBH (OAc) added₃(0.076g, 0.357mmol, 1.2 eq.) and the mixture was stirred at room temperature for 100 min. Then NaBH (OAc) is added₃(0.076g, 0.357mmol, 1.2 equiv.) and the reaction mixture is heated at 40 ℃ to 50 ℃ for about 220 minutes during which time another portion of NaBH (OAc) is added₃(0.038g, 0.179mmol, 0.6 equiv.). The reaction mixture was then stirred at room temperature over the weekend. The DCE was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, over anhydrous Na ₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by FCC (SiHP; DCM: MeOH) to afford the product as a pale yellow glass (0.043g, 43mg, 0.076mmol, 26% yield). ESI-MS: 526.7[ M + H]⁺。

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

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 (0.043g, 0.082mmol, 1.0 equiv.), lithium hydroxide monohydrate (0.020g, 0.466mmol, 5.7 equiv.), methanol (5.043 g)mL) and water (1mL) were heated at 45 ℃ to 50 ℃ for 3 hours, and then stirred at room temperature overnight. 2M aqueous HCl (0.147mL, 3.6 equiv.) was added and the mixture was evaporated in vacuo. The residue is passed through FCC (C18 HP; H)₂MeCN) to afford the product as an off-white solid (0.030g, 0.058mmol, 71% yield). ESI-MS: 512.3[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.33(dd，J＝8.2，1.6Hz，1H)，8.21(dd，J＝5.1，0.9Hz，1H)，8.10-8.01(m，2H)，7.70(ddd，J＝8.6，6.9，1.6Hz，1H)，7.53(d，J＝8.7Hz，1H)，7.44-7.33(m，2H)，7.33-7.27(m，2H)，7.11(d，J＝8.6Hz，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).

Step 28.1 preparation of 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

To 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 (0.087g, 0.121mmol, 1 eq.) in 1, 4-bis

To a solution in an alkane (5mL) was added a bis

4M HCl in alkane (0.9mL, 3.615mmol, 30 equiv.) and the resulting mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was poured into water, basified with aqueous NaOH (2M) and extracted into DCM. The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to give the product as a white solid (0.034g, 0.055mmol, 45% yield). ESI-MS: 622.7[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.31-8.27(m，1H)，8.13(d，J＝3.0Hz，1H)，7.81(s，1H)，7.69(d，J＝13.7Hz，1H)，7.28(d，J＝7.5Hz，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＝24.0Hz，4H)，2.75(d，J＝7.8Hz，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).

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

a) Tert-butyl (3S) -3- { [ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl ] amino) piperidine-1-carboxylate

The title compound was synthesized according to the procedure outlined in step 4a substituting tert-butyl (3S) -3-aminopiperidine-1-carboxylate (1.5 equivalents) for (3S) -1- (pyridin-3-yl) piperidin-3-amine. After adding NaBH ₄After that, the mixture was stirred for 3 hours. Passing the residue through FCC (Al)₂O₃(ii) a DCM: MeOH ═ 9: 1) to give the product as a yellow solid (5.6g, 15.1mmol, 94% yield). AP-MS: 372.4[ M + H]⁺

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

Will be provided with

MS, tert-butyl (3S) -3- { [ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl]A mixture of amino } piperidine-1-carboxylic acid ester (3.0g, 8.1mmol, 1 eq), 2-methylpyridine-4-carbaldehyde (0.9g, 8.1mmol, 1 eq), and DCE (30mL) was stirred at room temperature overnight. The reaction mixture was then cooled to 0 ℃ and NaBH (OAc) was added₃(2.6g, 12.1mmol, 1.5 equiv.). Thereafter, the reaction was carried out at 45 ℃ for 3 hours. The mixture was then filtered through a pad of celite, washed with DCM and the filtrate concentrated in vacuo. The residue was partitioned between DCM and 10% aqueous NaOH. The aqueous layer was washed with DCM. The combined organic layers were washed with brine, over anhydrous MgSO₄Dried, filtered and concentrated in vacuo. The residue was purified by FCC (SiHP, DCM/MeOH) to give the product as a yellow oil (2.4g, 5.0mmol, 62% yield). ESI-MS: 477.6[ M + H ]⁺

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

Tert-butyl (3S) -3- { [ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl][ (2-methylpyridin-4-yl) methyl]Amino } piperidine-1-carboxylic acid ester (2.4g, 5.0mmol, 1 eq.) in 1, 4-bis

Solutions in alkane (20mL) were used in two

4M HCl in alkane (6.5mL, 25.2mmol, 5 equiv.). The resulting slurry was stirred throughout the weekend. Then will be reversedThe volatiles in the mixture were evaporated and the residue was partitioned between DCM and 15% aqueous NaOH. The organic layer was washed with brine and Na₂SO₄Dried, filtered and concentrated to give the product as a yellow oil (1.6g, 4.2mmol, 83% yield). ESI-MS: 377.5[ M + H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.29-8.23(m，1H)，8.18(dd，J＝8.1，1.6Hz，1H)，7.93(s，1H)，7.71(ddd，J＝8.6，6.9，1.7Hz，1H)，7.63-7.59(m，1H)，7.36(ddd，J＝8.0，6.9，1.0Hz，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＝12.3Hz，1H)，1.51-1.36(m，1H)，1.33-1.18(m，1H).

Step 30.3 preparation of- ({ [ (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- ({ [ (2-methylpyridin-4-yl) methyl)][ (3S) -piperidin-3-yl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one (0.12g, 0.3mmol, 1 eq.), 2, 4-dichloropyrimidine (0.052g, 0.4mmol, 1.1 eq.), K₂CO₃A mixture of (0.066g, 0.5mmol, 1.5 equiv.) and acetonitrile (2.5mL) was heated at 80 ℃ for 1.5 h. Then 2M aqueous NaOH was added and the reaction mixture was washed with DCM. The organics were washed with brine and Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiHP: DCM/MeOH) to give the product as a light yellow solid (0.076g, 0.2mmol, 49% yield). A sample of 0.026g was repurified by preparative HPLC to afford the compound as a formate salt as a light yellow solid (0.013g, 0.03mmol, 8% yield). ESI-MS: 489.2[ M + H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.28(d，J＝5.0Hz，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.15(s，1H)，8.03-7.97(m，2H)，7.71(ddd，J＝8，6，6.9，1.7Hz，1H)，7.64-7.60(m，1H)，7.37(ddd，J＝8.0，6.9，1.0Hz，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).

Step 31.preparation of 7-chloro-1-cyclopropyl-4-oxo-1, 4-dihydro-1, 6-naphthyridine-3-carbaldehyde

a)4, 6-dichloropyridine-3-carbonyl chloride

4, 6-dichloropyridine-3-carboxylic acid (1.0g, 5.2mmol, 1 eq.) and SOCl₂(4.0mL, 54.7mmol, 10.5 equiv.) was heated at 80 ℃ for 2 hours. The mixture was then cooled to room temperature and co-evaporated with DCM to give the product as a yellow oil (1.1g, 5.2mmol, 99% yield) which was used in the next step without further purification.

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

TEA (2.9mL, 20.8mmol, 4 equiv.) was added to acetonitrile (5mL), followed by ethyl 3- (dimethylamino) prop-2-enoate (1.1g, 7.8mmol, 1.5 equiv.) and 4, 6-dichloropyridine-3-carbonyl chloride (1.1g, 5.2mmol, 1 equiv.). The reaction mixture was stirred at 65 ℃ overnight, then cooled to room temperature and cyclopropylamine (0.4g, 7.9mmol, 1 eq) was added. The resulting mixture was heated at reflux for 3 hours and heating was continued overnight. Subsequently, the reaction mixture is concentrated Concentrate, dilute with EtOAc, sequentially with NaHCO₃Washing with aqueous solution, water, and brine, and adding anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by FCC (SiHP; Hex/AcOEt 0 to 100%) to give the product as a yellow solid (0.4g, 1.3mmol, 25% yield).

ESI-MS：293.8[M+H]⁺

¹H NMR(300MHz，DMSO-d6)δ9.07(s，1H)，8.50(s，1H)，8.01(s，1H)，4.24(q，J＝7.1Hz，2H)，3.62(tt，J＝7.2，3.9Hz，1H)，1.32-1.21(m，5H)，1.15-1.08(m，2H).

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

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

ESI-MS：265.8[M+H]⁺

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

The title compound was synthesized according to the procedure outlined in step 7d substituting 7-chloro-1-cyclopropyl-4-oxo-1, 4-dihydro-1, 6-naphthyridine-3-carboxylic acid for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid. The first stage of the reaction is extended to react with NaBH₄Stir together overnight while shortening the second stage with PTSA to 3 hours. Furthermore, DCM and NaHCO were used during the work-up₃The aqueous solution is washed. The residue after evaporation of the volatiles was purified by FCC (SiHP; Hex: AcOEt 4: 1) to obtain To product as a white solid (0.05g, 0.2mmol, 42% yield).

ESI-MS：223.0[M+H]⁺

e) 7-chloro-1-cyclopropyl-4-oxo-1, 2, 3, 4-tetrahydro-1, 6-naphthyridine-3-carbaldehyde

A mixture of MeONa (0.05g, 0.8mmol, 3.9 equiv.) and ethyl formate (0.07mL of 0.9mmol, 3.9 equiv.) was treated with a solution of 7-chloro-1-cyclopropyl-1, 2, 3, 4-tetrahydro-1, 6-naphthyridin-4-one (0.05g, 0.2mmol, 1 equiv.) in anhydrous DCM (5mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours and ice water was added. The organic layer was washed with 2M aqueous NaOH and the aqueous phase was acidified to pH 6 with concentrated HCl and washed with DCM. The combined organic extracts were extracted with MgSO₄Dried, filtered and concentrated to give the crude product as a yellow solid (0.053g, 0.2mmol, 94% yield), which was used directly in the next step.

ESI-MS：250.9[M+H]⁺

f) 7-chloro-1-cyclopropyl-4-oxo-1, 4-dihydro-1, 6-naphthyridine-3-carbaldehyde

7-chloro-1-cyclopropyl-4-oxo-1, 2, 3, 4-tetrahydro-1, 6-naphthyridine-3-carbaldehyde (0.053g, 0.2mmol, 1 eq) was dissolved in anhydrous MeOH (5mL) and MnO was added₂(0.09g, 1.1mmol, 5 equiv.). The reaction mixture was stirred at room temperature overnight. The volatiles in the mixture were then evaporated and 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 (0.036g, 0.1mmol, 68% yield).

AP-MS：249.0[M+H]⁺

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

Reacting 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 (0.06g, 0.1mmol, 1 eq.), 2- (cyclohex-1-en-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.046g, 0.2mmol, 2 eq.), Na₂CO₃(0.072g, 0.2mmol, 2 equiv.), bis

A mixture of alkane (3mL) and water (0.3mL) was purged with argon for 10 minutes. Pd (PPh) was then added₃)₄(0.006g, 0.005mmol, 0.05 equiv.) and the mixture was irradiated with microwaves at 140 ℃ for 1 hour. The reaction mixture was then filtered through a pad of celite. The residue is adsorbed on silica and passed through FCC (with NH)₃DCM deactivated SiHP; DCM: MeOH 8: 2) and repurification by preparative HPLC to give the product as a white solid (0.031g, 0.05mmol, 47% yield).

ESI-MS：592.7[M+H]⁺

Step 33.3 preparation of 3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one

Charging a dry reactor vessel with (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl]Piperidin-3-amine (0.342g, 1.2mmol, 1 eq), 4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.2g, 1.2mmol, 1 eq), and anhydrous DCE (10 mL). The reaction was carried out at 60 ℃ for 2 hours and then cooled to 0 DEG C. Addition of NaBH (OAc)₃(0.34g, 1.6mmol, 1.4 equiv.) and the reaction mixture was stirred at room temperature overnight. Then additional NaBH (OAc) is added₃(0.122g, 0.6mmol, 0.5 equiv.) the reaction was heated while stirring at 50 ℃ for an additional 12 hours. Followed by addition of H₂O, followed by addition of NaHCO₃And the resulting mixture was washed with DCM. The organic layer was washed with brine and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and additionally by RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a pale yellow powder (0.29g, 0.6mmol, 51% yield). 0.12g of the sample was repurified by preparative HPLC. The collected fractions were neutralized with 1N aqueous NaOH, extracted with EtOAc and washed with anhydrous Na₂SO₄Dried and concentrated in vacuo. The residue was suspended in water and lyophilized to give the product as a beige powder (0.08g, 0.2mmol, 14% yield).

ESI-MS：454.2[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ11.68(s，1H)，8.30(d，J＝5.1Hz，1H)，8.12(d，J＝3.1Hz，1H)，8.11-8.09(m，1H)，7.94(s，1H)，7.60(ddd，J＝8.5，6.9，1.6Hz，1H)，7.50(d，J＝8.3Hz，1H)，7.32-7.17(m，4H)，7.01(d，J＝8.5Hz，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).

Step 34.1-cyclopropyl-6-fluoro-7-hydroxy-3- ({ [ (3S) -l- (6-methylpyridin-3-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one

Reacting 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 (0.1g, 0.2mmol, 1 eq.), 1,4-two

Alkane (1mL) and H₂A mixture of O (1mL) was purged with argon, followed by the addition of KOH (0.013g, 0.2mmol, 1.3 equivalents), tBuXPhos (0.006g, 0.015mmol, 0.08 equivalents), and Pd₂(dba)₃(0.003g, 0.004mmol, 0.02 eq.). The reaction vial was capped and the reaction mixture was heated at 100 ℃ for 75 minutes. The mixture was then purged again with argon and additional KOH (0.006g, 0.1mmol, 0.6 equiv.), tBuXPhos (0.006g, 0.015mmol, 0.08 equiv.) and Pd were added₂(dba)₃(0.003g, 0.004mmol, 0.02 eq.) and the reaction was continued at 100 ℃ for 2 hours. Then H is added₂O, and reacting the mixture in DCM and NH₄And partitioning between Cl aqueous solutions. The aqueous layer was washed with additional 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) as an off-white solid ][ (2-methylpyridin-4-yl) methyl]Amino } methyl) -1, 4-dihydroquinolin-4-one (0.055g, 0.1mmol, 57% yield).

ESI-MS：528.3[M+H]⁺

¹H NMR(300MHz，DMSO-d6)δ10.97(s，1H)，8.28(d，J＝5.0Hz，1H)，8.13(d，J＝2.9Hz，1H)，7.78(s，1H)，7.74(d，J＝11.5Hz，1H)，7.44(d，J＝7.5Hz，1H)，7.28-7.12(m，3H)，7.02(d，J＝8.5Hz，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).

Step 35.8 preparation of 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

a)3- [ (2-bromophenyl) amino ] propionic acid

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

b) 8-bromo-1, 2, 3, 4-tetrahydroquinolin-4-one

Reacting 3- [ (2-bromophenyl) amino group at 60 DEG C]Propionic acid (2.7g, 12.0mmol, 1 eq) was added in one portion to polyphosphoric acid (14.46mL, 78.4mmol, 7.1 eq). The resulting mixture was heated at 110 ℃ for 12 hours with stirring. The reaction mixture was slowly poured into ice water. The solution was washed with EtOAc (4X 100 mL). The organic layer was sequentially washed with saturated NaHCO₃The solution, water and brine were washed with anhydrous Na ₂SO₄Dried, 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 (0.518g, 2.3mmol, 21% yield).

ESI-MS：225.9[M+H]⁺

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

c) 8-bromo-1-methyl-1, 2, 3, 4-tetrahydroquinolin-4-one

Will K₂CO₃(0.7g, 5.2mmol, 3 equiv.) is added to a solution of 8-bromo-1, 2, 3, 4-tetrahydroquinolin-4-one (0.46g, 1.7mmol, 1 equiv.) in anhydrous DMF (10mL) and the resulting mixture is stirred at room temperature for 20 minutes. Subsequently, methyl iodide (0.22mL, 3.5mmol, 2 equiv.) was added and the mixture was heated at 120 ℃ overnight. The reaction mixture was then cooled to room temperature and additional K was added₂CO₃(0.7g, 5.2mmol, 3 equiv.) and methyl iodide (0.22mL, 3.5mmol, 2 equiv.). The mixture was heated at 120 ℃ overnight. The reaction mixture was then cooled again to room temperature and an additional amount of K was added₂CO₃(0.7g, 5.2mmol, 3 equiv.) and methyl iodide (0.215mL, 3.5mmol, 2 equiv.). The mixture was heated at 120 ℃ over the weekend. DMF was then 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 (0.105g, 0.4mmol, 25% yield).

ESI-MS：239.9[M+H]⁺

d) 8-bromo-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

In a dry round bottom flask, 8-bromo-1-methyl-1, 2, 3, 4-tetrahydroquinolin-4-one (0.105g, 0.4mmol, 1 eq.) and ethyl formate (0.106mL, 1.3mmol, 3 eq.) are combined in dry THF (4mL) under an inert atmosphere. 1M NaHMDS (1.2mL, 0.7mmol, 1.7 equiv.) in THF was then 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). MnO of₂(0.013g, 0.2mmol, 0.5 equiv.) was added to the above methanol solution and stirred at room temperature for 3 hours, followed by stirring for another 20 hours. Subsequently, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by FCC (SiHP; DCM: MeOH 95: 5) to give asProduct as a brown solid (0.03g, 0.1mmol, 23% yield).

ESI-MS：265.9[M+H]⁺

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

8-bromo-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.063g, 0.2mmol, 1 eq.) dissolved in anhydrous DCE (1.5mL) and (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl- ] dissolved in anhydrous DCE (1.5mL) ]Piperidin-3-amine (0.084g, 0.3mmol, 1.2 equivalents) was added dropwise to each other in the reaction vial. The solution was purged with argon for 10 minutes. AcOH drops were added dropwise through the syringe needle followed by the addition of a crop of dried MgSO₄And the resulting mixture was again purged with argon. The reaction vial was capped and the reaction mixture was stirred at room temperature for 3.5 hours. The mixture was then cooled in an ice NaCl bath and NaBH (OAc) was added in portions₃(0.09g, 0.4mmol, 1.8 equiv.). The reaction mixture was heated at 55 ℃ for 3 hours. Anhydrous DCE (1mL) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was then 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 RP-FCC (Si-C18; H)₂O/ACN) to give the product as a colorless oil (0.012g, 0.02mmol, 9% yield).

ESI-MS：546.3[M+H]⁺

Step 36.7 preparation of chloro-6-fluoro-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1- (prop-2-yl) -1, 4-dihydro-1, 8-naphthyridin-4-one

a) Ethyl 2- (2, 6-dichloro-5-fluoropyridine-3-carbonyl) -3- (dimethylamino) propan-2-enoic acid ester

2, 6-dichloro-5-fluoropyridine-3-carboxylic acid (5.4g, 25.8mmol, 1 eq.) was suspended in SOCl₂(9.4mL, 129.2mmol, 5.0 equiv.) and the reaction mixture was stirred at 80 ℃ for 2 hours, during which time the mixture became a clear solution. The reaction mixture was co-concentrated with DCM. The residue was added to a mixture of ethyl 3- (dimethylamino) prop-2-enoate (3.7mL, 25.8mmol, 1 eq), DIPEA (9.5mL, 54.3mmol, 2.1 eq) and toluene (20mL) at room temperature over 5 min. The resulting solution was stirred at room temperature for 15 minutes and then heated after that time at 90 ℃ for 3.5 hours. The reaction mixture was then washed with DCM and H₂And (4) distributing among the O. The washed organic layer was washed with anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by FCC (SiHP; Hex/AcOEt) to give the product as an orange oil (2.8g, 8.4mmol, 32% yield).

ESI-MS：335.0[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.04(d，J＝7.9Hz，1H)，7.95(s，1H)，3.91(q，J＝7.1Hz，2H)，3.39(s，3H)，2.93(s，3H)，0.94(t，J＝7.1Hz，3H).

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

2- (2, 6-dichloro-5-fluoropyridine-3-carbonyl) -3- (dimethylamino) prop-2-enoate (1.05g, 3.1mmol, 1 eq) in EtOH (16mL) and Et₂A solution in a mixture of O (6mL) was treated with propan-2-amine (0.3mL, 3.4mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 15 minutes. Then evaporating the solvent to obtain To the crude product as orange oil (1.2g, 3.4mmol, 99% yield), it was used in the next step without further purification.

ESI-MS：349.0[M+H]⁺

c) 7-chloro-6-fluoro-4-oxo-1- (prop-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid ester

Reacting 2- (2, 6-dichloro-5-fluoropyridine-3-carbonyl) -3- [ (prop-2-yl) amino]A solution of prop-2-enoic acid ester (0.85g, 2.6mmol, 1 eq) in ACN (8mL) was dissolved with K₂CO₃(0.5g, 3.8mmol, 1.6 equiv.) and the reaction mixture is stirred at 80 ℃ for 2 h. Thereafter by addition of H₂And O, quenching the reaction. The reaction mixture was then washed with water using different solvents (ACN, NMP and DMAc)]The same conditions were set up but from a smaller amount of 2- (2, 6-dichloro-5-fluoropyridine-3-carbonyl) -3- [ (propan-2-yl) amino]Three other crude mixtures of experimental reactions starting with prop-2-enoate (0.1g, 0.3mmol) were mixed. The resulting mixture was washed with DCM. The combined organic layers were over anhydrous MgSO₄Dried, filtered and concentrated. The residue was dissolved in 5mL DCM and heptane was added. The precipitate was filtered off and dried under vacuum to provide ethyl 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (0.81g, 2.6mmol, 85% yield) as an off-white solid.

ESI-MS：313.9[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.71(s，1H)，8.48(d，J＝7.9Hz，1H)，5.53-5.43(m，1H)，4.26(q，J＝7.1Hz，2H)，1.50(s，3H)，1.49(s，3H)，1.29(t，J＝7.1Hz，3H).

d) 7-chloro-6-fluoro-4-oxo-1- (prop-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid

Ethyl 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (0.81g, 2.6mmol, 1 eq), concentrated aqueous HCl (2mL), H₂O (6mL) and 1, 4-bis

A mixture of alkanes (12mL) was stirred at 100 ℃ for 4 hours. Subsequently, the reaction mixture was cooled to room temperature and the precipitate was filtered off and dried to give the product as an off-white solid (0.67g, 0.2mmol, yield 90%) which was used in the next step without further purification.

¹H NMR (400MHz, DMSO-d6) δ 14.40(s, 1H), 9.01(s, 1H), 8.73(d, J ═ 7.6Hz, 1H), 5.61 (heptad, J ═ 6.4Hz, 1H), 1.56(d, J ═ 6.7Hz, 6H).

e) 7-chloro-6-fluoro-1- (prop-2-yl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridin-4-one and 6-fluoro-7-methoxy-1- (prop-2-yl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridin-4-one

The title compound was synthesized following the procedure outlined in step 7d substituting 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and shortening the second stage to heating at reflux for 1.5 hours. The residue after concentrating 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 (0.46g, 0.1mmol, yield 81%) as a yellow solid,

ESI-MS：243.1[M+H]⁺

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

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

ESI-MS：239.3[M+H]⁺

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

f) 7-chloro-6-fluoro-4-oxo-1- (prop-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carbaldehyde

7-chloro-6-fluoro-1- (propan-2-yl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridin-4-one (0.46g, 1.9mmol, 1 equiv.) dissolved in anhydrous THF (2mL) was added to a solution of NaHMDS (2M in THF, 1.1mL, 2.3mmol, 1.2 equiv.) in anhydrous THF (2mL) at 0 ℃. The reaction mixture was stirred at the same temperature for 30 minutes and a solution of ethyl formate (0.2mL, 2.5mmol, 1.3 equivalents) in THF (2mL) was added. The reaction mixture was stirred for 1 hour, then saturated NH was added₄The reaction was quenched with aqueous Cl. The mixture was washed with AcOEt. The aqueous layer was further washed with AcOEt (× 3). The combined organic layers were washed with anhydrous Na ₂SO₄Dried, filtered, concentrated and dried under reduced pressure. Dissolving the residue in anhydrous 1, 4-bis

To an alkane (10mL) and MnO was added₂(0.82g, 9.5mmol, 4.2 equiv.). The resulting mixture was heated to 50 ℃ and stirred for 16 hours. 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 (0.29g, 1.1mmol, 57% yield) as a yellow solid.

AP-MS：269.0[M+H]⁺

¹H NMR(400MHz, DMSO-d6) δ 10.14(s, 1H), 8.68(s, 1H), 8.58(d, J ═ 7.7Hz, 1H), 5.51 (heptad, J ═ 6.7Hz, 1H), 1.52(d, J ═ 6.8Hz, 6H).

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

The dry reactor vessel was charged with (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl group in DCE (10mL)]Piperidin-3-amine (0.31g, 1.0mmol, 1.0 equiv.) and 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carbaldehyde (0.29g, 1.0mmol, 1.0 equiv.). The mixture was heated at 50 ℃ for 4 hours and then cooled to 0 ℃. Add NaBH (OAc) } ₃(0.43g, 2.0mmol, 2.0 equiv.) and the resulting mixture was stirred at room temperature for 16 hours. Subsequently, with H₂O and NaHCO₃The reaction mixture was quenched with aqueous solution and washed with DCM. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated in vacuo. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1). The product was passed through FCC (SiHP; DCM/MeOH/NH)₃) And RP-FCC (Si-C18; h₂O/ACN) to give the product as a white solid (0.40g, 0.7mmol, 70% yield).

ESI-MS：549.4[M+H]⁺

¹H NMR (400MHz, methanol-d 4) δ 8.42-8.34(m, 1H), 8.24-8.15(m, 2H), 8.06(d, J ═ 3.0Hz, 1H), 7.34(dd, J ═ 8.6, 3.0Hz, 1H), 7.30(s, 1H), 7.27-7.22(m, 1H), 7.11(d, J ═ 8.6Hz, 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), 2.22-2.00 (m, 1H), 2.77-2.53 (m, 1H), 1H), 1.7-2.53 (m, 1H).

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

1, 3-dimethyl-1H-pyrazole-5-carbaldehyde (0.076g, 0.6mmol, 1.1 equiv.) and 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ]A solution of amino } methyl) -1, 4-dihydroquinolin-4-one in DCE (5.0mL) was stirred at 60 ℃ for 1 hour. Then NaBH (OAc) is added₃(0.3g, 1.4mmol, 2.5 equivalents) and the reaction mixture was stirred at 60 ℃ for 24 h. After this time, the reaction was quenched by addition of 1M NaOH (50 mL). The resulting mixture was then washed with DCM (3X 50 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried, 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 (0.14g, 0.3mmol, 53% yield).

ESI-MS：457.5[M+H]⁺

¹H NMR(300MHz，DMSO-d6)δ8.30(d，J＝3.0Hz，1H)，8.20(dd，J＝8.0，1.6Hz，1H)，7.92(dd，J＝4.5，1.3Hz，1H)，7.87(s，1H)，7.72(ddd，J＝8.5，6.8，1.6Hz，1H)，7.64(d，J＝8.5Hz，1H)，7.38(ddd，J＝8.0，6.8，1.1Hz，1H)，7.29(ddd，J＝8.6，3.1，1.4Hz，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).

Step 38.1 preparation of 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

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

A mixture of ethyl 3- (dimethylamino) prop-2-enoate (0.6mL, 4.2mmol, 1 equiv.) and DIPEA (1.5mL, 8.8mmol, 2.1 equiv.) was stirred at room temperature and a solution of 4-bromo-2-fluorobenzoyl chloride (0.57mL, 4.2mmol, 1 equiv.) in toluene (5mL) was added over 5 minutes. The yellow solution was placed in an oil bath at 85 ℃ to 90 ℃. After heating for 3 hours, the mixture was washed with DCM and H ₂And (4) diluting with oxygen. The separated organic layer was washed with anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by FCC (SiHP; Hex: AcOEt 2: 3) to give the title product as a yellow oil (1.24g, 3.6mmol, 81% yield).

ESI-MS：344.0[M+H]⁺

b) Ethyl 7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester

Reacting ethyl 2- [ 4-bromo-2-fluorobenzoyl]-3- (dimethylamino) prop-2-enoate (1.24g, 3.6mmol, 1 eq) and cyclopropylamine (0.4mL, 4.7mmol, 1.3 eq) were heated in toluene (10mL) at 110 ℃ for 2 h. The reaction mixture was concentrated and the residue was diluted in DMF (8 mL). Then, K is added₂CO₃(1.2g, 9.0mmol, 2.5 equiv.) and the resulting mixture was heated at 100 ℃ overnight. After cooling, the reaction mixture was diluted with DCM, washed with water, brine, and anhydrous Na₂SO₄Dried, filtered and evaporated. The residue was purified by FCC (SiHP; Hex: AcOEt 1: 4) to give the title product as a yellow solid (0.97g, 3.3mmol, 88% yield).

AP-MS：336.0[M+H]⁺

c) 7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

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

ESI-MS：308.0[M+H]⁺

d) 7-bromo-1-cyclopropyl-1, 2, 3, 4-tetrahydroquinolin-4-one

The title compound was synthesized according to the procedure outlined in step 7d substituting 7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid. The first stage of the reaction is extended to react with NaBH₄Stir together overnight and shorten the second with PTSA to 3 hours at room temperature. In addition, washing was performed using DCM. The crude product was purified by FCC (SiHP; Hex: AcOEt 1: 1) to give the title product as a yellow solid (0.52g, 2.0mmol, 65% yield).

ESI-MS：266.0[M+H]+

e) 7-bromo-1-cyclopropyl-4-oxo-1, 2, 3, 4-tetrahydroquinoline-3-carbaldehyde

The title compound was synthesized according to the procedure outlined in step 31e substituting 7-bromo-1-cyclopropyl-1, 2, 3, 4-tetrahydroquinolin-4-one for 7-chloro-1-cyclopropyl-1, 2, 3, 4-tetrahydro-1, 6-naphthyridin-4-one and using 4.0 equivalents of MeONa and ethyl formate. The reaction time was reduced to 3 hours and MgSO₄As a desiccant. The title compound was obtained as an orange solid (0.44g, 1.4mmol, 91% yield).

AP-MS：294.0[M+H]⁺

f) 7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized according to the procedure outlined in step 31f substituting 7-chloro-1-cyclopropyl-4-oxo-1, 2, 3, 4-tetrahydroquinoline-3-carbaldehyde with 7-bromo-1-cyclopropyl-4-oxo-1, 2, 3, 4-tetrahydro-1, 6-naphthyridine-3-carbaldehyde. The reaction time was extended to stir over the weekend. The reaction mixture was passed directly through a pad of celite and the pad was washed thoroughly with a DCM/MeOH mixture. FCC purification (SiHP; DCM: MeOH 95: 5) afforded the title compound (0.17g, 0.6mmol, 98% yield) as a yellow solid.

AP-MS：292.0[M+H]⁺

g) Tert-butyl 3- (1-cyclopropyl-3-formyl-4-oxo-1, 4-dihydroquinolin-7-yl) morpholine-4-carboxylate

7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde (0.03g, 0.1mmol, 1 eq.) and 4- [ (tert-butoxy) carbonyl]Morpholine-3-carboxylic acid (0.07g, 0.3mmol, 3.0 equivalents), [4, 4 ' -bis (1, 1-dimethylethyl) -2, 2 ' -bipyridine-N1, N1 ']Bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl-N]phenyl-C]A mixture of iridium (III) hexafluorophosphate (0.001g, 0.001mmol, 0.01 equiv.), 4 '-di-tert-butyl-2, -2' bipyridine (0.004g, 0.015mmol, 0.148 equiv.) and nickel (II) chloride dimethoxyethane adduct (0.002g, 0.009mmol, 0.09 equiv.) was stirred under argon at room temperature in a Penn PhDM2 photoreactor (100% LED) for 1 hour. The reaction mixture was evaporated in vacuo. The residue was suspended in DCM, washed with water, and dried over anhydrous Na ₂SO₄Dried and evaporated in vacuo. The residue was purified by FCC (SiHP; Hex: AcOEt 1: 1) to give the title product as a white solid (0.024g, 0.06mmol, 56% yield).

ESI-MS：399.6[M+H]⁺

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

Tert-butyl 3- (1-cyclopropyl-3-formyl-4-oxo-1, 4-dihydroquinolin-7-yl) morpholine-4-carboxylate (0.024g, 0.06mmol, 1 eq.) and (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl]Piperidin-3-amine (0.027g, 0.08mmol, 1.5 equiv.) is suspended in DCE (5 mL). After 30 minutes, add NaBH (OAc)₃(0.034g, 0.2mmol, 2.8 equivalents) and the resulting mixture was stirred at room temperature overnight. The residue was passed through FCC (RF-C18 column, ACN/H)₂O) purification to give the title product as a white solid: (0.017g, 0.02mmol, 42% yield).

ESI-MS：679.6[M+H]⁺

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

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 (0.017g, 0.02mmol, 1 eq) was dissolved in anhydrous 1, 4-bis

In an alkane (2 mL). Will be provided withThe solution was cooled in an ice bath and added dropwise to

4M HCl in alkane (1 mL). The reaction mixture was concentrated. The residue was then diluted with DCM and NaHCO₃The organic layer was washed and evaporated. The residue was lyophilized to give the title product 1-cyclopropyl-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl) as a white solid][ (2-methylpyridin-4-yl) -methyl]Amino } methyl) -7- (morpholin-3-yl) -1, 4-dihydroquinolin-4-one (0.009g, 0.02mmol, 62% yield).

ESI-MS：579.5[M+H]⁺

¹H NMR (400MHz, methanol-d 4) δ 8.28(d, J ═ 8.3Hz, 1H), 8.16(d, J ═ 5.1Hz, 1H), 8.11-8.08(m, 2H), 8.01(s, 1H), 7.52-7.45(m, 1H), 7.36(dd, J ═ 8.6, 3.0Hz, 1H), 7.25-7.21(m, 2H), 7.12(d, J ═ 8.6Hz, 1H), 4.11(dd, J ═ 10.1, 3.3Hz, 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), 3.83 (m, 2H), 2.90 (m, 2H), 3.75-3.8 (m, 1H), 1H), 3.8.8.6H, 1H), 1.74-1.61(m, 2H), 1.39-1.28(m, 2H), 0.97-0.89(m, 2H).

Preparation example:

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

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

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

ESI-MS：278.4[M+H]⁺

Preparation of (3S) -1- (pyridin-3-yl) piperidin-3-amine

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

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

The title compound was synthesized according to step 4a 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 (942mg, 3.2mmol, 62% yield). ESI-MS: 299.3[ M + H]⁺

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

Using (3S) -N- [ (2-methoxypyridin-4-yl) methyl according to step 4b ]-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-methyl-4-oxo-1, 4-dihydroquinolin-3-carbaldehyde was used instead of 3-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was passed through RP-FCC (SiC 18; H)₂O: MeCN) to afford the product as a yellow powder (1.15g, 2.0mmol, 65% yield). ESI-MS: 470.2[ M + H]⁺

¹H NMR(400MHz，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).

Example 2.1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

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

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

Preparation of 1- (pyridin-3-yl) piperidin-3-amines

With tert-butyl N- [1- (pyridin-3-yl) piperidin-3-yl according to step 1b]Carbamate instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate to synthesize the title compound. The product was obtained as the hydrochloride salt (111mg, 0.500mmol, 43% yield). ESI-MS: 178.15[ M + H ]⁺

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

The title compound was synthesized following the procedure outlined in step 4a substituting 2-methylpyridine-4-carboxaldehyde for 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxaldehyde 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 provide the product as a colorless oil (50mg, 0.17mmol, 41% yield). ESI-MS: 283[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.36-8.31(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).

Aliphatic H overlaps with the solvent peak.

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

According to the method outlined in step 4bMethod using DCM as solvent and 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-methyl-4-oxo-1, 4-dihydroquinolin-3-carbaldehyde was used instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to provide the product as a colorless oil (28mg, 0.06mmol, 33% yield). ESI-MS: 454[ M + H ]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.32-8.28(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).

Aliphatic H overlaps with the solvent peak.

EXAMPLE 3.3- ({ [ (2-methoxypyridin-4-yl) methyl ] [1- (pyridazin-3-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4 one

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

The title compound was synthesized following the procedure outlined in step 4a substituting 2-methoxypyridine-4-carbaldehyde for 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde and tert-butyl 3-aminopiperidine-1-carboxylate 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 yellow oil (3795g, 7.556mmol, 26% yield). ESI-MS: 322.3[ M + H]⁺

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

Following the procedure outlined in step 4b, tert-butyl 3- { [ (2-methoxypyridin-4-yl) methyl was used]Amino } piperidine-1-carboxylic acid ester instead 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-dihydroquinolin-3-carbaldehyde was used instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was passed through RP-FCC (SiC18, H) ₂MeCN) to afford the product as a light yellow powder (363mg, 0.722mmol, 25% yield). ESI-MS: 493.80[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.22-8.17(m，1H)，8.02-7.98(m，1H)，7.97(s，1H)，7.72(ddd，J＝8.6，6.9，1.7Hz，1H)，7.65-7.60(m，1H)，7.38(ddd，J＝8.0，6.9，1.0Hz，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).

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

Following the procedure outlined in step 2b, tert-butyl 3- { [ (2-methoxypyridin-4-yl) methyl was used][ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl]Amino } piperidine-1-carboxylic acid ester instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate to synthesize the title compound. The product is the free base. The product was obtained as a yellow oil (650mg, 1.656mmol, 22% yield). ESI-MS: 393.3[ M + H ]]⁺

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

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 (30mg, 0.06mmol, 31% yield). ESI-MS: 471[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.49-8.46(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).

Some aliphatic H overlaps with the solvent peak.

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

¹H NMR (400MHz, 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), 2.05-1H), 1.95-1H (m, 1H).

Aliphatic H overlaps with the solvent peak.

Example 4.3- ({ [ (2-methoxypyridin-4-yl) methyl ] [1- (pyrazin-2-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

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

¹H NMR(300MHz，DMSO-d₆)δ8.33(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).

Some aliphatic H overlaps with the solvent peak.

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

¹H NMR (400MHz, 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), 1.05-1H, 1H), 1.75-1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1, 2H, 1H, 2H, 1H, 2H, 1, 2H, 1, 2, 1H, 2H, 1, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1.

Aliphatic H overlaps with the solvent peak.

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

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

The title compound was synthesized according to the procedure outlined in step 4a substituting tert-butyl (3S) -3-aminopiperidine-1-carboxylate for (3S) -1- (pyridin-3-yl) piperidin-3-amine. The residue was passed through FCC (neutral Al)₂O₃DCM: MeOH 9: 1) to afford the product as a yellow solid (5.600g, 15.07mmol, 94% yield). ESI-MS: 372.2[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.23(dd，J＝8.1，1.6Hz，1H)，8.11(s，1H)，7.78(ddd，J＝8.5，6.8，1.6Hz，1H)，7.73-7.64(m，1H)，7.43(ddd，J＝8.0，6.8，1.2Hz，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).

Some aliphatic H overlaps with the solvent signal.

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

Following the procedure outlined in step 4b, tert-butyl (3S) -3- { [ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl was used]Amino } piperidine-1-carboxylic acid ester instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one. After addition of the reducing agent, the reaction was continued at 45 ℃ for 3 hours. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to provide the title compound (610mg, 1.280mmol, 86% yield) as a pale yellow solid. ESI-MS: 477.5[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.27(d，J＝5.0Hz，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，7.95(s，1H)，7.72(ddd，J＝8.5，6.9，1.6Hz，1H)，7.62(d，J＝8.5Hz，1H)，7.38(ddd，J＝7.9，6.8，1.1Hz，1H)，7.22-7.08(m，2H)，4.05(br s，1H)，3.82(s，3H)，3.70(s，2H)，3.59(d，J＝2.8Hz，2H)，2.36(s，3H)，1.97(d，J＝12.6Hz，1H)，1.67(d，J＝12.6Hz，1H)，1.53(br s，1H)，1.33(brs，11H).

Some aliphatic H overlaps with the solvent signal.

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

Following the procedure outlined in step 1b, tert-butyl (3S) -3- { [ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl was used][ (2-methylpyridin-4-yl) methyl]Amino } piperidine-1-carboxylic acid ester instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate to synthesize the title compound. The title compound was obtained as the free base. Product as a white powder (375mg, 1.000mmol, 79% yield). ESI-MS: 377.5[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.26(dd，J＝4.9，0.9Hz，1H)，8.18(dd，J＝8.1，1.6Hz，1H)，7.94(s，1H)，7.72(ddd，J＝8.6，6.9，1.7Hz，1H)，7.62(dd，J＝8.8，1.0Hz，1H)，7.37(ddd，J＝8.0，6.8，1.1Hz，1H)，7.18(dd，J＝6.9，1.6Hz，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).

Some aliphatic H overlaps with the solvent signal.

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

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

¹H NMR(300MHz，DMSO-d₆)δ8.61(d，J＝5.9Hz，1H)，8.58(d，J＝2.7Hz，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＝8.6Hz，1H)，7.44(ddd，J＝8.0，6.8，1.0Hz，1H)，4.49(d，J＝12.6Hz，1H)，4.40(s，2H)，4.04(s，2H)，3.94(d，J＝13.1Hz，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).

Example 6.3- ({ [ (2-methoxypyridin-4-yl) methyl ] [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

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

Following the procedure outlined in step 2a, tert-butyl N- [ (3S) -piperidin-3-yl was used]Carbamate instead of tert-butyl N- (piperidin-3-yl) carbamate the title compound was synthesized. The residue was purified by FCC (SiHP, Hex: AcOEt 1: 9) to give the product as a yellow oil (575mg, 1.90mmol, 7% yield). ESI-MS: 278[ M + H ]⁺

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

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

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

The title compound was synthesized following the procedure outlined in step 4a, using TEA as base, 2-methoxypyridine-4-carbaldehyde instead of 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde and (3S) -1- (pyridin-3-yl) piperidin-3-amine hydrochloride instead 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 (0.94g, 3.20mmol, 62% yield). ESI-MS: 299[ M + H [ ]]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.30-8.22(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).

Aliphatic H overlaps with the solvent peak.

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

Following the procedure outlined in step 4b, using a mixture of DCE: DMF (v/v 5: 7) as solvent, with (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 4-oxo-1, 4-dihydroquinolin-3-carbaldehyde was used instead of 2-methoxypyridine-4-carbaldehyde to synthesize the title compound. The residue was purified by preparative HPLC to provide the product as a yellow solid (85mg, 0.20mmol, 48% yield). ESI-MS: 456[ M + H ] ]⁺

¹H NMR(400MHz，DMSO-d₆)δ11.77-11.65(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).

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

Following the procedure outlined in step 9b, 5-bromo-2-methylpyridine was used instead of 7-bromo-1-methyl-1, 4-dihydroquinolin-4-one, and 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3S) -piperidin-3-yl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one instead of 1-methylpiperazine with 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (Sphos) and tris (dibenzylideneacetone) dipalladium (0) (Pd)₂dba₃) Instead of 2-dicyclohexylphosphine-2 ', 6' dimethoxybiphenyl [2- (2 '-amino-1, 1' -biphenyl ]]Palladium (II) methanesulfonate (spoos Pd 3G) to synthesize the title compound.

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

¹H NMR(400MHz，DMSO-d₆)δ8.31-8.27(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).

Aliphatic H overlaps with the solvent peak.

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

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

¹H NMR(400MHz，DMSO-d₆)δ8.34(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).

Aliphatic H overlaps with the solvent peak.

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

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

Following the procedure outlined in step 4b, (3S) -1- (pyridin-3-yl) piperidin-3-amine was used in place of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidine-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one and 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinolin-3-carbaldehyde was used instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. Product as a yellow solid (55mg, 0.11mmol, 77% yield). ESI-MS: 491[ M + H ]⁺

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

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

¹H NMR(400MHz，DMSO-d₆)δ8.27(d，J＝3.0Hz，1H)，8.01(d，J＝5.2Hz，1H)，7.92(dd，J＝4.6，1.3Hz，1H)，7.83(s，1H)，7.69(d，J＝13.6Hz，1H)，7.33(d，J＝7.5Hz，1H)，7.28(ddd，J＝8.5，3.0，1.3Hz，1H)，7.15(dd，J＝8.5，4.5Hz，1H)，6.97(dd，J＝5.3，1.3Hz，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).

Some aliphatic H overlaps with the solvent signal.

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

Following the procedure outlined in step 4b, 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl) -was used]Amino } methyl) -1, 4-dihydroquinolin-4-one instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by preparative HPLC to provide the product as a yellow solid (13mg, 0.02mmol, 31% yield). ESI-MS: 596[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.30-8.25(m，2H)，7.92(dd，J＝4.5，1.3Hz，1H)，7.82(s，1H)，7.70(d，J＝13.6Hz，1H)，7.33(d，J＝7.5Hz，1H)，7.28(ddd，J＝8.6，3.1，1.3Hz，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).

Some aliphatic H overlaps with the solvent signal.

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

Following the procedure outlined in step 4b, 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 1-cyclopropyl-6, 7-difluoro-4-oxo-1, 4-dihydroquinolin-3-carbaldehyde was used instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was purified by preparative HPLC to provide the product as a white solid (0.60g, 1.14mmol, 58% yield). The product was converted to the hydrochloride salt. ESI-MS: 532[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.43(d，J＝3.1Hz，1H)，8.11-7.96(m，5H)，7.89(d，J＝5.3Hz，1H)，7.70(dd，J＝8.9，5.3Hz，1H)，6.96(d，J＝5.3Hz，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).

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

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

Following the procedure outlined in step 4b, (3S) -1- (pyridin-3-yl) piperidin-3-yl was substituted for 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl with (3S) -1- (pyridin-3-yl) piperidin-3-amine]Amino } methyl) -1, 4-dihydroquinolin-4-one. The reaction was allowed to proceed overnight without the use of molecular sieves before the addition of sodium triacetoxyborohydride. The residue was purified by FCC (SiHP, DCM: MeOH 0-25%) to afford the crude product as a yellow oil (1.7g, 6.02mmol, 66% yield, 84% purity). ESI-MS: 283[ M + H]⁺

Following the procedure outlined in step 4b, 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-dihydroquinolin-3-carbaldehyde was used instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was purified by preparative HPLC to provide the product as a yellow solid (0.34g, 0.65mmol, 28% yield). ESI-MS: 516[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.29(d，J＝3.0Hz，1H)，8.22(d，1H)，8.07(dd，J＝10.8，8.7Hz，1H)，8.01(s，1H)，7.99-7.93(m，2H)，7.64(ddd，J＝8.7，3.0，1.2Hz，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).

Some aliphatic H overlaps with the solvent signal.

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

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

¹H NMR(300MHz，DMSO-d₆)δ8.31-8.25(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).

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

Following the procedure outlined in step 5, with 5-bromo-2-nitropyrazinePyridine instead of 3-bromopyridazine and 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3S) -piperidin-3-yl radical]Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl with amino } methyl) -1, 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one. The residue was passed through FCC (SiC18, H)₂O: MeCN) to provide the title compound as a yellow solid (0.08g, 0.27mmol, 60% yield). ESI-MS: 499[ M + H ]]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.30(dd，J＝4.9，0.9Hz，1H)，8.26(d，J＝3.0Hz，1H)，8.19(dd，J＝8.0，1.6Hz，1H)，8.08(d，J＝9.3Hz，1H)，8.03(s，1H)，7.72(ddd，J＝8.5，6.8，1.6Hz，1H)，7.63(d，J＝8.3Hz，1H)，7.45(dd，J＝9.3，3.1Hz，1H)，7.37(ddd，J＝8.0，6.8，1.1Hz，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).

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

Following the procedure outlined in step 6, sodium tert-butoxide was used as base and di

Alkane as solvent, 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ][ (3S) -piperidin-3-yl radical]Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl with amino } methyl) -1, 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one and 3-bromo-4-fluoropyridine instead of 3-chloropyrazine. The residue was passed through FCC (SiC18, H)₂O: MeCN) to provide the title compound (21 mg) as a yellow solid0.03mmol, 16% yield). The product was converted to the hydrochloride salt. ESI-MS: 532 and 534[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆) δ 8.79(s, 1H), 8.60(d, J ═ 6.0Hz, 1H), 8.48(d, J ═ 6.7Hz, 1H), 8.26(s, 1H), 8.16(dd, J ═ 8.0, 1.6Hz, 1H), 8.08-7.91(m, 2H), 7.78(ddd, J ═ 8.6, 6.8, 1.6Hz, 1H), 7.68(d, J ═ 8.6Hz, 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), 3.01(m, 2H), 3.53 (m, 1H), 2H), 3.53-3.53 (m, 1H), 1H, 3.7H, 7H, 5H, 1H, 5H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, and some of the aliphatic signals overlap.

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

Following the procedure outlined in step 5, 3-bromopyridazine was replaced with 5-bromo-2-fluoropyridine and 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ][ (3S) -piperidin-3-yl radical]Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl with amino } methyl) -1, 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one. The residue was passed through FCC (SiC18, H)₂O: MeCN) to provide the title compound as a yellow solid (6mg, 0.013mmol, 55% yield). ESI-MS: 472[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.29(d，J＝5.1Hz，1H)，8.20(dd，J＝8.1，1.5Hz，1H)，8.02(s，1H)，7.84-7.81(m，1H)，7.72(ddd，J＝8.5，6.8，1.6Hz，1H)，7.65-7.53(m，2H)，7.41-7.34(m，1H)，7.26-7.21(m，2H)，6.98(dd，J＝8.9，3.5Hz，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).

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

The title compound was synthesized according to the procedure outlined in step 6, using MeCN as solvent, replacing 3-chloropyrazine with 4, 6-dichloropyrimidine. The residue was purified by preparative HPLC to provide the title compound as a yellow solid (120mg, 0.25mmol, 62% yield).

¹H NMR(400MHz，DMSO-d₆) δ 8.30-8.26(m, 2H), 8.19(dd, J ═ 8.0, 1.6Hz, 1H), 8.00(s, 1H), 7.71(ddd, J ═ 8.6, 6.9, 1.7Hz, 1H), 7.62(d, J ═ 8.6Hz, 1H), 7.37(ddd, J ═ 8.0, 6.9, 1.0Hz, 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), 2.37.95 (s, 2H), 1.95-1H), 1.79 (m, 1H), aliphatic signals (m, 1H), 1H, and a solvent.

The product was converted to the hydrochloride salt. ESI-MS: 490[ M + H [ ]]⁺

¹H NMR (400MHz, deuterium oxide) δ 8.14(s, 1H), 8.10(dd, J ═ 8.2, 1.5Hz, 1H), 8.01(d, J ═ 5.8Hz, 1H), 7.91(s, 1H), 7.85-7.79(m, 1H), 7.61(d, J ═ 8.6Hz, 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), 1.67-1.54H).

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

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

The title compound was synthesized following the procedure outlined in step 4a, substituting 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde with 1-methyl-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carbaldehyde. The crude was used in the next step without further purification. ESI-MS: 428[ M + H]⁺

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

Following the procedure outlined in step 4b, 1-methyl-7- (4-methylpiperazin-1-yl) -3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl) -was used]Amino } methyl) -1, 4-dihydroquinolin-4-one instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by preparative HPLC to provide the product as a yellow solid (35mg, 0.06mmol, 22% yield). ESI-MS: 552[ M + H ]]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.31-8.27(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).

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

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

¹H NMR(400MHz，DMSO-d₆)δ8.28(d，J＝5.0Hz，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.03-7.97(m，2H)，7.71(ddd，J＝8.6，6.9，1.7Hz，1H)，7.64-7.60(m，1H)，7.37(ddd，J＝8.0，6.9，1.0Hz，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).

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

Following the procedure 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 radical]Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl with amino } methyl) -1, 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one. The residue was purified by preparative HPLC to provide the product as a yellow oil (40mg, 0.08mmol, 62% yield). ESI-MS: 484[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.61-8.56(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).

Example 21.3- ({ [ (2-ethylpyridin-4-yl) methyl ] [1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

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

Following the procedure outlined in step 4b, using DCM as solvent and (2-ethylpyridin-4-yl) methylamine in place 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 instead of 2-methylpyridine-4-carbaldehyde. The crude product was used in the next step without further purification. The product was obtained as a golden oil (723mg, 2.26mmol, 98% yield). ESI-MS: 320[ M + H ] ]⁺

¹H NMR(300MHz，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 signal.

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

Following the procedure outlined in step 4b, using DCM as solvent, tert-butyl 3- { [ (2-ethylpyridin-4-yl) methyl]Amino } piperidine-1-carboxylic acid ester instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one and the replacement of 2-methylpyridine-4-carboxaldehyde with 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxaldehydeTo the title compound. The residue was purified by FCC (SiHP, DCM: MeOH 95: 5) to give the product as a gold oil (50mg, 0.10mmol, 39% yield). ESI-MS: 491[ M + H]⁺

¹H NMR (300MHz, methanol-d₄) δ 8.42-8.32(m, 1H), 8.21(d, J ═ 5.1Hz, 1H), 8.05(d, J ═ 33.4Hz, 1H), 7.86-7.74(m, 2H), 7.67(d, J ═ 8.6Hz, 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 ═ 7Hz, 2H), 2.21-2.09(m, 1H), 1.83-1.61(m, 2H), 1.9 (m, 1H), 1H, 9(m, 1H), 1H, 26(m, 1H), 1H, 14H, 26H, 14H, and an aliphatic signal.

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

Following the procedure outlined in step 1b, tert-butyl 3- { [ (2-ethylpyridin-4-yl) methyl was used][ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl]Amino } piperidine-1-carboxylic acid ester instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate, with Et₂2N HCl in o instead of two

The title compound was synthesized as 4M HCl in an alkane. The crude product was used in the next step without further purification. The product was obtained as a yellow oil (40mg, 0.10mmol, 42% yield). ESI-MS: 391[ M + H]⁺

¹H NMR(300MHz，DMSO-d_s)δ8.32-8.28(m，1H)，8.19(dd，J＝8.0，1.6Hz，1H)，7.94(s，1H)，7.76-7.67(m，1H)，7.62(d，J＝8.5Hz，1H)，7.41-7.33(m，1H)，7.22-7.17(m，2H)，3.82(s，3H)，3.81-3.77(m，1H)，3.70(s，2H)，3.14-3.05(m，1H)，2.87-2.77(m，1H)，2.65(q，2H)，2.59-2.54(m，1H)，2.41-2.31(m，2H)，2.02-1.89(m，2H)，1.72-1.60(m，1H)，1.53-1.39(m，2H)，1.38-1.27(m，2H)，1.13(t，J＝7.6Hz，3H)，

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

Following the procedure outlined in step 3, using 3- ({ [ (2-ethylpyridin-4-yl) methyl](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one in place of 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3S) -piperidin-3-yl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by FCC (SiHP, DCM: MeOH, 95: 5) to give the product as a yellow solid (20mg, 0.042mmol, 42% yield). ESI-MS: 468[ M + H ]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.35-8.28(m，2H)，8.23-8.16(m，1H)，8.05(s，1H)，7.94-7.88(m，1H)，7.76-7.68(m，1H)，7.66-7.59(m，1H)，7.41-7.34(m，1H)，7.32-7.23(m，3H)，7.18-7.12(m，1H)，4.02-3.92(m，1H)，3.86(s，3H)，3.80-3.74(m，2H)，3.73-3.67(m，1H)，3.66-3.54(m，2H)，2.91-2.79(m，1H)，2.71-2.60(m，4H)，2.07-1.96(m，1H)，1.81-1.72(m，1H)，1.65-1.40(m，2H)，1.15(t，J＝7.6Hz，3H).

Example 22.1-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

The title compound was synthesized following the procedure outlined in step 11. The residue was purified by FCC (SiHP, DCM: MeOH) and repurified by preparative HPLC to provide the product as a beige solid (3mg, 0.006mmol, 6% yield). ESI-MS: 471[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ11.51(s，1H)，8.29-8.25(m，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.02(s，1H)，7.85(s，1H)，7.72(ddd，J＝8.6，6.9，1.6Hz，1H)，7.62(d，J＝8.5Hz，1H)，7.37(ddd，J＝8.1，6.9，1.0Hz，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).

EXAMPLE 23.7-bromo-1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

Preparation of 7-bromo-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized according to the procedure outlined in step 9c substituting 7-bromo-1-methyl-1, 4-dihydroquinolin-4-one for 1-methyl-7- (4-methylpiperazin-1-yl) -1, 4-dihydroquinolin-4-one. The residue was triturated with ethyl acetate to give the product as a yellow powder (2.02g, 7.59mmol, 71%). ESI-MS: 267[ M + H]⁺

¹H NMR(300MHz，DMSO-d_a)δ10.15(s，1H)，8.61(s，1H)，8.22-8.15(m，1H)，8.06-8.00(m，1H)，7.75-7.68(m，1H)，3.96(s，3H).

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

The title compound was synthesized following the procedure outlined in step 4a substituting 7-bromo-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde for 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde. The residue was purified by FCC (SiHP, DCM: MeOH 4: 1) to give the product as a yellow solid (474mg, 1.11mmol, 98% yield). ESI-MS: 428[ M + H ]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.32-8.26(m，1H)，8.14-8.10(m，1H)，8.06(s，1H)，7.95-7.92(m，1H)，7.91-7.89(m，1H)，7.57-7.53(m，1H)，7.32-7.27(m，1H)，7.20-7.14(m，1H)，3.83(s，3H)，3.80-3.75(m，1H)，3.67(s，2H)，3.58-3.52(m，1H)，2.82-2.72(m，1H)，2.69-2.56(m，3H)，1.90(d，J＝9.7Hz，1H)，1.80-1.69(m，1H)，1.60-1.44(m，1H)，1.35-1.20(m，1H).

Preparation of 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

Following the procedure outlined in step 4b, using 7-bromo-1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl)]Amino } methyl) -1, 4-dihydroquinolin-4-one instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to give the product as a yellow solid (380mg, 0.71mmol, 62% yield). The product was converted to the hydrochloride salt. ESI-MS: 534[ M + H ]]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.31-8.27(m，2H)，8.09(d，J＝8.6Hz，1H)，8.02(s，1H)，7.94-7.90(m，1H)，7.87-7.85(m，1H)，7.56-7.50(m，1H)，7.33-7.21(m，3H)，7.19-7.13(m，1H)，3.99-3.91(m，1H)，3.85(s，3H)，3.82-3.53(m，5H)，2.90-2.80(m，1H)，2.75-2.64(m，2H)，2.38(s，3H)，2.04-1.96(m，1H)，1.81-1.74(m，1H)，1.64-1.40(m，2H).

¹H NMR (300MHz, deuterium oxide) Δ 8.35-8.31(m, 1H), 8.23-8.19(m, 1H), 8.05(s, 1H), 8.00-7.93(m, 2H), 7.91-7.87(m, 2H), 7.83-7.78(m, 2H), 7.72-7.66(m, 1H), 7.65-7.61(m, 1H), 4.66-4.59(m, 2H), 4.54-4.37(m, 2H), 4.12-4.05(m, 1H), 3.85-3.73(m, 4H), 3.66-3.51(m, 2H), 3.22-3.12(m, 1H), 2.44(s, 3H), 2.38-2.25(m, 1H), 2.23-1.98(m, 1H), 1.83-1H, 1H).

EXAMPLE 24.3- ({ [ (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

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

The title compound was synthesized according to the procedure outlined in step 4a substituting tert-butyl (3R, 4R) -3-amino-4-hydroxypiperidine-1-carboxylate for (3S) -1- (pyridin-3-yl) piperidin-3-amine. The crude product was purified by FCC (SiHP, DCM: MeOH) to provide the title compound (170mg, 0.05mmol, 93% yield) as a white solid. ESI-MS: 389[ M + H ]]⁺

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

Following the procedure outlined in step 4b, tert-butyl (3R, 4R) -4-hydroxy-3- { [ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl was used]Amino } piperidine-1-carboxylic acid ester instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to afford the product as a white solid (200mg, 0.41mmol, 93% yield). ESI-MS: 493[ M + H ]]⁺

¹H NMR(400MHz，DMSO-d₆) δ 8.27(dd, J ═ 8.1, 1.6Hz, 1H), 8.20-8.13(m, 1H), 8.04(s, 1H), 7.75(ddd, J ═ 8.6, 6.9, 1.6Hz, 1H), 7.64(d, J ═ 8.6Hz, 1H), 7.42(ddd, J ═ 8.0, 6.9, 1.0Hz, 1H), 7.06(s, 1H), 7.02(d, J ═ 5.0Hz, 1H), 6.00(d, J ═ 2.6Hz, 1H), 4.16-3.82(m, 5H), 3.79(s, 3H), 3.71-3.63(m, 1H), 3.20-3.14(m, 1H), 2.81-2.64(m, 2.24H), 2.19 (s, 3H), 3.09-3.63 (m, 1H), 1.14 (m, 1H), 2.81-2.64(m, 24H), 1H, and an aliphatic signal.

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

Following the procedure outlined in step 1b, tert-butyl (3R, 4R) -4-hydroxy-3- { [ (1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methyl was used][ (2-methylpyridin-4-yl) methyl]Amino } piperidine-1-carboxylic acid ester instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Synthesis of the title Compound from CarbamateA compound (I) is provided. The residue was used without further purification. Product as a yellow solid (157mg, 0.39mmol, 98% yield). ESI-MS: 393[ M + H ] in]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.26(dd，J＝8.1，1.6Hz，1H)，8.15(dd，J＝5.1，0.8Hz，1H)，8.02(s，1H)，7.74(ddd，J＝8.6，6.9，1.6Hz，1H)，7.62(d，J＝8.6Hz，1H)，7.41(ddd，J＝8.0，6.9，1.0Hz，1H)，7.08(s，1H)，7.05(d，J＝5.2Hz，1H)，5.81(d，J＝2.4Hz，1H)，4.09-4.03(m，1H)，3.78(s，3H)，3.75-3.67(m，2H)，3.57(s，6H)，3.16-307(m，2H)，2.85-2.78(m，1H)，2.24(s，3H)，1.89-1.81(m，1H).

Preparation of 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

Following the procedure outlined in step 5, 3-bromopyridazine was replaced with 3-bromopyridine and 3- ({ [ (3R, 4R) -4-hydroxypiperidin-3-yl][ (2-methylpyridin-4-yl) methyl]Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl with amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to give the product as a yellow solid (82mg, 0.17mmol, 53% yield). ESI-MS: 470[ M + H ] ]⁺

¹H NMR(400MHz，DMSO-d₆) δ 8.33(d, J ═ 3.0Hz, 1H), 8.29(dd, J ═ 8.1, 1.6Hz, 1H), 8.17(d, J ═ 5.1Hz, 1H), 8.06(s, 1H), 7.94(dd, J ═ 4.5, 1.3Hz, 1H), 7.76(ddd, J ═ 8.6, 6.9, 1.7Hz, 1H), 7.65(d, J ═ 8.6Hz, 1H), 7.45-7.40(m, 1H), 7.33(ddd, J ═ 8.5, 3.1, 1.4Hz, 1H), 7.17(dd, J ═ 8.5, 4.5Hz, 1H), 7.14(s, 1H), 7.10-7.92 (m, 1.5H), 1H (3.85H), 3.7.7.7.7.7 (d, 2-7.7.6H, 1H), 3.7.7.7.7.7H, 3.7.7H, 3.7.7.7 (d, 3.6H, 1H), 7.7.7.7H, 1H, 2H, 3.6H, 2 (13.7.7.7H), 3.6H, 2 m, 3.6H, 2 m, 3.7.7.7H, 3.7H, 3.6H, 2 m, 3, 3.6H, 1H, 3.6H, 2, 1H, 2, 1H, 3.6H, 2, 3.6H, 2, 1H, 2, 3.6H, 1H, 3.6H, 1H, 3.6H, 1H, 2, 3, 2 m, 3.6H, 3 m, 3, 3.6H, 2, 3.6H, 3, 2 m, 3.6 m, 3, 2 m, 3 m, 2 m, 3, 3.6H, 3, 2, 3 m, 2 m, 1H, 3, 2, 1H, 3.6H, 2, 3, 2 m, 3, 2, 3, 1H, 3, 3.6 m, 3, 2 m, 1H, 3, 1H, 2, 3, 2, 1H, 2 m, 3, 2, 3, 2, 1H, 2, 1H, 3, 2, 3, 2, 3, 2, 1H) 2.00-1.92(m, 1H), 1.47-1.33(m, 1H) some aliphatic hs overlap with the solvent signal.

EXAMPLE 25.7-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

Preparation of 7-chloro-6-fluoro-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

The title compound was synthesized according to the procedure outlined in step 7c substituting ethyl 7-chloro-6-fluoro-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylate for ethyl 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylate. The solvent was removed in vacuo. The mixture was acidified and the precipitate was collected and dried (0.60g, 2.34mmol, 95% yield). ESI-MS: 256[ M + H ] ]⁺

Preparation of 7-chloro-6-fluoro-1-methyl-1, 2, 3, 4-tetrahydroquinolin-4-one

The title compound was synthesized according to the procedure outlined in step 7d substituting 7-chloro-6-fluoro-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid. Product as a yellow solid (0.23g, 1.08mmol, 46% yield). ESI-MS: 214[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ7.51(d，J＝9.4Hz，1H)，7.05(d，J＝6.0Hz，1H)，3.46(dd，J＝7.7，6.5Hz，2H)，2.95(s，3H)，2.66(dd，J＝7.7，6.4Hz，2H).

Preparation of 7-chloro-6-fluoro-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized according to the procedure outlined in step 7e substituting 7-chloro-6-fluoro-1-methyl-1, 2, 3, 4-tetrahydroquinolin-4-one for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -1, 2, 3, 4-tetrahydroquinolin-4-one. The crude was purified by FCC (SiHP, Hex: AcOEt, 1: 1) to provide the desired product as a yellow solid (0.07g, 0.29mmol, 34% yield). ESI-MS: 240[ M + H ]]⁺

¹H NMR(400MHz，DMSO-d₆)δ10.15(s，1H)，8.63(s，1H)，8.15(d，J＝6，0Hz，1H)，8.10(d，J＝9.1Hz，1H)，3.97(s，3H).

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

Following the procedure outlined in step 4b, (3S) -1- (pyridin-3-yl) piperidin-3-yl was substituted for 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl with (3S) -1- (pyridin-3-yl) piperidin-3-amine]Amino } methyl) -1, 4-dihydroquinolin-4-one and 7-chloro-6-fluoro-1-methyl-4-oxo-1, 4-dihydroquinolin-3-carbaldehyde was used instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The crude was used directly in the next step. ESI-MS: 401[ M + H ]⁺

Preparation of 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

Following the procedure outlined in step 4b, using 7-chloro-6-fluoro-1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl)]Amino } methyl) -1, 4-dihydroquinolin-4-one instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to provide the desired product as yellow crystals (40mg, 0.08mmol, 63% yield). ESI-MS: 506[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.32-8.25(m，2H)，8.06(s，1H)，7.99-7.95(m，2H)，7.91(dd，J＝4.5，1.3Hz，1H)，7.32-7.26(m，1H)，7.25-7.21(m，2H)，7.15(dd，J＝8.5，4.5Hz，1H)，3.98-3.91(m，1H)，3.86(s，3H)，3.81-3.66(m，3H)，3.64-3.53(m，2H)，2.91-2.81(m.1H)，2.75-2.61(m，2H)，2.37(s，3H)，2.04-1.95(m，1H)，1.81-1.72(m，1H)，1.64-1.39(m，2H).

Example 26.3- ({ [ (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

Preparation of tert-butyl N- [ (3S, 5S) -5-fluoro-1- (pyridin-3-yl) piperidin-3-yl ] carbamate

Following the procedure outlined in step 5, 3-bromopyridine was used instead of 3-bromopyridazine and tert-butyl N- [ (3S, 5S) -5-fluoropiperidin-3-yl]Carbamate instead 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 (SiHP, DCM: MeOH, 9: 1) to give the product as a white solid (97mg, 0.33mmol, 72% yield). ESI-MS: 296[ M + H ] ]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.32-8.28(m，1H)，7.98-7.93(m，1H)，7.34-7.29(m，1H)，7.22-7.16(m，1H)，7.07-7.01(m，1H)，5.08-4.92(m，1H)，3.97-3.87(m，1H)，3.79-3.68(m，2H)，3.12-3.06(m，1H)，3.03-2.97(m，1H)，2.71-2.62(m，1H)，2.15-2.04(m，1H)，1.80-1.56(m，1H)，1.42(s，9H).

Preparation of (3S, 5S) -5-fluoro-1- (pyridin-3-yl) piperidin-3-amine

Following the procedure outlined in step 1b, tert-butyl N- [ (3S, 5S) -5-fluoro-1- (pyridin-3-yl) piperidin-3-yl was used]Carbamate instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate to synthesize the title compound. The crude product was used in the next step without further purification. The product was obtained as a yellow oil (64mg, 0.33mmol, 99% yield). ESI-MS: 195[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.31-8.26(m，1H)，7.96-7.90(m，1H)，7.33-7.26(m，1H)，7.22-7.15(m，1H)，5.08-4.86(m，1H)，3.95-3.79(m，1H)，3.77-3.67(m，1H)，3.21-3.15(m，1H)，3.09-2.97(m，2H)，2.18-2.04(m，1H)，1.73-1.58(m，2H)，1.57-1.47(m，1H)，1.43-1.33(m，1H).

Preparation of 3- ({ [ (3S, 5S) -5-fluoro-1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

Following the procedure outlined in step 4a, using (3S, 5S) -5-fluoro-1- (pyridin-3-yl) piperidin-3-amine instead 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 give the product as a yellow oil (68mg, 0.185mmol, 54% yield). ESI-MS: 485[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆) δ 8.32-8.28(m, 1H), 8.25-8.21(m, 1H), 8.08(s, 1H), 7.96-7.90(m, 1H), 7.79-7.71(m, 1H), 7.70-7.64(m, 1H), 7.44-7.37(m, 1H), 7.35-7.29(m, 1H), 7.20-7.13(m, 1H), 5.10-4.88(m, 1H), 3.85(s, 5H), 3.69(s, 2H), 3.18-2.88(m, 2H), 2.68-2.58(m, 1H), 2.14(s, 2H), 1.71-1.47(m, 1H). aliphatic H overlaps with the solvent signal.

Preparation of 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

Following the procedure outlined in step 4b, using DCM as solvent, 3- ({ [ (3S, 5S) -5-fluoro-1- (pyridin-3-yl) piperidin-3-yl)]Amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to afford the product as a yellow solid (50mg, 0.11mmol, 57% yield). ESI-MS: 472[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.33-8.29(m，2H)，8.23-8.18(m，1H)，8.08(s，1H)，7.93-7.90(m，1H)，7.76-7.70(m，1H)，7.66-7.62(m，1H)，7.42-7.36(m，1H)，7.33-7.24(m，3H)，7.18-7.13(m，1H)，5.14-4.98(m，1H)，4.07-3.93(m，2H)，3.87(s，3H)，3.83-3.71(m，2H)，3.71-3.59(m，2H)，3.10-2.88(m，3H)，2.39(s，3H)，2.30-2.21(m，1H)，2.03-1.82(m，1H).

Aliphatic H overlaps with the solvent signal.

Example 27.1-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

Preparation of tert-butyl N- [ (3S, 5R) -5-methyl-1- (pyridin-3-yl) piperidin-3-yl ] carbamate

Following the procedure outlined in step 5, 3-bromopyridine was used instead of 3-bromopyridazine and tert-butyl N- [ (3S, 5R) -5-methylpiperidin-3-yl]Carbamate instead 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 (SiHP, hexane 100% to AcOEt 100%) to give the product as a colorless oil (142mg, 0.49mmol, yield 70%). ESI-MS: 292[ M + H ]⁺

¹H NMR (300MHz, chloroform-d) δ 8.32(d, J ═ 2.9Hz, 1H), 8.07(dd, J ═ 4.6, 1.4Hz, 1H), 7.41-7.28(m, 1H), 7.20(dd, J ═ 8.4, 4.6Hz, 1H), 4.44(s, 1H), 4.04-3.95(m, 1H), 3.74(s, 1H), 3.67-3.51(m, 1H), 2.38(dt, J ═ 12.4, 10.6Hz, 2H), 2.07(s, 2H), 1.97-1.80(m, 1H), 1.49(s, 9H), 1.00(d, J ═ 6.6Hz, 3H).

Preparation of (3S, 5R) -5-methyl-1- (pyridin-3-yl) piperidin-3-amine

Following the procedure outlined in step 1b, tert-butyl N- [ (3S, 5R) -5-methyl-1- (pyridin-3-yl) piperidin-3-yl was used]Carbamate instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate to synthesize the title compound. Product as yellow oil (83mg, 0.47mmol, 92% yield). ESI-MS: 192[ M + H ]]⁺

Preparation of 1-methyl-3- ({ [ (3S, 5R) -5-methyl-1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

The title compound was synthesized following the procedure outlined in step 4a substituting (3S) -1- (pyridin-3-yl) piperidin-3-amine with (3S, 5R) -5-methyl-1- (pyridin-3-yl) piperidin-3-amine. Product as a white solid (120mg, 0.33mmol, 76% yield). ESI-MS: 363[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.29(d，J＝3.0Hz, 1H), 8.22(dd, J ═ 8.1, 1.6Hz, 1H), 8.08(s, 1H), 7.91(dd, J ═ 4.5, 1.3Hz, 1H), 7.80-7.71(m, 1H), 7.67(d, J ═ 8.5Hz, 1H), 7.46-7.35(m, 1H), 7.30(ddd, J ═ 8.5, 3.0, 1.4Hz, 1H), 7.16(dd, J ═ 8.5, 4.5Hz, 1H), 4.06-3.93(m, 1H), 3.85(s, 3H), 3.75-3.71(m, 1H), 3.68(s, 3H), 2.37-2.10(m, 3H), 1.95(d, 12.91, 7H), 3.6H, 6H), and some aliphatic signals overlap.

Preparation of 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

Following the procedure outlined in step 4b, 1-methyl-3- ({ [ (3S, 5R) -5-methyl-1- (pyridin-3-yl) piperidin-3-yl) -is used]Amino } methyl) -1, 4-dihydroquinolin-4-one instead of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl]Amino } methyl) -1, 4-dihydroquinolin-4-one. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to afford the product as a yellow solid (55mg, 0.12mmol, 63% yield). ESI-MS: 468[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.34-8.27(m，2H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.05(s，1H)，7.90(dd，J＝4.5，1.3Hz，1H)，7.77-7.68(m，1H)，7.66-7.56(m，1H)，7.38(ddd，J＝8.0，6.8，1.1Hz，1H)，7.33-7.22(m，3H)，7.14(dd，J＝8.5，4.5Hz，1H)，4.03-3.98(m，1H)，3.87(s，3H)，3.83-3.53(m，5H)，2.88-2.68(m，2H)，2.38(s，3H)，2.35-2.25(m，1H)，2.05-1.96(m，1H)，1.39-1.17(m，2H)，1.00-0.90(m，3H).

EXAMPLE 28.7-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

Preparation of 7-chloro-1-cyclopropyl-6-fluoro-1, 2, 3, 4-tetrahydroquinolin-4-one

The title compound was synthesized according to the procedure outlined in step 7d substituting 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid. The residue was purified by FCC (SiHP, Hex: AcOEt 2: 1). Product as a yellow solid (6.98g, 29.14mmol, 82% yield). ESI-MS: 240[ M + H ] ]⁺

¹H NMR(400MHz，DMSO-d₆)δ7.55(d，J＝9.3Hz，1H)，7.39(d，J＝6.2Hz，1H)，3.52(dd，J＝7.5，6.3Hz，2H)，2.61(dd，J＝7.5，6.3Hz，2H)，2.47-2.41(m，1H)，0.96-0.86(m，2H)，0.76-0.66(m，2H).

Preparation of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized according to the procedure outlined in step 7e substituting 7-chloro-1-cyclopropyl-6-fluoro-1, 2, 3, 4-tetrahydroquinolin-4-one for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -1, 2, 3, 4-tetrahydroquinolin-4-one. The crude was used directly in the next step without purification. The product obtained (3.86g, 14.53mmol, yield 60%) as a yellow solid. ESI-MS: 266[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ10.11(s，1H)，8.41(s，1H)，8.36(d，J＝6.1Hz，1H)，8.09(d，J＝9.1Hz，1H)，3.78-3.70(m，1H)，1.32-1.24(m，2H)，1.22-1.12(m，2H).

Preparation of 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

Following the procedure outlined in step 4b, 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 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinolin-3-carbaldehyde was used instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) to afford the product as a yellow solid (105mg, 0.19mmol, 57% yield). ESI-MS: 549[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.27(d，J＝2.9Hz，1H)，8.15(d，J＝6.2Hz，1H)，8.00-7.90(m，4H)，7.31-7.26(m，1H)，7.15(dd，J＝8.5，4.5Hz，1H)，6.95(dd，J＝5.3，1.3Hz，1H)，6.77(s，1H)，3.91-3.84(m，1H)，3.75(s，5H)，3.64(s，3H)，3.59-3.50(m，1H)，2.86-2.59(m，3H)，1.97(d，J＝10.8Hz，1H)，1.78(d，J＝11.9Hz，1H)，1.63-1.42(m，2H)，1.27-1.19(m，2H)，0.96-0.87(m，2H).

EXAMPLE 29 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

Following the procedure outlined in step 3, 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl) was replaced with methylpiperidine-4-carboxylate][ (3S) -piperidin-3-yl radical]Amino } methyl) -1, 4-dihydroquinolin-4-one and the use of 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 instead of 3-bromopyridine. The residue was purified by preparative HPLC to provide the product as a white powder (26mg, 0.04mmol, 23% yield). ESI-MS: 595[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.31-8.28(m，2H)，7.98-7.95(m，1H)，7.92-7.90(m，1H)，7.85(s，1H)，7.30-7.23(m，3H)，7.17-7.12(m，1H)，7.08-7.04(m，1H)，6.69-6.67(m，1H)，3.96-3.87(m，3H)，3.79-3.66(m，6H)，3.62(s，3H)，3.59-3.50(m，2H)，3.01-2.92(m，2H)，2.87-2.79(m，1H)，2.73-2.58(m，2H)，2.39(s，3H)，2.08(s，1H)，2.01-1.89(m，3H)，1.78-1.37(m，5H).

Example 30.1-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

Following the procedure outlined in step 5, 4-bromo-2-methylene-1, 2-dihydropyridine was used instead of 3-bromopyridazine and 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3S) -piperidin-3-yl radical]Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl with amino } methyl) -1, 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one. The residue was redissolved in DCM and washed with 15% NaOH. The product was purified by FCC (SiHP; DCM/MeOH) and passed through RP-FCC (SiC18, H) ₂O∶CH₃CN) to afford the title compound as a yellow oil (75mg, 0.16mmol, 60% yield). The product was converted to the hydrochloride salt. ESI-MS: 468[ M-H ]]^-

1H NMR(400MHz，DMSO-d6)δ12.91(s，1H)，8.59(d，J＝6.0Hz，1H)，8.25(s，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.00(s，1H)，7.97-7.93(m，1H)，7.77(ddd，J＝8.6，6.9，1.7Hz，1H)，7.73(d，J＝7.5Hz，1H)，7.67(d，J＝8.6Hz，1H)，7.43(ddd，J＝8.0，6.9，1.0Hz，1H)，6.85-6.80(m，1H)，6.40(s，1H)，4.39(d，J＝12.8Hz，1H)，4.29(s，2H)，3.96(s，1H)，3.93(s，2H)，3.85(s，3H)，3.41(t，J＝12.0Hz，1H)，3.06(t，J＝12.9Hz，1H)，2.95(s，1H)，2.58(s，3H)，2.15(d，J＝11.1Hz，1H)，1.87(d，J＝11.6Hz，2H)，1.44(d，J＝13.3Hz，1H).

Example 31.1-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

Preparation of tert-butyl N- [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl ] carbamate.

The title was prepared following the procedure outlined in step 1aAnd (3) obtaining the product. The product was additionally dissolved in DCM and stirred at room temperature overnight with addition of MPA scavenger. Subsequently passing the reaction mixture through

Filtration, washing with DCM and evaporation afforded the product as a yellow solid (1.85g, 6.35mmol, 64% yield). ESI-MS: 292.3[ M + H]⁺

Preparation of (3S) -1- (6-methylpyridin-3-yl) piperidin-3-amine

In analogy to step 1b, tert-butyl N- [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl is used]Carbamate instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate to synthesize the title compound. The reaction was carried out overnight at 45 ℃. Subsequently, the reaction mixture was basified with 15% NaOH, extracted with DCM, washed with brine, dried over sodium sulfate, filtered and evaporated to afford the product as an orange oil (1g, 5.23mmol, yield 82%) which was used in the next step without further purification. ESI-MS: 192.2[ M + H ]⁺

Preparation of 1-cyclopropyl-6, 7-difluoro-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

The title compound was synthesized following the procedure outlined in step 4a, substituting 1-cyclopropyl-6, 7-difluoro-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde for 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde and (3S) -1- (6-methylpyridin-3-yl) piperidin-3-amine for (3S) -1- (pyridin-3-yl) piperidin-3-amine with a solvent system from MeOH to a mixture of MeOH: DCM (5: 1). The crude product was purified by FCC (SiHP; DCM-DCM: MeOH 9: 1) to afford the title compound as a yellow oil (0.95g, 2.24mmol, 80% yield). ESI-MS: 425[ M + H]⁺

1H NMR(400MHz，DMSO-d6)δ8.13-8.12(m，1H)，8.09-8.07(m，1H)，8.07-8.04(m，1H)，8.04-8.01(m，1H)，7.24-7.20(m，1H)，7.05-7.02(m，1H)，3.72-3.61(m，3H)，3.58-3.52(m，1H)，3.49-3.42(m，1H)，2.75-2.66(m，1H)，2.66-2.57(m，1H)，2.33(s，3H)，1.92-1.84(m，1H)，1.78-1.70(m，1H)，1.58-1.47(m，1H)，1.29-1.21(m，3H)，1.08-1.02(m，2H).

Preparation of 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

Following the procedure outlined in step 4b, 1-cyclopropyl-6, 7-difluoro-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl) -is used]Amino } methyl) -1, 4-dihydroquinolin-4-one instead 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 instead of 2-methylpyridine-4-carbaldehyde to synthesize the title compound. The mixture was stirred at room temperature over the weekend. After addition of sodium triacetoxyborohydride, the reaction was heated to 45 ℃ for 1 hour, to 55 ℃ for 2 hours, and finally to 70 ℃ for 1 hour. The residue was purified by FCC (SiHP, DCM: MeOH 95: 5) and passed through RP-FCC (SiC 18; H) ₂MeCN) to provide the title compound as a yellow powder (0.635g, 1.16mmol, 52% yield). The product was converted to the hydrochloride salt. ESI-MS: 546[ M + H]⁺

1H NMR (400MHz, methanol-d 4) Δ 8.27-8.23(m, 1H), 8.12-8.07(m, 1H), 8.07-7.97(m, 3H), 7.92-7.88(m, 1H), 7.63-7.58(m, 1H), 6.99-6.95(m, 1H), 6.81(s, 1H), 4.23-4.14(m, 1H), 4.08-3.90(m, 3H), 3.85-3.80(m, 1H), 3.78(s, 3H), 3.54-3.46(m, 1H), 3.24-3.09(m, 1H), 3.00-2.91(m, 1H), 2.29-2.19(m, 1H), 2.05-1.97(m, 1H), 1.81-1H), 1.00-2.91 (m, 1H), 1H, 36-36H, 1H, 2H, 1H, 2H, 1H, 2H.

Example 32.3- ({ [ (3S) -1- (5-bromopyrimidin-2-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

Following the procedure outlined in step 5, 3-bromopyridazine was replaced with 5-bromo-2-fluoropyrimidine and 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3S) -piperidin-3-yl radical]Amino } methyl) -1Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl by 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one. The reaction was carried out overnight. Washing with AcOEt

A pad. Next, the filtrate was stirred with MPA scavenger for 15 minutes, filtered, evaporated and the residue purified by FCC (SiHP, DCM: MeOH, 9: 1) to give the product as a white solid (0.076g, 0.142mmol, 67% yield). ESI-MS: 533.4[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.39(s，2H)，8.25(d，J＝5.0Hz，1H)，8.18(dd，J＝8.1，1.6Hz，1H)，7.94(s，1H)，7.71(ddd，J＝8.6，6.8，1.6Hz，1H)，7.61(d，J＝8.5Hz，1H)，7.37(ddd，J＝8.0，6.8，1.1Hz，1H)，7.20-7.15(m，2H)，4.78-4.69(m，1H)，4.54-4.44(m，1H)，3.81(s，3H)，3.75(s，2H)，3.70-3.55(m，2H)，3.00(t，J＝11.8Hz，1H)，2.87-2.75(m，1H)，2.62-2.55(m，1H)，2.33(s，3H)，2.06-1.96(m，1H)，1.81-1.62(m，2H)，1.36-1.26(m，1H).

The product was converted to the hydrochloride salt. ESI-MS: 533.3[ M + H]⁺. As a yellow powder product.

¹H NMR (400MHz, deuterium oxide) δ 8.39(d, J ═ 6.1Hz, 1H), 8.32(s, 2H), 8.15(s, 1H), 8.06(dd, J ═ 8.2, 1.5 Hz, 1H), 7.94(ddd, J ═ 8.6, 7.0, 1.6Hz, 1H), 7.88-7.82(m, 2H), 7.75(d, J ═ 8.7Hz, 1H), 7.60(ddd, J ═ 8.1, 7.1, 0.9Hz, 1H), 4.72-4.51(m, 4H), 4.10-4.03(m, 1H), 3.93(s, 3H), 3.93-3.88(m, 1H), 3.85-3.77(m, 1H), 3.46-3.38(m, 1H), 3.01-2H (m, 1H), 3.49-2H, 1H, 3.1H, 1H, and 1H.

EXAMPLE 33.7-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

The title compound was synthesized according to step 15. The residue was purified by FCC (SiHP, DCM: MeOH, 9: 1) and repurified by preparative HPLC to afford the product as a yellow solid (0.080g, 0.043mmol, 35% yield). ESI-MS: 533.3[ M + H ]⁺。

¹H NMR(400MHz，DMSO-d₆)δ8.36-8.22(m，2H)，8，16(d，J＝6.1Hz，1H)，7.97(d，J＝9.4Hz，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＝11.8Hz，1H)，3.83-3.61(m，5H)，3.57-3.48(m，1H)，2.84(t，J＝11.3Hz，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).

Example 34.3- ({ [5, 5-difluoro-1- (pyridin-3-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

Preparation of tert-butyl N- [5, 5-difluoro-1- (pyridin-3-yl) piperidin-3-yl ] carbamate

The procedure outlined in step 1a was followed, replacing tert-butyl N- [ (3S) -piperidin-3-yl) with tert-butyl N- (5, 5-difluoropiperidin-3-yl) carbamate (1.1 equivalents)]Carbamate to synthesize the title compound. The reaction was carried out at 115 ℃ for 1 day. The residue was purified by FCC (SiHP; Hex: AcOEt) to give the product as a pale yellow oil (0.150g, 0.479mmol, 84% yield). ESI-MS: 314.3[ M + H]⁺

Preparation of 5, 5-difluoro-1- (pyridin-3-yl) piperidin-3-amine

Following the procedure outlined in step 1b, tert-butyl N- [5, 5-difluoro-1- (pyridin-3-yl) piperidin-3-yl ] is used]Carbamate instead of tert-butyl M [ (3S)1- (pyridin-3-yl) piperidin-3-yl group]Carbamate to synthesize the title compound. The reaction was carried out for 24 hours. The product (0) was isolated as a yellow oil.078g, 0.366mmol, 76% yield). ESI-MS: 241.1[ M + H]⁺

Preparation of 3- ({ [5, 5-difluoro-1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

The title compound was synthesized following the procedure outlined in step 4a substituting 5, 5-difluoro-1- (pyridin-3-yl) piperidin-3-amine for (3S) -1- (pyridin-3-yl) piperidin-3-amine. The reaction is carried out in the absence of molecular sieves. The product was isolated as a yellow oil (0.130g, 0.338mmol, 97% yield). ESI-MS: 385.2[ M + H]⁺

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

The title compound was synthesized according to step 16. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and passed through RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a yellow solid (0.050g, 0.102mmol, 30% yield). ESI-MS: 490.4[ M + H]⁺

The product was converted to the hydrochloride salt. The product was obtained as a pale yellow solid. ESI-MS: 490.3[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.74(d，J＝2.9Hz，1H)，8.60(d，J＝6.1Hz，1H)，8.28(dd，J＝9.0，2.9Hz，1H)，8.24-8.17(m，3H)，8.03(s，1H)，7.93(dd，J＝6.1，1.7Hz，1H)，7.85(dd，J＝9.0，5.4Hz，1H)，7.76(ddd，J＝8.6，6.9，1.7Hz，1H)，7.66(d，J＝8.6Hz，1H)，7.49-7.34(m，1H)，4.51-4.39(m，2H)，4.31-4.13(m，2H)，3.88(s，3H)，3.86-3.74(m，2H)，3.49(dd，J＝33.0，13.9Hz，1H)，3.38(t，J＝12.2Hz，1H)，3.18-3.03(m，1H)，2.67-2.62(m，3H)，2.62-2.53(m，1H)，2.47-2.35(m，1H).

Example 35.3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

The title compound was synthesized following the procedure outlined in step 15 substituting 4-oxo-1, 4-dihydroquinoline-3-carbaldehyde for 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde and extending the first phase of the reaction to stirring overnight. The crude reaction mixture was evaporated and the residue was purified by FCC (SiHP, DCM: MeOH 15%) and passed through FCC (SiC18, H) ₂O: MeCN) was purified twice more to provide the title compound as a beige solid (0.022g, 0.050mmol, 18% yield). ESI-MS: 440.2[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ11.69(s，1H)，8.36-8.23(m，2H)，8.11(dd，J＝8.2，1.5Hz，1H)，7.95(s，1H)，7.92(dd，J＝4.5，1.3Hz，1H)，7.61(ddd，J＝8.4，6.8，1.5Hz，1H)，7.51(d，J＝8.1Hz，1H)，7.34-7.25(m，3H)，7.22(d，J＝5.2Hz，1H)，7.15(dd，J＝8.5，4.5Hz，1H)，3.91(d，J＝11.7Hz，1H)，3.83-3.70(m，2H)，3.65(s，2H)，2.89-2.77(m，1H)，2.76-2.58(m，2H)，2.47-2.43(m，1H)，2.40(s，3H)，2.04-1.92(m，1H)，1.82-1.72(m，1H)，1.66-1.38(m，2H).

Example 36.1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl ] [ (3S) -1- (2-nitropyridin-3-yl) piperidin-3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one

The title compound was synthesized according to step 17. The residue was combined with the residue from a similar reaction (0.133mmol of starting material) and passed through RP-FCC (SiC 18; H)₂MeCN) to afford the product as an orange solid (0.117g, 0.345mmol, 68% yield). ESI-MS: 499.3[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.27(d，J＝5.0Hz，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.09(dd，J＝4.4，1.3Hz，1H)，7.98-7.89(m，2H)，7.77-7.59(m，3H)，7.38(ddd，J＝8.0，6.9，1.1Hz，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＝11.1Hz，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).

EXAMPLE 37.7-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

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

The title compound was synthesized according to the procedure outlined in step 4b, substituting 7-bromo-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde and (3S) -1- (6-methylpyridin-3-yl) piperidin-3-amine for the mixture of 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde and (3S) -1- (pyridin-3-yl) piperidin-3-amine, and the solvent system from MeOH to MeOH: DCM (1: 1). DCM is also used for

And (6) washing the pad. The product was isolated as a yellow solid (0.900g, 2.039mmol, 97% yield). ESI-MS: 443.1[ M + H]⁺

Preparation 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

Following the procedure outlined in step 16, using 7-bromo-1-methyl-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl]Replacement of 3- ({ [5, 5-difluoro-1- (pyridin-3-yl) piperidin-3-yl) by amino } methyl) -1, 4-dihydroquinolin-4-one]Amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one and the temperature of the second stage of the reaction is raised to 50 ℃ to synthesize the title compound. The filtrate obtained was partitioned between water and DCM. Then, the organic layer was extracted with anhydrous MgSO₄Dried, filtered and evaporated. The residue was passed through twice FCC (with NH)₃DCM deactivated SiHP, DCM: MeOH9: 1) and passed through two RP-FCC (SiC 18; h₂MeCN) to give the product as a yellow solid (0.450g, 0.825mmol, 40% yield). ESI-MS: 546.3[ M + H]⁺

The product was converted to the hydrochloride salt. As product of an orange powder. ESI-MS: 546.3[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.36(d，J＝5.3Hz，1H)，8.21(d，J＝3.0Hz，1H)，8.08(d，J＝8.6Hz，1H)，8.04(s，1H)，7.87(s，1H)，7.67-7.55(m，1H)，7.53(d，J＝8.7Hz，1H)，7.48-7.36(m，2H)，7.30(d，J＝8.7Hz，1H)，4.21-3.53(m，9H)，3.03-2.81(m，1H)，2.82-2.59(m，2H)，2.43(s，6H)，2.12-1.91(m，1H)，1.87-1.71(m，1H)，1.67-1.33(m，2H).

EXAMPLE 38.3- ({ [ (2, 6-dimethylpyridin-4-yl) methyl ] [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

The title compound was synthesized according to step 18. The residue was purified by preparative HPLC to give the product as a beige solid (0.031g, 0.065mmol, 45% yield). ESI-MS: 468.3[ M + H]⁺

¹H NMR (300MHz, methanol-d₄)δ8.34(dd，J＝8.3，1.5Hz，1H)，8.24(d，J＝2.9Hz，1H)，7.95(s，1H)，7.90(dd，J＝4.7，1.3Hz，1H)，7.76(ddd，J＝8.6，6.9，1.6Hz，1H)，7.64(d，J＝8.5Hz，1H)，7.49-7.38(m，2H)，7.24(dd，J＝8.6，4.8Hz，1H)，7.01(s，2H)，4.05-3.94(m，1H)，3.84(s，3H)，3.81(d，J＝9.0Hz，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).

Example 39.1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] [ (pyridin-4-yl) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one

The title compound was synthesized following the procedure outlined in step proC, substituting pyridine-4-carbaldehyde for 2, 6-dimethylpyridine-4-carbaldehyde. The residue was purified by preparative HPLC to give the product as a beige solid (0.031g, 0.071mmol, 49% yield). ESI-MS: 440.3[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.54-8.37(m，2H)，8.29(d，J＝2.9Hz，1H)，8.19(dd，J＝8.2，1.5Hz，1H)，8.07(s，1H)，7.91(dd，J＝4.5，1.3Hz，1H)，7.72(ddd，J＝8.5，6.8，1.6Hz，1H)，7.63(d，J＝8.4Hz，1H)，7.52-7.42(m，2H)，7.37(ddd，J＝8.0，6.8，1.1Hz，1H)，7.33-7.24(m，1H)，7.14(dd，J＝8.5，4.5Hz，1H)，4.02-3.91(m，1H)，3.87(s，3H)，3.84-3.52(m，5H)，2.85(t，J＝11.4Hz，1H)，2.77-2.58(m，2H)，2.06-1.92(m，1H)，1.83-1.70(m，1H)，1.66-1.36(m，2H).

EXAMPLE 40.7-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

(3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl]Preparation of piperidin-3-amine following the procedure outlined in step 4a, 2 equivalents of NaBH were used₄And NaOAc, using 2-methylpyridine-4-carbaldehyde and (3S) -1- (6-methylpyridin-3-yl) piperidin-3-amine (1 equivalent) instead of 1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde and (3S) -1- (pyridin-3-yl) piperidin-3-amine to synthesize the title compound. The solvent used was DCE. The second stage is extended up to 3 hours. The residue is passed through FCC (with NH) ₃DCM deactivated SiHP; DCM: MeOH 9: 1) and purified by RP-FCC (SiC 18; h₂MeCN) to afford the product as a yellow oil (3.05g, 9.863 mmo)l, yield 69%). ESI-MS: 297.3[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.36-8.32(m，1H)，8.11(d，J＝2.9Hz，1H)，7.25-7.22(m，1H)，7.20(dd，J＝8.5，3.1Hz，1H)，7.17(dd，J＝5.1，1.4Hz，1H)，7.04(d，J＝8.5Hz，1H)，3.78(s，2H)，3.73-3.61(m，1H)，3.52-3.44(m，1H)，2.71-2.63(m，1H)，2.61-2.52(m，2H)，2.48-2.42(m，4H)，2.36-2.32(m，3H)，1.96-1.88(m，1H)，1.78-1.68(m，1H)，1.57-1.43(m，1H)，1.28-1.14(m，1H).

Preparation 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

Following the procedure outlined in step 15, using (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl]Piperidin-3-amine (1 equivalent) in place of (3S) -N- [ (2-methylpyridin-4-yl) methyl]-1- (pyridin-3-yl) piperidin-3-amine and extension of the first phase of the reaction to 12 hours to synthesize the title compound. The crude reaction mixture was taken up in water and NaHCO₃The solutions were partitioned. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was passed through FCC (SiHP; DCM: MeOH 95: 5) and RP-FCC (SiC 18; H)₂MeCN) to give the product as a yellow powder (3.205g, 5.677mmol, 76%). ESI-MS: 546.4[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.29-8.25(m，1H)，8.16(d，J＝6.2Hz，1H)，8.13(d，J＝2.9Hz，1H)，7.97(d，J＝9.5Hz，1H)，7.91(s，1H)，7.26-7.18(m，2H)，7.17-7.13(m，1H)，7.02(d，J＝8.5Hz，1H)，3.82-3.70(m，3H)，3.66-3.50(m，4H)，2.83-2.69(m，2H)，2.65-2.54(m，1H)，2.36(s，3H)，2.33(s，3H)，2.08-1.92(m，1H)，1.80-1.72(m，1H)，1.62-1.41(m，2H)，1.27-1.18(m，2H)，1.00-0.82(m，2H).

The product was converted to the hydrochloride salt. As a product. ESI-MS: 546.7[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.38(d，J＝5.4Hz，1H)，8.26-8.13(m，2H)，8.05-7.65(m，3H)，7.50-7.33(m，3H)，4.15-3.80(m，3H)，3.80-3.61(m，3H)，3.61-3.52(m，2H)，2.94(br，1H)，2.83-2.70(m，1H)，2.50-2.40(m，6H)，2.00(br，1H)，1.89-1.75(m，1H)，1.63(br，1H)，1.57-1.44(m，1H)，1.33-1.18(m，2H)，0.94(s，2H).

EXAMPLE 41.1-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

The title compound was synthesized according to step 19. The residue was purified by FCC (SiHP; DCM: MeOH) and repurified by FCC (SiHP; DCM: MeOH) to give the product as a yellow solid (0.077g, 0.159mmol, 60% yield). ESI-MS: 484.7[ M + H]⁺

¹H NMR(300MHz，DMSO-d₆)δ8.28(d，J＝5.0Hz，1H)，8.18(d，J＝8.0Hz，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＝7.6，2.6Hz，1H)，5.50(d，J＝2.7Hz，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＝12.1Hz，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).

The product was converted to the hydrochloride salt. The product was obtained as a pale yellow solid. ESI-MS: 484.2[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.34-8.28(m，2H)，8.06(s，1H)，7.83-7.76(m，2H)，7.74(d，J＝6.1Hz，1H)，7.69(d，J＝8.6Hz，1H)，7.48(ddd，J＝8.0，7.0，1.0Hz，1H)，7.35(d，J＝7.7Hz，1H)，6.26(dd，J＝7.8，2.8Hz，1H)，5.74(d，J＝2.8Hz，1H)，4.18-4.11(m，3H)，3.91(s，3H)，3.91-3.82(m，3H)，3.42(s，3H)，3.19-3.10(m，1H)，2.97-2.87(m，2H)，2.52(s，3H)，2.22-2.14(m，1H)，1.92-1.75(m，2H)，1.63-1.50(m，1H).

EXAMPLE 42.7-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

Preparation of 7-chloro-1-cyclopropyl-6-fluoro-1, 2, 3, 4-tetrahydro-1, 8-naphthyridin-4-one

Following the procedure outlined in step 7d, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-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 NaBH was added₄The title compound was synthesized by extending the time of (1) to 1 hour, extending stirring at room temperature to 16 hours before adding PTSA, and shortening the reflux time to 4 hours. Extraction was performed using DCM. The residue was purified by FCC (SiHP; Hex: AcOEt 2: 1) to give the product as a yellow solid (5.974g, 24.823mmol, 70% yield). ESI-MS: 241.1[ M + H ]⁺

¹H NMR(400MHz，DMSO-d₆)δ7.90(d，J＝7.9Hz，1H)，3.62-3.56(m，2H)，2.68-2.61(m，3H)，0.88-0.82(m，2H)，0.72-0.67(m，2H).

Preparation of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carbaldehyde

The title compound was synthesized according to the procedure outlined in step 7e substituting 7-chloro-1-cyclopropyl-6-fluoro-1, 2, 3, 4-tetrahydro-1, 8-naphthyridin-4-one for 1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -1, 2, 3, 4-tetrahydroquinolin-4-one. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) to give the product as a white solid (0.381g, 1.429mmol, 31% yield). ESI-MS: 267.9[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ10.09(s，1H)，8.54(d，J＝7.7Hz，1H)，8.52(s，1H)，3.75-3.68(m，1H)，1.21-1.15(m，2H)，1.15-1.09(m，2H).

Preparation 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

Following the procedure outlined in step 15, using (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl]Piperidin-3-amine and 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carbaldehyde (1 eq) instead of (3S) -N- [ (2-methylpyridin-4-yl) methyl]-1- (pyridin-3-yl) piperidin-3-amine and 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde to synthesize the title compound. In the absence of Na₂SO₄The reaction is carried out with introduction of NaBH (OAc) at the start of the reaction₃. The residue was purified by FCC (SiHP, DCM: MeOH, 9: 1) to give the product as a yellow solid (0.077g, 0.141mmol, 46% yield). ESI-MS: 547.8[ M + H ]⁺

The product was converted to the hydrochloride salt. ESI-MS: 547.2[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.34(d，J＝7.8Hz，1H)，8.24(d，J＝5.5Hz，1H)，8.17(d，J＝3.0Hz，1H)，8.06(s，1H)，7.85(dd，J＝9.0，3.0Hz，1H)，7.48(d，J＝9.0Hz，1H)，7.46-7.44(m，1H)，7.42-7.39(m，1H)，4.09-4.01(m，1H)，3.95(s，2H)，3.90-3.82(m，1H)，3.80-3.70(m，2H)，3.62-3.54(m，1H)，3.06-2.90(m，2H)，2.89-2.80(m，1H)，2.54(s，3H)，2.45(s，3H)，2.20-2.10(m，1H)，1.98-1.90(m，1H)，1.78-1.61(m，2H)，1.27-1.20(m，2H)，0.95-0.89(m，2H)，1.20(m，2H)，0.95-0.89(m，2H).

Example 43.1-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

The title compound was synthesized according to step 20. The residue was dissolved in DCM, washed with water

Filtered and passed through RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a white powder (0.026g, 0.049mmol, 44% yield). ESI-MS: 529.7[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.21(d，J＝5.2Hz，1H)，8.07(d，J＝2.9Hz，1H)，7.75-7.71(m，2H)，7.33(dd，J＝8.6，3.0Hz，1H)，7.28(s，1H)，7.26-7.22(m，1H)，7.11(d，J＝8.6Hz，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).

Example 44.1-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

The title compound was synthesized according to step 21. The residue was dissolved in DCM, washed with water

Filtered and passed through RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a white powder (0.037g, 0.066mmol, 60% yield). ESI-MS: 543.2[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.17(d，J＝5.2Hz，1H)，8.10(d，J＝9.9Hz，1H)，8.08(d，J＝2.9Hz，1H)，7.96(s，1H)，7.35(dd，J＝8.6，3.0Hz，1H)，7.26(s，1H)，7.24-7.20(m，1H)，7.12(d，J＝8.6Hz，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).

EXAMPLE 45.1-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

The title compound was synthesized according to step 22. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and by RP-FCC (SiC18, H)₂O∶CH₃CN) and preparative HPLC. The title compound was isolated as the free base (0.036g, 0.066mmol, 36% yield). As a white powder product. ESI-MS: 542.4[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.16(d，J＝5.3Hz，1H)，8.09(d，J＝2.9Hz，1H)，7.95(s，1H)，7.89(d，J＝11.6Hz，1H)，7.51(d，J＝7.2Hz，1H)，7.35(dd，J＝8.6，3.0Hz，1H)，7.25(s，1H)，7.24-7.20(m，1H)，7.12(d，J＝8.6Hz，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)，

The product was converted to the hydrochloride salt. As a yellow solid product. ESI-MS: 542.3[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.24(d，1H)，8.19(d，1H)，7.95(s，1H)，7.92-7.86(m，2H)，7.53(d，1H)，7.52-7.47(m，2H)，7.44-7.42(m，1H)，4.12-3.89(m，7H)，3.85-3.74(m，2H)，3.56-3.49(m，1H)，3.10-3.00(m，2H)，2.92-2.82(m，1H)，2.56(s，3H)，2.43(s，3H)，2.23-2.15(m，1H)，2.01-1.94(m，1H)，1.82-1.62(m，2H)，1.38-1.32(m，2H)，1.01-0.96(m，2H).

EXAMPLE 46.1-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

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

The title compound was synthesized according to step 23. The residue is passed through FCC (with NH)₃DCM-deactivated SiHP, DCM: MeOH 9: 1) to give the product as a yellow solid (0.055g, 0.077mmol, 42% yield). ESI-MS: 710.9[ M + H]⁺

Preparation of 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

Following the procedure outlined in step 1b, tert-butyl (2R) -4- [ 1-cyclopropyl-6-fluoro-3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl) -is used][ (2-methylpyridin-4-yl) methyl]Amino } methyl) -4-oxo-1, 4-dihydroquinolin-7-yl]-2-methylpiperazine-1-carboxylic ester instead of tert-butyl N- [ (3S)1- (pyridin-3-yl) piperidin-3-yl]Carbamate to synthesize the title compound. The residue after evaporation was taken up in NH in MeOH₃The solution was basified and purified by preparative HPLC to give the product as a white solid (0.026g, 0.043mmol, 55% yield). ESI-MS: 610.8[ M + H]⁺

The product was converted to the hydrochloride salt. The product was obtained as a pale yellow solid. ESI-MS: 610.3[ M + H]⁺

¹H NMR (400MHz, deuterium oxide) δ 8.34-8.29(m, 1H), 8.12(s, 1H), 8.07(d, J ═ 2.9Hz, 1H), 7.92(dd, J ═ 9.1, 2.9Hz, 1H), 7.75-7.71(m, 2H), 7.69(d, J ═ 12.9Hz, 1H), 7.53(d, J ═ 9.1Hz, 1H), 7.45(d, J ═ 7H).2Hz，1H)，4.67-4.50(m，2H)，4.48-4.27(m，2H)，4.02-3.94(m，1H)，3.84-3.75(m，2H)，3.75-3.66(m，1H)，3.65-3.57(m，1H)，3.57-3.41(m，4H)，3.41-3.30(m，1H)，3.29-3.19(m，1H)，3.16-2.99(m，2H)，2.51(s，3H)，2.42(s，3H)，2.32-2.23(m，1H)，2.15-1.98(m，2H)，1.82-1.72(m，1H)，1.35(d，J＝6.6Hz，3H)，1.32-1.25(m，2H)，0.98-0.90(m，2H).

Example 47.1-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

The title compound was synthesized according to step 24. The residue was purified by FCC (SiHP, DCM: MeOH 9: 1) and repurified by preparative HPLC. Using DCM/NaHCO ₃Extracting with anhydrous Na₂SO₄The product was obtained as the free base after drying the organic layer and evaporation. The title compound was isolated as a pale yellow solid (0.019g, 0.032mmol, 17% yield). ESI-MS: 596.8[ M + H]⁺

The product was converted to the hydrochloride salt. ESI-MS: 596.4[ M + H]⁺

¹H NMR (400MHz, deuterium oxide) δ 8.02(s, 1H), 7.82(d, J ═ 5.2Hz, 1H), 7.74-7.58(m, 2H), 7.35-7.22(m, 2H), 7.05(d, J ═ 8.6Hz, 1H), 6.86(d, J ═ 5.3Hz, 1H), 6.73(s, 1H), 3.75-3.47(m, 5H), 3.44-3.17(m, 10H), 2.94-2.77(m, 1H), 2.69-2.54(m, 1H), 2.55-2.42(m, 1H), 2.36-2.20(m, 3H), 2.06-1.96(m, 1H), 1.93-1.75(m, 4H), 1.65-1.38(m, 2.06-1H), 1.06-2.06 (m, 1H), 1.06-0H).

EXAMPLE 48.1-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

The title compound was synthesized following the procedure outlined in step 24, substituting 1- (2, 2-difluoroethyl) piperazine for piperazine. After the residue was purified by FCC (SiHP, DCM: MeOH), it was stirred in DCM with MPA scavenger. The sample was then repurified by preparative HPLC to give the product as a yellow solid (0.053g, 0.08mmol, 44% yield). ESI-MS: 660.9[ M + H ]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.28(d，J＝5.1Hz，1H)，8.12(d，J＝3.0Hz，1H)，7.82(s，1H)，7.71(d，J＝13.5Hz，1H)，7.34(d，J＝7.4Hz，1H)，7.23-7.18(m，2H)，7.16(d，J＝5.2Hz，1H)，7.01(d，J＝8.5Hz，1H)，6.18(tt，J＝55.6，4.2Hz，1H)，3.81-3.76(m，1H)，3.76-3.72(m，2H)，3.60(s，2H)，3.58-3.55(m，1H)，3.52-3.46(m，1H)，3.22-3.16(m，4H)，2.88-2.77(m，2H)，2.77-2.72(m，6H)，2.62-2.54(m，1H)，2.37(s，3H)，2.32(s，3H)，2.00-1.92(m，1H)，1.79-1.72(m，1H)，1.58-1.43(m，2H)，1.25-1.17(m，2H)，0.93-0.82(m，2H).

The product was converted to the hydrochloride salt. ESI-MS: 660.3[ M + H]⁺. As a yellow solid product.

¹H NMR (400MHz, pyridine-d)₅)δ8.58(d，J＝5.0Hz，1H)，8.55(d，J＝3.0Hz，1H)，8.41(d，J＝13.4Hz，1H)，7.95(s，1H)，7.36-7.33(m，2H)，7.28(dd，J＝8.5，3.0Hz，1H)，7.23(d，J＝7.4Hz，1H)，7.03(d，J＝8.5Hz，1H)，6.22(tt，J＝55.9，4.3Hz，1H)，4.14-4.05(m，1H)，4.03(s，2H)，3.92-3.77(m，2H)，3.58-3.45(m，1H)，3.34-3.25(m，1H)，3.25-3.16(m，4H)，3.15-3.03(m，1H)，2.90-2.76(m，3H)，2.76-2.70(m，4H)，2.56-2.50(m，4H)，2.48(s，3H)，2.13-2.01(m，1H)，1.72-1.62(m，1H)，1.60-1.43(m，2H)，1.18-1.03(m，2H)，0.95-0.80(m，2H).

EXAMPLE 49.1-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

Preparation of 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

The title compound was synthesized according to step 25 a. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1). The sample obtained was dissolved in DCM and stirred with MPA scavenger for 10 minutes. The scavenger was filtered off and the filtrate was evaporated under reduced pressure to give the product as a beige powder (0.047g, 0.068mmol, 37% yield). ESI-MS: 666.8[ M + H]⁺

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).

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

The title compound was synthesized according to step 25 b. The residue was purified by FCC (SiHP; DCM: MeOH 95: 5) to give the product as an off-white powder (0.023g, 0.038mmol, 56% yield). ESI-MS: 566.3[ M + H ]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.31-8.27(m，1H)，8，16(d，J＝8.7Hz，1H)，8.14(d，J＝3.1Hz，1H)，8.01(s，1H)，7.56(d，J＝1.9Hz，1H)，7.36(dd，J＝8.7，1.8Hz，1H)，7.26-7.19(m，3H)，7.01(d，J＝8.5Hz，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).

EXAMPLE 50.3- ({ [ (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

Preparation of 1- (oxetan-3-yl) -4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized according to step 26 a. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and passed through RP-FCC (SiC 18; H)₂O: MeCN) to give the product as a beige solid (0.037g, 0.139mmol, 21% yield). ESI-MS: 230.1[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ10.20(s，1H)，8.47(s，1H)，8.34(dd，J＝8.0，1.6Hz，1H)，7.83(ddd，J＝8.7，7.1，1.7Hz，1H)，7.60-7.55(m，1H)，7.51(d，J＝8.5Hz，1H)，5.82(p，J＝6.9Hz，1H)，5.13-5.06(m，2H)，5.00-4.94(m，2H)，

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

The title compound was synthesized according to step 26 b. The residue was purified by preparative HPLC to give the product as a white solid (0.037g, 0.073mmol, 36% yield). ESI-MS: 510.3[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.38(dd，J＝8.2，1.5Hz，1H)，8.21(s，1H)，8.20-8.18(m，1H)，8.10(d，J＝3.0Hz，1H)，7.77-7.71(m，1H)，7.47(ddd，J＝8.0，7.0，1.0Hz，1H)，7.39(d，J＝8.9Hz，1H)，7.36(dd，J＝8.6，3.0Hz，1H)，7.32-7.29(m，1H)，7.29-7.25(m，1H)，7.12(d，J＝8.6Hz，1H)，5.80-5.72(m，1H)，5.20(td，J＝7.2，2.5Hz，2H)，4.86(t，J＝6.7Hz，2H)，3.96-3.87(m，5H)，3.66-3.56(m，1H)，3.08-2.95(m，1H)，2.89(t，J＝11.1Hz，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).

EXAMPLE 51.2- [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

Preparation of methyl 2- (3-formyl-4-oxo-1, 4-dihydroquinolin-1-yl) acetate

The title compound was synthesized according to step 27 a. The residue was purified by FCC (SiHP; hexane: DCM: EtOAc) to provide the product as a white solid (0.073g, 0.294 mmol). ESI-MS: 246.3[ M + H ]⁺

¹H NMR(300MHz，DMSO-d₆)δ10.21(s，1H)，8.66(s，1H)，8.31(dd，J＝8.0，1.6Hz，1H)，7.81(ddd，J＝8.6，7.1，1.7Hz，1H)，7.63(d，J＝8.5Hz，1H)，7.55(ddd，J＝8.0，7.1，D.9Hz，1H)，5.43(s，2H)，3.72(s，3H).

Preparation 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

The title compound was synthesized according to step 27 b. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) to afford the product as a pale yellow glass (0.043g, 0.076mmol, 26% yield). ESI-MS: 526.7[ M + H]⁺

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

The title compound was synthesized according to step 27c. The residue is passed through FCC (C18 HP; H)₂MeCN) to afford the product as an off-white solid (0.030g, 0.058mmol, 71% yield). ESI-MS: 512.3[ M + H]⁺

¹H NMR (400MHz, methanol-d)₄)δ8.33(dd，J＝8.2，1.6Hz，1H)，8.21(dd，J＝5.1，0.9Hz，1H)，8.10-8.01(m，2H)，7.70(ddd，J＝8.6，6.9，1.6Hz，1H)，7.53(d，J＝8.7Hz，1H)，7.44-7.33(m，2H)，7.33-7.27(m，2H)，7.11(d，J＝8.6Hz，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).

Example 52.1-cyclopropyl-7- {4, 7-diazaspiro [25] 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

Preparation 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

The tert-butyl 4, 7-diazaspiro [2.5] was used according to the procedure outlined in step 24]Octane-4-carboxylate (2.09 equivalents) instead of piperazine and 2.2 equivalents of Cs were used₂CO₃To synthesize the title compound. After the residue was purified by FCC (SiHP, DCM: MeOH), it was stirred in DCM with MPA scavenger. The product was isolated as a yellow oil (0.087g, 0.120mmol, 57% yield). AP-MS: 722.9[ M + H]⁺

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

The title compound was synthesized according to step 28. Passing the residue through FCC (Si)HP, DCM: MeOH 9: 1) to give the product as a white solid (0.034g, 0.055mmol, 45% yield). ESI-MS: 622.7[ M + H]⁺

¹H NMR(400MHz，DMSO-d₆)δ8.31-8.27(m，1H)，8.13(d，J＝3.0Hz，1H)，7.81(s，1H)，7.69(d，J＝13.7Hz，1H)，7.28(d，J＝7.5Hz，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＝24.0Hz，4H)，2.75(d，J＝7.8Hz，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).

The product was converted to the hydrochloride salt. ESI-MS: 622.4[ M + H]⁺. The product was obtained as a white solid.

¹H NMR(400MHz，DMSO-d₆)δ8.29(d，J＝5.0Hz，1H)，8.13(d，J＝3.0Hz，1H)，7.82(s，1H)，7.71(d，J＝13.6Hz，1H)，7.30(d，1H)，7.24-7.20(m，2H)，7.20-7.15(m，1H)，7.02(d，J＝8.5Hz，1H)，3.83-3.72(m，3H)，3.62-3.56(m，3H)，3.55-3.46(m，1H)，3.26-3.18(m，2H)，3.12-3.03(m，4H)，2.81-2.70(m，2H)，2.64-2.55(m，1H)，2.38(s，3H)，2.33(s，4H)，2.02-1.93(m，1H)，1.80-1.72(m，1H)，1.59-1.43(m，2H)，1.28-1.18(m，2H)，0.93-0.83(m，2H)，0.71-0.59(m，4H).

Example 53.1-methyl-3- ({ [ (3S) -1- (5-methyl-1, 3, 4-

Oxadiazol-2-yl) piperidin-3-yl][ (2-methylpyridin-4-yl) methyl]Amino } methyl) -1, 4-dihydroquinolin-4-one

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

The title compound was synthesized according to step 29 a. Passing the residue through FCC (Al)₂O₃(ii) a DCM: MeOH 9: 1) to give the product as a yellow solid (5.6g, 15.1mmol, 94% yield). AP-MS: 372.4[ M + H]⁺

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

The title compound was synthesized according to step 29 b. The residue was purified by FCC (SiHP, DCM/MeOH) to give the product as a yellow oil (2.4g, 5.0mmol, 62% yield). ESI-MS: 477.6[ M + H]⁺

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

The title compound was synthesized according to step 29 c. The product was obtained as a yellow oil (1.6g, 4.2mmol, 83% yield).

ESI-MS：377.5[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.29-8.23(m，1H)，8.18(dd，J＝8.1，1.6Hz，1H)，7.93(s，1H)，7.71(ddd，J＝8.6，6.9，1.7Hz，1H)，7.63-7.59(m，1H)，7.36(ddd，J＝8.0，6.9，1.0Hz，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＝12.3Hz，1H)，1.51-1.36(m，1H)，1.33-1.18(m，1H).

Preparation of 1-methyl-3- ({ [ (3S) -1- (5-methyl-1, 3, 4-)

Oxadiazol-2-yl) piperidin-3-yl][ (2-methylpyridin-4-yl) methyl]Amino } methyl) -1, 4-dihydroquinolin-4-one

Following the procedure outlined in step 5, 1-methyl-3- ({ [ (2-methylpyridin-4-yl) methyl][ (3s) -piperidin-3-yl radical]Replacement of 3- ({ [ (2-methoxypyridin-4-yl) methyl with amino } methyl) -1, 4-dihydroquinolin-4-one](piperidin-3-yl) amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one with 2-bromo- 5-methyl-1, 3, 4-

The title compound was synthesized by substituting 3-bromopyridazine with oxadiazole (1 equivalent) and reducing the reaction time to heating overnight. After filtration through celite, MPA scavenger was added and the resulting mixture was stirred for 15 minutes. Subsequently, the mixture was filtered and evaporated. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) to give the product as a white powder (0.025g, 0.06mmol, 41% yield). ESI-MS: 459.2[ M + H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.27(d，J＝5.0Hz，1H)，8.20(dd，J＝8.0，1.6Hz，1H)，7.98(s，1H)，7.75-7.70(m，1H)，7.62(d，J＝8.6Hz，1H)，7.38(ddd，J＝8.0，6.9，1.0Hz，1H)，7.21(s，1H)，7.19(dd，J＝5.1，1.5Hz，1H)，3.96-3.90(m，1H)，3.83(s，3H)，3.79-3.56(m，5H)，3.15-3.07(m，1H)，2.96-2.87(m，1H)，2.77-2.69(m，1H)，2.36(s，3H)，2.28(s，3H)，2.05-1.97(m，1H)，1.82-1.74(m，1H)，1.67-1.55(m，1H)，1.50-1.38(m，1H).

EXAMPLE 54.3- ({ [ (3S) -1- (2-Chloropyrimidin-4-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1-methyl-1, 4-dihydroquinolin-4-one

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

The title compound was synthesized according to step 30. The residue was purified by FCC (SiHP: DCM/MeOH) to give the product as a yellowish solid (0.076g, 0.1mmol, 48% yield). A sample of 0.026g was repurified by preparative HPLC to provide the compound formate salt as a yellowish solid (0.013g, 0.03mmol, 8% yield).

ESI-MS：489.2[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.28(d，J＝5.0Hz，1H)，8.19(dd，J＝8.1，1.6Hz，1H)，8.15(s，1H)，8.03-7.97(m，2H)，7.71(ddd，J＝8.6，6.9，1.7Hz，1H)，7.64-7.60(m，1H)，7.37(ddd，J＝8.0，6.9，1.0Hz，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).

Example 55.1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] [ (1, 2-thiazol-5-yl) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one

Preparation of 1-methyl-3- ({ [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] [ (1, 2-thiazol-5-yl) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one

The title compound was synthesized following the procedure outlined in step 18, substituting 1, 2-thiazole-5-carbaldehyde (1.2 equivalents) for 2, 6-dimethylpyridine-4-carbaldehyde. The residue was purified by preparative HPLC to give the product as a beige solid (0.032g, 0.07mmol, 50% yield). ESI-MS: 446.2[ M + H]⁺

¹H NMR (300MHz, methanol-d 4) δ 8.39-8.33(m, 1H), 8.31(d, J ═ 1.7Hz, 1H), 8.20(d, J ═ 3.0Hz, 1H), 8.18(s, 1H), 7.89(dd, J ═ 4.6, 1.3Hz, 1H), 7.78(ddd, J ═ 8.5, 6.8, 1.6Hz, 1H), 7.74-7.67(m, 1H), 7.47(ddd, J ═ 8.1, 6.8, 1.2Hz, 1H), 7.38(ddd, J ═ 8.6, 3.0, 1.3Hz, 1H), 7.25-7.16(m, 2H), 4.27-4.15(m, 2H), 4.02-3.81(m, 3.81), 3.81-7.16 (m, 2H), 4.27-4.15(m, 2H), 3.81-3.81 (m, 3.81, 3H), 1.81-7.3H, 1.3 (m-7.3, 1H), 1H, 1.3 m-7.3, 1H), 3H, 1H, 1.3 m, 1H, 2H, 1H, 3H, 1H, 2H, 1H, 2H, 1H, 3H, 1H, 2H, 1H, 3H, 1H, 2H, 1H, 3H, 1H, 2H, 1H, 3H, 1H, 2H, 1H, 2H, 3H, 2H, 1H, 2H, 1H, 3H, 2H, 1H, 3H, 2H, 1H, 3, 1H, 2H, 3H, 1H, 3, 1H, 3, 2H, 3H, 2H, 3, 1H, 3, 1H, 3, 1, 3, 1H, 3, 1H, 3, 1H, 3, 1, 3, 1H, 3.

EXAMPLE 56.7-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

Preparation of 4, 6-dichloropyridine-3-carbonyl chloride

The title compound was synthesized according to step 31 a. The product was obtained as a yellow oil (1.1g, 5.2mmol, 99% yield) and used in the next step without further purification.

Preparation of ethyl 7-chloro-1-cyclopropyl-4-oxo-1, 4-dihydro-1, 6-naphthyridine-3-carboxylate

The title compound was synthesized according to step 31 b. The residue was purified by FCC (SiHP; Hex: AcOEt0 to 100%) to give the product as a yellow solid (0.38g, 1.3mmol, 25% yield).

ESI-MS：293.8[M+H]⁺

¹H NMR(300MHz，DMSO-d6)δ9.07(s，1H)，8.50(s，1H)，8.01(s，1H)，4.24(q，J＝7.1Hz，2H)，3.62(tt，J＝7.2，3.9Hz，1H)，1.32-1.21(m，5H)，1.15-1.08(m，2H).

Preparation of 7-chloro-1-cyclopropyl-4-oxo-1, 4-dihydro-1, 6-naphthyridine-3-carboxylic acid

The title compound was synthesized according to step 31 c. The product was obtained as a white solid (0.14g, 0.5mmol, 99% yield).

ESI-MS：265.8[M+H]⁺

Preparation of 7-chloro-1-cyclopropyl-1, 2, 3, 4-tetrahydro-1, 6-naphthyridin-4-one

The title compound was synthesized according to step 31 d. The residue was purified by FCC (SiHP; Hex: AcOEt 4: 1) to give the product as a white solid (0.05g, 0.2mmol, 42% yield). ESI-MS: 223.0[ M + H]⁺

Preparation of 7-chloro-1-cyclopropyl-4-oxo-1, 2, 3, 4-tetrahydro-1, 6-naphthyridine-3-carbaldehyde

The title compound was synthesized according to step 31 e. The crude product was obtained as a yellow solid (0.053g, 0.2mmol, 94% yield) and used directly in the next step. ESI-MS: 250.9[ M + H ]⁺

Preparation of 7-chloro-1-cyclopropyl-4-oxo-1, 4-dihydro-1, 6-naphthyridine-3-carbaldehyde

The title compound was synthesized according to step 31 f. The residue was purified by FCC (SiHP; DCM: MeOH 95: 5) to give the product as a pale yellow solid (0.036g, 0.2mmol, 68% yield).

ESI-MS：249.9[M+H]⁺

Preparation of 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

Following the procedure outlined in step 15, using (3S) -1- (6-methylpyridin-3-yl) -N- [ (2-methylpyridin-4-yl) methyl]Piperidin-3-amines instead of (3S) -N- [ (2-methylpyridin-4-yl) methyl]-1- (pyridin-3-yl) piperidin-3-amine and 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-1, 6-naphthyridine-3-carbaldehyde was used instead of 7-chloro-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde to synthesize the title compound. The time for the first and second stages of the procedure was extended to stir the entire weekend and for 24 hours, respectively. After dilution with DCM, the reaction mixture was diluted with NaHCO₃Washed with brine and then with anhydrous Na₂SO₄Dried and evaporated. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and repurified by FCC (SiHP; AcOEt: MeOH 9: 1) to give the product as a yellow solid (0.04g, 0.08mmol, 34% yield).

AP-MS：529.7[M+H]⁺

The product was converted to the hydrochloride salt. As a yellow solid product.

ESI-MS：529.2[M+H]⁺

¹H NMR (300MHz, methanol-d 4) δ 9.14(s, 1H), 8.26(d, J ═ 5.6Hz, 1H), 8.18(d, J ═ 3.0Hz, 1H), 7.98(s, 1H), 7.95-7.85(m, 2H), 7.57-7.47(m, 2H), 7.47-7.41(m, 1H), 4.11-4.02(m, 1H), 3.97(s, 2H), 3.91-3.67(m, 3H), 3.51-3.38(m, 1H), 3.07-2.76(m, 3H), 2.57(s, 3H), 2.46(s, 3H), 2.21-2.10(m, 1H), 1.99-1.92(m, 1H), 1.77-1.60(m, 1H), 1.24.02-2H), 1.90-1H (m, 1H).

Example 57.7- (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

The title compound was synthesized according to step 32. The filtrate was evaporated under silica and purified by FCC (SiHP deactivated with NH 3: DCM; DCM: MeOH 8: 2) and repurified by preparative HPLC to give the product as a white solid (0.031g, 0.05mmol, 47% yield).

ESI-MS：592.7[M+H]⁺

The product was converted to the hydrochloride salt. The product was obtained as a pale yellow solid.

ESI-MS：592.9[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.29(d，J＝5.1Hz，1H)，8.14(d，J＝3.0Hz，1H)，7.89(s，1H)，7.82(d，J＝6.4Hz，1H)，7.76(d，J＝11.3Hz，1H)，7.31(dd，J＝8.6，3.0Hz，1H)，7.24(s，1H)，7.20(d，J＝5.1Hz，1H)，7.08(d，J＝8.6Hz，1H)，6.15-6.10(m，1H)，3.88-3.72(m，3H)，3.68-3.58(m，3H)，3.57-3.51(m，1H)，2.85-2.69(m，2H)，2.66-2.57(m，1H)，2.43-2.38(m，2H)，2.36(s，3H)，2.34(s，3H)，2.27-2.18(m，2H)，2.07-1.88(m，1H)，1.82-1.70(m，3H)，1.70-1.62(m，2H)，1.61-1.39(m，2H)，1.25-1.17(m，2H)，0.95-0.84(m，2H).

Example 58.3- ({ [ (3S) -1- (6-methylpyridin-3-yl) piperidin-3-yl ] [ (2-methylpyridin-4-yl) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one

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

The title compound was synthesized according to step 33. The residue was suspended in water and lyophilized to give the product as a beige powder (0.08g, 0.2mmol, 14% yield).

ESI-MS：454.2[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ11.68(s，1H)，8.30(d，J＝5.1Hz，1H)，8.12(d，J＝3.1Hz，1H)，8.11-8.09(m，1H)，7.94(s，1H)，7.60(ddd，J＝8.5，6.9，1.6Hz，1H)，7.50(d，J＝8.3Hz，1H)，7.32-7.17(m，4H)，7.01(d，J＝8.5Hz，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).

Example 59.1-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

Preparation of 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

The title compound was synthesized according to step 34. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) to give the product as a beige solid (0.06g, 0.1mmol, 57% yield).

ESI-MS：528.3[M+H]⁺

¹H NMR(300MHz，DMSO-d6)δ10.97(s，1H)，8.28(d，J＝5.0Hz，1H)，8.13(d，J＝2.9Hz，1H)，7.78(s，1H)，7.74(d，J＝11.5Hz，1H)，7.44(d，J＝7.5Hz，1H)，7.28-7.12(m，3H)，7.02(d，J＝8.5Hz，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).

EXAMPLE 60.8-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

Preparation of 3- [ (2-bromophenyl) amino ] propionic acid

The title compound was synthesized according to step 35 a. The crude product was obtained as a yellow solid (2.7g, 11.1mmol, 95% yield) which was used in the next step without further purification.

Preparation of 8-bromo-1, 2, 3, 4-tetrahydroquinolin-4-one

The title compound was synthesized according to step 35 b. The residue was purified by FCC (SiHP; Hex: AcOEt 8: 2) to give the product as a yellow viscous solid (0.52g, 2.3mmol, 21% yield).

ESI-MS：225.9[M+H]⁺

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

Preparation of 8-bromo-1-methyl-1, 2, 3, 4-tetrahydroquinolin-4-one

The title compound was synthesized according to step 35 c. The residue was purified by FCC (SiHP; Hex: AcOEt 50% to 80%) to give the product as a yellow oil (0.1g, 0.4mmol, 25% yield).

ESI-MS：239.9[M+H]⁺

Preparation of 8-bromo-1-methyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized according to step 35 d. The residue was purified by FCC (SiHP; DCM: MeOH 95: 5) to give the product as a brown solid (0.03g, 0.1mmol, 23% yield).

ESI-MS：265.9[M+H]⁺

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

The title compound was synthesized according to step 35 e. The residue was purified by FCC (SiHP; DCM: MeOH 93: 7) and then by RP-FCC (Si-C18; H) ₂O/ACN) to give the product as a colorless oil (0.012g, 0.02mmol, 9% yield).

ESI-MS：546.3[M+H]⁺

The product was converted to the hydrochloride salt. As a yellow solid product.

ESI-MS：547.6[M+H]⁺

¹H NMR (400MHz, methanol-d 4) δ 8.65-8.57(m, 1H), 8.41(d, J ═ 3.0Hz, 1H), 8.38-8.33(m, 1H), 8.31(dd, J ═ 8.0, 1.6Hz, 1H), 8.26-8.22(m, 1H), 8.22-8.17(m, 2H), 8.15(dd, J ═ 7.6, 1.6Hz, 1H), 7.70(d, J ═ 9.1Hz, 1H), 7.44-7.29(m, 1H), 4.81(s, 2H), 4.67-4.57(m, 1H), 4.57-4.41(m, 2H), 4.31(s, 3H), 3.92-3.81(m, 1H), 3.73-3.57(m, 3.73-4.57 (m, 1H), 3.48H), 3.31 (m, 3H), 3.73-3.64 (m, 2H), 3.48H), 1.89-1.69(m, 1H).

EXAMPLE 61.7-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

Preparation of ethyl 2- (2, 6-dichloro-5-fluoropyridine-3-carbonyl) -3- (dimethylamino) propan-2-enoic acid ester

The title compound was synthesized according to step 36 a. The residue was purified by FCC (SiHP; Hex/AcOEt) to give the product as an orange oil (2.8g, 8.4mmol, 32% yield).

ESI-MS：335.0[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ8.04(d，J＝7.9Hz，1H)，7.95(s，1H)，3.91(q，J＝7.1Hz，2H)，3.39(s，3H)，2.93(s，3H)，0.94(t，J＝7，1Hz，3H).

Preparation of ethyl 2- (2, 6-dichloro-5-fluoropyridine-3-carbonyl) -3- [ (propan-2-yl) amino ] prop-2-enoate

The title compound was synthesized according to step 36 b. The crude product was obtained as an orange oil (1.2g, 3.4mmol, 99% yield) and used in the next step without further purification.

Preparation of ethyl 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylate

The title compound was synthesized according to step 36 c. The product was obtained as an off-white solid (0.8g, 2.6 mmol).

ESI-MS：313.9[M+H]⁺

¹H NMR (400MHz, DMSO-d6) δ 8.71(s, 1H), 8.48(d, J ═ 7.9Hz, 1H), 5.47 (heptad, J ═ 6.5Hz, 1H), 4.26(q, J ═ 7.1Hz, 2H), 1.50(d, J ═ 6.8Hz, 6H), 1.29(t, J ═ 7.1Hz, 3H).

Preparation of 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid

The title compound was synthesized according to step 36 d. The product was obtained as an off-white solid (0.67g, 0.2mmol, 90% yield) and used in the next step without further purification.

¹H NMR (400MHz, DMSO-d6) δ 14.40(s, 1H), 9.01(s, 1H), 8.73(d, J ═ 7.6Hz, 1H), 5.61 (heptad, J ═ 6.4Hz, 1H), 1.56(d, J ═ 6.7Hz, 6H).

Preparation of 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

The title compound was synthesized according to step 36 e. The residue was purified by FCC (SiHP; Hex: AcOEt 1: 1) to give the product as a yellow solid (0.46g, 0.1mmol, 81% yield)

ESI-MS：243.1[M+H]⁺

¹H NMR (400MHz, DMSO-d6) δ 7.88(d, J ═ 8.0Hz, 1H), 4.88 (heptad, J ═ 6.7Hz, 1H), 3.52-3.44(m, 2H), 2.67-2.59(m, 2H), 1.17(d, J ═ 8H), 1H6.8Hz，7H).

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

ESI-MS：239.3[M+H]⁺

¹H NMR(400MHz，DMSO-d6)δ7.66(d，J＝10.3Hz，1H)，4.99-4.88(m，1H)，3.96(s，3H)，3.46-3.39(m，2H)，2.55-2.51(m，2H)，1.18(d，J＝6.8Hz，6H).

Preparation of 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 2, 3, 4-tetrahydro-l, 8-naphthyridine-3-carbaldehyde and 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carbaldehyde

The title compound was synthesized according to step 36 f. The residue was purified by FCC (SiHP; DCM: AcOEt 9: 1) to the product as a yellow solid (0.29g, 1.0mmol, 57% yield). AP-MS: 269.0[ M + H]⁺

¹H NMR (400MHz, DMSO-d6) δ 10.14(s, 1H), 8.68(s, 1H), 8.58(d, J ═ 7.7Hz, 1H), 5.51 (heptad, J ═ 6.7Hz, 1H), 1.52(d, J ═ 6.8Hz, 6H).

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

The title compound was synthesized according to step 36 g. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1). The product was passed through FCC (SiHP; DCM/MeOH/NH)₃) And RP-FCC (Si-C18; h₂O/ACN) to give the product as a white solid (0.40g, 0.7mmol, 70% yield).

ESI-MS：549.4[M+H]⁺

¹H NMR (400MHz, methanol-d 4)68.42-8.34(m, 1H), 8.24-8.15(m, 2H), 8.06(d, J ═ 3.0Hz, 1H), 7.34(dd, J ═ 8.6, 3.0Hz, 1H), 7.30(s, 1H), 7.27-7.22(m, 1H), 7.11(d, J ═ 8.6Hz, 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), 2.0.6H, 1H), 2.6H, 2.1H, 2.6H, 1H, 2.6, 2.1H, and 1H0-1.85(m，1H)，1.77-1.57(m，2H)，1.53-1.36(m，6H).

Example 62.6-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

Preparation of 6-fluoro-7-methoxy-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridin-3-carbaldehyde the procedure outlined in step 36f was followed, using 6-fluoro-7-methoxy-1- (propan-2-yl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridin-4-one instead of 7-chloro-6-fluoro-1- (propan-2-yl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridin-4-one and using 6.1 equivalents of MnO ₂To synthesize the title compound. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) to give the product (0.09g, 0.3mmol) as a yellow solid.

ESI-MS：265.4[M+H]⁺

¹H NMR(400MHz，DMSO-d6)810.15(s，1H)，8.57(s，1H)，8.28(d，J＝9.8Hz，1H)，5.59-5.48(m，1H)，4.13(s，3H)，1.54(d，J＝6.8Hz，6H).

Preparation of 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

The title compound was synthesized according to the procedure outlined in step 36g substituting 6-fluoro-7-methoxy-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carbaldehyde for 7-chloro-6-fluoro-4-oxo-1- (propan-2-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carbaldehyde. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1) and repurified by preparative HPLC to give the product as a white solid (0.022g, 0.04mmol, 12% yield).

ESI-MS：545.3[M+H]⁺

¹H NMR (400MHz, methanol-d 4) δ 8.19(d, J ═ 5.2Hz, 1H), 8.14(d, J ═ 9.9Hz, 1H), 8.09(s, 1H), 8.07 (H, H), and a suitable NMR standard(d，J＝2.9Hz，1H)，7.34(dd，J＝8.6，3.0Hz，1H)，7.30(s，1H)，7.25(d，J＝5.3Hz，1H)，7.11(d，J＝8.6Hz，1H)，5.68(hept，J＝6.5Hz，1H)，4.14(s，3H)，3.90-3.80(m，5H)，3.64-3.56(m，1H)，3.00-2.91(m，1H)，2.89-2.81(m，1H)，2.74-2.65(m，1H)，2.44-2.37(m，6H)，2.17-2.09(m，1H)，1.97-1.87(m，1H)，1.74-1.59(m，2H)，1.46(d，J＝6.8Hz，6H).

Example 63.3- ({ [ (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

Preparation of 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

The title compound was synthesized according to step 37. The residue was purified by FCC (SiHP; DCM: MeOH 9: 1). The final compound was suspended in water and lyophilized to the product as a pale yellow powder (0.14g, 0.3mmol, 53% yield).

ESI-MS：457.5[M+H]⁺

¹H NMR(300MHz，DMSO-d6)δ8.30(d，J＝3.0Hz，1H)，8.20(dd，J＝8.0，1.6Hz，1H)，7.92(dd，J＝4.5，1.3Hz，1H)，7.87(s，1H)，7.72(ddd，J＝8.5，6.8，1.6Hz，1H)，7.64(d，J＝8.5Hz，1H)，7.38(ddd，J＝8.0，6.8，1.1Hz，1H)，7.29(ddd，J＝8.6，3.1，1.4Hz，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).

EXAMPLE 64.1-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

Preparation of ethyl 2- [ 4-bromo-2-fluorobenzoyl ] -3- (dimethylamino) prop-2-enoate

The title compound was synthesized according to step 38 a. The residue was purified by FCC (SiHP; Hex: AcOEt 2: 3) to give the title product as a yellow oil (1.24g, 3.6mmol, 81% yield).

ESI-MS：344.0[M+H]⁺

Preparation of ethyl 7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester

The title compound was synthesized according to step 38 b. The residue was purified by FCC (SiHP; Hex: AcOEt 1: 4) to give the title product as a yellow solid (0.97g, 3.3mmol, 88% yield).

AP-MS：336.0[M+H]⁺

Preparation of 7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

The title compound was synthesized according to step 38 c. The product was obtained as a yellow solid (0.8g, 3.5mmol, 92% yield).

ESI-MS：308.0[M+H]⁺

Preparation of 7-bromo-1-cyclopropyl-1, 2, 3, 4-tetrahydroquinolin-4-one

The title compound was synthesized according to step 38 d. The crude product was purified by FCC (SiHP; Hex: AcOEt 1: 1) to give the title product as a yellow solid (0.52g, 2.0mmol, 65% yield).

ESI-MS：266.0[M+H]⁺

Preparation of 7-bromo-1-cyclopropyl-4-oxo-1, 2, 3, 4-tetrahydroquinoline-3-carbaldehyde

The title compound was synthesized according to step 38 e. The title compound was obtained as an orange solid (0.44g, 1.4mmol, 91% yield).

AP-MS：294.0[M+H]⁺

Preparation of 7-bromo-1-cyclopropyl-4-oxo-1, 4-dihydroquinoline-3-carbaldehyde

The title compound was synthesized according to step 38 f. FCC purification (SiHP; DCM: MeOH 95: 5) afforded the product as a yellow solid (0.17g, 0.6mmol, 98% yield).

AP-MS：292.0[M+H]⁺

Preparation of tert-butyl 3- (1-cyclopropyl-3-formyl-4-oxo-1, 4-dihydroquinolin-7-yl) morpholine-4-carboxylate

The title compound was synthesized according to step 38 g. The residue was purified by FCC (SiHP; Hex: AcOEt 1: 1) to give the title product as a white solid (0.024g, 0.06mmol, 56% yield).

ESI-MS：399.6[M+H]⁺

Preparation of 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

The title compound was synthesized according to step 38 h. The residue was passed through FCC (RF-C18 column, ACN/H) ₂O) to give the title product as a white solid (0.017g, 0.02mmol, 42% yield).

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

The title compound was synthesized according to step 38 i. The product was obtained as a white solid (0.009g, 0.02mmol, 62% yield).

ESI-MS：579.5[M+H]⁺

¹H NMR (400MHz, methanol-d 4) δ 8.28(d, J ═ 8.3Hz, 1H), 8.16(d, J ═ 5.1Hz, 1H), 8.11-8.08(m, 2H), 8.01(s, 1H), 7.52-7.45(m, 1H), 7.36(dd, J ═ 8.6, 3.0Hz, 1H), 7.25-7.21(m, 2H), 7.12(d, J ═ 8.6Hz, 1H), 4.11(dd, J ═ 10.1, 3.3Hz, 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), 3.83 (m, 2H), 2.90 (m, 2H), 3.75-3.8 (m, 1H), 1H), 3.8.8.6H, 1H), 1.74-1.61(m, 2H), 1.39-1.28(m, 2H), 0.97-0.89(m, 2H).

Bioassay and data:

as noted above, the compounds of the invention are STING modulators and are useful for treating diseases through modulation of STING activity. The biological activity of the compounds of the invention may be determined by any suitable assay for determining the activity of the compounds as STING modulators, as well as cell lines and in vivo models.

Fluorescence thermal displacement assay

The compounds of the invention were tested for binding to human STING in a fluorescence thermal shift assay. STING was preincubated with the compound for 20 min in a volume of 16 μ l in 50mM Hepes, 150mM NaCl, pH 7.5, followed by the addition of 4 μ l of SyproOrange dye dilution (thermo fisher, cat # S-6651). The final STING concentration was 0.1 mg/ml. Thermal unfolding (thermal unfolding) was performed in a real-time PCR QuantStaudio 6 Flex system (Applied Biosystems) from 25 ℃ to 99 ℃ in a continuous variation mode with a variation rate of 0.033 ℃ per second. Data were analyzed using Protein Thermal Shift software (ThermoFisher).

Using the fluorescence thermal displacement measurement described above, examples 1 to 64 exhibited Δ Tm [ ° c ] values within the following ranges: Δ Tm < 10 ℃; and ++ -. DELTA.Tm > 10 ℃. For example, the Δ Tm [ ° c ] for FTS measurements for the following examples is:

NA-unusable

THP-1 Dual reporter assay

Testing of the Compounds of the invention Using THP-1 dual cells (Invivogen, Cat. number thpd-nfis) allows simultaneous study of the NF-. kappa.B pathway and the Interferon Regulatory Factor (IRF) pathwayAnd (4) activity. THP-1 dual cells contain a luciferase reporter gene under the control of an ISG54 (interferon stimulated gene) minimal promoter bound to five interferon stimulated response elements and a secreted embryonic alkaline phosphatase reporter gene under the control of an IFN (interferon) - β minimal promoter fused to five copies of the NF-. kappa.B consensus transcriptional response element and three copies of the c-Rel binding site. After 18 hours of stimulation with STING agonist, the media was collected and transferred to fresh cell culture plates. To verify the activity of the IRF pathway, the luminescence activity was measured immediately after adding 10. mu.l of medium to 50. mu.l (or 40. mu.l) of luminescence reagent (Invivogen, catalog number rep-qlc2) using a standard laboratory plate reader. To verify the activity of the NF-. kappa.B pathway, 20. mu.l (or 10. mu.l) of medium was mixed with 80. mu.l of detection medium (Invivogen, catalog number rep-qb2) and incubated at 37 ℃ with 5% CO ₂For 2 hours (or 1 hour) in a humid atmosphere. Next, the absorbance at 630nm (or 655nm) was recorded using a standard laboratory plate reader.

The compounds of the present disclosure as exemplified in examples 1 to 64 exhibit EC50 values within the following ranges: EC + ═ EC₅₀≥10μM；++＝1μM＜EC₅₀＜10μM；+++＝EC₅₀≤1μM。

In vivo antitumor efficacy

The efficacy of example 1 was evaluated in established CT26 murine colon cancer allografts in female Balb/C mice. Example 1 was formulated in 10% Captisol in PBS and administered intravenously once every five days, three times. Solutions were prepared fresh prior to each application. The CT26 tumor responded significantly to treatment with example 1 at a moderate effective dose of 2mg/kg and a full effective dose of 3mg/kg (see fig. 1(i) to (iii)). A delay in tumor growth was observed in both treatment groups when compared to the control group. By the end of the study, 3 and 6 complete responses were recorded on day 42 for mice treated with 2mg/kg and 3mg/kg E5Dx3, respectively. For these groups, TGI reached 52% and 80% on day 11 (at least 90% of the animals in each group participated in the last day of the study), respectively (see figure 2).

Re-challenge studies were performed on mice with complete responses. CT26 cells were injected ventrally (flank) opposite the original inoculation site. Naive mice were included in the re-challenge study as a control for tumor growth kinetics. None of the three mice with a complete response previously dosed at 2mg/kg showed tumors. In the case of six mice with complete response previously dosed at 3mg/kg, two of them developed tumors, however a significant delay in tumor growth was observed (see fig. 3(i) to (iii)).

In particular, the invention relates to the following items:

1. a compound of formula (I) or a salt, stereoisomer, tautomer, or N-oxide thereof:

wherein

X¹Is CR¹Or N;

X²is CR³Or N;

R¹、R²and R³Independently is H; OH; CN; halogen; c₁-C₄-an alkyl group; c₁-C₄-an alkoxy group; an aryloxy group; a benzyloxy group; c (═ O) R^E；NR^FC(＝O)R^E；NR^F-(C₁-C₄-alkylene) -C (═ O) R^E(ii) a Or a 4-to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclic group; carbocyclyl-C₁-C₂-an alkyl group; a heterocyclic group; heterocyclyloxy or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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-mentioned group is independently unsubstituted or substituted with one or more identical or different substituents R^XSubstitution;

R⁴is a 5-or 6-membered aromatic carbocyclic or heterocyclic ring, or a 9-or 10-membered aromatic carbocyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least one nitrogen atom and optionally one or more selected from O, N or SThe same or different further heteroatoms, wherein the N-atoms and/or S-atoms are independently oxidized or unoxidized, and wherein each substitutable carbon or heteroatom in the above rings is independently unsubstituted or substituted with one or more same or different substituents R ^XSubstitution;

R⁵is a 5-or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 with one or more identical or different substituents R^YSubstitution;

and wherein

R^NIs H, CH₃、HO(C＝O)-C₁-C₄-alkyl, or a 3-or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic group comprises 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^XSubstitution;

R^Ais H; halogen; CN; OH; c₁-C₃-an alkyl group; c₁-C₃-an alkoxy group; or a 3-to 6-membered saturated, partially or fully unsaturated or aromatic carbocyclic group; or heterocyclyl, wherein the above-mentioned heterocyclyl 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-mentioned groups is independently unsubstituted or substituted with one or more identical or different substituents RX;

R^CAnd R^DIndependently is H, or C₁-C₂-an alkyl group; or

R^CAnd R^DTogether 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 heterocyclic ring comprises 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 heterocyclic ring is independently unsubstituted or substituted with one or more identical or different substituents R^XSubstitution;

R^Eis H, C₁-C₂Alkyl, phenyl, benzyl, OR^GOr NR^HR^I(ii) a Or a 5-or 6-membered saturated, partially or fully unsaturated heterocyclyl group, wherein the heterocyclyl comprises 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 groups is independently unsubstituted or substituted with one or more identical or different substituents R^FSubstitution;

R^Fis H, C₁-C₂Alkyl radical, C₃-C₆-cycloalkyl, phenyl, benzyl, or C (═ O) NR^HR^I；

R^GIs H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C ₁-C₂-alkyl, heterocyclyl, or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises one or more identical or different heteroatoms selected from O, N or S, wherein the N-atoms are independently oxidized or unoxidized;

R^Hand R^IIndependently H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl, or heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises one or more identical or different heteroatoms selected from O, N or S, wherein the N-atoms are independently oxidized or unoxidized; or

R^HAnd R^ITogether with the nitrogen atom to which they are bonded form a 5-or 6-membered saturated, partially or fully unsaturated or aromatic hetero ringA ring, wherein the heterocyclic ring comprises 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 heterocyclic ring is independently unsubstituted or substituted with one or more identical or different substituents R^XSubstitution;

R^Xis halogen, CN, NO₂、C₁-C₂Alkyl radical, C₁-C₂-alkoxy, C (═ O) R^EOr two R^XTo form ═ O;

R^Yis halogen; CN; OH; c ₁-C₂-an alkyl group; c₁-C₂-alkyl-OH; c₃-C₆-a cycloalkyl group; c₁-C₂-an alkoxy group; NR (nitrogen to noise ratio)^CR^D；S(＝O)₂NR^CR^D；C(＝O)R^E(ii) a Or a 5-or 6-membered saturated, partially or fully unsaturated or aromatic carbocyclic group; carbocyclyl-C₁-C₂-an alkyl group; a heterocyclic group; and heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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-mentioned group is independently unsubstituted or substituted with one or more identical or different substituents R^XSubstitution; or two R^YTo form ═ O; or two R attached to the same or adjacent carbon atoms^YA 3-membered carbocyclic ring may be formed.

2. The compound according to item 1, wherein

R^AIs H.

3. The compound according to item 1 or 2, wherein

R^NIs H, CH₃Or cyclopropyl, preferably CH₃。

4. The compound according to any one of items 1 to 3, wherein

R¹、R²And R³Is H.

5. The compound according to any one of items 1 to 4, wherein

R⁵Is a 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 with one or more identical or different substituents R ^YAnd (4) substitution.

6. The compound according to any one of items 1 to 5, wherein

R⁵Is 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^YAnd (4) substitution.

7. The compound according to any one of items 1 to 6, wherein

R⁵Is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted by one or more identical or different substituents R^YSubstitution; and R wherein the nitrogen atom of the piperidine ring is preferably pyridyl^YAnd (4) substitution.

8. The compound according to any one of items 1 to 7, wherein

R⁴Is pyridyl, wherein each substitutable carbon or heteroatom in the ring is independently unsubstituted or substituted by one or more identical or different substituents R^XAnd (4) substitution.

9. The compound according to any one of items 1 to 8, wherein

X¹Is CR¹(ii) a And

X²is CR³；

And wherein

R¹And R³Preferably H.

10. The compound of any of clauses 1 to 9, 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 } meth-yl -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 ] amino } 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-1-yl) -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, and, 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 -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, and, 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) piperidine- 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) -l, 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 ] quinolin-1, 4-one The group ] [ (3S) -1- (pyridin-3-yl) piperidin-3-yl ] amino } methyl) -4-oxo-1, 4-dihydroquinolin-7-yl ] piperidine-4-carboxylic acid 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 and 1-cyclopropyl-6, 7-difluoro-3- ({ [ (2-methoxypyridin-4-yl) methyl ] [ (3S) -1- (6-methylpyridin-3-yl) piperidine- 3-yl ] amino } methyl) -1, 4-dihydroquinolin-4-one.

11. The compound according to any one of items 1 to 10, wherein the compound according to formula (I) is preferably selected from the group consisting of 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 -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) piperidine- 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, and mixtures thereof, 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.

12. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of items 1 to 11 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

13. A compound according to any one of items 1 to 11 or a pharmaceutical composition according to item 12 for use in medicine.

14. A compound according to any one of items 1 to 11 or a pharmaceutical composition according to item 12 for use in the treatment of a disease selected from cancer, pre-cancerous syndrome and infectious disease; or in immunogenic compositions or as vaccine adjuvants.

15. A compound according to any one of items 1 to 11 or a pharmaceutical composition according to item 12 for use in the treatment of a disease selected from the group consisting of an inflammatory disease, an allergic disease and an autoimmune disease.

Claims (16)

1. A compound of formula (I) or a salt, stereoisomer, tautomer, or N-oxide thereof,

wherein the content of the first and second substances,

X¹is CR¹Or N;

X²is CR³Or N;

R¹、R²and R³Independently H, OH, CN, halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, aryloxy, benzyloxy, C (═ O) R^E、NR^FC(＝O)R^E、NR^F-(C₁-C₄-alkylene) -C (═ O) R^EOr 4-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, heterocyclyloxy or heterocyclyl-C ₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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^XSubstitution;

R⁴is a 5-or 6-membered aromatic carbocyclic or heterocyclic ring,Or a 9-or 10-membered aromatic carbobicyclic or heterobicyclic ring, wherein the heterocyclic or heterobicyclic ring comprises at least one nitrogen atom and optionally one or more additional heteroatoms, same or different, selected from O, N or S, wherein the N-atom and/or S-atom is independently oxidized or not oxidized, and wherein each substitutable carbon or heteroatom in the above rings is independently unsubstituted or substituted with one or more same or different substituents R^XSubstitution;

R⁵is a 5-or 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R ^YSubstitution;

and wherein

R^NIs H, C₁-C₄-alkyl, HO (C ═ O) -C₁-C₄-alkyl, or a 3-or 4-membered saturated carbocyclic or heterocyclic group, wherein the heterocyclic ring comprises 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^XSubstitution;

R^Ais H, halogen, CN, OH, C₁-C₃Alkyl radical, C₁-C₃-alkoxy or a 3-to 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic or heterocyclic group, wherein the above-mentioned heterocyclic group comprises 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 not oxidized, 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^XSubstitution;

R^Cand R^DIndependently is H or C₁-C₂-an alkyl group; or

R^CAnd R^DTogether with the nitrogen atom to which they are bound, form a 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom in the heterocyclic ring is independently unsubstituted or is substituted with one or more identical or different substituents R ^XSubstitution;

R^Eis H, C₁-C₂Alkyl, phenyl, benzyl, OR^GOr NR^HR^I(ii) a Or a 5-or 6-membered saturated, partially or fully unsaturated heterocyclyl, wherein the heterocyclyl 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 groups is independently unsubstituted or substituted with one or more identical or different substituents R^FSubstitution;

R^Fis H, C₁-C₂Alkyl radical, C₃-C₆-cycloalkyl, phenyl, benzyl or C (═ O) NR^HR^I；

R^GIs H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-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 are independently oxidized or not oxidized;

R^Hand R^IIndependently H, C₁-C₂-alkyl, or 5-or 6-membered aromatic carbocyclyl, carbocyclyl-C₁-C₂-alkyl, heterocyclyl or heterocyclyl-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 are independently oxidized or not oxidized; or

R^HAnd R^ITogether with the nitrogen atom to which they are bound A 5-or 6-membered saturated, partially or fully unsaturated, or aromatic heterocyclic ring, wherein the heterocyclic ring comprises 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 heterocyclic ring is independently unsubstituted or substituted with one or more identical or different substituents R^XSubstitution;

R^Xis halogen, CN, NO₂、C₁-C₂Alkyl radical, C₁-C₂-haloalkyl group, C₁-C₂-alkoxy, C (═ O) R^EOr two R^XForm ═ O, or two R^XTogether with the carbon atom to which they are bonded form a 3-to 5-membered saturated, partially or fully unsaturated, or aromatic carbocyclic ring;

R^Yis halogen, CN, OH, C₁-C₂Alkyl radical, C₁-C₂alkyl-OH, C₃-C₆-cycloalkyl, C₁-C₂Alkoxy, NR^CR^D、S(＝O)₂NR^CR^D、C(＝O)R^EOr 5-or 6-membered saturated, partially or fully unsaturated, or aromatic carbocyclic group, carbocyclic group-C₁-C₂-alkyl, heterocyclyl, and heterocyclyl-C₁-C₂-alkyl, wherein the above-mentioned heterocyclic ring comprises 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 not oxidized, 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 ^XSubstitution; or two R^YTo form ═ O; or two R attached to the same or adjacent carbon atoms^YA 3-membered carbocyclic ring can be formed.

2. The compound of claim 1, wherein

R^AIs H.

3. A compound according to claim 1 or 2, wherein

R^NIs H, CH₃Or cyclopropyl, preferably CH₃。

4. A compound according to any one of claims 1 to 3, wherein:

R¹、R²and R³Is H.

5. The compound according to any one of claims 1 to 4, wherein:

R⁵is a 6-membered saturated heterocyclic ring, wherein the heterocyclic ring comprises 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 not oxidized, and wherein each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more identical or different substituents R^YAnd (4) substitution.

6. The compound according to any one of claims 1 to 5, wherein:

R⁵is 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^YAnd (4) substitution.

7. The compound according to any one of claims 1 to 6, wherein:

R⁵is piperidine, wherein each substitutable carbon atom in the piperidine ring is independently unsubstituted or substituted with one or more identical or different substituents R ^YSubstitution; and wherein the nitrogen atom of the piperidine ring is via R^YSubstituted, R^YIs pyridyl, which is unsubstituted or substituted by one or more identical or different substituents R^XIs substituted in which R^XPreferably methyl.

8. The compound according to any one of claims 1 to 7, wherein:

R⁴is pyridyl, in which each of the rings may be substitutedIndependently unsubstituted or substituted by one or more identical or different substituents R^XAnd (4) substitution.

9. The compound according to any one of claims 1 to 8, wherein:

X¹is CR¹(ii) a And

X²is CR³；

And wherein

R¹And R³Preferably H.

10. The compound according to any one of claims 1 to 9, 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) piperidine- 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- The group) 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, and mixtures thereof, 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 -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, and, 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) piperidine- 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 ] quinolin-1, 4-one The group ] [ (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) piperi-ne Pyridin-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- (pyrido-3-yl) amino } methyl) 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-4-yl) methyl ] amino } methyl) -1, 4-dihydroquinolin-4-one, and mixtures thereof Pyridin-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 ], [ solution (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) -l, 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-oxo-4-yl) piperidine Piperazin-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, 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.

11. The compound according to any one of claims 1 to 10, wherein the compound according to formula (I) is selected from the group consisting of 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) piperidine -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, and mixtures thereof, 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, and, 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, methods of making and using the same, 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, and pharmaceutically acceptable salts thereof, 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.

12. The compound according to any one of claims 1 to 9, wherein the compound according to formula (I) is selected from 1-methyl-3- ({ [ (3S) -1- (5-methyl-1, 3, 4-

Oxadiazol-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 radical]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; and is 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.

13. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 12 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

14. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in medicine.

15. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in the treatment of a disease selected from cancer, pre-cancerous syndrome and infectious disease; or in immunogenic compositions or as vaccine adjuvants.

16. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in the treatment of a disease selected from inflammatory, allergic and autoimmune diseases.

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