JPWO2014034719A1 - Quinoline derivative having TLR inhibitory action - Google Patents

Abstract

Inhibits TLR3, 7 and / or 9 and is effective in preventing and / or treating cardiomyopathy due to autoimmune disease, inflammation, allergy, asthma, graft rejection, GvHD or sepsis, by the following general formula (1) Or a salt thereof or a solvate thereof. (B: (substituted) carbocycle / heterocycle; W: C2-6 alkenylene, etc .; X, V: bond, C (0) NH, NHC (0), etc .; U: bond, C1-6 alkylene, where X, (Except when V and U are all connected)

Description

  The present invention has a nucleic acid receptor inhibitory action and is caused by inhibition of a signal downstream of the nucleic acid receptor, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis ( MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis cardiomyopathy The present invention relates to a novel compound useful as a prophylactic and / or therapeutic agent.

  As pathogens enter the body, the immune system quickly identifies and eliminates them. In mammals, the immune system can be broadly divided into innate immunity and acquired immunity. In acquired immunity, a myriad of receptors having different antigen specificities are expressed on the surface of T cells and B cells by a method called gene rearrangement, and deal with any unknown foreign antigen (Non-patent Document 1).

  On the other hand, the innate immune system carried by macrophages, dendritic cells, etc. was thought to eliminate microorganisms with a nonspecific immune response, but discovery of a Toll-like receptor (TLR) As a result of the rapid progress of various researches centering on cells and dendritic cells, it has become clear that there is a characteristic microbial recognition mechanism that does not have as high affinity and specificity as antigen recognition in the adaptive immune system. (Non-Patent Document 2). In particular, nucleic acid recognition receptors that transmit signals into cells typified by TLR not only play a role in catching infection at the front line, but also transmit signals to cells and turn on the activation of the innate immune system. There is an important role to do. In that sense, induction of gene expression of cytokines and chemokines such as type I interferon and the group of molecules involved in antigen presentation induced by activation of the innate immune system known so far, and subsequent activity of the adaptive immune system It has become clear that the pathway leads to activation of specific immune responses by coordinating with the development (Non-patent Document 2).

  Of the nucleic acid receptors, TLR3 recognizes virus-derived double-stranded RNA, and TLR7 similarly recognizes virus-derived single-stranded RNA. TLR9 recognizes and activates bacterial CpG DNA. CpG DNA repeats at a certain frequency with a characteristic sequence of bacterial genomic DNA that is unmethylated CpG sequences. In mammalian genomic DNA, the frequency of CpG sequences is low and methylated frequently, so there is no immunostimulatory effect (Non-patent Document 3).

  Much research has been done on TLRs 7 and 9 that have been reported as RNA and DNA sensors so far, and the details have become quite clear. TLRs 7 and 9 function as receptors that recognize extracellular RNA and DNA in endosomes and lysosomes, and induce gene expression of type I interferons and inflammatory cytokines. Both of these are via a MyD88-dependent signal transduction pathway, whereas the former involves IRAK1 / IKKα-IRF-7, while the latter involves MyD88, which involves NF-κB, IRF-5, and MAP kinase pathways. Is known to associate with IRF-1 and IRF-4 in addition to IRF-7 and IRF-5 (Non-Patent Documents 4, 5, and 6), but IRF transcription factors involved downstream of TLR9 The type and role differ depending on the cell type.

  As shown above, the nucleic acid receptor recognizes RNA or DNA as a ligand, but under normal conditions, the self-nucleic acid is not recognized as a ligand and does not activate innate immunity. This is because the self-nucleic acid released by cell death is degraded before being recognized by the nucleic acid receptor by a nuclease in the serum. In addition, intracellular localization not in the cell surfaces of TLR3, 7 and 9 but in endosomes is considered as a mechanism that does not recognize self-nucleic acids. However, under the circumstances where autoimmune reactions and inflammation are occurring, such a defense mechanism may be disrupted, forming a complex with an endogenous protein and activating a nucleic acid receptor signal (Non-Patent Document). 7).

  By inhibiting nucleic acid receptors from these, RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or It is considered possible to improve cardiomyopathy due to sepsis. As shown below, these several diseases have a specific relationship with TLR.

Regarding RA, it has been reported that onset and pathology were suppressed in a pristane-induced rat arthritis model by inhibiting TLR9 using a nucleic acid sequence having a TLR9 inhibitory effect (Non-patent Document 8). In addition, hydroxychloroquine, an antimalarial drug, is known to have an inhibitory action on TLR7 and 9 by suppressing acidification of endosomes, and is approved as a therapeutic drug for RA and SLE in most countries except Japan ( Non-patent document 9).
Regarding SLE, the attenuation of antinuclear antibodies observed in SLE-like pathogens in TLR9 knockout mice has been reported (Non-patent Document 10), and similar results have been reported in experiments using TLR9-inhibiting nucleic acids. (Non-Patent Document 11). Furthermore, a low molecular weight compound having a similar action has also been reported (CPG 52364: Patent Document 1).

  In TLR7 knockout mice (MRL / lpr mice that spontaneously develop SLE-like symptoms), it is known that the onset of SLE-like symptoms such as a decrease in urinary protein and blood IgG is suppressed (non-patented) Reference 12, 13). Furthermore, suppression of SLE-like symptoms has also been reported by administering an inhibitory nucleic acid (Non-patent Document 11). From these reports, it is inferred that TLR7 is also very useful as a target of SLE. In the EAE model, which is a model of MS in mice, there is a report that TLR2 and TLR9 knockout mice have a weak pathological condition, and the involvement of TLR has been shown (Non-Patent Document 14).

  It has been reported that salivary gland epithelial cells of SS patients are highly sensitive to apoptosis due to activation of TLR3, and TLR is considered to be involved (Non-patent Document 15).

  In enteritis such as IBD, it has been shown that various TLRs are involved in inflammation using a mouse enteritis model. When TLR inhibition acts on a diseased body, TLR activation is suppressed on the diseased body. Although the case where it works is reported and it is generally not thought that only an inhibitory effect functions in a pathological condition recovery | restoration, involvement with TLR is shown (nonpatent literature 16).

  There was a report that the contractility of cardiomyocytes was lost by the inflammatory cytokine produced by the ligand CpG-B DNA, and its effect was attenuated in TLR9 knockout mice (Non-patent Document 17). From these facts, it is considered to be involved in cardiomyopathy due to sepsis.

  Hydroxychloroquine is known to have a TLR9 inhibitory action and is already used in clinical practice, but it is not so strong as a TLR9 inhibitory action, and a drug having a stronger TLR9 inhibitory action has a stronger drug effect. I can expect. Hydroxychloroquine has concerns about side effects such as chloroquine retinopathy, but there is a possibility that such side effects may be eliminated by compounds having different skeletons.

  Therefore, a low molecular weight drug that exhibits a strong nucleic acid receptor inhibitory action and can be administered orally will be used in future RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, vasculitis and other autoimmune diseases, inflammation It is considered useful in the treatment of cardiomyopathy due to allergies, asthma, graft rejection, GvHD or sepsis.

  As a quinoline derivative, a neurokinin 3 (NK-3) receptor modulator characterized by having an aryl or heteroarylalkylcarbamoyl group at the 4-position of quinoline is known, and its therapeutic effect on central diseases and inflammatory diseases is known. Known (Patent Document 2). In addition, it has been known that it has the ability to modulate melanin-concentrating hormone (MCH) receptor and has an effect as a therapeutic agent for diabetes and obesity (Patent Documents 3, 4, and 5). Furthermore, the effect as a inflammatory disease therapeutic agent is also known, for example, having the ability to inhibit VLA-4 (Patent Document 6) and the effect of suppressing the immunostimulatory action by oligodeoxynucleotides having a CpG motif. (Non-Patent Documents 18 and 19, and Patent Documents 7 and 8) differ from the group of compounds contained in the present invention in terms of the substitution mode.

International Publication No. 2008/152471 International Publication No. 2000/064877 International Publication No. 2004/052370 International Publication No. 2004/052371 JP 2005-519876 Gazette JP 2005-535583 A International Publication No. 2000/076982 International Publication No. 2008/030455

Satoshi Uematsu et al. Virus, 54: 145-152 (2004) Takaoka Yukinori et al. Virus, 58: 37-46 (2008) Takeda K et al. , Annu. Rev. Immunol. , 21: 335-376 (2003) Honda K et al. , Proc. Natl. Acad. Sci. USA, 101: 15416-15421 (2004) Negishi H et al. , Proc. Natl. Acad. Sci. USA, 102: 15989-15994 (2005). Negishi H et al. , Proc. Natl. Acad. Sci. USA, 103: 15136-15141 (2006) Kim, Y. et al. M et al. , Nature, 452: 234-238 (2008). S Herman et al. , Ann. Rheum. Dis. , 70: A39 doi: 10.136 / ard. 2010.148973.8 (2011) Naoto Yokogawa, Current Therapy, 28: 85-91, 2010 Sean R. Christensen et al. , J .; Exp. Med. 202: 321-331 (2005) Rahul D. Poweret al. , J Am Soc Nephrol 18: 1721-1731 (2007) Sean R. Christensen et al. , Immunity, 25: 417-428 (2006). Kevin M. Nickerson al. , J .; Immunol, 184: 1840-1848 (2010) Socorro Miranda-Hernandez, al. , J Immunol, 187: 791-804 (2011) Manoussakis MN, al. , J Autoimmun, 35 (3): 212-218 (2010) Elke Cario, Inflamm Bowel Dis, 14 (3): 411-21 (2008) Pascal Knefermannal. , Cardiovascular Research, 78: 26-35 (2008) Journal of Medicinal Chemistry (2003), 46 (7), 1242-1249 Bioorganic & Medicinal Chemistry (2007), 15 (1), 324-332

  An object of the present invention is to provide a novel compound having a low molecular weight nucleic acid receptor inhibitory action. More particularly, RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis prevention and / or cardiomyopathy Another object is to provide a medicament useful for treatment.

  In view of the above situation, as a result of searching for compounds having an inhibitory action on TLR3, 7, and / or 9, the present inventors have found that the quinoline derivative represented by the following general formula (1) expresses human TLR3 endogenously. Test using ECV304 derived from human vascular endothelial cells, test using HEK293 cells derived from human fetal kidney cells expressing human TLR7, HEK293 cells derived from human fetal kidney cells expressing human TLR9 And the present invention has been completed.

That is, this invention relates to the invention shown below.
[1]
The following general formula (1):

[Where:
Ring A represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group,
Here, ring A is a C _1-6 alkyl group, a phenyl group, a hydroxy C _1-3 alkyl group, an amino C _1-6 alkyl group, a C _1-3 alkylamino C _1-6 alkyl group, or a C _1-3 alkyl. From carbamoyl C _1-6 alkylcarbonyl group, C _1-3 alkylcarbamoyl C _1-6 alkyl group, C _1-6 alkyloxycarbonyl group, benzyloxy C _1-6 alkyl group and benzyloxycarbonyl C _1-6 alkyl group May have 1 to 3 substituents selected from the group consisting of
Y represents a bond or a phenylene group;
Z represents a bond, a C _1-6 alkylene group, a N—R ⁷ group or an oxygen atom;
Here, R ⁷ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Either R ² or R ⁴ represents an R ⁸ group and the other is represented by formula (2):

{Where
Ring B represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (3):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
May have 1 to 3 substituents selected from the group consisting of
X and V are the same or different and each represents a bond, an oxygen atom, N—R ¹¹ , a C (O) NH group or a NHC (O) group,
Here, R ¹¹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Here, when ring B is a 5- or 6-membered saturated nitrogen-containing heterocyclic group,
U represents a bond or a C _1-6 alkylene group;
W represents a C _1-6 alkylene group or a C _2-6 alkenylene group, wherein the C _1-6 alkylene group or C _2-6 alkenylene group may have one or two oxo groups,
However, X, V and U do not show a bond at the same time,
Here, when ring B is a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
X = NH group, W = C _1-6 alkylene group, V = NH group, and U = bond are shown, or X = NHC (O) group, W = C _1-6 alkylene group, V = NH group, And U = C _{1-6 represents an} alkylene group}
Indicate
R ¹ , R ³ , R ⁵ , R ⁶ and R ⁸ are the same or different and may be substituted with a hydrogen atom; a C _1-3 alkyl group; a C _1-3 alkyloxy group; a C _1-3 alkyl group. A good 5- or 6-membered saturated heterocyclic group; or a C _6-10 aryl C _1-3 alkyl group,
However,
Y represents a phenylene group,
Z represents a bond, and R ² represents formula (4):

{Where
W represents a C _1-6 alkylene group,
Ring B represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (5):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
1 to 3 substituents selected from the group consisting of:
Unless indicated
^{Additionally,} N 1 - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide, and ^N 1 - [4 - methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (2-morpholinoethyl) except succinamide]
Or a salt thereof, or a solvate thereof.

[2]
Ring A is a piperazinyl group, piperidinyl group or morpholinyl group, Ring B is a piperazinyl group, piperidinyl group, morpholinyl group, pyridyl group or quinolyl group, and Ring C is a cyclopropyl group, phenyl group, piperidinyl group or piperazinyl group The compound or a salt thereof, or a solvate thereof according to the above [1], which is a group.

[3]
N ¹ - (-4- 1- benzyl-yl) -N ⁴ - (quinolin-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-morpholino-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (3- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- methoxybenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2,4- difluorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide;
6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide,
N- (1-benzylpiperidin-4-yl) -6-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} hexanamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide ,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide;
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N ^{1, N 3} - bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide;
2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide;
2- (4-methylpiperazin-1-yl) -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- 4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Carboxamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide,
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4- methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - (4-methyl-2 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} quinolin-6-yl) succinamide,
N ¹ - [4- benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (-4- 1- benzyl-yl) succinamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide,
2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide,
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide,
6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine,
N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
tert-butyl 4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazine-1-carboxylate,
(E) -3- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide,
3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide,
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ,
(E) -1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine,
1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl} piperidin-4-amine,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] oxy} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide,
Benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide;
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-{[4- (4-methylpiperazin-1-yl) phenyl] amino} quinoline-2-carboxamide ,
And a compound selected from the group consisting of N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine, or a salt thereof, or a solvate thereof.

[4]
The following general formula (1):

[Where:
Ring A represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group,
Here, ring A is a C _1-6 alkyl group, a phenyl group, a hydroxy C _1-3 alkyl group, an amino C _1-6 alkyl group, a C _1-3 alkylamino C _1-6 alkyl group, or a C _1-3 alkyl. From carbamoyl C _1-6 alkylcarbonyl group, C _1-3 alkylcarbamoyl C _1-6 alkyl group, C _1-6 alkyloxycarbonyl group, benzyloxy C _1-6 alkyl group and benzyloxycarbonyl C _1-6 alkyl group May have 1 to 3 substituents selected from the group consisting of
Y represents a bond or a phenylene group;
Z represents a bond, a C _1-6 alkylene group, a N—R ⁷ group or an oxygen atom;
Here, R ⁷ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Either R ² or R ⁴ represents an R ⁸ group and the other is represented by formula (2):

{Where
Ring B represents a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (3):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
May have 1 to 3 substituents selected from the group consisting of
X and V are the same or different and each represents a bond, an oxygen atom, N—R ¹¹ , a C (O) NH group or a NHC (O) group,
Here, R ¹¹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
U represents a bond or a C _1-6 alkylene group;
W represents a C _1-6 alkylene group or a C _2-6 alkenylene group, wherein the C _1-6 alkylene group or C _2-6 alkenylene group may have one or two oxo groups,
However, X, V and U do not indicate a bond at the same time}
Indicate
R ¹ , R ³ , R ⁵ , R ⁶ and R ⁸ are the same or different and may be substituted with a hydrogen atom; a C _1-3 alkyl group; a C _1-3 alkyloxy group; a C _1-3 alkyl group. A good 5- or 6-membered saturated heterocyclic group; or a C _6-10 aryl C _1-3 alkyl group,
However,
Y represents a phenylene group,
Z represents a bond, and R ² represents formula (4):

{Where
W represents a C _1-6 alkylene group, ring B represents a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (5):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
1 to 3 substituents selected from the group consisting of:
Except when indicating
Or at least one inhibitor selected from the group consisting of TLR3, TLR7, and TLR9, which comprises a compound represented by the formula:

[5]
Ring A is a piperazinyl group, piperidinyl group or morpholinyl group, Ring B is a phenyl group, piperazinyl group, piperidinyl group, morpholinyl group, pyridyl group or quinolyl group, and Ring C is a cyclopropyl group, phenyl group, piperidinyl group The inhibitor according to the above [4], which is a group or a piperazinyl group.

[6]
N ¹ - (-4- 1- benzyl-yl) -N ⁴ - (quinolin-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-morpholino-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (3- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- methoxybenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2,4- difluorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide;
6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide,
N- (1-benzylpiperidin-4-yl) -6-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} hexanamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide ,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide;
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N ^{1, N 3} - bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide;
2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide;
2- (4-methylpiperazin-1-yl) -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- 4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Carboxamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide,
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4- methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - (4-methyl-2 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} quinolin-6-yl) succinamide,
N ¹ - [4- benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (-4- 1- benzyl-yl) succinamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide,
2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide,
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide,
6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine,
N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
tert-butyl 4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazine-1-carboxylate,
(E) -3- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide,
3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide,
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ,
(E) -1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine,
1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl} piperidin-4-amine,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] oxy} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide,
Benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [4- methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (2-morpholinoethyl) succinamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide;
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-{[4- (4-methylpiperazin-1-yl) phenyl] amino} quinoline-2-carboxamide ,
And N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine or a salt thereof, or a solvate thereof, as an active ingredient, At least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9;

[7]
Autoimmune disease, inflammation, allergy, asthma, graft rejection, graft, comprising the compound according to any one of [4] to [6] above, or a salt thereof, or a solvate thereof as an active ingredient A preventive and / or therapeutic agent for cardiomyopathy due to host disease or sepsis.

[8]
The preventive and / or therapeutic agent according to [7] above, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, Behcet's syndrome or vasculitis .

  The present invention also relates to a disease caused by activation of at least one signal selected from the group consisting of TLR3, TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS). ), Multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis and other autoimmune diseases, inflammation, allergy, asthma, graft rejection and graft-versus-host disease (GvHD) And the like, or a salt thereof, or a solvate thereof, for the manufacture of a preventive and / or therapeutic agent.

  In addition, the present invention provides a TLR3, wherein an effective amount of the compound according to any one of the above [4] to [6], or a salt thereof, or a solvate thereof is administered to a patient. Diseases resulting from activation of at least one signal selected from the group consisting of TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS) , Prevention and / or treatment methods for inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection and graft-versus-host disease (GvHD) About.

  Moreover, this invention relates to the compound as described in any one of said [4]-[6] for use as a pharmaceutical, its salt, or those solvates.

  The present invention also relates to a disease caused by activation of at least one signal selected from the group consisting of TLR3, TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) , Multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) Alternatively, the present invention relates to the compound according to any one of [4] to [6] above, or a salt thereof, or a solvate thereof for use in prevention and / or treatment of cardiomyopathy due to sepsis or the like.

  The quinoline derivative of the present invention, or a salt thereof, or a solvate thereof, which is an active ingredient of a TLR3, 7, and / or 9 inhibitor, is RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, It is useful as an agent for preventing and / or treating autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or cardiomyopathy due to sepsis.

It is a figure which shows the time-dependent change of the arthritis score by the compound of Example 19. In the figure, ** and *** indicate a risk rate of less than 1% (p <0.01) and less than 0.1% (p <0. 001). FIG. 14 shows the anti-type 2 collagen IgG antibody titer 15 days after additional sensitization with the compound of Example 19. In the figure, ** indicates that the risk rate is less than 1% (p <0.01) in Steel's multiple comparison test using the control group as a comparison control. It is a figure which shows the time-dependent change of the arthritis score by the compound of Example 39. In the figure, ** indicates that the risk rate is less than 1% (p <0.01) in Steel's multiple comparison test using the control group as a comparison control. It is a figure which shows the anti- type 2 collagen IgG antibody titer 15 days after the additional sensitization by the compound of Example 39. In the figure, * indicates that each of the risk ratios is less than 5% (p <0.05) in Steel's multiple comparison test using the control group as a comparison control.

  Hereinafter, the present invention will be described in detail. The definitions of terms in the present invention are as follows.

  As used herein, “5- or 6-membered saturated nitrogen-containing heterocyclic group” refers to a monocyclic 5- or 6-membered saturated cyclic group containing one or more nitrogen atoms. Specifically, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, etc. are mentioned, for example.

As used herein, “C _6-10 aryl group” means an aryl group having 6 to 10 carbon atoms. Specifically, a phenyl group, an azulenyl group, a naphthyl group, etc. are mentioned, for example.

  As used herein, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

As used herein, “C _1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group.

As used herein, “C _1-3 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl groups and the like.

As used herein, “amino C _1-6 alkyl group” means the above C _1-6 alkyl group substituted with an amino group. Specifically, for example, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminoisobutyl, amino-sec-butyl, amino-tert-butyl, aminopentyl, aminoisopentyl, amino-2- Methylbutyl, aminoneopentyl, amino-1-ethylpropyl, aminohexyl, aminoisohexyl, amino-4-methylpentyl, amino-3-methylpentyl, amino-2-methylpentyl, amino-1-methylpentyl, amino- 3,3-dimethylbutyl, amino-2,2-dimethylbutyl, amino-1,1-dimethylbutyl, amino-1,2-dimethylbutyl, amino-1,3-dimethylbutyl, amino-2,3-dimethyl Butyl, amino-1-ethylbutyl, amino-2-ethyl Butyl group and the like.

As used herein, “C _1-3 alkylamino C _1-6 alkyl group” means the above amino C _1-6 alkyl group in which a C _1-3 alkyl group is substituted at the amino group site. Specifically, for example, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminoisopropyl, methylaminobutyl, methylaminoisobutyl, methylamino-sec-butyl, methylamino-tert-butyl, methylaminopentyl, methylamino Isopentyl, methylamino-2-methylbutyl, methylaminoneopentyl, methylamino-1-ethylpropyl, methylaminohexyl, methylaminoisohexyl, methylamino-4-methylpentyl, methylamino-3-methylpentyl, methylamino -2-methylpentyl, methylamino-1-methylpentyl, methylamino-3,3-dimethylbutyl, methylamino-2,2-dimethylbutyl, methylamino-1,1-dimethylbutyl, methylamino-1 2-dimethylbutyl, methylamino-1,3-dimethylbutyl, methylamino-2,3-dimethylbutyl, methylamino-1-ethylbutyl, methylamino-2-ethylbutyl, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl , Ethylaminoisopropyl, ethylaminobutyl, ethylaminoisobutyl, ethylamino-sec-butyl, ethylamino-tert-butyl, ethylaminopentyl, ethylaminoisopentyl, ethylamino-2-methylbutyl, ethylaminoneopentyl, ethylamino -1-ethylpropyl, ethylaminohexyl, ethylaminoisohexyl, ethylamino-4-methylpentyl, ethylamino-3-methylpentyl, ethylamino-2-methylpentyl, ethylamino-1-methyl Rupentyl, ethylamino-3,3-dimethylbutyl, ethylamino-2,2-dimethylbutyl, ethylamino-1,1-dimethylbutyl, ethylamino-1,2-dimethylbutyl, ethylamino-1,3-dimethyl Butyl, ethylamino-2,3-dimethylbutyl, ethylamino-1-ethylbutyl, ethylamino-2-ethylbutyl, propylaminomethyl, propylaminoethyl, propylaminopropyl, propylaminoisopropyl, propylaminobutyl, propylaminoisobutyl, Propylamino-sec-butyl, propylamino-tert-butyl, propylaminopentyl, propylaminoisopentyl, propylamino-2-methylbutyl, propylaminoneopentyl, propylamino-1-ethylpropyl, prop Propylaminohexyl, propylaminoisohexyl, propylamino-4-methylpentyl, propylamino-3-methylpentyl, propylamino-2-methylpentyl, propylamino-1-methylpentyl, propylamino-3,3-dimethyl Butyl, propylamino-2,2-dimethylbutyl, propylamino-1,1-dimethylbutyl, propylamino-1,2-dimethylbutyl, propylamino-1,3-dimethylbutyl, propylamino-2,3-dimethyl Butyl, propylamino-1-ethylbutyl, propylamino-2-ethylbutyl, isopropylaminomethyl, isopropylaminoethyl, isopropylaminopropyl, isopropylaminoisopropyl, isopropylaminobutyl, isopropylaminoisobuty , Isopropylamino-sec-butyl, isopropylamino-tert-butyl, isopropylaminopentyl, isopropylaminoisopentyl, isopropylamino-2-methylbutyl, isopropylaminoneopentyl, isopropylamino-1-ethylpropyl, isopropylaminohexyl, isopropylamino Isohexyl, isopropylamino-4-methylpentyl, isopropylamino-3-methylpentyl, isopropylamino-2-methylpentyl, isopropylamino-1-methylpentyl, isopropylamino-3,3-dimethylbutyl, isopropylamino-2, 2-dimethylbutyl, isopropylamino-1,1-dimethylbutyl, isopropylamino-1,2-dimethylbutyl, isopropylamino-1 3-dimethylbutyl, isopropyl-amino-2,3-dimethylbutyl, and isopropyl amino-1-ethylbutyl or isopropylamino-2-ethylbutyl group.

As used herein, “hydroxy C _1-3 alkyl group” means the above C _1-3 alkyl group substituted with a hydroxyl group. Specific examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl groups and the like.

As used herein, “C _1-6 alkyloxy group” means a group to which the C _1-6 alkyl group is bonded via an oxygen atom. Specifically, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyl Oxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 1-ethylbutoxy or 2-ethylbutoxy group.

As used herein, the “C _1-6 alkyloxycarbonyl group” means a group in which the C _1-6 alkyloxy group is bonded to a carbonyl group. Specifically, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxy Carbonyl, neopentyloxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, , 2-dimethyl-butoxycarbonyl, 1,3-dimethyl-butoxycarbonyl, 2,3-dimethyl-butoxycarbonyl, 1-ethyl-butoxycarbonyl or 2-ethyl-butoxycarbonyl group.

As used herein, “benzyloxy C _1-6 alkyl group” means the C _1-6 alkyl group substituted with a benzyloxy group. Specifically, for example, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxyisopropyl, benzyloxybutyl, benzyloxyisobutyl, benzyloxy-sec-butyl, benzyloxy-tert-butyl, benzyloxypentyl, benzyl Oxyisopentyl, benzyloxy-2-methylbutyl, benzyloxyneopentyl, benzyloxy-1-ethylpropyl, benzyloxyhexyl, benzyloxyisohexyl, benzyloxy-4-methylpentyl, benzyloxy-3-methylpentyl, benzyl Oxy-2-methylpentyl, benzyloxy-1-methylpentyl, benzyloxy-3,3-dimethylbutyl, benzyloxy-2,2-dimethylbutyl, benzyloxy Ci-1,1-dimethylbutyl, benzyloxy-1,2-dimethylbutyl, benzyloxy-1,3-dimethylbutyl, benzyloxy-2,3-dimethylbutyl, benzyloxy-1-ethylbutyl or benzyloxy-2 -An ethyl butyl group etc. are mentioned.

As used herein, “benzyloxycarbonyl C _1-6 alkyl group” means the C _1-6 alkyl group substituted with a benzyloxycarbonyl group. Specifically, for example, benzyloxycarbonylmethyl, benzyloxycarbonylethyl, benzyloxycarbonylpropyl, benzyloxycarbonylsopropyl, benzyloxycarbonylbutyl, benzyloxycarbonylsobutyl, benzyloxycarbonyl sec-butyl, benzyloxycarbonyl tert -Butyl, benzyloxycarbonylpentyl, benzyloxycarbonylsopentyl, benzyloxycarbonyl 2-methylbutyl, benzyloxycarbonylneopentyl, benzyloxycarbonyl 1-ethylpropyl, benzyloxycarbonylhexyl, benzyloxycarbonylsohexyl, benzyloxycarbonyl 4 -Methylpentyl, benzyloxycarbonyl 3-methylpentyl, benzyloxy Carbonyl 2-methylpentyl, benzyloxycarbonyl 1-methylpentyl, benzyloxycarbonyl 3,3-dimethylbutyl, benzyloxycarbonyl 2,2-dimethylbutyl, benzyloxycarbonyl 1,1-dimethylbutyl, benzyloxycarbonyl 1,2 -Dimethylbutyl, benzyloxycarbonyl 1,3-dimethylbutyl, benzyloxycarbonyl 2,3-dimethylbutyl, benzyloxycarbonyl 1-ethylbutyl or benzyloxycarbonyl 2-ethylbutyl group and the like can be mentioned.

As used herein, the “C _1-3 alkylcarbamoyl group” means a carbamoyl group substituted with the C _1-3 alkyl group. Specific examples include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl groups and the like.

As used herein, “C _1-3 alkylcarbamoyl C _1-6 alkyl group” means the C _1-6 alkyl group substituted with the C _1-3 alkylcarbamoyl group. Specifically, for example, methylcarbamoylmethyl, ethylcarbamoylmethyl, propylcarbamoylmethyl, isopropylcarbamoylmethyl, methylcarbamoylethyl, ethylcarbamoylethyl, propylcarbamoylethyl, isopropylcarbamoylethyl, methylcarbamoyl-n-propyl, ethylcarbamoyl-n -Propyl, propylcarbamoyl-n-propyl, isopropylcarbamoyl-n-propyl, methylcarbamoylisopropyl, ethylcarbamoylisopropyl, propylcarbamoylisopropyl, isopropylcarbamoylisopropyl, methylcarbamoyl-n-butyl, ethylcarbamoyl-n-butyl, propylcarbamoyl- n-butyl, isopropylcarbamoyl-n-butyl, methyl Rubamoyl isobutyl, ethylcarbamoylisobutyl, propylcarbamoylisobutyl, isopropylcarbamoylisobutyl, methylcarbamoyl-sec-butyl, ethylcarbamoyl-sec-butyl, propylcarbamoyl-sec-butyl, isopropylcarbamoyl-sec-butyl, methylcarbamoyl-tert-butyl , Ethylcarbamoyl-tert-butyl, propylcarbamoyl-tert-butyl, isopropylcarbamoyl-tert-butyl, methylcarbamoylpentyl, ethylcarbamoylpentyl, propylcarbamoylpentyl, isopropylcarbamoylpentyl, methylcarbamoylisopentyl, ethylcarbamoylisopentyl, propylcarbamoyl Isopentyl, isopropylca Vamoylisopentyl, methylcarbamoyl-2-methylbutyl, ethylcarbamoyl-2-methylbutyl, propylcarbamoyl-2-methylbutyl, isopropylcarbamoyl-2-methylbutyl, methylcarbamoylneopentyl, ethylcarbamoylneopentyl, propylcarbamoylneopentyl, isopropylcarbamoyl Neopentyl, methylcarbamoyl 1-ethylpropyl, ethylcarbamoyl 1-ethylpropyl, propylcarbamoyl 1-ethylpropyl, isopropylcarbamoyl 1-ethylpropyl, methylcarbamoyl-n-hexyl, ethylcarbamoyl-n-hexyl, propylcarbamoyl-n- Hexyl, isopropylcarbamoyl-n-hexyl, methylcarbamoylisohexyl, ethylcarba Moylisohexyl, propylcarbamoylisohexyl, isopropylcarbamoylisohexyl, methylcarbamoyl-4-methylpentyl, ethylcarbamoyl-4-methylpentyl, propylcarbamoyl-4-methylpentyl, isopropylcarbamoyl-4-methylpentyl, methylcarbamoyl-3 -Methylpentyl, ethylcarbamoyl-3-methylpentyl, propylcarbamoyl-3-methylpentyl, isopropylcarbamoyl-3-methylpentyl, methylcarbamoyl-2-methylpentyl, ethylcarbamoyl-2-methylpentyl, propylcarbamoyl-2-methyl Pentyl, isopropylcarbamoyl-2-methylpentyl, methylcarbamoyl-1-methylpentyl, ethylcarbamoyl-1-methyl Nyl, propylcarbamoyl-1-methylpentyl, isopropylcarbamoyl-1-methylpentyl, methylcarbamoyl-3,3-dimethylbutyl, ethylcarbamoyl-3,3-dimethylbutyl, propylcarbamoyl-3,3-dimethylbutyl, isopropylcarbamoyl -3,3-dimethylbutyl, methylcarbamoyl-2,2-dimethylbutyl, ethylcarbamoyl-2,2-dimethylbutyl, propylcarbamoyl-2,2-dimethylbutyl, isopropylcarbamoyl-2,2-dimethylbutyl, methylcarbamoyl -1,1-dimethylbutyl, ethylcarbamoyl-1,1-dimethylbutyl, propylcarbamoyl-1,1-dimethylbutyl, isopropylcarbamoyl-1,1-dimethylbutyl, methylcarbamoy -1,2-dimethylbutyl, ethylcarbamoyl-1,2-dimethylbutyl, propylcarbamoyl-1,2-dimethylbutyl, isopropylcarbamoyl-1,2-dimethylbutyl, methylcarbamoyl-1,3-dimethylbutyl, ethylcarbamoyl -1,3-dimethylbutyl, propylcarbamoyl-1,3-dimethylbutyl, isopropylcarbamoyl-1,3-dimethylbutyl, methylcarbamoyl-2,3-dimethylbutyl, ethylcarbamoyl-2,3-dimethylbutyl, propylcarbamoyl -2,3-dimethylbutyl, isopropylcarbamoyl-2,3-dimethylbutyl, methylcarbamoyl-1-ethylbutyl, ethylcarbamoyl-1-ethylbutyl, propylcarbamoyl-1-ethylbutyl, isopropylcarb Examples include a vamoyl-1-ethylbutyl, methylcarbamoyl-2-ethylbutyl, ethylcarbamoyl-2-ethylbutyl, propylcarbamoyl-2-ethylbutyl, isopropylcarbamoyl-2-ethylbutyl group, and the like.

As used herein, the “C _1-3 alkylcarbamoyl C _1-6 alkylcarbonyl group” means a group in which a carbonyl group is bonded to the C _1-3 alkylcarbamoyl C _1-6 alkyl group. Specifically, for example, methylcarbamoylmethylcarbonyl, ethylcarbamoylmethylcarbonyl, propylcarbamoylmethylcarbonyl, isopropylcarbamoylmethylcarbonyl, methylcarbamoylethylcarbonyl, ethylcarbamoylethylcarbonyl, propylcarbamoylethylcarbonyl, isopropylcarbamoylethylcarbonyl, methylcarbamoyl-n -Propylcarbonyl, ethylcarbamoyl-n-propylcarbonyl, propylcarbamoyl-n-propylcarbonyl, isopropylcarbamoyl-n-propylcarbonyl, methylcarbamoylisopropylcarbonyl, ethylcarbamoylisopropylcarbonyl, propylcarbamoylisopropylcarbonyl, isopropylcarbamoylisopro Carbonyl, methylcarbamoyl-n-butylcarbonyl, ethylcarbamoyl-n-butylcarbonyl, propylcarbamoyl-n-butylcarbonyl, isopropylcarbamoyl-n-butylcarbonyl, methylcarbamoylisobutylcarbonyl, ethylcarbamoylisobutylcarbonyl, propylcarbamoylisobutylcarbonyl, Isopropylcarbamoylisobutylcarbonyl, methylcarbamoyl-sec-butylcarbonyl, ethylcarbamoyl-sec-butylcarbonyl, propylcarbamoyl-sec-butylcarbonyl, isopropylcarbamoyl-sec-butylcarbonyl, methylcarbamoyl-tert-butylcarbonyl, ethylcarbamoyl-tert- Butylcarbonyl, propylcarbamo -Tert-butylcarbonyl, isopropylcarbamoyl-tert-butylcarbonyl, methylcarbamoylpentylcarbonyl, ethylcarbamoylpentylcarbonyl, propylcarbamoylpentylcarbonyl, isopropylcarbamoylpentylcarbonyl, methylcarbamoylisopentylcarbonyl, ethylcarbamoylisopentylcarbonyl, propylcarbamoylisopentyl Carbonyl, isopropylcarbamoylisopentylcarbonyl, methylcarbamoyl-2-methylbutylcarbonyl, ethylcarbamoyl-2-methylbutylcarbonyl, propylcarbamoyl-2-methylbutylcarbonyl, isopropylcarbamoyl-2-methylbutylcarbonyl, methylcarbamoylneopentylcarbonyl, Echi Rucarbamoyl neopentylcarbonyl, propylcarbamoyl neopentylcarbonyl, isopropylcarbamoyl neopentylcarbonyl, methylcarbamoyl 1-ethylpropylcarbonyl, ethylcarbamoyl 1-ethylpropylcarbonyl, propylcarbamoyl 1-ethylpropylcarbonyl, isopropylcarbamoyl 1-ethylpropylcarbonyl, methyl Carbamoyl-n-hexylcarbonyl, ethylcarbamoyl-n-hexylcarbonyl, propylcarbamoyl-n-hexylcarbonyl, isopropylcarbamoyl-n-hexylcarbonyl, methylcarbamoylisohexylcarbonyl, ethylcarbamoylisohexylcarbonyl, propylcarbamoylisohexylcarbonyl, isopropyl Carbamoyl Sohexylcarbonyl, methylcarbamoyl-4-methylpentylcarbonyl, ethylcarbamoyl-4-methylpentylcarbonyl, propylcarbamoyl-4-methylpentylcarbonyl, isopropylcarbamoyl-4-methylpentylcarbonyl, methylcarbamoyl-3-methylpentylcarbonyl, ethyl Carbamoyl-3-methylpentylcarbonyl, propylcarbamoyl-3-methylpentylcarbonyl, isopropylcarbamoyl-3-methylpentylcarbonyl, methylcarbamoyl-2-methylpentylcarbonyl, ethylcarbamoyl-2-methylpentylcarbonyl, propylcarbamoyl-2-methyl Pentylcarbonyl, isopropylcarbamoyl-2-methylpentylcarbonyl, methylcarbamoyl 1-methylpentylcarbonyl, ethylcarbamoyl-1-methylpentylcarbonyl, propylcarbamoyl-1-methylpentylcarbonyl, isopropylcarbamoyl-1-methylpentylcarbonyl, methylcarbamoyl-3,3-dimethylbutylcarbonyl, ethylcarbamoyl-3,3 -Dimethylbutylcarbonyl, propylcarbamoyl-3,3-dimethylbutylcarbonyl, isopropylcarbamoyl-3,3-dimethylbutylcarbonyl, methylcarbamoyl-2,2-dimethylbutylcarbonyl, ethylcarbamoyl-2,2-dimethylbutylcarbonyl, propyl Carbamoyl-2,2-dimethylbutylcarbonyl, isopropylcarbamoyl-2,2-dimethylbutylcarbonyl, methylcarbamoyl-1,1-di Methylbutylcarbonyl, ethylcarbamoyl-1,1-dimethylbutylcarbonyl, propylcarbamoyl-1,1-dimethylbutylcarbonyl, isopropylcarbamoyl-1,1-dimethylbutylcarbonyl, methylcarbamoyl-1,2-dimethylbutylcarbonyl, ethylcarbamoyl -1,2-dimethylbutylcarbonyl, propylcarbamoyl-1,2-dimethylbutylcarbonyl, isopropylcarbamoyl-1,2-dimethylbutylcarbonyl, methylcarbamoyl-1,3-dimethylbutylcarbonyl, ethylcarbamoyl-1,3-dimethyl Butylcarbonyl, propylcarbamoyl-1,3-dimethylbutylcarbonyl, isopropylcarbamoyl-1,3-dimethylbutylcarbonyl, methylcarbamoyl-2, -Dimethylbutylcarbonyl, ethylcarbamoyl-2,3-dimethylbutylcarbonyl, propylcarbamoyl-2,3-dimethylbutylcarbonyl, isopropylcarbamoyl-2,3-dimethylbutylcarbonyl, methylcarbamoyl-1-ethylbutylcarbonyl, ethylcarbamoyl- 1-ethylbutylcarbonyl, propylcarbamoyl-1-ethylbutylcarbonyl, isopropylcarbamoyl-1-ethylbutylcarbonyl, methylcarbamoyl-2-ethylbutylcarbonyl, ethylcarbamoyl-2-ethylbutylcarbonyl, propylcarbamoyl-2-ethylbutylcarbonyl And isopropylcarbamoyl-2-ethylbutylcarbonyl group.

As used herein, the term _{"C 1-3} alkyloxy _{C 1-3} alkyl group", a hydroxyl group means said hydroxy _{C 1-3} alkyl group substituted with a _{C 1-3} alkyl group. Specifically, for example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, isopropoxypropyl, methoxyisopropyl, ethoxy Examples include isopropyl, propoxyisopropyl, isopropoxyisopropyl groups and the like.

As used herein, “C _3-8 cycloalkyl group” means a monocyclic 3-8 membered saturated cyclic group in which all of the atoms constituting the ring are carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

As used herein, “C _3-8 cycloalkyl C _1-3 alkyl group” means the above C _1-3 alkyl group substituted with the above C _3-8 cycloalkyl group. Specific examples include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, and a cyclooctylmethyl group.

As used herein, “C _6-10 aryl C _1-3 alkyl group” means the above C _1-3 alkyl group substituted with a C _6-10 aryl group. Specific examples include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, azulenylmethyl, azulenylethyl, azulenylpropyl, azulenylisopropyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylisopropyl and the like.

As used herein, “C _6-10 aryloxy C _1-3 alkyl group” means the above hydroxy C _1-3 alkyl group in which the hydroxyl group is substituted with a C _6-10 aryl group. Specifically, for example, phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, phenyloxyisopropyl, azulenyloxymethyl, azulenyloxyethyl, azulenyloxypropyl, azulenyloxyisopropyl, naphthyloxymethyl, naphthyloxyethyl Naphthyloxypropyl, naphthyloxyisopropyl group and the like.

  As used herein, a “5- to 10-membered aromatic nitrogen-containing heterocyclic group” includes at least one nitrogen atom and may have one or more heteroatoms other than nitrogen atoms. A good monocyclic, polycyclic or condensed aromatic heterocyclic group is shown. Specifically, for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, pyrrolyl group, pyrazolyl group, isoxazolyl group, oxazolyl group, isothiazolyl group, thiazolyl group, oxadiazolyl group, thiadiazolyl group, indolyl Group, indazolyl group, purinyl group, benzoxazolyl group, benzothiazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group and the like.

  As used herein, “5- or 6-membered saturated heterocyclic group” refers to a 5- or 6-membered saturated cyclic group containing one or more heteroatoms. Specifically, for example, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydrothienyl, tetrahydro-2H-thiopyranyl, pyrazolidinyl, imidazolidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, 1,3- Dioxolanyl, 1,2-dioxanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithianyl, 1,3-dithianyl, 1,4-dithianyl, Morpholinyl, 1,2-oxadinanyl, 1,3-oxadinanyl, thiomorpholinyl, 1,2-thiadinanyl, 1,3-thiadinanyl, 1,2-oxathianyl, 1,3-oxathianyl, isothiazolidinyl, thiazolidinyl, isoxa Lydinyl, oxazolidinyl, 1,2,3-triazolidinyl, 1,2,4-triazolidinyl, 1,2,3-oxadiazolidinyl, 1,3,4-oxadiazolidinyl, 1,2,3-thiadiazo Lysinyl, 1,3,4-thiadiazolidinyl, 1,2,3-dioxazolidinyl, 1,2,4-dioxazolidinyl, 1,2,3-dioxathiolanyl, 1 2,4-dioxathiolanyl group and the like.

As used herein, “C _1-3 alkyloxy group” means a group to which the C _1-3 alkyl group is bonded via an oxygen atom. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group.

As used herein, “C _1-6 alkylene group” means a divalent straight chain or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Specifically, for example, methylene group, ethylene group, trimethylene group, isopropylene group, n-butylene group, isobutylene group, tert-butylene group, n-pentylene group, 2-methylbutylene group, 2,2-dimethyltriene. A methylene group, n-hexylene group, etc. are mentioned.

As used herein, “C _2-6 alkenylene group” means a divalent, linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having one double bond. To do. Specifically, for example, vinylene group, 1-propenylene group, 2-propenylene group, 1-butenylene group, 2-butenylene group, 3-butenylene group, 1-pentenylene group, 2-pentenylene group, 3-pentenylene group, 4-pentenylene group, 4-methyl-3-pentenylene group, 1-hexenylene group, 2-hexenylene group, 3-hexenylene group, 4-hexenylene group, 5-hexenylene group and the like can be mentioned.

  In the formulas (1), (2) and (3), the 5- or 6-membered saturated nitrogen-containing heterocyclic group is preferably a piperazinyl group, a piperidinyl group or a morpholinyl group.

  In formulas (2) and (3), the 5- to 10-membered aromatic nitrogen-containing heterocyclic group is preferably a pyridyl group or a quinolyl group.

In formulas (2) and (3), the C _6-10 aryl group is preferably a phenyl group.

  In formulas (2) and (3), the halogen atom is preferably a fluorine atom or a chlorine atom.

In formulas (1) and (2), the C _1-6 alkyl group is preferably a methyl group.

In formula (1), the C _1-3 alkyl group is preferably a methyl group.

In formula (1), the amino C _1-6 alkyl group is preferably an aminobutyl group or an aminohexyl group.

In formula (1), the C _1-3 alkylamino C _1-6 alkyl group is preferably a methylaminobutyl group or a methylaminohexyl group.

In formula (1), the hydroxy C _1-3 alkyl group is preferably a hydroxyethyl group.

In formulas (1), (2) and (3), the C _1-3 alkyloxy group is preferably a methoxy group.

In formula (1), the C _1-6 alkyloxycarbonyl group is preferably a tert-butoxycarbonyl group.

In formula (1), the benzyloxy C _1-6 alkyl group is preferably a benzyloxyethyl group.

In formula (1), the benzyloxycarbonyl C _1-6 alkyl group is preferably a benzyloxycarbonylpentyl group.

In formula (1), the C _1-3 alkylcarbamoyl C _1-6 alkyl group is preferably a methylcarbamoylpentyl group.

In formula (1), the C _1-3 alkylcarbamoyl C _1-6 alkylcarbonyl group is preferably a methylcarbamoylethylcarbonyl group.

In formula (3), the C _3-8 cycloalkyl group is preferably a cyclopropyl group.

In formula (1), the C _6-10 aryl C _1-3 alkyl group is preferably a benzyl group.

In the formula (1), the saturated heterocyclic group of C _1-3 alkyl may also be 5 or 6 membered substituted with group may piperazinyl group is preferable be substituted with C _1-3 alkyl groups, a methyl group A substituted piperazinyl group is more preferred.

In formulas (1), (2) and (3), the C _1-6 alkylene group is preferably a methylene group, an ethylene group, a trimethylene group or a pentylene group.

In formula (2), the C _2-6 alkenylene group is preferably a vinylene group or a 1-propenylene group.

  In formula (1), as ring A, a piperazinyl group, a piperidinyl group and a morpholinyl group are preferable.

Examples of the substituent that the ring A may have include a C _1-6 alkyl group, a phenyl group, a hydroxy C _1-3 alkyl group, a C _1-3 alkylcarbamoyl C _1-6 alkylcarbonyl group, and a C _1-3 alkyl. A carbamoyl C _1-6 alkyl group, a C _1-6 alkyloxycarbonyl group, a benzyloxy C _1-6 alkyl group, a benzyloxycarbonyl C _1-6 alkyl group and a C _6-10 aryl C _1-3 alkyl group are preferred, A methyl group, phenyl group, hydroxyethyl group, methylcarbamoylethylcarbonyl group, methylcarbamoylpentyl group, tert-butoxycarbonyl group, benzyloxyethyl group, benzyloxycarbonylpentyl group and benzyl group are more preferred.

  In formula (2), as ring B, a phenyl group, a piperazinyl group, a piperidinyl group, a morpholinyl group, a pyridyl group and a quinolyl group are preferable.

As the substituent that the ring B may have, a C _1-6 alkyl group, a C _3-8 cycloalkyl C _1-3 alkyl group and a group represented by the formula (3) are preferable, and a methyl group, cyclopropylmethyl The group and the group represented by the formula (3) are more preferable.

In formula (3), as ring C, a C _3-8 cycloalkyl group, a C _6-10 aryl group, and a 5- or 6-membered saturated nitrogen-containing heterocyclic group are preferable, and a cyclopropyl group, a phenyl group, piperidinyl More preferred are groups and piperazinyl groups.

As the substituent which ring C may have, a halogen atom, a C _1-6 alkyl group and a C _1-3 alkyloxy group are preferable, and a fluorine atom, a chlorine atom, a methyl group and a methoxy group are more preferable.

In Formula (1), when Y represents a bond, Z is preferably a bond, a C _1-6 alkylene group, and an oxygen atom, and more preferably a bond, a trimethylene group, and an oxygen atom.

In formula (1), when Y represents a phenylene group, Z is preferably a bond and N—R ⁷ (wherein R ⁷ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group), Bonds and NH groups are more preferred.

In formula (3), as T, a bond, a C _1-6 alkylene group and an NH alkylene group are preferable, and a bond, a methylene group and an NHCH ₂ group are more preferable.

In the formula (2), the combination of X, W, V and U is preferably the following.
X = bond, W = C _2-6 alkenylene group, V = C (O) NH, and U = bond;
X = bond, W = C _1-6 alkylene group, V = C (O) NH, and U = bond;
X = bond, W = C _2-6 alkenylene group, V = NH, and U = bond;
X = bond, W = C _1-6 alkylene group, V = NH, and U = bond;
X = oxygen atom, W = C _1-6 alkylene group, V = NH, and U = bond;
X = NH group, W = C _1-6 alkylene group, V = C (O) NH group, and U = bond;
X = NH group, W = C _1-6 alkylene group, V = NH group, and U = bond;
X = NH group, W = C _1-6 alkylene group having one or two oxo groups, V = NH group, and U = bond;
X = NH group, W = C _1-6 alkylene group having one oxo group, V = NHC (O) group, and U = bond;
X = NH group, W = C _1-6 alkylene group having one oxo group, V = N (2-nitrobenzenesulfonyl) group, and U = bond;
X = NH group, W = C _1-6 alkylene group having one oxo group, V = oxygen atom, and U = bond;
X = NH group, W = C _1-6 alkylene group having one or two oxo groups, V = bond, and U = bond;
X = NH group, W = C _1-6 alkylene group having one or two oxo groups, V = NH group, and U = C _1-6 alkylene group;
X = NH group, W = C _1-6 alkylene group having one oxo group, V = NMe group, and U = bond;
X = NMe, W = C _1-6 alkylene group having one oxo group, V = NH, and U = bond;
X = C (O) NH group, W = C _1-6 alkylene group, V = bond, and U = bond;
X = C (O) NH group, W = C _1-6 alkylene group, V = NHC (O) group, and U = bond;
X = C (O) NH group, W = C _1-6 alkylene group, V = C (O) NH group, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = C (O) NH group, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = NHC (O) group, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = NH group, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = N (2-nitrobenzenesulfonyl) group, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = oxygen atom, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = bond, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = NH group, and U = C _1-6 alkylene group;
X = NHC (O) group, W = C _1-6 alkylene group, V = NMe group, and U = bond;
X = NHC (O) group, W = C _1-6 alkylene group, V = C (O) NH group, and U = C _1-6 alkylene group; and X = NHC (O) group, W = oxo group. 1 C _1-6 alkylene group, V = bond, and U = bond.

As a specific example of the quinoline derivative of the present invention,
N ¹ - (-4- 1- benzyl-yl) -N ⁴ - (quinolin-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-morpholino-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (3- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- methoxybenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2,4- difluorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide;
6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide,
N- (1-benzylpiperidin-4-yl) -6-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} hexanamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide ,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide;
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N ^{1, N 3} - bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide;
2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide;
2- (4-methylpiperazin-1-yl) -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- 4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Carboxamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide,
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4- methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - (4-methyl-2 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} quinolin-6-yl) succinamide,
N ¹ - [4- benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (-4- 1- benzyl-yl) succinamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide,
2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide,
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide,
6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine,
N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
tert-butyl 4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazine-1-carboxylate,
(E) -3- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide,
3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide,
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ,
(E) -1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine,
1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl} piperidin-4-amine,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] oxy} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide,
Benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide;
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-{[4- (4-methylpiperazin-1-yl) phenyl] amino} quinoline-2-carboxamide ,
And N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine.

As a specific example of the active ingredient of at least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9 of the present invention,
N ¹ - (-4- 1- benzyl-yl) -N ⁴ - (quinolin-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-morpholino-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (3- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- methoxybenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2,4- difluorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide;
6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide,
N- (1-benzylpiperidin-4-yl) -6-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} hexanamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide ,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide;
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N ^{1, N 3} - bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide;
2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide;
2- (4-methylpiperazin-1-yl) -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- 4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Carboxamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide,
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4- methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - (4-methyl-2 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} quinolin-6-yl) succinamide,
N ¹ - [4- benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (-4- 1- benzyl-yl) succinamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide,
2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide,
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide,
6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine,
N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
tert-butyl 4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazine-1-carboxylate,
(E) -3- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide,
3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide,
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ,
(E) -1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine,
1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl} piperidin-4-amine,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] oxy} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide,
Benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [4- methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (2-morpholinoethyl) succinamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide;
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-{[4- (4-methylpiperazin-1-yl) phenyl] amino} quinoline-2-carboxamide ,
And N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine.

  The quinoline derivative of the present invention, or a salt thereof, or a solvate thereof includes not only the quinoline derivative of the present invention but also a pharmaceutically acceptable salt thereof, various hydrates and solvates thereof, Substances having a form, and substances that are prodrugs of these substances are included.

  Specific examples of acceptable salts in the quinoline derivative of the present invention include inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (eg, methane). And acid addition salts with sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.

  Examples of solvates of the quinoline derivative of the present invention and pharmaceutically acceptable salts thereof include hydrates and various solvates (for example, solvates with alcohols such as ethanol).

  The quinoline derivative of the present invention can be produced by combining known methods. Although the manufacturing method of a quinoline derivative is shown in the following reaction process drawing, a manufacturing method is not limited to this. Moreover, you may perform each reaction, protecting a functional group as needed. The protection and deprotection conditions can be performed with reference to commonly used methods (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

  The quinoline derivative of the present invention can be produced by combining known methods. Although the manufacturing method of a quinoline derivative is shown in the following reaction process drawing, a manufacturing method is not limited to this.

In general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X represents an NHC (O) group, and Y and Z represent a bond, the compound (1) of the present invention Can be produced from the quinoline derivative (6).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , W, V, U, A, B, Y, and Z are the same as defined above, and E is a halogen atom. Or a leaving group such as a triflate group is shown. ]

[Step 1] The quinoline derivative (8) can be produced by reacting the quinoline derivative (6) with the amine derivative (7). If necessary, sodium iodide or potassium iodide may be added and reacted. The reaction solvent is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol and isopropanol; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide Ether solvents such as diethyl ether, tetrahydrofuran and dioxane; sulfoxide solvents such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane; The reaction temperature is room temperature to 120 ° C., preferably 50 ° C. to 100 ° C., and the reaction time is 1 hour to 3 days, preferably 3 hours to 24 hours. As the amine derivative (7) used in the above reaction, a commercially available one can be used as it is, or it can be suitably produced by a known method, but is not limited thereto.

[Step 2] The nitro group of the quinoline derivative (8) can be reacted in a solvent in the presence of a reducing agent to produce the quinoline derivative (9). This reduction reaction may be performed by (a) catalytic hydrogenation in which a nitro group is reduced using a catalytic hydrogen reduction catalyst in a suitable inert solvent under a hydrogen atmosphere, or (b) a metal or metal salt in a suitable inert solvent. It is carried out by metal reduction in which the nitro group is reduced using a mixture of acid, metal, metal or metal salt and alkali metal hydroxide, sulfide or ammonium salt as a reducing agent. (A) In the case of catalytic hydrogenation, examples of the solvent include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol, ethanol and isopropanol; hydrocarbon solvents such as n-hexane and cyclohexane; dioxane and tetrahydrofuran. Ether solvents such as diethyl ether and diethylene glycol dimethyl ether; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide; For example, palladium, palladium-black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used alone or in combination. The reaction temperature is -20 to 150 ° C, preferably 0 to 100 ° C. The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours. (B) In the case of metal reduction, a mixture of iron, iron sulfate, lead, tin, tin chloride and inorganic acids such as hydrochloric acid and sulfuric acid, a mixture of iron or zinc and organic acids such as acetic acid, or iron, iron sulfate, A mixture of zinc or tin and an alkali metal hydroxide such as sodium hydroxide, a sulfide such as ammonium sulfide, or an ammonium salt such as aqueous ammonia or ammonium chloride is used as the reducing agent. Examples of the solvent include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol or ethanol; ether solvents such as tetrahydrofuran and dioxane. The reaction temperature is, for example, 0 to 150 ° C., preferably 50 to 120 ° C. when zinc and acetic acid are used as the reducing agent. The reaction time is 1 minute to 12 hours, preferably 1 minute to 6 hours.

[Step 3] The dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (10) is performed using a condensing agent in the presence or absence of a base in the solvent and in the presence or absence of a condensation accelerator. Thus, the present compound (1) can be produced. The solvent is not particularly limited. For example, halogen hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; ester solvents such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; tetrahydrofuran And ethers such as dioxane; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; water and the like can be used alone or in combination. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine , Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate Alkali carbonates such as sodium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc. It is possible to use the genus, and the like. Although there is no restriction | limiting in particular as a condensation promoter, DMAP, HOAt, HOBt, HODhbt, HONB, HOPfp, HOPht, HOSu etc. can be used. Although there is no restriction | limiting in particular as a condensing agent, DCC, DIPCI, WSCI, WSC * HCl, DEPC, BOP, PyBOP, TBTU etc. can be used. The reaction temperature is -20 to 100 ° C, preferably 0 to 40 ° C. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

  Alternatively, the compound (1) of the present invention can also be produced by performing the condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (11) in the presence of a base in a solvent. The solvent is not particularly limited. For example, halogen hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; ester solvents such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; tetrahydrofuran And ethers such as dioxane; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; water and the like can be used alone or in combination. The base is not particularly limited. For example, organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, sodium hydride, hydrogenated Alkali metal hydrides such as potassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used. The reaction temperature is -20 to 100 ° C, preferably 0 to 40 ° C. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In the general formula (1), ^{R 2} represents ^{R 8, R 8} represents a _{C 1-3} alkyl group, ^{R 4} represents the formula (2), when the Y and Z represents a bond, quinoline derivatives ( 8) can be produced from the quinoline derivative (12).

[Wherein R ¹ , R ³ , R ⁵ , R ⁶ , A, Y, and Z are the same as defined above, and E is independently a leaving group such as a halogen atom or a triflate group. R ¹² represents a C _1-3 alkyl group. ]

[Step 4] The quinoline derivative (13) can be produced by reacting the quinoline derivative (12) having a leaving group with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.

[Step 5] The quinoline derivative (8) can be produced by reacting the quinoline derivative (13) with the alcohol derivative (14). If necessary, a quaternary ammonium salt such as tetrabutylammonium sulfate may be added and reacted. The base is not particularly limited, and examples thereof include pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5. -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine; sodium methoxide, potassium Alcoholates such as methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide; inorganic such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate Bases, preferably sodium hydroxide, sodium methoxide That. The reaction solvent is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol and isopropanol; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide Ether solvents such as diethyl ether, tetrahydrofuran and dioxane; sulfoxide solvents such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane; water and mixed solvents thereof. The reaction temperature is room temperature to 120 ° C., preferably 50 ° C. to 100 ° C., and the reaction time is 1 hour to 3 days, preferably 3 hours to 24 hours. As the alcohol derivative (14) used in the above reaction, a commercially available product can be used as it is or can be appropriately produced by a known method, but is not limited thereto.

In the general formula (1), ^{R 2} represents ^{R 8, R 8} represents a saturated heterocyclic group may 5 or 6 membered substituted with _{C 1-3} alkyl group, Ring A is a 5 or 6-membered When it represents a saturated nitrogen-containing heterocyclic group, R ⁴ represents formula (2), and Y and Z represent a bond, the quinoline derivative (8) can be produced from the quinoline derivative (12).

[Wherein R ¹ , R ³ , R ⁵ , R ⁶ , and A are the same as defined above, and E independently represents a leaving group such as a halogen atom or a triflate group. ]

[Step 6] The quinoline derivative (8) can be produced by reacting the quinoline derivative (12) with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.

In general formula (1), R ² represents R ⁸ , R ⁴ represents formula (2), X represents N—R ¹¹ , R ¹¹ represents a C _1-6 alkyl group, and X and W When the bond is an amide bond, the compound (1) of the present invention can be produced from the quinoline derivative (9).

[Wherein R ¹ , R ³ , R ⁵ , R ⁶ , R ¹¹ , A, B, Y, Z, W, V, and U are as defined above. ]

[Step 7] The quinoline derivative (13) can be produced by 2-nitrobenzenesulfonyl (Ns) reaction of the amino group of the quinoline derivative (9). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 8] The quinoline derivative (15) can be produced by Mitsunobu reaction between the quinoline derivative (13) and the alcohol derivative (14). Reagents, bases and reaction conditions used are not particularly limited as long as they are usually used for Mitsunobu reaction. For example, as described in Swamy, KCK et al., Chem. Rev. 2009, 109, 2551, etc. Can be used. Reagents, diethyl azodicarboxylate, combinations of azodicarboxylic acid reagent and PPh _3, such as diisopropylazodicarboxylate, or the use of cyano methylene phosphorane reagents such as cyanomethylene trimethyl phosphorane or cyano methylene tributyl phosphorane Can do. The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene Halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile. The reaction temperature in this step varies depending on the raw materials and the solvent to be used, but is usually -20 to 120 ° C, preferably 0 ° C to 60 ° C, and the reaction time is usually 10 minutes to 1 day, preferably 10 minutes. ~ 6 hours. As the alcohol derivative (14) used in the above reaction, a commercially available product can be used as it is or can be appropriately produced by a known method, but is not limited thereto.

[Step 9] The quinoline derivative (16) can be produced by deprotecting the Ns group of the quinoline derivative (15). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 10] The compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (16) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.

In general formula (1), R ² represents R ⁸ , R ⁴ represents formula (2), X represents a NHC (O) group, Z represents a N—R ⁷ group, and V represents a N—R. ^{When 11} groups are represented and R ⁷ and R ¹¹ represent a hydrogen atom, the compound (1) of the present invention can be produced from the quinoline derivative (17).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, and U represent the same as defined above, and P represents a protecting group. . ]

[Step 11] The compound (1) of the present invention can be produced by deprotecting the quinoline derivative (17). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

In general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X represents a NHC (O) group, and Z represents a N—R ⁷ group, the compound of the present invention ( 1) can be produced from the quinoline derivative (18).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, B, Y, Z, W, V, and U are the same as defined above, E Represents a leaving group such as a halogen atom or a triflate group. ]

[Step 12] The quinoline derivative (19) can be produced by a dehydration condensation reaction of the quinoline derivative (18) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.

[Step 13] The compound (1) of the present invention can be produced by an amino coupling reaction of the quinoline derivative (19) and the amine derivative (20). The metal catalyst, ligand, base, and reaction conditions are not particularly limited as long as they are reagents and conditions that are usually used in amination reactions. For example, AR Muci, SL Buchwald, Top. Curr. Chem., 219, 131- 209, (2002) etc. can be used. It is also possible to apply a method of an amination reaction performed in a solvent or without a solvent, in the presence or absence of a base, and in the presence of a metal catalyst. In that case, microwave irradiation may be performed. The metal catalyst is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0 ), Tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), palladium such as tetrakis (triphenylphosphine) palladium (0) Complexes; monovalent copper reagents such as cuprous iodide, cuprous bromide, cuprous cyanide may be used alone, but (2-biphenyl) di-tert-butylphosphine, (2- Biphenyl) dicyclohexylphosphine, tricyclohexylphosphine, 1,3-bis (phenyl) Suphono) propane, 2,2′-bis (diphenylphosphanyl) -1,1′-binaphthyl, 2- (dicyclohexylphosphono) biphenyl, 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl , Tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine and the like can also be used in combination. Although there is no restriction | limiting in particular as a base, For example, Alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc. can be used. . The solvent is not particularly limited. For example, amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as toluene; water alone Or they can be used in combination. The reaction temperature is preferably 0 to 200 ° C, more preferably 100 ° C to 150 ° C. The reaction time is preferably 1 minute to 5 days, more preferably 30 minutes to 6 hours.

In the general formula (1), when R ² represents R ⁸ , R ⁴ represents the formula (2), and Z represents a bond, the compound (1) of the present invention can be produced from the quinoline derivative (19). .

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, Y, and Z are the same as defined above, and E is elimination of a halogen atom or a triflate group, etc. R ¹³ and R ¹⁴ represent a hydrogen atom or a C _1-6 alkyl group, and R ¹³ and R ¹⁴ may be combined to form a ring. ]

[Step 14] The compound (1) of the present invention can be produced by the Suzuki-Miyaura coupling reaction of the quinoline derivative (19) and the borane compound (21). The metal catalyst, base and reaction conditions to be used are not particularly limited as long as they are reagents and conditions usually used for the Suzuki-Miyaura coupling reaction. Miyaura, A.A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, (1995) etc. can be used. The metal catalyst to be used is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) Palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) Palladium complexes such as dichloride and tetrakis (triphenylphosphine) palladium (0), preferably [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium ( 0). The base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium. Sodium carbonate and cesium carbonate. Although there is no restriction | limiting in particular as a solvent, For example, Ethers, such as tetrahydrofuran, a dioxane, ethylene glycol dimethyl ether; Aromatic hydrocarbons, such as toluene; Amides, such as N, N-dimethylformamide, N-methylpyrrolidone; Dimethyl sulfoxide Water or the like can be used alone or in combination. Preferred are tetrahydrofuran, ethylene glycol dimethyl ether, N, N-dimethylformamide, water, and mixed solvents thereof. The reaction temperature is 0 to 200 ° C, preferably 60 to 150 ° C. The reaction time is 1 hour to 48 hours, preferably 30 minutes to 20 hours. As the borane compound (21) used in the above reaction, a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.

In the general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X represents an NHC (O) group, and V represents a C (O) NH group, the compound of the present invention (1) can be produced from the quinoline derivative (9).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, and U represent the same as defined above, and P represents a protecting group. . ]

[Step 15] The quinoline derivative (24) can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (22) or a condensation reaction of the carboxylic acid derivative (23). It can be performed in the same manner as in the above-described step 3.

[Step 16] The quinoline derivative (25) can be produced by deprotecting the quinoline derivative (24). The deprotection reaction can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 17] The compound (1) of the present invention can be produced by a dehydration condensation reaction between the quinoline derivative (25) and the amine derivative (26) or amine derivative (27). It can be performed in the same manner as in the above-described step 3.

In general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X represents an NHC (O) group, and V represents an NHC (O) group, the compound of the present invention ( 1) can be produced from the quinoline derivative (9).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, and U represent the same as defined above, and P represents a protecting group. . ]

[Step 18] The quinoline derivative (30) can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (28) or a condensation reaction of the carboxylic acid derivative (29). It can be performed in the same manner as in the above-described step 3.

[Step 19] The quinoline derivative (31) can be produced by deprotecting the quinoline derivative (30). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 20] The compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (31) and the carboxylic acid derivative (32). It can be performed in the same manner as in the above-described step 3.

In the general formula (1), when R ² represents R ⁸ , R ⁴ represents the formula (2), and X represents an NHC (O) group, the compound (1) of the present invention is produced from the quinoline derivative (9). can do.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, and W are as defined above, and E is a halogen atom or a triflate group. And the like. ]

[Step 21] The quinoline derivative (35) can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (33) or a condensation reaction of the carboxylic acid derivative (34). It can be performed in the same manner as in the above-described step 3.

[Step 22] The compound (1) of the present invention can be produced by an alkylation reaction of the quinoline derivative (35) with the amine derivative (26) or the amine derivative (27). Alkylation can be performed in a solvent in the presence of a base. The solvent is not particularly limited. For example, amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile alone or The base can be used in combination, and is not particularly limited. For example, alkali metals such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium metal Metals, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, lithium diisopropylamide, sodium diisopropylamide and potassium dioxide Isop Use pyramide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc. can do. Although reaction temperature changes with -10-200 degreeC and reaction conditions, Preferably it is 0 to 120 degreeC. The reaction time varies from 1 hour to 72 hours depending on the reaction conditions, but is preferably 1 hour to 36 hours. As the amine derivative (24) used in the above reaction, a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.

In the general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), and X represents a C (O) NH group, the compound (1) of the present invention is obtained from the quinoline derivative (9). Can be manufactured.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown. ]

[Step 23] The quinoline derivative (36) can be produced by Sandmeyer reaction of the quinoline derivative (9) (Chem. Rev., 40, 251-277, 1947). Diazotization can be carried out by reacting sodium nitrite, amyl nitrite or the like under acidic conditions. As the acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like can be used. A quinoline derivative (36) can be obtained by allowing a halogenating agent to act on the obtained diazonium salt. As the halogenating agent, copper chloride, copper bromide, potassium iodide, iodine or the like can be used. The solvent is not particularly limited as long as it does not inhibit the reaction, and ester solvents such as ethyl acetate and isopropyl acetate; ether solvents such as diethyl ether, tetrahydrofuran and dioxane, water and the like can be used alone or in combination. Preferably it is water. The reaction temperature is generally −10 to 100 ° C., preferably 0 to 40 ° C. The reaction time is 5 minutes to 1 day, preferably 1 to 12 hours.

[Step 24] The quinoline derivative (36) can be lithiated and then reacted with carbon dioxide to produce the carboxylic acid derivative (37). As the lithiation reagent, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium hexamethyldisilazide, or the like can be used. The solvent is not particularly limited as long as it does not inhibit the reaction. For example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether can be used alone or in combination. Tetrahydrofuran is preferred. The reaction temperature is −100 to 30 ° C., preferably −80 ° C. to 0 ° C. The reaction time is 1 hour to 48 hours, preferably 30 minutes to 20 hours.

[Step 25] The compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (37) and the amine derivative (38). It can be performed in the same manner as in the above-described step 3.

In the general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), and X represents an N—R ¹¹ group, the compound (1) of the present invention is produced from the quinoline derivative (9). can do.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown. ]

  [Step 26] The compound (1) of the present invention can be produced by an alkylation reaction of the quinoline derivative (9) and the alkyl derivative (39). This can be performed in the same manner as in step 22 described above.

In the general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X represents an N—R ¹¹ group, and V represents a C (O) NH group, the compound of the present invention (1) can be produced from the quinoline derivative (13).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, X, W, and U are the same as defined above; Independently, a protecting group is shown. ]

[Step 27] The quinoline derivative (41) can be produced by Mitsunobu reaction between the quinoline derivative (13) and the carboxylic acid derivative (40). It can be performed in the same manner as in the above-described step 8.

[Step 28] The quinoline derivative (42) can be produced by deprotecting the protecting group of the quinoline derivative (41). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 29] The quinoline derivative (44) can be produced by a dehydration condensation reaction between the quinoline derivative (42) and the amine derivative (43). It can be performed in the same manner as in the above-described step 3.

[Step 30] The compound (1) of the present invention can be produced by deprotecting the protecting group of the quinoline derivative (44). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

In general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X and V are the same or different and represent an N—R ¹¹ group, and U represents a bond, the present invention Compound (1) can be produced from the quinoline derivative (13).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, X, W, and U are as defined above, and P is a protecting group Indicates. ]

[Step 31] The quinoline derivative (46) can be produced by Mitsunobu reaction of the quinoline derivative (13) and the alcohol derivative (45). It can be performed in the same manner as in the above-described step 8.

[Step 32] The compound (1) of the present invention can be produced by deprotecting the quinoline derivative (46). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

In General Formula (1), R ² represents R ⁸ , R ⁴ represents Formula (2), Y and Z represent a bond, X represents an oxygen atom, V represents a N—R ¹¹ group, When U represents a bond, the compound (1) of the present invention can be produced from the quinoline derivative (47).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, X, W, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown. ]

[Step 33] The quinoline derivative (51) can be produced by Mitsunobu reaction of the quinoline derivative (47) and the alcohol derivative (50). It can be performed in the same manner as in the above-described step 8.

[Step 34] The alcohol derivative (50) can be produced by Mitsunobu reaction of the amine derivative (48) and the alcohol derivative (49). It can be performed in the same manner as in the above-described step 8.

[Step 35] The compound (1) of the present invention can be produced by reacting the quinoline derivative (51) with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.

In general formula (1), R ² represents R ⁸ , R ⁴ represents formula (2), X represents an NHC (O) group, Y represents a bond, and Z represents a C _1-6 alkylene group. When shown, the compound (1) of the present invention can be prepared from the quinoline derivative (6).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown, and n is an integer of 1 to 4. ]

[Step 36] The quinoline derivative (53) can be produced by the Sonogashira reaction of the quinoline derivative (6) and the alkyne derivative (52). The palladium catalyst, the copper catalyst, the base, and the reaction conditions are not particularly limited as long as they are reagents and conditions used in a normal Sonogashira reaction. For example, Heravi, Majid M .; Sadjadi, Sodeh, Tetrahedron, 65 (37), 7761-7775, (2009) etc. can be used. The palladium catalyst is not particularly limited. For example, bis (triphenylphosphine) palladium (II) dichloride, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), Bis (tri-tert-butylphosphine) palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (Triphenylphosphine) palladium (0) or the like can be used. The copper catalyst is not particularly limited, but copper (I) iodide is preferable. The base is not particularly limited, but pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] Non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine and other organic bases are used. be able to. The solvent is not particularly limited. For example, amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as toluene; water alone Or they can be used in combination. 0-120 degreeC of reaction temperature is preferable, More preferably, it is 0-60 degreeC. The reaction time is preferably 1 minute to 3 days, more preferably 1 hour to 24 hours. As the alkyne derivative (52) used in the above reaction, a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.

[Step 37] The quinoline derivative (54) can be produced by the methanesulfonyl (Ms) reaction of the hydroxyl group of the quinoline derivative (53). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 38] The quinoline derivative (55) can be produced by an alkylation reaction of the quinoline derivative (54) and the amine derivative (7). This can be performed in the same manner as in step 22 described above.

[Step 39] The quinoline derivative (56) can be produced by the reduction reaction of the quinoline derivative (55). It can be performed in the same manner as in Step 2 described above.

[Step 40] The compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (56) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.

In general formula (1), R ² represents R ⁸ , R ⁴ represents formula (2), X represents a bond, W represents a C _2-6 alkenylene group, and V represents a C (O) NH group. The present compound (1) can be produced from the quinoline derivative (36).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, and U are as defined above, and E is a halogen atom or a triflate group. And n represents an integer of 0 to 4. ]

[Step 41] The quinoline derivative (58) can be produced by the Heck reaction of the quinoline derivative (36) and the alkene derivative (57). The palladium catalyst, ligand, base, and reaction conditions are not particularly limited as long as they are reagents and conditions used in a normal Hecking reaction. For example, McCartney, Dennis; Guiry, Patrick J. Chemical Society Reviews, 40 (10 ), 5122-5150, (2011) and the like. Microwave irradiation may be performed. The palladium catalyst is not particularly limited. For example, palladium acetate (II), palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0 ), Tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium (0), etc. be able to. The base is not particularly limited, but pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] Non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine and other organic bases are used. be able to. The ligand is not particularly limited, but tri-o-tolylphosphine, (2-biphenyl) di-tert-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tricyclohexylphosphine, 1,3-bis (phenylphosphones) C) Propane, 2,2'-bis (diphenylphosphanyl) -1,1'-binaphthyl, 2- (dicyclohexylphosphono) biphenyl, 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl , Tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine and the like can be used. The solvent is not particularly limited. For example, amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as toluene; water alone Or they can be used in combination. The reaction temperature is preferably 0 to 200 ° C, more preferably 100 ° C to 150 ° C. The reaction time is preferably 1 minute to 5 days, more preferably 30 minutes to 6 hours. As the alkene derivative (57) used in the above reaction, a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.

[Step 42] The quinoline derivative (59) can be produced by deprotecting the quinoline derivative (58). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 43] The compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (59) and the amine derivative (26). It can be performed in the same manner as in the above-described step 3.

In general formula (1), R ² represents R ⁸ , R ⁴ represents formula (2), X represents a bond, W represents a C _2-6 alkenylene group, and V represents an N—R ¹¹ group. When U represents a bond, the compound (1) of the present invention can be produced from the quinoline derivative (36).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, and U are as defined above, and E is a halogen atom or a triflate group. Etc., P represents a protecting group, and n represents an integer of 0 to 4. ]

[Step 44] The quinoline derivative (62) can be produced by the Heck reaction of the quinoline derivative (36) and the alkene derivative (61). This can be performed in the same manner as in the above-described step 41.

[Step 45] The alkene derivative (61) can be produced by the protection reaction of the alkene derivative (60). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 46] The compound (1) of the present invention can be produced by deprotecting the protecting group of the quinoline derivative (62). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

In general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X represents a bond, and W represents a C _1-6 alkylene group, the present compound (1) is It can be produced from the quinoline derivative (63).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, V, and U are the same as defined above, and n is 0-4. Indicates an integer. ]

[Step 47] The compound (1) of the present invention can be produced by a catalytic hydrogen reduction reaction of the quinoline derivative (63). Examples of the solvent include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol, ethanol and isopropanol; hydrocarbon solvents such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether. System solvents; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide or a mixed solvent thereof can be used. As the catalyst, for example, palladium, palladium-black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used alone or in combination. The reaction temperature is -20 to 150 ° C, preferably 0 to 100 ° C. The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.

In the general formula (1), when R ⁴ represents R ⁸ , R ² represents the formula (2), and X represents a C (O) NH group, the compound (1) of the present invention is derived from the isatin derivative (64). Can be manufactured.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, V, and U are as defined above. ]

[Step 48] The quinoline derivative (66) can be produced by reacting the isatin derivative (64) with the ketone derivative (65). Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. An alkali metal bicarbonate or the like can be used. The solvent is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol and isopropyl alcohol: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether Etc .; Aromatic hydrocarbons such as toluene; Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Dimethyl sulfoxide, water and the like can be used alone or in combination. The reaction temperature is usually −0 to 120 ° C., preferably 60 ° C. to 120 ° C., and the reaction time is usually 10 minutes to 3 days, preferably 12 hours to 24 hours. As the isatin derivative (64) and the ketone derivative (65) used in the above reaction, commercially available ones can be used as they are or can be appropriately produced by known methods, but are not limited thereto.

[Step 49] The compound (1) of the present invention can be produced by a dehydration condensation reaction between the quinoline derivative (66) and the amine derivative (38). It can be performed in the same manner as in the above-described step 3.

In general formula (1), when R ⁴ represents R ⁸ , R ² represents formula (2), and X represents a C (O) NH group, compound (67) should also be produced by the following method. Can do.

[Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , A, Y, and Z are the same as defined above. ]

[Step 50] The quinoline derivative (66) can be produced by reacting the aniline derivative (67) with the aldehyde derivative (68) and the α-ketocarboxylic acid derivative (69). The solvent is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol and isopropyl alcohol: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether Etc .; Aromatic hydrocarbons such as toluene; Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Dimethyl sulfoxide, water and the like can be used alone or in combination. The reaction temperature is usually −0 to 120 ° C., preferably 40 ° C. to 100 ° C., and the reaction time is usually 10 minutes to 1 day, preferably 10 minutes to 6 hours. As the aniline derivative (67), aldehyde derivative (68) and α-ketocarboxylic acid derivative (69) used in the above reaction, commercially available ones can be used as they are, or they can be appropriately produced by known methods. It is not limited to.

In general formula (1), when R ⁴ represents R ⁸ , R ² represents formula (2), Y and Z represent a bond, and X represents a C (O) NH group, the compound (1) ) Can be prepared from the quinoline derivative (70).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, Y, Z, W, V, and U are as defined above, and E is a halogen atom Or a leaving group such as a triflate group is shown. ]

[Step 51] The quinoline derivative (71) can be produced by reacting the quinoline derivative (70) with the amine derivative (7). It can be carried out in the same manner as the above-mentioned step 1.

[Step 52] The quinoline derivative (72) can be produced by deprotecting the protecting group of the quinoline derivative (71). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 53] The compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (72) and the amine derivative (38). It can be performed in the same manner as in the above-described step 3.

In general formula (1), when R ² represents R ⁸ , R ⁴ represents formula (2), X represents an NHC (O) group, and Z represents an oxygen atom, the compound (1) of the present invention is It can be produced from the quinoline derivative (6).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, B, W, V, U, Y and Z are the same as defined above, and E is a halogen atom or A leaving group such as a triflate group is shown. ]

[Step 54] The quinoline derivative (8) can be produced by reacting the quinoline derivative (6) with the alcohol derivative (73). It can be carried out in the same manner as the above-mentioned step 1.

[Step 55] The quinoline derivative (9) can be produced by the reduction reaction of the quinoline derivative (8). It can be performed in the same manner as in Step 2 described above.

[Step 56] The compound (1) of the present invention can be produced by a dehydration condensation reaction of the quinoline derivative (9) and the carboxylic acid derivative (10) or a condensation reaction of the carboxylic acid derivative (11). It can be performed in the same manner as in the above-described step 3.

  If necessary, ring A may be converted as follows.

[Wherein, Y, Z and A represent the same as defined above, R ¹⁵ represents hydrogen or a C _1-5 alkyl group, and P represents a protecting group. ]

[Step 57] The amine derivative (75) can be produced by deprotecting the protecting group of the protected amine (74). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 58] The amine derivative (77) can be produced by reductive alkylation of the amine derivative (75) and the aldehyde derivative (76). The reductive alkylation reaction can be performed using a reducing reagent in a solvent in the presence or absence of an acid. At that time, the dehydration operation may be performed using a Dean-Stark apparatus or the like. The solvent is not particularly limited. Fluoroacetic acid or the like can be used alone or in combination. Although there is no restriction | limiting in particular as an acid, For example, Lewis acids, such as proton acids, such as propionic acid and benzoic acid, titanium tetrachloride, boron trifluoride, and stannic chloride, can be used. There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, Contact using borohydride reagents such as lithium triethylborohydride, lithium aluminum hydride, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used. As a hydrogen source for catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum Black etc. can be used. As the aldehyde derivative (76) used in the above reaction, a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.

  If necessary, ring A may be converted as follows.

[Wherein, Y, Z and A represent the same as defined above, R ¹⁶ represents a C _1-6 alkyl group, and E represents a leaving group such as a halogen atom or a triflate group. ]

[Step 59] The ring A derivative (79) can be produced by an alkylation reaction between the ring A derivative (75) and the alkyl halide derivative (78). This can be performed in the same manner as in step 22 described above.

  If necessary, ring A may be converted as follows.

[Wherein, Y, Z and A represent the same as defined above, R ¹⁷ and R ¹⁸ represent a C _1-3 alkyl group, and n represents an integer of 1 to 6. ]

[Step 60] Carboxylic acid derivative (81) can be produced by reacting ring A derivative (75) with acid anhydride (80). The solvent is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; N, N-dimethylformamide, N-methyl Amides such as pyrrolidone; dimethyl sulfoxide and the like can be used alone or in combination. The reaction temperature is usually 0 ° C to 120 ° C, preferably 40 ° C to 100 ° C, and the reaction time is usually 10 minutes to 3 days, preferably 12 hours to 24 hours.

[Step 61] The ring A derivative (83) can be produced by a dehydration condensation reaction between the carboxylic acid derivative (81) and the amine derivative (82). It can be performed in the same manner as in the above-described step 3.

  If necessary, ring B may be converted as follows.

[Wherein, B and V are the same as defined above, R ¹⁹ represents hydrogen, a C _1-5 alkyl group, or the same ring C as defined above, and P represents a protecting group. ]

[Step 62] An amine derivative (85) can be produced by deprotecting the ring B derivative (84). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Step 63] The ring B derivative (87) can be produced by a reductive alkylation reaction between the amine derivative (85) and the aldehyde derivative (86). This can be performed in the same manner as in step 58 described above.

  As the amine derivative (38) used in the above production method, a commercially available one can be used as it is, or it can be suitably produced by a known method, and when V represents an NHC (O) group and U represents a bond, For example, it can be produced by the following method, but is not limited thereto.

[Wherein, B, W, V and U are as defined above, and P represents a protecting group. ]

[Step 64] The amide derivative (90) can be produced by a dehydration condensation reaction between the carboxylic acid derivative (88) and the amine derivative (89). It can be performed in the same manner as in the above-described step 3.

[Step 65] The amine derivative (38) can be produced by deprotecting the protecting group of the amine derivative (90). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

  As the carboxylic acid derivative (11) used in the above production method, a commercially available one can be used as it is, or it can be appropriately produced by a known method, and for example, it can be produced by the following method.

[Wherein, B, W, V, and U are as defined above. ]

[Step 66] Carboxylic acid derivative (11) can be produced by acid chloride reaction of carboxylic acid derivative (10). The solvent is not particularly limited. For example, halogen hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; aromatic hydrocarbons such as toluene and benzene; ethers such as tetrahydrofuran and dioxane; acetonitrile and propio Nitriles such as nitriles; amides such as N, N-dimethylformamide and N-methylpyrrolidone can be used alone or in combination. Although there is no restriction | limiting in particular as a reagent, Oxalyl dichloride, phosphorus oxychloride, thionyl chloride, etc. can be used. If necessary, DMF or the like can be used as a catalyst. The reaction temperature is -20 to 100 ° C, preferably -20 to 60 ° C. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

As the carboxylic acid derivative (10) used in the above production method, a commercially available one can be used as it is, or it can be suitably produced by a known method, V represents N—R ¹¹ , and R ¹¹ represents 2-nitrosulfonyl. When a group is represented and U represents a bond, it can be produced, for example, by the following method.

[Wherein, B, W, V and U are as defined above, P represents a protecting group, and E represents a leaving group such as a halogen atom or a triflate group. ]

[Step 67] An amine derivative (95) can be produced by a reductive alkylation reaction between a ketone derivative (91) and an amine derivative (92). This can be performed in the same manner as in step 58 described above.

[Step 68] The amine derivative (95) can be produced by an alkylation reaction of the amine derivative (93) and the carboxylic acid derivative (94). This can be performed in the same manner as in step 22 described above.

[Step 69] The amine derivative (96) can be produced by 2-nitrobenzenesulfonyl (Ns) reaction of the amino group of the amine derivative (95). This can be carried out in the same manner as in step 7 described above.

[Step 70] Carboxylic acid derivative (10) can be produced by deprotecting the protecting group of amine derivative (96). It can be performed with reference to a commonly used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

  As the carboxylic acid derivative (96), a commercially available product can be used as it is, or it can be appropriately produced by a known method. For example, it can also be produced by the following method, but it is limited thereto. It is not a thing.

[Wherein, B, W and U are as defined above, and P represents a protecting group. ]

[Step 71] An amine derivative (97) can be produced by 2-nitrobenzenesulfonyl (Ns) reaction of the amine derivative (93). This can be carried out in the same manner as in step 7 described above.

[Step 72] Carboxylic acid derivative (96) can be produced by Mitsunobu reaction of amine derivative (97) and alcohol derivative (98). It can be performed in the same manner as in the above-described step 8.

  Substituents and the like in the above general formula are oxidized, reduced, alkylated, amidated, esterified, hydrolyzed with reference to commonly used methods (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.). The desired product can be obtained by appropriate conversion by reductive amination or the like. In addition, when a protecting group is used, the protecting group is not particularly limited, and those that can be introduced by a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) can be used as appropriate. However, the present invention is not limited to this.

  Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

  Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between the isomers. For example, a racemic mixture is obtained by a general racemic resolution method such as a method of optically resolving a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to optically pure isomers. Further, the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

  The TLR3, 7 and / or 9 inhibitor of the present invention and the preventive and / or therapeutic agent for cardiomyopathy due to autoimmune disease, inflammation, allergy, asthma, graft rejection, GvHD or sepsis are represented by the general formula (1). Containing a quinoline derivative, a salt thereof, or a solvate thereof as an active ingredient, and can be used as a pharmaceutical composition. In that case, the compound of the present invention may be used alone, but it is usually used in combination with a pharmaceutically acceptable carrier and / or diluent.

  The administration route is not particularly limited, but can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, inhalants and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by utilizing known preparation methods.

  When preparing an oral solid preparation, the compound represented by the general formula (1) is a pharmaceutically acceptable excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a corrigent. After adding a flavoring agent, tablets, coated tablets, granules, powders, capsules and the like can be produced using conventional methods. The additive may be one commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like. . Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, tartaric acid and the like.

  When preparing an oral liquid preparation, an oral solution, syrup, etc. are added to the compound represented by the general formula (1) by adding a corrigent, a buffer, a stabilizer, a corrigent and the like using a conventional method. An elixir or the like can be produced. Examples of the flavoring agent include those listed above. Examples of the buffering agent include sodium citrate, and examples of the stabilizing agent include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneously using a conventional method. Intramuscular and intravenous injections can be manufactured. Examples of the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA (sodium edetate), thioglycolic acid, and thiolactic acid. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride. Examples of the isotonic agent include sodium chloride and glucose.

  When preparing a suppository, a known suppository carrier such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, etc., and a surfactant (for example, , Tween (registered trademark)) and the like can be added and then manufactured using a conventional method.

  In addition to the above, it is possible to appropriately prepare a preferable preparation using a conventional method.

  The dose of the quinoline derivative represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc., but usually as a compound represented by the general formula (1) for adults 0.1 mg to 1000 mg per day, preferably 1 mg to 1000 mg, more preferably 1 mg to 500 mg is preferably administered orally or parenterally in one or several divided doses.

EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
brs: broad singlet
J: Coupling constant
Hz: Hertz
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
CD ₃ OD: Deuterated methanol
¹ H-NMR: Proton nuclear magnetic resonance
WSC · HCl: 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride
HOBT · H ₂ O: 1-hydroxybenzotriazole hydrate
Ms: Methanesulfonyl
Ns: 2-nitrobenzenesulfonyl
TBDPS: tert-butyldiphenylsilyl
THF: tetrahydrofuran
DMF: Dimethylformamide
PLC: preparative thin layer chromatography
DEAD: Diethyl azodicarboxylate
TBAF: Tetrabutylammonium trifluoride
TFA: trifluoroacetic acid
Boc: tert-butoxycarbonyl
BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
PyBOP: Hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium
quant .: Quantitative

Example 1
N ¹ - (1-benzyl-piperidin-4-yl) -N ⁴ - (quinolin-6-yl) succinamide manufacturing 4-oxo-4- (quinolin-6-ylamino) butyric acid (70 mg, 0.27 mmol), 1 -Benzylpiperidin-4-amine (77 mg, 0.41 mmol), WSC · HCl (78 mg, 0.41 mmol), HOBT · H ₂ O (62 mg, 0.41 mmol) are dissolved in methylene chloride (3 mL) at room temperature. Stir overnight. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: methanol = 10: 1) to obtain the title compound (99 mg, 88%) as a brown amorphous substance.

Example 2
N ¹ - ^{(1-benzyl-piperidin-4-yl)} -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide production process 1
Preparation of methyl 4-{[2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutanoate

  To a solution of 2- (4-methylpiperazin-1-yl) quinolin-6-amine (289 mg, 1.19 mmol) in methylene chloride (2 mL) was added triethylamine (181 mg, 1.79 mmol). Methyl 4-chloro-4-oxobutanoate (215 mg, 1.43 mmol) was added in an ice bath. It returned to room temperature and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (387 mg, crude) as a tan solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.37 (3H, s), 2.52-2.59 (4H, m), 2.70 (2H, t, J = 6.6 Hz), 2.79 (2H, t, J = 6.3 Hz ), 3.69-3.78 (7H, m), 6.98 (1H, d, J = 9.0 Hz), 7.39 (1H, d, J = 9.0 Hz), 7.60 (1H, s), 7.64 (1H, d, J = 8.8 Hz), 7.85 (1H, d, J = 9.5 Hz), 8.08 (1H, s).

Process 2
Preparation of 4-{[2- (4-Methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid

  To a solution of methyl 4-{[2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutanoate (387 mg, crude) in methanol (3 mL) was added 4M hydroxyl group. Aqueous sodium solution (1 mL) was added. Stir at room temperature for 3 hours. Under ice-cooling, the mixture was neutralized with 4N hydrochloric acid-ethyl acetate solution and concentrated under reduced pressure to give the title compound (811 mg, crude) as a tan solid.

Process 3
N ¹ - ^{(1-benzyl-piperidin-4-yl)} -N 4 - [2- (4-methylpiperazin-1-yl) quinolin-6-yl] Production of succinamic 4 - {[2- (4-methylpiperazin -1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 1-benzylpiperidin-4-amine were used in the same manner as in Example 1 to obtain the title compound (2 step yield: 15%). Obtained as a brown solid.

Example 3
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide production process 1
Preparation of methyl 4-oxo-4-{[2- (piperidin-1-yl) quinolin-6-yl] amino} butanoate

  Use 2- (piperidin-1-yl) quinolin-6-amine and methyl 4-chloro-4-oxobutanoate as in Step 1 of Example 2 to give the title compound (91%) as tan Obtained as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.64-1.72 (6H, m), 2.70 (2H, t, J = 6.6 Hz), 2.79 (2H, t, J = 6.3 Hz), 3.67-3.73 (4H , m), 3.73 (3H, s), 6.98 (1H, d, J = 9.3 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 7.57 (1H, s), 7.62 (1H, d, J = 9.0 Hz), 7.81 (1H, d, J = 9.3 Hz), 8.05 (1H, d, J = 2.2 Hz).

Process 2
Preparation of 4-oxo-4-{[2- (piperidin-1-yl) quinolin-6-yl] amino} butyric acid

  Methyl 4-oxo-4-{[2- (piperidin-1-yl) quinolin-6-yl] amino} butanoate is used in the same manner as in Step 2 of Example 2 to give the title compound (crude) as tan Obtained as a solid.

Process 3
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide manufacturing 4-oxo-4 - {[2- (piperidin-1-yl) quinoline The title compound (2 step yield 49%) was obtained as a tan solid in the same manner as in Example 1 using -6-yl] amino} butyric acid and 1-benzylpiperidin-4-amine.

Example 4
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - (2-morpholino-6-yl) succinamide production process 1
Preparation of methyl 4-[(2-morpholinoquinolin-6-yl) amino] -4-oxobutanoate

  The title compound (91%) was obtained as a tan solid in the same manner as in Step 1 of Example 2 using 2-morpholinoquinolin-6-amine and methyl 4-chloro-4-oxobutanoate.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.68-2.75 (2H, m), 2.76-2.84 (2H, m), 3.69 (4H, t, J = 4.5 Hz), 3.73 (3H, s), 3.86 (4H, t, J = 4.9 Hz), 6.96 (1H, d, J = 9.3 Hz), 7.41 (1H, dd, J = 9.0, 2.2 Hz), 7.63 (1H, brs), 7.66 (1H, d, J = 8.8 Hz), 7.88 (1H, d, J = 9.3 Hz), 8.11 (1H, s).

Process 2
Preparation of 4-[(2-morpholinoquinolin-6-yl) amino] -4-oxobutyric acid

  Methyl 4-[(2-morpholinoquinolin-6-yl) amino] -4-oxobutanoate was used in the same manner as in Step 2 of Example 2 to obtain the title compound (crude) as a tan solid. .

Process 3
N ¹ - (4-1-benzyl-piperidin-yl) ^-N 4 - (2-morpholino-6-yl) succinamide manufacturing 4 - [(2-morpholino-6-yl) amino] -4-oxobutanoic acid And 1-benzylpiperidin-4-amine were used in the same manner as in Example 1 to obtain the title compound (2 step yield: 84%) as a tan solid.

Example 5
N ¹ - ^{(1-benzyl-piperidin-4-yl)} -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] Production of succinamide

Process 1
Preparation of 6-nitro-2- (4-phenylpiperidin-1-yl) quinoline

  To a solution of 2-chloro-6-nitroquinoline (300 mg, 1.44 mmol) in ethanol (6 mL), 4-phenylpiperidine (697 mg, 4.32 mmol) was added. The temperature was raised to 80 ° C. and stirred for 4 hours. It returned to room temperature, ethanol was depressurizingly distilled, water was added to the residue, and chloroform extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (chloroform) to obtain the title compound (450 mg, 94%) as a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.73-1.85 (2H, m), 2.00-2.08 (2H, m), 2.88 (1H, tt, J = 12.1, 3.7 Hz), 3.13 (2H, dt, J = 13.1, 2.0 Hz), 4.79-4.90 (2H, m), 7.13 (1H, d, J = 9.5 Hz), 7.20-7.36 (5H, m), 7.66 (1H, d, J = 9.0 Hz), 7.97 (1H, d, J = 9.3 Hz), 8.30 (1H, dd, J = 9.2, 2.6 Hz), 8.54 (1H, d, J = 2.4 Hz).

Process 2
Preparation of 2- (4-phenylpiperidin-1-yl) quinolin-6-amine

６−ニトロ−２−（４−フェニルピペリジン−１−イル）キノリン（386 mg）のTHF（6 mL）溶液に、10％Pd−C（200 mg）を加えた。系中を水素で置換し、室温で一晩攪拌した。系中をAr置換し、反応液をセライトろ過し、ろ液を減圧濃縮し、表題化合物（383 mg, crude）を緑色固体として得た。

To a solution of 6-nitro-2- (4-phenylpiperidin-1-yl) quinoline (386 mg) in THF (6 mL) was added 10% Pd-C (200 mg). The system was replaced with hydrogen and stirred overnight at room temperature. The system was purged with Ar, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (383 mg, crude) as a green solid.

1H-NMR (400MHz, CDCl ₃ ) δ: 1.76-1.89 (2H, m), 1.94-2.03 (2H, m), 2.77 (1H, tt, J = 12.1, 3.5 Hz), 2.95-3.06 (2H, m ), 3.68 (2H, brs), 4.56-4.65 (2H, m), 6.83 (1H, d, J = 2.7 Hz), 7.00 (1H, d, J = 9.0 Hz), 7.03 (1H, dd, J = 8.9, 2.6 Hz), 7.18-7.35 (5H, m), 7.60 (1H, d, J = 7.6 Hz), 7.72 (1H, d, J = 9.3 Hz).

Process 3
Preparation of methyl 4-oxo-4-{[2- (4-phenylpiperidin-1-yl) quinolin-6-yl] amino} butanoate

２−（４−フェニルピペリジン−１−イル）キノリン−６−アミンとメチル ４−クロロ−４−オキソブタノエートを用いて、実施例２の工程１と同様にして、表題化合物（quant.）を黄褐色固体として得た。

In the same manner as in Step 1 of Example 2, using 2- (4-phenylpiperidin-1-yl) quinolin-6-amine and methyl 4-chloro-4-oxobutanoate, the title compound (quant.) Was obtained as a tan solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.75-1.87 (2H, m), 1.95-2.04 (2H, m), 2.68-2.85 (5H, m), 2.98-3.12 (2H, m), 3.73 ( 3H, s), 4.63-4.75 (2H, m), 7.04 (1H, d, J = 9.3 Hz), 7.17-7.29 (5H, m), 7.40 (1H, dd, J = 11.2, 2.4 Hz), 7.60 (1H, s), 7.65 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J = 9.3 Hz), 8.08 (1H, s).

Process 4
Preparation of 4-oxo-4-{[2- (4-phenylpiperidin-1-yl) quinolin-6-yl] amino} butyric acid

メチル ４−オキソ−４−｛［２−（４−フェニルピペリジン−１−イル）キノリン−６−イル］アミノ｝ブタノエートを用いて、実施例２の工程２と同様にして、表題化合物（crude）を黄褐色固体として得た。

Methyl 4-oxo-4-{[2- (4-phenylpiperidin-1-yl) quinolin-6-yl] amino} butanoate is used in the same manner as in Step 2 of Example 2 for the title compound (crude). Was obtained as a tan solid.

Process 5
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2- (4-phenyl-piperidin-1-yl) quinolin-6-yl] succinamide manufacturing 4-oxo-4 - {[2- ( 4-phenylpiperidin-1-yl) quinolin-6-yl] amino} butyric acid and 1-benzylpiperidin-4-amine were used in the same manner as in Example 1 to obtain the title compound (2 step yield: 63%). Obtained as a tan solid.

Example 6
N ¹ - [1- (2- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using {[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 1- (2-chlorobenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (26%) was obtained as a yellow solid.

Example 7
N ¹ - [1- (3- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using {[4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 1- (3-chlorobenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (27%) was obtained as a yellow solid.

Example 8
N ¹ - [1- (4- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using {[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 1- (4-chlorobenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (6%) was obtained as a yellow solid.

Example 9
N ¹ - [1- (4- methoxybenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4- Performed using {[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 1- (4-methoxybenzyl) piperidin-4-amine In the same manner as in Example 1, the title compound (9%) was obtained as a yellow solid.

Example 10
N ¹ - [1- (2,4- difluorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] Production of succinamide 4-{[4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 1- (2,4-difluorobenzyl) piperidin-4-amine Used to give the title compound (24%) as a yellow solid as in Example 1.

Example 11
Process for producing 4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide 1
Preparation of tert-butyl 4- (N-benzyl-2,2,2-trifluoroacetamido) piperidine-1-carboxylate

  To a solution of tert-butyl 4- (benzylamino) piperidine-1-carboxylate (2.90 g, 10 mmol) in methylene chloride (30 mL) under ice-cooling, pyridine (1.58 g, 20 mmol), trifluoroacetic anhydride The product (3.15 g, 15 mmol) was added. Stir at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3.77 g, crude) as a yellow oil.

Process 2
Preparation of N-benzyl-2,2,2-trifluoro-N- (piperidin-4-yl) acetamide

  To a solution of tert-butyl 4- (N-benzyl-2,2,2-trifluoroacetamido) piperidine-1-carboxylate (3.77 g, crude, theoretical 15 mmol) in methanol (20 mL) was added 4N HCl / EtOAc. (20 mL) was added and stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, an aqueous sodium carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.20 g, crude) as a yellow oil.

Process 3
4- [4- (N-benzyl-2,2,2-trifluoroacetamido) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6 Yl] -4-oxobutanamide

  4-{[4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and N-benzyl-2,2,2-trifluoro-N- ( The title compound (crude) was obtained as a yellow amorphous in the same manner as in Example 1 using piperidin-4-yl) acetamide.

Process 4
Preparation of 4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide 4 -[4- (N-benzyl-2,2,2-trifluoroacetamido) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl ] To a solution of 4-oxobutanamide (82 mg, 0.13 mmol) in methanol (1 mL) was added 2M aqueous potassium carbonate (1 mL), and the mixture was stirred at room temperature for 8 hours. Methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: methanol = 4: 1) to obtain the title compound (46 mg, yield of 4 steps 46%) as a yellow solid.

Example 12
Production process 1 of N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide
Preparation of 6-iodo-4-methyl-2- (4-methylpiperazin-1-yl) quinoline

  To a solution of 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine (100 mg, 0.39 mmol) in water (2 mL) under ice-cooling, sulfuric acid (200 μL), sodium nitrite (35 mg, 0.51 mmol) was added and stirred at the same temperature for 30 minutes. Potassium iodide (388 mg, 2.34 mmol) was added, and the mixture was further stirred for 10 minutes. Water and 8M aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 90: 10) to obtain the title compound (48 mg, 33%) as a brown solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.41 (3H, s), 2.55 (3H, s), 2.57-2.65 (4H, m), 3.79-3.87 (4H, m), 6.81 (1H, s) , 7.42 (1H, d, J = 8.8 Hz), 7.74 (1H, dd, J = 8.8, 2.0 Hz), 8.08 (1H, d, J = 2.2 Hz).

Process 2
Preparation of 4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxylic acid

  To a solution of 6-iodo-4-methyl-2- (4-methylpiperazin-1-yl) quinoline (100 mg, 0.27 mmol) in THF (4 mL) at −78 ° C., n-butyllithium (hexane solution, 500 μL, 0.32 mmol) was added dropwise. The mixture was stirred at the same temperature for 30 minutes, and the reaction solution was dropped onto dry ice. After completion of dropping, the temperature was returned to room temperature and stirred for 2 hours. Water was added to the reaction solution, the solution was made basic with 8M aqueous sodium hydroxide solution, and impurities were extracted with chloroform. The aqueous layer was neutralized with 6N HCl aqueous solution and concentrated under reduced pressure to obtain the title compound (32 mg, crude) as a brown amorphous.

Process 3
Preparation of N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide 4- Methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxylic acid and 3-amino-N- (1-benzylpiperidin-4-yl) propionamide were used in the same manner as in Example 1. The title compound (43%) was obtained as a yellow amorphous.

Example 13
Production process 1 of 1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide
Preparation of tert-butyl (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) carbamate

  In the same manner as in Example 1 using 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 3-[(tert-butoxycarbonyl) amino] propionic acid, the title compound ( 72%) was obtained as a yellow amorphous.

Process 2
Preparation of 3-amino-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propionamide trihydrochloride

  tert-Butyl (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) carbamate (308 mg, 0.72 mmol) in methanol (13 mL) 4N HCl / EtOAc (6.5 mL) was added to the suspension solution, and the mixture was stirred at room temperature for 5 hours. Concentration under reduced pressure gave the title compound (308 mg, crude) as a yellow solid.

Process 3
Preparation of 1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide 3- Example 1 with amino-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propionamide trihydrochloride and 1-benzylpiperidine-4-carboxylic acid In the same manner, the title compound (2-step yield: 87%) was obtained as a yellow solid.

Example 14
Preparation of 6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide

Process 1
Preparation of 6-bromo-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide

  Use 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 6-bromohexanoic acid chloride in the same manner as in Step 1 of Example 2 to obtain the title compound (58%). Obtained as a brown amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.58 (2H, m), 1.74-1.96 (4H, m), 2.38 (3H, s), 2.41 (2H, t, J = 7.2 Hz), 2.57 (3H, s), 2.58-2.64 (4H, m), 3.39-3.45 (2H, m), 3.73-3.78 (4H, m), 6.83 (1H, s), 7.42 (1H, d, J = 8.8 Hz ), 7.50 (1H, brs), 7.65 (1H, d, J = 8.8 Hz), 8.24 (1H, d, J = 2.2 Hz).

Process 2
Preparation of 6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide 6-Bromo-N -To a solution of [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide (100 mg, 231 μmol) in DMF (1.5 mL), potassium carbonate (63.7 mg, 461 μmol) ), 1-benzylpiperidin-4-amine (88 mg, 461 μmol) and potassium iodide (77 mg, 461 μmol) were added, and the mixture was stirred at 60 ° C. for 2 hours. It returned to room temperature, saturated sodium hydrogencarbonate aqueous solution was added, and chloroform extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: ammonia saturated methanol = 90: 10) to give the title compound (98 mg, 78%) as a brown solid.

Example 15
Preparation of N- (1-benzylpiperidin-4-yl) -6-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} hexanamide 4-Methyl-2 In the same manner as in Step 2 of Example 14, using-(4-methylpiperazin-1-yl) quinolin-6-amine and N- (1-benzylpiperidin-4-yl) -6-bromohexanamide, The title compound (32%) was obtained as a brown amorphous.

Example 16
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide 4-Methyl- Similar to Example 1 using 2- (4-methylpiperazin-1-yl) quinolin-6-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) propan-1-amine To give the title compound (52%) as a yellow oil.

Example 17
Preparation of N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide

Process 1
Preparation of benzyl [2- (1-benzylpiperidine-4-carboxamido) ethyl] carbamate

  The title compound (crude) was obtained as a yellow solid in the same manner as in Example 1 using 1-benzylpiperidine-4-carboxylic acid and benzyl (2-aminoethyl) carbamate.

Process 2
Production of N- (2-aminoethyl) -1-benzylpiperidine-4-carboxamide

  To a solution of benzyl [2- (1-benzylpiperidine-4-carboxamido) ethyl] carbamate (395 mg) in THF (6 mL) was added 10% Pd-C (100 mg). The system was replaced with hydrogen and stirred overnight at room temperature. The system was purged with Ar, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (300 mg, crude) as a yellow solid.

Process 3
Preparation of N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide 4-Methyl-2- (4- Methylpiperazin-1-yl) quinoline-6-carboxylic acid and N- (2-aminoethyl) -1-benzylpiperidine-4-carboxamide were used in the same manner as in Example 1 to obtain the title compound (3-step yield). 25%) was obtained as a yellow solid.

Example 18
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide Manufacturing process 1
Preparation of methyl 2-[(1-benzylpiperidin-4-yl) amino] acetate

  To a solution of 4-amino-N-benzylpiperidine (50 g, 263 mmol) in acetonitrile (500 mL) / DMF (200 mL) was added potassium carbonate (27.2 g, 197 mmol). Methyl bromoacetate (20.1 g, 131 mmol) was added, and the mixture was stirred at 60 ° C. for 5 hours. It returned to room temperature, saturated sodium hydrogencarbonate aqueous solution was added, and chloroform extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: ammonia saturated methanol = 97: 3 → 90: 10, gradient) to give the title compound (34.7 g, crude, theoretical amount 34.4 g) as a pale yellow oil. Obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.36-1.50 (2H, m), 1.76-1.84 (2H, m), 1.96-2.06 (2H, m), 2.40-2.50 (1H, m), 2.80- 2.87 (2H, m), 3.44 (2H, s), 3.49 (2H, s), 3.72 (3H, s), 7.21-7.32 (5H, m).

Process 2
Preparation of methyl 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamide] acetate

  To a solution of methyl 2-[(1-benzylpiperidin-4-yl) amino] acetate (34.7 g, crude, theoretical amount 34.4 g, 131 mmol) in methylene chloride (200 mL) was added triethylamine (26.5 g, 262 mmol). added. Under ice cooling, a solution of 2-nitrobenzenesulfonyl chloride (40.6 g, 183 mmol) in methylene chloride (200 mL) was added, and the mixture was stirred overnight at room temperature. Water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 → 1: 9, gradient) to give the title compound (54.2 g, yield of 2 steps 92.5%) as a blue-green oil. It was.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.54-1.74 (4H, m), 1.98-2.10 (2H, m), 2.84-2.92 (2H, m), 3.45 (2H, s), 3.67 (3H, s), 3.74-3.86 (1H, m), 4.13 (2H, s), 7.20-7.32 (5H, m), 7.60-7.72 (3H, m), 8.14-8.20 (1H, m).

Process 3
Preparation of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid

  To a solution of methyl 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetate (54.2 g, 121 mmol) in methanol (700 mL) was added 4M aqueous sodium hydroxide (60.5 mL, 242 mmol) was added. Stir at room temperature for 4 hours. Under ice-cooling, the solution was neutralized with 4N hydrochloric acid-ethyl acetate solution and concentrated under reduced pressure. Extraction was performed with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (48.2 g, crude) was obtained as a tan amorphous.

Process 4
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide Preparation of 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid In the same manner as in Example 1, the title compound (56%) was obtained as a yellow solid.

Example 19
Preparation of 2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 2- [N- ( 1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide (120 mg, 0.18 mmol ) Was dissolved in DMF (1 mL), potassium carbonate (37 mg, 0.27 mmol) and thiophenol (30 mg, 0.27 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: ammonium saturated methanol = 100: 3 → 10: 1) to obtain the title compound (72 mg, 82%) as a pale yellow amorphous.

Example 20
Production process 1 of N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide
Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide

  The title compound (78%) was obtained as a yellow amorphous in the same manner as in Step 2 of Example 18 using 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.35 (3H, s), 2.50-2.55 (7H, m), 3.70-3.78 (4H, m), 6.83 (1H, s), 7.24-7.27 (1H, m), 7.47 (1H, ddd, J = 7.6, 7.6, 1.2 Hz), 7.54 (1H, d, J = 9.0 Hz), 7.61 (1H, d, J = 2.4 Hz), 7.65 (1H, ddd, J = 7.6, 7.6, 1.5 Hz), 7.72 (1H, dd, J = 7.8, 1.0 Hz), 7.85 (1H, dd, J = 8.1, 1.0 Hz),

Process 2
Preparation of methyl 2- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfonamide} acetate

  To a solution of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide (400 mg, 0.91 mmol) in THF (4 mL) was added 2-hydroxy. Methyl acetate (122 mg, 1.36 mmol), DEAD (2.2 M toluene solution, 0.62 mL, 1.36 mmol) and triphenylphosphine (357 mg, 1.36 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18) to give the title compound (86%) as a yellow amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.36 (3H, s), 2.50 (3H, s), 2.51-2.56 (4H, m), 3.73 (3H, s), 3.74-3.80 (4H, m) , 4.63 (2H, s), 6.83 (1H, s), 7.32 (1H, dd, J = 9.0, 2.4 Hz), 7.41 (1H, ddd, J = 8.3, 6.4, 2.2 Hz), 7.52-7.68 (4H , m), 7.85 (1H, d, J = 2.4 Hz).

Process 3
Preparation of 2- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfonamido} acetic acid

  Similar to step 2 of Example 2 using methyl 2- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfonamide} acetate. The title compound (crude) was obtained as a brown amorphous.

Process 4
N- (1-Benzylpiperidin-4-yl) -2- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfonamido} acetamide Manufacturing of

  Using 2- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfonamido} acetic acid and 1-benzylpiperidin-4-amine, In the same manner as in Example 1, the title compound (2 step yield: 41%) was obtained as a yellow amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.45-1.57 (2H, m), 1.79-1.86 (2H, m), 2.06-2.16 (2H, m), 2.35 (3H, s), 2.47 (3H, s), 2.50-2.56 (4H, m), 2.70-2.84 (2H, m), 3.47 (2H, s), 3.72-3.84 (5H, m), 4.51 (2H, s), 6.47 (1H, d, J = 8.0 Hz), 6.83 (1H, s), 7.22-7.34 (6H, m), 7.38-7.42 (1H, m), 7.49 (1H, dd, J = 8.0, 7.2 Hz), 7.55 (1H, d , J = 9.0 Hz), 7.63-7.70 (3H, m).

Process 5
Preparation of N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide N- (1-benzyl Examples using piperidin-4-yl) -2- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfonamido} acetamide In the same manner as in 19, the title compound (58%) was obtained as a yellow amorphous.

Example 21
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine of the manufacturing process 1
N- (3-hydroxypropyl) -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide, and N, N ′-(propane- 1,3-diyl) bis {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide}

  Similar to Step 2 of Example 20 using N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide and 1,3-propanediol. N- (3-hydroxypropyl) -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide (75%) N, N ′-(propane-1,3-diyl) bis {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide} (25%) was obtained as a yellow amorphous.

N- (3-hydroxypropyl) -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.74 (2H, tt, J = 6.4, 6.4 Hz), 2.36 (3H, s), 2.49 (3H, s), 2.52-2.57 (4H, m), 3.74 -3.80 (4H, m), 3.82 (2H, t, J = 6.1 Hz), 3.99 (2H, t, J = 6.6 Hz), 6.85 (1H, s). 7.22 (1H, dd, J = 8.8, 2.4 Hz), 7.35-7.47 (2H, m), 7.56-7.67 (4H, m).

N, N ′-(propane-1,3-diyl) bis {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide}
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.78 (2H, tt, J = 7.1, 7.1 Hz), 2.37 (6H, s), 2.44 (6H, s), 2.52-2.56 (8H, m), 3.73 -3.80 (8H, m), 3.91-3.98 (4H, m), 6.81 (2H, s), 7.08 (2H, dd, J = 8.8, 2.4 Hz), 7.35-7.65 (12H, m).

Process 2
N- (1-benzylpiperidin-4-yl) -N- (3- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfone Amido} propyl) -2-nitrobenzenesulfonamide

  N- (3-hydroxypropyl) -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide and N- (1-benzylpiperidine-4 -Ill) -2-Nitrobenzenesulfonamide was used in the same manner as in Step 2 of Example 20 to obtain the title compound (52%) as a yellow amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.54-1.86 (6H, m), 2.00-2.10 (2H, m), 2.36 (3H, s), 2.50-2.66 (8H, m), 2.82-2.90 ( 2H, m), 3.42-3.49 (4H, m), 3.72-3.82 (4H, m), 3.86 (2H, t, J = 6.1 Hz), 6.85 (1H, s), 7.12 (1H, dd, J = 8.8, 2.2 Hz), 7.21-7.42 (6H, m), 7.50-7.66 (7H, m), 7.84 (1H, d, J = 2.4 Hz), 7.96 (1H, dd, J = 7.6, 1.2 Hz).

Process 3
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] Production N propane-1,3-diamine -(1-Benzylpiperidin-4-yl) -N- (3- {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrophenylsulfonamide } Propyl) -2-nitrobenzenesulfonamide was used in the same manner as in Example 19 to obtain the title compound (89%) as a yellow oil.

Example 22
Preparation of N ¹ , N ³ -bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine N, N ′-(propane-1,3 -Diyl) bis {N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide} in the same manner as in Example 19 The compound (70%) was obtained as a yellow solid.

Example 23
Process for producing N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide 1
Preparation of 2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid

  To a solution of isatin (600 mg, 4.1 mmol) in ethanol (8 mL), 1- [4- (4-methylpiperazin-1-yl) phenyl] ethanone (1.34 g, 6.1 mmol), potassium hydroxide (690 mg, 12.3 mmol) was added and stirred at reflux overnight. The mixture was returned to room temperature, neutralized with 6N hydrochloric acid, and concentrated under reduced pressure. Water and ether were added to the residue, and the solid was collected by filtration to give the title compound (758 mg, crude) as a yellow solid.

Process 2
Production of N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide 2 Similar to Example 1 with-[4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid and 3-amino-N- (1-benzylpiperidin-4-yl) propionamide To give the title compound (84% yield over 2 steps) as a yellow solid.

Example 24
Preparation of 2- [4- (4-Methylpiperazin-1-yl) phenyl] -N- (2-morpholinoethyl) quinoline-4-carboxamide 2- [4- (4-Methylpiperazin-1-yl) phenyl] The title compound (2 step yield: 46%) was obtained as a yellow solid in the same manner as in Example 1 using quinoline-4-carboxylic acid and 2-morpholinoethanamine.

Example 25
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide 2- [ Example 1 using 4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) propan-1-amine In the same manner as described above, the title compound (2 step yield: 44%) was obtained as a yellow amorphous substance. Maleic acid (90 mg, 0.69 mmol) was added to an ethanol (1 mL) solution of the obtained title compound (125 mg, 0.23 mmol), recrystallized, and the title compound trimaleate (158 mg, 73% )

Example 26
Preparation of N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide 2- (4-Methyl In the same manner as in Example 1 using piperazin-1-yl) quinoline-4-carboxylic acid and 3-amino-N- (1-benzylpiperidin-4-yl) propionamide, the title compound (2-step yield) 50%) was obtained as a slightly yellow solid.

Example 27
Preparation of 2- (4-methylpiperazin-1-yl) -N- (2-morpholinoethyl) quinoline-4-carboxamide 2- (4-Methylpiperazin-1-yl) quinoline-4-carboxylic acid and 2-morpholino Using ethanamine, the title compound (2 step yield: 44%) was obtained as a pale yellow solid in the same manner as in Example 1.

Example 28
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide 2- (4-Methylpiperazine- 1-yl) quinoline-4-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) propan-1-amine as in Example 1 using the title compound (2 steps) Yield 52%) was obtained as a yellow amorphous. Maleic acid (232 mg, 2.0 mmol) was added to a solution of the obtained title compound (239 mg, 0.50 mmol) in ethyl acetate (2 mL), recrystallized, and the title compound trimaleate (379 mg, 92 %).

Example 29
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- 4-Carboxamide Production Process 1
Preparation of 6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid

  4- (4-Methylpiperazin-1-yl) benzaldehyde (667 mg, 3.26 mmol) is added to an ethanol solution (1.3 mL) of 3,4-dimethoxyaniline (500 mg, 3.26 mmol), and the mixture is stirred at reflux for 15 minutes. did. 2-Oxopropanoic acid (0.23 mL, 3.26 mmol) was added to the reaction solution, and the mixture was further stirred for 3 hours by reflux. The temperature was returned to room temperature, and the precipitate was collected by filtration. Methanol (8 mL) was added to the solid, suspended with heating, and filtered to obtain the title compound (538 mg, 41%) as a yellow solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.35 (3H, s), 2.59-2.67 (4H, m), 3.26-3.36 (4H, m), 3.89 (3H, s), 3.97 (3H, s), 7.08 (2H, d, J = 8.8 Hz), 7.43 (1H, s), 8.08-8.14 (3H, m), 8.19 (1H, s).

Process 2
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- Preparation of 4-carboxamide 6,7-Dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid and 3-amino-N- (1-benzylpiperidin-4-yl) ) The title compound (90%) was obtained as a pale yellow solid in the same manner as in Example 1 using propionamide.

Example 30
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Preparation of carboxamide 6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxylic acid and 3-([1,4′-bipiperidin] -1′-yl) The title compound (71%) was obtained as a pale yellow solid in the same manner as in Example 1 using propan-1-amine.

Example 31
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide production process 1
N ¹ - (4-1-benzyl-piperidin-yl) ^-N 4 - (2-chloro-4-methyl-6-yl) production of succinamide

  In the same manner as in Example 1, using 2-chloro-4-methylquinolin-6-amine and 4-[(1-benzylpiperidin-4-yl) amino] -4-oxobutyric acid, the title compound (44% ) Was obtained as a brown amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.44-1.56 (2H, m), 1.87-1.96 (2H, m), 2.08-2.18 (2H, m), 2.60 (3H, s), 2.62-2.70 ( 2H, m), 2.73-2.86 (4H, m), 3.50 (2H, s), 3.77-3.90 (1H, m), 5.68 (1H, d, J = 6.4 Hz), 7.17 (1H, s), 7.22 -7.34 (5H, m), 7.54 (1H, dd, J = 9.0, 2.2 Hz), 7.88 (1H, d, J = 9.0 Hz), 8.41 (1H, d, J = 2.2 Hz), 9.20 (1H, s).

Process 2
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - producing N ¹ of {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide - (1-benzyl-piperidin-4-yl) ^-N 4 - (2-chloro-4-methyl-6-yl) succinamide (100 mg, 0.22 mmol), tetrakis (triphenylphosphine) palladium (0) (25 mg, 0.02 mmol), 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine (98 mg, 0.32 mmol), 2M aqueous sodium carbonate solution (2 mL) was mixed with THF (4 mL), and the mixture was stirred at reflux for 5 hours. It returned to room temperature, saturated sodium hydrogencarbonate aqueous solution was added, and chloroform extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 30: 1 → 7: 1, gradient) to obtain the title compound (94 mg, 72%) as a yellow solid.

Example 32
N ¹ - ^{(1-benzyl-piperidin-4-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide production process 1
Preparation of 2,4-bis (4-methylpiperazin-1-yl) -6-nitroquinoline and 4-bromo-2- (4-methylpiperazin-1-yl) -6-nitroquinoline

  To a solution of 2,4-dibromo-6-nitroquinoline (174 mg, 0.52 mmol) in acetonitrile (4 mL) was added 1-methylpiperazine, and the mixture was stirred at 60 ° C. for 3 hours. The temperature was returned to room temperature, ether was added, and the solid was collected by filtration. A saturated aqueous sodium hydrogen carbonate solution was added to the solid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: methanol = 10: 1), and 2,4-bis (4-methylpiperazin-1-yl) -6-nitroquinoline (16 mg, 8%) was converted to orange. As a color solid, 4-bromo-2- (4-methylpiperazin-1-yl) -6-nitroquinoline (5 mg, 3%) was obtained as a yellow solid.

2,4-bis (4-methylpiperazin-1-yl) -6-nitroquinoline
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 2.44 (3H, s), 2.54 (4H, t, J = 5.1 Hz), 2.70-2.81 (4H, m), 3.18-3.28 (4H, m), 3.83 (4H, t, J = 4.6 Hz), 6.41 (1H, s), 7.61 (1H, d, J = 9.3 Hz), 8.24 (1H, d, J = 9.3 Hz), 8.72 (1H, s).

4-Bromo-2- (4-methylpiperazin-1-yl) -6-nitroquinoline
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 2.55 (4H, t, J = 4.9 Hz), 3.85 (4H, t, J = 4.9 Hz), 7.38 (1H, s), 7.65 (1H, d, J = 9.3 Hz), 8.31 (1H, dd, J = 2.7, 9.3 Hz), 8.88 (1H, d, J = 2.7 Hz).

Process 2
Preparation of 2,4-bis (4-methylpiperazin-1-yl) quinolin-6-amine

  The title compound (92%) was obtained as a yellow-green oil in the same manner as in Step 2 of Example 5 using 2,4-bis (4-methylpiperazin-1-yl) -6-nitroquinoline.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.37 (3H, s), 2.42 (3H, s), 2.56-2.62 (4H, m), 2.65-2.75 (4H, m), 3.12-3.24 (4H, m), 3.64-3.70 (4H, m), 6.41 (1H, s), 6.99 (1H, dd, J = 8.8, 2.7 Hz), 7.02 (1H, d, J = 2.2 Hz), 7.59 (1H, d , J = 8.6 Hz).

Process 3
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 2,4-bis (4- Methylpiperazin-1-yl) quinolin-6-amine and 4-[(1-benzylpiperidin-4-yl) amino] -4-oxobutyric acid were used in the same manner as in Example 1 to obtain the title compound (60% ) Was obtained as a pale yellow solid.

Example 33
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - [4- methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide production process 1
Preparation of 4-methoxy-2- (4-methylpiperazin-1-yl) -6-nitroquinoline

  Sodium methoxide was added to a solution of 4-bromo-2- (4-methylpiperazin-1-yl) -6-nitroquinoline (35 mg, 0.10 mmol) in methanol (3 mL), and the mixture was stirred overnight with reflux. It returned to room temperature, water was added, and chloroform extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: methanol = 10: 1) to give the title compound (25 mg, 83%) as a yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.38 (3H, s), 2.56 (4H, t, J = 4.6 Hz), 3.86 (4H, t, J = 4.6 Hz), 4.04 (3H, s), 6.04 (1H, s), 7.58 (1H, d, J = 9.3 Hz), 8.27 (1H, dd, J = 2.7, 9.3 Hz), 8.89 (1H, d, J = 2.7 Hz).

Process 2
Preparation of 4-methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-amine

  The title compound (quant.) Was obtained as a yellow-green solid in the same manner as in Step 2 of Example 5 using 4-methoxy-2- (4-methylpiperazin-1-yl) -6-nitroquinoline.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.39 (3H, s), 2.57-2.69 (4H, m), 3.67-3.75 (4H, m), 3.98 (3H, s), 6.25 (1H, s) , 7.02 (1H, J = dd, 8.8, 2.7 Hz), 7.18 (1H, d, J = 2.4 Hz), 7.55 (1H, d, J = 8.6 Hz).

Process 3
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - [4-methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide manufacturing 4-methoxy-2- ( 4-methylpiperazin-1-yl) quinolin-6-amine and 4-[(1-benzylpiperidin-4-yl) amino] -4-oxobutyric acid were used in the same manner as in Example 1 to obtain the title compound ( 63%) was obtained as a pale yellow solid.

Example 34
Process for producing 2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide 1
Preparation of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- (2-chloro-4-methylquinolin-6-yl) acetamide

  In the same manner as in Example 1, using 2-chloro-4-methylquinolin-6-amine and 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid, The compound (33%) was obtained as a reddish brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.56-1.70 (2H, m,) 1.74-1.89 (2H, m), 2.08-2.16 (2H, m), 2.63 (3H, s), 2.98-2.98 ( 2H, m), 3.48 (2H, s), 4.02-4.14 (1H, m), 4.16 (2H, s), 7.20-7.32 (5H, m), 7.40-7.54 (2H, m), 7.58-7.73 ( 3H, m), 7.89 (1H, d, J = 9.0 Hz), 8.12 (1H, d, J = 7.8 Hz), 8.29 (1H, d, J = 2.2 Hz), 8.58 (1H, s).

Process 2
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- Production of 6-yl} acetamide

  2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamide] -N- (2-chloro-4-methylquinolin-6-yl) acetamide and 1-methyl-4- [4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine is used in the same manner as in Step 2 of Example 31 to give the title compound (crude) in yellow Obtained as amorphous.

Process 3
Preparation of 2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide 2 -[N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamide] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-6 The title compound (12%) was obtained as a yellow solid in the same manner as in Example 19 using -yl} acetamide.

Example 35
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - (4-methyl-2 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} quinolin-6-yl) succinamide of producing N ¹ - (4-1-benzyl-piperidin-yl) ^-N 4 - (2-chloro-4-methyl-6-yl) succinamide (100 mg, 0.22 mmol), 4- (4- methylpiperazin -1 -Yl) aniline (49 mg, 0.26 mmol), palladium (II) acetate (5 mg, 0.02 mmol), BINAP (27 mg, 0.04 mmol), cesium carbonate (140 mg, 0.43 mmol) in dioxane (2 mL) Mix and stir overnight with reflux. It returned to room temperature, saturated sodium hydrogencarbonate aqueous solution was added, and chloroform extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: ammonia saturated methanol = 20: 1 → 10: 1, gradient) to obtain the title compound (85 mg, 64%) as a yellow solid.

Example 36
N ¹ - [4- benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (-4- 1- benzyl-yl) succinamide production process 1
Preparation of 4-benzyl-2- (4-methylpiperazin-1-yl) -6-nitroquinoline

  Triacetoxy hydrogenation in a solution of 4-benzyl-6-nitro-2- (piperazin-1-yl) quinoline (35 mg, 0.1 mmol) and 37% aqueous formaldehyde (0.7 mL, 100 mmol) in methylene chloride (1 mL) Sodium boron (32 mg, 0.15 mmol) and acetic acid (0.03 mL) were added under ice cooling. Stir overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to obtain the title compound (36 mg, quant.) As a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.36 (3H, s), 2.52 (4H, t, J = 4.9 Hz), 3.80 (4H, t, J = 4.9 Hz), 4.35 (2H, s), 6.79 (1H, s), 7.20-7.37 (5H, m), 7.67 (1H, d, J = 9.0 Hz), 8.27 (1H, dd, J = 9.0, 2.4 Hz), 8.75 (1H, d, J = 2.4 Hz).

Process 2
Preparation of 4-benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine

  The title compound (quant.) Was obtained as a brown oil in the same manner as in Step 2 of Example 5 using 4-benzyl-2- (4-methylpiperazin-1-yl) -6-nitroquinoline.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.35 (3H, s), 2.52-2.59 (4H, m), 3.62-3.68 (4H, m), 4.23 (2H, s), 6.70 (1H, s) , 6.95 (1H, d, J = 2.4 Hz), 7.00 (1H, dd, J = 8.8, 2.7 Hz), 7.16-7.32 (5H, m), 7.60 (1H, d, J = 8.8 Hz).

Process 3
N ¹ - [4-benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (1-benzyl-piperidin-4-yl) succinamide manufacturing 4-benzyl-2- ( 4-methylpiperazin-1-yl) quinolin-6-amine and 4-[(1-benzylpiperidin-4-yl) amino] -4-oxobutyric acid were used in the same manner as in Example 1 to obtain the title compound ( 61%) was obtained as a pale yellow solid.

Example 37
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide production process 1
Preparation of 3- (4-methyl-6-nitroquinolin-2-yl) prop-2-yn-1-ol

  2-Chloro-4-methyl-6-nitroquinoline (100 mg, 0.45 mmol), 2-propyn-1-ol (0.08 mL, 1.35 mmol), bis (triphenylphosphine) palladium (II) dichloride (32 mg, 0.045 mmol), copper (I) iodide (26 mg, 0.14 mmol), and triethylamine (1 mL, 7.2 mmol) were mixed with dioxane (0.5 mL) and stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol = 10/1. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to obtain the title compound (66 mg, 60%) as a brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.83 (1H, t, J = 6.6 Hz), 2.80 (3H, s), 4.60 (2H, d, J = 6.6 Hz), 7.50 (1H, s), 8.20 (1H, d, J = 9.3 Hz), 8.48 (1H, dd, J = 9.2, 2.4 Hz), 8.93 (1H, d, J = 2.4 Hz).

Process 2
Preparation of 3- (4-methyl-6-nitroquinolin-2-yl) prop-2-yn-1-yl methanesulfonate

  To a solution of 3- (4-methyl-6-nitroquinolin-2-yl) prop-2-yn-1-ol (66 g, 0.27 mmol) in methylene chloride (1 mL) was added triethylamine (0.06) under ice cooling. mL, 0.39 mmol) and methanesulfonyl chloride (0.025 mL, 0.32 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to obtain the title compound (crude) as a brown solid.

Process 3
Preparation of 4-methyl-2- [3- (4-methylpiperazin-1-yl) prop-1-in-1-yl] -6-nitroquinoline

  3- (4-Methyl-6-nitroquinolin-2-yl) prop-2-yn-1-yl methanesulfonate and 4-methylpiperazine were used in the same manner as in Step 2 of Example 14 to obtain the title compound ( Two step yield 30%) was obtained as an orange solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.33 (3H, s), 2.45-2.67 (4H, m), 2.70-2.78 (7H, m), 3.67 (2H, s), 7.49 (1H, s) , 8.17 (1H, d, J = 9.3 Hz), 8.47 (1H, d, J = 9.3, 2.4 Hz), 8.92 (1H, d, J = 2.4 Hz).

Process 4
Preparation of 4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-amine

  In a manner similar to that described in Step 2 of Example 5, using 4-methyl-2- [3- (4-methylpiperazin-1-yl) prop-1-in-1-yl] -6-nitroquinoline, the title The compound (crude) was obtained as an orange oil.

Process 5
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide manufacturing 4- Performed with methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-amine and 4-[(1-benzylpiperidin-4-yl) amino] -4-oxobutyric acid In the same manner as in Example 1, the title compound (69%) was obtained as a pale yellow solid.

Example 38
Production process 1 of 2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide
Preparation of 2-[(1-benzylpiperidin-4-yl) oxy] acetyl chloride

  To a solution of 2-[(1-benzylpiperidin-4-yl) oxy] acetic acid (15 mg, 0.059 mmol) in methylene chloride (1 mL) under ice-cooling, DMF (10 μL), oxalyl dichloride (15 mg, 0.12 mmol) was added. It returned to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped with toluene to obtain a tan amorphous (20 mg, crude).

Process 2
Preparation of 2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 4-Methyl-2- (4-Methylpiperazin-1-yl) quinolin-6-amine (116 mg, 0.45 mmol) was dissolved in methylene chloride (2.2 mL), and diisopropylethylamine (0.2 mL, 1.13 mmol) was added. In an ice bath, 2-[(1-benzylpiperidin-4-yl) oxy] acetyl chloride (20 mg, crude) was added. It returned to room temperature and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: ammonia saturated methanol = 98: 2) to obtain the title compound (21 mg, 10%) as a pale yellow solid.

Example 39
Production process 1 of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide
Preparation of methyl 2-[(1-methylpiperidin-4-yl) amino] acetate

  To a solution of N-methyl-4-piperidone (27.2 g, 240 mmol) and glycine methyl ester (25.0 g, 200 mmol) in methylene chloride (250 mL) was added sodium triacetoxyborohydride (63.6 g, 300 mmol) on ice. Added under cold. Stir at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and extraction was performed 10 times with chloroform: methanol = 8: 1. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (32.6 g, crude) was obtained as a tan oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.45-1.57 (2H, m), 1.84-1.94 (2H, m), 2.08-2.20 (2H, m), 2.32 (3H, s), 2.48-2.58 ( 1H, m), 2.80-2.93 (2H, m), 3.44 (2H, s), 3.74 (3H, s).

Process 2
Preparation of methyl 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamide] acetate

  The title compound (55.5%) was obtained as a brown oil in the same manner as in Step 2 of Example 18 using methyl 2-[(1-methylpiperidin-4-yl) amino] acetate.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.58-1.78 (4H, m), 1.98-2.08 (2H, m), 2.25 (3H, s), 2.82-2.90 (2H, m), 3.68 (3H, s), 3.74-3.86 (1H, m), 4.13 (2H, s), 7.64-7.73 (3H, m), 8.16-8.22 (1H, m).

Process 3
Preparation of 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid

  Methyl 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamide] acetate is used to obtain the title compound (crude) as a brown amorphous in the same manner as in Step 2 of Example 2. It was.

Process 4
N- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide Manufacturing of

  Using 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid, In the same manner as in Example 1, the title compound (79%) was obtained as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.82-1.90 (4H, m), 2.08-2.18 (2H, m), 2.27 (3H, s), 2.36 (3H, s), 2.52-2.57 (7H, m), 2.88 -2.94 (2H, m), 3.70-3.75 (4H, m), 4.06-4.14 (3H, m), 6.83 (1H, s), 7.24 (1H, dd, J = 8.0, 2.4 Hz) , 7.55-7.70 (4H, m), 7.99 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 8.0 Hz), 8.35 (1H, brs).

Process 5
Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide N- [4-Methyl Example of using 2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide In the same manner as in 19, the title compound (66%) was obtained as a light brown solid.

Example 40
Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide 4-Methyl- The title compound was prepared in the same manner as in Example 1 using 2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [4- (4-methylpiperazin-1-yl) phenyl] acetic acid. (30%) was obtained as a light brown solid.

Example 41
Production process 1 of 2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 1
Preparation of N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrobenzenesulfonamide

  The title compound (91%) was obtained as a light brown solid in the same manner as in Step 2 of Example 18 using 1- (cyclopropylmethyl) piperidin-4-amine.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.04-0.10 (2H, m), 0.47-0.53 (2H, m), 0.76-0.87 (1H, m), 1.54-1.65 (2H, m), 1.80- 1.89 (2H, m), 2.05-2.18 (2H, m), 2.23 (2H, d, J = 7.2 Hz), 2.84-2.92 (2H, m), 3.34-3.44 (1H, m), 5.30 (1H, brs), 7.70-7.78 (2H, m), 7.83-7.89 (1H, m), 8.12-8.20 (1H, m).

Process 2
Preparation of methyl 2- {N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrophenylsulfonamide} acetate

  In the same manner as in Step 2 of Example 20, using N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrobenzenesulfonamide and methyl 2-hydroxyacetate, the title compound (46%) was obtained. Obtained as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.05-0.10 (2H, m), 0.46-0.53 (2H, m), 0.75-0.90 (1H, m), 1.56-1.78 (4H, m), 1.92- 2.06 (2H, m), 2.21 (2H, d, J = 6.4 Hz), 3.05-3.12 (2H, m), 3.67 (3H, s), 3.75-3.86 (1H, m), 4.15 (2H, s) , 7.62-7.72 (3H, m), 8.15-8.21 (1H, m).

Process 3
Preparation of 2- {N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrophenylsulfonamido} acetic acid

  Methyl 2- {N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrophenylsulfonamido} acetate is used in the same manner as in Step 2 of Example 2 to give the title compound (crude). Obtained as a pale yellow solid.

Process 4
2- {N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrophenylsulfonamido} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6 -Ile] acetamide production

  4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- {N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrophenylsulfonamido} acetic acid In the same manner as in Example 1, the title compound (crude) was obtained as a pale yellow solid.

Process 5
Preparation of 2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 2- {N- [1- (cyclopropylmethyl) piperidin-4-yl] -2-nitrophenylsulfonamido} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl The title compound (2 step yield: 22%) was obtained as a light brown amorphous using acetamide in the same manner as in Example 19.

Example 42
Production process 1 of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide
Preparation of methyl 2- [2-nitro-N- (pyridin-4-ylmethyl) phenylsulfonamide] acetate

  Using 2-nitro-N- (pyridin-4-ylmethyl) benzenesulfonamide and 2-hydroxymethyl acetate in the same manner as in Step 2 of Example 20, the title compound (66%) was obtained as a light brown amorphous. .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 3.62 (3H, s), 4.09 (2H, s), 4.69 (2H, s), 7.22 (2H, d, J = 5.6 Hz), 7.64-7.78 (3H , m), 8.06-8.08 (1H, m), 8.57 (2H, d, J = 5.5 Hz).

Process 2
Preparation of 2- [2-nitro-N- (pyridin-4-ylmethyl) phenylsulfonamido] acetic acid

  The title compound (crude) was obtained as a light brown amorphous using methyl 2- [2-nitro-N- (pyridin-4-ylmethyl) phenylsulfonamido] acetate in the same manner as in Step 2 of Example 2.

Process 3
Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [2-nitro-N- (pyridin-4-ylmethyl) phenylsulfonamido] acetamide

  Example 1 using 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [2-nitro-N- (pyridin-4-ylmethyl) phenylsulfonamido] acetic acid In the same manner as above, the title compound (crude) was obtained as a light brown amorphous.

Process 4
Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide N- [4-Methyl-2- (4-Methylpiperazin-1-yl) quinolin-6-yl] -2- [2-nitro-N- (pyridin-4-ylmethyl) phenylsulfonamido] acetamide was used in the same manner as in Example 19, The title compound (34%) was obtained as a light brown solid.

Example 43
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide production process 1
tert-Butyl 4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazine-1-carboxylate Manufacturing of

  tert-Butyl 4- (6-amino-4-methylquinolin-2-yl) piperazine-1-carboxylate and 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid In the same manner as in Step 1 and Step 2 of Example 38, the title compound (crude) was obtained as a yellow solid.

Process 2
Preparation of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide

  tert-Butyl 4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazine-1-carboxylate In the same manner as in Step 2 of Example 13, the title compound (2 step yield: 74%) was obtained as a tan amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.78-1.90 (4H, m), 2.08-2.20 (2H, m), 2.53 (3H, s), 2.91-3.05 (6H, m), 3.48 (2H, s), 3.64-3.72 (4H, m), 4.08-4.20 (3H, m), 6.81 (1H, s), 7.20-7.32 (6H, m), 7.54-7.70 (4H, m), 7.97 (1H, d, J = 2.2 Hz), 8.12 (1H, d, J = 7.6 Hz), 8.35 (1H, s).

Process 3
4- [4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -4-Oxobutyric acid production

  2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide (197 mg , 0.3 mmol) in THF (4 mL) was added succinic anhydride (32 mg, 0.32 mmol) and stirred at 60 ° C. overnight. The mixture was returned to room temperature and concentrated under reduced pressure to give the title compound (232 mg, crude) as a yellow solid.

Process 4
4- [4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] Preparation of -N-methyl-4-oxobutanamide

  4- [4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] The title compound (2 step yield: 81%) was obtained as a brown amorphous in the same manner as in Example 1 using -4-oxobutyric acid and methylamine.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.78-1.92 (4H, m), 2.06-2.17 (2H, m), 2.52-2.58 (5H, m), 2.70-2.76 (2H, m), 2.80 ( 3H, d, J = 4.9 Hz), 2.90-2.98 (2H, m), 3.48 (2H, s), 3.60-3.80 (8H, m), 4.02-4.16 (3H, m), 6.09 (1H, brs) , 6.80 (1H, s), 7.20-7.32 (6H, m), 7.56-7.70 (4H, m), 8.01 (1H, d, J = 2.2 Hz), 8.13 (1H, d, J = 7.3 Hz), 8.48 (1H, brs).

Process 5
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Preparation of butanamide 4- [4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazine- The title compound (76%) was obtained as a pale yellow solid in the same manner as in Example 19 using 1-yl] -N-methyl-4-oxobutanamide.

Example 44
Preparation of 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide Process 1
6- [4- (6- {2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -Production of N-methylhexanamide

  2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide and 6- The title compound (crude) was obtained as a pale yellow amorphous in the same manner as in Step 2 of Example 14 using bromo-N-methylhexanamide.

Process 2
Preparation of 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide 6- [4- (6- {2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] The title compound (2 step yield: 48%) was obtained as a pale yellow amorphous in the same manner as Example 19 using -N-methylhexaneamide.

Example 45
Preparation of 2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide 2- [N- (1-benzyl) Piperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide was used in the same manner as in Example 19, The title compound (78%) was obtained as a brown amorphous.

Example 46
Preparation of 2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 4-Methyl Step 1 and step of Example 38 using 2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2-[(1-benzylpiperidin-4-yl) (methyl) amino] acetic acid. Similar to 2, the title compound (42%) was obtained as a tan oil.

Example 47
Production process 1 of 2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 1
Preparation of N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide

  N- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide and methanol were used in the same manner as in Step 2 of Example 20 to obtain the title compound. (85%) was obtained as a tan amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.36 (3H, s), 2.50 (3H, s), 2.51-2.56 (4H, m), 3.45 (3H, s), 3.74-3.80 (4H, m) , 6.85 (1H, s), 7.24 (1H, dd, J = 8.8, 2.4 Hz), 7.38-7.47 (2H, m), 7.58-7.70 (4H, m).

Process 2
Production of N, 4-dimethyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine

  In the same manner as in Example 19 using N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-nitrobenzenesulfonamide, the title compound ( 88%) was obtained as a tan amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.36 (3H, s), 2.54 (3H, s), 2.54-2.58 (4H, m), 2.92 (3H, s), 3.65-3.71 (4H, m) , 6.73 (1H, d, J = 2.4 Hz), 6.81 (1H, s), 6.98 (1H, dd, J = 8.8, 2.4 Hz), 7.58 (1H, d, J = 8.8 Hz).

Process 3
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6 -Ile] acetamide production

  Using N, 4-dimethyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid In the same manner as in Step 1 and Step 2 of Example 38, the title compound (crude) was obtained as a tan amorphous.

Process 4
Preparation of 2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide 2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamide] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl The title compound (80%) was obtained as a light brown amorphous in the same manner as in Example 19 using acetamide.

Example 48
Production process 1 of 1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine
Preparation of N- (1-benzylpiperidin-4-yl) -N- (3-hydroxypropyl) -2-nitrobenzenesulfonamide

  Using the N- (1-benzylpiperidin-4-yl) -2-nitrobenzenesulfonamide and 1,3-propanediol in the same manner as in Step 2 of Example 20, the title compound (58%) was converted to a light brown amorphous Got as.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.60-1.92 (6H, m), 2.00-2.10 (2H, m), 2.86-2.95 (2H, m), 3.44 (2H, t, J = 7.2 Hz) , 3.47 (2H, s), 3.68-2.78 (3H, m), 7.22-7.33 (5H, m), 7.56-7.62 (1H, m), 7.63-7.70 (2H, m), 8.01-8.06 (1H, m).

Process 2
Preparation of N- (1-benzylpiperidin-4-yl) -N- {3-[(2-chloro-4-methylquinolin-6-yl) oxy] propyl} -2-nitrobenzenesulfonamide

  Step 2 of Example 20 using 2-chloro-4-methylquinolin-6-ol and N- (1-benzylpiperidin-4-yl) -N- (3-hydroxypropyl) -2-nitrobenzenesulfonamide. In the same manner as described above, the title compound (15%) was obtained as a light brown amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.60-1.70 (2H, m), 1.78-1.93 (2H, m), 2.00-2.08 (2H, m), 2.18-2.26 (2H, m), 2.63 ( 3H, s), 2.86-2.96 (2H, m), 3.48 (2H, s), 3.54 (2H, t, J = 7.2 Hz), 3.72-3.82 (1H, m), 4.08-4.17 (2H, m) , 7.15 (1H, d, J = 2.4 Hz), 7.21 (1H, s,), 7.26-7.33 (5H, m), 7.36 (1H, dd, J = 7.2, 3.2 Hz), 7.56-7.70 (3H, m), 7.92 (1H, d, J = 9.2 Hz), 8.01-8.06 (1H, m).

Process 3
N- (1-benzylpiperidin-4-yl) -N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) -2-nitrobenzene Production of sulfonamides

  Using N- (1-benzylpiperidin-4-yl) -N- {3-[(2-chloro-4-methylquinolin-6-yl) oxy] propyl} -2-nitrobenzenesulfonamide and 1-methylpiperazine In the same manner as in Step 1 of Example 32, the title compound (crude) was obtained as a light brown amorphous.

Process 4
Preparation of 1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine N- (1-benzyl With piperidin-4-yl) -N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) -2-nitrobenzenesulfonamide, In the same manner as in Example 19, the title compound (2 step yield: 13%) was obtained as a pale yellow oil.

Example 49
Process for producing N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide 1
tert-Butyl 4- (4-methyl-6- {2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} quinolin-2-yl) piperazine-1-carboxylate Manufacturing of

  tert-Butyl 4- (6-amino-4-methylquinolin-2-yl) piperazine-1-carboxylate and 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid In the same manner as in Example 1, the title compound (47%) was obtained as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.80-1.95 (4H, m), 2.03-2.15 (2H, m), 2.25 (3H, s), 2.53 (3H, s) , 2.85-2.94 (2H, m), 3.52-3.60 (4H, m), 3.65-3.73 (4H, m), 4.00-4.11 (1H, m), 4.13 (2H, s), 6.81 (1H, s) , 7.24-7.30 (1H, m), 7.55-7.70 (4H, m), 8.00 (1H, d, J = 2.4 Hz), 8.13 (1H, d, J = 7.2 Hz), 8.39 (1H, brs).

Process 2
Preparation of N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide

  tert-Butyl 4- (4-methyl-6- {2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} quinolin-2-yl) piperazine-1-carboxylate In the same manner as in Step 2 of Example 13, the title compound (81%) was obtained as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.81-1.90 (4H, m), 2.06-2.16 (2H, m), 2.26 (3H, s), 2.53 (3H, s), 2.85-2.93 (2H, m), 2.97-3.03 (4H, m), 3.65-3.70 (4H, m), 4.03-4.15 (3H, m), 6.82 (1H, s), 7.23 (1H, dd, J = 9.2, 2.4 Hz) , 7.56-7.70 (4H, m), 7.98 (1H, d, 2.4 Hz), 8.12 (1H, d, J = 8.0 Hz), 8.34 (1H, brs).

Process 3
N- [2- (4- {2-[(tert-butyldiphenylsilyl) oxy] ethyl} piperazin-1-yl) -4-methylquinolin-6-yl] -2- [N- (1-methylpiperidine -4-yl) -2-nitrophenylsulfonamido] acetamide

  N- [4-Methyl-2- (piperazin-1-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide and (2 Using -bromoethoxy) (tert-butyl) diphenylsilane, the title compound (74%) was obtained as a pale yellow amorphous in the same manner as in Step 2 of Example 14.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.04 (9H, s), 1.84-1.93 (4H, m), 2.08-2.19 (2H, m), 2.27 (3H, s), 2.53 (3H, s) , 2.59-2.66 (6H, m), 2.87-2.95 (2H, m), 3.63-3.68 (4H, m), 3.85 (1H, t, J = 6.0 Hz), 4.05-4.16 (3H, m), 6.80 (1H, s), 7.23-7.28 (1H, m), 7.35-7.46 (6H, m), 7.54-7.62 (3H, m), 7.64-7.74 (5H, m), 7.98 (1H, d, J = 2.0 Hz), 8.12 (1H, d, J = 8.0 Hz), 8.34 (1H, s).

Process 4
N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2- [N- (1-methylpiperidin-4-yl) -2-nitro Phenylsulfonamide] acetamide production

  N- [2- (4- {2-[(tert-butyldiphenylsilyl) oxy] ethyl} piperazin-1-yl) -4-methylquinolin-6-yl] -2- [N- (1-methylpiperidine -4-yl) -2-nitrophenylsulfonamido] acetamide (1.1 g, 1.27 mmol) in DMF (20 mL), water (20 mL) in acetic acid (1.1 mL, 19.2 mmol), TBAF (2.2 mL, 2.54 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol = 10/1. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform alone → chloroform: ammonium saturated methanol = 85: 15) to obtain the title compound (622 mg, 78%) as a yellow amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.80-1.90 (4H, m), 2.05-2.16 (2H, m), 2.26 (3H, s), 2.54 (3H, s), 2.58-2.67 (6H, m), 2.85-2.94 (2H, m), 3.68 (2H, t, J = 5.2 Hz), 3.70-3.77 (4H, m), 4.02-4.15 (3H, m), 6.82 (1H, s), 7.24 -7.26 (1H, m), 7.55-7.71 (4H, m), 7.99 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 7.6 Hz), 8.33 (1H, s).

Process 5
Preparation of N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide N -{2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenyl Sulfonamide] acetamide was used in the same manner as in Example 19 to obtain the title compound (83%) as a white solid.

Example 50
Production process 1 of N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide
Preparation of tert-butyl 4- (4-methyl-6-nitroquinolin-2-yl) -5,6-dihydropyridine-1 (2H) -carboxylate

  2-Chloro-4-methyl-6-nitroquinoline and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -5,6-dihydropyridine-1 The title compound (76%) was obtained as a brown solid in the same manner as in Step 2 of Example 31 using (2H) -carboxylate.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.51 (9H, s), 2.80 (3H, s), 2.82-2.86 (2H, m), 3.66-3.75 (2H, m), 4.23 (2H, brs) , 6.81 (1H, brs), 7.57 (1H, s), 8.14 (1H, d, J = 9.3 Hz), 8.44 (1H, dd, J = 9.3, 2.7 Hz), 8.92 (1H, d, J = 2.4 Hz).

Process 2
Preparation of tert-butyl 4- (6-amino-4-methylquinolin-2-yl) piperidine-1-carboxylate

  tert-Butyl 4- (4-methyl-6-nitroquinolin-2-yl) -5,6-dihydropyridine-1 (2H) -carboxylate in the same manner as in Step 2 of Example 5 was used to prepare the title compound. (81%) was obtained as a light brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.52-1.59 (2H, m), 1.72-1.84 (2H, m), 1.90-1.98 (2H, m), 2.57 (3H, s), 2.78-3.02 (3H, m), 4.27 (2H, brs), 7.02-7.06 (2H, m), 7.13 (1H, d, J = 9.0, 2.7 Hz), 7.82-7.90 (1H, m) .

Process 3
tert-Butyl 4- (4-Methyl-6- {2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} quinolin-2-yl) piperidine-1-carboxylate Manufacturing of

  tert-Butyl 4- (6-amino-4-methylquinolin-2-yl) piperidin-1-carboxylate and 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid In the same manner as in Example 1, the title compound (crude) was obtained as a yellow amorphous.

Process 4
Preparation of N- [4-methyl-2- (piperidin-4-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide

  tert-Butyl 4- (4-Methyl-6- {2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} quinolin-2-yl) piperidine-1-carboxylate In the same manner as in Step 2 of Example 13, the title compound (2 step yield: 13%) was obtained as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.68-1.82 (6H, m), 1.85-1.92 (2H, m), 2.00-2.08 (2H, m), 2.19 (3H, s), 2.56 (3H, s), 2.69-2.94 (5H, m), 3.13-3.20 (2H, m), 3.97-4.07 (1H, m), 4.08 (3H, s), 7.10 (1H, s), 7.32 (1H, dd, J = 9.2, 2.4 Hz), 7.54-7.64 (3H, m), 7.84 (1H, d, J = 8.8 Hz), 8.06 (1H, d, J = 7.2 Hz), 8.16 (1H, d, J = 2.4 Hz), 8.43 (1H, s).

Process 5
N- [4-Methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide Manufacturing of

  N- [4-Methyl-2- (piperidin-4-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide and formaldehyde Was used to give the title compound (92%) as a pale yellow solid in a manner similar to Step 1 of Example 36.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.75-1.81 (4H, m), 1.85-1.94 (4H, m), 2.00-2.08 (4H, m), 2.19 (3H, s), 2.28 (3H, s), 2.55 (3H, s), 2.70-2.86 (3H, m), 2.91-2.98 (2H, m), 3.97-4.06 (1H, m), 4.07 (2H, s), 7.10 (1H, s) , 7.32 (1H, dd, J = 9.2, 2.4 Hz), 7.54-7.64 (3H, m), 7.82 (1H, d, J = 8.8 Hz), 8.07 (1H, d, J = 8.0 Hz), 8.15 ( 1H, d, J = 2.4 Hz), 8.42 (1H, s).

Step 6
Preparation of N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide N- [4-Methyl Example of using 2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide In the same manner as in 19, the title compound (75%) was obtained as a pale yellow amorphous product.

Example 51
Preparation of N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide

Process 1
Preparation of tert-butyl 4-[(4-methyl-6-nitroquinolin-2-yl) oxy] piperidine-1-carboxylate

  To a solution of 2-chloro-4-methyl-6-nitroquinoline (600 mg, 2.70 mmol) in toluene (9 mL), tert-butyl 4-hydroxypiperidine-1-carboxylate (814 mg, 4.1 mmol), tetrasulfate Butylammonium (92 mg, 0.27 mmol) and 8N aqueous sodium hydroxide solution (3.4 mL) were added, and the mixture was stirred at room temperature overnight and further at 50 ° C. for 5 hr. It returned to room temperature, it filtered, and the filtrate was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (chloroform) to obtain the title compound (crude) as a brown solid.

Process 2
Preparation of 4-methyl-6-nitro-2- (piperidin-4-yloxy) quinoline

  tert-Butyl 4-[(4-Methyl-6-nitroquinolin-2-yl) oxy] piperidine-1-carboxylate is used in a manner similar to Example 13, Step 2 to give the title compound (crude) in brown Obtained as a solid.

Process 3
Preparation of 4-methyl-2-[(1-methylpiperidin-4-yl) oxy] -6-nitroquinoline

  Using 4-methyl-6-nitro-2- (piperidin-4-yloxy) quinoline and formaldehyde in the same manner as in Step 1 of Example 36, the title compound (3 step yield: 6%) was obtained as a light brown solid. Obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.85-1.96 (2H, m), 2.09-2.18 (2H, m), 2.34 (3H, s), 2.34-2.43 (2H, m), 2.69 (3H, s), 2.69-2.79 (2H, m), 5.35-5.42 (1H, m), 6.87 (1H, s), 7.85 (1H, d, J = 8.8 Hz), 8.37 (1H, dd, J = 9.2, 2.8 Hz), 8.81 (1H, d, J = 2.8 Hz).

Process 4
Preparation of 4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-amine

  Using 4-methyl-2-[(1-methylpiperidin-4-yl) oxy] -6-nitroquinoline in the same manner as in Step 2 of Example 5, the title compound (crude) was obtained as a brown oil. It was.

Process 5
N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfone Amido] acetamide production

  4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-amine and 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid. The title compound (crude) was obtained as a brown solid in the same manner as in Example 1.

Step 6
Preparation of N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide N- { 4-Methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide In the same manner as in Example 19, the title compound (3 step yield: 41%) was obtained as a pale yellow amorphous.

Example 52
Production process 1 of N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide
Preparation of benzyl 2-[(1-methylpiperidin-4-yl) amino] acetate

  The title compound (crude) was obtained as a tan oil in the same manner as in Step 1 of Example 39 using N-methyl-4-piperidone (27.2 g, 240 mmol) and glycine benzyl ester.

Process 2
Preparation of benzyl 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamide] acetate

  To a solution of benzyl 2-[(1-methylpiperidin-4-yl) amino] acetate (6.98 g, crude, theoretical amount 6.51 g, 24.8 mmol) in methylene chloride (100 mL) was added triethylamine (5.02 g) under ice-cooling. , 49.6 mmol) and trifluoroacetic anhydride (7.81 g, 37.2 mmol) were added. It returned to room temperature and stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 3 → 90: 20, gradient) to obtain the title compound (6.90 g, two-step yield 77.6%) as a light brown amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.56-1.83 (4H, m), 1.98-2.07 (2H, m), 2.27 (3H, s), 2.86-2.94 (2H, m), 3.78-3.88 ( 1H, m), 4.09 (2H, s), 5.17 (2H, s), 7.30-7.39 (5H, m)

Process 3
Preparation of 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetic acid

  To a solution of benzyl 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamide] acetate (6.90 g, 19.3 mmol) in methanol (60 mL) was added 10% Pd-C ( 690 mg) was added. The system was replaced with hydrogen and stirred overnight at room temperature. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The title compound (5.00 g, crude) was obtained as a white amorphous.

Process 4
2,2,2-trifluoro-N- (2- {methyl [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -2-oxoethyl) -N- ( Preparation of 1-methylpiperidin-4-yl) acetamide

  N, 4-dimethyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamide] The title compound (2 step yield: 69%) was obtained as a brown oil in the same manner as in Step 1 and Step 2 of Example 38 using acetic acid.

Process 5
Preparation of N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide 2, 2,2-trifluoro-N- (2- {methyl [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -2-oxoethyl) -N- (1- The title compound (39%) was obtained as a brown solid in the same manner as in Step 4 of Example 11 using methylpiperidin-4-yl) acetamide.

Example 53
Preparation of tert-butyl 4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazine-1-carboxylate tert-butyl 4- ( Examples using 4-methyl-6- {2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} quinolin-2-yl) piperazine-1-carboxylate In the same manner as in 19, the title compound (81%) was obtained as a pale yellow amorphous.

Example 54
Production process 1 of (E) -3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide
(E) Preparation of 3-tert-butyl 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acrylate

  6-iodo-4-methyl-2- (4-methylpiperazin-1-yl) quinoline (400 mg, 1.08 mmol), tert-butyl acrylate (0.78 mL, 5.4 mmol), tris (dibenzylideneacetone) dipalladium ( 104 mg, 0.108 mmol), tri (o-tolyl) phosphine (191 mg, 0.65 mmol) and diisopropylethylamine (0.73 mL, 4.32 mmol) were mixed with DMF (5 mL), and the mixture was stirred at 120 ° C. for 4 hours. It returned to room temperature, saturated sodium hydrogencarbonate aqueous solution was added, and it extracted with toluene. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform only → chloroform: methanol = 90: 10, gradient) to obtain the title compound (318 mg, 80%) as a brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.55 (9H, s), 2.34 (3H, s), 2.55-2.67 (4H, m), 2.59 (3H, s), 3.75-3.82 (4H, m) , 6.38 (1H, d, J = 15.6 Hz), 6.83 (1H, s), 7.64 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 16.0 Hz), 7.71 (1H, dd, J = 8.4, 2.0 Hz), 7.83 (1H, d, J = 1.2 Hz).

Process 2
(E) Preparation of 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acrylic acid

  To a solution of (E) -tert-butyl 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acrylate (218 mg, 0.59 mmol) in methylene chloride (5 mL), Under ice-cooling, TFA (2 mL) was added and stirred overnight. The reaction solution was concentrated under reduced pressure to obtain the title compound (crude) as a light brown solid.

Process 3
Production of (E) -3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide (E) -3 -[4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acrylic acid and 1-methylpiperidin-4-amine were used in the same manner as in Example 1 to obtain the title compound ( A two-step yield of 19%) was obtained as a light brown solid.

Example 55
Preparation of 3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide (E) -3- [4 -Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide was used in the same manner as in Step 2 of Example 5, The title compound (46%) was obtained as a pale yellow solid.

Example 56
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Manufacturing process 1
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2- [N- (1-methylpiperidin-4-yl)- 2-Nitrophenylsulfonamide] acetamide production

  N- [4-Methyl-2- (piperazin-1-yl) quinolin-6-yl] -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide and 2- The title compound (crude) was obtained as a pale yellow amorphous in the same manner as in Step 1 of Example 36 using (benzyloxy) acetaldehyde.

Process 2
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Preparation of N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2- [N- (1-methylpiperidin-4-yl) ) -2-Nitrophenylsulfonamido] acetamide was used in the same manner as in Example 19 to give the title compound (2 step yield: 33%) as a pale yellow oil.

Example 57
(E) Production process 1 of 1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine
Preparation of tert-butyl allyl (1-methylpiperidin-4-yl) carbamate

N-allyl-1-methylpiperidin-4-amine (800 mg, 5.16 mmol) and Boc ₂ O (1.12 g, 5.16 mmol) were mixed with THF (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel chromatography (chloroform only → chloroform: methanol = 90: 10, gradient) to give the title compound (795 mg, 71%) as a brown solid. It was.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.45 (9H, s) 1.63-1.73 (4H, m), 1.94-2.04 (2H, m), 2.26 (3H, s), 2.84-2.91 (2H, m ), 3.68-3.80 (2H, m), 3.93-4.01 (1H, m), 5.02-5.14 (2H, m), 5.72-5.84 (1H, m).

Process 2
(E) Preparation of {tert-butyl {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} (1-methylpiperidin-4-yl) carbamate

  As in Step 1 of Example 54, using 6-iodo-4-methyl-2- (4-methylpiperazin-1-yl) quinoline and tert-butyl allyl (1-methylpiperidin-4-yl) carbamate. The title compound (crude) was obtained as a pale yellow oil.

Process 3
Preparation of (E) -1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine (E) -tert Step of Example 13 using -butyl {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} (1-methylpiperidin-4-yl) carbamate In the same manner as in 2, the title compound (2 step yield: 28%) was obtained as a pale yellow solid.

Example 58
Preparation of 1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl} piperidin-4-amine (E) -1-Methyl-N -{3- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine in the same manner as in Step 2 of Example 5 The compound (64%) was obtained as a pale yellow oil.

Example 59
Production process 1 of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide
Preparation of benzyl 4- (2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -2-oxoethoxy) piperidine-1-carboxylate

  Example using 4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-amine and 2-({1-[(benzyloxy) carbonyl] piperidin-4-yl} oxy) acetic acid In the same manner as in Steps 1 and 2 of 38, the title compound (crude) was obtained as a brown solid.

Process 2
Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide benzyl 4- (2-{[4-methyl- 2- (4-Methylpiperazin-1-yl) quinolin-6-yl] amino} -2-oxoethoxy) piperidine-1-carboxylate in the same manner as in Step 2 of Example 5, the title compound ( (2 step yield 77%) was obtained as a yellow solid.

Example 60
Preparation of N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide 4-Methyl-2- In the same manner as in Step 1 and Step 2 of Example 38, using (4-methylpiperazin-1-yl) quinolin-6-amine and 2-[(1-methylpiperidin-4-yl) oxy] acetic acid, The title compound (95%) was obtained as a pale yellow solid.

Example 61
Preparation of 2-{[1- (cyclopropylmethyl) piperidin-4-yl] oxy} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide N- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide and cyclopropanecarboxaldehyde were used in Step 1 of Example 36. Similarly, the title compound (87%) was obtained as a pale yellow solid.

Example 62
Preparation of N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide Process 1
Preparation of benzyl 4- (4-methyl-6-nitroquinolin-2-yl) piperazine-1-carboxylate

  The title compound (89%) was obtained as a yellow solid in the same manner as in Step 1 of Example 32 using 2-chloro-4-methyl-6-nitroquinoline and benzyl piperazine-1-carboxylate.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.67 (3H, s), 3.64-3.70 (4H, m), 3.82-3.88 (4H, m), 5.19 (2H, s), 6.90 (1H, s) , 7.32-7.40 (5H, m), 7.67 (1H, d, J = 9.3 Hz), 8.31 (1H, d, J = 9.6, 2.7 Hz), 8.72 (1H, d, J = 2.4 Hz).

Process 2
Preparation of benzyl 4- (6-amino-4-methylquinolin-2-yl) piperazine-1-carboxylate

  To a solution of benzyl 4- (4-methyl-6-nitroquinolin-2-yl) piperazine-1-carboxylate (1.0 g, 2.46 mmol) in methanol (20 mL), zinc powder (1.0 g), acetic acid (10 mL ) And stirred at room temperature for 3 hours. The mixture was neutralized with 4M NaOH aqueous solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: ethyl acetate = 90: 10 → 66: 34, gradient) to obtain the title compound (920 mg, quant.) As a yellow amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.52 (3H, s), 3.60-3.69 (8H, m), 5.18 (2H, s), 6.78 (1H, s), 6.97 (1H, d, J = 2.4 Hz), 7.04 (1H, dd, J = 8.8, 2.4 Hz), 7.28-7.41 (6H, m).

Process 3
Benzyl 4- (4-methyl-6- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} quinolin-2-yl) piperazine-1-carboxyl Rate manufacturing

  Benzyl 4- (6-amino-4-methylquinolin-2-yl) piperazine-1-carboxylate and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamide] The title compound (76%) was obtained as a brown amorphous in the same manner as in Step 1 and Step 2 of Example 38 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.80-2.12 (6H, m), 2.30 (3H, s), 2.56 (3H, s), 2.92-3.03 (2H, m), 3.62-3.75 (8H, m), 3.82-3.92 (1H, m), 4.17 (2H, s), 5.18 (2H, s), 6.80 (1H, s), 7.31-7.41 (5H, m), 7.47 (1H, dd, J = 8.8, 2.0 Hz), 7.64 (1H, d, J = 8.8 Hz), 8.10 (1H, s), 8.21 (1H, s).

Process 4
2,2,2-trifluoro-N- (2-{[4-methyl-2- (piperazin-1-yl) quinolin-6-yl] amino} -2-oxoethyl) -N- (1-methylpiperidine -4-yl) acetamide production

  Benzyl 4- (4-methyl-6- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} quinolin-2-yl) piperazine-1-carboxyl The title compound (crude) was obtained as a brown solid in the same manner as in Step 2 of Example 5 using the rate.

Process 5
N-methyl-6- [4- (4-methyl-6- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} quinolin-2-yl ) Preparation of piperazin-1-yl] hexanamide

  2,2,2-trifluoro-N- (2-{[4-methyl-2- (piperazin-1-yl) quinolin-6-yl] amino} -2-oxoethyl) -N- (1-methylpiperidine Using 4--4-yl) acetamide and 6-bromo-N-methylhexanamide, the title compound (2 step yield 59%) was obtained as a tan amorphous in the same manner as in Step 2 of Example 14.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.33-1.74 (8H, m), 1.90-2.06 (4H, m), 2.19 (2H, t, J = 7.3 Hz), 2.29 (3H, s), 2.35 -2.43 (2H, m), 2.40-2.60 (8H, m), 2.80-2.88 (5H, m), 3.44 (2H, s), 3.69-3.78 (4H, m), 5.45 (1H, brs), 6.84 (1H, s), 7.52 (1H, dd, J = 9.0, 2.4 Hz), 7.67 (1H, d, 8.8 Hz), 8.24 (1H, d, J = 2.2 Hz), 9.48 (1H, s).

Step 6
Preparation of N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide N-methyl-6- [4- (4-methyl-6- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} quinolin-2-yl ) Piperazin-1-yl] hexanamide was used in the same manner as in Step 4 of Example 11 to obtain the title compound (77%) as a brown amorphous.

Example 63
Production process 1 of benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate
Benzyl 6- [4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl ] Hexanoate production

  2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide and benzyl 6 Using bromohexanoate, the title compound (94%) was obtained as a yellow solid in the same manner as in Step 2 of Example 14.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.31-1.41 (2H, m), 1.50-1.60 (2H, m), 1.64-1.90 (6H, m), 2.06-2.16 (2H, m), 2.34- 2.41 (4H, m), 2.51-2.58 (7H, m), 2.88-2.97 (2H, m), 3.47 (2H, s), 3.67-3.74 (4H, m), 4.02-4.18 (3H, m), 5.12 (2H, s), 6.81 (1H, s), 7.21-7.38 (11H, m), 7.54-7.69 (4H, m), 7.96 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 7.8 Hz), 8.35 (1H, s).

Process 2
Preparation of benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate Benzyl 6- [ Using 4- (6- {2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate In the same manner as in Example 19, the title compound (94%) was obtained as a yellow solid.

Example 64
^(N 1 - (1-benzyl-piperidin-4-yl) ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide) of Preparation 4 - {[4 -Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 1-benzylpiperidin-4-amine are prepared in the same manner as in Example 1. be able to. It can also be purchased from Aurora Fine Chemical.

Example 65
N ¹ - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (2-morpholinoethyl) succinamide manufacturing 4 - {[4-methyl-2- ( 4-Methylpiperazin-1-yl) quinolin-6-yl] amino} -4-oxobutyric acid and 2-morpholinoethanamine can be used in the same manner as in Example 1. It can also be purchased from Aurora Fine Chemical.

Example 66
Preparation of N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide

Process 1
Preparation of N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-chloroquinoline-2-carboxamide

  4-chloroquinoline-2-carboxylic acid (170 mg, 0.82 mmol) and 3-amino-N- (1-benzylpiperidin-4-yl) propanamide (256 mg, 0.98 mmol), PyBOP (510 mg, 0.98 mmol) ), Diisopropylethylamine (318 mg, 2.46 mmol) was dissolved in DMF (4.1 mL) and stirred at room temperature for 6 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate: toluene = 1: 4. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ammonia saturated methanol = 20: 1 → 10: 1) to obtain the title compound (290 mg, 78%) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.35-1.50 (2H, m), 1.82-1.95 (2H, m), 2.10 (2H, t, J = 10.5 Hz), 2.56 (2H, t, J = 6.1 Hz), 2.76 (2H, d, J = 11.7 Hz), 3.46 (2H, s), 3.78-3.88 (3H, m), 5.60-5.80 (1H, m), 7.20-7.35 (4H, m), 7.68-7.75 (1H, m), 7.75-7.85 (1H, m), 8.13 (1H, d, J = 8.5 Hz), 8.27 (1H, d, J = 8.6 Hz), 8.35 (1H, d, J = 2.4 Hz), 8.64 (1H, t, J = 6.1 Hz).

Process 2
Production of N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide N -{3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-chloroquinoline-2-carboxamide (60 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.013 mmol), 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenyl] piperazine (48 mg, 0.16 mmol), 2M sodium carbonate Aqueous solution (0.27 mL) was mixed with THF (2 mL) and stirred overnight under reflux. The temperature was returned to room temperature, water was added, and the mixture was extracted with chloroform: methanol = 10: 1. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: methanol = 10: 1), and further purified using PLC (chloroform: ammonia saturated methanol = 10: 1) to give the title compound (43 mg, 55%) Was obtained as a yellow oil.

Example 67
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-{[4- (4-methylpiperazin-1-yl) phenyl] amino} quinoline-2-carboxamide Preparation of N- {3-[(1-Benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-chloroquinoline-2-carboxamide (60 mg, 0.13 mmol) of 1,4-dioxane (2 mL) solution with 4- (4-methylpiperazin-1-yl) aniline (30 mg, 0.16 mmol), BINAP (33 mg, 0.026 mmol), palladium (II) acetate (3 mg, 0.013 mmol), cesium carbonate ( 87 mg, 0.26 mmol) was added, and the mixture was stirred for 6 hours under reflux. The temperature was returned to room temperature, water was added, and the mixture was extracted with chloroform: methanol = 10: 1. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: methanol = 10: 1), and further purified using PLC (ethyl acetate: ammonia saturated methanol = 10: 1) to give the title compound (58 mg, 72% ) Was obtained as a yellow solid.

Example 68
Preparation of N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine 4-chloro-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline ( 50 mg, 0.15 mmol) in toluene (1.5 mL) to 4- (4-methylpiperazin-1-yl) aniline (34 mg, 0.18 mmol), tri-tert-butylphosphine (13.4 mg, 0.045 mmol), tris (Dibenzylideneacetone) dipalladium (0) (9 mg, 0.015 mmol) and tert-butoxy sodium (29 mg, 0.30 mmol) were added, and the mixture was stirred at 60 ° C. overnight and further under reflux for 3 hours. The temperature was returned to room temperature, water was added, and the mixture was extracted with chloroform: methanol = 10: 1. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 → 10: 1, chloroform: ammonia saturated methanol = 10: 1) and further recrystallized (chloroform-ether-hexane) to give the title The compound (55 mg, 74%) was obtained as a yellow solid.

  Structural formulas and physical property values of the compounds obtained by the above examples are shown below.

[Test Example 1] TLR9 activation inhibition test using TLR9-expressing reporter cells 1) Establishment of TLR9-expressing reporter cells Human TLR9-expressing cells were obtained by expressing cells expressing human TLR9 in HEK293, a human fetal kidney cell line, from Invivogen. (HTLR9 / 293xL). hTLR9 / 293xL was subcultured using Dulbecco's modified Eagle medium (DMEM (sigma)) containing 10% fetal bovine serum, penicillin, and streptomycin. PGL4.28 (Promega) in which a firefly luciferase gene was linked to the NFκB recognition sequence 4 times was introduced by lipofection using Fugene6 (Roche). Hygromycin and blasticidin resistant cell clones were selected and used as TLR9 expression reporter cells (hTLR9 NFκB-luc / 293 × L).
2) TLR9 plated at activation inhibition test hTLR9 NFκB-luc / 96 well-white 293xL microtiter plate ^{1.0 × 10 4 / 80μL, 37} ℃ in CO ₂ incubator, and cultured overnight. A test compound (10 μL) diluted with DMEM was added to a final concentration of 0.01, 0.03, 0.1, 0.3, 1 μM. One hour later, CpG-B DNA (ODN2006) (Invivogen) as a TLR9 ligand was added to a final concentration of 1 μM (10 μL). Luciferase activity was measured as TLR9 activity after incubation in a CO ₂ incubator for a total of 100 μL for 4 hours. Luciferase activity was measured by adding 60 μL of Bright Glo (Promega) and measuring the amount of luminescence with a multi-microplate reader ARVO (Perkin Elmer). The 50% inhibitory concentration (IC ₅₀ value) of each test compound was calculated with the luciferase activity when no test compound was added as 100%.

3) Results Table 1 shows the activity values (IC ₅₀ values) of the compounds obtained in the above examples.

  From the above, it was confirmed that the compound of the present invention has a strong TLR9 inhibitory action. Therefore, the quinoline derivative represented by the general formula (1) of the present invention is used as a TLR9 inhibitor as a disease associated with activation of TLR9 signal, such as RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet. It has been found useful as an active ingredient of a prophylactic and / or therapeutic agent for cardiomyopathy due to syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis.

[Test Example 2] TLR7 activation inhibition test using TLR7-expressing reporter cells 1) Establishment of TLR7-expressing reporter cells Human TLR7-expressing cells are cells obtained by expressing human TLR7 in a human fetal kidney cell line, Invivogen. (HTLR7 / 293xL). hTLR7 / 293xL was subcultured using Dulbecco's modified Eagle medium (DMEM (sigma)) containing 10% fetal bovine serum, penicillin, and streptomycin. PGL4.28 (Promega) in which a firefly luciferase gene was linked to the NFκB recognition sequence 4 times was introduced by lipofection using Fugene6 (Roche). Hygromycin and blasticidin resistant cell clones were selected and used as TLR7 expression reporter cells (hTLR7 NFκB-luc / 293 × L).
2) The TLR7 activation Inhibition Test hTLR7 NFκB-luc / 293xL plated at 1.0 × ¹⁰ 4 / 80μL in a 96 well white microtiter plate, 37 ° C. in a CO ₂ incubator, and cultured overnight. A test compound (10 μL) diluted with DMEM was added to a final concentration of 0.03, 0.1, 0.3, 1, 3, 10 μM. One hour later, Imiquimod (Invivogen), a TLR7 ligand, was added to a final concentration of 10 μM (10 μL). Luciferase activity was measured as TLR7 activity after incubation in a CO ₂ incubator for a total of 100 μL for 4 hours. Luciferase activity was measured by adding 60 μL of Bright Glo (Promega) and measuring the amount of luminescence with a multi-microplate reader ARVO (Perkin Elmer). The 50% inhibitory concentration (IC ₅₀ value) of each test compound was calculated with the luciferase activity when no test compound was added as 100%.
3) Results Table 2 shows the activity values (IC ₅₀ values) of the compounds obtained in the above examples.

  From the above, it was confirmed that the compound of the present invention has a strong TLR7 inhibitory action. Therefore, the quinoline derivative represented by the general formula (1) of the present invention is used as a TLR7 inhibitor for diseases associated with activation of TLR7 signal such as RA, SLE, SS, MS, IBD, psoriatic arthritis, Behcet. It was found to be useful as an active ingredient of a prophylactic and / or therapeutic agent for cardiomyopathy caused by syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis.

[Test Example 3] Disease state-suppressing effect of TLR9 activation-inhibiting compound using rheumatoid arthritis model The therapeutic effect of rheumatoid arthritis (RA) of the compounds of Examples 19 and 39 was compared with the mouse collagen-induced arthritis model (mouse) CIA model). (FDA, CBER, CDER, CDRH: Guidance for industry-Clinical development for drugs, devices, and biologics for the treatment. 19).

(1) Use animals and group setting As animals, male DBA / 1J mice (Nippon Charles River Co., Ltd.) were used. The body weight of 7-week-old DBA / 1J mice was measured, and grouping was performed using a single-block blocking assignment using this as an index. The group composition is as follows: control group (administration medium (0.5% hydroxymethylpropylcellulose aqueous solution) administration group), Example 19 or 39 compound 25 mg / kg administration group, Example 19 or 39 compound 50 mg / kg administration Grouped.

(2) Test method A 0.2% type 2 collagen solution is prepared by mixing 0.3% type 2 collagen solution (collagen technical workshop) and physiological saline (Otsuka Pharmaceutical) in a ratio of 2: 1. did. Next, an equal amount of 0.2% type 2 collagen solution and Adjuvant Complete Freund (DIFCO) were mixed, and a first sensitive emulsion was prepared with a handy microhomogenizer NS-310E (Microtech Nithion) under ice cooling. After shaving the ridges of the animals with clippers, 0.05 mL each of the first sensitizing emulsion was intradermally administered to the left and right sides of the ridges. After the completion of the first sensitization, the drug solution was orally administered once a day until 34 days after the first sensitization (14 days after the additional sensitization).

  Additional sensitization was performed by the following procedure 20 days after the first sensitization. A 0.2% type 2 collagen solution was prepared by mixing 0.3% type 2 collagen solution and physiological saline at a ratio of 2: 1. Next, an equal amount of 0.2% type 2 collagen solution and Adjuvant Incomplete Freund (DIFCO) were mixed, and an additional sensitive emulsion was prepared with a handy microhomogenizer NS-310E under ice cooling. Additional sensitization was performed by administering 0.1 mL of the prepared additional sensitizing emulsion into the ridge skin to induce arthritis. The primary endpoint, limb swelling, was determined by arthritis by three judges in a blinded manner, 3 times: initial assessment 7 days after additional sensitization, intermediate assessment 10 or 11 days later, and final assessment 14 days later. The score (arthritis score) was determined. As the evaluation criteria for swelling, the following four criteria were applied to each limb, and the total of the limbs was used as the individual arthritis score.

0 point: no swelling 1 point: swelling in one finger or slight swelling in the entire limb 2 points: swelling in 2 to 4 fingers, or obvious swelling in the entire limb Case 3 points: When all fingers are swollen, or the whole limb is swollen, or the whole limb is clearly swollen, and swollen by more than 2 fingers

  As a secondary evaluation item, plasma anti-type 2 collagen IgG antibody titer was measured by ELISA using an orbital blood sample 15 days after additional sensitization.

(3) Test result In FIG. 1, the time-dependent change of the arthritis score was shown by the average value. It is a figure which shows a time-dependent change of the arthritis score of a mouse collagen induction arthritis model in the control group (drug non-administration group) and the compound of Example 19 25 mg / kg administration group and 50 mg / kg administration group. In the control group, an increase in the arthritis score was observed after 7 days from the additional sensitization. In contrast, the administration group of the compound of Example 19 exhibited a significant inhibitory effect suggesting dose dependency at a dose of 50 mg / kg. In the figure, ** and *** indicate a risk rate of less than 1% (p <0.01) and less than 0.1% (p <0.01), respectively, in Steel's multiple comparison test using the control group as a comparative control. 0.001).

  In FIG. 2, the anti-type 2 collagen IgG antibody titer 15 days after the additional sensitization is shown as an average value. Anti-type 2 collagen IgG antibody titer 15 days after additional sensitization of mouse collagen-induced arthritis model in the control group (drug non-administration group), the 25 mg / kg administration group and the 50 mg / kg administration group of the compound of Example 19. FIG. In contrast to the control group, the 25 and 50 mg / kg administration groups of the compound of Example 19 showed a significant inhibitory effect suggesting dose dependency. In the figure, ** indicates that the risk rate is less than 1% (p <0.01) in Steel's multiple comparison test using the control group as a comparison control.

FIG. 3 shows the change over time in the arthritis score as an average value. It is a figure which shows the time-dependent change of the arthritis score of a mouse collagen induced arthritis model in the control group (drug non-administration group), the compound of Example 39 25 mg / kg administration group and the 50 mg / kg administration group. In the control group, an increase in the arthritis score was observed after 7 days from the additional sensitization. In contrast, the administration group of the compound of Example 39 showed a significant inhibitory effect at a dose of 50 mg / kg, suggesting dose dependency. In the figure, ** indicates that the risk rate is less than 1% (p <0.01) in Steel's multiple comparison test using the control group as a comparison control.

  In FIG. 4, the anti-type 2 collagen IgG antibody titer 15 days after the additional sensitization is shown as an average value. The anti-type 2 collagen IgG antibody titer 15 days after the additional sensitization of the mouse collagen-induced arthritis model in the control group (drug non-administration group), the compound of Example 39 in the 25 mg / kg administration group and the 50 mg / kg administration group. FIG. In contrast to the control group, the 25 and 50 mg / kg administration groups of the compound of Example 39 showed a significant inhibitory effect suggesting dose dependency. In addition, * in a figure shows that a risk rate is less than 5% (p <0.05) in Steel multiple comparison test which made the control group the comparison control.

  From the results of arthritis score and anti-type 2 collagen IgG antibody titer, the compounds of Examples 19 and 39 are effective as therapeutic agents for rheumatoid arthritis.

  The quinoline derivative of the present invention or a salt thereof, or a solvate thereof has an excellent TLR3, 7 and / or 9 inhibitory action, and is an autoimmune disease, inflammation, allergy, asthma, graft rejection or GvHD. Useful for prophylactic and / or therapeutic agents. The present invention provides a preventive and / or therapeutic agent for cardiomyopathy due to autoimmune disease, inflammation, allergy, asthma, graft rejection, GvHD or sepsis, and is useful in the pharmaceutical industry and has industrial applicability. doing.

Claims (8)

The following general formula (1):

[Where:
Ring A represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group,
Here, ring A is a C _1-6 alkyl group, a phenyl group, a hydroxy C _1-3 alkyl group, an amino C _1-6 alkyl group, a C _1-3 alkylamino C _1-6 alkyl group, or a C _1-3 alkyl. From carbamoyl C _1-6 alkylcarbonyl group, C _1-3 alkylcarbamoyl C _1-6 alkyl group, C _1-6 alkyloxycarbonyl group, benzyloxy C _1-6 alkyl group and benzyloxycarbonyl C _1-6 alkyl group May have 1 to 3 substituents selected from the group consisting of
Y represents a bond or a phenylene group;
Z represents a bond, a C _1-6 alkylene group, a N—R ⁷ group or an oxygen atom;
Here, R ⁷ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Either R ² or R ⁴ represents an R ⁸ group and the other is represented by formula (2):

{Where
Ring B represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (3):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
May have 1 to 3 substituents selected from the group consisting of
X and V are the same or different and each represents a bond, an oxygen atom, N—R ¹¹ , a C (O) NH group or a NHC (O) group,
Here, R ¹¹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Here, when ring B is a 5- or 6-membered saturated nitrogen-containing heterocyclic group,
U represents a bond or a C _1-6 alkylene group;
W represents a C _1-6 alkylene group or a C _2-6 alkenylene group, wherein the C _1-6 alkylene group or C _2-6 alkenylene group may have one or two oxo groups,
However, X, V and U do not show a bond at the same time,
Here, when ring B is a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
X = NH group, W = C _1-6 alkylene group, V = NH group, and U = bond are shown, or X = NHC (O) group, W = C _1-6 alkylene group, V = NH group, And U = C _{1-6 represents an} alkylene group}
Indicate
R ¹ , R ³ , R ⁵ , R ⁶ and R ⁸ are the same or different and may be substituted with a hydrogen atom; a C _1-3 alkyl group; a C _1-3 alkyloxy group; a C _1-3 alkyl group. A good 5- or 6-membered saturated heterocyclic group; or a C _6-10 aryl C _1-3 alkyl group,
However,
Y represents a phenylene group,
Z represents a bond, and R ² represents formula (4):

{Where
W represents a C _1-6 alkylene group,
Ring B represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (5):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
1 to 3 substituents selected from the group consisting of:
Unless indicated
^{Additionally,} N 1 - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide, and ^N 1 - [4 - methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (2-morpholinoethyl) except succinamide]
Or a salt thereof, or a solvate thereof.   Ring A is a piperazinyl group, piperidinyl group or morpholinyl group, Ring B is a piperazinyl group, piperidinyl group, morpholinyl group, pyridyl group or quinolyl group, and Ring C is a cyclopropyl group, phenyl group, piperidinyl group or piperazinyl group The compound according to claim 1, which is a group, or a salt thereof, or a solvate thereof. N ¹ - (-4- 1- benzyl-yl) -N ⁴ - (quinolin-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-morpholino-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (3- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- methoxybenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2,4- difluorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide;
6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide,
N- (1-benzylpiperidin-4-yl) -6-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} hexanamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide ,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide;
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N ^{1, N 3} - bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide;
2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide;
2- (4-methylpiperazin-1-yl) -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- 4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Carboxamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide,
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4- methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - (4-methyl-2 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} quinolin-6-yl) succinamide,
N ¹ - [4- benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (-4- 1- benzyl-yl) succinamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide,
2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide,
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide,
6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine,
N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
tert-butyl 4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazine-1-carboxylate,
(E) -3- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide,
3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide,
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ,
(E) -1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine,
1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl} piperidin-4-amine,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] oxy} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide,
Benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide;
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-{[4- (4-methylpiperazin-1-yl) phenyl] amino} quinoline-2-carboxamide ,
And a compound selected from the group consisting of N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine, or a salt thereof, or a solvate thereof. The following general formula (1):

[Where:
Ring A represents a 5- or 6-membered saturated nitrogen-containing heterocyclic group,
Here, ring A is a C _1-6 alkyl group, a phenyl group, a hydroxy C _1-3 alkyl group, an amino C _1-6 alkyl group, a C _1-3 alkylamino C _1-6 alkyl group, or a C _1-3 alkyl. From carbamoyl C _1-6 alkylcarbonyl group, C _1-3 alkylcarbamoyl C _1-6 alkyl group, C _1-6 alkyloxycarbonyl group, benzyloxy C _1-6 alkyl group and benzyloxycarbonyl C _1-6 alkyl group May have 1 to 3 substituents selected from the group consisting of
Y represents a bond or a phenylene group;
Z represents a bond, a C _1-6 alkylene group, a N—R ⁷ group or an oxygen atom;
Here, R ⁷ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Either R ² or R ⁴ represents an R ⁸ group and the other is represented by formula (2):

{Where
Ring B represents a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (3):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
May have 1 to 3 substituents selected from the group consisting of
X and V are the same or different and each represents a bond, an oxygen atom, N—R ¹¹ , a C (O) NH group or a NHC (O) group,
Here, R ¹¹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
U represents a bond or a C _1-6 alkylene group;
W represents a C _1-6 alkylene group or a C _2-6 alkenylene group, wherein the C _1-6 alkylene group or C _2-6 alkenylene group may have one or two oxo groups,
However, X, V and U do not indicate a bond at the same time}
Indicate
R ¹ , R ³ , R ⁵ , R ⁶ and R ⁸ are the same or different and may be substituted with a hydrogen atom; a C _1-3 alkyl group; a C _1-3 alkyloxy group; a C _1-3 alkyl group. A good 5- or 6-membered saturated heterocyclic group; or a C _6-10 aryl C _1-3 alkyl group,
However,
Y represents a phenylene group,
Z represents a bond, and R ² represents formula (4):

{Where
W represents a C _1-6 alkylene group, ring B represents a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, ring B is a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group, a C _3-8 cycloalkyl C _1-3 alkyl group, and formula (5):

(Where
T represents a bond, an N—R ⁹ group, an NH—C _1-6 alkylene group or a C _1-6 alkylene group;
Here, R ⁹ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group,
Ring C represents a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered saturated nitrogen-containing heterocyclic group, or a 5- to 10-membered aromatic nitrogen-containing heterocyclic group,
Here, the ring C may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-3 alkyloxy group and an NH—R ¹⁰ group,
Here, R ¹⁰ represents a hydrogen atom, a C _1-6 alkyl group or a 2-nitrobenzenesulfonyl group)
1 to 3 substituents selected from the group consisting of:
Except when indicating
Or at least one inhibitor selected from the group consisting of TLR3, TLR7, and TLR9, which comprises a compound represented by the formula:   Ring A is a piperazinyl group, piperidinyl group or morpholinyl group, Ring B is a phenyl group, piperazinyl group, piperidinyl group, morpholinyl group, pyridyl group or quinolyl group, and Ring C is a cyclopropyl group, phenyl group, piperidinyl group The inhibitor according to claim 4, which is a group or a piperazinyl group. N ¹ - (-4- 1- benzyl-yl) -N ⁴ - (quinolin-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-piperidinoethoxy quinolin-6-yl) succinamide,
N ¹ - (-4- 1- benzyl-yl) ^-N 4 - (2-morpholino-6-yl) succinamide,
N ¹ - (-4- 1- ^benzyl-yl) -N 4 - [2- (4- phenyl-piperidin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (3- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- chlorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (4- methoxybenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [1- (2,4- difluorobenzyl) piperidin-4-yl] ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
4- [4- (benzylamino) piperidin-1-yl] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -4-oxobutanamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} -3-oxopropyl) piperidine-4-carboxamide;
6-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] hexanamide,
N- (1-benzylpiperidin-4-yl) -6-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} hexanamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
N- [2- (1-benzylpiperidine-4-carboxamido) ethyl] -4-methyl-2- (4-methylpiperazin-1-yl) quinoline-6-carboxamide;
2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide ,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- (1-benzylpiperidin-4-yl) -2-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] amino} acetamide;
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 3 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N ^{1, N 3} - bis [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propane-1,3-diamine,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide;
2- [4- (4-methylpiperazin-1-yl) phenyl] -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide;
2- (4-methylpiperazin-1-yl) -N- (2-morpholinoethyl) quinoline-4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -2- (4-methylpiperazin-1-yl) quinoline-4-carboxamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline- 4-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -6,7-dimethoxy-2- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-4- Carboxamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} succinamide,
N ¹ - ^{(-4-1-benzyl-piperidin-yl)} -N 4 - [2,4-bis (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4- methoxy-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- {4-methyl-2- [4- (4-methylpiperazin-1-yl) phenyl] quinolin-6-yl} acetamide,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - (4-methyl-2 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} quinolin-6-yl) succinamide,
N ¹ - [4- benzyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (-4- 1- benzyl-yl) succinamide,
N ¹ - (1-benzyl-piperidin-4-yl) ^-N 4 - {4-methyl-2- [3- (4-methylpiperazin-1-yl) propyl] quinolin-6-yl} succinamide,
2-[(1-benzylpiperidin-4-yl) oxy] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- [4- (4-methylpiperazin-1-yl) phenyl] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] amino} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(pyridin-4-ylmethyl) amino] acetamide,
4- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methyl-4-oxo Butanamide,
6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] -N-methylhexanamide,
2-[(1-benzylpiperidin-4-yl) amino] -N- [4-methyl-2- (piperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) (methyl) amino] -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
2-[(1-benzylpiperidin-4-yl) amino] -N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
1-benzyl-N- (3-{[4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] oxy} propyl) piperidin-4-amine,
N- {2- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methylquinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [4-methyl-2- (1-methylpiperidin-4-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {4-methyl-2-[(1-methylpiperidin-4-yl) oxy] quinolin-6-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N-methyl-N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) amino] acetamide,
tert-butyl 4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazine-1-carboxylate,
(E) -3- [4-Methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) acrylamide,
3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -N- (1-methylpiperidin-4-yl) propionamide,
N- (2- {4- [2- (benzyloxy) ethyl] piperazin-1-yl} -4-methylquinolin-6-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ,
(E) -1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] allyl} piperidin-4-amine,
1-methyl-N- {3- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] propyl} piperidin-4-amine,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2- (piperidin-4-yloxy) acetamide,
N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] -2-[(1-methylpiperidin-4-yl) oxy] acetamide,
2-{[1- (cyclopropylmethyl) piperidin-4-yl] oxy} -N- [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] acetamide,
N-methyl-6- [4- (4-methyl-6- {2-[(1-methylpiperidin-4-yl) amino] acetamido} quinolin-2-yl) piperazin-1-yl] hexanamide,
Benzyl 6- [4- (6- {2-[(1-benzylpiperidin-4-yl) amino] acetamido} -4-methylquinolin-2-yl) piperazin-1-yl] hexanoate,
N ¹ - (-4-1-benzyl-piperidin-yl) ^-N 4 - [4-methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] succinamide,
N ¹ - [4- methyl-2- (4-methylpiperazin-1-yl) quinolin-6-yl] ^-N 4 - (2-morpholinoethyl) succinamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4- [4- (4-methylpiperazin-1-yl) phenyl] quinoline-2-carboxamide;
N- {3-[(1-benzylpiperidin-4-yl) amino] -3-oxopropyl} -4-{[4- (4-methylpiperazin-1-yl) phenyl] amino} quinoline-2-carboxamide ,
And N, 2-bis [4- (4-methylpiperazin-1-yl) phenyl] quinolin-4-amine or a salt thereof, or a solvate thereof, as an active ingredient, At least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9;   Autoimmune disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease comprising the compound according to any one of claims 4 to 6, or a salt thereof, or a solvate thereof as an active ingredient Alternatively, a preventive and / or therapeutic agent for cardiomyopathy due to sepsis.   The prophylactic and / or therapeutic agent according to claim 7, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, Behcet's syndrome or vasculitis.

Images