WO2013161871A1

WO2013161871A1 - Thiophene derivative having tlr-inhibiting activity

Info

Publication number: WO2013161871A1
Application number: PCT/JP2013/062049
Authority: WO
Inventors: 俊司竹村; 達明西山; 裕一朗天竺桂; 正毅山火; 章泰纐纈; 宙久徳田; 祥元三宅
Original assignee: 興和株式会社
Priority date: 2012-04-25
Filing date: 2013-04-24
Publication date: 2013-10-31
Also published as: JPWO2013161871A1

Abstract

Provided is a novel compound that inhibits at least one selected from the group consisting of TLR3, TLR7, and TLR9 and has excellent preventive and therapeutic activity against autoimmune disease, inflammation, allergy, and the like. The present invention is a compound represented by the following general formula (1): [where X is an optionally substituted carbocycle or heterocycle optionally formed via alkylene or alkenylene groups; ring Y is an optionally substituted carbocycle or heterocycle; R² and R³ are the same or different and are a hydrogen atom, C_1-6 alkyl group or C_1-6 alkyloxy group; Q¹ is a bond or an optionally substituted C_1-6 alkylene group or C_2-6 alkenylene group; R¹ is a bond, oxygen atom, or optionally substituted NH group; and the combination of q, m, and n is (q, m, n) = (0, 1, 0), (0, 0, 1), (0, 1, 1), (1, 1, 0), (1, 0, 1) or (1, 1, 1)]; or a salt thereof or solvate of the same.

Description

Thiophene derivative having TLR inhibitory action

The present invention has a Toll-like receptor (TLR) inhibitory action, and diseases caused by inhibition of signals downstream of TLR, 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, graft-versus-host disease (GvHD) Or a novel compound useful as an agent for preventing and / or treating cardiomyopathy caused by sepsis.

When pathogens enter the body, the immune system immediately 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 by nonspecific immune responses. With rapid progress, 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).

Among the TLRs, TLR3 recognizes virus-derived double-stranded RNA, and TLR7 similarly recognizes virus-derived single-stranded RNA. TLR9 recognizes bacterial CpG (cytosine guanine) DNA and is activated. CpG DNA repeats at a certain frequency with a characteristic sequence of bacterial genomic DNA that is not methylated. 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 are mediated by a MyD88-dependent signal transduction pathway, whereas the former involves IRAK1 / IKKα-IRF-7, while the latter involves NF-κB, IRF-5 and MAP kinase pathways. MyD88 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 vary depending on the cell type.

As shown above, TLR recognizes RNA or DNA as a ligand, but under normal conditions, 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 TLR by a nuclease in the serum. The intracellular localization of TLR3, 7 and 9 not in the cell surface but in the endosome is also considered as a mechanism that does not recognize self-nucleic acids. However, under the circumstances where autoimmune reaction or inflammation occurs, it is considered that such a defense mechanism breaks down, forms a complex with an endogenous protein, and activates a TLR signal (Non-patent Document 7). .

By inhibiting TLR from these, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, It is considered possible to improve cardiomyopathy due to Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis. As shown below, these several diseases have a specific relationship with TLR.

Regarding rheumatoid arthritis (RA), it has been reported that the onset and pathology of pristane-induced rat arthritis were suppressed by inhibiting TLR9 using a nucleic acid sequence having TLR9 inhibitory activity (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).

Systemic lupus erythematosus (SLE) has been reported to attenuate antinuclear antibodies observed in SLE-like disease in TLR9 knockout mice (Non-Patent Document 10). The same applies to experiments using nucleic acids having TLR9 inhibitory activity. Results have been reported (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 protein in urine and a decrease in 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 patients with Sjogren's syndrome (SS) 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 inflammatory bowel disease (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 Have been reported to act in a suppressive manner on the pathology, and it is generally not thought that only the inhibitory action functions to recover the pathological condition, but involvement with TLR has been shown (Non-patent Document 16).

There has been a report that the contractility of cardiomyocytes has been lost by inflammatory cytokines produced by the ligand CpG-B DNA, and its action was attenuated in TLR9 knockout mice (Non-patent Document 17). It is thought that it is concerned with the cardiomyopathy resulting from sepsis from such a thing.

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 it is also possible that compounds with different skeletons can eliminate such side effects.

Therefore, low-molecular-weight drugs that exhibit strong TLR inhibitory action and can be administered orally are future rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS), inflammation In the treatment of cardiomyopathy caused by inflammatory bowel disease (IBD), autoimmune diseases such as psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis It is considered useful.

On the other hand, as thiophene derivatives, effects as a therapeutic agent for central nervous system diseases (Patent Document 2) and a cancer therapeutic agent (Patent Documents 3, 4, and 5) are known. In addition, p38 MAP kinase inhibitor (Patent Document 6), prostaglandin E synthase inhibitor (Patent Document 7), calcium channel modulator (Patent Document 8), matrix metalloproteinase-12 inhibitor (Non-Patent Document 18), immunity An effect as a therapeutic agent for immune allergic diseases such as an inhibitor of cell activation (Patent Document 9) is also known. However, in any of these documents, there is no description or suggestion related to the TLR inhibitory action.

International Publication No. 2008/152471 JP-A-11-322711 Special Table 2007-502308 Special table 2007-517843 gazette International Publication No. 2003/099812 JP 2006-522784 A International Publication No. 2009/098282 International Publication No. 2010/027875 JP 2008-528519 A

An object of the present invention is to provide a novel compound having a low molecular TLR inhibitory action. More specifically, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis, etc. It is to provide a medicament useful for the prevention and / or treatment of cardiomyopathy caused by autoimmune disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis.

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 thiophene derivative represented by the following general formula (1) expresses human TLR3 internally. 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 found that it has a TLR inhibitory action, and has completed the present invention.

That is, this invention relates to the invention shown below.
[1]
Formula (1):

[Where:
X is the following formula (2):

{Where,
Ring A represents a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring,
Ring B represents a saturated or unsaturated aliphatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Here, ring A and ring B are each a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkyloxy group, a C _1-3 alkyloxy C _1-6 alkyl group, a cyano group, or a carboxy C _{1. -5} alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, It may have 1 to 3 substituents selected from a diC _1-6 alkylamino group and a diC _1-6 alkylamino C _1-6 alkyl group,
Q ² represents a single bond or a C _1-6 alkylene group, wherein the C _1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group 1 to 2 substituents selected from a C _1-3 alkyloxy C _1-6 alkyl group and a C _6-10 aryl C _1-3 alkyl group,
R ⁴ represents a single bond, an oxygen atom or an NH group, wherein the NH group is a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group, C _1-3 may have an alkylsulfonyl group, and _{C 6-10} aryl _{C 1-3} substituent selected from alkyl groups}
Or formula (3):

{Where,
Ring C represents a saturated or unsaturated nitrogen-containing aliphatic heterocycle or nitrogen-containing aromatic heterocycle, wherein the ring C is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, or a C _1-6 alkyl Oxy group, C _1-3 alkyloxy C _1-6 alkyl group, cyano group, carboxy C _1-5 alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group A substituent selected from a C _1-3 alkylcarbamoyl C _1-5 alkyl group, a C _1-6 alkylamino group, a diC _1-6 alkylamino group, and a diC _1-6 alkylamino C _1-6 alkyl group, You may have 1 to 3
Q ³ represents a single bond, 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 is a halogen atom, oxo group, hydroxyl group, C 2 1 to 2 substituents selected from a _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group and a C _6-10 aryl C _1-3 alkyl group May}
Indicate
Ring Y represents a saturated or unsaturated aliphatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Here, the ring Y is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkyloxy group, a C _1-3 alkyloxy C _1-6 alkyl group, a cyano group, a carboxy C _1-5 alkyl group. Benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, di-C _{1- A 6} alkylamino group, a di-C _1-6 alkylamino C _1-6 alkyl group, and a group of formula (4):

{Where,
Q ⁴ represents a single bond, 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 is a halogen atom, an oxo group, a hydroxyl group, C 1 to 2 substituents selected from a _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group and a C _6-10 aryl C _1-3 alkyl group You can,
R ⁵ represents a single bond, an oxygen atom or an NH group, wherein the NH group is a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group, may have a C _1-3 alkylsulfonyl group, and _{C 6-10} aryl _{C 1-3} substituent selected from alkyl groups,
Ring D represents a saturated or unsaturated aliphatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Here, the ring D is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkyloxy group, a C _1-3 alkyloxy C _1-6 alkyl group, a cyano group, or a carboxy C _1-5 alkyl group. Benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, di-C _1- 1 to 3 substituents selected from a ₆ alkylamino group and a di-C _1-6 alkylamino C _1-6 alkyl group}
1 to 3 substituents selected from:
Provided that when X represents the formula (3) and the ring C represents a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, the ring Y represents a saturated or unsaturated fat having a substituent represented by the formula (4). An aromatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Provided that when ring Y has a substituent represented by formula (4) and ring D represents an aromatic carbocycle, ring Y is a saturated or unsaturated aliphatic carbocyclic ring, saturated or unsaturated nitrogen-containing An aliphatic heterocycle or a nitrogen-containing aromatic heterocycle;
Provided that when X represents the formula (3) and Q ³ represents an alkylene group having an oxo group, the ring Y is a saturated or unsaturated aliphatic carbocyclic ring, or a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring. Wherein the ring Y is a halogen atom, C _1-6 alkyl group, hydroxyl group, C _1-6 alkyloxy group, C _1-3 alkyloxy C _1-6 alkyl group, cyano group, carboxy C _{1- 5} alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, di _May have 1 to 3 substituents selected from a C _1-6 alkylamino group, a diC _1-6 alkylamino C _1-6 alkyl group, and a group of formula (4);
Q ¹ represents a single bond, 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 is a halogen atom, an oxo group, a hydroxyl group, C 1 1 to 2 substituents selected from a _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group and a C _6-10 aryl C _1-3 alkyl group You can,
Provided that when X represents the formula (3) and Q ³ represents a C _1-6 alkylene group having an oxo group, Q ¹ represents a C _1-6 alkylene group or a C _2-6 alkenylene group, where The C _1-6 alkylene group or C _2-6 alkenylene group in Q ¹ is a halogen atom, an oxo group, a hydroxyl group, a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _{1 It} may have 1 or 2 substituents selected from a _-6 alkyl group and a C _6-10 aryl C _1-3 alkyl group,
R ¹ represents a single bond, an oxygen atom or an NH group, wherein the NH group is a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group, may have a C _1-3 alkylsulfonyl group, and _{C 6-10} aryl _{C 1-3} substituent selected from alkyl groups,
R ² and R ³ may be the same or different from each other, each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkyloxy group, and the combination of q, m and n is (q, m, n ) = (0,1,0), (0,0,1), (0,1,1), (1,1,0), (1,0,1) or (1,1,1) is there]
Or a salt thereof, or a solvate thereof.

[2]
X represents formula (2),
Here, ring B represents an aromatic carbocycle, a saturated aliphatic carbocycle, or a nitrogen-containing aromatic heterocycle, wherein the ring B is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, C _{1- 6} alkyloxy group, C _1-3 alkyloxy C _1-6 alkyl group, cyano group, carboxy C _1-5 alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 Substitution selected from alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, di-C _1-6 alkylamino group and di-C _1-6 alkylamino C _1-6 alkyl group May have 1 to 3 groups,
The compound according to the above [1], or a salt thereof, or a solvate thereof.

[3]
X represents formula (2),
Here, ring A represents a pyrrolidine ring, a piperidine ring, a piperazine ring or a tetrahydropyridine ring,
Ring B is a benzene ring, cyclohexane ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadiazole ring or Showing the thiadiazole ring,
Here, ring A and ring B are each a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkyloxy group, a C _1-3 alkyloxy C _1-6 alkyl group, a cyano group, or a carboxy C _{1. -5} alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, 1 to 3 substituents selected from a diC _1-6 alkylamino group and a diC _1-6 alkylamino C _1-6 alkyl group may be present,
The compound according to [2] above, or a salt thereof, or a solvate thereof.

[4]
X represents formula (3),
Here, ring C represents a saturated nitrogen-containing aliphatic heterocycle or a nitrogen-containing aromatic heterocycle, wherein the ring C is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkyloxy Group, C _1-3 alkyloxy C _1-6 alkyl group, cyano group, carboxy C _1-5 alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, A substituent selected from a C _1-3 alkylcarbamoyl C _1-5 alkyl group, a C _1-6 alkylamino group, a diC _1-6 alkylamino group and a diC _1-6 alkylamino C _1-6 alkyl group; You may have up to 3
Q ³ represents a single bond or a C _2-6 alkenylene group, wherein the C _2-6 alkenylene group is a halogen atom, an oxo group, a hydroxyl group, a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, C _1-3 alkyloxy _{C 1-6} alkyl group and a _{C 6-10} aryl _{C 1-3} substituent selected from alkyl groups may have 1 to 2,
The compound according to the above [1], or a salt thereof, or a solvate thereof.

[5]
Q ¹ represents a single bond or a C _1-6 alkylene group, wherein the C _1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, C _1-3 alkyloxy _{C 1-6} alkyl group and a _{C 6-10} aryl _{C 1-3} substituent selected from alkyl groups may have 1 to 2,
The compound according to any one of [1] to [4] above, or a salt thereof, or a solvate thereof.

[6]
Ring Y represents an aromatic carbocyclic ring, a saturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring, wherein said ring Y is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, C _{1- 6} alkyloxy group, C _1-3 alkyloxy C _1-6 alkyl group, cyano group, carboxy C _1-5 alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 An alkyl group, a C _1-3 alkylcarbamoyl C _1-5 alkyl group, a C _1-6 alkylamino group, a diC _1-6 alkylamino group, a diC _1-6 alkylamino C _1-6 alkyl group, and a formula ( 1 to 3 substituents selected from the group 4) may be included.
The compound according to any one of [1] to [5] above, or a salt thereof, or a solvate thereof.

[7]
Ring Y is a benzene ring, piperidine ring, pyrrolidine ring, piperazine ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring Represents an oxadiazole ring or a thiadiazole ring, wherein the ring Y is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkyloxy group, a C _1-3 alkyloxy C _1-6 alkyl group Cyano group, carboxy C _1-5 alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, di _{C 1-6} alkylamino group, _{di-C 1-6} alkyl Mino C _1-6 alkyl group, and a substituent selected from the group may have 1 to 3 of formula (4),
The compound according to [6] above, or a salt thereof, or a solvate thereof.

[8]
Ring Y has a substituent represented by formula (4),
Here, ring D represents a saturated aliphatic carbocyclic ring, aromatic carbocyclic ring or saturated nitrogen-containing aliphatic heterocyclic ring, wherein the ring D is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, C _1-6 alkyloxy group, C _1-3 alkyloxy C _1-6 alkyl group, cyano group, carboxy C _1-5 alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _{1 -5} alkyl group, C _1-3 alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, di-C _1-6 alkylamino group and di-C _1-6 alkylamino C _1-6 alkyl group May have 1 to 3 substituents,
Q ⁴ represents a single bond or a C _1-6 alkylene group, wherein the C _1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, C _1-3 alkyloxy _{C 1-6} alkyl group and a _{C 6-10} aryl _{C 1-3} can have one or two substituents selected from alkyl groups,
R ⁵ represents a single bond or an NH group, wherein the NH group is a C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group, a C _1- _May have a substituent selected from a ₃ alkylsulfonyl group and a C _6-10 aryl C _1-3 alkyl group,
The compound according to any one of [1] to [7] above, or a salt thereof, or a solvate thereof.

[9]
The ring D represents a cyclohexane ring, a benzene ring, a pyrrolidine ring, a piperidine ring or a piperazine ring, wherein the ring D is a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkyloxy group, a C 1 _1-3 alkyloxy C _1-6 alkyl group, cyano group, carboxy C _1-5 alkyl group, benzyloxycarbonyl C _1-5 alkyl group, carbamoyl group, amide group, carbamoyl C _1-5 alkyl group, C _1- 1 to 3 substituents selected from _3- alkylcarbamoyl C _1-5 alkyl group, C _1-6 alkylamino group, di-C _1-6 alkylamino group and di-C _1-6 alkylamino C _1-6 alkyl group May have,
The compound according to [8] above, or a salt thereof, or a solvate thereof.

[10]
[1] to [9], wherein the combination of q, m, and n is (q, m, n) = (0, 1, 0), (0, 0, 1), or (1, 1, 1). Or a salt thereof, or a solvate thereof.

[11]
The compound represented by the general formula (1) is
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 1) ,
2-[(1-benzylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (Example 2),
N- {3-[(1-benzylpiperidin-4-yl) amino] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 3),
5- [4- (4-Methylpiperazin-1-yl) phenyl] -N- {3-[(1-methylpiperidin-4-yl) amino] propyl} thiophene-2-carboxamide (Example 4),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Example 5),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) oxy] acetamide (Example 6),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] Thiophene-2-carboxamide (Example 7),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methylpiperidin-4-yl) phenyl] thiophene-2-carboxamide (Example 8) ,
N- {5- [4- (4-Methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Example 9),
(E) -N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-ene -1-yl] thiophene-2-carboxamide (Example 10),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide ( Example 11),
N- [3-([1,4′bipiperidin] -1′-yl) propyl] -3-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide Example 12),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(piperidin-4-yl) amino] acetamide (Example 13),
N- {3-([1,4′-bipiperidin] -1′-yl) propyl} -3-methoxy-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide ( Example 14),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) Amino] acetamide (Example 15),
2-[(1-Methylpiperidin-4-yl) amino] -N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl} acetamide (Example 16),
2-[(1-Methylpiperidin-4-yl) amino] -N- (5- {4-[(1-methylpiperidin-4-yl) oxy] phenyl} thiophen-2-yl) acetamide (Example 17 ),
2- [4- (dimethylamino) piperidin-1-yl] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (Example 18),
(R) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Example 19),
(S) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Example 20),
2-[(5-hydroxypentyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide ( Example 21),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 22),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- (4- {4- [6- (methylamino) -6-oxohexyl] piperazin-1-yl} Phenyl) thiophene-2-carboxamide (Example 23),
Benzyl 6- {4- [4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) phenyl] piperazin-1-yl} hexanoate (Example 24),
1′-methyl-N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl}-[1,4′-bipiperidine] -4-carboxamide (Example 25),
N-methyl-6- {4- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] piperazin-1-yl} hexanamide ( Example 26),
N- (5- {4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide (Example 27),
2-[(3-hydroxypropyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide ( Example 28),
2- (4-Methylpiperazin-1-yl) -N- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] acetamide Example 29),
N- (5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ( Example 30),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] -3-phenylpropanamide Example 31),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine -3-carboxamide (Example 32),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1-methylpiperidin-4-yl) methylsulfonamido] acetamide (Examples) 33),
4-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- 4-yl) amino] pentanamide (Example 34),
1- (piperidin-4-yl) -3- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} urea (Example 35),
4-methoxy-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- 4-yl) amino] butanamide (Example 36),
N- {5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide ( Example 37),
N- {5- [3-Cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Examples) 38),
2- (4-methylpiperazin-1-yl) -5- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) benzamide (Example 39),
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Propanamide (Example 40),
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} propanamide (Example 41),
Benzyl 2- [4- (4- {5- [3-([1,4′-bipiperidin] -1′-yl) propanamido] thiophen-2-yl} phenyl) -5,6-dihydropyridine-1 ( 2H) -yl] acetate (Example 42),
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} propanamide (Example 43),
2-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} acetamide (Example 44),
4-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} butanamide (Example 45),
5-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} pentanamide (Example 46),
6-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} hexanamide (Example 47),
N- {5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Examples) 48),
N- (5- {4- [2- (4-Methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Example 49),
N- (5- {4- [4- (4-Methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Example 50),
N- [5- (4-{[5- (4-Methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-yl] -2-[(1-methylpiperidin-4-yl) amino] Acetamide (Example 51),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-{[(1-methylpiperidin-4-yl ) Methyl] amino} acetamide (Example 52),
N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (pyrrolidin-1-yl) pentanamide (Example 53),
5-([1,4′-bipiperidin] -1′-yl) -N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) pentane An amide (Example 54),
N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (piperidin-1-yl) pentanamide (Example 55),
N- (5- {4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Example 56),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] thiophene-2 Carboxamide (Example 57),
6-[(Dimethylamino) methyl] -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} nicotinamide Example 58),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4- (4-methylpiperazin-1-yl) benzamide (Example 59),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4-{[(1-methylpiperidin-4-yl ) Amino] methyl} benzamide (Example 60),
2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl } Acetamide (Example 61),
2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene -2-yl} acetamide (Example 62) and
N- {5- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Examples) 63)
The compound according to the above [1], a salt thereof, or a solvate thereof, which is at least one compound selected from the group consisting of:

[12]
At least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9, comprising as an active ingredient the compound according to any one of [1] to [11] above or a salt thereof, or a solvate thereof. .

[13]
Autoimmune disease, inflammation, allergy, asthma, graft rejection, graft pair, comprising as an active ingredient the compound according to any one of [1] to [11] above or a salt thereof, or a solvate thereof A prophylactic and / or therapeutic agent for cardiomyopathy caused by host disease or sepsis.

[14]
The preventive and / or therapeutic agent according to [13] 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 .

Further, the present invention is selected from the group consisting of TLR3, TLR7 and TLR9 containing the compound according to any one of [1] to [11] above, or a salt thereof, or a solvate thereof as an active ingredient. The present invention relates to a preventive and / or therapeutic agent for diseases caused by activation of at least one signal. More specifically, the present invention relates to rheumatoid arthritis (RA), systemic, comprising the compound according to any one of the above [1] to [11], or a salt thereof, or a solvate thereof as an active ingredient. 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, allergies, asthma, grafts The present invention relates to a preventive and / or therapeutic agent for cardiomyopathy due to rejection, graft-versus-host disease (GvHD) or sepsis.

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) Or the use of the compound according to any one of the above [1] to [11], or a salt thereof, or a solvate thereof for the manufacture of an agent for preventing and / or treating cardiomyopathy due to sepsis, etc. .

Further, the present invention provides a TLR3 characterized by administering an effective amount of the compound according to any one of the above [1] to [11], or a salt thereof, or a solvate thereof, 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 of autoimmune diseases such as inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis cardiomyopathy And / or a therapeutic method.

The present invention also relates to the compound according to any one of [1] to [11] above, or a salt thereof, or a solvate thereof for use as a medicament.

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 [1] to [11] above, or a salt thereof, or a solvate thereof for use in prevention and / or treatment of cardiomyopathy due to sepsis.

The compound represented by the general formula (1) or a salt thereof, or a solvate thereof, which is an active ingredient of at least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9 of the present invention is RA, Useful for the prevention and / or treatment of autoimmune diseases such as SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis cardiomyopathy .

It is a figure which shows the time-dependent change of the arthritis score by the compound of Example 5. 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 5. In the figure, * and ** are respectively less than 5% (p <0.05) and less than 1% (p <0.01) in Steel's multiple comparison test using the control group as a comparison control. It shows that.

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

As used herein, “saturated aliphatic carbocycle” refers to a 4- to 7-membered aliphatic carbocycle having no multiple bond between adjacent ring carbon atoms. Examples of the “saturated aliphatic carbocycle” include cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane and the like.

As used herein, “unsaturated aliphatic carbocycle” refers to a 4- to 7-membered aliphatic carbocycle having one or more multiple bonds between adjacent ring member atoms. Examples of the “unsaturated aliphatic carbocycle” include, for example, cyclobutene ring, cyclopentene ring, cyclohexene ring, 1,3-cyclohexadiene ring, 1,4-cyclohexadiene ring, 1,3-cycloheptadiene ring, 1, Examples include 4-cycloheptadiene ring.

As used herein, “saturated nitrogen-containing aliphatic heterocycle” means that there are no multiple bonds between adjacent ring member atoms, one or more nitrogen atoms as ring member atoms, and the rest Represents a 4- to 7-membered aliphatic heterocyclic ring in which the ring member atom is a carbon atom, nitrogen atom, oxygen atom, or sulfur atom. Examples of the “saturated nitrogen-containing aliphatic heterocycle” include azetidine ring, pyrrolidine ring, piperidine ring, azepane ring, piperazine ring and the like.

As used herein, an “unsaturated nitrogen-containing aliphatic heterocycle” has one or more multiple bonds between adjacent ring member atoms, and contains one or more nitrogen atoms as ring member atoms. And a 4- to 7-membered aliphatic heterocyclic ring in which the remaining ring member atoms are carbon atoms, nitrogen atoms, oxygen atoms, or sulfur atoms. Examples of the “unsaturated nitrogen-containing aliphatic heterocycle” include azetine ring, pyrroline ring, tetrahydropyridine ring, dihydropyridine ring, tetrahydropyrazine ring, dihydropyrazine ring, tetrahydroazepine ring, oxazine ring and thiazine ring. .

As used herein, “aromatic carbocycle” means a 6 to 10 membered aromatic carbocycle in which all ring member atoms are carbon atoms. Examples of the “aromatic carbocycle” include a benzene ring, an azulene ring, a naphthalene ring and the like.

As used herein, “nitrogen-containing aromatic heterocycle” means one or more nitrogen atoms as ring member atoms, and the remaining ring members are hetero atoms other than nitrogen atoms (oxygen or sulfur atoms). Or a 5- to 9-membered aromatic heterocycle which is a carbon atom. Examples of the “nitrogen-containing aromatic heterocycle” include pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadi An azole ring, a thiadiazole ring, an indole ring, etc. are mentioned.

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 straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of the “C _1-6 alkyl group” include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-methylbutyl group, Examples include 2,2-dimethylpropyl group and n-hexyl group.

As used herein, “C _1-6 alkyloxy group” means a group in which a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms is bonded to an oxygen atom. Examples of the “C _1-6 alkyloxy group” include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, 2- Examples include methylbutoxy group, 2,2-dimethylpropoxy group, n-hexyloxy group and the like.

As used herein, “carboxy C _1-5 alkyl group” means a straight-chain saturated hydrocarbon group having 1 to 5 carbon atoms substituted with a carboxy group at the end. Examples of the “carboxy C _1-5 alkyl group” include carboxymethyl group, carboxyethyl group, carboxypropyl group, carboxybutyl group, carboxypentyl group and the like.

As used in the present invention, “benzyloxycarbonyl C _1-5 alkyl group” means a straight-chain saturated hydrocarbon group having 1 to 5 carbon atoms substituted with a benzyloxycarbonyl group. Examples of the “benzyloxycarbonyl C _1-5 alkyl group” include benzyloxycarbonylmethyl group, benzyloxycarbonylethyl group, benzyloxycarbonylpropyl group, benzyloxycarbonylbutyl group, benzyloxycarbonylpentyl group and the like.

As used in the present invention, “carbamoyl C _1-5 alkyl group” means a straight-chain saturated hydrocarbon group having 1 to 5 carbon atoms substituted with a carbamoyl group at the terminal. Examples of the “carbamoyl C _1-5 alkyl group” include carbamoylmethyl group, carbamoylethyl group, carbamoylpropyl group, carbamoylbutyl group, carbamoylpentyl group and the like.

As used in the present invention, the “C _1-3 alkylcarbamoyl C _1-5 alkyl group” means the carbamoyl C _1-5 alkyl group substituted at the end with a C _1-3 alkyl group. Examples of the “C _1-3 alkylcarbamoyl C _1-5 alkyl group” include, for example, a 1-methylamino-1-oxoethane-2-yl group, a 1-methylamino-1-oxopropan-3-yl group, Methylamino-1-oxobutan-4-yl group, 1-methylamino-1-oxopentan-5-yl group, 1-methylamino-1-oxohexane-6-yl group, 1-ethylamino-1-oxoethane -2-yl group, 1-ethylamino-1-oxopropan-3-yl group, 1-ethylamino-1-oxobutan-4-yl group, 1-ethylamino-1-oxopentan-5-yl group, 1-ethylamino-1-oxohexane-6-yl group, 1-oxo-1-n-propylaminoethane-2-yl group, 1-oxo-1-n-propylaminopropane-3-yl 1-oxo-1-n-propylaminobutan-4-yl group, 1-oxo-1-n-propylaminopentan-5-yl group, 1-oxo-1-n-propylaminohexane-6- Yl group and the like.

As used in the present invention, “C _1-6 alkylamino group” means an amino group in which a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms is substituted. Examples of the “C _1-6 alkylamino group” include, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, tert-butylamino group, n- Examples include pentylamino group, 2-methylbutylamino group, 2,2-dimethylpropylamino group, n-hexylamino group and the like.

As used herein, the “di-C _1-6 alkylamino group” is an amino group in which a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms is the same or different and is disubstituted. means. Examples of the “di-C _1-6 alkylamino group” include (ethyl) (methyl) amino group, (isopropyl) (n-propyl) amino group, (n-butyl) (isobutyl) amino group, (tert-butyl) ) (N-pentyl) amino group, (2,2-dimethylpropyl) (2-methylbutyl) amino group, dimethylamino group, diethylamino group, di-n-propylamino group, di-isopropylamino group, di-n- Examples thereof include a butylamino group, a di-tert-butylamino group, a di-n-pentylamino group, and a di-n-hexylamino group.

As used herein, the term _{"di-C 1-6} alkylamino _{C 1-6} alkyl _{group", C 1-6} group that the _{di-C 1-6} alkylamino group at the end of the alkyl group is substituted Means. Examples of the “di-C _1-6 alkylamino C _1-6 alkyl group” include (ethyl) (methyl) aminomethyl group, (isopropyl) (n-propyl) aminomethyl group, (n-butyl) (isobutyl) Aminomethyl group, (tert-butyl) (n-pentyl) aminomethyl group, (2,2-dimethylpropyl) (2-methylbutyl) aminomethyl group, dimethylaminomethyl group, diethylaminomethyl group, di-n-propylamino Methyl group, di-isopropylaminomethyl group, di-n-butylaminomethyl group, di-t-butylaminomethyl group, di-n-pentylaminomethyl group, di-n-hexylaminomethyl group, (ethyl) ( Methyl) aminoethyl group, (isopropyl) (n-propyl) aminoethyl group, (n-butyl) (isobutyl) amino group Group, (tert-butyl) (n-pentyl) aminoethyl group, (2,2-dimethylpropyl) (2-methylbutyl) aminoethyl group, dimethylaminoethyl group, diethylaminoethyl group, di-n-propylaminoethyl group Group, di-isopropylaminoethyl group, di-n-butylaminoethyl group, di-tert-butylaminoethyl group, di-n-pentylaminoethyl group, di-n-hexylaminoethyl group and the like.

As used herein, “C _1-6 alkylene group” means a saturated divalent straight chain or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of the “C _1-6 alkylene group” include methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, isobutylene group, tert-butylene group, n-pentylene group, 2-methylbutylene. Group, 2,2-dimethylpropylene group, n-hexylene group and the like.

As used herein, “C _2-6 alkenylene group” means a divalent linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms containing one double bond. . Examples of the “C _2-6 alkenylene group” include vinylene group, propenylene group, 1-butenylene group, 2-butenylene group, 1-pentenylene group, 2-pentenylene group, 1-hexenylene group, 2-hexenylene group, 3 -A hexenylene group and the like.

As used herein, “hydroxy C _1-6 alkyl group” means a linear or branched C _1-6 alkyl group having a terminal substituted with a hydroxyl group. Examples of the “hydroxy C _1-6 alkyl group” include, for example, hydroxymethyl group, hydroxyethyl group, hydroxy-n-propyl group, hydroxyisopropyl group, hydroxy-n-butyl group, hydroxyisobutyl group, hydroxy-tert-butyl group Hydroxy-n-pentyl group, hydroxy-2-methylbutyl group, hydroxy-2,2-dimethylpropyl group, hydroxy-n-hexyl group and the like.

As used herein, “C _1-3 alkyloxy C _1-6 alkyl group” means a hydroxy group of a hydroxy C _1-6 alkyl group substituted with a linear or branched C _1-3 alkyl group. Means the group. Examples of the “C _1-3 alkyloxy C _1-6 alkyl group” include methoxymethyl group, methoxyethyl group, methoxy-n-propyl group, methoxyisopropyl group, methoxy-n-butyl group, methoxyisobutyl group, methoxy -Tert-butyl group, methoxy-n-pentyl group, methoxy-2-methylbutyl group, methoxy-2,2-dimethylpropyl group, methoxy-n-hexyl group, ethoxymethyl group, ethoxyethyl group, ethoxy-n-propyl Group, ethoxyisopropyl group, ethoxy-n-butyl group, ethoxyisobutyl group, ethoxy-tert-butyl group, ethoxy-n-pentyl group, ethoxy-2-methylbutyl group, ethoxy-2,2-dimethylpropyl group, ethoxy- n-hexyl group, n-propoxymethyl group, n-propoxy group Til, n-propoxy-n-propyl, n-propoxyisopropyl, n-propoxy-n-butyl, n-propoxyisobutyl, n-propoxy-tert-butyl, n-propoxy-n-pentyl N-propoxy-2-methylbutyl group, n-propoxy-2,2-dimethylpropyl group, n-propoxy-n-hexyl group and the like.

As used herein, “C _1-3 alkylsulfonyl group” means a sulfonyl group substituted with a linear or branched C _1-3 alkyl group. Examples of the “C _1-3 alkylsulfonyl group” include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group and the like.

As used herein, “C _6-10 aryl C _1-3 alkyl group” means a straight or branched C _1-3 alkyl group substituted with a _6-10 membered aromatic carbocycle. To do. Examples of the “C _6-10 aryl C _1-3 alkyl group” include benzyl group, phenethyl group, 1-phenyl-n-propan-1-yl group, 2-phenyl-n-propan-1-yl group, 3-phenyl-n-propan-1-yl group, 1-phenyl-isopropan-2-yl group, 2-phenyl-isopropan-2-yl group, azulenemethyl group, 1-azulenethan-1-yl group 2-azulenethan-1-yl group, 1-azulene-n-propan-1-yl group, 2-azulene-n-propan-1-yl group, 3-azulene-n-propan-1-yl group, 1-azulene-isopropan-2-yl group, 2-azulene-isopropan-2-yl group, naphthalen-1-yl-methyl group, 1-naphthalen-1-yl-ethane-1-yl group, 2- Naphthalene-1- Ru-ethane-1-yl group, 1-naphthalen-1-yl-n-propan-1-yl group, 2-naphthalen-1-yl-n-propan-1-yl group, 3-naphthalen-1-yl -N-propan-1-yl group, 1-naphthalen-1-yl-isopropan-2-yl group, 2-naphthalen-1-yl-isopropan-2-yl group and the like.

In general formulas (1), (2), (3), and (4), the saturated nitrogen-containing aliphatic heterocyclic ring is preferably a piperidine ring, a piperazine ring, or a pyrrolidine ring.

In general formulas (1), (2), (3) and (4), the unsaturated nitrogen-containing aliphatic heterocyclic ring is preferably a 1,2,3,6-tetrahydropyridine ring.

In general formulas (1), (2), and (4), the aromatic carbocycle is preferably a benzene ring.

In general formulas (1), (2), (3) and (4), the nitrogen-containing aromatic heterocycle is preferably a pyridine ring, an indole ring or a pyrazole ring.

In general formulas (1), (2), (3), and (4), the halogen atom is preferably a bromine atom.

In general formulas (1), (2), (3) and (4), the C _1-6 alkyl group is preferably a methyl group, an isopropyl group or an isobutyl group.

In the general formulas (1), (2), (3) and (4), the C _1-6 alkyloxy group is preferably a methoxy group.

In the general formulas (1), (2), (3) and (4), the carboxy C _1-5 alkyl group is preferably a carboxybutyl group.

In general formulas (1), (2), (3) and (4), the benzyloxycarbonyl C _1-5 alkyl group is preferably a benzyloxycarbonylmethyl group or a benzyloxycarbonylpentyl group.

In the general formulas (1), (2), (3) and (4), the carbamoyl C _1-5 alkyl group is preferably a carbamoylpentyl group.

In the general formulas (1), (2), (3) and (4), the C _1-3 alkylcarbamoyl C _1-5 alkyl group is preferably a 1-methylamino-1-oxohexane-6-yl group. .

In general formulas (1), (2), (3) and (4), the C _1-6 alkylamino group is preferably a methylamino group.

In the general formulas (1), (2), (3) and (4), the diC _1-6 alkylamino group is preferably a dimethylamino group.

In the general formulas (1), (2), (3) and (4), the C _1-6 alkylene group is preferably a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group.

In general formulas (1), (2), (3), and (4), the hydroxy C _1-6 alkyl group is preferably a hydroxy-n-propyl group or a hydroxy-n-pentyl group.

In the general formulas (1), (2), (3) and (4), the C _1-3 alkyloxy C _1-6 alkyl group is preferably a methoxyethyl group.

In general formulas (1), (2), and (4), the C _1-3 alkylsulfonyl group is preferably a methylsulfonyl group.

In general formulas (1), (2), (3), and (4), the C _6-10 aryl C _1-3 alkyl group is preferably a benzyl group.

In general formula (2), ring A is preferably a pyrrolidine ring, piperidine ring, piperazine ring or tetrahydropyridine ring, more preferably a piperidine ring, piperazine ring or tetrahydropyridine ring.

In the general formula (2), examples of the substituent that the ring A may have include a C _1-6 alkyl group, a C _1-3 alkylcarbamoyl C _1-5 alkyl group, and a benzyloxycarbonyl C _1-5 alkyl group. A methyl group, an isopropyl group, a 1-methylamino-1-oxopentan-5-yl group, a benzyloxycarbonylmethyl group, and a benzyloxycarbonylpentyl group are more preferable.

In general formula (2), ring B is preferably an aromatic carbocyclic ring, a saturated aliphatic carbocyclic ring, or a nitrogen-containing aromatic heterocyclic ring. A benzene ring, a cyclohexane ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, or a pyrazine ring. , Triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadiazole ring, thiadiazole ring are more preferable, benzene ring, cyclohexane ring, pyridine ring, pyrazole ring are more preferable. .

In general formula (2), the substituent that ring B may have is preferably a hydroxyl group, a C _1-6 alkyloxy group, a cyano group, or a carbamoyl group. Here, the C _1-6 alkyloxy group is more preferably a methoxy group.

In general formula (2), Q ² is preferably a single bond or a C _1-6 alkylene group, more preferably a single bond, a methylene group, an ethylene group, an n-propylene group, an n-butylene group or an n-pentylene group. .

In general formula (2), the substituent that Q ² may have is preferably an oxo group.

In the general formula (2), the substitution position of R ^{4 to} the ring B is not particularly limited as long as substitution is possible. For example, when the ring B is a 6-membered ring, to the ring B of the thiophene ring as the mother nucleus Preferably, it is the 3rd or 4th position counted from the bonding position of, for example, when the ring B is a 5-membered ring, it is preferably the 3rd position counted from the bonding position to the ring B of the thiophene ring which is the mother nucleus. preferable.

In general formula (3), ring C is preferably a saturated nitrogen-containing aliphatic heterocycle or nitrogen-containing aromatic heterocycle, and a piperidine ring, pyrrolidine ring, piperazine ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring , A triazine ring, a pyrrole ring, a pyrazole ring, an isoxazole ring, an oxazole ring, an isothiazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, and an indole ring, more preferably a piperazine ring and an indole ring.

In the general formula (3), the substituent that the ring C may have is preferably a C _1-6 alkyl group and a diC _1-6 alkylamino C _1-6 alkyl group, a methyl group, a dimethylaminopropyl group Is more preferable.

In the general formula (3), Q ³ is preferably a single bond or a C _2-6 alkenylene group, and the C _2-6 alkenylene group is more preferably a propenylene group.

In general formula (3), the substituent that Q ³ may have is preferably an oxo group.

In general formula (1), ring Y is preferably an aromatic carbocyclic ring, a saturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring. A benzene ring, piperidine ring, pyrrolidine ring, piperazine ring, pyridine ring, Pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadiazole ring or thiadiazole ring are preferable, benzene ring, piperidine ring, pyrrolidine ring Further preferred are a piperazine ring and a pyridine ring.

In the general formula (1), examples of the substituent that the ring Y may have include a C _1-6 alkyl group, a diC _1-6 alkylamino group, a diC _1-6 alkylamino C _1-6 alkyl group, And groups of formula (4) are preferred, methyl groups, dimethylamino groups, dimethylaminomethyl groups and groups of formula (4) are more preferred.

When ring Y has a substituent in general formula (1), the substitution position is not particularly limited as long as substitution is possible. For example, when ring Y is a 6-membered ring, R ¹ is bonded to ring Y. It is preferable that at least one is substituted at the 4-position counting from 1, for example, when the ring Y is a 5-membered ring, at least one is substituted at the 2-position counting from the bonding position of R ¹ to the ring Y. preferable.

In general formula (4), ring D is preferably an aromatic carbocyclic ring, a saturated aliphatic carbocyclic ring, or a saturated nitrogen-containing aliphatic heterocyclic ring, and a benzene ring, a cyclohexane ring, a pyrrolidine ring, a piperazine ring, or a piperidine ring. More preferred are benzene, cyclohexane, piperazine and piperidine rings.

In the general formula (4), examples of the substituent that the ring D may have include a C _1-6 alkyl group, a diC _1-6 alkylamino group, and a diC _1-6 alkylamino C _1-6 alkyl group. A methyl group, a dimethylamino group, and a dimethylaminomethyl group are more preferable.

In formula (4), Q ⁴ is preferably a single bond or a C _1-6 alkylene group, more preferably a single bond or a methylene group.

In general formula (4), R ⁵ is preferably a single bond or an NH group.

In general formula (1), Q ¹ is preferably a single bond or a C _1-6 alkylene group, more preferably a single bond, a methylene group, an ethylene group, an n-propylene group, an n-butylene group or an n-pentylene group. .

In general formula (1), the substituent of Q ¹ is preferably a C _1-6 alkyl group, a C _1-3 alkyloxy C _1-6 alkyl group, or a C _6-10 aryl C _1-3 alkyl group, An isobutyl group, a methoxyethyl group, and a benzyl group are more preferable.

In the general formula (1), when R ¹ is an NH group and is substituted, the substituent is preferably a hydroxy C _1-6 alkyl group or a C _1-3 alkylsulfonyl group, and a hydroxy-n-propyl group More preferred are a hydroxy-n-pentyl group and a methylsulfonyl group.

In general formula (1), the combination of q, m and n is preferably (q, m, n) = (0, 1, 0), (0, 0, 1) or (1, 1, 1). .

As a more preferable compound of the thiophene derivative represented by the general formula (1),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 1) ,
2-[(1-benzylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (Example 2),
N- {3-[(1-benzylpiperidin-4-yl) amino] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 3),
5- [4- (4-Methylpiperazin-1-yl) phenyl] -N- {3-[(1-methylpiperidin-4-yl) amino] propyl} thiophene-2-carboxamide (Example 4),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Example 5),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) oxy] acetamide (Example 6),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] Thiophene-2-carboxamide (Example 7),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methylpiperidin-4-yl) phenyl] thiophene-2-carboxamide (Example 8) ,
N- {5- [4- (4-Methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Example 9),
(E) -N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-ene -1-yl] thiophene-2-carboxamide (Example 10),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide ( Example 11),
N- [3-([1,4′bipiperidin] -1′-yl) propyl] -3-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide Example 12),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(piperidin-4-yl) amino] acetamide (Example 13),
N- {3-([1,4′-bipiperidin] -1′-yl) propyl} -3-methoxy-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide ( Example 14),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) Amino] acetamide (Example 15),
2-[(1-Methylpiperidin-4-yl) amino] -N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl} acetamide (Example 16),
2-[(1-Methylpiperidin-4-yl) amino] -N- (5- {4-[(1-methylpiperidin-4-yl) oxy] phenyl} thiophen-2-yl) acetamide (Example 17 ),
2- [4- (dimethylamino) piperidin-1-yl] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (Example 18),
(R) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Example 19),
(S) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Example 20),
2-[(5-hydroxypentyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide ( Example 21),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 22),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- (4- {4- [6- (methylamino) -6-oxohexyl] piperazin-1-yl} Phenyl) thiophene-2-carboxamide (Example 23),
Benzyl 6- {4- [4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) phenyl] piperazin-1-yl} hexanoate (Example 24),
1′-methyl-N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl}-[1,4′-bipiperidine] -4-carboxamide (Example 25),
N-methyl-6- {4- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] piperazin-1-yl} hexanamide ( Example 26),
N- (5- {4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide (Example 27),
2-[(3-hydroxypropyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide ( Example 28),
2- (4-Methylpiperazin-1-yl) -N- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] acetamide Example 29),
N- (5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ( Example 30),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] -3-phenylpropanamide Example 31),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine -3-carboxamide (Example 32),
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1-methylpiperidin-4-yl) methylsulfonamido] acetamide (Examples) 33),
4-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- 4-yl) amino] pentanamide (Example 34),
1- (piperidin-4-yl) -3- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} urea (Example 35),
4-methoxy-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- 4-yl) amino] butanamide (Example 36),
N- {5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide ( Example 37),
N- {5- [3-Cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Examples) 38),
2- (4-methylpiperazin-1-yl) -5- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) benzamide (Example 39),
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Propanamide (Example 40),
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} propanamide (Example 41),
Benzyl 2- [4- (4- {5- [3-([1,4′-bipiperidin] -1′-yl) propanamido] thiophen-2-yl} phenyl) -5,6-dihydropyridine-1 ( 2H) -yl] acetate (Example 42),
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} propanamide (Example 43),
2-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} acetamide (Example 44),
4-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} butanamide (Example 45),
5-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} pentanamide (Example 46),
6-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} hexanamide (Example 47),
N- {5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Examples) 48),
N- (5- {4- [2- (4-Methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Example 49),
N- (5- {4- [4- (4-Methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Example 50),
N- [5- (4-{[5- (4-Methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-yl] -2-[(1-methylpiperidin-4-yl) amino] Acetamide (Example 51),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-{[(1-methylpiperidin-4-yl ) Methyl] amino} acetamide (Example 52),
N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (pyrrolidin-1-yl) pentanamide (Example 53),
5-([1,4′-bipiperidin] -1′-yl) -N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) pentane An amide (Example 54),
N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (piperidin-1-yl) pentanamide (Example 55),
N- (5- {4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Example 56),
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] thiophene-2 Carboxamide (Example 57),
6-[(Dimethylamino) methyl] -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} nicotinamide Example 58),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4- (4-methylpiperazin-1-yl) benzamide (Example 59),
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4-{[(1-methylpiperidin-4-yl ) Amino] methyl} benzamide (Example 60),
2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl } Acetamide (Example 61),
2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene -2-yl} acetamide (Example 62) and
N- {5- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (Examples) 63),
A compound selected from the group consisting of:

The thiophene derivative represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof includes not only the thiophene derivative of the present invention, but also a pharmaceutically acceptable salt thereof, various hydrations thereof. Substances, solvates, substances having crystalline polymorphs, and substances that become prodrugs of these substances.

Specific examples of salts acceptable as the thiophene derivative represented by the general formula (1) of the present invention include inorganic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid). And acid addition salts with organic acids (for example, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.).

Examples of the solvate of the thiophene derivative represented by the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof include hydrates and various solvates (for example, solvates with alcohols such as ethanol). Etc.).

The thiophene derivative represented by the general formula (1) of the present invention can be produced by a known method. Although the manufacturing method of a thiophene derivative is shown in the following reaction process drawing, a manufacturing method is not limited to this.

In the general formula (1), when m = 1, n = 0, and q = 0, the compound (I) of the present invention can be produced from the 2-nitrothiophene derivative (II).

[Where:
R ¹ , R ² , R ³ , X, Q ¹ and ring Y are the same as defined above, A ¹ represents a leaving group, R ⁶ and R ⁷ represent a hydrogen atom or C _1-6 alkyl Group, R ⁶ and R ⁷ may be combined to form a ring, and R ⁸ represents a halogen atom.]

[Step 1] The coupling reaction between the thiophene derivative (II) having a leaving group and the borane compound (III) can produce the thiophene derivative (IV) using the Suzuki-Miyaura coupling reaction. The metal catalyst, base and reaction conditions used are not particularly limited as long as they are reagents and conditions used for the Suzuki-Miyaura coupling reaction. Miyaura, A .; Suzuki, Chem. Rev. The methods described in 1995, 95, 2457-2483, (1995) and the like 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. The solvent is not particularly limited, and examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; 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. Preferred are tetrahydrofuran, ethylene glycol dimethyl ether, N, N-dimethylformamide, water, and mixed solvents thereof. The reaction temperature is 0 ° C. to 200 ° C., preferably 60 ° C. to 150 ° C. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 20 hours. As the borane compound (III) 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.

Further, the thiophene derivative (IV) can be produced by a coupling reaction between the thiophene derivative (II) having a leaving group and the halogen compound (III ′). The solvent is not particularly limited. For example, halogenated 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; Ethers such as tetrahydrofuran and 1,4-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 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). If necessary, a ligand such as o-tritoluylphosphine, triphenylphosphine, 1,1'-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, and the like may be added. If necessary, an organic base such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, and trimethylamine may be added. The reaction temperature is −20 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C. The reaction time is 5 minutes to 2 days, preferably 1 hour to 20 hours.

[Step 2] The aminothiophene derivative (V) can be produced by reacting the nitro group of the thiophene derivative (IV) in a solvent in the presence of a reducing agent. This reduction method is (a) catalytic hydrogenation in which a nitro group is reduced using a catalytic hydrogen reduction catalyst in a hydrogen atmosphere in a suitable inert solvent, or (b) a metal in a suitable inert solvent. Alternatively, the reduction is carried out by metal reduction using a metal salt and acid or a mixture of metal or metal salt and alkali metal hydroxide, sulfide or ammonium salt as a reducing agent to reduce the nitro group. (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; -Ether solvents such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide, etc., or mixed solvents thereof can be used. . As the catalytic hydrogen reduction 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 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time is 30 minutes to 48 hours, preferably 1 hour 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 1,4-dioxane. The reaction temperature is, for example, 0 ° C. to 150 ° C., preferably 50 ° C. 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 between the aminothiophene derivative (V) and the carboxylic acid derivative (VI) uses a condensing agent in the presence or absence of a base in the solvent and in the presence or absence of a condensation accelerator. Or after the carboxylic acid is made the active intermediate. The solvent is not particularly limited. For example, halogenated 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; Ethers such as tetrahydrofuran and 1,4-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. 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 active intermediate is not particularly limited, and an acid halide, a mixed acid anhydride with pivalic acid, or the like, or p-nitrophenyl ester can be used. The reaction temperature is −20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In addition, the reaction between the aminothiophene derivative (V) and the acid halide derivative (VI ′) can be performed in a solvent in the presence or absence of a base. The solvent is not particularly limited. For example, halogenated 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; Ethers such as tetrahydrofuran and 1,4-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 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In the general formula (1), when m = 0, n = 1, and q = 0, the compound (I) of the present invention can be produced from the thiophenecarbonyl derivative represented by the general formula (VII).

[Where:
R ¹ , R ² , R ³ , X, Q ¹ and ring Y are the same as defined above, A ¹ represents a leaving group, A ² represents OH or a leaving group, R ⁶ and R ⁷ represents a hydrogen atom or a C _1-6 alkyl group, and R ⁶ and R ⁷ may be combined to form a ring. ]

The thiophene derivative (I) can be produced by a combination of Step 4 and Step 5.
[Step 4] The coupling reaction between the thiophene derivative (VII) having a leaving group or a condensed derivative of the thiophene derivative (VII) and the amine derivative (VIII) and the borane compound (III) is a Suzuki-Miyaura coupling reaction. Can be used. The metal catalyst, base and reaction conditions to be used are not particularly limited as long as they are reagents and conditions generally used for the Suzuki-Miyaura coupling reaction. Miyaura, A.A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, (1995) 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. The solvent is not particularly limited. For example, ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene and toluene; N, N-dimethylformamide, N-methylpyrrolidone and the like Amides of dimethyl sulfoxide, water and 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 ° C. to 200 ° C., preferably 60 ° C. to 150 ° C. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 20 hours. As the borane compound (III) 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 5] The reaction of thiophene derivative (VII) or a coupling derivative of thiophene derivative (VII) with borane compound (III) and amine derivative (VIII) is carried out in the presence or absence of a base in a solvent. The condensation can be carried out using a condensing agent in the presence or absence of an accelerator, or using carboxylic acid as an active intermediate. The solvent is not particularly limited. For example, halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; esters such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; tetrahydrofuran Ethers such as 1,4-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 Mosquito Alkali metal hydrides such as lithium, 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 hydrogen carbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used. 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 active intermediate is not particularly limited, and an acid halide, a mixed acid anhydride with pivalic acid, or the like, or p-nitrophenyl ester can be used. The reaction temperature is generally −20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C. (depending on the starting materials and reagents used). The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In the general formula (1), when m = 1, n = 1, and q = 0, the compound (I) of the present invention can be produced from the 2-amino-thiophene derivative (V).

[Wherein R ¹ , R ² , R ³ , X, Q ¹ and ring Y are the same as defined above. ]

[Step 6] The thiophene derivative (I) can be produced by a urea formation reaction between the amine-containing thiophene derivative (V) and the amine derivative (VIII). The solvent is not particularly limited. For example, halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; esters such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; Ethers such as tetrahydrofuran and 1,4-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. . A base may be added as necessary, and the base is not particularly limited. For example, organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, and trimethylamine Can be used. The reaction reagent for forming urea is not particularly limited, and phenyl chloroformate, 4-nitrophenyl chloroformate, carbonyldiimidazole, triphosgene and the like can be used. The reaction temperature is generally −20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C. (depending on the starting materials and reagents used). The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In the general formula (1), when m = 1, n = 1, and q = 1, the compound (I) of the present invention can be produced from the 2-amino-thiophene derivative (V).

[Wherein R ¹ , R ² , R ³ , X, Q ¹ and ring Y are the same as defined above, A ¹ represents a leaving group, and R ⁸ represents a halogen atom. ]

[Step 7] A thiophene derivative (X) having a leaving group can be produced by a dehydration condensation reaction between the aminothiophene derivative (V) and the carboxylic acid derivative (IX). The dehydration condensation reaction can be carried out using a condensing agent in the presence or absence of a base in a solvent, in the presence or absence of a condensation accelerator, or after using a carboxylic acid as an active intermediate. . The solvent is not particularly limited. For example, halogenated 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; Ethers such as tetrahydrofuran and 1,4-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. 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 active intermediate is not particularly limited, and an acid halide, a mixed acid anhydride with pivalic acid, or the like, or p-nitrophenyl ester can be used. The reaction temperature is −20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

Moreover, the thiophene derivative (X) having a leaving group can be produced by the reaction of the aminothiophene derivative (V) and the acid halide derivative (IX ′). The reaction can be performed in a solvent in the presence or absence of a base. The solvent is not particularly limited. For example, halogenated 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; Ethers such as tetrahydrofuran and 1,4-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 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

[Step 8] The thiophene derivative (I) can be produced by the reaction of the thiophene derivative (X) amine derivative (VIII) having a leaving group. The reaction 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 1,4-dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile Can be used alone or in combination, and the base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, metal lithium, metal sodium, metal Alkali metals such as potassium, alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropyl Amides, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyl lithium, s-butyl lithium, tert-butyl lithium, etc. Can be used. Although depending on the reaction conditions, the reaction temperature is −10 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C. The reaction time is 1 hour to 72 hours, preferably 1 hour to 36 hours.

The borane compound (III) used in the above production method can be used as it is, or can be produced appropriately by a known method. For example, it can be produced by the following method. It is not limited.

[Wherein X represents the same as defined above, A ³ represents a leaving group, R ⁶ and R ⁷ represent a hydrogen atom or a C _1-6 alkyl group, and R ⁶ and R ⁷ represent Together, they may form a ring. ]

[Step 9] In this step, borane compound (III) is produced from compound (XI) using a metal catalyst. 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) are preferred, and bis (triphenylphosphine) palladium (II) dichloride is preferred. If necessary, a ligand such as o-tritoluylphosphine, triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, and the like may be added. Examples of the base to be used include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium acetate and the like, preferably potassium acetate. The solvent to be used is not particularly limited. For example, ethers such as tetrahydrofuran and 1,4-dioxane; 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. A mixed solvent of 1,4-dioxane and water is preferred. The reaction temperature is 0 ° C. to 200 ° C., preferably 80 ° C. to 150 ° C. The reaction time is 1 hour to 48 hours, preferably 2 hours to 24 hours.
In addition, the carboxylic acid derivative (VI) used in the above production method can be used as it is, or can be appropriately produced by a known method, for example, it can be produced by the following method. It is not limited.

[Where:
R ¹ , Ring D, Q ¹ , Q ⁴ , R ⁵ and Ring Y are the same as defined above, P is a protecting group, W ¹ , W ² , W ⁴ and W ⁶ are leaving groups, An aldehyde group, an amino group or a hydroxyl group is shown, and W ³ , W ⁵ and W ⁷ are C═O or NH. However, when W ¹ and W ⁴ are a leaving group or an aldehyde group, W ² and W ⁶ represent an amino group or a hydroxyl group, and when W ² and W ⁶ are a leaving group or an aldehyde group, W ¹ and W ⁴ Represents an amino group or a hydroxyl group (note that the compounds (XV) and (XV ′) represent a case where the ring Y has a substituent formed by Q ⁴ , R ⁵ and the ring D in the carboxylic acid derivative (VI)). Is shown.)]

[Step 10] In this step, compound (XIII) or compound (XV) is produced from compound (XII), compound (XIV) or (XIV ') by a) reductive amination or b) alkylation. a) Reductive amination can be carried out 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. For example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol , Acetic acid, trifluoroacetic acid and 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 hydride lithium, 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. b) Alkylation can be carried out 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 1,4-dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile Can be used alone or in combination, and the base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, metal lithium, metal sodium, metal Alkali metals such as potassium, alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropyl Amides, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyl lithium, s-butyl lithium, tert-butyl lithium, etc. Can be used. The reaction temperature is −10 ° C. to 200 ° C., and varies depending on the reaction conditions, but is preferably 0 ° C. to 120 ° C. The reaction time varies from 1 hour to 72 hours depending on the reaction conditions, but is preferably 1 hour to 36 hours.

[Step 11] There is no particular limitation on the deprotection of the protecting group, but a method that can be introduced by a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) or the like can be used as appropriate. However, the present invention is not limited to this.

The amine derivative (VIII) used in the above production method can be used as it is, or can be produced appropriately by a known method, for example, it can be produced by the following method, but is not limited thereto. Is not to be done.

[Where:
R ¹ , Ring D, Q ¹ , Q ⁴ , R ⁵ and Ring Y are the same as defined above, P is a protecting group, W ¹ , W ² , W ⁴ and W ⁶ are leaving groups or An aldehyde group, an amino group, or a hydroxyl group is represented, and W ³ , W ^5, and W ⁷ represent C═O or NH. However, when W ¹ and W ⁴ are a leaving group or an aldehyde group, W ² and W ⁶ represent an amino group or a hydroxyl group, and when W ² and W ⁶ are a leaving group or an aldehyde group, W ¹ and W ⁴ Represents an amino group or a hydroxyl group (note that compounds (XIX) and (XX) represent the case where ring Y has a substituent formed by Q ⁴ , R ⁵ and ring D in amine derivative (VIII)). )]

[Step 12] In this step, compound (XVII) or compound (XIX) is produced from compound (XVI), compound (XVIII) or (XVIII ′) by a) reductive amination or b) alkylation. a) Reductive amination can be carried out 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. For example, halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; esters such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; tetrahydrofuran Ethers such as 1,4-dioxane; nitriles such as acetonitrile and propionitrile; alcohols such as methanol, ethanol and isopropanol; organic acids such as acetic acid and trifluoroacetic acid 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 hydride lithium, 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, etc. can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum black, etc. Etc. can be used. b) Alkylation can be carried out 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 1,4-dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile Can be used alone or in combination, and the base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, metal lithium, metal sodium, metal Alkali metals such as potassium, alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropyl Amides, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyl lithium, s-butyl lithium, tert-butyl lithium, etc. Can be used. Although depending on the reaction conditions, the reaction temperature is −10 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C. The reaction time is 1 hour to 72 hours, preferably 1 hour to 36 hours.

[Step 13] Although there is no particular limitation on the deprotection of the protecting group, a method that can be introduced by a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) or the like can be used as appropriate. However, the present invention is not limited to this.

Substituents on the X and Y rings in the above general formula, R ² , R ^{3 and the} like are oxidized, reduced with reference to methods generally used as necessary (Comprehensive Organic Transformation Second Edition, John Wiley & Sons, Inc.), The desired product can be obtained by appropriate conversion by alkylation, amidation, esterification, hydrolysis, 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 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, or an agent for preventing and / or treating autoimmune disease, inflammation, allergy, asthma, graft rejection and GvHD is a thiophene derivative represented by the general formula (1): The salt or a solvate thereof is contained 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 buffer 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 thiophene derivative represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc. Preferably, 0.1 mg to 1000 mg, preferably 1 mg to 100 mg, more preferably 1 mg to 10 mg per day is orally or parenterally administered 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
¹ H-NMR: proton nuclear magnetic resonance
DIPEA: Diisopropylethylamine
TEA: Triethylamine
WSC · HCl: 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride
HOBt · HCl: 1-hydroxybenzotriazole hydrochloride
Ms: Methanesulfonyl
THF: tetrahydrofuran
DMF: N, N-dimethylformamide
PLC: preparative thin layer chromatography
DEAD: Diethyl azodicarboxylate
TBAF: Tetrabutylammonium fluoride
TFA: trifluoroacetic acid
Boc: tert-butoxycarbonyl
crude: Crude product
Pd-C: Palladium carbon
TBS: tert-butyldimethylsilyl

Example 1 Production of N- [3-([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide

Step 1:
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide

5-Bromothiophene-2-carboxylic acid (200 mg, 0.97 mmol), [1,4′-bipiperidine] -1′-propanamine hydrochloride (0.42 g, 1.26 mmol), WSC · HCl (278 mg, 1.45 mmol) ), HOBT · H ₂ O (196 mg, 1.45 mmol) and triethylamine (390 mg, 3.86 mmol) were dissolved in methylene chloride (5 mL) and stirred at room temperature 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 silica gel chromatography (chloroform: methanol = 10: 1) to give the title compound (433 mg, quantitative) as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.42-1.49 (2H, m), 1.56-1.83 (10H, m), 1.88-1.96 (2H, m), 2.31-2.43 (1H, m), 2.48- 2.57 (6H, m), 3.05-3.12 (2H, m), 3.48-3.55 (2H, m), 7.00 (1H, d, J = 3.9 Hz), 7.32 (1H, d, J = 3.9 Hz).

Step 2:
Preparation of 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine

To a solution of 1-methyl-4- (bromophenyl) piperazine (12.6 g, 49.4 mmol) in 1,4-dioxane (150 mL), bis (pinacolato) diboron (15.1 g, 59.3 mmol), bis (diphenylphosphinoferrocene ) Palladium dichloride (II) (2.02 g, 2.47 mmol), diphenylphosphinoferrocene (1.37 g, 2.47 mmol) and potassium acetate (14.5 g, 148 mmol) were added, and the mixture was stirred at 80 ° C for 16 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 = 97: 3 → 90: 10, gradient) to obtain the title compound (9.53 g, 64%) as a reddish brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.32 (12H, s), 2.35 (3H, s), 2.52-2.58 (4H, m), 3.25-3.32 (4H, m), 6.89 (2H, d, J = 8.8 Hz), 7.70 (2H, d, J = 8.8 Hz).

Step 3:
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide N- [ 3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide (70 mg, 0.17 mmol), tetrakis (triphenylphosphine) palladium (0) (10 mg, 0.009 mmol), 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine (66 mg, 0.22 mmol), 2M carbonic acid Aqueous sodium (0.22 mL) was mixed with 1,4-dioxane (2 mL) and refluxed overnight. 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: ammonium saturated methanol = 10: 1) to obtain the title compound (70 mg, 82%) as a pale yellow solid.

Example 2 Production of 2-[(1-benzylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide

Step 1:
Preparation of 1-methyl-4- [4- (5-nitrothiophen-2-yl) phenyl] piperazine

Performed with 5-bromo-2-nitrothiophene and 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine In the same manner as in Step 1 of Example 1, the title compound (51%) was obtained as a red solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.37 (3H, s), 2.55-2.62 (4H, m), 3.31-3.36 (4H, m), 6.92 (2H, d, J = 9.2 Hz), 7.10 (1H, d, J = 4.0 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.88 (1H, d, J = 4.4 Hz).

Step 2:
Preparation of 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine

1-methyl-4- [4- (5-nitrothiophen-2-yl) phenyl] piperazine (324 mg) was dissolved in methanol (5 mL), and 10% Pd-C (160 mg) was added. The system was replaced with hydrogen and stirred at room temperature for 6 hours. The reaction solution was filtered through celite, and the filtrate was 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 (173 mg, 59%) as a green solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.36 (3H, s), 2.55-2.60 (4H, m), 3.18-3.24 (4H, m), 3.74 (2H, brs), 6.15 (1H, d, J = 3.7 Hz), 6.78 (1H, d, J = 3.9 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz).

Step 3:
Preparation of methyl 2- [N- (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 using 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).

Step 4:
Preparation of methyl 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetate

To a solution of methyl 2- [N- (1-benzylpiperidin-4-yl) amino] acetate (34.7 g, crude, theoretical amount 34.4 g, 131 mmol) in methylene chloride (200 mL), triethylamine (26.5 g, 262 mmol) ) Was added. Under ice-cooling, a solution of 2-nitrobenzenesulfonyl chloride (40.6 g, 183 mmol) in methylene chloride (200 mL) was added and 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 resulting residue was purified using silica gel chromatography (hexane: ethyl acetate = 4: 1 → 1: 9, gradient) to give the title compound (54.2 g, 2 step yield 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).

Step 5:
Preparation of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid

2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl acetate (54.2 g, 121 mmol) in methanol (700 mL) was added to a 4M aqueous sodium hydroxide solution (60.5 242 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.

Step 6:
Preparation of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetyl chloride

To a solution of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid (162 mg, 375 μmol) in methylene chloride (5 mL), DMF (10 μL), Oxalyl chloride (95.2 mg, 750 μmol) 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 (225 mg, crude).

Step 7: 2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2 -Il} acetamide production

1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine (51.4 mg, 0.19 mmol) is dissolved in methylene chloride (1.4 mL), and diisopropylethylamine (48.2 mg, 0.38 mmol) is added. added. In an ice bath, 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetyl chloride 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 by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to obtain the title compound (75.3 mg, crude) as a brown solid.

Step 8:
Preparation of 2-[(1-benzylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide 2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (75.3 mg, 0.11 mmol) was dissolved in acetonitrile (1.1 mL), and potassium carbonate (45 mg, 0.33 mmol) and thiophenol (24.7 mg, 0.22 mmol) were added. Stir at room temperature overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using PLC (chloroform: ammonium saturated methanol = 10: 1). The obtained compound was recrystallized from chloroform-hexane to give the title compound (32.2 mg, 2 step yield 34%) as a pale brown solid.

Example 3 Production of N- {3-[(1-benzylpiperidin-4-yl) amino] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide

Step 1:
Preparation of 5-bromo-N- (3-hydroxypropyl) thiophene-2-carboxamide

Using 5-bromothiophene-2-carboxylic acid and 3-aminopropanol, the title compound (91%) was obtained as a slightly brown solid in the same manner as in Step 1 of Example 1.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.74-1.84 (2H, m), 2.69 (1H, t, J = 7.7 Hz), 3.56-3.62 (2H, m), 3.71-3.78 (2H, m) , 6.48 (1H, brs), 7.03 (1H, d, J = 3.9 Hz), 7.22 (1H, d, J = 4.1 Hz).

Step 2:
Preparation of N- {3- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} -5-bromothiophene-2-carboxamide

To a solution of 5-bromo-N- (3-hydroxypropyl) thiophene-2-carboxamide (145 mg, 0.55 mmol) in THF (2.8 mL) was added N- (1-benzylpiperidin-4-yl) -2-nitrobenzenesulfone. Amide (242 mg, 0.66 mmol), DEAD (2.2 M toluene solution, 0.3 mL, 0.66 mmol) and triphenylphosphine (173 mg, 0.66 mmol) were added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18) to give the title compound (272 mg, crude) as a pale green amorphous substance.

Step 3:
N- {3- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2- Production of carboxamide

N- {3- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} -5-bromothiophene-2-carboxamide and 1-methyl-4- [4- (4 Using 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, the title compound (crude) is obtained as an orange amorphous in the same manner as in Step 3 of Example 1. It was.

Step 4:
Preparation of N- {3-[(1-benzylpiperidin-4-yl) amino] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide N- {3- With [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide, In the same manner as in Step 8 of Example 2, the title compound (30%) was obtained as a pale brown solid.

Example 4 Production of 5- [4- (4-methylpiperazin-1-yl) phenyl] -N- {3-[(1-methylpiperidin-4-yl) amino] propyl} thiophene-2-carboxamide

Step 1:
Preparation of 5-bromo-N- {3- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} thiophene-2-carboxamide

As in Step 2 of Example 3, using 5-bromo-N- (3-hydroxypropyl) thiophene-2-carboxamide and N- (1-methylpiperidin-4-yl) -2-nitrobenzenesulfonamide. The title compound (29%) was obtained as a yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.64-2.06 (8H, m), 2.25 (3H, s), 2.84-2.90 (2H, m), 3.43 (2H, t, J = 6.4 Hz), 3.49 -3.55 (2H, m), 3.65-3.74 (1H, m), 6.82 (1H, brs), 7.04 (1H, dd, J = 4.0, 1.2 Hz), 7.27 (1H, d, J = 5.2 Hz), 7.60-7.76 (3H, m), 7.98 (1H, d, J = 6.0 Hz).

Step 2:
5- [4- (4-Methylpiperazin-1-yl) phenyl] -N- {3- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} thiophene-2- Carboxamide production

5-Bromo-N- {3- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} thiophene-2-carboxamide and 1-methyl-4- [4- (4 Using 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, the title compound (crude) was converted to a pale orange amorphous in the same manner as in Step 3 of Example 1. Obtained.

Step 3:
Preparation of 5- [4- (4-methylpiperazin-1-yl) phenyl] -N- {3-[(1-methylpiperidin-4-yl) amino] propyl} thiophene-2-carboxamide 5- [4- With (4-methylpiperazin-1-yl) phenyl] -N- {3- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl} thiophene-2-carboxamide, In the same manner as in Step 8 of Example 2, the title compound (40%) was obtained as an orange solid.

Example 5 Production of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide

Step 1:
Preparation of methyl 2-[(1-methylpiperidin-4-yl) amino] acetate

To a solution of 1-methyl-4-piperidone (27.2 g, 240 mmol) and glycine methyl ester (25.0 g, 200 mmol) in methylene chloride (250 mL), add sodium triacetoxyborohydride (63.6 g, 300 mmol) to 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 a mixed solvent (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).

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

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

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).

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

Using methyl 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetate in the same manner as in Step 5 of Example 2, the title compound (crude) was obtained as a brown amorphous substance. It was.

Step 4:
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamide] Production of acetamide

Using 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine and 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid In the same manner as in Step 1 of Example 1, the title compound (crude) was obtained as a black-brown oil.

Step 5:
Preparation of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide N- {5- With [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide, In the same manner as in Step 8 of Example 2, the title compound (2 step yield: 6%) was obtained as a black-brown oil.

Example 6 Production of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) oxy] acetamide

Step 1:
Preparation of 2-[(1-methylpiperidin-4-yl) oxy] acetyl chloride

2-[(1-Methylpiperidin-4-yl) oxy] acetic acid (100 mg, 0.34 mmol) is added to methylene chloride (2 mL), and with ice cooling, DMF (10 μL), oxalyl dichloride (50 μL, 0.51 mmol) ) Was added. The mixture was returned to room temperature, stirred for 2 hours, and concentrated under reduced pressure to obtain the title compound (crude) as a tan amorphous.

Step 2:
Preparation of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) oxy] acetamide 1-methyl-4 -[4- (5-aminothiophen-2-yl) phenyl] piperazine (47 mg, 0.17 mmol) was dissolved in methylene chloride (3 mL), and triethylamine (100 μL, 0.68 mmol) was added to make a solution. 2-[(1-Methylpiperidin-4-yl) oxy] acetyl chloride 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. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to obtain the title compound (56 mg, 77%) as a brown solid.

Example 7 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) ) Phenyl] thiophene-2-carboxamide

Step 1:
Preparation of 4- (4-bromophenyl) -1,2,3,6-tetrahydropyridine

Concentrated hydrochloric acid (5 mL) was added to 4- (4-bromophenyl) -4-hydroxypiperidine (1.2 g, 4.68 mmol), and the mixture was stirred at 100 ° C for 8 hours. It returned to room temperature, the sodium hydroxide aqueous solution was added, it was made basic, and chloroform extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (1.08 g, 97%) was obtained as a brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.39-2.47 (2H, m), 3.10 (2H, t, J = 5.8 Hz), 3.52 (2H, dd, J = 6.1, 3.0 Hz), 6.13-6.17 (1H, m), 7.25 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.8 Hz).

Step 2:
Preparation of 4- (4-bromophenyl) -1-methyl-1,2,3,6-tetrahydropyridine

Using 4- (4-bromophenyl) -1,2,3,6-tetrahydropyridine and formaldehyde, the title compound (crude) was obtained as a slightly pink solid in the same manner as in Step 1 of Example 5.

Step 3:
Preparation of 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,2,3,6-tetrahydropyridine

Using 4- (4-bromophenyl) -1-methyl-1,2,3,6-tetrahydropyridine and bis (pinacolato) diboron in the same manner as in Step 2 of Example 1, the title compound (3-step yield) was obtained. 82%) was obtained as a blackish brown color.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.34 (12H, s), 2.49 (3H, s), 2.63-2.69 (2H, m), 2.85 (2H, t, J = 5.8 Hz), 3.26-3.30 (2H, m), 6.11 (1H, brs), 7.39 (2H, d, J = 8.3 Hz), 7.76 (2H, d, J = 8.3 Hz).

Step 4:
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] Preparation of thiophene-2-carboxamide N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide and 1-methyl-4- [4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,2,3,6-tetrahydropyridine in the same manner as in Step 3 of Example 1, The title compound (72%) was obtained as a yellow solid.

Example 8 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methylpiperidin-4-yl) phenyl] thiophene-2-carboxamide N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] Thiophene-2-carboxamide (10 mg, 0.02 mmol) was dissolved in ethanol (1 mL), concentrated hydrochloric acid (10 μL) and 10% palladium carbon (10 mg) were added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. . The reaction mixture was filtered and concentrated, and the resulting residue was purified using silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to give the title compound (6 mg, 62%) as a white solid Got as.

Example 9 Production of N- {5- [4- (4-methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide

Step 1:
Preparation of 4- (5-nitro-2-thienyl) cyclohexanone

Concentrated nitric acid (210 μL) was added to acetic anhydride (1.5 mL), cooled to −10 ° C., and 4- (2-thienyl) cyclohexanone (562 mg, 3.11 mmol) dissolved in acetic anhydride (1.5 mL) was slowly added. The mixture was stirred at −10 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (hexane: ethyl acetate = 100 : 0 → 75: 25, gradient) to give the title compound (298 mg, 43%) as a brown solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.95-2.01 (2H, m), 2.39-2.42 (2H, m), 2.51-2.54 (4H, m), 3.31-3.36 (1H, m), 6.87 ( 1H, d, J = 4.9 Hz), 7.81 (1H, d, J = 4.9 Hz).

Step 2:
Preparation of 1-methyl-4- [4- (5-nitrothiophen-2-yl) cyclohexyl] piperazine

4- (5-Nitro-2-thienyl) cyclohexanone (332 mg, 1.47 mmol) is dissolved in methylene chloride, and 1-methylpiperazine (191 mg, 1.91 mmol), acetic acid (150 μL), sodium triacetoxyborohydride ( 488 mg, 2.2 mmol) and stirred at room temperature for 1.5 hours, water was added to the reaction solution and extracted with chloroform, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and filtered. The residue obtained by concentration was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to give the title compound (223 mg, 49%) as a brown oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.61-1.64 (2H, m), 1.75-1.79 (4H, m), 1.98-2.01 (2H, m), 2.25-2.28 (4H, br m), 2.44 -2.46 (8H, m), 3.01-3.07 (1H, m), 6.80 (1H, dd, J = 3.9, 1.0 Hz), 7.77 (1H, d, J = 3.9 Hz).

Step 3:
Preparation of 1-methyl-4- [4- (5-aminothiophen-2-yl) cyclohexyl] piperazine

1-Methyl-4- [4- (5-nitrothiophen-2-yl) cyclohexyl] piperazine (80 mg, 0.26 mmol) was dissolved in methanol (3 mL), 10% palladium carbon was added, and hydrogen atmosphere was added. The mixture was stirred at room temperature for 14 hours, filtered and concentrated to give the title compound (22 mg, crude) as a brown oil.

Step 4:
Preparation of benzyl 2-[(1-methylpiperidin-4-yl) amino] acetate

Using 1-methyl-4-piperidone (27.2 g, 240 mmol) and glycine benzyl ester in the same manner as in Step 1 of Example 5, the title compound (crude) was obtained as a tan oil.

Step 5:
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) under ice-cooling, triethylamine (5.02 g) , 49.6 mmol), trifluoroacetic anhydride (7.81 g, 37.2 mmol) was 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: 2 → 90: 10, gradient) to obtain the title compound (6.90 g, 2 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)

Step 6:
Preparation of 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetic acid

Benzyl 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamide] acetate (6.90 g, 19.3 mmol) in a methanol (60 mL) solution in 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.

Step 7:
2,2,2-trifluoro-N- [2-({5- [4- (4-methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl} amino) -2-oxoethyl] -N- ( Preparation of 1-methylpiperidin-4-yl) acetamide

1-methyl-4- [4- (5-aminothiophen-2-yl) cyclohexyl] piperazine and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetic acid Was used to obtain the title compound (crude) as a brown oil in the same manner as in Step 6 and Step 7 of Example 2.

Step 8:
Preparation of N- {5- [4- (4-methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino]

acetamide

2,2,2 -Trifluoro-N- [2-({5- [4- (4-methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl} amino) -2-oxoethyl] -N- (1-methylpiperidine- 4-yl) acetamide (66 mg) was dissolved in 8M ammonia-methanol, stirred at room temperature for 5.5 hours and concentrated to give a residue. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to obtain the title compound (30 mg, yield of 3 steps, 26%) as a yellow solid.

Example 10 (E) -N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [3- (4-methylpiperazin-1-yl) -3-oxoprop Preparation of 1-en-1-yl] thiophene-2-carboxamide

Step 1:
Preparation of (E) -tert-butyl 3- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) acrylate

N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide (80 mg, 0.2 mmol) is dissolved in 1,4-dioxane (2 mL) O-tritoluylphosphine (18 mg, 0.06 mmol), tert-butyl acrylate (150 μL, 1 mmol), diisopropylamine (100 μL, 0.6 mmol), tris (dibenzylideneacetone) dipalladium (0) (18 mg, 0.02 mmol) was added and the mixture was stirred at 100 ° C. for 19 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue obtained was subjected to silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient). To give the title compound (55 mg, 60%) as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.44 (2H, m), 1.50 (9H, s), 1.57-1.63 (8H, m), 1.72-1.80 (4H, m), 1.89-1.92 ( 2H, m), 2.32-2.35 (1H, m), 2.49-2.50 (4H, m), 3.05-3.08 (2H, m), 3.51 (2H, q, J = 5.5 Hz), 6.19 (1H, d, J = 15.6 Hz), 7.11 (1H, d, J = 3.9 Hz), 7.45 (1H, d, J = 3.9 Hz), 7.58 (1H, d, J = 15.6 Hz), 8.43 (1H, s).

Step 2:
(E) -N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-ene Preparation of -1-yl] thiophene-2-carboxamide (E) -tert-butyl 3- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophene-2 -Yl) acrylate (55 mg, 0.12 mmol) was added to 4M hydrochloric acid-ethyl acetate (1 mL), and the mixture was stirred at room temperature for 4 hours and concentrated. , 4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) acrylic acid was obtained as a white solid. The resulting (E) -3- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) acrylic acid is added to methylene chloride and N -Methylpiperazine (15 mg, 0.15 mmol), triethylamine (50 μL, 0.36 mmol), WSC · HCl (28 mg, 0.15 mmol), HOBt (20 mg, 0.15 mmol) were added, and after stirring at room temperature for 15 hours, Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on silica gel (chloroform: methanol = 98: 2 → 82: 18, gradient) to give the title compound (48 mg, 82%) as a colorless amorphous.

Example 11 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2 -Manufacture of carboxamide

Step 1:
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-4-methylthiophene-2-carboxamide

Using 5-bromo-4-methylthiophene-2-carboxylic acid and [1,4′-bipiperidine] -1′-propanamine hydrochloride in the same manner as in Step 1 of Example 1, the title compound (crude) was prepared. Obtained.

Step 2:
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide Preparation N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-4-methylthiophene-2-carboxamide and 1-methyl-4- [4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine was used to obtain the title compound (10%) as a pale yellow solid in the same manner as in Step 3 of Example 1. .

Example 12 N- [3-([1,4′bipiperidin] -1′-yl) propyl] -3-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2- Carboxamide production

Step 1:
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-3-methylthiophene-2-carboxamide

Using 5-bromo-3-methylthiophene-2-carboxylic acid and [1,4′-bipiperidine] -1′-propanamine hydrochloride, the title compound (crude) was prepared in the same manner as in Step 1 of Example 1. Obtained.

Step 2:
Preparation of N- [3-([1,4′bipiperidin] -1′-yl) propyl] -3-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-3-methylthiophene-2-carboxamide and 1-methyl-4- [4- (4,4,4 The title compound (51%) was obtained as a pale yellow solid in the same manner as in Step 3 of Example 1 using 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine.

Example 13 Production of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(piperidin-4-yl) amino] acetamide

Step 1:
Preparation of tert-butyl 4-[(2-methoxy-2-oxoethyl) amino] piperidine-1-carboxylate

The title compound (crude) was obtained as a white oil in the same manner as in Step 1 of Example 5 using 1-Boc-4-piperidone and glycine methyl ester.

Step 2:
Preparation of tert-butyl 4- [N- (2-methoxy-2-oxoethyl) -2-nitrophenylsulfonamido] piperidine-1-carboxylate

tert-Butyl 4-[(2-methoxy-2-oxoethyl) amino] piperidine-1-carboxylate and 2-nitrobenzenesulfonyl chloride were used in the same manner as in Step 4 of Example 2 to obtain the title compound (crude). Obtained as a white powder.

Step 3:
Preparation of 2- {N- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-nitrophenylsulfonamido} acetic acid

tert-Butyl 4- [N- (2-methoxy-2-oxoethyl) -2-nitrophenylsulfonamido] piperidine-1-carboxylate was used in the same manner as in Step 5 of Example 2 to obtain the title compound (crude ) Was obtained as a yellow powder.

Step 4:
tert-Butyl 4- {N- [2-({5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2-nitrophenylsulfonamide } Production of piperidine-1-carboxylate

1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine and 2- {N- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-nitrophenylsulfonamide } Using acetic acid, the title compound (crude) was obtained as a brown powder in the same manner as in Step 6 of Example 2 and Step 7 of Example 2.

Step 5:
Preparation of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [2-nitro-N- (piperidin-4-yl) phenylsulfonamido] acetamide

tert-Butyl 4- {N- [2-({5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2-nitrophenylsulfonamide } To a solution of piperidine-1-carboxylate (0.63 g, 0.9 mmol) in methanol (10 mL) was added 4N HCl / EtOAc (5 mL), and the mixture was stirred at room temperature for 4 hours. Concentration under reduced pressure gave a residue. Water was added to the residue and extracted with chloroform. The aqueous layer was neutralized with a saturated aqueous sodium bicarbonate solution. Extraction was performed with a mixed solvent (chloroform / methanol = 10/1), and the organic layer was dried over sodium sulfate. The residue obtained by concentration under reduced pressure was purified using silica gel chromatography (chloroform: ammonia saturated methanol = 90: 10) to obtain the title compound (0.45 g, 2 step yield 36%) as a brown solid.

Step 6
Preparation of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(piperidin-4-yl) amino] acetamide N- {5- [4- Step 4 of Example 2 using (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [2-nitro-N- (piperidin-4-yl) phenylsulfonamido] acetamide In the same manner as the above, the title compound (61%) was obtained as a light brown solid.

Example 14 N- {3-([1,4′-bipiperidin] -1′-yl) propyl} -3-methoxy-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2 -Manufacture of carboxamide

Step 1:
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-3-methoxythiophene-2-carboxamide

Using 5-bromo-3-methoxythiophene-2-carboxylic acid and [1,4′-bipiperidine] -1′-propanamine hydrochloride in the same manner as in Step 1 of Example 1, the title compound (crude) was prepared. Obtained.

Step 2:
N- {3-([1,4′-bipiperidin] -1′-yl) propyl} -3-methoxy-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide Preparation N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-3-methoxythiophene-2-carboxamide and 1-methyl-4- [4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, the title compound (2 step yield 1%) was pale yellow as in Step 3 of Example 1. Obtained as a solid.

Example 15 N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine-4 -Il) amino] acetamide production

Step 1:
Preparation of 1-methyl-4- [4- (5-nitrothiophen-2-yl) phenyl] -1,2,3,6-tetrahydropyridine

2-Bromo-5-nitrothiophene and 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,2,3 , 6-Tetrahydropyridine was used in the same manner as in Step 1 of Example 1 to obtain the title compound (79%) as a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.43 (3H, s), 2.61 (2H, t, J = 2.4 Hz), 2.70 (2H, t, J = 5.6 Hz), 3.15 (2H, q, J = 3.1 Hz), 6.18-6.20 (1H, m), 7.23 (1H, d, J = 4.4 Hz), 7.47 (2H, dd, J = 6.8, 2.0 Hz), 7.59 (2H, dd, J = 6.8, 2.0 Hz), 7.90 (1H, d, J = 4.4 Hz).

Step 2:
Preparation of 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine

In the same manner as in Step 2 of Example 2, using 1-methyl-4- [4- (5-nitrothiophen-2-yl) phenyl] -1,2,3,6-tetrahydropyridine, the title compound ( crude) as a brown solid.

Step 3:
2,2,2-trifluoro-N- [2-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} amino ) -2-Oxoethyl] -N- (1-methylpiperidin-4-yl) acetamide

5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1- Methylpiperidin-4-yl) acetamido] acetic acid was used in the same manner as in Steps 6 and 7 of Example 2 to obtain the title compound (crude) as a brown solid.

Step 4:
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) Preparation of amino]

acetamide

2,2,2-trifluoro-N- [2-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} amino) -2-oxoethyl] -N- (1-methylpiperidin-4-yl) acetamide in the same manner as in Step 8 of Example 9, the title compound (3 step yield 55%) Was obtained as a pale yellow solid.

Example 16 Preparation of 2-[(1-methylpiperidin-4-yl) amino] -N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl} acetamide N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] The title compound (82%) was obtained as a yellow solid in the same manner as in Example 8 using acetamide.

Example 17 2-[(1-Methylpiperidin-4-yl) amino] -N- (5- {4-[(1-methylpiperidin-4-yl) oxy] phenyl} thiophen-2-yl) acetamide Manufacturing

Step 1:
Preparation of tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] piperidine-1-carboxylate

The title compound (crude) was obtained as a pale yellow solid in the same manner as in Step 2 of Example 1 using tert-butyl 4- (4-iodophenoxy) piperidine-1-carboxylate and bis (pinacolato) diboron. .

Process 2
Preparation of tert-butyl 4- [4- (5-nitrothiophen-2-yl) phenoxy] piperidine-1-carboxylate

2-Bromo-5-nitrothiophene and tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] piperidine-1-carboxylate Was used to give the title compound (62%) as a yellow solid in a manner similar to Step 3 of Example 1.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.52 (9H, s), 1.72-1.81 (2H, m), 1.90-1.99 (2H, m), 3.32-3.41 (2H, m), 3.67-3.74 ( 2H, m), 4.11-4.18 (1H, m), 6.97 (2H, d, J = 8.2 Hz), 7.13 (1H, d, J = 4.8 Hz), 7.57 (2H, d, J = 8.0 Hz), 7.89 (1H, d, J = 4.7 Hz).

Process 3
Preparation of tert-butyl 4- [4- (5-aminothiophen-2-yl) phenoxy] piperidine-1-carboxylate

Using tert-butyl 4- [4- (5-nitrothiophen-2-yl) phenoxy] piperidine-1-carboxylate, the title compound (quantitative) was converted to a brown solid in the same manner as in Step 2 of Example 2. Got as.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.70-1.80 (2H, m), 1.84-1.97 (2H, m), 3.30-3.37 (2H, m), 3.67-3.80 ( 4H, m), 4.42-4.50 (1H, m), 6.15 (1H, d, J = 3.6 Hz), 6.79 (1H, d, J = 3.6 Hz), 6.87 (2H, d, J = 8.8 Hz), 7.37 (2H, d, J = 8.5 Hz).

Step 4:
tert-butyl 4- [4- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophen-2-yl) phenoxy] piperidine- 1-carboxylate production

tert-Butyl 4- [4- (5-aminothiophen-2-yl) phenoxy] piperidine-1-carboxylate and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) ) Acetamide] The title compound (2 step yield: 39%) was obtained in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.72-2.10 (10H, m), 2.29 (3H, s), 2.90-3.02 (2H, m), 3.31-3.38 (2H, m), 3.65-3.74 (2H, m), 3.82-3.89 (1H, m), 4.18 (2H, s), 4.45-4.50 (1H, m), 6.61 (1H, d, J = 4.0 Hz), 6.88 (2H, d, J = 8.8 Hz), 6.92 (1H, d, J = 3.8 Hz), 7.46 (2H, d, J = 8.8 Hz).

Step 5:
2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- [2-oxo-2-({5- [4- (piperidin-4-yloxy) phenyl] thiophene-2 -Il} amino) ethyl] acetamide production

tert-butyl 4- [4- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophen-2-yl) phenoxy] piperidine- The title compound (crude) was obtained using 1-carboxylate in the same manner as in Step 5 of Example 13.

Step 6:
2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- {2-[(5- {4-[(1-methylpiperidin-4-yl) oxy] phenyl} thiophene -2-yl) amino] -2-oxoethyl} acetamide

2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- [2-oxo-2-({5- [4- (piperidin-4-yloxy) phenyl] thiophene-2 -Il} amino) ethyl] acetamide and formaldehyde were used in the same manner as in Step 1 of Example 5 to obtain the title compound (2 step yield 55%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.78-2.07 (10H, m), 2.28-2.31 (8H, m), 2.65-2.73 (2H, m), 2.94-2.97 (2H, m), 3.80- 3.90 (1H, m), 4.16 (2H, s), 4.28-4.36 (1H, m), 6.60 (1H, d, J = 4.0 Hz), 6.88 (2H, d, J = 8.8 Hz), 6.92 (1H , d, J = 4.0 Hz), 7.45 (2H, d, J = 8.8 Hz), 8.85 (1H, brs).

Step 7:
Preparation of 2-[(1-methylpiperidin-4-yl) amino] -N- (5- {4-[(1-methylpiperidin-4-yl) oxy] phenyl} thiophen-2-yl)

acetamide

2, 2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- {2-[(5- {4-[(1-methylpiperidin-4-yl) oxy] phenyl} thiophene-2 -Il) amino] -2-oxoethyl} acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (73%) as a pale yellow solid.

Example 18 Production of 2- [4- (dimethylamino) piperidin-1-yl] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide 1 Steps 6 and 7 of Example 2 with methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine and 2- [4- (dimethylamino) piperidin-1-yl] acetic acid Similarly, the title compound (48%) was obtained as a brown solid.

Example 19 (R) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidin-2- Carboxamide production

Step 1:
Production of (R) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid

(R) -tert-butyl pyrrolidine-2-carboxylate hydrochloride (1 g, 5 mmol) was dissolved in acetic acid (3 mL), 1-methyl-4-piperidone (622 mg, 5.5 mmol), trihydrogenated Sodium acetoxyboron (488 mg, 2.2 mg mmol) was added, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with chloroform, and the organic layer was dried over sodium sulfate and filtered. The residue obtained by concentration was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 80: 20, gradient), and (R) tert-butyl 1- (1-methylpiperazin-4-yl) Pyrrolidine-2-carboxylate (1.07 g, crude) was obtained as a yellow oil. The obtained (R) tert-butyl 1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylate (1.07 g, 4 mmol) was dissolved in acetic acid, and 4M hydrochloric acid-ethyl acetate was added under ice cooling. In addition, the mixture was stirred at room temperature for 7 hours and then concentrated to obtain the title compound (1.1 g, crude) as a white solid.

Step 2:
Preparation of (R) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Performed with (R) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid and 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine Analogously to steps 6 and 7 of example 2, the title compound (40%) was obtained as a pale yellow solid.

Example 20 (S) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidin-2- Carboxamide production

Step 1:
Production of (S) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid

(S) -tert-Butyl pyrrolidine-2-carboxylate hydrochloride and 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine as in Step 1 of Example 19 The title compound (crude) was obtained as a slightly yellow solid.

Step 2:
Preparation of (S) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Performed with (S) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid and 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine In the same manner as in Step 2 of Example 19, the title compound (49%) was obtained as a slightly yellow solid.

Example 21 2-[(5-hydroxypentyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl } Preparation of Acetamide N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide and 5- The title compound (89%) was obtained as a pale yellow oil in the same manner as in Step 1 of Example 5 using hydroxypentanal.

Example 22 Production of N- [3-([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide

Step 1:
Preparation of tert-butyl 4- [4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) phenyl] piperazine-1-carboxylate

N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide and tert-butyl 4- [4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate was used in the same manner as in Step 3 of Example 1 to obtain the title compound (91.7%) as a pale yellow amorphous product. .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.37-1.44 (2H, m), 1.49 (9H, s), 1.48-1.56 (2H, m), 1.59-1.83 (8H, m), 1.88-1.96 ( 2H, m), 2.30-2.40 (1H, m), 2.46-2.55 (6H, m), 3.07-3.14 (2H, m), 3.18-3.22 (4H, m), 3.52-3.62 (6H, m), 6.92 (2H, d, J = 8.8 Hz), 7.10 (1H, d, J = 3.9 Hz), 7.48-7.54 (3H, m)

Step 2:
Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide tert-Butyl 4- [ 4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) phenyl] piperazine-1-carboxylate was used to In the same manner as in Step 5, the title compound (87%) was obtained as a pale yellow solid.

Example 23 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- (4- {4- [6- (methylamino) -6-oxohexyl] piperazine-1 Preparation of -yl} phenyl) thiophene-2-carboxamide N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene -2-Carboxamide (50 mg, 0.10 mmol) in acetonitrile (1 mL) was added potassium carbonate (16.8 mg, 0.12 mmol), potassium iodide (20.1 mg, 0.12 mmol), 6-bromo-N-methylhexanamide. (23.1 mg, 0.11 mmol) was added. Stir at 80 ° C. for 4 hours. After returning to room temperature, a saturated aqueous sodium hydrogen carbonate solution 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. The obtained residue was purified using PLC (chloroform: ammonia saturated methanol = 10: 1) to obtain the title compound (47.3 mg, 75%) as a light brown solid.

Example 24 Benzyl 6- {4- [4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) phenyl] piperazine-1- Yl} hexanoate N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide and benzyl 6 Using bromohexanoate, the title compound (69%) was obtained as a pale yellow solid in the same manner as in Example 23.

Example 25 Production of 1′-methyl-N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl}-[1,4′-bipiperidine] -4-carboxamide 1:
1′-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl}-[1,4′-bipiperidine] -4-Production of carboxamide

1'-methyl- [1,4'-bipiperidine] -4-carboxylic acid and 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2- The title compound (crude) was obtained as a slightly yellow solid in the same manner as in Steps 6 and 7 of Example 2 using amine.

Step 2:
Preparation of 1′-methyl-N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl}-[1,4′-bipiperidine] -4-carboxamide 1′-methyl —N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl}-[1,4′-bipiperidine] -4-carboxamide In the same manner as in Example 8, the title compound (2 step yield: 31%) was obtained as a pale yellow solid.

Example 26 N-methyl-6- {4- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] piperazin-1-yl} Hexanamide production

Step 1:
Preparation of tert-butyl 4- [4- (5-nitrothiophen-2-yl) phenyl] piperazine-1-carboxylate

2-bromo-5-nitrothiophene and tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate Was used to give the title compound (44%) as a pale red solid in a manner similar to Step 3 of Example 1.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49 (9H, s), 3.22-3.30 (4H, m), 3.56-3.62 (4H, m), 6.93 (2H, d, J = 8.8 Hz), 7.12 (1H, d, J = 4.2 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.88 (1H, d, J = 4.4 Hz).

Step 2:
Preparation of tert-butyl 4- [4- (5-aminothiophen-2-yl) phenyl] piperazine-1-carboxylate

tert-Butyl 4- [4- (5-nitrothiophen-2-yl) phenyl] piperazine-1-carboxylate was used to treat the title compound (96%) as a brown amorphous in the same manner as in Step 2 of Example 2. Got as.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49 (9H, s), 3.10-3.16 (4H, m), 3.55-3.61 (4H, m), 3.75 (2H, brs), 6.15 (1H, d, J = 3.7 Hz), 6.79 (1H, d, J = 3.7 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz).

Step 3:
tert-butyl 4- [4- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophen-2-yl) phenyl] piperazine- 1-carboxylate production

tert-Butyl 4- [4- (5-aminothiophen-2-yl) phenyl] piperazine-1-carboxylate and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) ) Acetamide] The title compound (66%) was obtained as a black-brown amorphous in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.34-1.50 (11H, m), 1.78-1.85 (2H, m), 1.98-2.10 (2H, m), 2.29 (3H, s), 2.92-3.06 ( 6H, m), 3.14-3.20 (4H, m), 3.85 (1H, brs), 4.17 (2H, s), 6.61 (1H, d, J = 4.1 Hz), 6.89 (2H, d, J = 8.5 Hz ), 6.92 (1H, d, J = 4.1 Hz), 7.45 (2H, d, J = 8.8 Hz).
Step 4:
2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- [2-oxo-2-({5- [4- (piperazin-1-yl) phenyl] thiophene-2 -Il} amino) ethyl] acetamide production

tert-Butyl 4- [4- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophen-2-yl) phenyl] piperazine- The title compound (57%) was obtained as a brown amorphous in the same manner as in Step 5 of Example 13 using 1-carboxylate.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.32-1.56 (2H, m), 1.76-1.86 (2H, m), 1.96-2.10 (2H, m), 2.29 (3H, s), 2.92-2.98 ( 2H, m), 3.01-3.06 (4H, m), 3.14-3.20 (4H, m), 3.80-3.89 (1H, m), 4.17 (2H, s), 6.61 (1H, d, J = 4.0 Hz) , 6.89 (2H, d, J = 8.8 Hz), 6.92 (1H, d, J = 4.0 Hz), 7.45 (2H, d, J = 8.8 Hz), 8.85 (1H, brs).

Step 5:
N-methyl-6- {4- [4- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophen-2-yl) Of phenyl] piperazin-1-yl} hexanamide

2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- [2-oxo-2-({5- [4- (piperazin-1-yl) phenyl] thiophene-2 The title compound (crude) was obtained as a yellow oil in the same manner as in Example 23 using -yl} amino) ethyl] acetamide and 6-bromo-N-methylhexaneamide.

Step 6:
Of N-methyl-6- {4- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] piperazin-1-yl} hexanamide Preparation N-methyl-6- {4- [4- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophen-2-yl ) Phenyl] piperazin-1-yl} hexanamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (2 step yield: 40%) as a brown solid.

Example 27 N- (5- {4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) Amino] acetamide production

Step 1:
Preparation of 2-[(4-methylpiperazin-1-yl) methyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol

Using 4-bromo-2-[(4-methylpiperazin-1-yl) methyl] phenol and bis (pinacolato) diboron in the same manner as in Step 2 of Example 1, the title compound (crude) was converted into a blackish brown oil Got as.

Step 2:
Preparation of 2-[(4-methylpiperazin-1-yl) methyl] -4- (5-nitrothiophen-2-yl) phenol

2-Bromo-5-nitrothiophene and 2-[(4-methylpiperazin-1-yl) methyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Using phenol, the title compound (crude) was obtained as a blackish brown oil in the same manner as in Step 3 of Example 1.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.33 (3H, s), 2.40-2.82 (8H, m), 3.78 (2H, S), 6.88 (1H, d, J = 8.6 Hz), 7.09 (1H , d, J = 4.2 Hz), 7.24-7.29 (1H, m), 7.46 (1H, d, J = 8.6 Hz), 7.88 (1H, d, J = 4.4 Hz).
Step 3:
Preparation of 4- (5-aminothiophen-2-yl) -2-[(4-methylpiperazin-1-yl) methyl] phenol

Using 2-[(4-methylpiperazin-1-yl) methyl] -4- (5-nitrothiophen-2-yl) phenol in the same manner as in Step 2 of Example 2, the title compound (crude) was obtained. Obtained as a black-brown oil.

Step 4:
2,2,2-trifluoro-N- {2-[(5- {4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) amino] -2 Preparation of -oxoethyl} -N- (1-methylpiperidin-4-yl) acetamide

4- (5-aminothiophen-2-yl) -2-[(4-methylpiperazin-1-yl) methyl] phenol and 2- [2,2,2-trifluoro-N- (1-methylpiperidine- 4-yl) acetamide] The title compound (crude) was obtained as a brown amorphous in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

Step 5:
N- (5- {4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino]

acetamide

2,2,2-trifluoro-N- {2-[(5- {4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) amino] Using -2-oxoethyl} -N- (1-methylpiperidin-4-yl) acetamide in the same manner as in Step 8 of Example 9, the title compound (4 step yield: 2%) was obtained as a pale yellow solid. Got as.

Example 28 2-[(3-hydroxypropyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl } Production of acetamide

Step 1:
2-[{3-[(tert-Butyldimethylsilyl) oxy] propyl} (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl ] Preparation of thiophen-2-yl} acetamide

N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide and 3-[(tert- (Butyldimethylsilyl) oxy] propanal was used to obtain the title compound (crude) as in Step 1 of Example 5.

Step 2:
2-[(3-hydroxypropyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide Preparation 2-[{3-[(tert-Butyldimethylsilyl) oxy] propyl} (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) To a solution of (phenyl) thiophen-2-yl} acetamide (12 mg, 0.016 mmol) in THF (1 mL) was added TBAF (33 μL, 0.033 mmol) and stirred for 1 hour. In another flask, 2-[{3-[(tert-butyldimethylsilyl) oxy] propyl} (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazine- To a solution of 1-yl) phenyl] thiophen-2-yl} acetamide (150 mg, 0.21 mmol) in THF (2 mL) was added TBAF (0.42 mL, 0.42 mmol) and stirred for 4 hours. The two reaction solutions were combined. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with a mixed solvent (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: ammonium saturated methanol = 10: 1) to obtain the title compound (8 mg, 9%) as a pale yellow solid.

Example 29 2- (4-Methylpiperazin-1-yl) -N- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] Production of acetamide

Step 1:
Preparation of 2- (4-methylpiperazin-1-yl) -N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetamide

In the same manner as in Step 2 of Example 1, using N- (4-bromophenyl) -2- (4-methylpiperazin-1-yl) acetamide and bis (pinacolato) diboron, the title compound (82%) was obtained. Obtained as a dark green solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.34 (12H, s), 2.34 (3H, s), 2.45-2.70 (8H, m), 3.14 (2H, s), 7.57 (2H, d, J = 8.3 Hz), 7.78 (2H, d, J = 8.6 Hz).

Step 2:
Preparation of 2- (4-methylpiperazin-1-yl) -N- [4- (5-nitrothiophen-2-yl) phenyl] acetamide

2-Bromo-5-nitrothiophene and 2- (4-methylpiperazin-1-yl) -N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Phenyl] acetamide was used in the same manner as in Step 1 of Example 1 to obtain the title compound (82%) as a dark green solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.34 (3H, s), 2.48-2.72 (8H, m), 3.17 (2H, s), 7.20 (1H, d, J = 4.4 Hz), 7.61 (2H , d, J = 8.8 Hz), 7.68 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 4.4 Hz), 9.31 (1H, brs).

Step 3:
Preparation of N- [4- (5-aminothiophen-2-yl) phenyl] -2- (4-methylpiperazin-1-yl) acetamide

In the same manner as in Step 2 of Example 2, using 2- (4-methylpiperazin-1-yl) -N- [4- (5-nitrothiophen-2-yl) phenyl] acetamide, the title compound (crude ) Was obtained as a purple solid.

Step 4:
2,2,2-trifluoro-N- {2-[(5- {4- [2- (4-methylpiperazin-1-yl) acetamido] phenyl} thiophen-2-yl) amino] -2-oxoethyl } Production of —N- (1-methylpiperidin-4-yl) acetamide

N- [4- (5-aminothiophen-2-yl) phenyl] -2- (4-methylpiperazin-1-yl) acetamide and 2- [2,2,2-trifluoro-N- (1-methyl) Piperidin-4-yl) acetamide] acetic acid was used in the same manner as in Steps 6 and 7 of Example 2 to obtain the title compound (2-step yield: 74%) as a brown amorphous substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.70-1.84 (2H, m), 1.96-2.10 (4H, m), 2.30 (3H, s), 2.34 (3H, s), 2.44-2.58 (4H, m), 2.62-2.72 (4H, m), 2.92-3.00 (2H, m), 3.15 (2H, s), 3.80-3.92 (1H, m), 4.18 (2H, s), 6.62 (1H, d, J = 3.8 Hz), 7.00 (1H, d, J = 3.7 Hz), 7.51 (2H, d, J = 8.6 Hz), 7.55 (2H, d, J = 8.6 Hz), 8.98 (1H, brs), 9.15 (1H, brs).

Step 5:
Preparation of 2- (4-methylpiperazin-1-yl) -N- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl]

acetamide

2,2,2-trifluoro-N- {2-[(5- {4- [2- (4-methylpiperazin-1-yl) acetamido] phenyl} thiophen-2-yl) amino] -2-oxoethyl } -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (66%) as a yellow solid.

Example 30 N- (5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino Acetamide production

Step 1:
Preparation of 3- (5-bromo-1H-indol-1-yl) -N, N-dimethylpropan-1-amine

5-Bromo-1H-indole (2.4 g, 12.2 mmol) is dissolved in DMF (50 mL), potassium iodide (2.0 g, 12.2 mmol), potassium carbonate (3.1 g, 36.8 mmol), 3-chloro-N , N-dimethylpropan-1-amine hydrochloride (2.2 g, 13.5 mmol) was added and stirred at 60 ° C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on silica gel (chloroform: methanol = 100: 0 → 90: 10, gradient). ) To give the title compound (820 mg, 24%) as a yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.93-2.00 (2H, m), 2.20-2.22 (8H, m), 4.19 (2H, t, J = 6.8 Hz), 6.43 (1H, d, J = 3.4 Hz), 7.12 (1H, d, J = 3.4 Hz), 7.25-7.28 (2H, m), 7.75 (1H, s).

Step 2:
Of N, N-dimethyl-3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indol-1-yl] propan-1-amine Manufacturing

In the same manner as in Step 2 of Example 1, using 3- (5-bromo-1H-indol-1-yl) -N, N-dimethylpropan-1-amine and bis (pinacolato) diboron, the title compound ( crude) as a yellow solid.

Step 3:
Preparation of N, N-dimethyl-3- [5- (5-nitrothiophen-2-yl) -1H-indol-1-yl] propan-1-amine

N, N-dimethyl-3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indol-1-yl] propan-1-amine and The title compound (36%) was obtained as a yellow solid in the same manner as in Step 3 of Example 1 using 2-bromo-5-nitrothiophene.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.95-2.02 (2H, m), 2.22-2.24 (8H, m), 4.23 (2H, t, J = 6.8 Hz), 6.56 (1H, d, J = 2.9 Hz), 7.19-7.21 (2H, m), 7.44-7.46 (2H, m), 7.91-7.92 (2H, m).

Step 4:
Preparation of 5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-amine

Similar to Step 2 of Example 2 using N, N-dimethyl-3- [5- (5-nitrothiophen-2-yl) -1H-indol-1-yl] propan-1-amine The title compound (crude) was obtained as a brown solid.

Step 5:
N- {2-[(5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-yl) amino] -2-oxoethyl} -2,2,2- Preparation of trifluoro-N- (1-methylpiperidin-4-yl) acetamide

5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidine-4) -Yl) acetamido] The title compound (crude) was obtained as a gray solid using acetic acid in the same manner as steps 6 and 7 of Example 2.

Step 6:
N- (5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide Production N- {2-[(5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-yl) amino] -2-oxoethyl} -2,2,2 Using -trifluoro-N- (1-methylpiperidin-4-yl) acetamide, the title compound (3 step yield: 39%) was obtained as a gray solid in the same manner as in Step 8 of Example 9.

Example 31 N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] -3-phenylpropane Amide production

Step 1:
Preparation of tert-butyl [1-({5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -1-oxo-3-phenylpropan-2-yl] carbamate

Example 1 Step 1 of Example 1 with 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine and 2-[(tert-butoxycarbonyl) amino] -3-phenylpropanoic acid. In the same manner as above, the title compound (crude) was obtained.

Step 2:
Preparation of 2-amino-N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -3-phenylpropanamide

tert-Butyl [1-({5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -1-oxo-3-phenylpropan-2-yl] carbamate In the same manner as in Step 5 of Example 13, the title compound (2 step yield: 75%) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.35 (3H, s), 2.54-2.62 (4H, m), 2.81 (1H, dd, J = 14.0, 9.2 Hz), 3.20-3.26 (4H, m) , 3.36 (1H, dd, J = 13.6, 4.0 Hz), 3.79 (1H, dd, J = 9.2, 4.4 Hz), 6.62 (1H, d, J = 4.0 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 4.0 Hz), 7.23-7.34 (5H, m), 7.48 (2H, d, J = 8.8 Hz), 10.25 (1H, brs).

Step 3:
Preparation of N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] -3-phenylpropanamide Examples using 2-amino-N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -3-phenylpropanamide and 1-methyl-4-piperidone In the same manner as in Step 1 of 5, the title compound (52%) was obtained as a pale yellow amorphous.

Example 32 N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidine-4- Yl) Preparation of pyrrolidine-3-carboxamide 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 1- (1-methylpiperidine- The title compound (4%) was obtained as a yellow solid in the same manner as in Steps 6 and 7 of Example 2 using 4-yl) pyrrolidine-3-carboxylic acid.

Example 33 N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1-methylpiperidin-4-yl) methylsulfonamide] acetamide N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide (64 mg, 0.15 mmol) was dissolved in THF (1 mL), triethylamine (30 μL, 0.21 mmol) and methanesulfonyl chloride (14 μL, 0.18 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Was collected by filtration. The obtained crystals were purified using silica gel chromatography (chloroform: saturated ammonia methanol = 90: 10) to give the title compound (32 mg, 42%) as a brown oil.

Example 34 4-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1- Methylpiperidin-4-yl) amino] pentanamide

Step 1:
tert-butyl [4-methyl-1-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} amino) -1- Of Oxopentan-2-yl] carbamate

Similar to Step 1 of Example 1 using 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and N-Boc-leucine The title compound (crude) was obtained.

Step 2:
Preparation of 2-amino-4-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} pentanamide

tert-butyl [4-methyl-1-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} amino) -1- The title compound (2 step yield 44%) was obtained in the same manner as in Step 5 of Example 13 using oxopentan-2-yl] carbamate.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.97 (3H, d, J = 6.4 Hz), 1.00 (3H, d, J = 6.4 Hz), 1.43 (1H, heptet, J = 6.0 Hz), 1.72- 1.92 (2H, m), 2.41 (3H, s), 2.56-2.63 (2H, m), 2.68 (2H, t, J = 6.4 Hz), 3.13 (2H, d, J = 3.2 Hz), 3.59 (1H , dd, J = 9.2, 3.6 Hz), 6.09 (1H, brs), 6.65 (1H, d, J = 4.0 Hz), 7.07 (1H, d, J = 4.0 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz), 10.10 (1H, brs).

Step 3:
4-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- Preparation of 4-yl) amino] pentanamide 2-amino-4-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- Using 2-yl} pentanamide and 4-methyl-1-piperidone, the title compound (3%) was obtained as a pale yellow amorphous in the same manner as in Step 1 of Example 5.

Example 35 Production of 1- (piperidin-4-yl) -3- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} urea

Step 1:
tert-Butyl 4- [4- (5- {3- [1- (tert-butoxycarbonyl) piperidin-4-yl] ureido} thiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -Production of carboxylates

tert-Butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate (356 mg, 1 mmol) was dissolved in dichloromethane and pyridine (81μL , 1 mmol), 4-nitrophenyl chloroformate (201 mg, 1 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were collected by filtration. DMF (6 mL) was added to the obtained crystals, tert-butyl 4-aminopiperidine-1-carboxylate (182 mg, 0.91 mmol), triethylamine (160 μL, 1.15 mmol) were added, and 0.5 hours at room temperature. After stirring, water and ethyl acetate were added to the reaction solution, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethyl acetate to give the title compound (335 mg, crude) as a pale yellow solid.

Step 2:
Preparation of 1- (piperidin-4-yl) -3- {5- [4- [1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} urea tert-butyl 4- [4- (5- {3- [1- (tert-butoxycarbonyl) piperidin-4-yl] ureido} thiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate (58 mg, 0.1 mmol) was dissolved in methylene chloride (2 mL), and TFA (2 mL) was added under ice cooling, followed by stirring for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were recrystallized from chloroform-hexane to give the title compound (24 mg, 60%) as a pale yellow solid.

Example 36 4-methoxy-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1- Methylpiperidin-4-yl) amino] butanamide

Step 1:
(9H-Fluoren-9-yl) methyl [4-methoxy-1-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2- Yil} amino) -1-oxobutan-2-yl] carbamate

5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 2-({[(9H-fluoren-9-yl) methoxy] carbonyl } The title compound (crude) was obtained in the same manner as in Step 1 of Example 1 using amino) -4-methoxybutanoic acid.

Step 2:
Preparation of 2-amino-4-methoxy-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} butanamide

(9H-Fluoren-9-yl) methyl [4-methoxy-1-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2- To a solution of (Il} amino) -1-oxobutan-2-yl] carbamate (220 mg, 0.46 mmol) in DMF (5 mL) was added morpholine (0.5 mL) and stirred overnight. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: saturated ammonia methanol = 90: 10) to obtain the title compound (31 mg, 2 step yield: 17%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.84-1.94 (1H, m), 2.16-2.28 (1H, m), 2.41 (3H, s), 2.54-2.62 (2H, m), 2.68 (2H, t, J = 6.0 Hz), 3.10-3.18 (2H, m), 3.49 (3H, s), 3.56-3.65 (2H, m), 3.66-3.73 (1H, m), 6.10 (1H, brs), 6.65 (1H, d, J = 3.6 Hz), 7.06 (1H, d, J = 4.4 Hz), 7.37 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.0 Hz).

Step 3:
4-methoxy-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- Preparation of 4-yl) amino] butanamide 2-amino-4-methoxy-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2 The title compound (10%) was obtained as a pale yellow amorphous in the same manner as in Step 1 of Example 5 using -yl} butanamide.

Example 37 N- {5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino Acetamide production

Step 1:
Preparation of 1- [2,5-dimethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -4-methylpiperazine

Using 1- (4-bromo-2,5-dimethoxyphenyl) -4-methylpiperazine and bis (pinacolato) diboron as in Step 2 of Example 1, the title compound (crude) was treated as a brown oil. Obtained.

Step 2:
Preparation of 1- [2,5-dimethoxy-4- (5-nitrothiophen-2-yl) phenyl] -4-methylpiperazine

2-Bromo-5-nitrothiophene and 1- [2,5-dimethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -4-methyl The title compound (2 step yield: 25%) was obtained as a red-brown solid in the same manner as in Step 3 of Example 1 using piperazine.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.38 (3H, s), 2.60-2.67 (4H, m), 3.17-3.26 (4H, m), 3.90 (3H, s), 3.98 (3H, s) , 6.57 (1H, s), 7.15 (1H, s), 7.31 (1H, d, J = 4.6 Hz), 7.90 (1H, d, J = 4.6 Hz).

Step 3:
Preparation of 5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-amine

Using 1- [2,5-dimethoxy-4- (5-nitrothiophen-2-yl) phenyl] -4-methylpiperazine in the same manner as in Step 2 of Example 2, the title compound (crude) Obtained as amorphous.

Step 4:
N- [2-({5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2,2,2- Preparation of trifluoro-N- (1-methylpiperidin-4-yl) acetamide

5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidine-4) -Yl) acetamido] The title compound (2 step yield 68%) was obtained as a reddish brown oil in the same manner as in steps 6 and 7 of Example 2 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.78-1.83 (2H, m), 1.92-2.10 (4H, m), 2.29 (3H, s), 2.40 (3H, s), 2.64-2.72 (4H, m), 2.90-3.00 (2H, m), 3.10-3.20 (4H, m), 3.84 (3H, s), 3.85 (3H, s), 4.18 (2H, s), 6.56 (1H, s), 6.67 (1H, d, J = 3.8 Hz), 7.03 (1H, s), 7.16 (1H, d, J = 4.2 Hz), 9.07 (1H, brs).

Step 5:
Of N- {5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide Production N- [2-({5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2,2,2 Using -trifluoro-N- (1-methylpiperidin-4-yl) acetamide, the title compound (75%) was obtained as a brown amorphous in the same manner as in Step 8 of Example 9.

Example 38 N- {5- [3-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide Step 1:
Preparation of 2- (4-methylpiperazin-1-yl) -5- (5-nitrothiophen-2-yl) benzonitrile

2-Bromo-5-nitrothiophene and 2- (4-methylpiperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile In the same manner as in Step 3 of Example 1, the title compound (crude) was obtained.

Step 2:
Preparation of 5- (5-aminothiophen-2-yl) -2- (4-methylpiperazin-1-yl) benzonitrile

The title compound (crude) was obtained in the same manner as in Step 2 of Example 2 using 2- (4-methylpiperazin-1-yl) -5- (5-nitrothiophen-2-yl) benzonitrile. .

Step 3:
N- [2-({5- [3-Cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2,2,2-trifluoro Preparation of —N- (1-methylpiperidin-4-yl) acetamide

5- (5-aminothiophen-2-yl) -2- (4-methylpiperazin-1-yl) benzonitrile and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4- Yl) acetamide] The title compound (3 step yield: 69%) was obtained as a light brown solid in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.76-1.84 (2H, m), 1.96-2.11 (4H, m), 2.30 (3H, s), 2.39 (3H, s), 2.63-2.68 (4H, m), 2.93-3.00 (2H, m), 3.24-3.29 (4H, m), 3.80-3.92 (1H, m), 4.18 (2H, s), 6.62 (1H, d, J = 4.0 Hz), 6.95 -5.99 (2H, m), 7.61 (1H, dd, J = 9.0, 2.2 Hz), 7.72 (1H, d, J = 2.2 Hz), 8.98 (1H, brs).

Step 4:
Preparation of N- {5- [3-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide N -[2-({5- [3-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2,2,2-trifluoro- The title compound (86%) was obtained as a pale-yellow crystalline powder in the same manner as in Step 8 of Example 9 using N- (1-methylpiperidin-4-yl) acetamide.

Example 39 Production of 2- (4-methylpiperazin-1-yl) -5- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) benzamide

Step 1:
Preparation of 2- (4-methylpiperazin-1-yl) -5- (5-nitrothiophen-2-yl) benzamide

To a solution of 2- (4-methylpiperazin-1-yl) -5- (5-nitrothiophen-2-yl) benzonitrile (300 mg, 0.91 mmol) in toluene (10 mL) was added acetaldehyde oxime (270 mg, 4.57). mmol) and tris (triphenylphosphine) rhodium chloride (93 mg, 0.091 mmol). The mixture was stirred at 100 ° C. for 10 hours. It returned to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 18: 1) to obtain the title compound (crude).

Step 2:
Preparation of 5- (5-aminothiophen-2-yl) -2- (4-methylpiperazin-1-yl) benzamide

The title compound (crude) was obtained in the same manner as in Step 2 of Example 2 using 2- (4-methylpiperazin-1-yl) -5- (5-nitrothiophen-2-yl) benzamide.

Step 3:
2- (4-Methylpiperazin-1-yl) -5- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophene-2 -Il) Production of benzamide

5- (5-Aminothiophen-2-yl) -2- (4-methylpiperazin-1-yl) benzamide and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) ) Acetamide] The title compound (35% yield over 3 steps) was obtained as a pale yellow solid in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.76-1.84 (2H, m), 1.96-2.10 (4H, m), 2.30 (3H, s), 2.37 (3H, s), 2.50-2.68 (4H, m), 2.94-3.00 (2H, m), 3.04-3.08 (4H, m), 3.80-3.90 (1H, m), 4.18 (2H, s), 5.74 (1H, brs), 6.94 (1H, d, J = 4.0 Hz), 7.10 (1H, d, J = 4.0 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.61 (1H, dd, J = 8.4, 2.4 Hz), 8.36 (1H, d, J = 2.8 Hz), 8.95 (1H, brs), 9.44 (1H, brs).

Step 4:
Preparation of 2- (4-methylpiperazin-1-yl) -5- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) benzamide 2- (4- Methylpiperazin-1-yl) -5- (5- {2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido} thiophen-2-yl) benzamide Was used to give the title compound (89%) as a pale yellow solid in a manner similar to Step 8 of Example 9.

Example 40 3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2 -Il} propanamide production

Step 1:
tert-Butyl 4- {4- [5- (3-([1,4′-bipiperidin] -1′-yl) propanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H ) -Carboxylate production

Tert-butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate (100 mg, 0.28 mmol) in methylene chloride (1 mL) Under ice cooling, DIPEA (54.2 mg, 0.42 mmol) and 3-bromopropanoyl chloride (58 mg, 0.34 mmol) were added and stirred for 1 hour. TEA (152 mg, 0.70 mmol) and 1,4′-bipiperidine (118 mg, 0.70 mmol) were added, and the mixture was further stirred 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 = 100: 0 → 82: 18) to obtain the title compound (71%) as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.50 (9H, s), 1.52-1.70 (8H, m), 1.96-2.04 (2H, m), 2.07-2.15 (2H, m), 2.27-2.40 ( 1H, m), 2.50-2.62 (8H, m), 2.68-2.72 (2H, m), 3.12-3.18 (2H, m), 3.64 (2H, t, J = 5.6 Hz), 4.05-4.11 (2H, m), 6.06 (1H, brs), 6.55 (1H, d, J = 4.0 Hz), 7.07 (1H, d, J = 4.0 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.55 (2H, d, J = 8.4 Hz), 12.24 (1H, brs).

Step 2:
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Preparation of propanamide tert-butyl 4- {4- [5- (3-([1,4′-bipiperidin] -1′-yl) propanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine The title compound (93%) was obtained as a pale gray solid in the same manner as in Step 5 of Example 13 using -1 (2H) -carboxylate.

Example 41 3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl Preparation of thiophen-2-yl} propanamide 3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridine-4] -Iyl) phenyl] thiophen-2-yl} propanamide and formaldehyde were used in the same manner as in Step 1 of Example 5 to obtain the title compound (58%) as a yellow solid.

Example 42 Benzyl 2- [4- (4- {5- [3-([1,4′-bipiperidin] -1′-yl) propanamido] thiophen-2-yl} phenyl) -5,6-dihydropyridine Preparation of -1 (2H) -yl] acetate 3-([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridine-4 -Iyl) phenyl] thiophen-2-yl} propanamide and benzyl chloroacetate were used in the same manner as in Example 23 to obtain the title compound (77%) as a pale yellow solid.

Example 43 3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl Preparation of thiophen-2-yl} propanamide 3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridine-4] -Iyl) phenyl] thiophen-2-yl} propanamide and acetone were used in the same manner as in Step 1 of Example 5 to obtain the title compound (5%) as a pale yellow solid.

Example 44 2-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl ] Preparation of thiophen-2-yl} acetamide

Step 1:
tert-Butyl 4- {4- [5- (2-([1,4′-bipiperidin] -1′-yl) acetamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H) -Production of carboxylates

Tert-butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate, chloroacetyl chloride, and 1,4′-bipiperidine In the same manner as in Step 1 of Example 40, the title compound (84%) was obtained as a light brown amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.50-1.82 (10H, m), 1.92-2.03 (2H, m), 2.26-2.35 (2H, m), 2.50-2.69 ( 5H, m), 2.95-3.02 (2H, m), 3.18 (2H, s), 3.62-3.67 (2H, m), 4.05-4.11 (2H, m), 6.07 (1H, m), 6.65 (1H, d, J = 3.9 Hz), 7.09 (1H, d, J = 3.9 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.55 (2H, d, J = 8.3 Hz), 9.66 (1H, brs) .

Step 2:
2-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Production of acetamide

tert-Butyl 4- {4- [5- (2-([1,4′-bipiperidin] -1′-yl) acetamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H) Using the carboxylate, the title compound (crude) was obtained as a light brown amorphous in the same manner as in Step 5 of Example 13.

Step 3:
2-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- Preparation of 2-yl} acetamide 2-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl The title compound (2 step yield: 85%) was obtained as a yellow solid in the same manner as in Step 1 of Example 5 using thiophen-2-yl} acetamide and formaldehyde.

Example 45 4-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl ] Preparation of thiophen-2-yl} butanamide

Step 1:
tert-Butyl 4- {4- [5- (4-([1,4′-bipiperidin] -1′-yl) butanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H) -Production of carboxylates

tert-butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate, 4-bromobutanoyl chloride and 1,4′-bipiperidine In the same manner as in Step 1 of Example 40, the title compound (18%) was obtained as a light brown amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.38-1.52 (2H, m), 1.50 (9H, s), 1.57-1.78 (6H, m), 1.82-2.09 (6H, m), 2.45-2.66 ( 11H, m), 3.03-3.13 (2H, m), 3.60-3.66 (2H, m), 4.05-4.12 (2H, m), 6.06 (1H, brs), 6.69 (1H, d, J = 4.0 Hz) , 7.05 (1H, d, J = 4.0 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.4 Hz), 10.80 (1H, brs).

Step 2:
4-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Production of butanamide

tert-Butyl 4- {4- [5- (4-([1,4′-bipiperidin] -1′-yl) butanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H) The title compound (crude) was obtained as a pale yellow solid in the same manner as in Step 5 of Example 13 using carboxylate.

Step 3:
4-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- Preparation of 2-yl} butanamide 4-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl The title compound (2 step yield: 54%) was obtained as a yellow solid in the same manner as in Step 1 of Example 5 using thiophen-2-yl} butanamide and formaldehyde.

Example 46 5-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl ] Preparation of thiophen-2-yl} pentanamide

Step 1:
tert-Butyl 4- {4- [5- (5-([1,4′-bipiperidin] -1′-yl) pentanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H ) -Carboxylate production

tert-butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate, 5-bromopentanoyl chloride and 1,4′-bipiperidine In the same manner as in Step 1 of Example 40, the title compound (75%) was obtained as a light brown amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.43-1.52 (2H, m), 1.50 (9H, s), 1.56-1.90 (12H, m), 1.96-2.04 (2H, m), 2.38-2.62 ( 11H, m), 3.00-3.05 (2H, m), 3.60-3.66 (2H, m), 4.01-4.10 (2H, m), 6.06 (1H, brs), 6.67 (1H, d, J = 4.0 Hz) , 7.06 (1H, d, J = 4.0 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 8.74 (1H, brs).

Step 2:
5-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Production of pentanamide

tert-Butyl 4- {4- [5- (5-([1,4′-bipiperidin] -1′-yl) pentanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H ) -Carboxylate was used to obtain the title compound (crude) as a pale yellow solid in the same manner as in Step 5 of Example 13.

Step 3:
5-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- Preparation of 2-yl} pentanamide 5-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) Phenyl] thiophen-2-yl} pentanamide and formaldehyde were used in the same manner as in Step 1 of Example 5 to obtain the title compound (2 step yield: 52%) as a yellow solid.

Example 47
6-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-Il} hexanamide production

Step 1:
tert-Butyl 4- {4- [5- (6-([1,4′-bipiperidin] -1′-yl) hexanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H ) -Carboxylate production

tert-butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate, 6-bromohexanoyl chloride and 1,4′-bipiperidine In the same manner as in Step 1 of Example 40, the title compound (66%) was obtained as a light brown amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.38-1.52 (4H, m), 1.50 (9H, s), 1.54-1.90 (12H, m), 1.96-2.10 (2H, m), 2.35-2.46 ( 5H, m), 2.50-2.60 (6H, m), 3.02-3.08 (2H, m), 3.62-3.66 (2H, m), 4.05-4.10 (2H, m), 6.06 (1H, brs), 6.66 ( 1H, d, J = 4.0 Hz), 7.06 (1H, d, J = 3.6 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.8 Hz), 8.48 (1H, brs).

Step 2:
6-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Hexanamide production

tert-Butyl 4- {4- [5- (6-([1,4′-bipiperidin] -1′-yl) hexanamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H ) -Carboxylate was used in the same manner as in Step 5 of Example 13 to obtain the title compound (crude) as a light brown amorphous.

Step 3:
6-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- Preparation of 2-yl} hexaneamide 6-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) Phenyl] thiophen-2-yl} hexanamide and formaldehyde were used in the same manner as in Step 1 of Example 5 to obtain the title compound (2 step yield: 79%) as a yellow solid.

Example 48
Preparation of N- {5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide

Step 1:
Preparation of 5- (4-methylpiperazin-1-yl) -2- (5-nitrothiophen-2-yl) benzonitrile

2-Bromo-5-nitrothiophene and 5- (4-methylpiperazin-1-yl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile In the same manner as in Step 3 of Example 1, the title compound (crude) was obtained.

Step 2:
Preparation of 2- (5-aminothiophen-2-yl) -5- (4-methylpiperazin-1-yl) benzonitrile

The title compound (crude) was obtained in the same manner as in Step 2 of Example 2 using 5- (4-methylpiperazin-1-yl) -2- (5-nitrothiophen-2-yl) benzonitrile. .

Step 3:
N- [2-({5- [2-Cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2,2,2-trifluoro Preparation of —N- (1-methylpiperidin-4-yl) acetamide

2- (5-Aminothiophen-2-yl) -5- (4-methylpiperazin-1-yl) benzonitrile and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4- Yl) acetamide] The title compound (3 step yield 57%) was obtained as a light brown solid in the same manner as in steps 6 and 7 of Example 2 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.73-1.80 (2H, m), 1.97-2.09 (4H, m), 2.30 (3H, s), 2.36 (3H, s), 2.50-2.60 (4H, m), 2.90-3.03 (2H, m), 3.20-3.29 (4H, m), 3.79-3.89 (1H, m), 4.18 (2H, s), 6.66 (1H, d, J = 4.0 Hz), 7.07 (1H, d, J = 8.8, 2.4 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.32 (1H, d, J = 4.4 Hz), 7.44 (1H, d, J = 8.8 Hz), 8.92 (1H, brs).

Step 4:
Preparation of N- {5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide N -[2-({5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2,2,2-trifluoro- Using N- (1-methylpiperidin-4-yl) acetamide, the title compound (81%) was obtained as a yellow amorphous in the same manner as in Step 8 of Example 9.

Example 49 N- (5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] Production of acetamide

Step 1:
Production of 4- (5-nitrothiophen-2-yl) phenol

As in Step 3 of Example 1, using 2-bromo-5-nitrothiophene and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol. The title compound (crude) was obtained.

Step 2:
Preparation of 1-methyl-4- {2- [4- (5-nitrothiophen-2-yl) phenoxy] ethyl} piperazine

4- (5-Nitrothiophen-2-yl) phenol (500 mg, 2.26 mmol) was dissolved in DMF (10 mL), potassium carbonate (624 mg, 3.4 mg), 1,2-dibromoethane (300 μL, 3.4 mg). mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours. Water was added and the precipitated crystals were collected by filtration. Acetonitrile was added to the crystals collected by filtration, 1-methylpiperazine (500 μL, 4.52 mmol) and potassium carbonate (625 mg, 4.5 mmol) were added, and the mixture was stirred at 60 ° C. for 13 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on silica gel (chloroform: methanol = 100: 0 → 80: 20, gradient) to give the title compound (151 mg, 14% yield over 2 steps) as a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.31 (3H, s), 2.48-2.51 (4H, m), 2.62-2.65 (4H, m), 2.85 (2H, t, J = 5.9 Hz), 4.16 (2H, t, J = 5.9 Hz), 6.97 (2H, dd, J = 6.8, 2.4 Hz), 7.13 (1H, d, J = 4.4 Hz), 7.56 (2H, dd, J = 6.8, 2.4 Hz) , 7.89 (1H, d, J = 4.4 Hz).

Step 3:
Preparation of 5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-amine

Using 1-methyl-4- {2- [4- (5-nitrothiophen-2-yl) phenoxy] ethyl} piperazine in the same manner as in Step 2 of Example 2, the title compound (crude) was converted into a brown amorphous Got as.

Step 4:
2,2,2-trifluoro-N- {2-[(5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) amino] -2-oxoethyl } Production of —N- (1-methylpiperidin-4-yl) acetamide

5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidine-4-] Yl) acetamide] The title compound (crude) was obtained as a brown amorphous in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

Step 5:
Preparation of N- (5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino]

acetamide

2,2,2-trifluoro-N- {2-[(5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) amino] -2-oxoethyl } -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (3 steps, yield 16%) as a yellow amorphous substance.

Example 50 N- (5- {4- [4- (4-Methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] Production of acetamide

Step 1:
Preparation of 1-methyl-4- {4- [4- (5-nitrothiophen-2-yl) phenoxy] butyl} piperazine

Use 4- (5-nitrothiophen-2-yl) phenol, 1,4-dibromobutane and 1-methylpiperazine in the same manner as in Step 2 of Example 49 to give the title compound (14%) as a yellow solid. Obtained.

Step 2:
Preparation of 5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-amine

Using 1-methyl-4- {4- [4- (5-nitrothiophen-2-yl) phenoxy] butyl} piperazine in the same manner as in Step 2 of Example 2, the title compound (crude) was converted into a brown amorphous Got as.

Step 3:
2,2,2-trifluoro-N- {2-[(5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) amino] -2-oxoethyl } Production of —N- (1-methylpiperidin-4-yl) acetamide

5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidine-4-] Yl) acetamide] The title compound (crude) was obtained as a brown amorphous in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

Step 4:
Preparation of N- (5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino]

acetamide

2,2,2-trifluoro-N- {2-[(5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) amino] -2-oxoethyl } -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (3 step yield: 13%) as a yellow amorphous.

Example 51 N- [5- (4-{[5- (4-Methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-yl] -2-[(1-methylpiperidin-4-yl ) Production of amino] acetamide

Step 1:
Preparation of 1-methyl-4- {5- [4- (5-nitrothiophen-2-yl) phenoxy] pentyl} piperazine

Use 4- (5-nitrothiophen-2-yl) phenol, 1,5-dibromopentane, and 1-methylpiperazine in the same manner as in Step 2 of Example 49 to give the title compound (14%) as a yellow solid. Obtained.

Step 2:
Preparation of 5- (4-{[5- (4-Methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-amine

Using 1-methyl-4- {5- [4- (5-nitrothiophen-2-yl) phenoxy] pentyl} piperazine in the same manner as in Step 2 of Example 2, the title compound (crude) was converted into a brown amorphous Got as.

Step 3:
2,2,2-trifluoro-N- (2-{[5- (4-{[5- (4-methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-yl] amino}- Preparation of 2-oxoethyl) -N- (1-methylpiperidin-4-yl) acetamide

5- (4-{[5- (4-Methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidine -4-yl) acetamide] The title compound (crude) was obtained as a brown amorphous in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

Step 4:
N- [5- (4-{[5- (4-Methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-yl] -2-[(1-methylpiperidin-4-yl) amino] Preparation of

acetamide

2,2,2-trifluoro-N- (2-{[5- (4-{[5- (4-methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-yl] Amino} -2-oxoethyl) -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to give the title compound (3 step yield 14%) as a yellow amorphous substance. Obtained.

Example 52 N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-{[(1-methylpiperidine- Preparation of 4-yl) methyl] amino} acetamide

Step 1:
tert-butyl 4- (4- {5- [2-({[1- (tert-butoxycarbonyl) piperidin-4-yl] methyl} amino) acetamido] thiophen-2-yl} phenyl) -5,6- Preparation of dihydropyridine-1 (2H) -carboxylate

tert-Butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate (100 mg, 0.28 mmol) in methylene chloride (1 mL) Under ice cooling, DIPEA (73 μL, 0.42 mmol) and chloroacetyl chloride were added and stirred for 30 minutes. 1-Boc-4-aminomethylpiperidine (150 mg), potassium carbonate (100 mg), and acetonitrile (1 ml) were added. The temperature was raised to 60 ° C. and stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added under ice cooling, 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 = 100: 0 → 81: 19, gradient) to obtain the title compound (156 mg, 91%) as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.12-1.25 (2H, m), 1.46 (9H, s), 1.50 (9H, s), 1.55-1.68 (1H, m), 1.72-1.79 (2H, m), 2.51-2.57 (2H, m), 2.59 (2H, d, J = 6.8 Hz), 2.65-2.78 (2H, m), 3.45 (2H, s), 3.61-3.67 (2H, m), 4.05 -4.21 (4H, m), 6.07 (1H, brs), 6.65 (1H, d, J = 3.6 Hz), 7.09 (1H, d, J = 4.0 Hz), 7.37 (2H, d, J = 8.4 Hz) , 7.55 (2H, d, J = 8.4 Hz), 9.79 (1H, brs)

Step 2:
tert-butyl 4- (4- {5- [2- (N-{[1- (tert-butoxycarbonyl) piperidin-4-yl] methyl} -2,2,2-trifluoroacetamido) acetamido] thiophene- Preparation of 2-yl} phenyl) -5,6-dihydropyridine-1 (2H) -carboxylate

tert-butyl 4- (4- {5- [2-({[1- (tert-butoxycarbonyl) piperidin-4-yl] methyl} amino) acetamido] thiophen-2-yl} phenyl) -5,6- The title compound (86%) was obtained as a yellow solid in the same manner as in Step 5 of Example 9 using dihydropyridine-1 (2H) -carboxylate and trifluoroacetic anhydride.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.07-1.23 (2H, m), 1.44 (9H, s), 1.50 (9H, s), 1.54-1.60 (2H, m), 1.98-2.10 (1H, m), 2.48-2.56 (2H, m), 2.63-2.74 (2H, m), 3.62-3.67 (2H, m), 3.48 (2H, d, J = 7.2 Hz), 4.04-4.32 (6H, m) , 6.07 (1H, brs), 6.65 (1H, d, J = 4.4 Hz), 7.07 (1H, d, J = 4.0 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.4 Hz), 9.01 (1H, brs).

Step 3:
2,2,2-trifluoro-N- [2-oxo-2-({5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} amino ) Ethyl] -N- (piperidin-4-ylmethyl) acetamide

tert-butyl 4- (4- {5- [2- (N-{[1- (tert-butoxycarbonyl) piperidin-4-yl] methyl} -2,2,2-trifluoroacetamido) acetamido] thiophene The title compound (crude) was obtained as a brown oil in the same manner as in Step 5 of Example 13 using 2-yl} phenyl) -5,6-dihydropyridine-1 (2H) -carboxylate.

Step 4:
2,2,2-trifluoro-N- [2-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} amino ) -2-Oxoethyl] -N-[(1-methylpiperidin-4-yl) methyl] acetamide

2,2,2-trifluoro-N- [2-oxo-2-({5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} amino ) Ethyl] -N- (piperidin-4-ylmethyl) acetamide was used in the same manner as in Step 1 of Example 5 to obtain the title compound (16%) as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.20-1.38 (2H, m), 1.50-1.73 (2H, m), 1.89-1.97 (2H, m), 2.26 (3H, s), 2.27-2.30 ( 1H, m), 2.42 (3H, s), 2.56-2.62 (2H, m), 2.66-2.71 (2H, m), 2.83-2.90 (2H, m), 3.12-3.15 (2H, m), 3.48 ( 2H, d, J = 7.2), 4.21 (2H, s), 6.10 (1H, brs), 6.65 (1H, d, J = 4.0 Hz), 7.05 (1H, d, J = 4.0 Hz), 7.37 (2H , d, J = 8.4 Hz), 7.51 (2H, d, J = 8.4 Hz.)

Step 5:
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-{[(1-methylpiperidin-4-yl ) Preparation of methyl] amino}

acetamide

2,2,2-trifluoro-N- [2-({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] ] Thiophen-2-yl} amino) -2-oxoethyl] -N-[(1-methylpiperidin-4-yl) methyl] acetamide in the same manner as in Step 8 of Example 9, the title compound (84 %) As a pale yellow solid.

Example 53 Production of N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (pyrrolidin-1-yl) pentanamide Step 1 :
Preparation of 1-methyl-4- {3- [4- (5-nitrothiophen-2-yl) phenoxy] propyl} piperazine

The title compound (25%) was obtained in the same manner as in Step 2 of Example 49 using 4- (5-nitrothiophen-2-yl) phenol, 1,3-dibromopropane, and 1-methylpiperazine.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.00 (2H, tt, J = 6.8, 6.8 Hz), 2.30 (3H, s), 2.35-2.60 (10H, m), 4.07 (2H, t, J = 6.0 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.13 (1H, d, J = 4.0 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.89 (1H, d, J = 4.0 Hz) ).

Step 2:
Preparation of 5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-amine

The title compound (crude) was obtained in the same manner as in Step 2 of Example 2 using 1-methyl-4- {3- [4- (5-nitrothiophen-2-yl) phenoxy] propyl} piperazine. .

Step 3:
Preparation of N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (pyrrolidin-1-yl) pentanamide 5- {4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-amine, 5-bromopentanoyl chloride and pyrrolidine were used in the same manner as in Step 1 of Example 40 to obtain the title compound (15 %) As a tan solid.

Example 54 5-([1,4′-bipiperidin] -1′-yl) -N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophene-2- Yl) Preparation of pentanamide Using 5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-amine, 5-bromopentanoyl chloride and 1,4′-bipiperidine The title compound (12%) was obtained as a brown amorphous product in the same manner as in Step 1 of Example 40.

Example 55 Preparation of N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (piperidin-1-yl) pentanamide 5- {4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-amine, 5-bromopentanoyl chloride and piperidine were used in the same manner as in Step 1 of Example 40 to obtain the title. The compound (15%) was obtained as a pale yellow solid.

Example 56 N- (5- {4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] Production of acetamide

Step 1:
2,2,2-trifluoro-N- {2-[(5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) amino] -2-oxoethyl } Production of —N- (1-methylpiperidin-4-yl) acetamide

5- {4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidine-4-] Yl) acetamide] The title compound (crude) was obtained in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

Step 2:
Preparation of N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino]

acetamide

2,2,2-trifluoro-N- {2-[(5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) amino] -2-oxoethyl } -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (2 step yield: 4%).

Example 57 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] Preparation of thiophene-2-carboxamide

Step 1:
tert-Butyl 4- [4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) -1H-pyrazol-1-yl] piperidine 1-carboxylate production

N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide and tert-butyl 4- [4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl] piperidine-1-carboxylate was used in the same manner as in Step 3 of Example 1 to obtain the title compound (crude). Obtained as a yellow solid.

Step 2:
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] thiophene-2 Preparation of carboxamide tert-butyl 4- [4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) -1H-pyrazole-1 -Il] piperidine-1-carboxylate (98 mg, 0.17 mmol) was dissolved in methylene chloride (2 mL), TFA (0.5 mL) was added and stirred for 0.5 h, the reaction mixture was concentrated, and the residue was Obtained. Methylene chloride (0.5 mL), acetic acid (2 mL), aqueous formaldehyde solution (36% aqueous solution, 15 μL, 0.18 mmol), sodium triacetoxyborohydride (21 mg, 0.1 mmol) were added to the resulting residue, and at room temperature. The mixture was stirred for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (chloroform: saturated ammonia methanol). = 90: 10) to give the title compound (23 mg, 21% yield over 2 steps) as a pale yellow solid.

Example 58 6-[(Dimethylamino) methyl] -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} nicotine Preparation of Amides Using 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 6-[(dimethylamino) methyl] nicotinic acid In the same manner as in Step 1 of Example 1, the title compound (46%) was obtained as a yellow solid.

Example 59 N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4- (4-methylpiperazine-1- Yl) Preparation of benzamide 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 4- (4-methylpiperazin-1-yl) The title compound (4%) was obtained as a yellow solid in the same manner as in Step 1 of Example 1 using benzoic acid.

Example 60 N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4-{[(1-methylpiperidine- Preparation of 4-yl) amino] methyl} benzamide

Step 1:
Preparation of methyl 4-{[N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl} benzoate

Methyl 4-{[(1-methylpiperidin-4-yl) amino] methyl} benzoate and 2-nitrobenzenesulfonyl chloride were used in the same manner as in Step 4 of Example 2 to obtain the title compound (62%) as light green Obtained as amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.58-1.70 (4H, m), 1.94-2.02 (2H, m), 2.20 (3H, s), 2.75-2.82 (2H, m), 3.82-3.94 ( 1H, m), 3.90 (3H, s), 4.60 (2H, s), 7.38 (2H, J = d Hz), 7.51-7.57 (1H, m), 7.62-7.68 (2H, m), 7.86-7.93 (3H, m).

Step 2:
Preparation of 4-{[N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl} benzoic acid

Methyl 4-{[N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl} benzoate is used to obtain the title compound (crude) in the same manner as in Step 5 of Example 2. Obtained as a yellow solid.

Step 3:
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4-{[N- (1-methylpiperidine-4 -Il) -2-Nitrophenylsulfonamido] methyl} benzamide

5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 4-{[N- (1-methylpiperidin-4-yl)- 2-Nitrophenylsulfonamido] methyl} benzoic acid was used in the same manner as in Step 1 of Example 1 to obtain the title compound (crude) as a brown solid.

Step 4:
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4-{[(1-methylpiperidin-4-yl ) Preparation of amino] methyl} benzamide N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4-{[N -(1-Methylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl} benzamide was used in the same manner as in Step 8 of Example 2 to give the title compound (2 step yield: 11%) as an orange solid. Got as.

Example 61 2- {6-[(dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- Production of 2-yl} acetamide

Step 1:
Preparation of methyl 2- {6-[(dimethylamino) methyl] pyridin-3-yl} acetate

To a solution of methyl 2- [6- (hydroxymethyl) pyridin-3-yl] acetate (190 mg, 1.05 mmol) in methylene chloride (3.5 mL) was added thionyl chloride (179 mg, 1.58 mmol) under ice cooling. Stir for 4 hours. After concentration under reduced pressure, methylene chloride (3.5 塩化 ml), TEA (214 mg, 2.1 mmol), and aqueous dimethylamine (9.5M, 0.16 mL, 1.52 mmol) were added under ice cooling. Stir overnight at room temperature. 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) to obtain the title compound (78.8 mg, 36%) as a brown oily substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.29 (6H, s), 3.58 (2H, s), 3.62 (2H, s), 3.71 (3H, s), 7,37 (1H, d, J = 8.1 Hz), 7.62 (1H, dd, J = 8.1, 2.4 Hz), 8.45 (1H, d, J = 2.2 Hz).

Step 2:
Production of 2- {6-[(dimethylamino) methyl] pyridin-3-yl} acetic acid

The title compound (crude) was obtained as a pale yellow solid in the same manner as in Step 5 of Example 2 using methyl 2- {6-[(dimethylamino) methyl] pyridin-3-yl} acetate.

Step 3:
tert-butyl 4- {4- [5- (2- {6-[(dimethylamino) methyl] pyridin-3-yl} acetamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine-1 (2H ) -Carboxylate production

tert-Butyl 4- [4- (5-aminothiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate and 2- {6-[(dimethylamino) methyl] pyridine-3 The title compound (crude) was obtained as a light brown amorphous in the same manner as in Step 1 of Example 1 using -yl} acetic acid.

Step 4:
2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl } Production of Acetamide tert-Butyl 4- {4- [5- (2- {6-[(Dimethylamino) methyl] pyridin-3-yl} acetamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine The title compound (2 step yield: 24%) was obtained as an orange solid in the same manner as in Step 5 of Example 13 using -1 (2H) -carboxylate.

Example 62 2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) Preparation of phenyl] thiophen-2-yl} acetamide 2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6-tetrahydropyridine- 4-yl) phenyl] thiophen-2-yl} acetamide and formaldehyde were used as in Step 1 of Example 5 to give the title compound (71%) as an orange solid.

Example 63 N- {5- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide Manufacturing of

Step 1:
Preparation of 1-methyl-4- [5- (5-nitrothiophen-2-yl) pyridin-2-yl] piperazine

2-bromo-5-nitrothiophene and 1-methyl-4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) piperidin-2-yl] piperazine The title compound (crude) was obtained as an orange solid in the same manner as in Step 3 of Example 1.

Step 2:
Preparation of 5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-amine

Using 1-methyl-4- [5- (5-nitrothiophen-2-yl) pyridin-2-yl] piperazine in the same manner as in Step 2 of Example 2, the title compound (2 step yield: 63%) ) Was obtained as a black-green solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.31 (3H, s), 2.47-2.57 (4H, m), 3.46-3.59 (4H, m), 3.75 (2H, brs), 6.14 (1H, d, J = 3.6 Hz), 6.62 (1H, d, J = 8.8 Hz), 6.74 (1H, d, J = 3.6 Hz), 7.54 (1H, dd, J = 8.4, 2.0 Hz), 8.31 (1H, d, J = 2.4 Hz).

Step 3:
2,2,2-trifluoro-N- [2-({5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl} amino) -2-oxoethyl] Preparation of —N- (1-methylpiperidin-4-yl) acetamide

5- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-amine and 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) ) Acetamide] The title compound (61%) was obtained as a light brown solid in the same manner as in Steps 6 and 7 of Example 2 using acetic acid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.75-1.84 (2H, m), 1.92-2.08 (4H, m), 2.29 (3H, s), 2.35 (3H, s), 2.50-2.55 (4H, m), 2.90-2.98 (2H, m), 3.55-3.62 (4H, m), 3.80-3.89 (1H, m), 4.16 (2H, s), 6.60 (1H, d, J = 4.1 Hz), 6.63 (1H, d, J = 8.8 Hz), 6.89 (1H, d, J = 3.9 Hz), 7.61 (1H, dd, J = 8.8, 2.7 Hz), 8.39 (1H, d, J = 2.4 Hz), 8.92 (1H, brs).

Step 4:
Production of N- {5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino]

acetamide

2 , 2,2-trifluoro-N- [2-({5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl} amino) -2-oxoethyl]- The title compound (quantitative) was obtained as a pale brown solid in the same manner as in Step 8 of Example 9 using N- (1-methylpiperidin-4-yl) acetamide.

The 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 are cells obtained by expressing human TLR9 in human fetal kidney cell line, 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 four 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 / 293xL).
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.

[Test Example 2] TLR7 activation inhibition test using TLR7-expressing reporter cells 1) Establishment of TLR7-expressing reporter cells Human TLR7-expressing cells were obtained by expressing cells expressing human TLR7 in 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 four 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 results of Test Examples 1 and 2, it was confirmed that the compound of the present invention has a strong TLR7 and 9 inhibitory action. Therefore, the thiophene derivative represented by the general formula (1) of the present invention is used as a TLR7 and 9 inhibitor as a disease associated with activation of TLR7 and 9 signals such as RA, SLE, SS, MS, IBD, psoriasis. It has been found to be useful as an active ingredient for preventive and therapeutic agents for autoimmune diseases such as osteoarthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection and GvHD.

[Test Example 3] Disease state-suppressing effect of TLR9 activation-inhibiting compound using rheumatoid arthritis model The therapeutic effect of the compound of Example 5 on rheumatoid arthritis (RA) was compared with a mouse collagen-induced arthritis model (mouse CIA model) which is an animal model of RA. ). (FDA, CBER, CDER, CDRH: Guidance for industry-Clinical development programs for devices, devices, and biological products for the treatment of RA. 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 was the control group (administration medium (0.5% hydroxymethylpropylcellulose aqueous solution) administration group), the compound of Example 5 administered with 25 mg / kg, and the compound of Example 5 administered with 50 mg / kg.

(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-sensitized 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 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. Then, 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 score by three judges in a blinded trial, 3 times in total: initial assessment 7 days after additional sensitization, intermediate assessment 10 days later, and final assessment 14 days later. The 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. FIG. 6 is a graph showing changes over time in arthritis scores of a mouse collagen-induced arthritis model in a control group (drug non-administration group) and the compound of Example 5 in a 25 mg / kg administration group and a 50 mg / kg administration group. In the control group, an increase in the arthritis score was observed after 7 days from the additional sensitization. On the other hand, the administration group of the compound of Example 5 showed a significant inhibitory effect suggesting dose dependency at a dose of 50 mg / kg. 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. 2 shows the average value of anti-type 2 collagen IgG antibody titer 15 days after the additional sensitization. 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 5 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 5 showed a significant inhibitory effect suggesting dose dependency. In the figure, * and ** indicate a risk rate of less than 5% (p <0.05) and less than 1% (p <0.01), respectively, in Steel's multiple comparison test using the control group as a comparison control. Indicates that

From the results of arthritis score and anti-type 2 collagen IgG antibody titer, the compound of Example 5 is effective as a therapeutic agent for rheumatoid arthritis.

The present invention for the first time finds that the thiophene derivative represented by the general formula (1) or a salt thereof, or a solvate thereof has an excellent TLR3, 7 and / or 9 inhibitory action, and autoimmunity. The present invention provides a preventive and / or therapeutic agent for cardiomyopathy due to disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis. The present invention provides a preventive and / or therapeutic agent for cardiomyopathy caused by autoimmune disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis, and is useful in the pharmaceutical industry. Has industrial applicability.

Claims

The following general formula (1):

[Where:
X is the following formula (2):

{Where,
Ring A represents a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring,
Ring B represents a saturated or unsaturated aliphatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Here, ring A and ring B are each a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, or a carboxy C 1. -5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, It may have 1 to 3 substituents selected from a diC 1-6 alkylamino group and a diC 1-6 alkylamino C 1-6 alkyl group,
Q 2 represents a single bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group 1 to 2 substituents selected from a C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 alkyl group,
R 4 represents a single bond, an oxygen atom or an NH group, wherein the NH group is a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group, C 1-3 may have an alkylsulfonyl group, and C 6-10 aryl C 1-3 substituent selected from alkyl groups}
Or formula (3):

{Where,
Ring C represents a saturated or unsaturated nitrogen-containing aliphatic heterocycle or nitrogen-containing aromatic heterocycle, wherein the ring C is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, or a C 1-6 alkyl Oxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group A substituent selected from a C 1-3 alkylcarbamoyl C 1-5 alkyl group, a C 1-6 alkylamino group, a diC 1-6 alkylamino group, and a diC 1-6 alkylamino C 1-6 alkyl group, You may have 1 to 3
Q 3 represents a single bond, 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 is a halogen atom, oxo group, hydroxyl group, C 2 1 to 2 substituents selected from a 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 alkyl group May}
Indicate
Ring Y represents a saturated or unsaturated aliphatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Here, the ring Y is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, a carboxy C 1-5 alkyl group. Benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1- A 6 alkylamino group, a di-C 1-6 alkylamino C 1-6 alkyl group, and a group of formula (4):

{Where,
Q 4 represents a single bond, 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 is a halogen atom, an oxo group, a hydroxyl group, C 1 to 2 substituents selected from a 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 alkyl group You can,
R 5 represents a single bond, an oxygen atom or an NH group, wherein the NH group is a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group, may have a C 1-3 alkylsulfonyl group, and C 6-10 aryl C 1-3 substituent selected from alkyl groups,
Ring D represents a saturated or unsaturated aliphatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Here, the ring D is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, or a carboxy C 1-5 alkyl group. Benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1- 1 to 3 substituents selected from a 6 alkylamino group and a di-C 1-6 alkylamino C 1-6 alkyl group}
1 to 3 substituents selected from:
Provided that when X represents the formula (3) and the ring C represents a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, the ring Y represents a saturated or unsaturated fat having a substituent represented by the formula (4). An aromatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring,
Provided that when ring Y has a substituent represented by formula (4) and ring D represents an aromatic carbocycle, ring Y is a saturated or unsaturated aliphatic carbocyclic ring, saturated or unsaturated nitrogen-containing An aliphatic heterocycle or a nitrogen-containing aromatic heterocycle;
Provided that when X represents the formula (3) and Q 3 represents a C 1-6 alkylene group having an oxo group, the ring Y is a saturated or unsaturated aliphatic carbocyclic ring, or a saturated or unsaturated nitrogen-containing group. An aliphatic heterocycle, wherein the ring Y is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, Carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkyl It may have 1 to 3 substituents selected from an amino group, a diC 1-6 alkylamino group, a diC 1-6 alkylamino C 1-6 alkyl group, and a group of the formula (4).
Q 1 represents a single bond, 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 is a halogen atom, an oxo group, a hydroxyl group, C 1 1 to 2 substituents selected from a 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 alkyl group You can,
Provided that when X represents the formula (3) and Q 3 represents a C 1-6 alkylene group having an oxo group, Q 1 represents a C 1-6 alkylene group or a C 2-6 alkenylene group, where The C 1-6 alkylene group or C 2-6 alkenylene group in Q 1 is a halogen atom, an oxo group, a hydroxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1 It may have 1 or 2 substituents selected from a -6 alkyl group and a C 6-10 aryl C 1-3 alkyl group,
R 1 represents a single bond, an oxygen atom or an NH group, wherein the NH group is a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group, may have a C 1-3 alkylsulfonyl group, and C 6-10 aryl C 1-3 substituent selected from alkyl groups,
R 2 and R 3 may be the same or different from each other, each represents a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkyloxy group, and the combination of q, m and n is (q, m, n) = (0,1,0), (0,0,1), (0,1,1), (1,1,0), (1,0,1) or (1,1,1) Is]
Or a salt thereof, or a solvate thereof.
X represents formula (2),
Here, ring B represents an aromatic carbocycle, a saturated aliphatic carbocycle, or a nitrogen-containing aromatic heterocycle, wherein the ring B is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, C 1- 6 alkyloxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 Substitution selected from alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1-6 alkylamino group and di-C 1-6 alkylamino C 1-6 alkyl group May have 1 to 3 groups,
The compound according to claim 1, or a salt thereof, or a solvate thereof.
X represents formula (2),
Here, ring A represents a pyrrolidine ring, a piperidine ring, a piperazine ring or a tetrahydropyridine ring,
Ring B is a benzene ring, cyclohexane ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadiazole ring or Showing the thiadiazole ring,
Here, ring A and ring B are each a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, or a carboxy C 1. -5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, 1 to 3 substituents selected from a diC 1-6 alkylamino group and a diC 1-6 alkylamino C 1-6 alkyl group may be present,
The compound of Claim 2, or its salt, or those solvates.
X represents formula (3),
Here, ring C represents a saturated nitrogen-containing aliphatic heterocycle or a nitrogen-containing aromatic heterocycle, wherein the ring C is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy Group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, A substituent selected from a C 1-3 alkylcarbamoyl C 1-5 alkyl group, a C 1-6 alkylamino group, a diC 1-6 alkylamino group and a diC 1-6 alkylamino C 1-6 alkyl group; You may have up to 3
Q 3 represents a single bond or a C 2-6 alkenylene group, wherein the C 2-6 alkenylene group is a halogen atom, an oxo group, a hydroxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups may have 1 to 2,
The compound according to claim 1, or a salt thereof, or a solvate thereof.
Q 1 represents a single bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups may have 1 to 2,
The compound according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof.
Ring Y represents an aromatic carbocyclic ring, a saturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring, wherein said ring Y is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, C 1- 6 alkyloxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 An alkyl group, a C 1-3 alkylcarbamoyl C 1-5 alkyl group, a C 1-6 alkylamino group, a diC 1-6 alkylamino group, a diC 1-6 alkylamino C 1-6 alkyl group, and a formula ( 1 to 3 substituents selected from the group 4) may be included.
The compound according to any one of claims 1 to 5, or a salt thereof, or a solvate thereof.
Ring Y is a benzene ring, piperidine ring, pyrrolidine ring, piperazine ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring Represents an oxadiazole ring or a thiadiazole ring, wherein the ring Y is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group Cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di C 1-6 alkylamino group, di-C 1-6 alkyl Mino C 1-6 alkyl group, and a substituent selected from the group may have 1 to 3 of formula (4),
The compound according to claim 6, or a salt thereof, or a solvate thereof.
Ring Y has a substituent represented by formula (4),
Here, ring D represents a saturated aliphatic carbocyclic ring, aromatic carbocyclic ring or saturated nitrogen-containing aliphatic heterocyclic ring, wherein the ring D is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, C 1-6 alkyloxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1 -5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1-6 alkylamino group and di-C 1-6 alkylamino C 1-6 alkyl group May have 1 to 3 substituents,
Q 4 represents a single bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 can have one or two substituents selected from alkyl groups,
R 5 represents a single bond or an NH group, wherein the NH group is a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group, a C 1- May have a substituent selected from a 3 alkylsulfonyl group and a C 6-10 aryl C 1-3 alkyl group,
The compound according to any one of claims 1 to 7, or a salt thereof, or a solvate thereof.
The ring D represents a cyclohexane ring, a benzene ring, a pyrrolidine ring, a piperidine ring or a piperazine ring, wherein the ring D is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1- 1 to 3 substituents selected from 3- alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1-6 alkylamino group and di-C 1-6 alkylamino C 1-6 alkyl group May have,
The compound according to claim 8, or a salt thereof, or a solvate thereof.
The combination of q, m, and n is (q, m, n) = (0, 1, 0), (0, 0, 1), or (1, 1, 1). Or a salt thereof, or a solvate thereof.
The compound represented by the general formula (1) is
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide;
2-[(1-benzylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide,
N- {3-[(1-benzylpiperidin-4-yl) amino] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide;
5- [4- (4-methylpiperazin-1-yl) phenyl] -N- {3-[(1-methylpiperidin-4-yl) amino] propyl} thiophene-2-carboxamide;
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide
N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) oxy] acetamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] Thiophene-2-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methylpiperidin-4-yl) phenyl] thiophene-2-carboxamide;
N- {5- [4- (4-Methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
(E) -N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-ene -1-yl] thiophene-2-carboxamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide;
N- [3-([1,4′bipiperidin] -1′-yl) propyl] -3-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide;
N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(piperidin-4-yl) amino] acetamide,
N- {3-([1,4′-bipiperidin] -1′-yl) propyl} -3-methoxy-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide;
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) Amino] acetamide,
2-[(1-methylpiperidin-4-yl) amino] -N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl} acetamide,
2-[(1-methylpiperidin-4-yl) amino] -N- (5- {4-[(1-methylpiperidin-4-yl) oxy] phenyl} thiophen-2-yl) acetamide,
2- [4- (dimethylamino) piperidin-1-yl] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide,
(R) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide;
(S) -N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide;
2-[(5-hydroxypentyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide;
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide;
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- (4- {4- [6- (methylamino) -6-oxohexyl] piperazin-1-yl} Phenyl) thiophene-2-carboxamide,
Benzyl 6- {4- [4- (5-{[3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl} thiophen-2-yl) phenyl] piperazin-1-yl} hexanoate ,
1′-methyl-N- {5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl}-[1,4′-bipiperidine] -4-carboxamide;
N-methyl-6- {4- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] piperazin-1-yl} hexanamide,
N- (5- {4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide ,
2-[(3-hydroxypropyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide;
2- (4-methylpiperazin-1-yl) -N- [4- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) phenyl] acetamide,
N- (5- {1- [3- (dimethylamino) propyl] -1H-indol-5-yl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] -3-phenylpropanamide,
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine -3-carboxamide,
N- {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1-methylpiperidin-4-yl) methylsulfonamido] acetamide,
4-methyl-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- 4-yl) amino] pentanamide,
1- (piperidin-4-yl) -3- {5- [4- [1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} urea,
4-methoxy-N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidine- 4-yl) amino] butanamide,
N- {5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- {5- [3-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
2- (4-methylpiperazin-1-yl) -5- (5- {2-[(1-methylpiperidin-4-yl) amino] acetamido} thiophen-2-yl) benzamide;
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} Propanamide,
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} propanamide,
Benzyl 2- [4- (4- {5- [3-([1,4′-bipiperidin] -1′-yl) propanamido] thiophen-2-yl} phenyl) -5,6-dihydropyridine-1 ( 2H) -yl] acetate,
3-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} propanamide,
2-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} acetamide,
4-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} butanamide,
5-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} pentanamide,
6-([1,4′-bipiperidin] -1′-yl) -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl} hexanamide,
N- {5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- (5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- (5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [5- (4-{[5- (4-Methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophen-2-yl] -2-[(1-methylpiperidin-4-yl) amino] Acetamide,
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2-{[(1-methylpiperidin-4-yl ) Methyl] amino} acetamide,
N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (pyrrolidin-1-yl) pentanamide,
5-([1,4′-bipiperidin] -1′-yl) -N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) pentane Amide,
N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (piperidin-1-yl) pentanamide,
N- (5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide,
N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] thiophene-2 -Carboxamide,
6-[(dimethylamino) methyl] -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} nicotinamide,
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4- (4-methylpiperazin-1-yl) benzamide ,
N- {5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -4-{[(1-methylpiperidin-4-yl ) Amino] methyl} benzamide,
2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl } Acetamide,
2- {6-[(Dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene -2-yl} acetamide, and
N- {5- [6- (4-Methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl} -2-[(1-methylpiperidin-4-yl) amino] acetamide,
The compound according to claim 1, or a salt thereof, or a solvate thereof, which is at least one compound selected from the group consisting of:
12. At least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9, comprising the compound according to any one of claims 1 to 11 or a salt thereof, or a solvate thereof as an active ingredient.
An autoimmune disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease, comprising the compound according to any one of claims 1 to 11 or a salt thereof, or a solvate thereof as an active ingredient A preventive and / or therapeutic agent for cardiomyopathy caused by sepsis.
The preventive and / or therapeutic agent according to claim 13, 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.