WO2013161871A1 - Thiophene derivative having tlr-inhibiting activity - Google Patents

Thiophene derivative having tlr-inhibiting activity Download PDF

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WO2013161871A1
WO2013161871A1 PCT/JP2013/062049 JP2013062049W WO2013161871A1 WO 2013161871 A1 WO2013161871 A1 WO 2013161871A1 JP 2013062049 W JP2013062049 W JP 2013062049W WO 2013161871 A1 WO2013161871 A1 WO 2013161871A1
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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
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興和株式会社
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/36Nitrogen atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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, C1-6 alkyl group or C1-6 alkyloxy group; Q1 is a bond or an optionally substituted C1-6 alkylene group or C2-6 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 derivatives having a TLR inhibitory effect

The present invention is Toll-like receptor; have (Toll-like receptor TLR) inhibitory action, diseases caused by the inhibition of TLR downstream signaling, for example, arthritis, 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 vasculitis such as inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD ) or to novel compounds useful as a prophylactic and / or therapeutic agent for cardiomyopathy caused by sepsis.

When pathogen enters the living body, the immune system will quickly identify eliminate those pathogens. In mammals can be divided into acquired immune and the immune system has a large natural immunity. The acquired immunity, receptors having different antigenic specificities countless individual in a way that gene rearrangement is expressed on T cells and B cell surface, to deal with any unknown foreign antigens (non-patent document 1).

On the other hand, the innate immune system carried by macrophages and dendritic cells, etc. has been thought to eliminate microorganisms in a non-specific immune response is performed with a focus on TLR discoveries and dendritic cells studies the rapid progress, affinity and specificity of more antigen recognition in the adaptive immune system is not high, the characteristic microbial recognition mechanism that is present has become clear (non-patent document 2). Especially nucleic acid recognition receptors transduce signals into the cell represented by TLR serves not only as to catch in the early front infection, then transmitted a signal to the cell, switching on the innate immune system activation there is an important role to. In this sense, hitherto known cytokines and chemokines, such as type I interferon induced by the natural activation of the immune system were then and gene expression induction of a group of molecules involved in antigen presentation, the subsequent adaptive immune system activity path of leads to specific immune responses triggered revealed in cooperation with the reduction (non-patent Document 2).

TLR3 of TLR recognizes a double-stranded RNA from viruses, TLR7 is found to recognize single-stranded RNA from a virus as well. TLR9 is activated by recognizing a bacterial CpG (cytosine-guanine) DNA. CpG DNA is repeated as often as is CpG sequences that are unmethylated in a characteristic sequence of bacterial genomic DNA. Because it is methylated frequency less frequent mammalian genomic DNA in the CpG sequence, no immunostimulatory activity (Non-Patent Document 3).

So far a number of studies have been made with respect to TLR7,9 that have been reported as RNA and DNA sensors, the details are becoming quite clear. TLR7,9 is a RNA or DNA present in the extracellular functions as recognizing receptor in endosomes and lysosomes, and induce gene expression of type I interferons and inflammatory cytokines. Although via this Both MyD88-dependent signaling pathway, the former whereas involving IRAK1 / IKKα-IRF-7, in the latter, the path of the NF-[kappa] B and IRF-5 and MAP kinases are involved. Other IRF-7 and IRF-5 in MyD88, but IRF-1 and IRF-4 is known to associate (non-patent document 4, 5, 6), IRF transcription factors involved in TLR9 downstream the types and roles are different depending on the type of cell.

Recognized as a TLR ligand RNA or DNA, as indicated above is, self nucleic acids in a normal state is not recognized as a ligand, it does not activate innate immunity. This is because the self-nucleic acid released by cell death are degraded before being recognized by TLR by nucleases in serum. Also of TLR3,7 and 9, rather than the cell surface, even cellular localization in endosomes, are considered as a mechanism which does not recognize self nucleic acids. However, such protection mechanisms in situations where autoimmune reactions or inflammation has occurred collapsed, forms a complex with endogenous protein is thought to activate TLR signaling (Non-Patent Document 7) .

By inhibiting TLR these reasons, 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 vasculitis such as inflammation, allergy, asthma, graft rejection, it may be possible to improve the cardiomyopathy caused by graft versus host disease (GvHD) or sepsis. It is shown specific relationship with TLR for some diseases such as shown below.

For rheumatoid arthritis (RA) by using a nucleic acid sequence having a TLR9 inhibitory activity, onset and pathology in pristane-induced rat arthritis model is reported to have been inhibited by inhibiting TLR9 (Non-Patent Document 8) . The hydroxychloroquine is an anti-malarial drugs are known to have inhibitory effects of TLR7 and 9 by acidification suppression of endosomes, it has been approved for the treatment of RA and SLE in most countries except Japan ( non-Patent Document 9).

For systemic lupus erythematosus (SLE) has been reported attenuation of antinuclear antibodies found in Byotai of SLE-like in TLR9 knockout mice (Non-Patent Document 10), the same also in experiments with nucleic acid having a TLR9 inhibitory action the results are reported (non-Patent Document 11). It has also been reported further low molecular weight compounds having a similar action (CPG52364: Patent Document 1).

Reduction of the protein in the urine even in TLR7 knockout mice (SLE-like MRL / lpr mice and spontaneously develops symptoms), the onset of the symptoms of a decline SLE-like blood IgG is known to be inhibited (Non-Patent literature 12, 13). It has also been reported the suppression of symptoms of SLE-like by further administering an inhibitory nucleic acid (Non-Patent Document 11). From these reports it is inferred that TLR7 is also very useful as a target for SLE. In the EAE model, a model for MS in mice have reported that weak onset of pathology in TLR2 and TLR9 knockout mice, TLR involvement is shown (Non-Patent Document 14).

In Sjogren's syndrome (SS) patients salivary gland epithelial cells, it has been made reports that susceptible to apoptosis by activation of TLR3, TLR involvement is considered (Non-Patent Document 15).

The enterocolitis, such as inflammatory bowel disease (IBD) has been shown various TLR is using colitis model in mice to be involved in inflammation, if the work inhibitory to Byotai by TLR inhibition, activation of TLR There have been reported cases suppressively acting on Byotai, only unconditionally inhibiting effect is not believed to function in the pathology recovery, involvement with TLR is shown (non-Patent Document 16).

By inflammatory cytokines produced by CpG-B DNA is a ligand, has been reported to contractility of the cardiac muscle cells is to be lost, its action in TLR9 knockout mice was attenuated (Non-Patent Document 17). It believed to be involved in cardiomyopathy due to sepsis from this.

Hydroxychloroquine are known to have a TLR9 inhibitory activity, is a drug that is already also used in clinical, not so strong as TLR9 inhibition by agents with a stronger TLR9 inhibition, stronger efficacy is It can be expected. The Hydroxychloroquine there are concerns of adverse effects of chloroquine retinopathy, etc., the compounds of different skeletal, such side effects concerns also conceivable possibility wiping.

Thus, showed strong TLR inhibitory action, orally administrable low molecular agents, the future of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS), inflammation sex bowel disease (IBD), psoriasis arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, in the treatment of cardiomyopathy due to graft versus host disease (GvHD) or sepsis it is considered to be useful.

On the other hand, the thiophene derivative, therapeutic agent for central nervous system diseases (Patent Document 2) are known effective as a cancer therapeutic agent (Patent Documents 3, 4 and 5). Moreover, p38 MAP kinase inhibitor (Patent Document 6) and prostaglandin E synthase inhibitors (Patent Document 7), calcium channel modulators (Patent Document 8), matrix metalloproteinase-12 inhibitors (Non-Patent Document 18), immunization cell activation inhibitor (Patent Document 9), etc., it is also known effect as immune allergic diseases therapeutics. However, In any of these documents, and suggests no description related to TLR inhibitory effect.

International Publication No. WO 2008/152471 JP 11-322711 discloses JP-T 2007-502308 JP JP-T 2007-517843 JP International Publication No. WO 2003/099812 JP-T 2006-522784 JP International Publication No. WO 2009/098282 International Publication No. WO 2010/027875 JP-T 2008-528519 JP

Uematsu Satoshira virus, 54: 145-152 (2004) Akirakyo Takaoka et al virus, 58: 37-46 (2008) Takeda K et al., Annu. , Rev. Immunol. , 21: 335-376 (2003) Honda K et al., Proc. Natl. Acad. Sci. USA, 101: 15416-15421 (2004) Negishi H et al., Proc. Natl. Acad. Sci. USA, 102: 15989-15994 (2005) Negishi H et al., Proc. Natl. Acad. Sci. USA, 103: 15136-15141 (2006) Kim, Y.M et al. , Nature, 452: 234-238 (2008 ) S Herman et al., Ann. Rheum. Dis. , 70: A39 doi: 10.1136 / ard.2010.148973.8 (2011) Naoto Yokokawa, Current Therapy, 28: 85-91,2010 Sean R.Christensen et al. , J. Exp. Med. , 202: 321-331 (2005) Rahul D.Pawaret al. , J Am Soc Nephrol 18: 1721-1731 (2007) Sean R.Christensen, et al. , Immunity, 25: 417-428 (2006 ) Kevin M.Nickerson, et al. , J. Immunol, 184: 1840-1848 (2010) Socorro Miranda-Hernandez, et al., J Immunol, 187: 791-804 ( 2011) Manoussakis MN, et al., J Autoimmun, 35 (3) : 212-218 (2010) Elke Cario, Inflamm Bowel Dis, 14 (3): 411-421 (2008) Pascal Knuefermannal., Cardiovascular Research, 78: 26-35 ( 2008) A.-C. Dublanchet et al. , Bioorg. Med. Chem. Lett. 15: 3787-3790 (2005)

An object of the present invention is to provide a novel compound having a TLR inhibitory effect of low molecular. More particularly 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. there autoimmune diseases, inflammation, allergy, asthma, graft rejection, to provide a medicament useful for the prevention and / or treatment of cardiomyopathy due to graft versus host disease (GvHD) or sepsis.

In view of the above circumstances, the present inventors have conducted extensive TLR3,7 and / or 9 inhibitory effect results of the compound were probed with, thiophene derivatives represented by the following general formula (1), endogenously expressed human TLR3 use to which test using ECV304 from human vascular endothelial cells, studies using HEK293 cells derived from human embryonic kidney cells expressing human TLR7, HEK293 cells derived from human embryonic kidney cells expressing the human TLR9 It found to have a TLR inhibitory activity in the test had, and have completed the present invention.

That is, the present invention relates to inventions illustrated below.
[1]
Equation (1):

Figure JPOXMLDOC01-appb-C000005

[In the formula,
X is, the following equation (2):

Figure JPOXMLDOC01-appb-C000006

{In the formula,
Ring A represents a nitrogen-containing aliphatic heterocyclic saturated or unsaturated,
Ring B represents an aliphatic carbocycle saturated or unsaturated, aromatic carbocyclic, a nitrogen-containing aliphatic heterocyclic saturated or unsaturated, or a nitrogen-containing aromatic heterocycle,
Wherein said each of ring A and ring B, halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a 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 substituent selected from alkyl groups may have one to three,
Q 2 is a single bond, or a C 1-6 an alkylene group, the C 1-6 alkylene group wherein 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 4 is a single bond, an oxygen atom or an NH group, wherein the NH group, C 1-6 alkyl, hydroxy C 1-6 alkyl group, 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 the formula (3):

Figure JPOXMLDOC01-appb-C000007

{In the formula,
Ring C is a saturated or unsaturated nitrogen-containing aliphatic heterocyclic, or show the nitrogen-containing aromatic heterocyclic ring, wherein said Ring C is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyl oxy group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group , C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, a substituent selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group may have 1 to 3,
Q 3 are a single bond, C 1-6 an alkylene group or a C 2-6 alkenylene group, wherein said C 1-6 alkylene group or C 2-6 alkenylene group, a halogen atom, an oxo group, a hydroxyl group, C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 has 1-2 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups it may be}
The shows,
Ring Y represents an aliphatic carbocycle saturated or unsaturated, aromatic carbocyclic, a nitrogen-containing aliphatic heterocyclic saturated or unsaturated, or a nitrogen-containing aromatic heterocycle,
Wherein said ring Y is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a 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 alkylamino C 1-6 alkyl groups, and groups of formula (4):

Figure JPOXMLDOC01-appb-C000008

{In the formula,
Q 4 are a single bond, C 1-6 an alkylene group or a C 2-6 alkenylene group, the C 1-6 alkylene group or C 2-6 alkenylene group wherein a halogen atom, an oxo group, a hydroxyl group, C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 has 1-2 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups at best,
R 5 represents a single bond, an oxygen atom or an NH group, wherein the NH group, C 1-6 alkyl, hydroxy C 1-6 alkyl group, 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 an aliphatic carbocycle saturated or unsaturated, aromatic carbocyclic, a nitrogen-containing aliphatic heterocyclic saturated or unsaturated, or a nitrogen-containing aromatic heterocycle,
Wherein said ring D is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a 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 a di-C 1-6 alkylamino C 1-6 substituent selected from alkyl groups may have 1 to 3}
Substituents selected from may have one to three,
However, X represents formula (3), and when ring C is showing the nitrogen-containing aliphatic heterocyclic saturated or unsaturated, ring Y is aliphatic saturated or unsaturated having a substituent represented by the formula (4) family carbocyclic indicates aromatic carbocyclic, saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocycle,
However, having a substituent ring Y is represented by the formula (4), and when ring D represents an aromatic carbocyclic ring Y is an aliphatic carbon ring saturated or unsaturated, nitrogen-containing saturated or unsaturated aliphatic heterocycle, or show the nitrogen-containing aromatic heterocycle,
However, X represents formula (3), and when an alkylene group having Q 3 is an oxo group, Ring Y saturated or unsaturated aliphatic carbon ring, or a saturated or nitrogen-containing aliphatic heterocyclic unsaturated are shown, wherein the ring Y is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a 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 alkylamino C 1-6 alkyl group, and may have 1 to 3 substituents selected from the group of the formula (4),
Q 1 is a single bond, C 1-6 an alkylene group or a C 2-6 alkenylene group, wherein said C 1-6 alkylene group or C 2-6 alkenylene group, a halogen atom, an oxo group, a hydroxyl group, C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 has 1-2 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups at best,
However, X represents formula (3), and when indicating a C 1-6 alkylene group Q 3 has an oxo group, Q 1 represents a C 1-6 alkylene group or C 2-6 alkenylene group, wherein C 1-6 alkylene group or C 2-6 alkenylene group for Q 1 represents 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 and C 6-10 aryl C 1-3 substituent selected from alkyl groups may have 1 to 2,
R 1 is a single bond, an oxygen atom or an NH group, wherein the NH group, C 1-6 alkyl, hydroxy C 1-6 alkyl group, 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 one another, a hydrogen atom, C 1-6 alkyl group or a C 1-6 alkyl group, and q, combinations of m and n (q, m, n ) = (0,1,0), at (0,0,1), (0,1,1), (1,1,0), (1,0,1) or (1,1,1) is there]
In the compound represented, or a salt or solvate thereof.

[2]
X represents formula (2),
Wherein the ring B is an aromatic carbocyclic ring, saturated aliphatic carbon ring, or show the nitrogen-containing aromatic heterocyclic ring, wherein said ring B is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1- 6 alkyl group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl substitutions, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, and a di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group group may have one to three,
A compound according to [1], or a salt or solvate thereof.

[3]
X represents formula (2),
Wherein the ring A is a pyrrolidine ring, piperidine ring represents piperazine ring or a tetrahydropyridine ring,
Ring B is a benzene ring, a cyclohexane ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, an oxadiazole ring or It shows a thiadiazole ring,
Wherein said each of ring A and ring B, halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, a substituent selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group which may have 1 to 3,
Compounds according to the above [2], or a salt or solvate thereof.

[4]
X represents formula (3),
Wherein the ring C is a nitrogen-containing aliphatic heterocyclic saturated, or show the nitrogen-containing aromatic heterocyclic ring, wherein said Ring C is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyloxy group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, a substituent selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group 1 It may have three to,
Q 3 are a single bond or a C 2-6 alkenylene group, wherein the C 2-6 alkenylene group, 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,
A compound according to [1], or a salt or solvate thereof.

[5]
Q 1 is, represents a single bond or a C 1-6 alkylene group, wherein said C 1-6 alkylene group, 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,
Compound, or a salt or solvate thereof, according to any one of the above [1] to [4].

[6]
Ring Y is an aromatic carbocyclic ring, a nitrogen-containing aliphatic heterocyclic saturated, or show the nitrogen-containing aromatic heterocyclic ring, wherein said ring Y is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1- 6 alkyl group, 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, a carbamoyl group, an amido group, a 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 alkylamino C 1-6 alkyl group, and formula ( a substituent selected from the group of 4) may have 1 to 3,
Compound, or a salt or solvate thereof, according to any one of the above [1] to [5].

[7]
Ring Y is a benzene ring, piperidine ring, pyrrolidine ring, piperazine ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring represents oxadiazole ring or a thiadiazole ring, wherein said ring Y is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl groups, C 1-3 alkylcarbamoyl C 1-5 alkyl groups, 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),
Compounds according to the above [6], or a salt or solvate thereof.

[8]
Having a substituent ring Y is represented by the formula (4),
Wherein the ring D is an aliphatic saturated carbocyclic ring, aromatic carbocyclic, or show the nitrogen-containing aliphatic heterocyclic saturated, said ring D in this case, a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyloxy group, 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, a carbamoyl group, an amido group, a carbamoyl C 1 selected from -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 the substituent may have one to three,
Q 4 are, represents a single bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group wherein 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, C 1-6 alkyl, hydroxy C 1-6 alkyl group, C 1-3 alkyloxy C 1-6 alkyl group, C 1- 3 alkylsulfonyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups may have,
Compound, or a salt or solvate thereof, according to any one of the above [1] to [7].

[9]
Said ring D is cyclohexane ring, benzene ring, pyrrolidine ring, indicates piperidine ring or piperazine ring, wherein said ring D is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyloxy groups, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group, C 1- 3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, one to three substituents selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group it may have,
The compound according to above [8], or a salt or solvate thereof.

[10]
q, combinations of m and n (q, m, n) = (0,1,0), a (0,0,1), or (1,1,1), the [1] to [9 compound, or a salt or solvate thereof, as claimed in any one of.

[11]
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-benzyl-4-yl) amino] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (Example 2),
N-{3 - [(1-benzyl-piperidin-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-methyl-piperidin-4-yl) amino] acetamide (Example 5),
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) oxy] acetamide (Example 6),
N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-carboxamide (example 7),
N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (1-methyl-piperidin-4-yl) phenyl] thiophene-2-carboxamide (Example 8) ,
N- {5- [4- (4- methylpiperazin-l-yl) cyclohexyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-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 (exemplary 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-methyl-piperidin-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-methyl-piperidin-4-yl) oxy] phenyl} thiophen-2-yl) acetamide (Example 17 ),
2- [4- (dimethylamino) piperidin-1-yl]-N-{5-r4- (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-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide (exemplary example 19),
(S) -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide (exemplary example 20),
2 - [(5-hydroxypentyl) (1-methyl-piperidin-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-oxo-hexyl] piperazin-1-yl} phenyl) thiophene-2-carboxamide (example 23),
Benzyl 6- {4- [4- (5 - {[3 - ([1,4'-bipiperidin] -1'-yl) propyl] carbamoyl} thiophene-2-yl) phenyl] piperazin-1-yl} hexanoate (example 24),
1'-methyl -N- {5- [4- (-4- 1- methyl-piperidin yl) phenyl] thiophen-2-yl} - [1,4'-bipiperidine] -4-carboxamide (Example 25),
N- methyl-6- {4- [4- (5- {2 - [(1-methyl-piperidin-4-yl) amino] acetamide} 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-methyl-piperidin-4-yl) amino] acetamide (example 27),
2 - [(3-hydroxypropyl) (1-methyl-piperidin-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] acetamide} thiophen-2-yl) phenyl] acetamide (embodiment example 29),
N-(5-{1- [3- (dimethylamino) propyl]-1H-indol-5-yl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide ( example 30),
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] -3-phenyl propanamide (embodiment 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) methyl sulfonamide] acetamide (Example 33),
4-methyl-N-{5-[4- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 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- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 4-yl) amino] butanamide (example 36),
N-{5-[2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide ( example 37),
N-{5-[3- cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (Example 38),
2- (4-methylpiperazin-l-yl) -5- (5- {2 - [(1-methyl-piperidin-4-yl) amino] acetamide} 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- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} propanamide (example 41),
Benzyl 2- [4- (4- {5- [3 - ([1,4'-bipiperidin] -1'-yl) propanamide] thiophen-2-yl} phenyl) -5,6-dihydropyridine-l ( 2H) - yl] acetate (example 42),
3 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- isopropyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} propanamide (example 43),
2 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} acetamide (example 44),
4 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} butanamide (example 45),
5 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} pentanamide (example 46),
6 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} hexanamide (example 47),
N-{5-[2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (Example 48),
N- (5- {4- [2- (4- methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (embodiment example 49),
N- (5- {4- [4- (4- methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (embodiment example 50),
N- [5- (4 - {[5- (4- methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-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 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-methyl-piperidin-4-yl) amino] acetamide (embodiment 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 (embodiment 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] thiophene-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-l-yl) pyridin-3-yl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (Example 63)
At least one compound selected from the group consisting of The compound according to [1], or a salt or solvate thereof.

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

[13]
The above [1] to any one compound or a salt thereof, or active ingredient solvate thereof according to [11], autoimmune diseases, inflammation, allergy, asthma, graft rejection, graft versus prevention and / or therapeutic agent for cardiomyopathy resulting from host disease or sepsis.

[14]
Autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, a Behcet's syndrome or vasculitis, prophylactic and / or therapeutic agent according to [13] .

Further, the present invention is selected from the group consisting of [1] to [11] the compound according to any one of, or a salt thereof or a solvate thereof as an active ingredient TLR3, TLR7 and TLR9, prevention and / or related therapeutic agents for diseases caused by the activation of at least one signal. More particularly, the present invention is the above-mentioned [1] A compound according to any one of to [11], or rheumatoid arthritis (RA), systemic lupus to a salt thereof, or a solvate thereof as an active ingredient lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS), autoimmune diseases such as inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, relates to the prevention and / or therapeutic agent for cardiomyopathy due graft versus host disease (GvHD) or sepsis.

Further, the present invention is, TLR3, TLR7 and at least one disease caused by activation of a signal selected from the group consisting of TLR9, for example, 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 for the manufacture of an agent for preventing and / or treating cardiomyopathy due sepsis, the above-mentioned [1] to a compound according to any one of [11], or the use of a salt, or a solvate thereof .

Further, the present invention is characterized by administering the above-mentioned [1] to a compound according to any one of [11], or a salt thereof, or an effective amount of a solvate thereof to the patient, TLR3, diseases caused by the activation of at least one signal selected from the group consisting of TLR7 and TLR9, for example, 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, prevention of cardiomyopathy due graft versus host disease (GvHD) or sepsis and / or methods of treatment.

Further, the present invention provides a compound according to any one of the above [1] to [11] for use as a medicament, or a salt thereof, or to their solvates.

Further, the present invention is, TLR3, TLR7 and at least one disease caused by activation of a signal selected from the group consisting of TLR9, for example, 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 for use in the prevention and / or treatment of cardiomyopathy such as septic, the above-mentioned [1] to a compound according to any one of [11], or a salt thereof, or to their solvates.

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

Is a diagram showing the time course of arthritic score with the compound of Example 5. ** in the figure, in comparison with the Steel of multiple comparison tests the control group, indicating that the risk rate is less than 1% (p <0.01). Is a diagram showing the anti-type II collagen IgG antibody titer in the additional sensitization 15 days with compound of Example 5. * And ** in the figure, in comparison with the Steel of multiple comparison tests the control group, less than 5% risk rate, respectively (p <0.05) and less than 1% (p <0.01) indicating that.

Hereinafter, the present invention will be described in detail. Definition of the term in the present invention is as follows.

As used herein, the term "saturated aliphatic carbon ring", no multiple bonds between adjacent ring carbon atoms, an aliphatic carbocyclic 4-7 membered. The "saturated aliphatic carbon ring", for example, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane and the like.

As used herein, the term "aliphatic carbocyclic unsaturated", having one or more multiple bonds between adjacent ring member atoms, an aliphatic carbocyclic 4-7 membered. The "unsaturated aliphatic carbon ring", for example, cyclobutene ring, cyclopentene ring, cyclohexene ring, 1,3-cyclohexadiene ring, 1,4-cyclohexadiene ring, 1,3-cycloheptadiene ring, 1, 4 cycloheptadiene ring, and the like.

As used herein, the term "nitrogen-containing aliphatic heterocyclic saturated", no multiple bonds between adjacent ring member atoms, containing one or more nitrogen atoms as ring atoms, the remaining ring member atom is a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, an aliphatic heterocyclic ring of 4 to 7 members. As the "nitrogen-containing aliphatic heterocyclic saturated", for example, azetidine ring, pyrrolidine ring, piperidine ring, azepane ring, piperazine ring and the like.

As used herein, the term "unsaturated nitrogen-containing aliphatic heterocyclic ring", have one or more multiple bonds between adjacent ring member atoms, containing one or more nitrogen atoms as ring atoms and shows the remaining ring atoms are carbon atoms, nitrogen atom, oxygen atom, or a sulfur atom, an aliphatic heterocyclic ring of 4 to 7 members. As the "nitrogen-containing aliphatic heterocyclic unsaturated", for example, Azechin ring, pyrroline ring, tetrahydropyridine ring, dihydropyridine ring, tetrahydropyrazine ring, dihydro pyrazine ring, tetrahydroazepine ring, oxazine ring, and thiazine rings and the like .

As used herein, the term "aromatic carbocyclic ring", the ring member atoms are all carbon atoms, it is meant an aromatic carbocyclic 6-10 membered. As the "aromatic carbocyclic ring", for example, a benzene ring, an azulene ring, a naphthalene ring and the like.

As used herein, a "nitrogen-containing aromatic heterocycle", contain one or more nitrogen atoms as ring atoms, the remaining ring members are hetero atoms other than nitrogen atom (oxygen or sulfur atom) or a carbon atom, an aromatic heterocyclic 5-9 membered. As the "nitrogen-containing aromatic heterocycle", for example, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, Okisaji azole ring, a thiadiazole ring, an indole ring, and the like.

As used herein, the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.

As used herein, "C 1-6 alkyl group" means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. As the "C 1-6 alkyl group", for example, a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, tert- butyl group, n- pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n- hexyl group.

As used herein, "C 1-6 alkyl group" means a straight or saturated hydrocarbon group having 1 to 6 carbon atoms branched chain is bonded to an oxygen atom radical. As the "C 1-6 alkyl group", for example, a methoxy group, an ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, tert- butoxy group, n- pentyloxy group, 2- methylbutoxy group, 2,2-dimethyl-propoxy group, n- hexyloxy group, and the like.

As used herein, the term "carboxy C 1-5 alkyl group", a carboxy group at the terminal means a saturated hydrocarbon group having 1 to 5 carbon atoms, straight-chain substituted. The "carboxy C 1-5 alkyl group", for example, carboxymethyl group, carboxyethyl group, carboxypropyl group, carboxybutyl group, carboxymethyl pentyl group.

As used herein, "benzyloxycarbonyl C 1-5 alkyl group", benzyloxycarbonyl group means a saturated hydrocarbon group having 1 to 5 carbon atoms, straight-chain substituted. The "benzyloxycarbonyl C 1-5 alkyl group", for example, benzyloxycarbonyl methyl group, benzyloxycarbonyl ethyl, benzyloxycarbonyl propyl group, benzyloxycarbonyl butyl group, and a benzyloxycarbonyl pentyl group.

As used herein, "carbamoyl C 1-5 alkyl group", a carbamoyl group at the terminal means a saturated hydrocarbon group having 1 to 5 carbon atoms, straight-chain substituted. As the "carbamoyl C 1-5 alkyl group", for example, carbamoylmethyl group, carbamoylethyl group, carbamoyl propyl group, carbamoyl butyl group, etc. carbamoyl pentyl group.

As used herein, "C 1-3 alkylcarbamoyl C 1-5 alkyl group", C 1-3 alkyl group at the terminal means the carbamoyl C 1-5 alkyl group substituted. As the "C 1-3 alkylcarbamoyl C 1-5 alkyl group", for example, 1-methyl-amino-1-oxoethane-2-yl group, 1-methyl-amino-1-oxo-propane-3-yl group, 1- methylamino-1-oxobutanoic 4-yl group, 1-methyl-amino-1-oxo-pentane-5-yl group, 1-methyl-amino-1-oxo-hexane-6-yl group, 1-ethyl-amino-1-oxoethane 2-yl group, 1-ethyl-amino-1-oxo-propane-3-yl group, 1-ethyl-amino-1-oxobutanoate 4-yl group, 1-ethyl-amino-1-oxo-pentane-5-yl group, 1-ethyl-amino-1-oxo-hexane-6-yl group, 1-oxo -1-n-propylamino-ethane-2-yl group, 1-oxo -1-n-propylamino-propane-3-b Group, 1-oxo -1-n-propylamino-butan-4-yl group, 1-oxo -1-n-propylamino-pentane-5-yl group, 1-oxo -1-n-propylamino-hexane-6 yl group.

As used herein, "C 1-6 alkylamino group" means a straight or branched-chain amino group is a saturated hydrocarbon group having 1 to 6 carbon atoms and 1 substitution. As the "C 1-6 alkylamino group", for example, methylamino group, ethylamino group, n- propylamino group, isopropylamino group, n- butylamino group, isobutylamino group, tert- butylamino group, n- pentylamino group, 2-methyl butyl group, 2,2-dimethylpropyl group, etc. n- hexylamino group.

As used herein, the term "di-C 1-6 alkylamino group", straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms are the same or different, a 2-substituted amino groups means. Examples of the "di-C 1-6 alkylamino group", for example, (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- butylamino group, di -tert- butyl amino group, di -n- pentylamino group, di -n- hexylamino group and the like.

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 It means. Examples of the "di-C 1-6 alkylamino C 1-6 alkyl group", for example, (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 - isopropyl aminomethyl group, di -n- butyl aminomethyl group, di -t- butyl aminomethyl group, di -n- pentyl aminomethyl group, di -n- hexyl aminomethyl group, (ethyl) ( methyl) aminoethyl group, (isopropyl) (n-propyl) aminoethyl group, (n- butyl) (isobutyl) Aminoe Le group, (tert-butyl) (n-pentyl) amino-ethyl group, (2,2-dimethylpropyl) (2-methylbutyl) amino ethyl group, dimethylaminoethyl group, diethylaminoethyl group, di -n- propyl aminoethyl group, di - isopropyl aminoethyl group, di -n- butyl aminoethyl group, di -tert- butyl aminoethyl group, di -n- pentyl-aminoethyl group, di -n- hexyl aminoethyl group and the like.

As used herein, the term "C 1-6 alkylene group" means a divalent linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms saturated. As the "C 1-6 alkylene group" include a methylene group, an ethylene group, n- propylene, isopropylene, n- butylene group, isobutylene group, tert- butylene, n- pentylene group, 2-methyl-butylene group, 2,2-dimethylpropylene group, n- hexylene.

As used herein, "C 2-6 alkenylene group" means a double bond containing one, divalent straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms, . The "C 2-6 alkenylene group", for example, vinylene group, propenylene group, butenylene group, 2-butenylene group, 1-pentenylene, 2-pentenylene group, 1-hexenylene, 2-hexenylene, 3 - hexenylene group and the like.

As used herein, the term "hydroxy C 1-6 alkyl group", a hydroxyl group at the terminal means a straight-chain or branched-chain C 1-6 alkyl group substituted. The "hydroxy C 1-6 alkyl group", for example, hydroxymethyl group, hydroxyethyl group, hydroxypropyl -n- propyl, hydroxy isopropyl group, hydroxy -n- butyl group, hydroxy isobutyl group, hydroxy -tert- butyl , hydroxy -n- pentyl group, hydroxy-2-methylbutyl group, hydroxy-2,2-dimethylpropyl group, hydroxy -n- hexyl.

As used herein, the term "C 1-3 alkyloxy C 1-6 alkyl group", a C 1-3 alkyl group straight or branched chain hydroxy group of the hydroxy C 1-6 alkyl group is substituted It refers to the group. As the "C 1-3 alkyloxy C 1-6 alkyl group", for example, methoxymethyl group, methoxyethyl group, a methoxy -n- propyl group, a methoxy isopropyl group, a methoxy -n- butyl group, methoxy isobutyl group, methoxy -tert- butyl group, a methoxy -n- pentyl group, a methoxy-2-methylbutyl group, a methoxy-2,2-dimethylpropyl group, a methoxy -n- hexyl group, ethoxymethyl group, ethoxyethyl group, ethoxy -n- propyl group, ethoxy isopropyl group, an ethoxy -n- butyl group, an ethoxy isobutyl group, an ethoxy -tert- butyl group, an ethoxy -n- pentyl group, an ethoxy-2-methylbutyl group, ethoxy-2,2-dimethylpropyl group, ethoxy - n- hexyl, n- propoxymethyl, n- propoxy Butyl group, n- propoxy -n- propyl, n- propoxy isopropyl, n- propoxy -n- butyl group, n- propoxy isobutyl group, n- propoxy -tert- butyl group, n- propoxy -n- pentyl , n- propoxy-2-methylbutyl group, n- propoxy-2,2-dimethylpropyl group, etc. n- propoxy -n- hexyl group.

As used herein, the term "C 1-3 alkylsulfonyl group" means a straight or sulfonyl group C 1-3 alkyl group branched chain is substituted. As the "C 1-3 alkylsulfonyl group", for example, methylsulfonyl group, ethylsulfonyl group, n- propyl sulfonyl group, such as isopropylsulfonyl group.

As used herein, a "C 6-10 aryl C 1-3 alkyl group", means a C 1-3 alkyl group which 6-10 membered straight or branched chain aromatic carbon ring is substituted in to. As the "C 6-10 aryl C 1-3 alkyl group", for example, benzyl group, phenethyl group, 1-phenyl -n--1-yl group, 2-phenyl -n--1-yl group, 3-phenyl -n--1-yl group, 1-phenyl - isopropane-2-yl group, 2-phenyl - isopropane-2-yl group, azulene methyl group, 1-azulene-1-yl group , 2-azulene-1-yl group, 1-azulene -n--1-yl group, 2-azulene -n--1-yl group, 3-azulene -n--1-yl group, 1-azulene - isopropane-2-yl group, 2-azulene - isopropane-2-yl group, naphthalen-1-yl - methyl group, 1-naphthalen-1-yl - ethane-1-yl group, 2- naphthalene-1 Le - ethane-1-yl group, 1-naphthalen-1-yl -n--1-yl group, 2-naphthalen-1-yl -n--1-yl group, 3-naphthalen-1-yl -n--1-yl group, 1-naphthalen-1-yl - isopropane-2-yl group, 2-naphthalen-1-yl - isopropane-2-yl group.

Formula (1), (2), (3), (4), examples of the nitrogen-containing aliphatic heterocyclic saturated, piperidine ring, piperazine ring, a pyrrolidine ring.

Formula (1), (2), (3), (4), examples of the nitrogen-containing aliphatic heterocyclic unsaturated, 1,2,3,6-tetrahydropyridine ring.

Formula (1), (2), in (4), the aromatic carbon ring, a benzene ring is preferred.

Formula (1), (2), (3), (4), examples of the nitrogen-containing aromatic heterocyclic ring, pyridine ring, indole ring, a pyrazole ring.

In the general formula (1), (2), (3), (4), the halogen atom, a bromine atom.

In the general formula (1), (2), (3), (4), as the C 1-6 alkyl group, a methyl group, an isopropyl group, an isobutyl group are preferable.

Formula (1), (2), (3), as (4) in, C 1-6 alkyloxy group, a methoxy group is preferred.

Formula (1), (2), (3), in (4), the carboxy C 1-5 alkyl group, carboxybutyl group.

Formula (1), (2), (3), in (4), as a benzyloxycarbonyl C 1-5 alkyl group, benzyloxycarbonylmethyl group, benzyloxycarbonyl pentyl group.

Formula (1), (2), (3), (4), examples of the carbamoyl C 1-5 alkyl group, carbamoyl-pentyl group are preferred.

Formula (1), (2), (3), in (4), as the C 1-3 alkylcarbamoyl C 1-5 alkyl group, 1-methyl-amino-1-oxo-hexane-6-yl group is preferred .

In the general formula (1), (2), (3), (4), as the C 1-6 alkylamino group, methylamino group is preferable.

Formula (1) and (2), (3), (4), as the di-C 1-6 alkylamino group, a dimethylamino group are preferred.

Formula (1) and (2), (3), (4), as the C 1-6 alkylene group, a methylene group, an ethylene group, a propylene group, butylene group, pentylene group.

Formula (1), (2), (3), in (4), as the hydroxy C 1-6 alkyl group, a hydroxy -n- propyl, hydroxy -n- pentyl group are preferred.

Formula (1), (2), (3), (4), as C 1-3 alkyloxy C 1-6 alkyl group, a methoxyethyl group is preferred.

Formula (1), as the (2), (4), C 1-3 alkylsulfonyl group, preferably methylsulfonyl group.

Formula (1) and (2), (3), (4), as the C 6-10 aryl C 1-3 alkyl group, a benzyl group is preferred.

In the general formula (2), the ring A, pyrrolidine ring, piperidine ring, piperazine ring, tetrahydropyridine ring are preferred, piperidine ring, piperazine ring, tetrahydropyridine ring is more preferable.

In the general formula (2), The substituent that may be possessed by the ring A, C 1-6 alkyl, C 1-3 alkylcarbamoyl C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group preferably, a methyl group, an isopropyl group, 1-methyl-amino-1-oxo-pentane-5-yl group, benzyloxycarbonylmethyl group, benzyloxycarbonyl pentyl group is more preferable.

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

In the general formula (2), The substituent that may be possessed by the ring B, a hydroxyl group, C 1-6 alkyloxy group, a cyano group and carbamoyl group. Examples of the C 1-6 alkyl group, a methoxy group is more preferable.

In the general formula (2), the Q 2, a single bond, C 1-6 alkylene group, more preferably a single bond, a methylene group, an ethylene group, n- propylene, n- butylene, more preferably n- pentylene .

In the general formula (2), as the substituent which may be possessed by Q 2, oxo group are preferred.

In the general formula (2), the substitution position of the of the R 4 ring B is not particularly limited as long as substitutions are possible, for example, when ring B is a 6-membered ring, a thiophene ring is a nucleus to ring B preferably of a 3- or 4-position counted from the coupling position, for example when ring B is a 5-membered ring, it is 3, calculated from the point of attachment to ring B of the thiophene ring is the mother nucleus preferable.

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

In the general formula (3), the substituent that may have ring C is, C 1-6 alkyl group and a di-C 1-6 alkylamino C 1-6 alkyl group is preferable, a methyl group, dimethylaminopropyl group It is more preferable.

In the general formula (3), as the Q 3, a single bond or a C 2-6 alkenylene group, more preferably a propenylene group herein as C 2-6 alkenylene group.

In the general formula (3), as the substituent which may be possessed by Q 3, oxo group are preferred.

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

In the general formula (1), The substituent that may be possessed by the ring Y, C 1-6 alkyl, di-C 1-6 alkylamino group, di C 1-6 alkylamino C 1-6 alkyl group, and preferably a group of formula (4), a methyl group, dimethylamino group, group of dimethylaminomethyl group and formula (4) is more preferable.

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

In the general formula (4), the ring D, aromatic carbocyclic, aliphatic saturated carbocyclic ring, preferably a nitrogen-containing aliphatic heterocyclic ring saturated, benzene ring, cyclohexane ring, pyrrolidine ring, piperazine ring, piperidine ring more preferably, a benzene ring, a cyclohexane ring, piperazine ring, piperidine ring is more preferred.

In the general formula (4), The substituent that may be possessed by the ring D, C 1-6 alkyl, di-C 1-6 alkylamino group, di C 1-6 alkylamino C 1-6 alkyl group preferably, a methyl group, a dimethylamino group, a dimethylaminomethyl group is more preferable.

In the general formula (4), as the Q 4, a single bond, C 1-6 alkylene group, more preferably a single bond, a methylene group is more preferable.

In the general formula (4), the R 5, a single bond, NH group.

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

In the general formula (1), examples of the substituent groups of Q 1, C 1-6 alkyl, C 1-3 alkyloxy C 1-6 alkyl group, C 6-10 aryl C 1-3 alkyl group are preferred, isobutyl, methoxyethyl group, a benzyl group is more preferable.

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

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

More preferred compounds 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-benzyl-4-yl) amino] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (Example 2),
N-{3 - [(1-benzyl-piperidin-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-methyl-piperidin-4-yl) amino] acetamide (Example 5),
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) oxy] acetamide (Example 6),
N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-carboxamide (example 7),
N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (1-methyl-piperidin-4-yl) phenyl] thiophene-2-carboxamide (Example 8) ,
N- {5- [4- (4- methylpiperazin-l-yl) cyclohexyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-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 (exemplary 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-methyl-piperidin-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-methyl-piperidin-4-yl) oxy] phenyl} thiophen-2-yl) acetamide (Example 17 ),
2- [4- (dimethylamino) piperidin-1-yl]-N-{5-r4- (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-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide (exemplary example 19),
(S) -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide (exemplary example 20),
2 - [(5-hydroxypentyl) (1-methyl-piperidin-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-oxo-hexyl] piperazin-1-yl} phenyl) thiophene-2-carboxamide (example 23),
Benzyl 6- {4- [4- (5 - {[3 - ([1,4'-bipiperidin] -1'-yl) propyl] carbamoyl} thiophene-2-yl) phenyl] piperazin-1-yl} hexanoate (example 24),
1'-methyl -N- {5- [4- (-4- 1- methyl-piperidin yl) phenyl] thiophen-2-yl} - [1,4'-bipiperidine] -4-carboxamide (Example 25),
N- methyl-6- {4- [4- (5- {2 - [(1-methyl-piperidin-4-yl) amino] acetamide} 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-methyl-piperidin-4-yl) amino] acetamide (example 27),
2 - [(3-hydroxypropyl) (1-methyl-piperidin-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] acetamide} thiophen-2-yl) phenyl] acetamide (embodiment example 29),
N-(5-{1- [3- (dimethylamino) propyl]-1H-indol-5-yl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide ( example 30),
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] -3-phenyl propanamide (embodiment 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) methyl sulfonamide] acetamide (Example 33),
4-methyl-N-{5-[4- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 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- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 4-yl) amino] butanamide (example 36),
N-{5-[2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide ( example 37),
N-{5-[3- cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (Example 38),
2- (4-methylpiperazin-l-yl) -5- (5- {2 - [(1-methyl-piperidin-4-yl) amino] acetamide} 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- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} propanamide (example 41),
Benzyl 2- [4- (4- {5- [3 - ([1,4'-bipiperidin] -1'-yl) propanamide] thiophen-2-yl} phenyl) -5,6-dihydropyridine-l ( 2H) - yl] acetate (example 42),
3 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- isopropyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} propanamide (example 43),
2 - ([1,4'- Bipiperijin] -1'-yl) -N- {5- [4- (-4- 1- methyl -1,2,3,6- Tetora Hidoro pyridin yl) phenyl] Chiofen - 2-yl} acetamide (example 44),
4 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} butanamide (example 45),
5 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} pentanamide (example 46),
6 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} hexanamide (example 47),
N-{5-[2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (Example 48),
N- (5- {4- [2- (4- methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (embodiment example 49),
N- (5- {4- [4- (4- methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (embodiment example 50),
N- [5- (4 - {[5- (4- methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-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 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-methyl-piperidin-4-yl) amino] acetamide (embodiment 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 (embodiment 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] thiophene-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-l-yl) pyridin-3-yl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (Example 63),
Mention may be made of a compound selected from the group consisting of.

Generally thiophene derivative represented by formula (1), or a salt or solvate thereof of the present invention not only the thiophene derivative of the present invention, a pharmaceutically acceptable salt thereof, hydration of their various It encompasses substances, and the substances to be prodrugs of these substances with goods and solvates, and crystalline polymorphs.

The acceptable salts thiophene derivatives represented by the general formula (1) of the present invention, specifically, an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid etc.) or organic acids (e.g., methanesulfonic acid, ethanesulfonic acid, acid addition salts with p- toluenesulfonic acid and the like).

Solvates as solvates thiophene derivative or a pharmaceutically acceptable salt thereof represented by the general formula (1), hydrates and various solvates (e.g., an alcohol such as ethanol in the present invention etc.) and the like.

Thiophene derivative represented by the general formula (1) of the present invention can be prepared by known methods. Shows a method for producing a thiophene derivative in the following reaction scheme, the preparation is not limited thereto.

In the general formula (1), when indicating the m = 1, n = 0, q = 0, the present invention compound (I) can be prepared from 2-nitro-thiophene derivative (II).

Figure JPOXMLDOC01-appb-C000009

[In the formula,
R 1, R 2, R 3 , X, Q 1, ring Y have the same meanings as defined above, A 1 represents a leaving group, R 6 and R 7 is a hydrogen atom or C 1-6 alkyl refers to the group, R 6 and R 7 together may form a ring, R 8 represents a halogen atom]

The coupling reaction of [Step 1] thiophene derivative having a leaving group (II) borane compound (III) is Suzuki - can be produced thiophene derivative (IV) using Miyaura coupling reaction. Metal catalyst used, bases and reaction conditions, usually, Suzuki - Miyaura is not particularly limited as long as the reagents and conditions used in the coupling reaction, for example, N. Miyaura, A. Suzuki, Chem. Rev. 1995,95,2457-2483, it is possible to use a method described in (1995) and the like. It is not particularly limited as metal catalyst used, for example, palladium (II), palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri -tert- butylphosphine) palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) dichloride, a palladium complex such as tetrakis (triphenylphosphine) palladium (0), preferably, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium ( 0). Is not particularly limited as bases, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert- butoxy sodium, tert- butoxy potassium or the like, preferably sodium carbonate, cesium carbonate. There are no particular restrictions on the solvent, such as tetrahydrofuran, 1,4-dioxane, ethers such as ethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene; N, N- dimethylformamide, N- methylpyrrolidone amides such as s; dimethyl sulfoxide, water and the like alone or in combination may be used. Preferably is tetrahydrofuran, ethylene glycol dimethyl ether, N, N- dimethylformamide, water, and mixed solvents thereof. The reaction temperature is, 0 ℃ ~ 200 ℃, preferably from 60 ℃ ~ 150 ℃. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 20 hours. Borane compound used in the above reaction (III) is either accept what commercial available, or can be appropriately prepared by a known method, but is not limited thereto.

Also, by the coupling reaction of a thiophene derivative having a leaving group and (II) a halogen compound (III '), it can be produced thiophene derivative (IV). There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane; ethyl acetate, ester solvents such as isopropyl acetate: toluene, aromatic hydrocarbons such as benzene and the like; ethers such as tetrahydrofuran and 1,4-dioxane; acetonitrile, nitriles such as propionitrile; N, N- dimethylformamide, N- amides such as methylpyrrolidone; can be used water, etc. alone or in combination . It is not particularly limited as metal catalyst used, for example, palladium (II), palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri -tert- butylphosphine) palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) dichloride, a palladium complex such as tetrakis (triphenylphosphine) palladium (0), preferably, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium ( 0). If necessary, o- preparative Little yl phosphine, triphenylphosphine, 1,1'-bis may be added (diphenylphosphino) ferrocene, tri -tert- butylphosphine, ligands such. If necessary, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine may be added an organic base trimethylamine. The reaction temperature is, -20 ℃ ~ 150 ℃, preferably 20 ℃ ~ 120 ℃. The reaction time is 5 minutes to 2 days, preferably 1 hour to 20 hours.

The nitro group of [Step 2] thiophene derivative (IV), the presence of a reducing agent, is reacted in a solvent, it is possible to produce the aminothiophene derivative (V). The reduction method, (a) in a suitable inert solvent, under hydrogen atmosphere, or a contact hydrogenation reduction of the nitro group using catalytic hydrogen reduction catalyst, or (b) a suitable inert solvent, metal or metal salt and an acid or a metal or metal salt and an alkali metal hydroxide is carried out by metal reduction reduction of the nitro group using mixtures of sulfides or ammonium salts such as the reducing agent. (A) if the contact hydrogenation, as the solvent, for example, water; organic acid solvent such as acetic acid; methanol, ethanol, alcohol solvents such as isopropanol; n-hexane, hydrocarbon solvents such as cyclohexane; 1,4 - dioxane, tetrahydrofuran, diethyl ether, ether solvents such as diethylene glycol dimethyl ether, ethyl acetate, ester solvents such as methyl acetate; N, N-aprotic polar solvent such as dimethylformamide or the like, or a mixed solvent thereof and the like can be used . The catalytic hydrogen reduction catalyst, e.g., palladium, palladium - black, palladium - carbon, platinum - carbon, platinum, platinum oxide, copper chromite, can be used Raney nickel alone or in combination. The reaction temperature is, -20 ℃ ~ 150 ℃, preferably from 0 ℃ ~ 100 ℃. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours. For (b) metal reduction, iron, mixtures of iron sulphate, lead, tin, tin chloride and hydrochloric acid, a mixture of inorganic acids such as sulfuric acid, iron or zinc and organic acids such as acetic acid, or iron, ferrous sulfate, zinc or tin with an alkali metal hydroxide such as sodium hydroxide, a sulfide such as ammonium sulfide, a mixture of aqueous ammonia or ammonium salts such as ammonium chloride is used as the reducing agent. As the solvent, for example, water; an alcohol solvent such as methanol or ethanol; organic acids solvent such as acetic acid tetrahydrofuran, ether solvents such as 1,4-dioxane. The reaction temperature is, for example, when using zinc and acetic acid as the reducing agent, 0 ° C. ~ 0.99 ° C., preferably from 50 ℃ ~ 120 ℃. The reaction time is 1 minute to 12 hours, preferably 1 minute to 6 hours.

Dehydration condensation reaction of [Step 3] the aminothiophene derivative (V) with a carboxylic acid derivative (VI) in the presence or absence of a base in a solvent, using a condensing agent in the presence or absence of a condensation accelerator or performed, or a carboxylic acid can be carried out condensation After the active intermediate. There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane; ethyl acetate, ester solvents such as isopropyl acetate: toluene, aromatic hydrocarbons such as benzene and the like; ethers such as tetrahydrofuran and 1,4-dioxane; acetonitrile, nitriles such as propionitrile; N, N- dimethylformamide, N- amides such as methylpyrrolidone; can be used water, etc. alone or in combination . There are no particular restrictions on the base, for example, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine,-diisopropylpentylamine, lithium hydride, sodium hydride and the like trimethylamine, hydrogenated alkali metal hydrides such as potassium, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, it can be used alkali metal bicarbonate such as potassium bicarbonate. There are no particular limitations on the condensation accelerator may be used DMAP, HOAt, HOBt, HODhbt, HONB, HOPfp, HOPht, the HOSu and the like. There are no particular limitations on the condensing agent, it may be used DCC, DIPCI, WSCI, WSC · HCl, DEPC, BOP, PyBOP, TBTU and the like. No particular restriction on the active intermediate, but can be used acid halides, mixed acid anhydride with pivalic acid, or p- nitrophenyl ester or the like. The reaction temperature is, -20 ℃ ~ 100 ℃, preferably 0 ℃ ~ 40 ℃. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

Further, reaction of the aminothiophene derivative (V) with an acid halide derivative (VI '), the presence or absence of a base in a solvent, can be performed. There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane; ethyl acetate, ester solvents such as isopropyl acetate: toluene, aromatic hydrocarbons such as benzene and the like; ethers such as tetrahydrofuran and 1,4-dioxane; acetonitrile, nitriles such as propionitrile; N, N- dimethylformamide, N- amides such as methylpyrrolidone; can be used water, etc. alone or in combination . There are no particular restrictions on the base, for example, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine,-diisopropylpentylamine, lithium hydride, sodium hydride and the like trimethylamine, hydrogenated alkali metal hydrides such as potassium, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, it can be used alkali metal bicarbonate such as potassium bicarbonate. The reaction temperature is, -20 ℃ ~ 100 ℃, preferably 0 ℃ ~ 40 ℃. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In the general formula (1), when indicating the m = 0, n = 1, q = 0, the present invention compound (I) can be prepared from thiophene carbonyl derivative represented by the general formula (VII).

Figure JPOXMLDOC01-appb-C000010

[In the formula,
R 1, R 2, R 3 , X, Q 1, ring Y have the same meanings as defined above, A 1 represents a leaving group, A 2 represents an OH or a leaving group, R 6 and R 7 means a hydrogen atom or a C 1-6 alkyl group may be R 6 and R 7 together form a ring. ]

Thiophene derivative (I) can be prepared by a combination of steps 4 and step 5.
The coupling reaction of condensation derivatives between [Step 4] thiophene derivative having a leaving group (VII) or thiophene derivative (VII) with an amine derivative (VIII), borane compounds (III) and the Suzuki - Miyaura coupling reaction it can be carried out using. Metal catalyst used, bases and reaction conditions, usually, Suzuki - Miyaura is not particularly limited as long as the reagents and conditions used in the coupling reaction, for example, N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, can be used the method described in (1995) and the like. It is not particularly limited as metal catalyst used, for example, palladium (II), palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri -tert- butylphosphine) palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) dichloride, a palladium complex such as tetrakis (triphenylphosphine) palladium (0), preferably, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium ( 0). Is not particularly limited as bases, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert- butoxy sodium, tert- butoxy potassium or the like, preferably sodium carbonate, cesium carbonate. There are no particular restrictions on the solvent, such as tetrahydrofuran, 1,4-dioxane, ethers such as ethylene glycol dimethyl ether; benzene, aromatic hydrocarbons such as toluene; N, N- dimethylformamide, N- methylpyrrolidone amides; dimethyl sulfoxide, water and the like may be used alone or in combination. Preferably is tetrahydrofuran, ethylene glycol dimethyl ether, N, N- dimethylformamide, water, and mixed solvents thereof. The reaction temperature is, 0 ℃ ~ 200 ℃, preferably from 60 ℃ ~ 150 ℃. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 20 hours. Borane compound used in the above reaction (III) is either accept what commercial available, or can be appropriately prepared by a known method, but is not limited thereto.

[Step 5] The reaction of the thiophene derivative (VII) or thiophene derivative (VII) and the coupling derivatives of the borane compounds (III), with an amine derivative (VIII) in the presence or absence of a base in a solvent, condensation or performed by using a condensing agent in the presence or absence of a promoting agent, it is possible to perform the condensation After the carboxylic acid as active intermediate. There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane; an ester such as ethyl acetate or isopropyl acetate: toluene, aromatic hydrocarbons such as benzene; tetrahydrofuran , ethers such as 1,4-dioxane; acetonitrile, nitriles such as propionitrile; N, N- dimethylformamide, amides such as N- methyl pyrrolidone; and the like can be used alone or in combination with water, There are no particular restrictions on the base, for example, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine,-diisopropylpentylamine, lithium hydride, sodium hydride and the like trimethylamine, hydrogenated mosquitoes An alkali metal hydride such as um, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, it can be used alkali metal bicarbonate such as potassium bicarbonate. There are no particular limitations on the condensation accelerator may be used DMAP, HOAt, HOBt, HODhbt, HONB, HOPfp, HOPht, the HOSu and the like. There are no particular limitations on the condensing agent, it may be used DCC, DIPCI, WSCI, WSC · HCl, DEPC, BOP, PyBOP, TBTU and the like. No particular restriction on the active intermediate, but can be used acid halides, mixed acid anhydride with pivalic acid, or p- nitrophenyl ester or the like. The reaction temperature is (the starting material used may vary depending on the reagent,) generally -20 ° C. ~ 100 ° C., preferably from 0 ℃ ~ 40 ℃. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In the general formula (1), when indicating the m = 1, n = 1, q = 0, the compound (I) 2-Amino - it can be prepared from thiophene derivatives (V).

Figure JPOXMLDOC01-appb-C000011

Wherein, R 1, R 2, R 3, X, Q 1, Ring Y, the same meanings as defined above. ]

[Step 6] by urea formation reaction with thiophene derivative having an amine (V) with the amine derivative (VIII), it can be produced thiophene derivative (I). There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane;, an ester such as ethyl acetate or isopropyl acetate: toluene, aromatic hydrocarbons such as benzene; ethers such as tetrahydrofuran and 1,4-dioxane; acetonitrile, nitriles such as propionitrile; N, N- dimethylformamide, N- amides such as methylpyrrolidone; can be used water, etc. alone or in combination . May be added to the base, if necessary, is not particularly limited, but a base, e.g., pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine,-diisopropylpentylamine, and trimethylamine it can be used. There are no particular limitations on the reaction reagent to form a urea, can be used phenyl chloroformate, 4-nitrophenyl chloroformate, carbonyl diimidazole, triphosgene or the like. The reaction temperature is (the starting material used may vary depending on the reagent,) generally -20 ° C. ~ 100 ° C., preferably from 0 ℃ ~ 60 ℃. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

In the general formula (1), when indicating the m = 1, n = 1, q = 1, the present invention compound (I) is 2-amino - can be prepared from thiophene derivatives (V).

Figure JPOXMLDOC01-appb-C000012

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

By dehydration condensation reaction between [Step 7] aminothiophene derivative (V) with a carboxylic acid derivative (IX), it can be produced thiophene derivative (X) having a leaving group. Dehydration condensation reaction can be carried out in the presence or absence of a base in a solvent, or carried out using a condensing agent in the presence or absence of a condensation promoting agent, a condensation After the carboxylic acid as active intermediate . There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane; ethyl acetate, ester solvents such as isopropyl acetate: toluene, aromatic hydrocarbons such as benzene and the like; ethers such as tetrahydrofuran and 1,4-dioxane; acetonitrile, nitriles such as propionitrile; N, N- dimethylformamide, N- amides such as methylpyrrolidone; can be used water, etc. alone or in combination . There are no particular restrictions on the base, for example, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine,-diisopropylpentylamine, lithium hydride, sodium hydride and the like trimethylamine, hydrogenated alkali metal hydrides such as potassium, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, it can be used alkali metal bicarbonate such as potassium bicarbonate. There are no particular limitations on the condensation accelerator may be used DMAP, HOAt, HOBt, HODhbt, HONB, HOPfp, HOPht, the HOSu and the like. There are no particular limitations on the condensing agent, it may be used DCC, DIPCI, WSCI, WSC · HCl, DEPC, BOP, PyBOP, TBTU and the like. No particular restriction on the active intermediate, but can be used acid halides, mixed acid anhydride with pivalic acid, or p- nitrophenyl ester or the like. The reaction temperature is, -20 ℃ ~ 100 ℃, preferably 0 ℃ ~ 40 ℃. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

Further, by reaction of aminothiophene derivative (V) with an acid halide derivative (IX '), it can be produced thiophene derivative (X) having a leaving group. The reaction is carried out in the presence or absence of a base in a solvent, it can be performed. There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane; ethyl acetate, ester solvents such as isopropyl acetate: toluene, aromatic hydrocarbons such as benzene and the like; ethers such as tetrahydrofuran and 1,4-dioxane; acetonitrile, nitriles such as propionitrile; N, N- dimethylformamide, N- amides such as methylpyrrolidone; can be used water, etc. alone or in combination . There are no particular restrictions on the base, for example, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine,-diisopropylpentylamine, lithium hydride, sodium hydride and the like trimethylamine, hydrogenated alkali metal hydrides such as potassium, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, sodium hydrogen carbonate, it can be used alkali metal bicarbonate such as potassium bicarbonate. The reaction temperature is, -20 ℃ ~ 100 ℃, preferably 0 ℃ ~ 40 ℃. The reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.

By reaction of [Step 8] thiophene derivative (X) amine derivative having a leaving group (VIII), can be produced thiophene derivative (I). The reaction may be performed in a solvent in the presence of a base. As the solvent, not particularly limited, but, for example N, N- dimethylformamide, amides such as N- methyl pyrrolidone; dimethyl sulfoxide; 1,4-dioxane, tetrahydrofuran and the like; acetonitrile, nitriles such as propionitrile s can be used alone or in combination. as the base, although not particularly limited, for example, lithium hydride, sodium hydride, alkali metal hydrides such as potassium hydride, metal lithium, metal sodium, metal alkali metals such as potassium, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, lithium diisopropylamide, sodium diisopropylamide amide, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert- butoxy sodium, tert- butoxy potassium, n- butyl lithium, s- butyl lithium, tert- butyl lithium, etc. it can be used. Varies depending on the reaction conditions, the reaction temperature is -10 ° C. ~ 200 ° C., preferably from 0 ℃ ~ 120 ℃. The reaction time is 1 hour to 72 hours, preferably 1 hour to 36 hours.

Incidentally, borane compounds used in the above production method (III), use as it is available, or can be suitably prepared by a known method, but for example can be manufactured by the following method, in which the present invention is not limited.

Figure JPOXMLDOC01-appb-C000013

[Wherein, X have the same meanings as defined above, A 3 represents a leaving group, R 6 and R 7 means a hydrogen atom or a C 1-6 alkyl group, R 6 and R 7 it may form a ring together. ]

With [Step 9] metal catalyst from the compound (XI) is a step for preparing a borane compound (III). It is not particularly limited as metal catalyst used, for example, palladium (II), palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri -tert- butylphosphine) palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) dichloride, a palladium complex such as tetrakis (triphenylphosphine) palladium (0), preferably bis (triphenylphosphine) palladium (II) dichloride. If necessary, o- preparative Little yl phosphine, triphenylphosphine, 1,1'-bis may be added (diphenylphosphino) ferrocene, tri -tert- butylphosphine, ligands such. Examples of the base used, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium acetate, preferably potassium acetate. Is not particularly limited as solvent used, for example, tetrahydrofuran, 1,4-dioxane and the like; aromatic hydrocarbons such as toluene; N, N- dimethylformamide, N- methylpyrrolidinone amides such Don ; dimethyl sulfoxide, water and the like alone or in combination may be used. Preferably a mixed solvent of 1,4-dioxane and water. The reaction temperature is, 0 ℃ ~ 200 ℃, preferably from 80 ℃ ~ 150 ℃. The reaction time is 1 hour to 48 hours, preferably 2 hours to 24 hours.
Incidentally, either a carboxylic acid derivative (VI) is used in the manufacturing method using as it is available, or can be suitably prepared by a known method, but for example can be manufactured by the following method, in which the present invention is not limited.

Figure JPOXMLDOC01-appb-C000014

[In the formula,
R 1, ring D, Q 1, Q 4, R 5, Ring Y have the same meanings as defined above, P is a protecting group, W 1, W 2, W 4, W 6 represents a leaving group, aldehyde group, an amino group or a hydroxyl group, W 3, W 5 and W 7 represents C = O at or NH.However, when W 1, W 4 is a leaving group or aldehyde group, W 2, W 6 represents an amino group or a hydroxyl group, when W 2, W 6 is a leaving group or aldehyde group, W 1, W 4 (Note an amino group or a hydroxyl group, compound (XV) and (XV '), in the carboxylic acid derivative (VI), the case having a substituent ring Y is formed by Q 4, R 5 and ring D shows.)]

[Step 10] The compound (XII), the compound (XIV), or a from (XIV ')) reductive amination or, b) a step for preparing compound by alkylation (XIII) or compound (XV). a) reductive amination may be carried out in a solvent, in the presence or absence of an acid using a reducing reagent. At that time, it may be carried out dehydration operation using a Dean-Stark apparatus or the like. There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol , it is possible to use acetic acid, trifluoroacetic acid, etc. alone or in combination. There are no particular restrictions on the acid, e.g., propionic acid, protonic acids such as benzoic acid, titanium tetrachloride, boron trifluoride, can be used a Lewis acid stannic chloride. There are no particular limitations on the reducing reagent, such as sodium triacetoxyborohydride, triacetoxyborohydride, tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, trimethoxy sodium borohydride, borohydride-based reagent lithium triethylborohydride and the like, lithium aluminum hydride, diisopropyl aluminum hydride, bis (2-methoxyethoxy) aluminum hydride reagents such as sodium aluminum hydride, contact with metal catalyst and a hydrogen source it is possible to use the reduction. As the hydrogen source for the catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, it can be used ammonium formate and the like, as the metal catalyst, for example, palladium-carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum it can be used such as black. b) alkylation can be performed in a solvent in the presence of a base. As the solvent, not particularly limited, but, for example N, N- dimethylformamide, amides such as N- methyl pyrrolidone; dimethyl sulfoxide; 1,4-dioxane, tetrahydrofuran and the like; acetonitrile, nitriles such as propionitrile s can be used alone or in combination. as the base, although not particularly limited, for example, lithium hydride, sodium hydride, alkali metal hydrides such as potassium hydride, metal lithium, metal sodium, metal alkali metals such as potassium, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, lithium diisopropylamide, sodium diisopropylamide amide, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert- butoxy sodium, tert- butoxy potassium, n- butyl lithium, s- butyl lithium, tert- butyl lithium, etc. it can be used. The reaction temperature is, -10 ℃ ~ 200 ℃, varies depending on the reaction conditions and preferably from 0 ℃ ~ 120 ℃. The reaction time is 1 hour to 72 hours, it varies depending on the reaction conditions and preferably 1 hour to 36 hours.

There is no particular restriction on the deprotection of [Step 11] protecting group, commonly used method to (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) and those that can be introduced appropriately used by the like, deprotection Although it is possible to perform, but is not limited thereto.

Incidentally, if amine derivative used in the above production method (VIII) are used as it is available, or can be suitably prepared by a known method, but for example can be manufactured by the following method, limited to not intended to be.

Figure JPOXMLDOC01-appb-C000015

[In the formula,
R 1, ring D, Q 1, Q 4, R 5, Ring Y have the same meanings as defined above, P is a protecting group, W 1, W 2, W 4, W 6 is a leaving group or aldehyde group or an amino group or a hydroxyl group, W 3, W 5 and W 7 represents C = O at or NH.However, when W 1, W 4 is a leaving group or aldehyde group, W 2, W 6 represents an amino group or a hydroxyl group, when W 2, W 6 is a leaving group or aldehyde group, W 1, W 4 (Note an amino group or a hydroxyl group, the compound (XIX) and (XX), in the amine derivative (VIII), shows a case having a substituent ring Y is formed by Q 4, R 5 and ring D there.)]

[Step 12] The compound (XVI), the compound (XVIII) or a from (XVIII ')) reductive amination or, b) is a step for preparing a compound by alkylation (XVII) or a compound (XIX). a) reductive amination may be carried out in a solvent, in the presence or absence of an acid using a reducing reagent. At that time, it may be carried out dehydration operation using a Dean-Stark apparatus or the like. There are no particular restrictions on the solvent, for example, 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as dichloromethane; an ester such as ethyl acetate or isopropyl acetate: toluene, aromatic hydrocarbons such as benzene; tetrahydrofuran , ethers such as 1,4-dioxane; acetonitrile, nitriles such as propionitrile; alcohols such as methanol, ethanol, and isopropanol; acetate, can be used alone or in combination of organic acids such as trifluoroacetic acid . There are no particular restrictions on the acid, e.g., propionic acid, protonic acids such as benzoic acid, titanium tetrachloride, boron trifluoride, can be used a Lewis acid stannic chloride. There are no particular limitations on the reducing reagent, such as sodium triacetoxyborohydride, triacetoxyborohydride, tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, trimethoxy sodium borohydride, borohydride-based reagent lithium triethylborohydride and the like, lithium aluminum hydride, diisopropyl aluminum hydride, bis (2-methoxyethoxy) aluminum hydride reagents such as sodium aluminum hydride, contact with metal catalyst and a hydrogen source it is possible to use the reduction. As the hydrogen source for the catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, can be used ammonium formate and the like, and as the metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum black and the like can be used. b) alkylation can be performed in a solvent in the presence of a base. As the solvent, not particularly limited, but, for example N, N- dimethylformamide, amides such as N- methyl pyrrolidone; dimethyl sulfoxide; 1,4-dioxane, tetrahydrofuran and the like; acetonitrile, nitriles such as propionitrile s can be used alone or in combination. as the base, although not particularly limited, for example, lithium hydride, sodium hydride, alkali metal hydrides such as potassium hydride, metal lithium, metal sodium, metal alkali metals such as potassium, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, alkali metal carbonates such as cesium carbonate, lithium diisopropylamide, sodium diisopropylamide amide, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert- butoxy sodium, tert- butoxy potassium, n- butyl lithium, s- butyl lithium, tert- butyl lithium, etc. it can be used. Varies depending on the reaction conditions, the reaction temperature is -10 ° C. ~ 200 ° C., preferably from 0 ℃ ~ 120 ℃. The reaction time is 1 hour to 72 hours, preferably 1 hour to 36 hours.

There is no particular restriction on the deprotection [Step 13] protecting group, commonly used method to (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) and those that can be introduced appropriately used by the like, deprotection Although it is possible to perform, but is not limited thereto.

X in the above general formula, the substituents and R 2, the method R 3, etc. generally used when necessary on the Y ring (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.) In reference, oxidation, reduction, alkylation, amidation, esterification, hydrolysis, by appropriately converted by reductive amination, etc., the desired product is obtained. When using a protecting group is not particularly limited as a protecting group generally used method to (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) What can be introduced by such can be suitably used but, the present invention is not limited to this.

Intermediates and target product obtained in each reaction above, purification methods commonly used in the field of synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, should be subjected to various chromatography isolation can be purified in accordance with the. The intermediates may also be subjected to the subsequent reaction without particular purification.

Furthermore, various isomers can be isolated by applying conventional methods utilizing the difference in the physicochemical properties between isomers. For example, a racemic mixture, for example, a method of optical resolution leads to diastereomer salts with a general optically active acid or tartaric acid, or, by a general racemic resolution method such as a method using an optically active column chromatography, it can lead to optically pure isomers. Also, diastereomeric mixtures, for example, can be resolved by fractional crystallization or various chromatography. Moreover, optically active compounds can also be prepared by using a suitable optically active starting material.

TLR3,7 and / or 9 inhibitor of the present invention, or autoimmune diseases, inflammation, allergy, asthma, graft rejection and GvHD prophylaxis and / or therapeutic agents, thiophene derivatives represented by the general formula (1), be one that contains a salt thereof, or a solvate thereof as an active ingredient, it can be used as a pharmaceutical composition. In that case, the compounds of the present invention may be used alone, usually used by blending pharmaceutically acceptable carriers and / or diluents.

Route of administration is not particularly limited, it can be appropriately selected depending on the therapeutic purpose. For example, oral agents, injections, suppositories, may be any of such inhalants. Pharmaceutical compositions suitable for these administration forms can be prepared by utilizing known preparation methods.

When preparing oral solid preparations, the general formula (1) acceptable excipients to the compound as a pharmaceutical represented by a binder, if necessary, disintegrants, lubricants, colorants, flavoring agents after the addition of flavoring such as, by using a conventional method, tablets, coated tablets, granules, powders, it is possible to produce a capsule or the like. Additives may be those commonly used in the art. For example, as the excipient, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. As the binder, for example, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, and shellac, calcium phosphate, polyvinylpyrrolidone, and . Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like. Examples of lubricants include purified talc, stearate salts, borax, polyethylene glycol, and the like. The flavoring agent, for example, white sugar, orange peel, citric acid, and tartaric acid.

When preparing oral liquid preparations, the compound represented by the general formula (1), flavoring agents, buffers, stabilizers, using conventional methods by adding a flavoring agent such as oral solutions, syrups, it can be produced elixirs. The flavoring agents may be those listed above, as the buffering agent, such as sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

When preparing injections, the formula pH adjusting agent to the compound represented by Formula (1), buffering agents, stabilizing agents, tonicity agents, adding a local anesthetic, etc., by using conventional methods subcutaneous , it can be produced intramuscular and intravenous injections. The pH adjusting agents and buffering agents such as sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA (disodium edetate), thioglycolic acid, and thiolactic acid. The local anesthetic, for example, procaine hydrochloride and lidocaine hydrochloride is. Examples of the tonicity agent include sodium chloride, dextrose, and the like.

For preparing suppositories, general formula (1) known suppository carrier compound represented by, for example, polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride or the like, a surfactant optionally (e.g. after the addition of Tween (registered trademark)) and the like, it can be produced by utilizing conventional methods.

In addition to the above, it is also possible to appropriately preferred formulations using conventional methods.

The dosage of the thiophene derivative represented by the general formula (1) of the present invention is age, body weight, symptoms, administration form and administration times, etc., usually as a compound represented by the general formula (1) to an adult 0.1 mg ~ 1000 mg per day, preferably 1 mg ~ 100 mg, more preferably 1 mg ~ 10 mg, preferably orally or parenterally administered in single or divided doses.

Then, further illustrate the present invention through examples thereof, the present invention is not limited to these examples. Incidentally, abbreviations used in the following examples have the following meanings.
s: singlet (singlet)
d: doublet (doublet)
t: triplet (triplet)
q: Kuarutetto (quartet)
m: multiplet (multiplet)
brs: broad singlet (broad singlet)
J: coupling constant (coupling constant)
Hz: Hertz (Hertz)
CDCl 3: heavy 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 on carbon
TBS: tert- butyldimethylsilyl

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

Step 1:
N- [3 - ([1,4'- bipiperidin] -1'-yl) propyl] -5-bromo-2-carboxamide

Figure JPOXMLDOC01-appb-C000016

5-Bromo-thiophene-2-carboxylic acid (200 mg, 0.97 mmol), [1,4'- bipiperidin] -1'-propanamine hydrochloride (0.42 g, 1.26 mmol), WSC · HCl (278 mg, 1.45mmol ), HOBT · H 2 O ( 196 mg, 1.45 mmol) and triethylamine (390 mg, a 3.86 mmol) was dissolved in methylene chloride (5 mL), and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 10: 1) as eluents, 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

Figure JPOXMLDOC01-appb-C000017

1-methyl-4- (bromophenyl) piperazine (12.6 g, 49.4 mmol) in 1,4-dioxane (0.99 mL) was added bis (pinacolato) diboron (15.1 g, 59.3 mmol), bis (diphenylphosphino ferrocene ) palladium dichloride (II) (2.02 g, 2.47 mmol), diphenylphosphino ferrocene (1.37 g, 2.47 mmol), potassium acetate (14.5 g, 148 mmol) was added, at 80 ° C., and stirred for 16 hours. Returned to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform. The organic layer was washed with 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 give the give the title compound (9.53 g, 64%) as a red-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:
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 carbonate aqueous solution of sodium (0.22 mL) were mixed in 1,4-dioxane (2 mL), overnight reflux. Returned to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: saturated ammonium methanol = 10: 1) to give the title compound (70 mg, 82%) obtained by a light yellow solid.

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

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

Figure JPOXMLDOC01-appb-C000018

Using 5-bromo-2-nitro-thiophene and 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, performed in a similar manner to step 3 of example 1 to give the title compound (51%) 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-amino-2-yl) phenyl] piperazine

Figure JPOXMLDOC01-appb-C000019

1-methyl-4- [4- (5-nitro-2-yl) phenyl] piperazine (324 mg) was dissolved in methanol (5 mL), was added 10% Pd-C (160 mg). Replacing the reaction system with hydrogen and stirred at room temperature for 6 hours. The reaction mixture 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 give the give 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:
2- [N- (-4- 1- benzyl-yl) amino] Production of methyl acetate

Figure JPOXMLDOC01-appb-C000020

In acetonitrile (500 mL) / DMF (200 mL) solution of 4-amino -N- benzylpiperidine (50 g, 263 mmol), was added potassium carbonate (27.2 g, 197 mmol). Methyl bromoacetate (20.1 g, 131 mmol) and the mixture was stirred for 5 hours at 60 ° C.. Returned to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: ammonia saturated methanol = 97: 3 → 90: 10, gradient) to give the title compound (34.7 g, crude, theory 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:
2- preparation of [N- (-4- 1- benzyl-yl) -2-nitrophenyl sulfonamide] acetate

Figure JPOXMLDOC01-appb-C000021

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

Figure JPOXMLDOC01-appb-C000022

2- methanol (700 mL) solution of [N- (-4- 1- benzyl-yl) -2-nitrophenyl sulfonamide] acetate (54.2 g, 121 mmol), 4M aqueous sodium hydroxide (60.5 mL, 242 mmol) was added. And the mixture was stirred at room temperature for 4 hours. Under ice-cooling, 4N hydrochloric acid - using ethyl acetate solution was neutralized, and concentrated under reduced pressure. Was extracted with chloroform, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (48.2 g, crude) as a tan amorphous.

Step 6:
2- [N- (-4- 1- benzyl-yl) -2-nitrophenyl sulfonamide Preparation of acetyl chloride

Figure JPOXMLDOC01-appb-C000023

2- [N- (1- benzyl-piperidin-4-yl) -2-nitrophenyl sulfonamide] acetate (162 mg, 375μmol) in methylene chloride (5 mL) solution of under ice-cooling, DMF (10 [mu] L), two oxalyl chloride (95.2 mg, 750μmol) was added. Returned to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, subjected to toluene azeotrope to give a tan amorphous (225 mg, crude) a.

Step 7: 2- [N- (-4- 1- benzyl-yl) -2-nitrophenyl sulfonamide] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophene -2 - yl} acetamide

Figure JPOXMLDOC01-appb-C000024

1-methyl-4- [4- (5-amino-2-yl) phenyl] piperazine (51.4 mg, 0.19 mmol) was dissolved in methylene chloride (1.4 mL), diisopropylethylamine (48.2 mg, 0.38 mmol), and added. In an ice bath was added 2- [N- (1- benzyl-piperidin-4-yl) -2-nitrophenyl sulfonamide] acetyl chloride. And stirred for 2 hours to warm to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with 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 give the give the title compound (75.3 mg, crude) as a brown solid.

Step 8:
2 - [(1-Benzyl-piperidin-4-yl) amino] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide 2- [N- (1-benzyl-piperidin-4-yl) -2-nitrophenyl sulfonamide] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide (75.3 mg, the 0.11 mmol) was dissolved in acetonitrile (1.1 mL), was added potassium carbonate (45 mg, 0.33 mmol), thiophenol (24.7 mg, a 0.22 mmol). And the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue PLC (chloroform: saturated ammonium methanol = 10: 1) was purified using. The resulting compound chloroform - Recrystallization from hexane to give the title compound (32.2 mg, 2 steps yield 34%) as a slightly brown solid.

EXAMPLE 3 N-- preparation of {3 [(1-Benzyl-piperidin-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

Figure JPOXMLDOC01-appb-C000025

Using 5-bromo-thiophene-2-carboxylic acid and 3-amino-propanol, in the same manner as in Step 1 of Example 1 to give the title compound (91%) as a slightly brown solid.

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:
N- preparation of {3- [N- (-4- 1- benzyl-yl) -2-nitrophenyl sulfonamide] propyl} -5-bromo-2-carboxamide

Figure JPOXMLDOC01-appb-C000026

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

Step 3:
N- {3- [N- (-4- 1- benzyl-yl) -2-nitrophenyl sulfonamide] propyl} -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2 production of carboxamide

Figure JPOXMLDOC01-appb-C000027

N-{3- [N-(4 1-benzyl-piperidin-yl) -2-nitrophenyl sulfonamide] propyl} -5 and bromothiophene-2-carboxamide 1-methyl-4- [4- (4, 4,5,5- using tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, in the same manner as in step 3 of example 1, to give the title compound (crude) as an orange amorphous It was.

Step 4:
N- {3 - [(-4- 1- benzyl-yl) amino] propyl} -5- of [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide prepared N- {3- [N-(-4-1-benzyl-piperidin-yl) -2-nitrophenyl sulfonamide] propyl} -5 using [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide, in a similar manner to step 8 of example 2 to give the title compound (30%) as a slightly brown solid.

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

Step 1:
5-bromo -N- preparation of {3- [N- (-4- 1- methyl-piperidin-yl) -2-nitrophenyl sulfonamide] propyl} thiophene-2-carboxamide

Figure JPOXMLDOC01-appb-C000028

Using 5-bromo-N-(3- hydroxypropyl) thiophene-2-carboxamide and N-(1-methylpiperidin-4-yl) -2-nitrobenzenesulfonamide was prepared in analogy to step 2 of Example 3 to give the title compound (29%) 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- (-4- 1- methyl-piperidin-yl) -2-nitrophenyl sulfonamide] propyl} thiophene-2 production of carboxamide

Figure JPOXMLDOC01-appb-C000029

5-bromo-N-{3- [N-(4 1-methyl-piperidin-yl) -2-nitrophenyl sulfonamide] propyl} thiophene-2-carboxamide and 1-methyl-4- [4- (4, 4,5,5- using tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, in the same manner as in step 3 of example 1, the title compound (crude) as a pale orange amorphous Obtained.

Step 3:
5- [4- (4-methylpiperazin-1-yl) phenyl] -N- {3 - [(-4- 1- methyl-piperidin-yl) amino] propyl} thiophene-2-carboxamide 5- [4- (4-methylpiperazin-1-yl) phenyl] -N- using {3- [N- (-4- 1- methyl-piperidin-yl) -2-nitrophenyl sulfonamide] propyl} thiophene-2-carboxamide, in a similar manner to step 8 of example 2 to give the title compound (40%) as an orange solid.

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

Step 1:
Methyl 2 - [(1-methylpiperidin-4-yl) amino] Production of acetate

Figure JPOXMLDOC01-appb-C000030

1-methyl-4-piperidone (27.2 g, 240 mmol) and glycine methyl ester (25.0 g, 200 mmol) in methylene (250 mL) chloride sodium triacetoxyborohydride to a solution (63.6 g, 300 mmol), ice It was added under cold. The mixture was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added, the 10 times extracted was performed 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) 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-nitrophenyl sulfonamide] acetate

Figure JPOXMLDOC01-appb-C000031

Methyl 2 - [(1-methyl-piperidin-4-yl) amino] using acetate and 2-nitrobenzenesulfonyl chloride, in the same manner as in Step 4 of Example 2 to give the title compound (55.5%) as a brown oil 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:
2- preparation of [N- (-4- 1- methyl-piperidin-yl) -2-nitrophenyl sulfonamide] acetic acid

Figure JPOXMLDOC01-appb-C000032

With methyl 2- [N- (1- methylpiperidin-4-yl) -2-nitrophenyl sulfonamide] acetate In the same manner as in step 5 of Example 2, to give the title compound (crude) as a brown amorphous It was.

Step 4:
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1- methylpiperidin-4-yl) -2-nitrophenyl sulfonamide] acetamide

Figure JPOXMLDOC01-appb-C000033

Using 1-methyl-4- [4- (5-amino-2-yl) phenyl] piperazine and 2-[N-(1-methylpiperidin-4-yl) -2-nitrophenyl sulfonamide] acetic acid in the same manner as in step 1 of example 1 to give the title compound (crude) as a black brown oily matter.

Step 5:
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-using [N-(-4-1-methylpiperidin-4-yl) -2-nitrophenyl sulfonamide] acetamide, in a similar manner to step 8 of example 2 to give the title compound (6% 2 step yield) as a dark brown oil.

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

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

Figure JPOXMLDOC01-appb-C000034

2 - [(1-methyl-piperidin-4-yl) oxy] acetate (100 mg, 0.34 mmol) was added to methylene chloride (2 mL), under ice-cooling, DMF (10 [mu] L), dichloride oxalyl (50 [mu] L, 0.51 mmol ) was added. Returned to room temperature, stirred 2 hours, concentrated under reduced pressure to give the title compound (crude) as a tan amorphous.

Step 2:
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methylpiperidin-4-yl) oxy] acetamide 1- methyl-4 - [4- (5-amino-2-yl) phenyl] piperazine (47 mg, 0.17 mmol) was dissolved in methylene chloride (3 mL), triethylamine (100 [mu] l, 0.68 mmol), after the added solution, in an ice bath 2 - [(1-methylpiperidin-4-yl) oxy] was added acetyl chloride. And stirred for 2 hours to warm to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with 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 give the give 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-yl preparation of) phenyl] thiophene-2-carboxamide

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

Figure JPOXMLDOC01-appb-C000035

4- (4-bromophenyl) -4-hydroxypiperidine (1.2 g, 4.68 mmol) in concentrated hydrochloric acid (5 mL) was added, and the mixture was stirred for 8 hours at 100 ° C.. Returned to room temperature, aqueous sodium hydroxide solution was added, basified, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (1.08 g, 97%) 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

Figure JPOXMLDOC01-appb-C000036

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

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

Figure JPOXMLDOC01-appb-C000037

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 steps yield the rate 82%) was obtained as a dark brown.

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-yl) phenyl] thiophene-2-carboxamide N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5-bromothiophene-2-carboxamide and 1-methyl-4- [4- (4 , using 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%) as a yellow solid.

EXAMPLE 8 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-yl) phenyl] thiophene-2-carboxamide (10 mg, 0.02 mmol) was dissolved in ethanol (1 mL), concentrated hydrochloric acid (10 [mu] L) and 10% palladium carbon (10 mg) was added, under hydrogen atmosphere and stirred at room temperature for 18 hours . The reaction solution was filtered, the residue obtained by concentration was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to give the title compound (6 mg, 62%) as a white solid It was obtained as a.

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

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

Figure JPOXMLDOC01-appb-C000038

Concentrated nitric acid in acetic anhydride (1.5 mL) and (210 uL) was added, cooled to -10 ° C., the dissolved 4- (2-thienyl) cyclohexanone (562 mg, 3.11 mmol) in acetic anhydride (1.5 mL) was slowly added , and the mixture was stirred for 1.5 hours at -10 ℃. To the reaction solution was extracted with water was added chloroform, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, the residue obtained by concentration after filtration was purified by silica gel chromatography (hexane: ethyl acetate = 100 : 0 → 75: 25, was purified using 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-nitro-2-yl) cyclohexyl] piperazine

Figure JPOXMLDOC01-appb-C000039

4- (5-nitro-2-thienyl) cyclohexanone (332 mg, 1.47 mmol) was dissolved in methylene chloride, 1-methylpiperazine (191 mg, 1.91 mmol), acetic acid (150 [mu] L), sodium triacetoxyborohydride ( 488 mg, was added to 2.2 mmol), after stirring for 1.5 hours at room temperature, the reaction solution was extracted with water was added chloroform, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered the residue obtained by concentration was subjected to silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to give the 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-amino-2-yl) cyclohexyl] piperazine

Figure JPOXMLDOC01-appb-C000040

1-methyl-4- [4- (5-nitro-2-yl) cyclohexyl] piperazine (80 mg, 0.26 mmol) was dissolved in methanol (3 mL), was added 10% palladium-carbon, under a hydrogen atmosphere after stirring for 14 hours at room temperature to give the title compound were concentrated by filtration (22 mg, crude) as a brown oil.

Step 4:
Benzyl 2 - [(1-methylpiperidin-4-yl) amino] Production of acetate

Figure JPOXMLDOC01-appb-C000041

1-methyl-4-piperidone (27.2 g, 240 mmol) and using glycine benzyl ester In the same manner as in step 1 of Example 5 to give the title compound (crude) as a tan oil.

Step 5:
Preparation of benzyl 2- [2,2,2-trifluoro-N-(-4-1-methylpiperidin-4-yl) acetamido] acetate

Figure JPOXMLDOC01-appb-C000042

Benzyl 2 - [(1-methyl-piperidin-4-yl) amino] acetate (6.98 g, crude, theory 6.51 g, 24.8 mmol) in methylene chloride (100 mL) solution of under ice-cooling, triethylamine (5.02 g , 49.6 mmol), trifluoroacetic anhydride (7.81 g, were added 37.2 mmol). Returned to room temperature and stirred for 2 hours. To the reaction solution, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform. The organic layer was washed with 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 give the give the title compound (6.90 g, 2 steps yield 77.6%) as a pale 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:
2- [2,2,2-trifluoro-N-(-4-1-methylpiperidin-4-yl) acetamido] Production of acetic acid

Figure JPOXMLDOC01-appb-C000043

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

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

Figure JPOXMLDOC01-appb-C000044

1-methyl-4- [4- (5-amino-2-yl) cyclohexyl] piperazine and 2- [2,2,2-trifluoro-N-(1-methylpiperidin-4-yl) acetamido] acetate using, in the same manner as in step 6 and step 7 of example 2, gave the title compound (crude) as a brown oil.

Step 8:
N- {5- [4- (4- methylpiperazin-l-yl) cyclohexyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide 2,2,2 - trifluoro -N- [2 - ({5- [4- (4- methylpiperazin-l-yl) cyclohexyl] thiophen-2-yl} amino) -2-oxoethyl]-N-(1-methylpiperidine - 4-yl) acetamide (66 mg) and 8M ammonia - was dissolved in methanol to give a residue and then concentrated stirred at room temperature for 5.5 hours. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to give the give the title compound (30 mg, 3 steps 26% yield) 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:
(E)-tert-butyl-3- preparation of (5 - - {[3 ([1,4'-bipiperidin] -1'-yl) propyl] carbamoyl} thiophene-2-yl) acrylate

Figure JPOXMLDOC01-appb-C000045

N- [3 - ([1,4'- bipiperidin] -1'-yl) propyl] -5-bromothiophene-2-carboxamide (80 mg, 0.2 mmol) dissolved in 1,4-dioxane (2 mL) and, o- preparative Little yl phosphine (18 mg, 0.06 mmol), tert- butyl acrylate (150 [mu] L, 1 mmol), diisopropylamine (100 [mu] L, 0.6 mmol), tris (dibenzylideneacetone) dipalladium (0) (18 mg, 0.02 mmol) and the mixture was stirred for 19 hours at 100 ° C.. Reaction water was extracted with added chloroform, and the organic layer was dried over sodium sulfate, the residue obtained by concentration after filtration was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, gradient) to using purified to give the title compound (55 mg, 60%) as a brown oil.

1 H-NMR (400MHz, 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 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) and 4M hydrochloric acid - added to ethyl acetate (1 mL), and concentrated after stirring for 4 hours at room temperature, (E) -3- (5 - {[3 - ([1 to give the 4'-bipiperidin] -1'-yl) propyl] carbamoyl} thiophene-2-yl) acrylic acid as a white solid. The resulting (E) -3- (5 - {[3 - ([1,4'- bipiperidin] -1'-yl) propyl] carbamoyl} thiophene-2-yl) acrylic acid in methylene chloride, N - methylpiperazine (15 mg, 0.15 mmol), triethylamine (50μL, 0.36 mmol), WSC · HCl (28 mg, 0.15 mmol), HOBt (20 mg, 0.15 mmol) was added and after stirring for 15 hours at room temperature, to the reaction solution was extracted with water was added chloroform, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, the residue obtained by concentration after filtration was purified by silica gel chromatography (chloroform: methanol = 98: 2 → 82: 18, was purified using 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 - production of the carboxamide

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

Figure JPOXMLDOC01-appb-C000046

And 5-bromo-4-methylthiophene-2-carboxylic acid [1,4'-bipiperidin] -1' using propanamine hydrochloride, in the same manner as in Step 1 of Example 1, the title compound (crude) Obtained.

Step 2:
N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -4-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide producing N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5-bromo-4-methyl-2-carboxamide 1-methyl-4- [4- (4,4 , using 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, in the same manner as in step 3 of example 1 to give the title compound (10%) as a pale yellow solid .

EXAMPLE 12 N- [3 - ([1,4 'bipiperidin] -1'-yl) propyl] -3-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2 production of carboxamide

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

Figure JPOXMLDOC01-appb-C000047

And 5-bromo-3-methylthiophene-2-carboxylic acid [1,4'-bipiperidin] -1' using propanamine hydrochloride, in the same manner as in Step 1 of Example 1, the title compound (crude) Obtained.

Step 2:
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, 5,5 using tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, in the same manner as in step 3 of example 1 to give the title compound (51%) as a pale yellow solid.

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

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

Figure JPOXMLDOC01-appb-C000048

Using 1-Boc-4-piperidone and glycine methyl ester In the same manner as in step 1 of Example 5 to give the title compound (crude) as a white oil.

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

Figure JPOXMLDOC01-appb-C000049

tert- butyl 4 - [(2-methoxy-2-oxoethyl) amino] piperidine-1 with carboxylate and 2-nitrobenzenesulfonyl chloride, in the same manner as in Step 4 of Example 2, the title compound (crude) It was obtained as a white powder.

Step 3:
2- preparation of {N- [1- (tert- butoxycarbonyl) piperidin-4-yl] -2-nitrophenyl sulfonamide} acetate

Figure JPOXMLDOC01-appb-C000050

tert- butyl 4- [N- (2- methoxy-2-oxoethyl) -2-nitrophenyl sulfonamide] piperidine -1-carboxylate In the same manner as in step 5 of Example 2, the title compound (crude ) 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-nitrophenyl sulfonamide production of} piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000051

1-methyl-4- [4- (5-amino-2-yl) phenyl] piperazine and 2-{N-[1- (tert-butoxycarbonyl) piperidin-4-yl] -2-nitrophenyl sulfonamide } with acetic acid in the same manner as in step 7 step 6 and example 2 example 2 to give the title compound (crude) as a brown powder.

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

Figure JPOXMLDOC01-appb-C000052

tert- butyl 4- {N- [2 - ({5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2-nitrophenyl sulfonamide } piperidine-1-carboxylate (0.63 g, 0.9 mmol) in methanol (10 mL) solution of, 4N HCl / EtOAc (5 mL) was added, followed by stirring at room temperature for 4 hours. It was concentrated under reduced pressure to obtain a residue. To the residue was added water and extracted with chloroform. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate. Mixture was extracted with a solvent (chloroform / methanol = 10/1), the organic layer was dried over sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (chloroform: ammonia saturated methanol = 90: 10) as eluents, to give the title compound (0.45 g, 2 steps yield 36%) as a brown solid.

Step 6
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(piperidin-4-yl) amino] acetamide N-{5-[4- (4-methylpiperazin-1-yl) phenyl] using thiophene-2-yl} -2- [2-nitro -N- (piperidin-4-yl) phenyl sulfonamide] acetamide step 8 of example 2 in the same manner as to give the title compound (61%) 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 - production of the carboxamide

Step 1:
N- [3 - ([1,4'- bipiperidin] -1'-yl) propyl] -5-bromo-3-methoxy-2-carboxamide

Figure JPOXMLDOC01-appb-C000053

And 5-bromo-3-methoxy-thiophene-2-carboxylic acid [1,4'-bipiperidin] -1' using propanamine hydrochloride, in the same manner as in Step 1 of Example 1, the title compound (crude) Obtained.

Step 2:
N- {3 - ([1,4'- bipiperidin] -1'-yl) propyl} -3-methoxy-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide producing N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5-bromo-3-methoxy-2-carboxamide and 1-methyl-4- [4- (4,4 5,5 using tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine, in the same manner as in step 3 of example 1, the title compound (1% 2 steps yield) pale yellow It was obtained as a solid.

Example 15 N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidine -4 - yl) amino] acetamide

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

Figure JPOXMLDOC01-appb-C000054

And 2-bromo-5-nitro-thiophene-1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,2,3 , using 6-tetrahydropyridine in the same manner as in step 3 of example 1 to give the title compound (79%) as a yellow solid.

1 H-NMR (400MHz, 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:
5- preparation of [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2-amine

Figure JPOXMLDOC01-appb-C000055

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

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

Figure JPOXMLDOC01-appb-C000056

5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2-amine and 2- [2,2,2-trifluoro-N-(1- using methyl piperidin-4-yl) acetamido] acetic acid in the same manner as in step 6 and 7 of example 2, gave 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) amino] acetamide 2,2,2-trifluoro -N- [2 - ({5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} amino) -2-oxoethyl] -N- (using 1-methyl-piperidin-4-yl) acetamide in the same manner as in step 8 of example 9, the title compound (3 steps 55% yield) It was obtained as a pale yellow solid.

EXAMPLE 16 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-yl) phenyl] thiophen-2-yl} -2 - [(1-methylpiperidin-4-yl) amino] with acetamide in the same manner as in example 8 to afford the title compound (82%) as a yellow solid.

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

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

Figure JPOXMLDOC01-appb-C000057

tert- butyl 4- (4-iodo-phenoxy) using piperidine-1-carboxylate and bis (pinacolato) diboron, in the same manner as in Step 2 of Example 1 to give the title compound (crude) as a pale yellow solid .

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

Figure JPOXMLDOC01-appb-C000058

2-bromo-5-nitro-thiophene and tert- butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] piperidine-1-carboxylate used, in the same manner as in step 3 of example 1 to give the title compound (62%) as a yellow solid.

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).

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

Figure JPOXMLDOC01-appb-C000059

Using tert- butyl 4- [4- (5-nitro-2-yl) phenoxy] piperidine-1-carboxylate In the same manner as in step 2 of Example 2, the title compound (quantitative) brown solid It was obtained as a.

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] acetamide} thiophen-2-yl) phenoxy] piperidine - preparation of 1-carboxylate

Figure JPOXMLDOC01-appb-C000060

tert- butyl 4- [4- (5-amino-2-yl) phenoxy] piperidine-1-carboxylate and 2- [2,2,2-trifluoro-N-(-4-1-methylpiperidin-4-yl ) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (39% 2 steps yield).

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-(4 1-methylpiperidin-4-yl) -N- [2- oxo-2 - ({5- [4- (piperidin-4-yloxy) phenyl] thiophene -2 - yl} amino) ethyl] acetamide

Figure JPOXMLDOC01-appb-C000061

tert- butyl 4- [4- (5- {2- [2,2,2-trifluoro-N-(1-methylpiperidin-4-yl) acetamido] acetamide} thiophen-2-yl) phenoxy] piperidine - using 1-carboxylate in the same manner as in step 5 of example 13 to give the title compound (crude).

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

Figure JPOXMLDOC01-appb-C000062

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

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:
2 - [(1-methylpiperidin-4-yl) amino]-N-(5-{4 - [(1-methylpiperidin-4-yl) oxy] phenyl} thiophen-2-yl) acetamide 2, 2,2-trifluoro-N-(-4-1-methylpiperidin-4-yl) -N- {2 - [(5- {4 - [(-4- 1- methyl-piperidin-yl) oxy] phenyl} thiophene -2 - yl) amino] -2-oxoethyl} using acetamide in the same manner as in step 8 of example 9, to give the title compound (73%) as a pale yellow solid.

Preparation of Example 18 2- [4- (dimethylamino) piperidin-1-yl]-N-{5-r4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide 1- with methyl 4- [4- (5-amino-2-yl) phenyl] piperazine and 2- [4- (dimethylamino) piperidin-1-yl] acetic acid, a step 6 and 7 of example 2 Similarly, to give the title compound (48%) as a brown solid.

Example 19 (R) -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2 production of carboxamide

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

Figure JPOXMLDOC01-appb-C000063

(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), hydrogenated tri acetoxyborohydride sodium hydrogen (488 mg, 2.2 mmol) was added and after stirring for 15 hours at room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, followed by extraction with chloroform, the organic layer was dried over sodium sulfate, filtered the residue obtained by concentration was subjected to silica gel chromatography (chloroform: methanol = 100: 0 → 80: 20, gradient) and purified using, (R) tert-butyl 1- (1-methylpiperazin-yl) pyrrolidine-2-carboxylate (1.07 g, crude) as a yellow oil. Ethyl acetate - obtained, (R) tert-butyl 1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylate (1.07 g, 4 mmol) was dissolved in acetic acid, under ice cooling 4M hydrochloric acid in addition the title compound was concentrated after stirring for 7 hours at room temperature the (1.1 g, crude) as a white solid.

Step 2:
(R)-N-preparation of {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide (R)-1-(4 1-methyl-piperazin yl) pyrrolidine-2-carboxylic acid and 1-methyl-4- [4- (5-amino-2-yl) phenyl] piperazine, performed in a similar manner to step 6 and 7 of example 2, gave the title compound (40%) as a slightly yellow solid.

Example 20 (S) -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methylpiperidin-4-yl) pyrrolidine-2 production of carboxamide

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

Figure JPOXMLDOC01-appb-C000064

(S)-tert-butyl-pyrrolidine-2-carboxylate hydrochloride and 1-methyl-4 using [4- (5-amino-2-yl) phenyl] piperazine, the same manner as in Step 1 of Example 19 There was obtained the title compound (crude) as a slightly yellow solid.

Step 2:
(S)-N-preparation of {5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide (S)-1-(4 1-methyl-piperazin yl) pyrrolidine-2-carboxylic acid and 1-methyl-4- [4- (5-amino-2-yl) phenyl] piperazine, performed in a similar manner to step 2 of example 19 to give the title compound (49%) as a slightly yellow solid.

Example 21 2 - [(5-hydroxypentyl) (l-methylpiperidin-4-yl) amino]-N-{5- [4-(4-methylpiperazin-1-yl) phenyl] thiophene-2-yl } acetamide N-{5- [4-(4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methylpiperidin-4-yl) amino] acetamide and 5 with hydroxy pentanal, in the same manner as in step 1 of example 5 to give the title compound (89%) as a pale yellow oil.

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

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

Figure JPOXMLDOC01-appb-C000065

N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5-bromothiophene-2-carboxamide and tert- butyl 4- [4- (4,4,5,5-tetra with methyl 1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate in the same manner as in step 3 of example 1 to give the title compound (91.7%) as a pale yellow amorphous .

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:
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} thiophene-2-yl) using phenyl] piperazine-1-carboxylate, example 13 in a similar manner to step 5 to give the title compound (87%) as a pale yellow solid.

EXAMPLE 23 N- [3 - ([1,4'- bipiperidin] -1'-yl) propyl] -5- (4- {4- [6- (methylamino) -6-oxo-hexyl] piperazine -1 - 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), and potassium carbonate (16.8 mg, 0.12 mmol), potassium iodide (20.1 mg, 0.12 mmol), 6- bromo -N- methyl hexanamide (23.1 mg, 0.11 mmol) was added. And stirred for 4 hours at 80 ° C.. Returned to room temperature, the reaction solution, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue PLC (chloroform: ammonia saturated methanol = 10: 1) as eluents, to give 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} thiophene-2-yl) phenyl] piperazine-1 yl} hexanoate manufacturing N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide and benzyl 6 - using the bromo hexanoate, in the same manner as in example 23 to give the title compound (69%) as a pale yellow solid.

EXAMPLE 25 1'-methyl -N- {5- [4- (-4- 1- methyl-piperidin yl) phenyl] thiophen-2-yl} - [1,4'-bipiperidine] -4-carboxamide Step 1:
1'-methyl -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} - [1,4'-bipiperidine] production of 4-carboxamide

Figure JPOXMLDOC01-appb-C000066

1'-methyl - [1,4'-bipiperidine] -4-carboxylic acid and 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2 with an amine, as in step 6 and 7 of example 2, gave the title compound (crude) as a slightly yellow solid.

Step 2:
1'-methyl -N- {5- [4- (-4- 1- methyl-piperidin yl) phenyl] thiophen-2-yl} - [1,4'-bipiperidine] -4-carboxamide 1'-methyl -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} - [1,4'-bipiperidine] -4-carboxamide using, in the same manner as in example 8 to afford the title compound (31% 2 steps yield) as a pale yellow solid.

EXAMPLE 26 N-Methyl-6- {4- [4- (5- {2 - [(1-methylpiperidin-4-yl) amino] acetamide} thiophen-2-yl) phenyl] piperazin-1-yl} production hexanamide

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

Figure JPOXMLDOC01-appb-C000067

2-bromo-5-nitro-thiophene and tert- butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine-1-carboxylate used, in the same manner as in step 3 of example 1 to give the title compound (44%) as a pale red solid.

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-amino-2-yl) phenyl] piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000068

Using tert- butyl 4- [4- (5-nitro-2-yl) phenyl] piperazine-1-carboxylate In the same manner as in step 2 of Example 2, the title compound (96%) brown amorphous It was obtained as a.

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- [4- 2,2,2-trifluoro-N-(1-methylpiperidin-4-yl) acetamido] acetamide} thiophen-2-yl) phenyl] piperazine - preparation of 1-carboxylate

Figure JPOXMLDOC01-appb-C000069

tert- butyl 4- [4- (5-amino-2-yl) phenyl] piperazine-1-carboxylate and 2- [2,2,2-trifluoro-N-(-4-1-methylpiperidin-4-yl ) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (66%) as a dark brown amorphous.

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-(-4-1-methylpiperidin-4-yl) -N- [2- oxo-2 - ({5- [4- (piperazin-1-yl) phenyl] thiophene -2 - yl} amino) ethyl] acetamide

Figure JPOXMLDOC01-appb-C000070

tert- butyl 4- [4- (5- {2- [4- 2,2,2-trifluoro-N-(1-methylpiperidin-4-yl) acetamido] acetamide} thiophen-2-yl) phenyl] piperazine - using 1-carboxylate in analogy to the procedure of step 5 of example 13 to give the title compound (57%) as a brown amorphous.

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-(-4-1-methylpiperidin-4-yl) acetamido] acetamide} thiophen-2-yl) manufacturing phenyl] piperazin-1-yl} hexanamide

Figure JPOXMLDOC01-appb-C000071

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

Step 6:
N- methyl-6 - of {4- [4- (5- {2 [(1-methyl-piperidin-4-yl) amino] acetamide} thiophen-2-yl) phenyl] piperazin-1-yl} hexanamide of N- methyl-6- {4- [4- (5- {2- [2,2,2-trifluoro-N-(1-methylpiperidin-4-yl) acetamido] acetamide} thiophen-2-yl ) using phenyl] piperazin-1-yl} hexanamide in the same manner as in step 8 of example 9, to give the title compound (40% 2 steps yield) 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) producing amino] acetamide

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

Figure JPOXMLDOC01-appb-C000072

4-bromo-2 - [(4-methylpiperazin-1-yl) methyl] using phenol and bis (pinacolato) diboron, in the same manner as in Step 2 of Example 1, the title compound (crude) dark brown oil It was obtained as a.

Step 2:
2 - [(4-methylpiperazin-1-yl) methyl] -4- (5-nitro-thiophen-2-yl) production of phenol

Figure JPOXMLDOC01-appb-C000073

2-bromo-5-nitro-thiophene and 2 - [(4-methylpiperazin-1-yl) methyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) with phenol in the same manner as in step 3 of example 1 to give the title compound (crude) as a black brown oily matter.

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:
4- (5-amino-2-yl) -2 - [(4-methylpiperazin-1-yl) methyl] Production of phenol

Figure JPOXMLDOC01-appb-C000074

2 - with [(4-methylpiperazin-1-yl) methyl] -4- (5-nitro-thiophen-2-yl) phenol In the same manner as in step 2 of Example 2, the title compound (crude) It was obtained as a dark brown oil.

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

Figure JPOXMLDOC01-appb-C000075

4- (5-amino-2-yl) -2 - [(4-methylpiperazin-1-yl) methyl] phenol and 2- [2,2,2-trifluoro-N-(1-methylpiperidine - using 4-yl) acetamido] acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (crude) as a brown amorphous.

Step 5:
N-(5-{4-hydroxy-3 - [(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide manufacturing 2,2,2-trifluoro -N- {2 - [(5- {4- hydroxy-3 - [(4-methylpiperazin-1-yl) methyl] phenyl} thiophene-2-yl) amino] using 2-oxoethyl}-N-(-4-1-methylpiperidin-4-yl) acetamide in analogy to the procedure of step 8 of example 9, the title compound (4 2% step yield) as a pale yellow solid It was obtained as a.

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

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

Figure JPOXMLDOC01-appb-C000076

N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methylpiperidin-4-yl) amino] acetamide and 3 - [(tert using butyldimethylsilyl) oxy] propanal, in the same manner as in step 1 of example 5 to give the title compound (crude).

Step 2:
2 - [(3-hydroxypropyl) (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide manufacturing 2 - [{3 - [(tert- butyldimethylsilyl) oxy] propyl} (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophene-2-yl} acetamide (12 mg, 0.016 mmol) in THF (1 mL) solution of, TBAF (33μL, 0.033 mmol) was added and stirred for 1 hour. In a separate flask, 2 - [{3 - [(tert- butyldimethylsilyl) oxy] propyl} (1-methylpiperidin-4-yl) amino] -N- {5- [4- (4- methylpiperazin - 1-yl) phenyl] thiophen-2-yl} acetamide (0.99 mg, in THF (2 mL) solution of 0.21 mmol), TBAF (0.42mL, 0.42 mmol) and the mixture was stirred for 4 hours. It combined two of the reaction solution. Saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with a mixed solvent (chloroform / methanol = 10/1). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue PLC (chloroform: saturated ammonium methanol = 10: 1) as eluents, to give the title compound (8 mg, 9%) as a pale yellow solid.

Example 29 2- (4-methylpiperazin-1-yl) -N- [4- (5- {2 - [(-4- 1- methyl-piperidin-yl) amino] acetamide} thiophen-2-yl) phenyl] acetamide

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

Figure JPOXMLDOC01-appb-C000077

N-(4-bromophenyl) -2- (4-methylpiperazin-1-yl) with acetamide and bis (pinacolato) diboron, in the same manner as in Step 2 of Example 1, the title compound (82%) It was 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:
2- (4-methylpiperazin-1-yl)-N-[4- (5-Nitro-2-yl) phenyl] acetamide

Figure JPOXMLDOC01-appb-C000078

And 2-bromo-5-nitro-thiophene 2- (4-methylpiperazin-1-yl)-N-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) phenyl] using acetamide in the same manner as in step 3 of example 1 to give 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:
N-[4- (5-Amino-2-yl) phenyl] -2- (4-methylpiperazin-1-yl) acetamide

Figure JPOXMLDOC01-appb-C000079

2- (4-methylpiperazin-1-yl) -N- using [4- (5-nitro-2-yl) phenyl] acetamide In the same manner as in step 2 of Example 2, the title compound (crude ) 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 } -N- (-4- 1- methyl-piperidin-yl) acetamide

Figure JPOXMLDOC01-appb-C000080

N-[4- (5-Amino-2-yl) phenyl] -2- (4-methylpiperazin-1-yl) acetamide and 2- [2,2,2-trifluoro-N-(1-methyl using piperidine-4-yl) acetamido] acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (74% 2 steps yield) as a brown amorphous.

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:
2- (4-methylpiperazin-1-yl) -N- [4- (5- {2 - [(-4- 1- methyl-piperidin-yl) amino] acetamide} 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-(-4-1-methylpiperidin-4-yl) with acetamide, as in the process of step 8 of example 9, to give 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-methyl-piperidin-4-yl) amino ] acetamide

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

Figure JPOXMLDOC01-appb-C000081

5-Bromo -1H- indole (2.4 g, 12.2 mmol) was dissolved in DMF (50 mL), potassium iodide (2.0 g, 12.2 mmol), potassium carbonate (3.1 g, 36.8 mmol), 3- chloro -N in addition N- dimethyl-1-amine hydrochloride (2.2 g, 13.5 mmol) and stirred for 16 hours at 60 ° C.. Water was added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was dried over sodium sulfate, the residue obtained by concentration after filtration was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 90: 10, gradient ) as eluents, 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:
N, N-dimethyl-3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl] propan-1-amine production

Figure JPOXMLDOC01-appb-C000082

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

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

Figure JPOXMLDOC01-appb-C000083

N, and N- dimethyl-3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl] propan-1-amine using 2-bromo-5-nitro-thiophene in the same manner as in step 3 of example 1 to give the title compound (36%) as a yellow solid.

1 H-NMR (400MHz, 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:
5- preparation of {1- [3- (dimethylamino) propyl]-1H-indol-5-yl} thiophene-2-amine

Figure JPOXMLDOC01-appb-C000084

N, N-dimethyl-3 using [5- (5-nitro-2-yl)-1H-indol-1-yl] propan-1-amine In the same manner as in step 2 of Example 2, the title compound (crude) 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 manufacturing trifluoroacetic-N-(1-methylpiperidin-4-yl) acetamide

Figure JPOXMLDOC01-appb-C000085

5- {1- [3- (dimethylamino) propyl]-1H-indol-5-yl} thiophene-2-amine and 2- [2,2,2-trifluoro-N-(1-methylpiperidine -4 - yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (crude) as a gray solid.

Step 6:
N-(5-{1- [3- (dimethylamino) propyl]-1H-indol-5-yl} thiophen-2-yl) -2 - [(1-methylpiperidin-4-yl) amino] acetamide prepared N- {2 - [(5- {1- [3- (dimethylamino) propyl]-1H-indol-5-yl} thiophen-2-yl) amino] -2-oxoethyl} -2,2,2 - with trifluoroacetic-N-(1-methylpiperidin-4-yl) acetamide in the same manner as in step 8 of example 9, to give the title compound (39% 3 steps yield) as a gray solid.

Example 31 N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] -3-phenylpropane production of amide

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

Figure JPOXMLDOC01-appb-C000086

1-methyl-4- [4- (5-amino-2-yl) phenyl] piperazine and 2 - [(tert- butoxycarbonyl) amino] -3-phenyl propanoic acid, Step 1 of Example 1 in the same manner as to give the title compound (crude).

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

Figure JPOXMLDOC01-appb-C000087

tert- butyl - with [1 ({5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -1-oxo-3-phenylpropan-2-yl] carbamate Te, in a similar manner to step 5 of example 13 to give the title compound (75% 2 steps yield).

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:
N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - of [(1-methyl-piperidin-4-yl) amino] -3-phenyl propanamide prepared using 2-amino -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -3-phenyl propanamide and 1-methyl-4-piperidone, example 5 step 1 in the same manner as to give the title compound (52%) as a pale yellow amorphous.

Example 32 N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -1- (1-methyl-4- yl) pyrrolidin-3-carboxamide 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-amine and 1- (1-methyl-piperidin - using 4-yl) pyrrolidine-3-carboxylic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (4%) as a yellow solid.

Example 33 N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2- [N- (1- methylpiperidin-4-yl) methyl sulfonamide] acetamide manufacturing N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide (64 mg, 0.15 the mmol) was dissolved in THF (1 mL), triethylamine (30μL, 0.21 mmol), methanesulfonyl chloride (14 [mu] L, after 2 hours of stirring at room temperature added 0.18 mmol), the reaction liquid crystals precipitated added water and chloroform It was collected by filtration. The resulting crystals silica gel chromatography (chloroform: saturated ammonia methanol = 90: 10) as eluents, 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- production of methyl piperidin-4-yl) amino] pentanamide

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

Figure JPOXMLDOC01-appb-C000088

5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] using thiophene-2-amine and N-Boc-leucine, as in step 1 of Example 1 There was obtained the title compound (crude).

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

Figure JPOXMLDOC01-appb-C000089

tert- butyl [4-methyl-1 - ({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} amino) -1- using oxo-2-yl] carbamate, in the same manner as in step 5 of example 13 to give the title compound (44% 2 steps yield).

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- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 4-yl) amino] production of pentanamide 2-amino-4-methyl -N- {5- [4- (1- methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene - using 2-yl} pentanamide with 4-methyl-1-piperidone, in the same manner as in step 1 of example 5 to give the title compound (3%) as a pale yellow amorphous.

Preparation of Example 35 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) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000090

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

Step 2:
1- (piperidin-4-yl) -3- {5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} production of 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, and 0.1 mmol) was dissolved in methylene chloride (2 mL), under ice-cooling, TFA (2 mL) was added and stirred for 1 hour. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals chloroform - was recrystallized from hexane to give the title compound (24 mg, 60%) as a slightly yellow solid.

Example 36 4-Methoxy-N-{5-[4- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1- production of methyl piperidin-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] thiophene-2 preparation of-yl} amino) -1-oxobutan-2-yl] carbamate

Figure JPOXMLDOC01-appb-C000091

5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-amine and 2 - ({[(9H-fluoren-9-yl) methoxy] carbonyl using} amino) -4-methoxy butanoic acid in the same manner as in step 1 of example 1 to give the title compound (crude).

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

Figure JPOXMLDOC01-appb-C000092
(9H-fluoren-9-yl) methyl [4-methoxy-1 - ({5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2 yl} amino) -1-oxobutan-2-yl] carbamate (220 mg, in DMF (5 mL) solution of 0.46 mmol), morpholine (0.5 mL) was added and the stirred overnight. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: saturated ammonia methanol = 90: 10) as eluents, to give the title compound (31 mg, 2 steps 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- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 4-yl) amino] butanamide Using 2-amino-4-methoxy -N- {5- [4- (1- methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene -2 - using yl} butanamide in the same manner as in step 1 of example 5 to give the title compound (10%) as a pale yellow amorphous.

Example 37 N- {5- [2,5- dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino ] acetamide

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

Figure JPOXMLDOC01-appb-C000093

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

Step 2:
1- [2,5-dimethoxy-4- (5-nitro-2-yl) phenyl] -4-methylpiperazine production

Figure JPOXMLDOC01-appb-C000094

And 2-bromo-5-nitro-thiophene 1 - [2,5-dimethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -4-methyl with piperazine, in the same manner as in step 3 of example 1 to give the title compound (25% 2 steps yield) as a red-brown solid.

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:
5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-amine:

Figure JPOXMLDOC01-appb-C000095

Using 1- [2,5-dimethoxy-4- (5-nitro-2-yl) phenyl] -4-methylpiperazine, in the same manner as in Step 2 of Example 2, the title compound (crude) Red It was obtained as an amorphous.

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

Figure JPOXMLDOC01-appb-C000096

5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-amine and 2- [2,2,2-trifluoro-N-(1-methylpiperidine -4 - yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (68% 2 steps yield) as a red-brown oil.

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:
N-{5-[2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methylpiperidin-4-yl) amino] acetamide producing N- [2 - ({5- [2,5- dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} amino) -2-oxoethyl] -2,2,2 - with trifluoroacetic-N-(-4-1-methylpiperidin-4-yl) acetamide in the same manner as in step 8 of example 9, to give the title compound (75%) as a brown amorphous.

Example 38 N- {5- [3- cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide step 1: Preparation of
2- (4-methylpiperazin-1-yl) -5-a (5-nitro-2-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000097

2-bromo-5-nitro-thiophene and 2- (4-methylpiperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile using, in the same manner as in step 3 of example 1 to give the title compound (crude).

Step 2:
5- (5-amino-2-yl) -2- (4-methylpiperazin-1-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000098

2- (4-methylpiperazin-1-yl) -5-using (5-nitro-2-yl) benzonitrile In the same manner as in step 2 of Example 2, gave the title compound (crude) .

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

Figure JPOXMLDOC01-appb-C000099

5- (5-amino-2-yl) -2- (4-methylpiperazin-1-yl) benzonitrile and 2- [2,2,2-trifluoro-N-(1-methylpiperidin-4- yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (69% 3 steps yield) as a light brown solid.

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:
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 - using N-(1-methylpiperidin-4-yl) acetamide in the same manner as in step 8 of example 9, to give the title compound (86%) as a pale yellow crystalline powder.

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

Step 1:
2- (4-methylpiperazin-l-yl) -5- (5-nitro-thiophen-2-yl) benzamide

Figure JPOXMLDOC01-appb-C000100

2- (4-methylpiperazin-l-yl) -5- (5-nitro-thiophen-2-yl) benzonitrile (300 mg, 0.91 mmol) in toluene (10 mL) solution of acetaldehyde oxime (270 mg, 4.57 mmol), tris (triphenylphosphine) rhodium chloride (93 mg, was added 0.091 mmol). At 100 ℃, the mixture was stirred for 10 hours. Allowed to warm to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 18: 1) eluant to give the title compound (crude).

Step 2:
5- (5-amino-2-yl) -2- (4-methylpiperazin-1-yl) benzamide

Figure JPOXMLDOC01-appb-C000101

2- (4-methylpiperazin-l-yl) -5- (5-nitro-thiophen-2-yl) with benzamide In the same manner as in step 2 of Example 2, gave the title compound (crude).

Step 3:
2- (4-methylpiperazin-l-yl) -5- (5- {2- [4- 2,2,2-trifluoro-N-(1-methylpiperidin-4-yl) acetamido] acetamide} thiophene -2 - yl) benzamide

Figure JPOXMLDOC01-appb-C000102

5- (5-amino-2-yl) -2- (4-methylpiperazin-1-yl) benzamide and 2- [2,2,2-trifluoro-N-(-4-1-methylpiperidin-4-yl ) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (3 steps 35% yield) as a pale yellow solid.

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:
2- (4-methylpiperazin-l-yl) -5- (5- {2 - [(1-methyl-piperidin-4-yl) amino] acetamide} thiophen-2-yl) benzamide 2- (4- methylpiperazine-1-yl) -5- (5- {2- [4- 2,2,2-trifluoro-N-(1-methylpiperidin-4-yl) acetamido] acetamide} thiophen-2-yl) benzamide used, in the same manner as in step 8 of example 9, to give the title compound (89%) as a pale yellow solid.

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

Step 1:
tert- butyl 4- {4- [5- (3 - ([1,4'-bipiperidin] -1'-yl) propanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H ) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000103

tert- butyl 4- [4- (5-amino-2-yl) phenyl] -5,6-dihydropyridine -1 (2H) - carboxylate (100 mg, 0.28 mmol) in methylene chloride (1 mL) solution of under ice-cooling, DIPEA (54.2 mg, 0.42 mmol) and 3-bromopropanoyl chloride (58 mg, 0.34 mmol) was added and stirred for 1 hour. TEA (152 mg, 0.70 mmol), and 1,4'-bipiperidine (118 mg, 0.70 mmol) was added and stirred for another 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with 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) as eluents, to give 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} propanamide tert- butyl 4- {4- [5- (3 - ([1,4'-bipiperidin] -1'-yl) propanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H) - using a carboxylate, in the same manner as in step 5 of example 13 to give the title compound (93%) as a slightly gray solid.

Example 41 3 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1- methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl ] thiophen-2-yl} propanamide 3 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1,2,3,6- tetrahydropyridine -4 - yl) using phenyl] thiophen-2-yl} propanamide and formaldehyde, in the same manner as in step 1 of example 5 to give the title compound (58%) as a yellow solid.

Example 42 Benzyl 2- [4- (4- {5- [3 - ([1,4'-bipiperidin] -1'-yl) propanamide] thiophen-2-yl} phenyl) -5,6-dihydropyridine -1 (2H) - yl] production of acetate 3 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1,2,3,6- tetrahydropyridine -4 - yl) phenyl] using thiophene-2-yl} propanamide benzyl chloroacetate, in the same manner as in example 23 to give 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 ] thiophen-2-yl} propanamide 3 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1,2,3,6- tetrahydropyridine -4 - yl) using phenyl] thiophen-2-yl} propanamide and acetone, in the same manner as in step 1 of example 5 to give 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 production 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) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000104

tert- butyl 4- [4- (5-amino-2-yl) phenyl] -5,6-dihydropyridine -1 (2H) - with carboxylate and chloroacetyl chloride and 1,4'-bipiperidine, performed in a similar manner to step 1 of example 40 to give the title compound (84%) as a pale 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} acetamide

Figure JPOXMLDOC01-appb-C000105

tert- butyl 4- {4- [5- (2 - ([1,4'-bipiperidin] -1'-yl) acetamido) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H) - using a carboxylate, in the same manner as in step 5 of example 13 to give the title compound (crude) as a pale brown amorphous.

Step 3:
2 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} acetamide 2 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1,2,3,6- tetrahydropyridin-4-yl) phenyl ] using thiophene-2-yl} acetamide and formaldehyde, in the same manner as in step 1 of example 5 to give the title compound (85% 2 steps yield) as a yellow solid.

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

Step 1:
tert- butyl 4- {4- [5- (4 - ([1,4'-bipiperidin] -1'-yl) butanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000106

tert- butyl 4- [4- (5-amino-2-yl) phenyl] -5,6-dihydropyridine -1 (2H) - with carboxylate and 4-bromo-butanoyl chloride and 1,4'-bipiperidine Te, in a similar manner to step 1 of example 40 to give the title compound (18%) as a pale 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

Figure JPOXMLDOC01-appb-C000107

tert- butyl 4- {4- [5- (4 - ([1,4'-bipiperidin] -1'-yl) butanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H) - using a carboxylate, in the same manner as in step 5 of example 13 to give the title compound (crude) as a pale yellow solid.

Step 3:
4 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-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 ] using thiophene-2-yl} butanamide and formaldehyde, in the same manner as in step 1 of example 5 to give the title compound (54% 2 steps yield) as a yellow solid.

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

Step 1:
tert- butyl 4- {4- [5- (5 - ([1,4'-bipiperidin] -1'-yl) pentanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H ) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000108

tert- butyl 4- [4- (5-amino-2-yl) phenyl] -5,6-dihydropyridine -1 (2H) - with carboxylate and 5-bromo-pentanoyl chloride and 1,4'-bipiperidine Te, in a similar manner to step 1 of example 40 to give the title compound (75%) as a pale 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 pentane amide

Figure JPOXMLDOC01-appb-C000109

tert- butyl 4- {4- [5- (5 - ([1,4'-bipiperidin] -1'-yl) pentanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H ) - with carboxylate in the same manner as in step 5 of example 13 to give the title compound (crude) as a pale yellow solid.

Step 3:
5 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} production of pentanamide 5 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1,2,3,6- tetrahydropyridin-4-yl) using phenyl] thiophen-2-yl} pentanamide with formaldehyde, in the same manner as in step 1 of example 5 to give the title compound (52% 2 steps yield) as a yellow solid.

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

Step 1:
tert- butyl 4- {4- [5- (6 - ([1,4'-bipiperidin] -1'-yl) hexanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H ) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000110

tert- butyl 4- [4- (5-amino-2-yl) phenyl] -5,6-dihydropyridine -1 (2H) - with carboxylate and 6-bromo-hexanoyl chloride and 1,4'-bipiperidine Te, in a similar manner to step 1 of example 40 to give the title compound (66%) as a pale 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} production hexanamide

Figure JPOXMLDOC01-appb-C000111

tert- butyl 4- {4- [5- (6 - ([1,4'-bipiperidin] -1'-yl) hexanamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H ) - with carboxylate in the same manner as in step 5 of example 13 to give the title compound (crude) as a pale brown amorphous.

Step 3:
6 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} manufacturing hexanamide 6 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (1,2,3,6- tetrahydropyridin-4-yl) using phenyl] thiophen-2-yl} hexanamide and formaldehyde, in the same manner as in step 1 of example 5 to give the title compound (79% 2 steps yield) as a yellow solid.

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

Step 1:
5- (4-methylpiperazin-1-yl) -2- (5-nitro-2-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000112

2-bromo-5-nitro-thiophene and 5- (4-methylpiperazin-1-yl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile using, in the same manner as in step 3 of example 1 to give the title compound (crude).

Step 2:
2- (5-amino-2-yl) -5- (4-methylpiperazin-1-yl) benzonitrile

Figure JPOXMLDOC01-appb-C000113

5- (4-methylpiperazin-1-yl) -2-using (5-nitro-2-yl) benzonitrile In the same manner as in step 2 of Example 2, gave the title compound (crude) .

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

Figure JPOXMLDOC01-appb-C000114

2- (5-amino-2-yl) -5- (4-methylpiperazin-1-yl) benzonitrile and 2- [2,2,2-trifluoro-N-(1-methylpiperidin-4- yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (57% 3 steps yield) as a light brown solid.

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:
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 in the same manner as in step 8 of example 9, to give the title compound (81%) as a yellow amorphous.

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

Step 1:
4- (5-Nitro-2-yl) production of phenol

Figure JPOXMLDOC01-appb-C000115

And 2-bromo-5-nitro-thiophene using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol In the same manner as in step 3 of Example 1 to give the title compound (crude).

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

Figure JPOXMLDOC01-appb-C000116

4- (5-Nitro-2-yl) phenol (500 mg, 2.26 mmol) was dissolved in DMF (10 mL), potassium carbonate (624 mg, 3.4 mmol), 1,2- dibromoethane (300 [mu] L, 3.4 mmol) was added and stirred for 2 hours at 60 ° C., the crystals were collected by filtration was added water precipitation. Acetonitrile was added to the crystals were collected by filtration, 1-methylpiperazine (500 [mu] L, 4.52 mmol), potassium carbonate (625 mg, 4.5 mmol) and the mixture was stirred for 13 hours at 60 ° C.. The reaction mixture was added with a saturated sodium bicarbonate solution, extracted with chloroform, the organic layer was dried over sodium sulfate, the residue obtained by concentration after filtration was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 80: 20, and purified using a gradient) to give the title compound (151 mg, 2 steps yield 14%) as a yellow solid.

1 H-NMR (400MHz, 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:
5- preparation of {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophene-2-amine

Figure JPOXMLDOC01-appb-C000117

Using 1-methyl-4- {2- [4- (5-nitro-2-yl) phenoxy] ethyl} piperazine In the same manner as in step 2 of Example 2, the title compound (crude) brown amorphous It was obtained as a.

Step 4:
2,2,2-trifluoro -N- {2 - [(5- {4- [2- (4- methylpiperazin-1-yl) ethoxy] phenyl} thiophene-2-yl) amino] -2-oxoethyl } -N- (-4- 1- methyl-piperidin-yl) acetamide

Figure JPOXMLDOC01-appb-C000118

5- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} thiophene-2-amine and 2- [2,2,2-trifluoro-N-(1-methylpiperidin-4- yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (crude) as a brown amorphous.

Step 5:
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} thiophene-2-yl) amino] -2-oxoethyl }-N-(-4-1-methylpiperidin-4-yl) with acetamide in the same manner as in step 8 of example 9, to give the title compound (16% 3 steps yield) as a yellow amorphous.

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

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

Figure JPOXMLDOC01-appb-C000119

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

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

Figure JPOXMLDOC01-appb-C000120

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

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

Figure JPOXMLDOC01-appb-C000121

5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiophene-2-amine and 2- [2,2,2-trifluoro-N-(1-methylpiperidin-4- yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (crude) as a brown amorphous.

Step 4:
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- using (1-methyl-piperidin-4-yl) acetamide in the same manner as in step 8 of example 9, to give the title compound (13% 3 steps yield) as a yellow amorphous.

EXAMPLE 51 N- [5- (4 - {[5- (4- methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-2-yl] -2 - [(1-methylpiperidin-4-yl preparation of) amino] acetamide

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

Figure JPOXMLDOC01-appb-C000122

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

Step 2:
5 - preparation of (4 {[5- (4-methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-2-amine

Figure JPOXMLDOC01-appb-C000123

Using 1-methyl-4- {5- [4- (5-nitro-2-yl) phenoxy] pentyl} piperazine In the same manner as in step 2 of Example 2, the title compound (crude) brown amorphous It was obtained as a.

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

Figure JPOXMLDOC01-appb-C000124

5- (4 - {[5- (4-methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-2-amine and 2- [2,2,2-trifluoro-N-(1-methylpiperidine 4-yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (crude) as a brown amorphous.

Step 4:
N- [5- (4 - {[5- (4- methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-2-yl] -2 - [(1-methylpiperidin-4-yl) amino] acetamide 2,2,2-trifluoro -N- (2 - {[5- (4 - {[5- (4- methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-2-yl] amino} -2-oxoethyl) -N- (using 1-methyl-piperidin-4-yl) acetamide in the same manner as in step 8 of example 9, the title compound (14% 3 steps yield) as a yellow amorphous Obtained.

Example 52 N- {5- [4- (1- methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} -2 - {[(1-methyl-piperidin - 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 dihydropyridine -1 (2H) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000125

tert- butyl 4- [4- (5-amino-2-yl) phenyl] -5,6-dihydropyridine -1 (2H) - carboxylate (100 mg, 0.28 mmol) in methylene chloride (1 mL) solution of , DIPEA under ice-cooling (73 [mu] L, 0.42 mmol), chloroacetyl chloride, and the mixture was stirred for 30 minutes. 1-Boc-4-aminomethyl-piperidine (150 mg), potassium carbonate (100 mg), was added acetonitrile (1 mL). The temperature was raised to 60 ° C., and stirred for 2 hours. Under ice cooling, a saturated aqueous solution of sodium hydrogen carbonate was added, and extracted with chloroform. The organic layer was washed with 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 give the give 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-trifluoroacetamide) acetamido] thiophene - 2-yl} phenyl) -5,6-dihydropyridin -1 (2H) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000126

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

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 preparation of) ethyl] -N- (piperidin-4-ylmethyl) acetamide

Figure JPOXMLDOC01-appb-C000127

tert- butyl 4- (4- {5- [2- (N - {[1- (tert- butoxycarbonyl) piperidin-4-yl] methyl} -2,2,2-trifluoroacetamide) acetamido] thiophene - 2-yl} phenyl) -5,6-dihydropyridin -1 (2H) - using a carboxylate, in the same manner as in step 5 of example 13 to give the title compound (crude) as a brown oil.

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

Figure JPOXMLDOC01-appb-C000128

2,2,2-trifluoro -N- [2- oxo-2 - ({5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl} amino ) ethyl] -N- (using piperidine-4-ylmethyl) acetamide in the same manner as in step 1 of example 5 to give 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 ) 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 - [(using 1-methyl-piperidin-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 N- (5- {4- [3- (4- methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (pyrrolidin-1-yl) production process 1 pentanamide :
Preparation of 1-methyl-4- {3- [4- (5-nitro-2-yl) phenoxy] propyl} piperazine

Figure JPOXMLDOC01-appb-C000129

4- (5-Nitro-2-yl) with phenol and 1,3-dibromopropane and 1-methylpiperazine, in the same manner as in Step 2 of Example 49 to give the title compound (25%).

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:
5- preparation of {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophene-2-amine

Figure JPOXMLDOC01-appb-C000130

Using 1-methyl-4- {3- [4- (5-nitro-2-yl) phenoxy] propyl} piperazine, in the same manner as in Step 2 of Example 2, gave the title compound (crude) .

Step 3:
N-(5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (pyrrolidin-1-yl) Preparation of pentanamide 5- {4- [3- (4-methylpiperazin-1-yl) propoxy] with phenyl} thiophene-2-amine and 5-bromo-pentanoyl chloride and pyrrolidine, in the same manner as in step 1 of example 40, 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 5 using {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophene-2-amine and the 5-bromo-pentanoyl chloride 1,4'-bipiperidine in the same manner as in step 1 of example 40 to give the title compound (12%) as a brown amorphous.

Preparation of Example 55 N- (5- {4- [3- (4- methylpiperazin-1-yl) propoxy] phenyl} thiophen-2-yl) -5- (piperidin-1-yl) pentanamide 5- using {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophene-2-amine and 5-bromo-pentanoyl chloride and piperidine, in the same manner as in step 1 of example 40, the title compound (15%) 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] acetamide

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

Figure JPOXMLDOC01-appb-C000131

5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiophene-2-amine and 2- [2,2,2-trifluoro-N-(1-methylpiperidin-4- yl) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (crude).

Step 2:
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-(-4-1-methylpiperidin-4-yl) with acetamide in the same manner as in step 8 of example 9, to give the title compound (4% 2 steps yield).

EXAMPLE 57 N- [3 - ([1,4'- bipiperidin] -1'-yl) propyl] -5- [1- (1-methylpiperidin-4-yl)-1H-pyrazol-4-yl] production of thiophene-2-carboxamide

Step 1:
tert- butyl 4- [4- (5 - {[3 - ([1,4'-bipiperidin] -1'-yl) propyl] carbamoyl} thiophene-2-yl)-1H-pyrazol-1-yl] piperidine -1-carboxylate

Figure JPOXMLDOC01-appb-C000132

N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5-bromothiophene-2-carboxamide and tert- butyl 4- [4- (4,4,5,5-tetra with methyl 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl] piperidine-1-carboxylate in the same manner as in step 3 of example 1, the title compound (crude) It was 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} thiophene-2-yl)-1H-pyrazole -1 - yl] piperidine-1-carboxylate (98 mg, 0.17 mmol) was dissolved in methylene chloride (2 mL), and stirred for 0.5 hours added TFA (0.5 mL), the reaction was concentrated and the residue Obtained. The resulting residue in methylene chloride (0.5 mL), acetic acid (2 mL), aqueous formaldehyde solution (36% aqueous solution, 15 [mu] L, 0.18 mmol), sodium triacetoxyborohydride (21 mg, 0.1 mmol) was added, at room temperature stirred for 2 hours, the reaction mixture was added with a saturated sodium bicarbonate solution, extracted with chloroform, the organic layer was dried over sodium sulfate, the residue obtained by concentration after filtration was purified by silica gel chromatography (chloroform: saturated ammonia methanol = 90: 10) as eluents, to give the title compound (23 mg, 2 steps yield 21%) as a pale yellow solid.

EXAMPLE 58 6 - [(dimethylamino) methyl] -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} nicotinic amides of manufacturing 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-amine and 6 - with [(dimethylamino) methyl] nicotinate in the same manner as in step 1 of example 1 to give the title compound (46%) as a yellow solid.

Example 59 N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -4- (4-methylpiperazin-1- yl) benzamide 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-amine and 4- (4-methylpiperazin-1-yl) with benzoic acid in analogy to step 1 of example 1 to give the title compound (4%) as a yellow solid.

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

Step 1:
Methyl 4 - preparation of {[N- (-4- 1- methyl-piperidin-yl) -2-nitrophenyl sulfonamide] methyl} benzoate

Figure JPOXMLDOC01-appb-C000133

Methyl 4 - with {[(1-methyl-piperidin-4-yl) amino] methyl} benzoate and 2-nitrobenzenesulfonyl chloride, in the same manner as in Step 4 of Example 2, pale green title compound (62%) It was obtained as an 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:
4 - preparation of {[N- (-4- 1- methyl-piperidin-yl) -2-nitrophenyl sulfonamide] methyl} benzoic acid

Figure JPOXMLDOC01-appb-C000134

Methyl 4 - using {[N- (1- methylpiperidin-4-yl) -2-nitrophenyl sulfonamide] methyl} benzoate In the same manner as in step 5 of Example 2, the title compound (crude) fine It was obtained as a yellow solid.

Step 3:
N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -4 - {[N- (1- methylpiperidine -4 - yl) -2-nitrophenyl sulfonamide] production of methyl} benzamide

Figure JPOXMLDOC01-appb-C000135

5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2-amine and 4 - {[N-(4 1-methyl-piperidin-yl) - using 2-nitrophenyl sulfonamide] methyl} benzoic acid in the same manner as in step 1 of example 1 to give 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 ) amino] methyl} benzamide N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -4 - {[N - (1-methylpiperidin-4-yl) with 2-nitrophenyl sulfonamide] methyl} benzamide in the same manner as in step 8 of example 2, the title compound (11% 2 steps yield) of an orange solid It was obtained as a.

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

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

Figure JPOXMLDOC01-appb-C000136

Methyl 2- [6- (hydroxymethyl) pyridin-3-yl] acetate (190 mg, 1.05 mmol) in methylene chloride (3.5 mL) solution of under ice-cooling, thionyl chloride (179 mg, 1.58 mmol) was added , and the mixture was stirred for 4 hours. Concentrated under reduced pressure, under ice-cooling, methylene chloride (3.5 ml), TEA (214 mg, 2.1 mmol), aqueous dimethylamine (9.5M, 0.16 mL, 1.52 mmol) was added. And the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with 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) as eluents, to give the title compound (78.8 mg, 36%) as a brown oil.

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

Figure JPOXMLDOC01-appb-C000137

Methyl 2 - using {6 [(dimethylamino) methyl] pyridin-3-yl} acetate In the same manner as in step 5 of Example 2 to give the title compound (crude) as a pale yellow solid.

Step 3:
tert- butyl 4- {4- [5- (2- {6 - [(dimethylamino) methyl] pyridin-3-yl} acetamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H ) - preparation of carboxylate

Figure JPOXMLDOC01-appb-C000138

tert- butyl 4- [4- (5-amino-2-yl) phenyl] -5,6-dihydropyridine -1 (2H) - carboxylate and 2- {6 - [(dimethylamino) methyl] pyridine -3 - yl} with acetic acid in the same manner as in step 1 of example 1 to give the title compound (crude) as a pale brown amorphous.

Step 4:
2- {6 - [(dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6- tetrahydropyridin-4-yl) phenyl] thiophene-2-yl } acetamide tert- butyl 4- {4- [5- (2- {6 - [(dimethylamino) methyl] pyridin-3-yl} acetamide) thiophen-2-yl] phenyl} -5,6-dihydropyridine -1 (2H) - using a carboxylate, in the same manner as in step 5 of example 13 to give the title compound (24% 2 steps yield) as an orange solid.

Example 62 2- {6 - [(dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-yl} acetamide 2- {6 - [(dimethylamino) methyl] pyridin-3-yl} -N- {5- [4- (1,2,3,6- tetrahydropyridine - using 4-yl) phenyl] thiophen-2-yl} acetamide and formaldehyde, in the same manner as in step 1 of example 5 to give the title compound (71%) as an orange solid.

Example 63 N- {5- [6- (4- methylpiperazin-l-yl) pyridin-3-yl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide production of

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

Figure JPOXMLDOC01-appb-C000139

And 2-bromo-5-nitro-thiophene 1-methyl-4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) piperidin-2-yl] piperazine used, in the same manner as in step 3 of example 1 to give the title compound (crude) as an orange solid.

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

Figure JPOXMLDOC01-appb-C000140

Using 1-methyl-4- [5- (5-nitro-2-yl) pyridin-2-yl] piperazine, in the same manner as in Step 2 of Example 2, the title compound (2 step yield 63% ) 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-l-yl) pyridin-3-yl] thiophen-2-yl} amino) -2-oxoethyl] -N-(-4-1-methylpiperidin-4-yl) acetamide

Figure JPOXMLDOC01-appb-C000141

5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophene-2-amine and 2- [2,2,2-trifluoro-N-(-4-1-methylpiperidin-4-yl ) acetamido] with acetic acid in the same manner as in step 6 and 7 of example 2, gave the title compound (61%) as a light brown solid.

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:
N- {5- [6- (4- methylpiperazin-l-yl) pyridin-3-yl] thiophen-2-yl} -2 - [(1-methylpiperidin-4-yl) amino] acetamide 2 , 2,2-trifluoro -N- [2 - ({5- [6- (4- methylpiperazin-l-yl) pyridin-3-yl] thiophen-2-yl} amino) -2-oxoethyl] - using N-(1-methylpiperidin-4-yl) acetamide in the same manner as in step 8 of example 9 to give the title compound (quantitative) as a light brown solid.

The physical properties of the above-mentioned embodiments the obtained compound are shown below.

Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157

Establishment human TLR9 expressing cells [Test Example 1] TLR9 expressing reporter cell TLR9 activation inhibition test using 1) TLR9 expression reporter cells, Invivogen company to HEK293 human embryonic kidney cell line was expressed human TLR9 cells more were purchased (hTLR9 / 293xL). hTLR9 / 293xL were subcultured using Dulbecco's modified Eagle's medium containing 10% fetal calf serum, penicillin, streptomycin (DMEM (sigma)). pGL4.28 linked firefly luciferase gene repeated four NFκB recognition sequence (Promega), was genetically introduced by lipofection using Fugene 6 (Roche). Hygromycin to select blasticidin-resistant cell clones, was TLR9 expressing reporter cell (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. Test compound diluted with DMEM to (10 [mu] L) was added to a final concentration of 0.01,0.03,0.1,0.3,1MyuM. CpG-B DNA after 1 hour a TLR9 ligand (ODN2006) (Invivogen) was added to a final concentration of 1 [mu] M (10 [mu] L). Luciferase activity was measured as TLR9 activity after incubation for 4 hours CO 2 incubator as the total 100 [mu] L. Luciferase activity was added 60μL of Bright Glo (Promega), and luminescence was measured by a multi microplate reader ARVO (Perkin Elmer). As 100% luciferase activity when no addition of test compound, was calculated 50% inhibition concentration of each test compound (IC 50 value).

3) Results activity of the above-mentioned embodiments obtained compound (IC 50 value) shown in Table 1.

Figure JPOXMLDOC01-appb-T000158

Establishment Human TLR7 expressing cell Test Example 2] TLR7 expressing reporter cell TLR7 activation inhibition test using 1) TLR7 expressing reporter cells, Invivogen company to HEK293 human embryonic kidney cell line was expressed human TLR7 cells more were purchased (hTLR7 / 293xL). hTLR7 / 293xL were subcultured using Dulbecco's modified Eagle's medium containing 10% fetal calf serum, penicillin, streptomycin (DMEM (sigma)). pGL4.28 linked firefly luciferase gene repeated four NFκB recognition sequence (Promega), was genetically introduced by lipofection using Fugene 6 (Roche). Hygromycin to select blasticidin-resistant cell clones were the TLR7 expressing reporter cell (hTLR7 NFκB-luc / 293xL).
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. Test compound diluted with DMEM to (10 [mu] L) was added to a final concentration of 0.03,0.1,0.3,1,3,10MyuM. A TLR7 ligand Imiquimod the (Invivogen) was added to a final concentration of 10μM after 1 hour (10 [mu] L). After incubation for 4 h CO 2 incubator as the sum 100μL luciferase activity was measured as a TLR7 activity. Luciferase activity was added 60μL of Bright Glo (Promega), and luminescence was measured by a multi microplate reader ARVO (Perkin Elmer). As 100% luciferase activity when no addition of test compound, was calculated 50% inhibition concentration of each test compound (IC 50 value).
3) Results activity of the above-mentioned embodiments obtained compound (IC 50 value) shown in Table 2.

Figure JPOXMLDOC01-appb-T000159

From the results of Test Examples 1 and 2, the compounds of the present invention was confirmed to have strong TLR7 and 9 inhibitory activity. Accordingly, a thiophene derivative represented by the general formula (1) of the present invention, as TLR7 and 9 inhibitors, diseases associated with the activation of TLR7 and 9 signal, for example, RA, SLE, SS, MS, IBD, psoriasis sex arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, to be useful as an active ingredient of a prophylactic agent or therapeutic agent for pathological conditions of transplant rejection and GvHD was found.

[Test Example 3] rheumatoid arthritis (RA) treatment effect of the compound of the condition suppression Example 5 of TLR9 activation inhibitory compounds using arthritis model, mice collagen-induced arthritis model (mouse CIA model is an animal model of RA was evaluated in). (FDA, CBER, CDER, CDRH:. Guidance for industry -Clinical development programs for drugs, devices, and biological products for the treatment of rheumatoid arthritis (RA) - (1999)).

(1) Animals used and the group setting animals were used male DBA / 1 J mice (Charles River Japan Inc.).
The weight of the DBA / 1 J mice 7 weeks old were measured were divided into groups with blocking allocation of single variables it to index. Group configuration, control - Le group (administered vehicle (0.5% hydroxypropyl methyl cellulose solution) administration group), the compound 25 mg / kg administered group in Example 5 was a compound 50 mg / kg administered group in Example 5.

(2) Test method 0.3% type II collagen solution (Collagen Technology Workshop) and physiological saline solution (Otsuka Pharmaceutical Industry) 2 was mixed in the ratio of 1, the preparation of type 2 collagen solution 0.2% did. Then, 0.2% type II collagen solution and Adjuvant Complete Freund a (DIFCO) with an equal volume mixed, the initial feeling effect emulsion was prepared by cooling with ice handy micro homogenizer NS-310E (Microtec Nichion). After shaved the ridge of the animal clippers, two left and right positions of the ridge portion, the first sense of action emulsion was administered in each 0.05mL intradermal. After the initial sensitization end, the first sensitization 34 days until (after the additional sensitization 14 days), was orally administered once of the chemical per day.

It was added sensitization by the following procedure in the first sensitization 20 days later. Type 2 collagen solution and saline 0.3% 2 were mixed to a ratio of 1 to prepare a type 2 collagen solution 0.2%. Then, 0.2% type II collagen solution and Adjuvant Incomplete Freund a (DIFCO) with an equal volume mixed to prepare an additional sense of action emulsion Handy Micro Homogenizer NS-310E under ice-cooling. The prepared additional intensifying function emulsion 0.1 mL, performs additional sensitization by administering to the ridge intradermally, to induce arthritis.
Judgment of limb swelling is the primary endpoint, the initial decision of 7 days after the additional sensitization, intermediate decision after 10 days, the final judgment of a total of three times after 14 days, arthritis by three of the judges under blind score ( It was carried out in arthritis score) judgment. Evaluation criteria of the swelling, the reference of four stages shown below is applied to each limb was the sum of the extremities and arthritic scores of the individual.

0 points: No swelling 1 point: 1 swelling in the finger is recognized, or limb whole to a slight case of swelling is observed 2 points: is observed obvious swelling in the entire 2 swelling is observed in ~ 4 finger, or a limb when 3 points: swelling is observed in all the fingers, or observed a strong swelling throughout limb, or obvious swelling was observed on the entire limb, and if the swelling is observed in two or more fingers

As a secondary endpoint, using the orbital blood samples after the additional sensitization 15 days, it was measured in the anti-type II collagen IgG antibody titers in plasma by ELISA.

(3) Test results Fig. 1 shows the time course of arthritic score with the average value. Control - Le group (drug-administered group), in the compounds 25 mg / kg dose group and 50 mg / kg administered group in Example 5, Mausukora - shows the time course of plasminogen induced arthritis model of arthritis score. The control group, and later after the additional sensitization 7 days, an increase in the arthritis score was observed. In contrast, the group administered the compound of Example 5, showed a significant inhibitory effect dose dependent suggesting a dose of 50 mg / kg. Incidentally, ** in the drawing, in comparison with the Steel of multiple comparison tests the control group, indicating that the risk rate is less than 1% (p <0.01).

Figure 2 shows the anti-type II collagen IgG antibody titer after additional sensitization 15 days average. Control - Le group (drug-administered group), in the compounds 25 mg / kg dose group and 50 mg / kg administered group in Example 5, Mausukora - anti type II collagen IgG antibody titer after adding sensitization 15 days of plasminogen induced arthritis model It illustrates. Control - against Le group, the 25 and 50 mg / kg administered group of the compound of Example 5, showed a significant inhibitory effect dose dependency is suggested. Incidentally, ** and * in the figure, in comparison with the Steel of multiple comparison tests the control group, risk rate of less than 5%, respectively (p <0.05) and less than 1% (p <0.01) indicating that it is.

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

The present invention is a thiophene derivative or a salt thereof represented by the general formula (1), or a solvate thereof, found for the first time to have excellent TLR3,7 and / or 9 inhibitory action, autoimmune diseases, there is provided inflammation, allergy, asthma, graft rejection, the prevention and / or therapeutic agent for cardiomyopathy due to graft versus host disease (GvHD) or sepsis. The present invention, autoimmune disease, inflammation, provide allergy, asthma, graft rejection, the prevention and / or therapeutic agent for cardiomyopathy due to graft versus host disease (GvHD) or sepsis are useful in the pharmaceutical industry , and has industrial applicability.

Claims (14)

  1. The following general formula (1):
    Figure JPOXMLDOC01-appb-C000001
    [In the formula,
    X is, the following equation (2):
    Figure JPOXMLDOC01-appb-C000002
    {In the formula,
    Ring A represents a nitrogen-containing aliphatic heterocyclic saturated or unsaturated,
    Ring B represents an aliphatic carbocycle saturated or unsaturated, aromatic carbocyclic, a nitrogen-containing aliphatic heterocyclic saturated or unsaturated, or a nitrogen-containing aromatic heterocycle,
    Wherein said each of ring A and ring B, halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a 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 substituent selected from alkyl groups may have one to three,
    Q 2 is a single bond, or a C 1-6 an alkylene group, the C 1-6 alkylene group wherein 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 4 is a single bond, an oxygen atom or an NH group, wherein the NH group, C 1-6 alkyl, hydroxy C 1-6 alkyl group, 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 the formula (3):
    Figure JPOXMLDOC01-appb-C000003
    {In the formula,
    Ring C is a saturated or unsaturated nitrogen-containing aliphatic heterocyclic, or show the nitrogen-containing aromatic heterocyclic ring, wherein said Ring C is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyl oxy group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group , C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, a substituent selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group may have 1 to 3,
    Q 3 are a single bond, C 1-6 an alkylene group or a C 2-6 alkenylene group, wherein said C 1-6 alkylene group or C 2-6 alkenylene group, a halogen atom, an oxo group, a hydroxyl group, C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 has 1-2 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups it may be}
    The shows,
    Ring Y represents an aliphatic carbocycle saturated or unsaturated, aromatic carbocyclic, a nitrogen-containing aliphatic heterocyclic saturated or unsaturated, or a nitrogen-containing aromatic heterocycle,
    Wherein said ring Y is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a 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 alkylamino C 1-6 alkyl groups, and groups of formula (4):
    Figure JPOXMLDOC01-appb-C000004
    {In the formula,
    Q 4 are a single bond, C 1-6 an alkylene group or a C 2-6 alkenylene group, the C 1-6 alkylene group or C 2-6 alkenylene group wherein a halogen atom, an oxo group, a hydroxyl group, C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 has 1-2 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups at best,
    R 5 represents a single bond, an oxygen atom or an NH group, wherein the NH group, C 1-6 alkyl, hydroxy C 1-6 alkyl group, 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 an aliphatic carbocycle saturated or unsaturated, aromatic carbocyclic, a nitrogen-containing aliphatic heterocyclic saturated or unsaturated, or a nitrogen-containing aromatic heterocycle,
    Wherein said ring D is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a 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 a di-C 1-6 alkylamino C 1-6 substituent selected from alkyl groups may have 1 to 3}
    Substituents selected from may have one to three,
    However, X represents formula (3), and when ring C is showing the nitrogen-containing aliphatic heterocyclic saturated or unsaturated, ring Y is aliphatic saturated or unsaturated having a substituent represented by the formula (4) family carbocyclic indicates aromatic carbocyclic, saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocycle,
    However, having a substituent ring Y is represented by the formula (4), and when ring D represents an aromatic carbocyclic ring Y is an aliphatic carbon ring saturated or unsaturated, nitrogen-containing saturated or unsaturated aliphatic heterocycle, or show the nitrogen-containing aromatic heterocycle,
    However, X represents formula (3), and when indicating a C 1-6 alkylene group Q 3 has an oxo group, Ring Y aliphatic carbocycle saturated or unsaturated, or saturated or unsaturated, nitrogen-containing represents an aliphatic heterocyclic ring, wherein said ring Y is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkyl amino group, di C 1-6 alkylamino group, di C 1-6 alkylamino C 1-6 alkyl group, and may have 1 to 3 substituents selected from the group of the formula (4),
    Q 1 is a single bond, C 1-6 an alkylene group or a C 2-6 alkenylene group, wherein said C 1-6 alkylene group or C 2-6 alkenylene group, a halogen atom, an oxo group, a hydroxyl group, C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 has 1-2 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups at best,
    However, X represents formula (3), and when indicating a C 1-6 alkylene group Q 3 has an oxo group, Q 1 represents a C 1-6 alkylene group or C 2-6 alkenylene group, wherein C 1-6 alkylene group or C 2-6 alkenylene group for Q 1 represents 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 and C 6-10 aryl C 1-3 substituent selected from alkyl groups may have 1 to 2,
    R 1 is a single bond, an oxygen atom or an NH group, wherein the NH group, C 1-6 alkyl, hydroxy C 1-6 alkyl group, 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 one another, a hydrogen atom, C 1-6 alkyl group or a C 1-6 alkyl group, and q, combinations of m and n, (q, m, n) = (0,1,0), (0,0,1), (0,1,1), (1,1,0), (1,0,1) or (1,1,1) in which]
    In the compound represented, or a salt or solvate thereof.
  2. X represents formula (2),
    Wherein the ring B is an aromatic carbocyclic ring, saturated aliphatic carbon ring, or show the nitrogen-containing aromatic heterocyclic ring, wherein said ring B is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1- 6 alkyl group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl substitutions, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, and a di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group group may have one to three,
    Compound, or a salt or solvate thereof, as claimed in claim 1.
  3. X represents formula (2),
    Wherein the ring A is a pyrrolidine ring, piperidine ring represents piperazine ring or a tetrahydropyridine ring,
    Ring B is a benzene ring, a cyclohexane ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, an oxadiazole ring or It shows a thiadiazole ring,
    Wherein said each of ring A and ring B, halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, a substituent selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group which may have 1 to 3,
    Compound, or a salt or solvate thereof, as claimed in claim 2.
  4. X represents formula (3),
    Wherein the ring C is a nitrogen-containing aliphatic heterocyclic saturated, or show the nitrogen-containing aromatic heterocyclic ring, wherein said Ring C is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyloxy group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, a substituent selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group 1 It may have three to,
    Q 3 are a single bond or a C 2-6 alkenylene group, wherein the C 2-6 alkenylene group, 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,
    Compound, or a salt or solvate thereof, as claimed in claim 1.
  5. Q 1 is, represents a single bond or a C 1-6 alkylene group, wherein said C 1-6 alkylene group, 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,
    Compound, or a salt or solvate thereof, according to any one of claims 1-4.
  6. Ring Y is an aromatic carbocyclic ring, a nitrogen-containing aliphatic heterocyclic saturated, or show the nitrogen-containing aromatic heterocyclic ring, wherein said ring Y is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1- 6 alkyl group, 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, a carbamoyl group, an amido group, a 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 alkylamino C 1-6 alkyl group, and formula ( a substituent selected from the group of 4) may have 1 to 3,
    A compound according to any one of claims 1 to 5, or a salt or solvate thereof.
  7. Ring Y is a benzene ring, piperidine ring, pyrrolidine ring, piperazine ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring represents oxadiazole ring or a thiadiazole ring, wherein said ring Y is a halogen atom, C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyl group, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl groups, C 1-3 alkylcarbamoyl C 1-5 alkyl groups, 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),
    Compound, or a salt or solvate thereof, as claimed in claim 6.
  8. Having a substituent ring Y is represented by the formula (4),
    Wherein the ring D is an aliphatic saturated carbocyclic ring, aromatic carbocyclic, or show the nitrogen-containing aliphatic heterocyclic saturated, said ring D in this case, a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyloxy group, 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, a carbamoyl group, an amido group, a carbamoyl C 1 selected from -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 the substituent may have one to three,
    Q 4 are, represents a single bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group wherein 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, C 1-6 alkyl, hydroxy C 1-6 alkyl group, C 1-3 alkyloxy C 1-6 alkyl group, C 1- 3 alkylsulfonyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups may have,
    Compound, or a salt or solvate thereof, according to any one of claims 1 to 7.
  9. Said ring D is cyclohexane ring, benzene ring, pyrrolidine ring, indicates piperidine ring or piperazine ring, wherein said ring D is a halogen atom, C 1-6 alkyl groups, hydroxyl group, C 1-6 alkyloxy groups, 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, a carbamoyl group, an amido group, a carbamoyl C 1-5 alkyl group, C 1- 3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, one to three substituents selected from di-C 1-6 alkylamino group and di C 1-6 alkylamino C 1-6 alkyl group it may have,
    Compound, or a salt or solvate thereof, as claimed in claim 8.
  10. q, combinations of m and n (q, m, n) = (0,1,0), a (0,0,1), or (1,1,1), one of the claims 1 to 9, compound, or a salt or solvate thereof, according to any one of claims.
  11. 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-benzyl-4-yl) amino] -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide,
    N- {3 - [(1- benzyl-piperidin-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-methyl-piperidin-4-yl) amino] acetamide
    N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) oxy] acetamide,
    N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene-2-carboxamide,
    N-[3 - ([1,4'-bipiperidin] -1'-yl) propyl] -5- [4- (1-methyl-piperidin-4-yl) phenyl] thiophene-2-carboxamide,
    N- {5- [4- (4- methylpiperazin-l-yl) cyclohexyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-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-methyl-piperidin-4-yl) amino] -N- {5- [4- (-4- 1- methyl-piperidin yl) phenyl] thiophen-2-yl} acetamide,
    2 - [(1-methyl-piperidin-4-yl) amino]-N-(5-{4 - [(4-1-methyl-piperidin-yl) oxy] phenyl} thiophen-2-yl) acetamide,
    2- [4- (dimethylamino) piperidin-1-yl]-N-{5-r4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} acetamide,
    (R) -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide,
    (S) -N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -1- (1-methyl-piperidin-4-yl) pyrrolidine-2-carboxamide,
    2 - [(5-hydroxypentyl) (1-methyl-piperidin-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-oxo-hexyl] piperazin-1-yl} phenyl) thiophene-2-carboxamide,
    Benzyl 6- {4- [4- (5 - {[3 - ([1,4'-bipiperidin] -1'-yl) propyl] carbamoyl} thiophene-2-yl) phenyl] piperazin-1-yl} hexanoate ,
    1'-methyl -N- {5- [4- (-4- 1- methyl-piperidin yl) phenyl] thiophen-2-yl} - [1,4'-bipiperidine] -4-carboxamide,
    N- methyl-6- {4- [4- (5- {2 - [(1-methyl-piperidin-4-yl) amino] acetamide} thiophen-2-yl) phenyl] piperazin-1-yl} hexanamide,
    N-(5-{4-hydroxy-3 - [(4-methylpiperazin-1-yl) methyl] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide ,
    2 - [(3-hydroxypropyl) (1-methyl-piperidin-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] acetamide} thiophen-2-yl) phenyl] acetamide,
    N-(5-{1- [3- (dimethylamino) propyl]-1H-indol-5-yl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide,
    N- {5- [4- (4- methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] -3-phenyl propanamide,
    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) methyl sulfonamide] acetamide,
    4-methyl-N-{5-[4- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 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- (-4-1-methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin - 4-yl) amino] butanamide,
    N-{5-[2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide,
    N-{5-[3- cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide,
    2- (4-methylpiperazin-l-yl) -5- (5- {2 - [(1-methylpiperidin-4-yl) amino] acetamide} 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- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} propanamide,
    Benzyl 2- [4- (4- {5- [3 - ([1,4'-bipiperidin] -1'-yl) propanamide] thiophen-2-yl} phenyl) -5,6-dihydropyridine-l ( 2H) - yl] acetate,
    3 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- isopropyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} propanamide,
    2 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} acetamide,
    4 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} butanamide,
    5 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} pentanamide,
    6 - ([1,4'-bipiperidin] -1'-yl) -N- {5- [4- (-4- 1- methyl-1,2,3,6-tetrahydropyridin-yl) phenyl] thiophene - 2-yl} hexanamide,
    N-{5-[2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide,
    N- (5- {4- [2- (4- methylpiperazin-1-yl) ethoxy] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide,
    N- (5- {4- [4- (4- methylpiperazin-1-yl) butoxy] phenyl} thiophen-2-yl) -2 - [(1-methyl-piperidin-4-yl) amino] acetamide,
    N- [5- (4 - {[5- (4- methylpiperazin-1-yl) pentyl] oxy} phenyl) thiophene-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-methyl-piperidin-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] thiophene-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-l-yl) pyridin-3-yl] thiophen-2-yl} -2 - [(1-methyl-piperidin-4-yl) amino] acetamide,
    At least one compound selected from the group consisting of A compound according to claim 1, or a salt or solvate thereof.
  12. Compound or a salt thereof, or a solvate thereof as an active ingredient, at least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9 according to any one of claims 1 to 11.
  13. As an active ingredient a compound or a salt thereof or a solvate thereof according to any one of claims 1 to 11, autoimmune diseases, inflammation, allergy, asthma, graft rejection, graft versus host disease or prevention and / or therapeutic agent for cardiomyopathy caused by sepsis.
  14. Autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, a Behcet's syndrome or vasculitis, prophylactic and / or therapeutic agent according to claim 13.
PCT/JP2013/062049 2012-04-25 2013-04-24 Thiophene derivative having tlr-inhibiting activity WO2013161871A1 (en)

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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939332A (en) * 1998-02-27 1999-08-17 Roche Diagnostics Corp. Phencyclidine analogs for immunoassay
JPH11322711A (en) * 1998-04-15 1999-11-24 Pfizer Prod Inc Heterocyclic carboxamide
WO2001074791A1 (en) * 2000-03-31 2001-10-11 Yamanouchi Pharmaceutical Co., Ltd. Diazepane derivatives or salts thereof
JP2002121153A (en) * 2000-09-06 2002-04-23 Pfizer Prod Inc Combined therapy for depression and anxiety
JP2004506734A (en) * 2000-08-21 2004-03-04 ファルマシア・アンド・アップジョン・カンパニーPharmacia & Upjohn Company Kinukurido substituted heteroaryl moiety for disease treatment
JP2005504058A (en) * 2001-08-24 2005-02-10 ファルマシア アンド アップジョン カンパニー リミティド ライアビリティー カンパニー Substituted heteroaryl-7-aza for the treatment of diseases [2.2.1] bicycloheptane
JP2006505530A (en) * 2002-09-02 2006-02-16 アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag The combination of alpha -7 nicotinic receptor agonists and statins
JP2007529490A (en) * 2004-03-19 2007-10-25 アロー セラピューティクス リミテッド Benzodiazepine for the treatment or prevention of infection Rsv
JP2007531757A (en) * 2004-03-30 2007-11-08 カイロン コーポレイション Substituted thiophene derivatives as anti-cancer agents
JP2008531723A (en) * 2005-03-03 2008-08-14 アムジエン・インコーポレーテツド Phthalazine, aza and Jiazafutarajin compounds and methods of use
JP2010508288A (en) * 2006-10-27 2010-03-18 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company Useful heterocyclic amide compounds as kinase inhibitors
JP2010513444A (en) * 2006-12-21 2010-04-30 アストラゼネカ アクチボラグ Novel compounds
JP2011506358A (en) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト Novel 2-substituted-thiazole-4-carboxamide derivatives, their preparation and use as pharmaceuticals
JP2011506361A (en) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト New 2-hetaryl-4- carboxamide derivatives, their preparation and use as pharmaceuticals
JP2011506362A (en) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 2-aryl thiazole-4-carboxamide derivatives, their preparation and use as pharmaceuticals

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939332A (en) * 1998-02-27 1999-08-17 Roche Diagnostics Corp. Phencyclidine analogs for immunoassay
JPH11322711A (en) * 1998-04-15 1999-11-24 Pfizer Prod Inc Heterocyclic carboxamide
WO2001074791A1 (en) * 2000-03-31 2001-10-11 Yamanouchi Pharmaceutical Co., Ltd. Diazepane derivatives or salts thereof
JP2004506734A (en) * 2000-08-21 2004-03-04 ファルマシア・アンド・アップジョン・カンパニーPharmacia & Upjohn Company Kinukurido substituted heteroaryl moiety for disease treatment
JP2002121153A (en) * 2000-09-06 2002-04-23 Pfizer Prod Inc Combined therapy for depression and anxiety
JP2005504058A (en) * 2001-08-24 2005-02-10 ファルマシア アンド アップジョン カンパニー リミティド ライアビリティー カンパニー Substituted heteroaryl-7-aza for the treatment of diseases [2.2.1] bicycloheptane
JP2006505530A (en) * 2002-09-02 2006-02-16 アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag The combination of alpha -7 nicotinic receptor agonists and statins
JP2007529490A (en) * 2004-03-19 2007-10-25 アロー セラピューティクス リミテッド Benzodiazepine for the treatment or prevention of infection Rsv
JP2007531757A (en) * 2004-03-30 2007-11-08 カイロン コーポレイション Substituted thiophene derivatives as anti-cancer agents
JP2008531723A (en) * 2005-03-03 2008-08-14 アムジエン・インコーポレーテツド Phthalazine, aza and Jiazafutarajin compounds and methods of use
JP2010508288A (en) * 2006-10-27 2010-03-18 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company Useful heterocyclic amide compounds as kinase inhibitors
JP2010513444A (en) * 2006-12-21 2010-04-30 アストラゼネカ アクチボラグ Novel compounds
JP2011506358A (en) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト Novel 2-substituted-thiazole-4-carboxamide derivatives, their preparation and use as pharmaceuticals
JP2011506361A (en) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト New 2-hetaryl-4- carboxamide derivatives, their preparation and use as pharmaceuticals
JP2011506362A (en) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 2-aryl thiazole-4-carboxamide derivatives, their preparation and use as pharmaceuticals

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FRANCISCO-JAVIER GAMO, ET AL.: 'Thousands of chemical starting points for antimalarial lead identification' NATURE vol. 465, no. 7296, 20 May 2010, LONDON, UNITED KINGDOM, pages 305 - 310+2PP *

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