JP2017171619A - Novel indole derivative and medicine comprising the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which can inhibit the formation of amyloid fibrils, an amyloid fibril formation inhibitor comprising the compound, and a neurodegenerative disease therapeutic or preventive.SOLUTION: An amyloid fibril formation inhibitor comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or their solvates [Rand Reach independently represent H, an alkyl group, a cyano group or the like; Rand Rindependently represent H, an alkyl group or the like; Rand Rmay together form a ring; Arand Arindependently represent a substituted/unsubstituted aryl group or a substituted/unsubstituted heteroaryl group; X and Y independently represent a single bond, -C(=O)- and the like, Z is O or CH; n is an integer of 1-3].SELECTED DRAWING: None

Description

  The present invention relates to an amyloid fibril formation inhibitor. The present invention particularly relates to a therapeutic or prophylactic agent for neurodegenerative diseases by inhibiting amyloid fibril formation.

  In Japan, the population is aging at an unprecedented rate, and the number of patients with dementia centered on Alzheimer's disease is increasing. At present, the number of patients with dementia in Japan is estimated to be about 4.5 million, and it is estimated that the number of patients will increase with aging in the future. Since care for these patients with dementia is an economic burden, it is urgent to establish an effective treatment as soon as possible.

  Pathological features commonly seen in Alzheimer's disease patients include: (1) neuronal loss, (2) formation of patchy amyloid deposits (senile plaques), and (3) fibrous mass in neurons. There are three accumulations of (neurofibrillary tangles) that cause cognitive impairment (Alzheimer-type dementia), a clinical manifestation of Alzheimer's disease. As treatment for Alzheimer-type dementia, symptomatic treatment for temporarily improving symptoms of dementia is performed using a cholinesterase inhibitor, an NMDA inhibitor or the like. However, the effect is extremely limited, and establishment of a fundamental therapy that suppresses the onset and progression of Alzheimer's disease is strongly desired.

  In order to establish the basic therapy for Alzheimer's disease, it is necessary to elucidate the pathogenesis of Alzheimer's disease. Alzheimer's disease is known to be familial (hereditary) Alzheimer's disease caused by genetic factors and sporadic Alzheimer's disease without genetic background. And risk factors are being clarified. Since familial Alzheimer's disease and sporadic Alzheimer's disease share the same pathological findings and clinical symptoms, it is predicted that a common mechanism exists in the onset process. Research on the mechanism is expected to lead to the elucidation of the onset mechanism of sporadic Alzheimer's disease.

  One of genes causing familial Alzheimer's disease is a gene encoding an amyloid precursor protein (hereinafter referred to as APP). APP is cleaved by β-secretase and γ-secretase to produce amyloid β (hereinafter referred to as Aβ). Aβ has Aβ40 consisting of 40 amino acids and Aβ42 with 2 amino acids added to the C-terminus of Aβ40 due to differences in the cleavage point in APP, but Aβ40 is superior in physiological production. In contrast, senile plaques contain a large amount of Aβ42. Furthermore, it has been clarified that mutant APP increases the expression ratio of Aβ42 and that Aβ42 is more likely to aggregate than Aβ40. Based on these facts, it has been proposed that Aβ42 aggregates first, and Aβ40 aggregates and accumulates using it as a nucleus, so that amyloid fibril formation proceeds and Alzheimer's disease develops.

  Aggregation of Aβ in the brain is caused by the binding of GM1 ganglioside (hereinafter referred to as GM1 in the present specification) constituting the nerve cell membrane to a complex (GM1 binding type Aβ: hereinafter referred to as GAβ in this specification). It has been found that the process starts from the formation of (non-patent documents 1 and 2). In addition, GM1 aggregates in a nerve cell membrane depending on cholesterol concentration to form a cluster, and that Aβ specifically binds to this GM1 cluster to form GAβ. It has been confirmed by analysis using vesicles (Non-patent Document 3). Furthermore, analysis using an antibody that specifically recognizes GAβ has confirmed that GAβ has a structure different from that of soluble Aβ (Non-patent Document 4). From these findings, it has been proposed that when Aβ binds to the GM1 cluster, it changes to GAβ having a different structure, and this GAβ becomes a “seed” that promotes the aggregation of Aβ. Since then, many research results supporting this hypothesis have been obtained (Non-Patent Documents 5 to 9).

  Until now, various compounds have been developed and subjected to clinical trials for the purpose of developing fundamental treatment and prevention methods for Alzheimer's disease. Well-known ones include, for example, inhibitors for β-secretase that cleaves the N-terminal side of Aβ when Aβ is generated, and inhibitors for γ-secretase that cleaves the C-terminal side of Aβ (patent) Document 1, Non-Patent Document 10). These inhibitors were expected to be able to suppress amyloid fibril formation by inhibiting Aβ production. However, both β-secretase and γ-secretase are not enzymes using only APP as a specific substrate, and as a result, γ-secretase particularly inhibits Notch signals that are deeply involved in development and differentiation. The problem is that serious side effects are caused by inhibiting the physiological metabolism of APP itself. Many low molecular weight compounds that inhibit Aβ polymerization have also been developed (Patent Documents 2 to 6). These compounds inhibit the elongation of amyloid fibrils or disrupt the fibrils by inhibiting Aβ polymerization. However, it is suggested that if the administration of the compound is stopped, the polymerization of Aβ is resumed, and the fiber fragmentation itself may give rise to a new seed of polymerization, which is sufficient for the formation of amyloid fibrils. However, it has not been able to obtain a sufficient suppression effect.

  On the other hand, a method for suppressing amyloid fibril formation using an antibody (4396C antibody) that specifically binds to GAβ has been reported (Patent Document 7). The 4396C antibody specifically inhibits the formation of amyloid fibrils by specifically recognizing and binding to GAβ and inhibiting Aβ polymerization by GAβ. However, there is a problem that it takes a great amount of time and money to produce the antibody, and the administration method of the drug using the antibody is limited, and there is a problem of delivery to the brain. There is a problem that it is difficult to use.

US Patent Application Publication No. 201200233156 International Publication No. 2009/103652 International Publication No. 2003/045923 US Pat. No. 7,687,512 US Patent Application Publication No. 201000063077 US Patent Application Publication No. 20060223812 Japanese Patent No. 4102850

Yanagisawa, K .; et al. , Nat. Med. , Vol. 1, pp. 1062-1066 (1995) Yanagisawa, K .; et al. , Neurobiol. Aging, Vol. 19, pp. S65-67 (1998) Kakio, A .; et al. , J. et al. Biol. Chem. , Vol. 276, pp. 24985-24990 (2001) Yanagisawa, K .; et al. , FEBS Lett. , Vol. 420, pp. 43-46 (1997) McLaurin, J. et al. , And Chakrabarty, A .; , J. et al. Biol. Chem. , Vol. 271, pp. 26482-26489 (1996) Choo-Smith, L.M. P. , And Surewicz, W .; K. , FEBS Lett. , Vol. 402, pp. 95-98 (1997) Choo-Smith, L.M. P. et al. , J. et al. Biol. Chem. , Vol. 272, pp. 22987-22990 (1997) Matsuzaki, K .; et al. , Biochemistry, Vol. 38, pp. 4137-4142 (1999) Koppaka, V.K. and Axelsen, P.A. H. , Biochemistry, Vol. 39, pp. 10011-10016 (2000) Shuto, D.C. et al. Bioorg. Med. Chem. Lett. , Vol. 13, pp. 4273-4276 (2003)

  The present invention has been made for the purpose of solving various problems of the prior art and providing a fundamental prevention / treatment method for neurodegenerative diseases such as Alzheimer's disease. Specifically, the polymerization of Aβ is specifically performed. An object of the present invention is to provide an amyloid fibril formation inhibitor that can be inhibited and is excellent in clinical application.

  As a result of intensive studies, the present inventors succeeded in obtaining a low molecular weight compound that inhibits Aβ polymerization by specifically binding to GAβ.

［式中、
Ｒ_１およびＲ_２は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ハロアルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ハロアルコキシ基、Ｃ_１−２０ヒドロキシアルキル基、Ｃ_１−２０アルコキシアルキル基、カルボキシル基、Ｃ_１−２０アルキルアミノアルキル基、Ｃ_１−２０アミノアルキル基、シアノ基、ＳＯ_２ＮＨ_２基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子であり、
Ｒ_３およびＲ_４は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ヒドロキシアルキル基、Ｃ_１−２０アルコキシアルキル基、Ｃ_１−２０アルキルアミノアルキル基またはＣ_１−２０アミノアルキル基であり、ここで、Ｒ_３およびＲ_４は、共同して環を形成してもよく、
Ａｒ_１およびＡｒ_２は、それぞれ独立して、置換もしくは非置換のＣ_５−１４アリール基、置換もしくは非置換のＣ_１−１４ヘテロアリール基、または水素原子であり、
ＸおよびＹは、それぞれ独立して、単結合、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−（ＣＨ_２）_ｍ−、−Ｃ（＝Ｏ）ＮＲ_ｘ−、−ＳＯ_２−、−ＳＯ_２−（ＣＨ_２）_ｍ−、−（ＣＨ_２）_ｍ−、−（ＣＨ_２）_ｍ−Ｏ−、または、−（ＣＨ_２）_ｍ−ＮＨ−
（式中、ｍは、１〜３の整数であり、Ｒ_ｘは、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ヒドロキシアルキル基、Ｃ_１−２０アルコキシアルキル基、カルボキシル基、Ｃ_１−２０アルキルアミノアルキル基、Ｃ_１−２０アミノアルキル基、シアノ基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子である）
であり、
Ｚは、酸素原子またはＣＨ_２であり、
ｎは、１〜３の整数である］
で表される化合物もしくはその薬学的に許容される塩またはそれらの溶媒和物を含んでなる、アミロイド線維形成抑制剤を提供するものである。 That is, the present invention, according to one embodiment, is represented by the general formula (I):

[Where:
R ₁ and R ₂ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group, or a C _1-20 hydroxyalkyl. Group, C _1-20 alkoxyalkyl group, carboxyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, cyano group, SO ₂ NH ₂ group, C _1-20 alkyl SO ₂ NH group or halogen Is an atom,
R ₃ and R ₄ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 hydroxyalkyl group, a C _1-20 alkoxyalkyl group, a C _1-20 alkylaminoalkyl group or a C _{1- A 20} aminoalkyl group, wherein R ₃ and R ₄ may together form a ring;
Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted C _5-14 aryl group, a substituted or unsubstituted C _1-14 heteroaryl group, or a hydrogen atom,
X and Y are each independently a single bond, —C (═O) —, —C (═O) — (CH ₂ ) _m —, —C (═O) NR _x —, —SO ₂ —, _{-SO 2 - (CH 2) m} -, - (CH 2) m -, - (CH 2) m -O-, or, _{- (CH} 2) m -NH-
(In the formula, m is an integer of 1 to 3, and R _x is a hydrogen atom, a C _1-20 alkyl group, a C _1-20 alkoxy group, a C _1-20 hydroxyalkyl group, or a C _1-20 alkoxyalkyl. Group, carboxyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, cyano group, C _1-20 alkyl SO ₂ NH group or halogen atom)
And
Z is an oxygen atom or CH ₂ ;
n is an integer of 1 to 3]
Or a pharmaceutically acceptable salt thereof, or a solvate thereof, to provide an amyloid fibril formation inhibitor.

［式中、
Ｒ_１およびＲ_２は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ハロアルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ハロアルコキシ基、シアノ基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子であり、
Ａｒ_１およびＡｒ_２は、それぞれ独立して、置換もしくは非置換のＣ_５−１４アリール基または置換もしくは非置換のＣ_１−１４ヘテロアリール基であり、
ＸおよびＹは、それぞれ独立して、単結合、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）ＮＲ_ｘ−、−ＳＯ_２−、または、−ＣＨ_２−
（式中、Ｒ_ｘは、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０アルコキシ基、シアノ基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子である）
である］
で表されるものであることが好ましい。 The compound represented by the general formula (I) is represented by the general formula (Ia):

[Where:
R ₁ and R ₂ are each independently a hydrogen atom, C _1-20 alkyl group, C _1-20 haloalkyl group, C _1-20 alkoxy group, C _1-20 haloalkoxy group, cyano group, C _{1- 20} alkyl SO ₂ NH group or a halogen atom,
Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted C _5-14 aryl group or a substituted or unsubstituted C _1-14 heteroaryl group;
X and Y are each independently a single bond, —C (═O) —, —C (═O) NR _x —, —SO ₂ —, or —CH ₂ —.
(Wherein R _x is a hydrogen atom, a C _1-20 alkyl group, a C _1-20 alkoxy group, a cyano group, a C _1-20 alkyl SO ₂ NH group or a halogen atom)
Is]
It is preferable that it is represented by these.

［式中、
Ｒ_１およびＲ_２は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ハロアルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ハロアルコキシ基またはハロゲン原子であり、
Ａｒ_１およびＡｒ_２は、それぞれ独立して、置換もしくは非置換のフェニル基、置換もしくは非置換のピリミジル基または置換もしくは非置換のピリジル基であり、
ＸおよびＹは、それぞれ独立して、単結合または−ＣＨ_２−である］
で表されるものであることが好ましい。 The compound represented by the general formula (I) is represented by the general formula (Ia ′):

[Where:
R ₁ and R ₂ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group or a halogen atom,
Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyrimidyl group or a substituted or unsubstituted pyridyl group,
X and Y are each independently a single bond or —CH ₂ —.
It is preferable that it is represented by these.

  Moreover, according to one embodiment, the present invention is a compound selected from the group consisting of compounds Nos. 1-180, 182-188, 190-203 and 205-245 described in Tables 1A to 1P, or a compound thereof An amyloid fibril formation inhibitor comprising a pharmaceutically acceptable salt or a solvate thereof is provided.

  The compounds are compound numbers 1 to 3, 5, 15, 16, 20 to 22, 24 to 26, 30 to 35, 39, 41, 42, 51, 58 to 60, 67, 70 to 76, 78 to 84, 92-94, 96, 98-105, 107-126, 128, 129, 133-135, 137, 140, 143-161, 163-180, 182-188, 190, 192-194, 198-200, 203, Preferably it is selected from the group consisting of 205-218 and 232 compounds.

  Alternatively, the compound may be compound numbers 26, 73, 102, 103, 108, 110, 113, 114, 116-118, 133, 135, 140, 146-149, 154, 160, 161, 167-169, 173. 175, 178-180, 187, 190, 199, 200, 203, 207, 208, 210 and 213 are preferably selected from the group consisting of compounds.

  Moreover, according to one embodiment of the present invention, there is provided a therapeutic or prophylactic agent for neurodegenerative diseases containing the amyloid fibril formation inhibitor.

  The neurodegenerative disease is preferably Alzheimer's disease.

  Moreover, according to one embodiment of the present invention, a compound selected from the group consisting of compound numbers 1-180, 182-188, 190-203 and 205-245, or a pharmaceutically acceptable salt thereof, or their A solvate is provided.

  Said compounds are compound numbers 1-4, 6-8, 11, 12, 14-35, 37, 38, 40-65, 69-76, 78-87, 89-180, 182-188, 190-203 and It is preferably selected from the group consisting of 205-217 compounds.

  The amyloid fibril formation inhibitor according to the present invention, like the existing anti-GAβ antibody (4396C antibody), specifically binds to GAβ and blocks the initiation of polymerization of amyloid fibrils, thereby reliably forming amyloid fibrils. Can be suppressed. Moreover, since the active ingredient of the amyloid fibril formation inhibitor according to the present invention is a low-molecular compound, (1) it can be easily synthesized and can be prepared in large quantities at low cost, and (2) it does not exhibit antigenicity. Therefore, it is superior to antibodies in that it is highly safe, (3) has high molecular stability, and can secure a stable GAβ binding ability in various dosage forms.

  Further, by using the amyloid fibril formation inhibitor according to the present invention, it is possible to provide a fundamental prevention / treatment method for neurodegenerative diseases such as Alzheimer's disease.

  Hereinafter, the present invention will be described in detail, but the present invention is not limited to the embodiments described in the present specification.

［式中、
Ｒ_１およびＲ_２は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ハロアルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ハロアルコキシ基、Ｃ_１−２０ヒドロキシアルキル基、Ｃ_１−２０アルコキシアルキル基、カルボキシル基、Ｃ_１−２０アルキルアミノアルキル基、Ｃ_１−２０アミノアルキル基、シアノ基、ＳＯ_２ＮＨ_２基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子であり、
Ｒ_３およびＲ_４は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ヒドロキシアルキル基、Ｃ_１−２０アルコキシアルキル基、Ｃ_１−２０アルキルアミノアルキル基またはＣ_１−２０アミノアルキル基であり、ここで、Ｒ_３およびＲ_４は、共同して環を形成してもよく、
Ａｒ_１およびＡｒ_２は、それぞれ独立して、置換もしくは非置換のＣ_５−１４アリール基、置換もしくは非置換のＣ_１−１４ヘテロアリール基、または水素原子であり、
ＸおよびＹは、それぞれ独立して、単結合、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−（ＣＨ_２）_ｍ−、−Ｃ（＝Ｏ）ＮＲ_ｘ−、−ＳＯ_２−、−ＳＯ_２−（ＣＨ_２）_ｍ−、−（ＣＨ_２）_ｍ−、−（ＣＨ_２）_ｍ−Ｏ−、または、−（ＣＨ_２）_ｍ−ＮＨ−
（式中、ｍは、１〜３の整数であり、Ｒ_ｘは、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ヒドロキシアルキル基、Ｃ_１−２０アルコキシアルキル基、カルボキシル基、Ｃ_１−２０アルキルアミノアルキル基、Ｃ_１−２０アミノアルキル基、シアノ基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子である）
であり、
Ｚは、酸素原子またはＣＨ_２であり、
ｎは、１〜３の整数である］
で表される化合物（以降、本明細書では、「化合物（Ｉ）」と記載する）もしくはその薬学的に許容される塩またはそれらの溶媒和物を含んでなる、アミロイド線維形成抑制剤である。 The present invention, according to a first embodiment, has the general formula (I):

[Where:
R ₁ and R ₂ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group, or a C _1-20 hydroxyalkyl. Group, C _1-20 alkoxyalkyl group, carboxyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, cyano group, SO ₂ NH ₂ group, C _1-20 alkyl SO ₂ NH group or halogen Is an atom,
R ₃ and R ₄ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 hydroxyalkyl group, a C _1-20 alkoxyalkyl group, a C _1-20 alkylaminoalkyl group or a C _{1- A 20} aminoalkyl group, wherein R ₃ and R ₄ may together form a ring;
Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted C _5-14 aryl group, a substituted or unsubstituted C _1-14 heteroaryl group, or a hydrogen atom,
X and Y are each independently a single bond, —C (═O) —, —C (═O) — (CH ₂ ) _m —, —C (═O) NR _x —, —SO ₂ —, _{-SO 2 - (CH 2) m} -, - (CH 2) m -, - (CH 2) m -O-, or, _{- (CH} 2) m -NH-
(In the formula, m is an integer of 1 to 3, and R _x is a hydrogen atom, a C _1-20 alkyl group, a C _1-20 alkoxy group, a C _1-20 hydroxyalkyl group, or a C _1-20 alkoxyalkyl. Group, carboxyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, cyano group, C _1-20 alkyl SO ₂ NH group or halogen atom)
And
Z is an oxygen atom or CH ₂ ;
n is an integer of 1 to 3]
Or a pharmaceutically acceptable salt thereof or a solvate thereof, or a amyloid fibril formation inhibitor comprising the compound represented by .

  “Amyloid fibrils” are insoluble substances formed by aggregation of Aβ in a fibrous form. Amyloid fibrils are formed by first binding Aβ to GM1 constituting the nerve cell membrane to form a complex GAβ, and then using Aβ as a “seed” to aggregate Aβ. The amyloid fibril formation inhibitor according to this embodiment suppresses the formation of amyloid fibrils by inhibiting the aggregation of Aβ with respect to GAβ.

  “Aβ” is a peptide produced by cleaving APP with β-secretase and γ-secretase, and includes Aβ40, Aβ42, etc., which differ in the number of amino acids due to differences in cleavage points in APP.

  “APP” includes RefSeq accession numbers NP_001129601.1, NP_001129602.1, NP_0011191232.2, NP_9588177.1 in the NCBI RefSeq database (http://www.ncbi.nlm.nih.gov/RefSeq/). In addition to human APP consisting of the amino acid sequences registered as NP_0011921231.1, NP_958816.1, NP_0011921230.1, NP_0004755.1, NP_001129488.1, NP_0011299603.1, it is cleaved by β-secretase and γ-secretase to produce Aβ. 80% or more, preferably 90% or more, and more preferably about 95% with the above amino acid sequence. Protein comprising the amino acid sequence identity with the above may be included. Amino acid sequence identity can be calculated using sequence analysis software or using programs routine in the art (FASTA, BLAST, etc.).

  In addition, “APP” includes substitution, deletion, insertion and / or substitution of one to several amino acids in the above amino acid sequence, as long as it is cleaved by β secretase and γ secretase to produce Aβ. Proteins consisting of added amino acid sequences can be included. Here, “1 to several” is, for example, “1 to 30”, preferably “1 to 10”, and particularly preferably “1 to 5”.

  The amyloid fibril formation inhibitor of this embodiment comprises Compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof.

In compound (I), R ₁ and R ₂ each independently represent a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group, C _1-20 hydroxyalkyl group, C _1-20 alkoxyalkyl group, carboxyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, cyano group, SO ₂ NH ₂ group, C _1-20 alkyl SO ₂ NH group or halogen atom, preferably hydrogen atom, C _1-20 alkyl group, C _1-20 haloalkyl group, C _1-20 alkoxy group, C _1-20 haloalkoxy group, cyano group, C _{1 -20} alkyl _SO 2 NH group, or a halogen atom, particularly preferably a hydrogen _{atom, C 1-20 alkyl, C 1-20} Haroaruki Group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group or a halogen atom.

In compound (I), R ₃ and R ₄ each independently represent a hydrogen atom, a C _1-20 alkyl group, a C _1-20 hydroxyalkyl group, a C _1-20 alkoxyalkyl group, or a C _1-20 alkylamino. An alkyl group or a C _1-20 aminoalkyl group, wherein R ₃ and R ₄ may together form a ring; The ring may be a single ring or a multi-ring (for example, a bicyclo ring).

C _1-20 alkyl group, C _1-20 haloalkyl group, C _1-20 alkoxy group, C _1-20 haloalkoxy group, C _1-20 hydroxyalkyl group, C _1-20 alkoxyalkyl group, C _1-20 The alkylaminoalkyl group, the C _1-20 aminoalkyl group and the C _1-20 alkyl SO ₂ NH group are preferably C _1-10 , particularly preferably C _1-6 . In addition, the alkyl moiety in the above group includes both linear and branched forms.

In compound (I), Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted C _5-14 aryl group, a substituted or unsubstituted C _1-14 heteroaryl group, or a hydrogen atom.

  In the present embodiment, the “aryl group” means an aromatic hydrocarbon ring group. The aryl group in this embodiment may be one in which two or more aromatic hydrocarbon rings are condensed. Examples of the aryl group include a phenyl group, an indenyl group, a naphthyl group, a phenanthryl group, and an anthryl group, and a phenyl group is preferable.

  In the present embodiment, the “heteroaryl group” means a group in which one or more carbon atoms on the ring of the aryl group are substituted with a heteroatom. Preferred heteroatoms are selected from the group consisting of oxygen atoms, nitrogen atoms and sulfur atoms. Examples of the heteroaryl group include pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, triazinyl group, tetrazolyl group, oxazolyl group, indolizinyl group, indolyl group, isoindolyl group, Indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, oxadiazolyl group, thiazolyl group, thiadiazolyl group, benzimidazolyl group, thieno group, furyl group, thienyl group, etc. A pyrimidyl group or a pyridyl group is preferable.

In this embodiment, the aryl group and heteroaryl group may not be substituted, and one or more hydrogen atoms may be substituted with a substituent. The substituents in this case are C _1-20 alkyl group, C _1-20 haloalkyl group, C _1-20 alkoxy group, C _1-20 haloalkoxy group, C _1-20 hydroxyalkoxy group, C _1-20 alkoxyalkyl. Group, C _1-20 haloalkoxyalkyl group, C _1-20 alkoxyalkoxy group, C _1-20 haloalkoxyalkoxy group, C _1-20 hydroxyalkyl group, C _1-20 aminoalkyl group, C _1-20 alkylamino Alkyl group, C _1-20 dialkylaminoalkyl group, C _1-20 alkylamino group, C _1-20 alkylaminocarbonyl group, C _1-20 dialkylaminocarbonyl group, C _1-20 alkoxycarbonyl group, C _1-20 alkoxycarbonylalkyl _{group, C 1-20} acyl _{groups, C 1-20} acyl Alkyl _{group, C 1-20} alkylthio _{group, C 1-20} alkylenedioxy _{group, C 1-20} halo alkylenedioxy group, a halogen atom, an amino group, a nitro group, aminosulfonyl _{group, C 1-20} alkylaminosulfonyl group , A C _1-20 alkylsulfonylamino group, an aryl group, a heteroaryl group, a cyano group, a thiol group, and a hydroxyl group. The number of substituents and the substitution position are not particularly limited, but the number of substituents is preferably 0 to 3.

In Compound (I), X and Y are each independently a single bond, X and Y are each independently a single bond, —C (═O) —, —C (═O) — (CH _{2 ) m -, - C (=} O) NR x -, - SO 2 -, - SO 2 - (CH 2) m -, - (CH 2) m -, - (CH 2) m -O-, or, - _{(CH 2)} a m -NH-, preferably a single bond, -C (= O) -, - C (= O) NR x -, - SO 2 -, or, -CH ₂ - is, Particularly preferred is a single bond or —CH ₂ —. Here, the notation of each group does not limit the direction of bonding of each group in the compound, and any single bond on the left side or right side of each group is a single bond on the Ar ₁ or Ar ₂ side. There may be.

M in the above formula is an integer of 1 to 3, preferably 1 or 2. R _x is a hydrogen atom, a C _1-20 alkyl group, a C _1-20 alkoxy group, a C _1-20 hydroxyalkyl group, a C _1-20 alkoxyalkyl group, a carboxyl group, or a C _1-20 alkylaminoalkyl group. C _1-20 aminoalkyl group, cyano group, SO ₂ NH ₂ group, C _1-20 alkyl SO ₂ NH group or halogen atom. C _1-20 alkyl group, C _1-20 alkoxy group, C _1-20 hydroxyalkyl group, C _1-20 alkoxyalkyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, and C _1-20 alkyl _SO 2 NH group, preferably a _{C 1-10,} particularly preferably _{C 1-6.} In addition, the alkyl moiety in the above group includes both linear and branched forms.

In compound (I), Z is an oxygen atom or CH ₂ , preferably an oxygen atom.

  In the compound (I), n is an integer of 1 to 3, preferably 1.

一般式（Ｉａ）中、Ｒ_１、Ｒ_２、Ａｒ_１、Ａｒ_２、ＸおよびＹは、一般式（Ｉ）におけるＲ_１、Ｒ_２、Ａｒ_１、Ａｒ_２、ＸおよびＹとそれぞれ同義である。一般式（Ｉａ）において、Ｒ_１およびＲ_２は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ハロアルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ハロアルコキシ基、シアノ基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子であり、Ａｒ_１およびＡｒ_２は、それぞれ独立して、置換もしくは非置換のＣ_５−１４アリール基または置換もしくは非置換のＣ_１−１４ヘテロアリール基であり、ＸおよびＹは、それぞれ独立して、単結合、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）ＮＲ_ｘ−、−ＳＯ_２−、または、−ＣＨ_２−（式中、Ｒ_ｘは、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０アルコキシ基、シアノ基、Ｃ_１−２０アルキルＳＯ_２ＮＨ基またはハロゲン原子である）であることが好ましい。 The compound (I) is preferably one represented by the following general formula (Ia).

In the general formula _{(Ia), R 1, R} 2, Ar 1, Ar 2, X and Y are respectively the same as _{R 1, R 2, Ar 1} , Ar 2, X and Y in the general formula (I) . In the general formula (Ia), R ₁ and R ₂ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group. , A cyano group, a C _1-20 alkyl SO ₂ NH group or a halogen atom, and Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted C _5-14 aryl group or a substituted or unsubstituted C _{1. -14} heteroaryl group, X and Y are each independently a single bond, -C (= O) -, - C (= O) NR x -, - SO 2 -, or, -CH ₂ - In the formula, R _x is preferably a hydrogen atom, a C _1-20 alkyl group, a C _1-20 alkoxy group, a cyano group, a C _1-20 alkyl SO ₂ NH group or a halogen atom.

一般式（Ｉａ’）中、Ｒ_１、Ｒ_２、Ａｒ_１、Ａｒ_２、ＸおよびＹは、一般式（Ｉ）におけるＲ_１、Ｒ_２、Ａｒ_１、Ａｒ_２、ＸおよびＹとそれぞれ同義である。一般式（Ｉａ’）において、Ｒ_１およびＲ_２は、それぞれ独立して、水素原子、Ｃ_１−２０アルキル基、Ｃ_１−２０ハロアルキル基、Ｃ_１−２０アルコキシ基、Ｃ_１−２０ハロアルコキシ基またはハロゲン原子であり、Ａｒ_１およびＡｒ_２は、それぞれ独立して、置換もしくは非置換のフェニル基、置換もしくは非置換のピリミジル基または置換もしくは非置換のピリジル基であり、ＸおよびＹは、それぞれ独立して、単結合または−ＣＨ_２−であることが好ましい。 The compound (I) is particularly preferably one represented by the following general formula (Ia ′).

In the general formula _{(Ia '), R 1,} R 2, Ar 1, Ar 2, X and Y are, in the general formula (I) _{R 1,} in _{R 2, Ar 1, Ar 2} , respectively X and Y synonymous is there. In the general formula (Ia ′), R ₁ and R ₂ each independently represent a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy. Each of Ar ₁ and Ar ₂ is independently a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyrimidyl group or a substituted or unsubstituted pyridyl group, and X and Y are Each independently is preferably a single bond or —CH ₂ —.

  Unless otherwise specified, the compound (I) used in the present embodiment also includes stereoisomers such as tautomers, geometric isomers (for example, E isomer, Z isomer, etc.), enantiomers and the like. .

  Compound (I) used in the present embodiment can be synthesized by appropriately combining various conventionally known methods with the chemical synthesis methods described in the following examples and chemical synthesis methods corresponding thereto.

  Alternatively, when compound (I) used in the present embodiment is selected from commercially available compounds, commercially available compounds may be purchased. Commercially available compounds are, for example, domestically, through Namiki Shoji Co., Ltd. or Kishida Chemical Co., Ltd., Ambinter, Enamine, Aurora Fine Chemicals LLC, UORSY, Vitas-M Laboratory, Interbiom, Interchim, RentanS , ChemDiv etc. can be purchased.

  The amyloid fibril formation inhibitor of the present embodiment includes not only those comprising the above compound (I) but also those comprising a pharmaceutically acceptable salt of the above compound (I) or a solvate thereof. Is done.

  In the present embodiment, “pharmaceutically acceptable” means not harmful when a drug is used. The pharmaceutically acceptable salt in the present embodiment is, for example, an alkali metal salt such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt or the like when an acidic group is present in the compound (I) Alkaline earth metal salts; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, Examples include amine addition salts such as ethanolamine, N-methylglucamine, and L-glucamine; or basic amino acid addition salts such as lysine, δ-hydroxylysine, and arginine. Further, for example, when a basic group is present in the compound (I), inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc .; methanesulfonic acid, benzenesulfonic acid, P-Toluenesulfonic acid, acetic acid, propionate, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbine Examples thereof include organic acid salts such as acid, nicotinic acid and salicylic acid; and acidic amino acid addition salts such as aspartic acid and glutamic acid.

  The pharmaceutically acceptable “solvate” in the present embodiment includes, for example, hydrate, alcoholate, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, chloroform, dichloroethane, dichloromethane, Diethyl ether, methyl t-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, isobutyl methyl ketone, toluene, benzene, o-xylene , M-xylene, p-xylene, ethyl acetate, propyl acetate, butyl acetate, propylene carbonate, diethyl carbonate, dimethyl carbonate, hexane, Tan, heptane, etc. solvates with pharmaceutically acceptable solvents selected from the group consisting of octane and cyclohexane and the like, preferably hydrates.

  The compound represented by compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof may be used alone or a mixture of two or more thereof as an active ingredient of an amyloid fibril formation inhibitor. it can. The amyloid fibril formation inhibitor of the present embodiment may be composed of only an active ingredient, but generally, as an optional ingredient, a known pharmaceutically acceptable diluent, carrier, excipient, etc. May be included.

  In order to produce the amyloid fibril formation inhibitor of the present embodiment, the compound represented by Compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof, if necessary, is publicly known according to a conventional method. What is necessary is just to formulate in combination with these carriers. In the amyloid fibril formation inhibitor, the compound represented by Compound (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof has an appropriate intake amount in a range corresponding to each form as an active ingredient. So long as it is contained. In the amyloid fibril formation inhibitor, the compound represented by Compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof is usually administered at a dose of 0.001 mg / kg (body weight) per day for an adult. As described above, the content in the drug is preferably determined so as to be preferably 0.01 mg / kg (body weight) or more. However, the content is not limited to this range, and may be appropriately determined depending on the patient's symptoms, age, sex, and the like. It can be adjusted. The upper limit of the dose is preferably 100 mg / kg (body weight) or less, more preferably 10 mg / kg (body weight) or less per day.

  The amyloid fibril formation inhibitor of the present embodiment can be formulated into various dosage forms. Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, Examples include ointments, creams, gels, patches, inhalants, injections and the like. Therefore, the amyloid fibril formation inhibitor of this embodiment can be administered by various methods such as oral administration, intraperitoneal administration, intradermal administration, intravenous administration, intramuscular administration, and intracerebral administration.

  When the amyloid fibril formation inhibitor is used as an oral preparation, it can be made into solid preparations such as tablets, capsules, powders and granules. In this case, suitable additives such as additives such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts, and if desired, binders, disintegrants, lubricants, coloring agents, fragrances, etc. Can be blended. When the solid preparation is a tablet or pill, it may be coated with a sugar coating such as sucrose, gelatin or hydroxypropylcellulose, or a film of a gastric or enteric substance, if desired. Alternatively, the oral preparation of an amyloid fibril formation inhibitor can be a liquid such as a syrup, and in this case, sterile water, physiological saline, ethanol, or the like can be used as a carrier. If desired, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, preservatives and the like may be added.

  When the amyloid fibril formation inhibitor is used as a parenteral preparation, it can be a liquid such as an injection or a rectal agent. In this case, the active ingredient is dissolved in a diluent such as distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. by conventional methods. Alternatively, it can be prepared by suspending and adding a disinfectant, a stabilizer, an isotonic agent, a soothing agent, or the like, if necessary. In addition, a solid composition can be produced and dissolved in sterile water or a sterile solvent for injection before use.

  Moreover, the parenteral preparation of an amyloid fibril formation inhibitor can be, for example, a sustained release preparation such as a microcapsule, and can also be directly administered into the brain. Sustained-release preparations can be prepared using a carrier that can prevent immediate release from the body. As a preferable carrier, for example, a biodegradable / biocompatible polymer such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid can be used. Liposomes can also be used as the carrier. Preferred liposomes may be, but are not limited to, those that have been purified and prepared by the reverse phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE).

  Furthermore, the amyloid fibril formation inhibitor of this embodiment may contain a pharmaceutically acceptable additive such as a coloring agent, a preservative, a fragrance, a flavoring agent, and a sweetening agent and other therapeutic agents as desired. it can.

  Moreover, it is preferable to mix | blend a stabilizer when formulating an amyloid fibril formation inhibitor. Examples of the stabilizer include albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like.

  The amount of the active ingredient contained in the preparation varies depending on various conditions, for example, the type of extraction solvent, the amount of solvent used, and the like. Therefore, the amount of the active ingredient may be sufficient in an amount smaller than the above preferable intake amount or may be necessary beyond the range.

  The amyloid fibril formation inhibitor of this embodiment can fundamentally and reliably suppress the formation of amyloid fibrils. Therefore, it is useful for uses such as treatment and prevention of diseases associated with amyloid fibril formation.

  According to a second embodiment, the present invention relates to a compound selected from the group consisting of compounds Nos. 1-180, 182-188, 190-203 and 205-245, or a pharmaceutically acceptable salt thereof, An amyloid fibril formation inhibitor comprising these solvates. The compounds of Compound Nos. 1-180, 182-188, 190-203, and 205-245 shown below can inhibit the polymerization of Aβ with respect to GAβ and suppress the formation of amyloid fibrils.

[1] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(3-chlorophenyl) methyl] acetamide (Compound No. 1),
[2] N-benzyl-2- (4- {1-[(3-chlorophenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 2),
[3] 1-benzyl-N- {1-[(benzylcarbamoyl) methyl] piperidin-4-yl} -N-methyl-1H-indole-3-carboxamide hydrochloride (Compound No. 3),
[4] N-benzyl-2-{[1- (1-benzyl-1H-indole-3-carbonyl) piperidin-4-yl] (methyl) amino} acetamide hydrochloride (Compound No. 4),
[5] N-benzyl-2- [4- (1-benzyl-1H-indole-3-carbonyl) piperazin-1-yl] acetamide (Compound No. 5),
[6] 1-({[(3-chlorophenyl) methyl] carbamoyl} methyl) -N-propyl-1H-indole-3-carboxamide (Compound No. 6),
[7] 1-{[(3-chlorophenyl) carbamoyl] methyl} -N-propyl-1H-indole-3-carboxamide (Compound No. 7),
[8] 1-({[2- (3-Chlorophenyl) ethyl] carbamoyl} methyl) -N-propyl-1H-indole-3-carboxamide (Compound No. 8),
[9] N-benzyl-2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] acetamide hydrochloride (Compound No. 9),
[10] N- (4-fluorophenyl) -2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] acetamide hydrochloride (Compound No. 10),
[11] N-benzyl-2- [4- (1-benzyl-1H-pyrrole-3-carbonyl) piperazin-1-yl] acetamide hydrochloride (Compound No. 11),
[12] 2- [4- (1-Benzyl-1H-pyrrole-3-carbonyl) piperazin-1-yl] -1- (2,3-dihydro-1H-isoindol-2-yl) ethane-1- On-hydrochloride (Compound No. 12),
[13] N-benzyl-2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] acetamide (Compound No. 13),
[14] N-benzyl-2- {4- [1- (propan-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} acetamide (Compound No. 14),
[15] N-benzyl-2- (4- {1-[(2-chlorophenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 15),
[16] N-benzyl-2- (4- {1-[(4-chlorophenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 16),
[17] N-benzyl-2- (4- {1-[(pyridin-2-yl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 17),
[18] N-benzyl-2- (4- {1-[(pyridin-3-yl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 18),
[19] N-benzyl-2- (4- {1-[(pyridin-4-yl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 19),
[20] N-benzyl-2- (4- {1-[(2-methoxyphenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 20),
[21] N-benzyl-2- (4- {1-[(3-methoxyphenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 21),
[22] N-benzyl-2- (4- {1-[(4-methoxyphenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound No. 22),
[23] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-methylacetamide (Compound No. 23),
[24] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N- (2-methylpropyl) acetamide (Compound No. 24),
[25] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(2-chlorophenyl) methyl] acetamide (Compound No. 25),
[26] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(4-chlorophenyl) methyl] acetamide (Compound No. 26),
[27] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(pyridin-2-yl) methyl] acetamide (Compound No. 27),
[28] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(pyridin-3-yl) methyl] acetamide (Compound No. 28),
[29] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(pyridin-4-yl) methyl] acetamide (Compound No. 29),
[30] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(2-methoxyphenyl) methyl] acetamide (Compound No. 30),
[31] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(3-methoxyphenyl) methyl] acetamide (Compound No. 31),
[32] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(4-methoxyphenyl) methyl] acetamide (Compound No. 32),
[33] N-benzyl-2- [5- (1-benzyl-1H-indole-3-carbonyl) -octahydropyrrolo [3,4-c] pyrrol-2-yl] acetamide (Compound No. 33),
[34] N-benzyl-2- [4- (1-benzyl-1H-indole-3-carbonyl) -1,4-diazepan-1-yl] acetamide (Compound No. 34),
[35] N-benzyl-2- [5- (1-benzyl-1H-indole-3-carbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl] acetamide (Compound No. 35) ,
[36] 3- [4- (4-Fluorobenzoyl) piperazine-1-carbonyl] -1-methyl-1H-indole (Compound No. 36),
[37] N-benzyl-2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] acetamide (Compound No. 37),
[38] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] acetic acid (Compound No. 38),
[39] 2- (4-Chlorophenyl) -1- [4- (1H-indole-2-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 39),
[40] 2- (4-Chlorophenyl) -1- [4- (1H-indazol-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 40),
[41] 2- (4-Chlorophenyl) -1- [4- (1-methyl-1H-indole-2-carbonyl) piperazin-1-yl] propan-1-one (Compound No. 41),
[42] 2- (4-Chlorophenyl) -1- [4- (1-methyl-1H-indazol-3-carbonyl) piperazin-1-yl] propan-1-one (Compound No. 42),
[43] 3- [4- (5-Fluoropyridine-2-carbonyl) piperazine-1-carbonyl] -1-methyl-1H-indole (Compound No. 43),
[44] 3- [4- (5-Chloropyridine-2-carbonyl) piperazine-1-carbonyl] -1-methyl-1H-indole (Compound No. 44),
[45] 1-methyl-3- [4- (5-phenylpyridine-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 45),
[46] 1-methyl-3- [4- (4-phenylpyridine-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 46),
[47] 1-methyl-3- [4- (6-phenoxypyridine-3-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 47),
[48] 1-methyl-3- [4- (6-phenoxypyridine-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 48),
[49] 2- [4- (1-Methyl-1H-indole-3-carbonyl) piperazine-1-carbonyl] quinoline (Compound No. 49),
[50] 3- [4- (1-Methyl-1H-indole-3-carbonyl) piperazine-1-carbonyl] isoquinoline (Compound No. 50),
[51] 3- [4- (1H-indole-3-carbonyl) piperazine-1-carbonyl] -1-methyl-1H-indole (Compound No. 51),
[52] 1-methyl-3- [4- (1-methyl-1H-indole-3-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 52),
[53] N-benzyl-2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound No. 53),
[54] N-benzyl-2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound No. 54),
[55] N-[(4-fluorophenyl) methyl] -2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound No. 55),
[56] N-[(4-hydroxyphenyl) methyl] -2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound No. 56),
[57] N-[(4-hydroxyphenyl) methyl] -2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound No. 57),
[58] 2- (4-Chlorophenyl) -1- {4- [1- (pyridin-2-carbonyl) -1H-indole-3-carbonyl] piperazin-1-yl} ethane-1-one (Compound No. 58 ),
[59] (2S) -2-Amino-3- (1H-indol-3-yl) -1- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] propane-1 -One (compound no. 59),
[60] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -1- (2,3-dihydro-1H-isoindol-2-yl) ethane-1- ON (Compound No. 60),
[61] 2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] -N- (2-phenylpropan-2-yl) propanamide (Compound No. 61),
[62] 3- {4-[(3-chlorophenyl) methanesulfonyl] piperazine-1-carbonyl} -1H-indole (Compound No. 62),
[63] 1- (4-Chlorophenyl) -4- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-carbonyl] pyrrolidin-2-one (Compound No. 63),
[64] 1- (4-Chlorophenyl) -4-[(3R) -3-methyl-4- (1-methyl-1H-indazole-3-carbonyl) piperazin-1-carbonyl] pyrrolidin-2-one (compound Number 64),
[65] S- (3-Chlorophenyl) -2-methyl-1-[(3R) -3-methyl-4- (1-methyl-1H-indazole-3-carbonyl) piperazin-1-yl] -1- Oxopropane-2-sulfonamide (Compound No. 65),
[66] 3- [4- (2,3-dihydro-1,4-benzodioxin-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 66),
[67] 2- [4- (2,3-dihydro-1,4-benzodioxin-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 67),
[68] 3- [4- (2,3-dihydro-1,4-benzodioxin-2-carbonyl) piperazine-1-carbonyl] -1-methyl-1H-indole (Compound No. 68),
[69] 1-benzoyl-3- [4- (3-chlorobenzenesulfonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 69),
[70] 2- (4- {1- [1- (4-Chlorophenyl) ethyl] -1H-indole-3-carbonyl} piperazin-1-yl) -1- (2,3-dihydro-1H-isoindole -2-yl) propan-1-one (Compound No. 70),
[71] 1- (2,3-Dihydro-1H-isoindol-2-yl) -2- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1- Il} propan-1-one (Compound No. 71),
[72] 3- (4-Phenylpiperazine-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound No. 72),
[73] 3- [4- (4-Methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 73),
[74] 2- (4-Chlorophenyl) -1- {4- [1- (4-chlorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-carbonyl] piperazin-1-yl} ethane-1 -One (compound no. 74),
[75] 2- (4-Chlorophenyl) -1- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} ethane-1-one (Compound No. 75) ),
[76] 1-benzyl-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indole (Compound No. 76),
[77] 2- [4- (Pyrimidin-2-yl) piperazine-1-carbonyl] -1H-indole (Compound No. 77),
[78] 1-benzyl-3- [4- (2,3-dihydro-1,4-benzodioxin-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 78),
[79] 2- [4- (4-Methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 79),
[80] 6-chloro-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 80),
[81] 5-fluoro-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 81),
[82] 3- [4- (4-Methoxyphenyl) piperazine-1-carbonyl] -7- (pyrimidin-2-yl) -1H-indole (Compound No. 82),
[83] 3- {4-[(4-chlorophenyl) methanesulfonyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound No. 83),
[84] 3- [4- (4-Chlorobenzoyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 84)
[85] 3- [4- (3-Chlorobenzenesulfonyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 85),
[86] N- (3-chlorophenyl) -4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxamide (Compound No. 86),
[87] 3- [4- (4-Methoxybenzoyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 87),
[88] 1- (1H-indol-3-yl) -2- [4- (4-methoxyphenyl) piperazin-1-yl] ethane-1,2-dione (Compound No. 88),
[89] 1- [4- (4-Methoxyphenyl) piperazin-1-yl] -2- [1- (pyrimidin-2-yl) -1H-indol-3-yl] ethane-1,2-dione ( Compound No. 89),
[90] 1- [4- (4-Methoxyphenyl) piperazin-1-yl] -2- (2-methyl-1H-indol-3-yl) ethan-1-one (Compound No. 90),
[91] 1- [4- (4-Methoxyphenyl) piperazin-1-yl] -2- [2-methyl-1- (pyrimidin-2-yl) -1H-indol-3-yl] ethane-1- ON (compound number 91),
[92] 3- {4-[(4-methoxyphenyl) methyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound No. 92),
[93] 3- [4- (5-Methoxypyridin-2-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 93),
[94] N- (4-methoxyphenyl) -4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxamide (Compound No. 94),
[95] 3- [4- (4-Methoxybenzenesulfonyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 95),
[96] 1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] -2- (7-methoxy-1H-indol-3-yl) ethan-1-one (Compound No. 96),
[97] 1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] -2- (4-methoxy-1H-indol-3-yl) ethan-1-one (Compound No. 97),
[98] 2- (4-Chloro-1H-indol-3-yl) -1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 98),
[99] 2- (5-Chloro-1H-indol-3-yl) -1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 99),
[100] 3- [4- (4-Chlorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 100),
[101] 3- [4- (4-Fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 101),
[102] 3- [4- (3-Methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 102),
[103] 3- [4- (2-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 103),
[104] 3- [4- (4-Methoxyphenyl) piperazine-1-carbonyl] -1- (1,3-thiazol-2-yl) -1H-indole (Compound No. 104),
[105] 3- [4- (4-Methoxyphenyl) piperazine-1-carbonyl] -1- (pyridazin-3-yl) -1H-indole (Compound No. 105),
[106] 2- (4,7-Dimethoxy-1H-indol-3-yl) -1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 106 ),
[107] 1- (pyrimidin-2-yl) -3- {4- [4- (trifluoromethoxy) phenyl] piperazine-1-carbonyl} -1H-indole (Compound No. 107),
[108] 3- {4- [4- (fluoromethoxy) phenyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound No. 108),
[109] 3- [4- (5-chloropyridin-2-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 109),
[110] 4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 110),
[111] 1- (3-fluoropyridin-2-yl) -3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indole (Compound No. 111),
[112] 1- (5-Fluoropyrimidin-2-yl) -3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indole (Compound No. 112)
[113] 5-Fluoro-3- [4- (3-fluoro-4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 113),
[114] 6-chloro-3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 114),
[115] 3- [4- (4-Chlorophenyl) piperazine-1-carbonyl] -5-fluoro-1- (pyrimidin-2-yl) -1H-indole (Compound No. 115),
[116] 4- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 116),
[117] 4- {4- [5-Fluoro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 117),
[118] 3- [4- (3-Fluoro-4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 118),
[119] 2-fluoro-4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 119),
[120] [(2S) -4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -1- [4- (trifluoromethoxy) phenyl] piperazin-2-yl] methanol ( Compound No. 120),
[121] [(2R) -4- (4-Chlorophenyl) -1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-2-yl] methanol (Compound No. 121),
[122] 3- [4- (4-Chloro-2-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 122),
[123] [(2S) -1- (4-Chlorophenyl) -4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-2-yl] methanol (Compound No. 123),
[124] 3- [4- (4-Chlorophenyl) piperazine-1-carbonyl] -2-methyl-1- (pyrimidin-2-yl) -1H-indole (Compound No. 124)
[125] 4- {4- [2-Methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 125),
[126] 2- [4- (4-Chlorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 126),
[127] 4- {4- [1- (pyrimidin-2-yl) -1H-indole-2-carbonyl] piperazin-1-yl} phenol (Compound No. 127),
[128] (2R) -4- (4-chlorophenyl) -1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-2-carboxylic acid (Compound No. 128),
[129] 3-[(2S) -4- (4-chlorophenyl) -2-methylpiperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 129),
[130] 3- [4- (Pyridin-4-carbonyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 130),
[131] 3- {4-[(Pyridin-4-yl) methyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound No. 131),
[132] 3-[(2S) -2-methyl-4- (pyridine-4-carbonyl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 132),
[133] 4- {4- [6-Fluoro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 133),
[134] 4-({4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} methyl) phenol (Compound No. 134),
[135] 4- [4- (1-Benzyl-6-fluoro-1H-indole-3-carbonyl) piperazin-1-yl] phenol (Compound No. 135),
[136] 3-[(2S) -2-methyl-4- (pyrimidin-2-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 136),
[137] 6-chloro-3- (4-phenylpiperazine-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound No. 137),
[138] 6-chloro-3- (4-phenylpiperidin-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound No. 138),
[139] 6-fluoro-1- (pyrimidin-2-yl) -3- [4- (pyrimidin-2-yl) piperazine-1-carbonyl] -1H-indole (Compound No. 139),
[140] 2- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 140),
[141] N-benzyl-2- {4- [2-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} acetamide (Compound No. 141),
[142] N-[(3-Chlorophenyl) methyl] -2- {4- [2-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} acetamide ( Compound No. 142),
[143] N- (2- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-yl) methanesulfonamide ( Compound No. 143),
[144] 6-chloro-3-[(3S) -4- (5-chloropyridin-2-yl) -3-methylpiperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 144),
[145] 6-chloro-3- [4- (pyridin-4-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 145),
[146] 2- [4- (1-Benzyl-2-methyl-1H-indole-3-carbonyl) piperazin-1-yl] -N-[(4-chlorophenyl) methyl] acetamide (Compound No. 146),
[147] 2- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} -N-[(4-chlorophenyl) methyl] acetamide ( Compound No. 147),
[148] 4- [4- (1-Benzyl-2-methyl-1H-indole-3-carbonyl) piperazin-1-yl] phenol (Compound No. 148),
[149] 4- {4- [6-Chloro-1- (pyridin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 149),
[150] 6-chloro-3- (4-cyclohexylpiperazine-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound No. 150),
[151] 2-[(2R) -4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -2-methylpiperazin-1-yl] -N-[( 4-chlorophenyl) methyl] acetamide (Compound No. 151),
[152] 2-[(2S) -4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -2-methylpiperazin-1-yl] -N-[( 4-chlorophenyl) methyl] acetamide (Compound No. 152),
[153] 3- [4- (4-Hydroxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole-6-carbonitrile (Compound No. 153),
[154] 2- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-amine (Compound No. 154),
[155] 6-chloro-N- {2-[(4-chlorophenyl) amino] ethyl} -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound No. 155),
[156] 4- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} benzoic acid (Compound No. 156),
[157] 2- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} -N- (5-chloropyridin-2-yl) Acetamide (Compound No. 157),
[158] 2-[(2S) -4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -2- (hydroxymethyl) piperazin-1-yl] -N -[(4-chlorophenyl) methyl] acetamide (Compound No. 158),
[159] 2-[(3S) -4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -3- (hydroxymethyl) piperazin-1-yl] -N -[(4-chlorophenyl) methyl] acetamide (Compound No. 159),
[160] 1- (4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenoxy) butan-2-ol (Compound No. 160),
[161] 6-chloro-3- [4- (pyridin-2-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 161),
[162] 3-[(2S) -2-methylpiperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 162),
[163] 2- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridine-3-carbonitrile (Compound No. 163),
[164] 4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} aniline (Compound No. 164),
[165] N- (4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenyl) methanesulfonamide (Compound No. 165),
[166] 6- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-ol (Compound No. 166),
[167] 3- {4- [4- (2-ethoxyethoxy) phenyl] piperazin-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound No. 167),
[168] 4- {4- [1- (2,6-difluorophenyl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 168),
[169] 3- {4- [3- (4-methoxyphenyl) propyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound No. 169),
[170] 6-chloro-N- {2-[(4-chlorophenyl) (methyl) amino] ethyl} -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound No. 170),
[171] 4- {4- [1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (Compound No. 171),
[172] 4- {4- [1- (pyrimidin-2-yl) -1H-indole-6-carbonyl] piperazin-1-yl} phenol (Compound No. 172),
[173] 1-benzyl-7- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indole (Compound No. 173),
[174] 4- [4- (1-Benzoyl-1H-indole-3-carbonyl) piperazin-1-yl] phenol (Compound No. 174),
[175] N-({1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] pyrrolidin-2-yl} methyl) aniline (Compound No. 175),
[176] N- (1-phenylpyrrolidin-3-yl) -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound No. 176),
[177] N- [2- (2,3-dihydro-1H-indol-1-yl) ethyl] -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound No. 177),
[178] 6-chloro-N- {2-[(4-chlorophenyl) (methyl) amino] ethyl} -N-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound No. 178),
[179] 6- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-ol (Compound No. 179),
[180] 4- [4- (1-phenyl-1H-indole-3-carbonyl) piperazin-1-yl] phenol (Compound No. 180),
[182] 1-[(6- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-yl) oxy] butane -2-ol (Compound No. 182),
[183] (4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenyl) methanol (Compound No. 183),
[184] 2-[(4-Chlorophenyl) (2-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] formamido} ethyl) amino] acetic acid (Compound No. 184),
[185] 2- {6-chloro-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indol-1-yl} pyrimidin-4-amine (Compound No. 185),
[186] 4- {4- [1- (benzenesulfonyl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound No. 186),
[187] 4- {4- [3-Chloro-1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (Compound No. 187),
[188] 1- (4- {4- [1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenoxy) butan-2-ol (Compound No. 188),
[190] 4- (4-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] methyl} piperazin-1-yl) phenol (Compound No. 190),
[191] 2- {3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-pyrrolo [2,3-c] pyridin-1-yl} pyrimidine (Compound No. 191),
[192] 2- {3- [4- (4-hydroxyphenyl) piperazine-1-carbonyl] -1H-indol-1-yl} -6-methylpyrimidine-4-carboxylic acid (Compound No. 192),
[193] 2- {3- [4- (4-Chlorophenyl) piperazine-1-carbonyl] -1H-indol-1-yl} -6-methylpyrimidine-4-carboxylic acid hydrochloride (Compound No. 193),
[194] 4- {4- [1- (4-chlorobenzoyl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (Compound No. 194),
[195] 2- {3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-pyrrolo [2,3-c] pyridin-1-yl} pyrimidine (Compound No. 195),
[196] 5- [4- (4-Chlorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-1,3-benzodiazole (Compound No. 196),
[197] 2- {3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} pyrimidine (Compound No. 197),
[198] 1- (pyrimidin-2-yl) -5- {4- [4- (trifluoromethyl) phenyl] piperazine-1-carbonyl} -1H-indole (Compound No. 198),
[199] 5- [4- (4-Fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 199),
[200] 5- [4- (4-Methylphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 200),
[201] 5- [4- (4-Chlorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-1,2,3-benzotriazole (Compound No. 201),
[202] 3-fluoro-5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 202),
[203] 1- (2,6-difluorophenyl) -5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound No. 203),
[205] 5- (4-Phenylpiperazine-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound No. 205),
[206] N-[(1-phenylpyrrolidin-2-yl) methyl] -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound No. 206),
[207] 4- [2- (Aminomethyl) -4- [6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl] phenol (Compound No. 207) ,
[208] 1- (2-Fluorophenyl) -5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound No. 208),
[209] 5- [4- (4-Fluorophenyl) piperazine-1-carbonyl] -1- (3-fluoropyridin-2-yl) -1H-indole (Compound No. 209),
[210] 2- {5- [4- (4-fluorophenyl) piperazin-1-carbonyl] -1H-indol-1-yl} pyrimidin-4-amine (Compound No. 210),
[211] 1- (pyrimidin-2-yl) -3- [4- (2,2,2-trifluoroethyl) piperazine-1-carbonyl] -1H-indole (Compound No. 211),
[212] 5- [4- (3,4-Difluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 212)
[213] 3-[(4-Fluorophenyl) methyl] -6- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound No. 213),
[214] 6-chloro-3- [4- (3,4-difluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 214),
[215] 6-chloro-3- [4- (4-ethoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound No. 215),
[216] 6-fluoro-1- (pyrimidin-2-yl) -3- {4- [4- (trifluoromethoxy) phenyl] piperazine-1-carbonyl} -1H-indole (Compound No. 216),
[217] 1- (pyrimidin-2-yl) -5- {4- [4- (trifluoromethoxy) phenyl] piperazine-1-carbonyl} -1H-indole (Compound No. 217),
[218] 1- [4- (4,7-Dimethoxy-1H-indol-2-carbonyl) piperazin-1-yl] -2- (1H-indol-3-yl) ethan-1-one (Compound No. 218) ),
[219] N-ethyl-2- [4- (7-ethyl-1H-indole-3-carbonyl) piperazin-1-yl] acetamide (Compound No. 219),
[220] 1-benzyl-3- [4- (morpholine-4-carbonyl) piperidine-1-carbonyl] -1H-indole (Compound No. 220),
[221] 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -1- (pyrrolidin-1-yl) ethan-1-one (Compound No. 221),
[222] 3- [4- (3-chlorobenzoyl) piperazine-1-carbonyl] -1-methyl-1H-indole (Compound No. 222),
[223] 2- [4- (1-Benzyl-1H-indole-2-carbonyl) piperazin-1-yl] -N-methylacetamide (Compound No. 223),
[224] 1- [2-oxo-2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethyl] -1H-indole-3-carboxamide (Compound No. 224),
[225] N- [1- (1-Benzyl-1H-indole-3-carbonyl) piperidin-4-yl] pyridine-4-carboxamide (Compound No. 225),
[226] 2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] -N- (4-methylphenyl) acetamide (Compound No. 226),
[227] 3- (4-Benzylpiperazine-1-carbonyl) -1-methyl-1H-indole (Compound No. 227),
[228] 3- (4-Benzoylpiperazine-1-carbonyl) -1-methyl-1H-indole (Compound No. 228),
[229] N-benzyl-1- (1-methyl-1H-indole-3-carbonyl) piperidine-4-carboxamide (Compound No. 229),
[230] N-benzyl-4- [4- (1H-indole-3-carbonyl) piperazin-1-yl] -4-oxobutanamide (Compound No. 230),
[231] 3- [4- (4-Fluorobenzoyl) piperazine-1-carbonyl] -1-methyl-1H-indole (Compound No. 231),
[232] 1-methyl-3- [4- (pyridine-4-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 232),
[233] 1-methyl-3- [4- (pyridine-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound No. 233),
[234] 1- [4- (1-Methyl-1H-indole-3-carbonyl) piperazin-1-yl] -2-phenylethane-1-one (Compound No. 234),
[235] 1- [4- (1-Methyl-1H-indole-3-carbonyl) piperazin-1-yl] -2-phenoxyethan-1-one (Compound No. 235),
[236] (2E) -1- [4- (1-Methyl-1H-indole-3-carbonyl) piperazin-1-yl] -3-phenylprop-2-en-1-one (Compound No. 236),
[237] 2- (4-Chlorophenyl) -1- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 237),
[238] 2- (4-Chlorophenoxy) -1- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 238),
[239] 1- [4- (1-Methyl-1H-indole-3-carbonyl) piperazin-1-yl] -4-phenylbutan-1-one (Compound No. 239),
[240] 2- (4-Fluorophenyl) -1- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound No. 240),
[241] 1- [4- (1-Methyl-1H-indole-3-carbonyl) piperazin-1-yl] -3-phenylpropan-1-one (Compound No. 241),
[242] N-benzyl-2- [4- (1-ethyl-1H-indole-3-carbonyl) piperazin-1-yl] acetamide (Compound No. 242),
[243] 2- [4- (1-Methyl-1H-indole-3-carbonyl) piperazin-1-yl] -1- (pyrrolidin-1-yl) ethan-1-one (Compound No. 243),
[244] 1- [4- (1-Ethyl-1H-indole-3-carbonyl) piperazin-1-yl] propan-2-ol (Compound No. 244), and
[245] 1- [2- (2-Phenyl-1H-indol-1-yl) acetyl] -N-[(pyridin-3-yl) methyl] piperidine-4-carboxamide (Compound No. 245).

  More preferably, the compound used in the present embodiment is compound numbers 1 to 3, 5, 15, 16, 20 to 22, 24 to 26, 30 to 35, 39, 41, 42, 51, 58 to 60, 67, 70-76, 78-84, 92-94, 96, 98-105, 107-126, 128, 129, 133-135, 137, 140, 143-161, 163-180, 182-188, 190, Selected from the group consisting of 192-194, 198-200, 203, 205-218 and 232 compounds. The above compounds have a strong inhibitory effect on amyloid fibril formation.

  The compounds used in this embodiment are particularly preferably compound numbers 26, 73, 102, 103, 108, 110, 113, 114, 116 to 118, 133, 135, 140, 146 to 149, 154, 160, 161, 167-169, 173-175, 178-180, 187, 190, 199, 200, 203, 207, 208, 210 and 213. The above compounds have a particularly strong inhibitory effect on amyloid fibril formation.

  The compounds of Compound Nos. 1-180, 182-188, 190-203, and 205-245 are the same as the compound (I) in the first embodiment, and the chemical synthesis methods described in the following Examples and chemical synthesis equivalent thereto The method can be synthesized by appropriately combining various conventionally known methods. Or when selecting from a commercially available compound, you may purchase a commercially available compound.

  The amyloid fibril formation inhibitor of this embodiment includes those comprising the above-mentioned specific compound, as well as those comprising a pharmaceutically acceptable salt of the above compound or a solvate thereof. The “pharmaceutically acceptable salt” and “solvate” in the present embodiment are the same as those defined in the first embodiment.

  The amyloid fibril formation inhibitor of this embodiment may be prepared in the same manner as the amyloid fibril formation inhibitor of the first embodiment, except that the specific compound is used as the compound (I) in the first embodiment. . In addition, compound 1-5, 9, 10, 13-39, 41, 43-58, 60-62, 66-73, 75-87, 89, 91-190, 192-194, 198-200, 202-210 , 212 to 234 and 237 to 245 are compounds having a structure represented by the general formula (I). Compounds 6 to 8, 11, 12, 40, 42, 59, 63 to 65, 74, 88, 90, 191, 195 to 197, 201, 211, and 235 to 236 have the structure represented by the general formula (I) And can be used in place of compound (I).

  According to the third embodiment, the present invention is a therapeutic or prophylactic agent for neurodegenerative diseases containing the amyloid fibril formation inhibitor. The therapeutic or prophylactic agent for neurodegenerative diseases according to this embodiment is a compound represented by Compound (I) or a compound selected from Compound Nos. 1-180, 182-188, 190-203 and 205-245, or a compound thereof An amyloid fibril formation inhibitor comprising one or a mixture of two or more selected from pharmaceutically acceptable salts or solvates thereof, and an optional component. The arbitrary component referred to here may be a normal pharmaceutical ingredient, and is prepared as various commonly used forms such as tablets, capsules, powders, granules, liquids and the like. In addition, the therapeutic agent or preventive agent for neurodegenerative diseases according to this embodiment may further contain other active ingredients for treating or preventing neurodegenerative diseases as optional components.

  In this embodiment, `` treatment '' means to prevent or alleviate the progression and worsening of the disease state in an animal suffering from a neurodegenerative disease, and not only completely cure the disease, It also includes alleviating the symptoms of the disease. In addition, “prevention” means to prevent the disease from occurring in an animal that may suffer from a neurodegenerative disease.

  In the present embodiment, “neurodegenerative disease” means all diseases associated with (or resulting from) neuronal tissue degeneration associated with Aβ aggregation and amyloid fibril formation. Although it does not specifically limit as a neurodegenerative disease, For example, Alzheimer's disease, Parkinson's disease, Down's syndrome, cerebral amyloid angiopathy, Huntington's disease etc. are mentioned.

  The neurodegenerative disease that is the target of the therapeutic or prophylactic agent of this embodiment is preferably Alzheimer's disease. “Alzheimer's disease” includes familial (hereditary) Alzheimer's disease as well as so-called Alzheimer's disease (spontaneous Alzheimer's disease).

  The animal that is the target of the therapeutic or prophylactic agent of the present embodiment is, for example, a mammal such as a mouse, rat, rabbit, dog, cow, pig, sheep, non-human primate, human, and preferably a human. .

  The therapeutic agent or preventive agent for neurodegenerative diseases according to this embodiment is useful for the fundamental treatment or prevention of neurodegenerative diseases associated with the formation of amyloid fibrils.

  According to a fourth embodiment, the present invention relates to a compound selected from the group consisting of compounds Nos. 1-180, 182-188, 190-203 and 205-245, or a pharmaceutically acceptable salt thereof, These solvates.

  The compounds of the present embodiment are preferably compound numbers 1 to 4, 6 to 8, 11, 12, 14 to 35, 37, 38, 40 to 65, 69 to 76, 78 to 87, 89 to 180, and 182. Selected from the group consisting of 188, 190-203 and 205-217 compounds.

  The compound of the present embodiment can be synthesized by appropriately combining various conventionally known methods with the chemical synthesis methods described in the following examples and the chemical synthesis methods corresponding thereto.

  The “pharmaceutically acceptable salt” and “solvate” in the present embodiment are the same as those defined in the first embodiment.

  The compound according to the present embodiment or a pharmaceutically acceptable salt thereof or a solvate thereof can inhibit the polymerization of Aβ with respect to GAβ and suppress the formation of amyloid fibrils. Therefore, it is useful for uses such as treatment and prevention of diseases associated with amyloid fibril formation.

  The following examples further illustrate the present invention. In addition, these do not limit this invention at all.

<1. Screening for compounds that inhibit amyloid fibril formation>
In order to find a compound that specifically recognizes GAβ and suppresses the formation of amyloid fibrils, virtual screening using a molecular docking simulation program DOCK4 (http://dock.compbio.ucsf.edu/) was performed. In conducting virtual screening, we first constructed a GAβ complex model by molecular dynamics simulation. In the GM1 molecule, the structure optimization based on the molecular orbital calculation was applied to the sugar chain region considered to be involved in the binding to Aβ, and a partial charge was assigned to each atom. The three-dimensional coordinate data and partial charge values of each atom of these optimized structures are incorporated into the ff99 parameter set of the empirical force field used in AMBER, and a molecule of 5 ns in a molecular system in which water molecules are arranged Kinetic calculations were performed. Molecular dynamics calculation was performed on the sugar chain region of GM1, and trajectory poses were sampled. Using the obtained trajectory pose, docking with the three-dimensional structure of Aβ40 (PDB ID: 1AML) registered in the Protein Data Bank was performed. As a result of docking, 2 million docking poses were obtained. Among them, a docking pose with the least structural distortion and the most stable energy is extracted and used as an atomic model of GAβ. Using this atomic model of GAβ as an initial structure, molecular dynamics calculation of 20 ns is performed, structure clustering is performed based on positional information of the main chain Cα atom of Aβ, and compounds are bonded from the obtained representative structures. Extracted promising things in the pocket.

  On the other hand, the 4396C antibody (Nagajuken, Yanagisawa et al., Patent No. 4102850), which is an anti-GAβ monoclonal antibody, was first established as an antibody that specifically recognizes and binds to GAβ and suppresses the formation of amyloid fibrils. is there. In general, the CDR-H3 region of an antibody mainly contributes to antigen binding, and the amino acid sequence thereof changes most depending on the target antigen. The structure was sampled to generate a large number of conformers. We clustered structures that cover a wide conformation space, and extracted structural models that represent limited clusters. By using this as an initial structure, a structure that is energetically stable and frequently generated in water is obtained by molecular dynamics calculation, and docked with the GAβ complex model obtained above, the GAβ-4396C antibody The three-party complex model was created. According to this model, the 4396C antibody Trp121 is located very close to Phe19 of Aβ, indicating that it is sufficiently likely to form an aromatic stacking interaction. Based on this docking model, the β-turn structure of the CDR-H3 region, which is important for the interaction between GAβ and the 4396C antibody, was examined. Asn120, Trp121, and Val122 located at the tip of the β-turn were able to recognize GAβ. It was concluded that it was extremely important. Based on this result, a scaffold that can serve as a mother nucleus of a low molecular weight compound that suppresses the formation of amyloid fibrils was extracted.

  Drug-like filtering is used to exclude compounds that are not desirable as drugs from a commercially available compound library consisting of a total of about 9 million compounds provided by Namiki Shoji Co., Ltd. and Kishida Chemical Co., Ltd., and clustering is performed using fingerprints. By extracting representative structures from these groups, a commercial compound library consisting of about 500,000 structures was created. A similar structure search was performed on the commercially available compound library using the scaffold extracted above as a query. For fingerprints for structure search, fingerprints of MACCS, Lingo, Circular, Path, and Tree were used. Among the above five types of fingerprints, as a result of searching by MACCS fingerprint, 4,344 compounds with a similarity of 0.8 or more and 1,220 compounds with a score of 0.9 or more were hit. In other fingerprints, the compound did not hit. From the hit compounds by the MACCS fingerprint, compounds having an aromatic substituent similar to the side chain of Trp were selected, and 542 compounds were extracted. Subsequently, a plurality of conformations including geometric isomers and optical isomers were generated from the two-dimensional structure of each compound, converted into three-dimensional structure coordinates, and docked with GAβ. From each docking pose, compounds satisfying the pharmacophore for forming aromatic stacking with Phe19 were selected and narrowed down to 299. Further, the structure of each compound was visually checked, and 185 compounds were selected so as not to be structurally biased. In a model created by docking a selected compound to the GAβ complex structure, the compound mimics the β-turn structure of the CDR-H3 region of the 4396C antibody and, like the 4396C antibody, an aromatic stacking interaction with Phe19 It was confirmed that this was formed.

で表される化合物が、ＧＡβ依存性アミロイド線維形成に対して阻害活性を有することが示唆された。その後、阻害活性を有した化合物の類似（ｓｉｍｉｌａｒｉｔｙ）検索を行い、ＧＡβ依存性アミロイド線維形成に対する阻害活性を評価した結果、上記一般式（Ｉ）で表される化合物が、ＧＡβ依存性アミロイド線維形成に対して阻害活性を有することが明らかになった。 About the compound narrowed down from the commercial compound by the above, the inhibitory activity with respect to GA (beta) dependence amyloid fibril formation was evaluated in the in vitro reproduction system mentioned later. As a result, the hit compound having the highest priority among those included in the series of hit compound groups is represented by the following general formula (I):

It was suggested that the compound represented by these has inhibitory activity with respect to GAβ-dependent amyloid fibril formation. Thereafter, a similarity search for compounds having inhibitory activity was performed, and the inhibitory activity against GAβ-dependent amyloid fibril formation was evaluated. As a result, the compound represented by the above general formula (I) was It became clear that it has inhibitory activity against.

<2. Selection of commercially available compounds (compounds 5, 9, 10, 13, 36, 39, 66-68, 77, 88 and 218-245)>
Commercially available compounds having a structure represented by the general formula (I) or commercially available compounds having a structure similar to the structure represented by the general formula (I) are mainly purchased from Enamine, UORSY, Ambinter, etc. did.

<3. Synthesis of novel compounds (compounds 1-4, 6-8, 11, 12, 14-35, 37, 38, 40-65, 69-76, 78-87, 89-180, 182-188, 190-203 and 205-217)>
Subsequently, the novel compound which has a structure represented by the said general formula (I) was synthesize | combined. The followings were used as equipment used and measurement conditions.

¹ H NMR spectra were measured using a Bruker Avance or Bruker Varian (400 MHz, 500 MHz, or 600 MHz). TMS (tetramethylsilane) was used as an internal standard.

  LC / MS analysis was performed using a quadrupole mass spectrometer LCMS-2010 (Shimadzu Corporation) (column: Shim-pack XR-ODS (3.0 × 30 mm, 2.2 μm)) using ESI (+) ions. Mode or APCI (+) ion mode and (−) ion mode. Flow rate conditions: 0.3 to 0.8 mL / min, acquisition time: 3 to 5 minutes, detection wavelength: 220 nm, oven temperature: 40 to 50 ° C.

  Prep-HPLC was performed under the following conditions. Silica gel column: Fuji C18 (300 × 25), YMC 250 × 20; wavelength: 220 nm; moving bed A: acetonitrile (0.1% HCl); moving bed B: water; flow rate condition: 25 mL / min, injection amount: 2 mL Run time: 20 minutes; equilibration time: 3 minutes.

Abbreviations used in the following examples are as follows.
AcOH: acetic acid BINAP: 2,2′-bis (diphenylphosphino) 1,1′-binaphthyl BnBr: benzyl bromide BnNH ₂ : benzylamine Boc: tertiary butoxycarbonyl Cu (OAc) ₂ : copper acetate DCM: dichloromethane DIEA : Diisopropylethylamine DMAP: 4- (N, N-dimethylamino) pyridine DMF: N, N-dimethylformamide DMT-MM: 4- (4,6-dimethoxy-1,3,5-triazin-2-yl)- 4-methylmorpholinium chloride EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HATU: 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3 -Tetramethyluronium hexafluorophosphate HOBt: 1-hydroxybe Nzotriazole TBS: tert-butyldimethylsilyl MS 4A: molecular sieves 4A
MsCl: methanesulfonyl chloride MW: microwave Na (OAc) ₃ BH: sodium triacetoxyborohydride NCS: N-chlorosuccinimide TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride THF: tetrahydrofuran TMSOTf: trimethylsilyl trifluoromethanesulfonate Pd ( OAc) ₂ : palladium acetate Pd ₂ (dba) ₃ : tris (dibenzylideneacetone) dipalladium selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetra Fluoroborate)

<< Synthesis of 1-({[(3-chlorophenyl) methyl] carbamoyl} methyl) -N-propyl-1H-indole-3-carboxamide (Compound 6) >>

(6-1) Synthesis of 1- (2-ethoxy-2-oxoethyl) -1H-indole-3-carboxylic acid (Compound 6-1) A solution of indole-3-carboxylic acid (1.0 g) in DMF (50 mL) To the mixture, 60% sodium hydride (0.55 g) was slowly added at -5 ° C., stirred at room temperature for 1 hour, then brought to -5 ° C., ethyl-2-bromoacetate (1.0 g) was added, and Stir for hours. The reaction mixture was cooled to room temperature, acidified with hydrochloric acid-ethyl acetate solution (5%), extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of 1- (2-ethoxy-2-oxoethyl) -1H-indole-3-carboxylic acid as a crude product.

(6-2) Synthesis of ethyl 2- [3- (propylcarbamoyl) -1H-indol-1-yl] acetate (Compound 6-2) 1- (2-Ethoxy-2-oxoethyl) -1H-indole-3 -Carboxylic acid (400 mg), propan-1-amine (95 mg), EDC (403 mg), HOBt (284 mg) and triethylamine (0.2 mL) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by recrystallization with ethanol to obtain ethyl 2- [3- (propylcarbamoyl) -1H-indol-1-yl. 446 mg (yield 98%) of acetate were obtained.

(6-3) Synthesis of 2- [3- (propylcarbamoyl) -1H-indol-1-yl] acetic acid (Compound 6-3) Ethyl 2- [3- (propylcarbamoyl) -1H-indol-1-yl Lithium hydroxide monohydrate (126 mg) was added to a solution of acetate (446 mg) in tetrahydrofuran (4 mL) / water (2 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the aqueous layer obtained by extraction with ethyl acetate was acidified with 5% hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 332 mg of 2- [3- (propylcarbamoyl) -1H-indol-1-yl] acetic acid (yield 85%).

(6-4) Synthesis of 1-({[(3-chlorophenyl) methyl] carbamoyl} methyl) -N-propyl-1H-indole-3-carboxamide (Compound 6) 2- [3- (propylcarbamoyl)- 1H-Indol-1-yl] acetic acid (122 mg), (3-chlorophenyl) methanamine (67 mg), EDC (117 mg), HOBt (83 mg) and triethylamine (0.09 mL) were dissolved in DMF (1 mL) at room temperature. Stir for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) and recrystallized from ethanol to give 1-({[ 84 mg (yield 30%) of (3-chlorophenyl) methyl] carbamoyl} methyl) -N-propyl-1H-indole-3-carboxamide were obtained.

  Compounds 7 and 8 were synthesized by the same method as above.

<< Synthesis of N-benzyl-2- (4- {1-[(2-chlorophenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound 15) >>

(15-1) Synthesis of N-benzyl-2-bromoacetamide (Compound 15-1) To a solution of phenylmethanamine (6.42 g) in dichloromethane (60 mL) was added potassium carbonate (12.42 g), and the mixture was cooled to 0 ° C. After cooling, 2-bromoacetyl bromide (12 g) was slowly added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was filtered, and the resulting crystals were washed with water and dried to obtain 12 g of N-benzyl-2-bromoacetamide (yield 88%).

(15-2) Synthesis of N-benzyl-2- (piperazin-1-yl) acetamide dihydrochloride (Compound 15-2) N-benzyl-2-bromoacetamide (8 g) and tert-butyl 1-piperazine carboxy The rate (6.88 g) was dissolved in DMF (70 mL), potassium carbonate (12.2 g) was added, and the mixture was stirred at room temperature for 18 hours, and then water (150 mL) was added and filtered. The obtained crystals were washed with water and dried to obtain 9.7 g of tert-butyl 4-[(benzylcarbamoyl) methyl] piperazine-1-carboxylate (yield 83%). The obtained crystals were dissolved in methanol (10 mL), 2N hydrochloric acid acetic acid solution (30 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent of the reaction solution was distilled off under reduced pressure to obtain 8 g (yield 93%) of N-benzyl-2- (piperazin-1-yl) acetamide dihydrochloride.

(15-3) Synthesis of 1-[(2-chlorophenyl) methyl] -1H-indole-3-carboxylic acid (Compound 15-3) To a solution of 1H-indole-3-carboxylic acid (483 mg) in DMF (7 mL) After adding 60% sodium hydride (264 mg) under ice cooling, the mixture was stirred at room temperature for 20 minutes, 2-chlorobenzyl bromide (646 mg) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was acidified, and the obtained crystals were collected by filtration to obtain 800 mg of 1-[(2-chlorophenyl) methyl] -1H-indole-3-carboxylic acid (yield 93%).

(15-4) Synthesis of N-benzyl-2- (4- {1-[(2-chlorophenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide (Compound 15) N-Benzyl To a solution of 2- (piperazin-1-yl) acetamide dihydrochloride (306 mg) and 1-[(2-chlorophenyl) methyl] -1H-indole-3-carboxylic acid (285 mg) in DMF (5 mL) was added HATU. (456 mg) and triethylamine (404 mg) were added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-benzyl-2- (4- {1- 320 mg (yield 64%) of [(2-chlorophenyl) methyl] -1H-indole-3-carbonyl} piperazin-1-yl) acetamide were obtained.

  Compounds 2-4, 11, 12, 14, 16-22, 70, 146 and 173 were synthesized by the same method as above.

<< Synthesis of 1-methyl-3- [4- (5-phenylpyridine-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound 45) >>

(45-1) Synthesis of tert-butyl 4- (1-methyl-1H-indole-3-carbonyl) piperazine-1-carboxylate (Compound 45-1) 1-methyl-1H-indole-3-carboxylic acid ( To a solution of 5 g) and tert-butyl piperazine-1-carboxylate (8 g) in DMF (100 mL), HOBt (6 g), EDC (8 g) and diisopropylethylamine (10 mL) were added and stirred at room temperature for 16 hours. The residue obtained by distilling off the solvent of the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl 4- (1-methyl-1H-indole-3-carbonyl). 8.7 g (89% yield) of piperazine-1-carboxylate was obtained.

(45-2) Synthesis of (1-methyl-1H-indol-3-yl) (piperazin-1-yl) methanone (Compound 45-2) tert-butyl 4- (1-methyl-1H-indole-3- Carbonyl) piperazine-1 carboxylate (8.7 g) was dissolved in methanol (30 mL) and hydrochloric acid (20 mL) and stirred at room temperature for 16 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain 6 g (yield 97%) of (1-methyl-1H-indol-3-yl) (piperazin-1-yl) methanone.

(45-3) Synthesis of methyl 5-phenylpicolinate (compound 45-3) To a solution of methyl 5-bromopicolinate (250 mg) and phenylboronic acid (250 mg) in DMF (10 mL), palladium (II) acetate (30 mg) , Cesium carbonate (1 g) and tri-o-tolylphosphine (40 mg) were added, and the mixture was stirred at 90 ° C. for 16 hours. The residue obtained by distilling off the solvent of the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 120 mg of methyl 5-phenylpicolinate (yield 49%).

(45-4) Synthesis of 5-phenylpicolinic acid (compound 45-4) Methyl 5-phenylpicolinate (120 mg) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (100 mg) was added, Stir at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was adjusted to pH = 6 with hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 100 mg (yield 89%) of 5-phenylpicolinic acid.

(45-5) Synthesis of 1-methyl-3- [4- (5-phenylpyridine-2-carbonyl) piperazine-1-carbonyl] -1H-indole (Compound 45) (1-methyl-1H-indole-3 To a solution of -yl) (piperazin-1-yl) methanone (140 mg), 5-phenylpicolinic acid (100 mg) in DMF (5 mL), HOBt (100 mg), EDC (130 mg) and diisopropylethylamine (0.5 mL) were added. And stirred at room temperature for 16 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-methyl-3- [4- (5-phenylpyridine-2-carbonyl). 80 mg (yield 33%) of piperazine-1-carbonyl] -1H-indole was obtained.

  Compounds 40 to 44, 46 to 52, 59, 63 and 64 were synthesized by the same method as above.

<< Synthesis of N-benzyl-2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound 54) >>

(54-1) Synthesis of 3- (piperazine-1-carbonyl) -1H-indole (Compound 54-1) To a solution of 1H-indole-3-carboxylic acid (161 mg) in dichloromethane (10 ml) was added thionyl chloride (238 mg). After stirring until the raw material disappeared, piperazine (430 mg) was added and stirred at room temperature for 10 minutes. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 229 mg (yield 100%) of 3- (piperazine-1-carbonyl) -1H-indole. .

(54-2) Synthesis of N-benzyl-2-bromopropanamide (Compound 54-2) Phenylmethanamine (321 mg) and triethylamine (505 mg) were dissolved in dichloromethane (10 ml), and 2-bromopropanoyl chloride (523 mg) was dissolved. ) And stirred at room temperature for 10 minutes. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 605 mg (yield 83%) of N-benzyl-2-bromopropanamide.

(54-3) Synthesis of N-benzyl-2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound 54) N-benzyl-2-bromopropanamide (242 mg), 3- (Piperazine-1-carbonyl) -1H-indole (229 mg) and diisopropylethylamine (387 mg) were dissolved in ethanol (10 ml), and the mixture was stirred with heating under reflux for 18 hours. The crude product was purified by HPLC to obtain 50 mg (13% yield) of N-benzyl-2- [4- (1H-indole-3-carbonyl) piperazin-1-yl] propanamide.

  Compounds 37, 57 and 62 were synthesized by the same method as described above.

<< Synthesis of N-[(4-hydroxyphenyl) methyl] -2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound 56) >>

(56-1) Synthesis of tert-butyl 4- (1-methyl-1H-indole-3-carbonyl) piperazine-1-carboxylate (Compound 56-1) 1-methyl-1H-indole-3-carboxylic acid ( To a solution of 5 g) and tert-butyl piperazine-1-carboxylate (8 g) in DMF (100 mL), HOBt (6 g), EDC (8 g) and diisopropylethylamine (10 mL) were added and stirred at room temperature for 16 hours. The residue obtained by distilling off the solvent of the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl 4- (1-methyl-1H-indole-3-carbonyl) piperazine. 8.7 g (yield 89%) of -1-carboxylate was obtained.

(56-2) Synthesis of (1-methyl-1H-indol-3-yl) (piperazin-1-yl) methanone (compound 56-2) tert-butyl 4- (1-methyl-1H-indole-3- Carbonyl) piperazine-1 carboxylate (8.7 g) was dissolved in methanol (30 mL) and hydrochloric acid (20 mL) and stirred at room temperature for 16 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain 6 g (yield 97%) of (1-methyl-1H-indol-3-yl) (piperazin-1-yl) methanone.

(56-3) Synthesis of methyl 2- (4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl) propanate (Compound 56-3) (1-methyl-1H-indole-3- Yl) (piperazin-1-yl) methanone (1.0 g) and methyl 2-bromopropanate (1.4 g) in methanol (20 mL) were added diisopropylethylamine (1.1 g) and heated under reflux for 18 hours. Stir. The residue obtained by distilling off the solvent of the reaction solution under reduced pressure was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to obtain methyl 2- (4- (1-methyl-1H-indole-3-carbonyl). 500 mg (yield 37%) of piperazin-1-yl) propanate were obtained.

(56-4) Synthesis of 2- (4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl) propanoic acid and sodium chloride (Compound 56-4) Methyl 2- (4- (1 To a solution of -methyl-1H-indole-3-carbonyl) piperazin-1-yl) propanate (500 mg) in methanol (15 mL) and tetrahydrofuran (5 mL) was added an aqueous solution (5 mL) of sodium hydroxide (243 mg) at room temperature. Stir for 2 hours. The reaction mixture was concentrated, adjusted to pH 4-5 with concentrated hydrochloric acid, and extracted with ethyl acetate. The obtained aqueous layer was concentrated to obtain 1.00 g of a mixture of 2- (4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl) propanoic acid and sodium chloride.

Synthesis of (56-5) N-[(4-hydroxyphenyl) methyl] -2- [4- (1-methyl-1H-indole-3-carbonyl) piperazin-1-yl] propanamide (Compound 56) -(4- (1-Methyl-1H-indole-3-carbonyl) piperazin-1-yl) propanoic acid and sodium chloride (120 mg), 4- (aminomethyl) phenol (47 mg), EDC (88 mg), diisopropylethylamine (147 mg) and HOBt (62 mg) were dissolved in DMF (5 mL) and stirred at room temperature for 3 hours. The reaction solution is concentrated and then purified by Prep-TLC (dichloromethane-methanol), whereby N-[(4-hydroxyphenyl) methyl] -2- [4- (1-methyl-1H-indole-3-carbonyl) 45 mg (yield 28%) of piperazin-1-yl] propanamide were obtained.

  Compounds 53 and 55 were synthesized by the same method as described above.

«2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -1- (2,3-dihydro-1H-isoindol-2-yl) ethane-1-one ( Synthesis of Compound 60) >>

Synthesis of (60-1) 1-benzyl-1H-indole-3-carboxylic acid (Compound 60-1) 1H-indole-3-carboxylic acid (2.5 g) in a DMF (25 mL) solution with 60% sodium hydride (1.4 g) was added, and after stirring at room temperature for 40 minutes, benzyl bromide (2.0 mL) was added dropwise, and the mixture was stirred at room temperature for 19 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was acidified, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the crystals obtained by distilling off the solvent under reduced pressure were washed with ethanol to give 2.8 g of 1-benzyl-1H-indole-3-carboxylic acid (yield 72%). )

(60-2) Synthesis of tert-butyl 4- (1-benzyl-1H-indole-3-carbonyl) piperazine-1-carboxylate (compound 60-2) 1-benzyl-1H-indole-3-carboxylic acid ( 1.4 g), tert-butyl piperazine-1-carboxylate (1.1 g), EDC (1.4 g), HOBt (1.0 g) and triethylamine (1.0 mL) were dissolved in dichloromethane (10 mL) at room temperature. For 19 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give tert-butyl 4- (1-benzyl-1H- Indole-3-carbonyl) piperazine-1-carboxylate (1.5 g, yield 66%) was obtained.

(60-3) Synthesis of 1-benzyl-3- (piperazine-1-carbonyl) -1H-indole (Compound 60-3) tert-butyl 4- (1-benzyl-1H-indole-3-carbonyl) piperazine- Trifluoroacetic acid (3.5 mL) was added dropwise to a solution of 1-carboxylate (1.5 g) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 18 hours. After the solvent of the reaction solution was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of 1-benzyl-3- (piperazine-1-carbonyl) -1H-indole (yield 88%).

(60-4) Synthesis of 2-bromo-1- (2,3-dihydro-1H-isoindol-2-yl) ethane-1-one (Compound 60-4) 2,3-dihydro-1H-isoindole (0.3 mL) in dichloromethane (5 mL) was added triethylamine (0.7 mL) and ice-cooled to 0 ° C., 2-bromoacetylbromide (0.4 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hours. . Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-bromo-1- (2,3 -Dihydro-1H-isoindol-2-yl) ethane-1-one 281 mg (yield 47%) was obtained.

(60-5) 2- [4- (1-Benzyl-1H-indole-3-carbonyl) piperazin-1-yl] -1- (2,3-dihydro-1H-isoindol-2-yl) ethane- Synthesis of 1-one (Compound 60) To a solution of 1-benzyl-3- (piperazine-1-carbonyl) -1H-indole (100 mg) and triethylamine (0.07 mL) in dichloromethane (5 mL) was added 2-bromo-1- (2,3-Dihydro-1H-isoindol-2-yl) ethane-1-one (91 mg) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was added with water, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- [4- (1-benzyl- 1H-indole-3-carbonyl) piperazin-1-yl] -1- (2,3-dihydro-1H-isoindol-2-yl) ethane-1-one was obtained in an amount of 42 mg (yield 29%).

  Compounds 23 to 35, 38, 58, 65, 69 and 78 were synthesized by the same method as above.

«2- (4-Chlorophenyl) -1- {4- [1- (4-chlorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-carbonyl] piperazin-1-yl} ethane-1-one Synthesis of (Compound 74) >>

(74-1) Synthesis of tert-butyl 4- [2- (4-chlorophenyl) acetyl] piperazine-1-carboxylate (Compound 74-1) tert-butyl piperazine-1-carboxylate (3.7 g) and 2 Pyridine (1.6 g) was added to a solution of-(4-chlorophenyl) acetyl chloride (3.8 g) in dichloromethane (60 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.7 g of tert-butyl 4- [2- (4-chlorophenyl) acetyl] piperazine-1-carboxylate as a crude product.

(74-2) Synthesis of 2- (4-chlorophenyl) -1- (piperazin-1-yl) ethane-1-one (Compound 74-2) tert-butyl 4- [2- (4-chlorophenyl) acetyl] Trifluoroacetic acid (15 mL) was added to a solution of piperazine-1-carboxylate (6.7 g) in dichloromethane (60 mL), and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The residue obtained by drying the organic layer with sodium sulfate and distilling off the solvent under reduced pressure is purified by recrystallization with ethanol to give 2- (4-chlorophenyl) -1- (piperazin-1-yl). 3.7 g (77% yield) of ethane-1-one was obtained.

(74-3) 2- (4-Chlorophenyl) -1- {4- [1- (4-chlorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-carbonyl] piperazin-1-yl} ethane Synthesis of -1-one (Compound 74) 2- (4-Chlorophenyl) -3- (trifluoromethyl) pyrazole-4-carbonyl chloride (200 mg), 2- (4-Chlorophenyl) -1- (piperazine-1- Yl) Ethan-1-one (154 mg) in dichloromethane (20 mL) was added triethylamine (0.03 mL) and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) and recrystallized from hexane-ethyl acetate to give 2- 220 mg of (4-chlorophenyl) -1- {4- [1- (4-chlorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-carbonyl] piperazin-1-yl} ethane-1-one Rate 67%).

<< Synthesis of 6-chloro-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 80) >>

(80-1) Synthesis of 1- (6-chloro-1H-indol-3-yl) -2,2,2-trifluoroethane-1-one (Compound 80-1) 6-Chloro-1H-indole ( To a solution of 5.0 g) in DMF (40 mL) was added trifluoroacetic anhydride (9.3 mL), and the mixture was stirred at 60 ° C. for 17 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with ethyl acetate, and washed with saturated brine. The organic layer is dried over sodium sulfate, and the solvent is distilled off under reduced pressure to give 9.0 g of 1- (6-chloro-1H-indol-3-yl) -2,2,2-trifluoroethane-1-one. Was obtained as a crude product.

(80-2) Synthesis of 6-chloro-1H-indole-3-carboxylic acid (Compound 80-2) 1- (6-Chloro-1H-indole-3-yl) -2,2,2-trifluoroethane 4-M potassium hydroxide aqueous solution (40 mL) was added to -1-one (9.0 g), and it stirred under heating-refluxing for 3.5 hours. The reaction solution was ice-cooled to 0 ° C., acidified with concentrated hydrochloric acid, and the precipitated solid was filtered with hexane and ethyl acetate and washed to obtain 5.4 g of 6-chloro-1H-indole-3-carboxylic acid ( Yield 84%) was obtained.

(80-3) Synthesis of 6-chloro-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indole (Compound 80-3) 6-chloro-1H-indole-3-carboxylic acid (243 mg), 1- (4-methoxyphenyl) piperazine (238 mg), EDC (309 mg), HOBt (218 mg) and triethylamine (0.23 mL) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give 470 mg of 6-chloro-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indole as a crude product. Obtained.

(80-4) Synthesis of 6-chloro-3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 80) 6-Chloro- To a solution of 3- [4- (4-methoxyphenyl) piperazine-1-carbonyl] -1H-indole (200 mg) in DMF (3 mL) was added 60% sodium hydride (24 mg), and the mixture was stirred at room temperature for 30 minutes. 2-Chloropyrimidine (74 mg) was added and stirred at 130 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6-chloro-3- [4- (4- 122 mg (51% yield) of methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole were obtained. The obtained compound was recrystallized with ethanol.

  Compounds 81, 114 and 115 were synthesized by the same method as above.

<< Synthesis of 3- [4- (4methoxyphenyl) piperazine-1-carbonyl] -7- (pyrimidin-2-yl) -1H-indole (Compound 82) >>

(82-1) Synthesis of 7- (pyrimidin-2-yl) -1H-indole (Compound 82-1) 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) -1H-indole (500 mg), 2-chloropyrimidine (353 mg), potassium carbonate (573 mg), and tetrakis (triphenylphosphine) palladium (0) (36 mg) under toluene, toluene (60 mL) / water (10 mL) was added and stirred at 100 ° C. for 22 hours. The reaction mixture was cooled to room temperature, dichloromethane (100 mL) and water (100 mL) were added, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 7- (pyrimidin-2-yl) -1H- 220 mg of indole (yield 55%) were obtained.

(82-2) Synthesis of 7- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (Compound 82-2) 7- (Pyrimidin-2-yl) -1H-indole (218 mg) in DMF ( 5 mL) solution was added trifluoroacetic anhydride (0.5 mL) and stirred at 60 ° C. for 16 hours. After cooling the reaction solution to room temperature, 10% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the resulting solid was collected by filtration to obtain 2,2,2-trifluoro-1- [7- (pyrimidin-2-yl). ) -1H-Indol-3-yl] ethane-1-one 245 mg was obtained as a crude product. 5N Aqueous sodium hydroxide solution (5 mL) was added to the obtained crude product, and the mixture was stirred for 1.5 hours while heating under reflux. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 217 mg (yield 81%) of 7- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid.

(82-3) Synthesis of 3- [4- (4methoxyphenyl) piperazin-1-carbonyl] -7- (pyrimidin-2-yl) -1H-indole (Compound 82) 7- (Pyrimidin-2-yl) 1H-indole-3-carboxylic acid (60 mg), 1- (4-methoxyphenyl) piperazine (66 mg), EDC (63 mg), HOBt (45 mg) and triethylamine (0.12 mL) were dissolved in dichloromethane (3 mL). And stirred at room temperature for 23 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [4- (4 methoxyphenyl) piperazine- 73 mg (yield 70%) of 1-carbonyl] -7- (pyrimidin-2-yl) -1H-indole was obtained. The obtained compound was recrystallized with ethanol.

<< Synthesis of 3- {4-[(4-chlorophenyl) methanesulfonyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound 83) >>

(83-1) Synthesis of tert-butyl 4- (1H-indole-3-carbonyl) piperazine-1-carboxylate (Compound 83-1) Indole-3-carboxylic acid (902 mg), tert-butyl piperazine-1- Carboxylate (1.0 g), EDC (1.2 g), HOBt (838 mg) and triethylamine (0.9 mL) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.8 g of tert-butyl 4- (1H-indole-3-carbonyl) piperazine-1-carboxylate as a crude product.

(83-2) Synthesis of tert-butyl 4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxylate (compound 83-2) tert-butyl 4- (1H -Indole-3-carbonyl) piperazine-1-carboxylate (1.8 g) in DMF (20 mL) was added with 60% sodium hydride (246 mg), stirred at room temperature for 30 minutes, and then 2-chloropyrimidine (767 mg). ) And stirred at 130 ° C. for 19 hours. The reaction mixture was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer is dried over sodium sulfate and the solvent is distilled off under reduced pressure to remove tert-butyl 4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxylate2. 2 g was obtained as a crude product.

(83-3) Synthesis of 3- (piperazin-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound 83-3) tert-butyl 4- [1- (pyrimidin-2-yl) ) -1H-indole-3-carbonyl] piperazine-1-carboxylate (2.2 g) in dichloromethane (5.6 mL) was added trifluoroacetic acid (5.6 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The organic layer is dried over sodium sulfate, and the solvent is distilled off under reduced pressure to give 1.5 g of 3- (piperazin-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole as a crude product. Obtained.

(83-4) Synthesis of 3- {4-[(4-chlorophenyl) methanesulfonyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound 83) 1- (Pyrimidine- 2-yl) -1H-indole-3-carboxylic acid (92 mg), (4-chlorophenyl) methanesulfonyl chloride (76 mg) and triethylamine (0.06 mL) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. . Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- {4-[(4-chlorophenyl) methane. 80 mg (54% yield) of [sulfonyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole were obtained. The obtained compound was recrystallized with ethanol.

  Compounds 61, 84 to 87, 92, 94, 95 and 130 to 132 were synthesized by the same method as above.

<< Synthesis of 3- [4- (5-methoxypyridin-2-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 93) >>

  Compounds 83-1 to 83-3 were synthesized by the same procedure as (83-1) to (83-3) above.

(93-1) Synthesis of 3- [4- (5-methoxypyridin-2-yl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 93) 3- (Piperazine -1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (92 mg), tris (dibenzylideneacetone) dipalladium (0) (5.5 mg), BINAP (4.5 mg) and sodium tert- Toluene (3 mL) was added to butoxide (34.5 mg) under a nitrogen stream, 2-bromo-5-methoxypyridine (0.05 mL) was added dropwise, and the mixture was stirred at 100 ° C. for 19 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [4- (5-methoxypyridine-2 37 mg (yield 30%) of -yl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole were obtained. The obtained compound was recrystallized with ethanol.

<< Synthesis of 2- (4,7-dimethoxy-1H-indol-3-yl) -1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (Compound 106) ≫

  Compound 83-1 was synthesized by the same procedure as described in (83-1) above.

Synthesis of (106-1) 3- (piperazine-1-carbonyl) -1H-indole (Compound 106-1) tert-Butyl 4- (1H-indole-3-carbonyl) piperazine-1-carboxylate (1.97 g ) In dioxane (20 mL) was added hydrochloric acid (5 mL) and stirred at room temperature for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain 3- (piperazine-1-carbonyl) -1H-indole as a crude product.

(106-2) Synthesis of 3,6-dimethoxy-2-nitrobenzaldehyde (Compound 106-2) A solution of 2,5-dimethoxybenzaldehyde (20.0 g) in acetic acid (50 mL) was cooled to 5 ° C. and concentrated nitric acid ( 15 mL) was added, and the mixture was stirred at 15 ° C. for 3 hours. The precipitated solid was collected by filtration and washed with acetic acid to obtain 3,6-dimethoxy-2-nitrobenzaldehyde as a crude product.

(106-3) Synthesis of 1,4-dimethoxy-2-nitro-3-[(E) -2-nitroethenyl] benzene (Compound 106-3) 3,6-Dimethoxy-2-nitrobenzaldehyde (16.0 g) Nitromethane (20 mL) and ammonium acetate (11.7 g) were added to an acetic acid (50 mL) solution, and the mixture was stirred at 80 ° C. for 4 hours. After cooling the reaction solution to room temperature, the obtained crystals are collected by filtration, washed with 2-propanol and dried to give 1,4-dimethoxy-2-nitro-3-[(E) -2-nitroethenyl] benzene. 9.6 g (yield 50%) was obtained.

Synthesis of (106-4) 4,7-dimethoxy-1H-indole (compound 106-4) of 1,4-dimethoxy-2-nitro-3-[(E) -2-nitroethenyl] benzene (6.56 g) To a tetrahydrofuran (100 mL) solution was added palladium hydroxide / carbon (2 g) and acetic acid (4.2 mL), hydrogen was added at 150 psi, and the mixture was stirred at 50 ° C. for 16 hr. After cooling the reaction solution to room temperature, the solution obtained by filtration was washed with 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.9 g of 4,7-dimethoxy-1H-indole. (Yield 63%) was obtained.

Synthesis of (106-5) methyl 2- (4,7-dimethoxy-1H-indol-3-yl) -2-oxoacetate (Compound 106-5) 4,7-dimethoxy-1H-indole (1.5 g) To a diethyl ether (70 mL) solution was added oxalyl chloride (2.7 g) under ice cooling at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes, and then sodium methoxide (0.9 g) was added. The solvent was distilled off under reduced pressure, ethyl acetate (50 mL) was added to the resulting residue, the pH was adjusted to 7, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give methyl 2- (4,7-dimethoxy-1H- 1.1 g (0% yield) of indol-3-yl) -2-oxoacetate was obtained.

(106-6) Synthesis of methyl 2- (4,7-dimethoxy-1H-indol-3-yl) acetate (Compound 106-6) Methyl 2- (4,7-dimethoxy-1H-indol-3-yl) To a solution of 2-oxoacetate (1.1 g) in dioxane-water (50 mL-5 mL) was added palladium carbon (0.1 g) and sodium hypophosphite monohydrate (2.9 g) at 80 ° C. Stir overnight. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give methyl 2- (4,7-dimethoxy-1H- Obtained in 0.6 g (yield 60%) of indol-3-yl) acetate.

Synthesis of (106-7) 2- (4,7-dimethoxy-1H-indol-3-yl) acetic acid (Compound 106-7) Methyl 2- (4,7-dimethoxy-1H-indol-3-yl) acetate A solution of sodium hydroxide (0.2 g) in water (1 mL) was added to a methanol-water (30 mL-3 mL) solution of (0.6 g), and the mixture was stirred at 30 ° C. overnight. The solvent was distilled off under reduced pressure, ethyl acetate (50 mL) was added to the resulting residue, the pH was adjusted to 6, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 0.5 g (yield 87%) of 2- (4,7-dimethoxy-1H-indol-3-yl) acetic acid.

(106-8) 2- (4,7-Dimethoxy-1H-indol-3-yl) -1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one (compound 106) Synthesis of 2- (4,7-dimethoxy-1H-indol-3-yl) acetic acid (0.35 g) and 3- (piperazine-1-carbonyl) -1H-indole (0.43 g) in DMF (5 mL) ) HATU (0.74 g) and triethylamine (0.3 g) were added to the solution and stirred at room temperature for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by preparative HPLC to give 2- (4,7-dimethoxy-1H-indol-3-yl). 0.07 g (yield 11%) of -1- [4- (1H-indole-3-carbonyl) piperazin-1-yl] ethane-1-one was obtained.

  Compounds 96 to 99 were synthesized by the same method as described above.

<< Synthesis of 3- {4- [4- (fluoromethoxy) phenyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound 108) >>

(108-1) Synthesis of 1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (Compound 108-1) Indole-3-carboxylic acid (8.0 g) in DMF (150 mL) solution was added to 60 % Sodium hydride (4.4 g) was slowly added under ice-cooling, stirred for 30 minutes under ice-cooling, 2-chloropyrimidine (6.3 g) was added, and the mixture was stirred at 120 ° C. for 18 hours. The reaction mixture was cooled to room temperature, water (100 mL) and ethyl acetate (100 mL) were added, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was acidified with concentrated hydrochloric acid and stirred at room temperature for 30 minutes. The obtained solid was collected by filtration and washed with water to give 1- (pyrimidin-2-yl) -1H-indole- 11.5 g (yield 96%) of 3-carboxylic acid was obtained.

(108-2) Synthesis of 4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound 108-2) 1- (Pyrimidine-2 -Yl) -1H-indole-3-carboxylic acid (478 mg), 1- (4-hydroxyphenyl) piperazine (356 mg), and DMT-MM (830 mg) were dissolved in DMF (10 mL) for 21 hours at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- {4- [1- (pyrimidine-2 -Il) -1H-indole-5-carbonyl] piperazin-1-yl} phenol 750 mg (yield 95%) was obtained.

(108-3) Synthesis of 3- {4- [4- (fluoromethoxy) phenyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound 108) 4- {4- A solution of [1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (70 mg) and cesium carbonate (114 mg) in DMF (4 mL) was cooled to 0 ° C. with ice, and bromo Fluoroethane (29 mg) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by preparative HPLC to give 3- {4- [4- (fluoromethoxy) phenyl] piperazine-1-carbonyl}. 30 mg (yield 39%) of -1- (pyrimidin-2-yl) -1H-indole was obtained.

  Compounds 143, 160, 165, 167, 182, 188 and 215 were synthesized by the same method as described above.

<< Synthesis of 5-fluoro-3- [4- (3-fluoro-4methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 113) >>

(113-1) of 2,2,2trifluoro-1- [5-fluoro-1- (pyrimidin-2-yl) -1H-indol-3-yl] ethane-1-one (compound 113-1) Synthesis To a solution of 5-fluoro-1H-indole (676 mg) in DMF (10 mL) was added trifluoroacetic anhydride (1.4 mL), and the mixture was stirred at room temperature for 18 hours. By adding 10% aqueous sodium hydrogen carbonate solution to the reaction solution, filtering and washing with water, 2,2,2trifluoro-1- [5-fluoro-1- (pyrimidin-2-yl) -1H-indole- 1.6 g of 3-yl] ethane-1-one were obtained as a crude product.

(113-2) Synthesis of 5-fluoro-1H-indole-3-carboxylic acid (compound 113-2) 2,2,2trifluoro-1- [5-fluoro-1- (pyrimidin-2-yl)- To 1H-indol-3-yl] ethane-1-one (1.6 g) was added 5N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 785 mg of 5-fluoro-1H-indole-3-carboxylic acid (yield 88%).

(113-3) Synthesis of tert-butyl 4- (5-fluoro-1H-indole-3-carbonyl) piperazine-1-carboxylate (compound 113-3) 5-fluoro-1H-indole-3-carboxylic acid ( 450 mg), tert-butyl piperazine-1-carboxylate (466 mg), EDC (630 mg), HOBt (446 mg) and triethylamine (0.46 mL) were dissolved in dichloromethane (25 mL) and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 870 mg of tert-butyl 4- (5-fluoro-1H-indole-3-carbonyl) piperazine-1-carboxylate as a crude product. It was.

(113-4) Synthesis of tert-butyl 4- [5-fluoro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxylate (compound 113-4) tert-butyl To a solution of 4- (5-fluoro-1H-indole-3-carbonyl) piperazine-1-carboxylate (870 mg) in DMF (15 mL) was added 60% sodium hydride (110 mg), and the mixture was stirred at room temperature for 30 minutes. 2-Chloropyrimidine (344 mg) was added and stirred at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature, water (20 mL) and dichloromethane (20 mL) were added, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to give tert-butyl 4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxylate 1 0.0 g was obtained as a crude product.

(113-5) Synthesis of 5-fluoro 3- (piperazine-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (compound 113-5) tert-butyl 4- [1- (pyrimidine- To a solution of 2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxylate (1.0 g) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.5 mL) and stirred at room temperature for 18 hours. . The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 750 mg of 5-fluoro-3- (piperazin-1-carbonyll) -1- (pyrimidin-2-yl) -1H-indole as a crude product. Got as.

(113-6) Synthesis of 5-fluoro-3- [4- (3-fluoro-4methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 113) -Fluoro 3- (piperazin-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (163 mg), dipalladium (II) acetate (2 mg), BINAP (14 mg) and sodium tert-butoxide (77 mg) ) Under a nitrogen stream, toluene (2 mL) was added, 4-bromo-2-fluoro-1-methoxybenzene (0.07 mL) was added dropwise, and the mixture was stirred at 100 ° C. for 19 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-fluoro-3- [4- (3- 7.6 mg (yield 3%) of fluoro-4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole was obtained. The obtained compound was recrystallized with ethanol.

  Compound 216 was synthesized by the same method as above.

<< Synthesis of 4- {4- [6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound 116) >>

  Compounds 80-1 and 80-2 were synthesized by the same procedure as in the above (80-1) and (80-2).

(116-1) Synthesis of 6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (Compound 116-1) 6-chloro-1H-indole-3-carboxylic acid (1. 0%) in DMF (30 mL) was added 60% sodium hydride (450 mg), and the mixture was stirred at room temperature for 30 min, 2-chloropyrimidine (644 mg) was added, and the mixture was stirred at 120 ° C. for 18 hr. The reaction mixture was cooled to room temperature, water (100 mL) and ethyl acetate (100 mL) were added, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was acidified with concentrated hydrochloric acid and stirred at room temperature for 30 minutes, and then the obtained solid was collected by filtration and washed with water to give 6-chloro-1- (pyrimidin-2-yl)- 1.2 g (89% yield) of 1H-indole-3-carboxylic acid was obtained.

(116-2) Synthesis of 4- {4- [6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound 116) 6-Chloro- 1- (Pyrimidin-2-yl) -1H-indole-3-carboxylic acid (1.0 g), 1- (4-hydroxyphenyl) piperazine (846 mg), and DMT-MM (1.5 g) were added to DMF (8 mL). ) And stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- {4- [6-chloro-1- 1.6 g (yield quant.) Of (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pheno was obtained. The obtained compound was recrystallized with ethanol.

  Compounds 117, 133, 140 and 149 were synthesized by the same method as described above.

<< Synthesis of 3- [4- (3-fluoro-4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 118) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

Synthesis of (118-1) 1- (3-fluoro-4-methoxyphenyl) piperazine (Compound 118-1) Piperazine (474 mg), palladium (II) acetate (23 mg), BINAP (143 mg) and sodium tert-butoxide ( 769 mg) was added toluene under a nitrogen stream, 4-bromo-2-fluoro-1-methoxybenzene (0.64 mL) was added dropwise, and the mixture was stirred with heating under reflux for 19 hours. The reaction mixture was cooled to room temperature, filtered through celite with ethyl acetate, and the resulting filtrate was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The obtained aqueous layer was made basic with sodium hydroxide, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 713 mg (yield 68%) of 1- (3-fluoro-4-methoxyphenyl) piperazine.

Synthesis of (118-2) 3- [4- (3-Fluoro-4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 118) 1- (Pyrimidine -2-yl) -1H-indole-3-carboxylic acid (191 mg), 1- (3-fluoro-4-methoxyphenyl) piperazine (168 mg), EDC (192 mg), HOBt (135 mg), and triethylamine (0. (07 mL) was dissolved in dichloromethane (8 mL) and stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [4- (3-fluoro-4- There were obtained 271 mg (yield 77%) of methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole. The obtained compound was recrystallized with ethanol.

  Compounds 107, 120 to 123, 129, 144 and 217 were synthesized by the same method as above.

<< Synthesis of 2-fluoro-4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound 119) >>

  Compounds 108-1, 118-1 and 118 were synthesized by the same procedure as (108-1), (118-1) and (118-2) above.

Synthesis of (119-1) 2-fluoro-4- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound 119) 3- [4 -(3-Fluoro-4-methoxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (156 mg) in a dichloromethane solution of boron tribromide in 1M dichloromethane (1. 9 mL) was added dropwise under ice cooling, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-fluoro-4- {4- [1- 50 mg (yield 33%) of (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol were obtained. The obtained compound was recrystallized with ethanol.

<< Synthesis of 3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -2-methyl-1- (pyrimidin-2-yl) -1H-indole (Compound 124) >>

(124-1) Synthesis of 2-methyl-1- (pyrimidin-2-yl) -1H-indole (Compound 124-1) To a solution of 2-methyl-1H-indole (1.3 g) in DMF (20 mL) was added 60. % Sodium hydride (440 mg) was added, and the mixture was stirred at room temperature for 30 min, 2-chloropyrimidine (1.4 g) was added, and the mixture was stirred at 120 ° C. for 18 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.3 g of 2-methyl-1- (pyrimidin-2-yl) -1H-indole as a crude product.

(124-2) 2,2,2-trifluoro-1- [2-methyl-1- (pyrimidin-2-yl) -1H-indol-3-yl] ethan-1-one (Compound 124-2) Synthesis of 2-methyl-1- (pyrimidin-2-yl) -1H-indole (2.3 g) in DMF (20 mL) was added trifluoroacetic anhydride (2.8 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with ethyl acetate, and washed with saturated brine. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to give 2,2,2-trifluoro-1- [2-methyl-1- (pyrimidin-2-yl) -1H-indole-3. -Il] ethane-1-one 3.0 g was obtained as an adult product.

(124-3) Synthesis of 2-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (Compound 124-3) 2,2,2-trifluoro-1- [2-methyl- To 1- (pyrimidin-2-yl) -1H-indol-3-yl] ethane-1-one (3.0 g) was added 5N aqueous sodium hydroxide solution (40 mL), and the mixture was stirred for 1.5 hours with heating under reflux. The reaction mixture was ice-cooled to 0 ° C. and extracted with dichloromethane. The resulting aqueous layer was acidified with concentrated hydrochloric acid, extracted with chloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was filtered and washed with dichloromethane, whereby 2methyl-1- (pyrimidin-2-yl) -1H-indole-3- Obtained 840 mg of carboxylic acid (22% yield).

(124-4) Synthesis of 3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -2-methyl-1- (pyrimidin-2-yl) -1H-indole (Compound 124) 2-Methyl-1- (Pyrimidin-2-yl) -1H-indole-3-carboxylic acid (99 mg), 1- (4 chlorophenyl) piperazine hydrochloride (119 mg), EDC (97 mg), HOBt (69 mg), and triethylamine (0.14 mL) ) Was dissolved in dichloromethane (4 mL) and stirred at room temperature for 40 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [4- (4-chlorophenyl) piperazine- 153 mg (yield 91%) of 1-carbonyl] -2-methyl-1- (pyrimidin-2-yl) -1H-indole was obtained. The obtained compound was recrystallized from hexane-ethyl acetate.

  Compounds 89 to 91 were synthesized by the same method as above.

<< Synthesis of 4- {4- [2-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound 125) >>

  Compounds 124-1 to 124-3 were synthesized by the same procedure as the above (124-1) to (124-3).

Synthesis of (125-1) 4- {4- [2-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol (Compound 125) -(Pyrimidin-2-yl) -1H-indole-3-carboxylic acid (76 mg), 1- (4-hydroxyphenyl) piperazine (70 mg), and DMT-MM (125 mg) were dissolved in DMF (3 mL). And stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- {4- [2-methyl-1- 99 mg (yield 80%) of (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} phenol were obtained. The obtained compound was recrystallized from hexane-ethyl acetate.

<< Synthesis of (2R) -4- (4-chlorophenyl) -1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-2-carboxylic acid (Compound 128) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

(128-1) Synthesis of 1-tert-butyl 2-methyl (2R) -4- (4-chlorophenyl) piperazine-1,2-dicarboxylate (Compound 128-1) 1-tert-butyl 2-methyl ( 2R) -piperazine-1,2-dicarboxylate (500 mg), 1-bromo-4-chlorobenzene (383 mg), palladium (II) acetate (15 mg), BINAP (75 mg), and sodium tert-butoxide (442 mg) Toluene was added under a nitrogen stream, and the mixture was stirred at 80 ° C. for 18 hours. The reaction mixture was cooled to room temperature, filtered through celite with ethyl acetate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-tert-butyl 2 -240 mg (yield 34%) of methyl (2R) -4- (4-chlorophenyl) piperazine-1,2-dicarboxylate was obtained.

Synthesis of (128-2) methyl (2R) -4- (4-chlorophenyl) piperazine-2-carboxylate (compound 128-2) 1-tert-butyl 2-methyl (2R) -4- (4-chlorophenyl) Trifluoroacetic acid (1 mL) was added to a solution of piperazine-1,2-dicarboxylate (240 mg) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 157 mg (yield 31%) of methyl (2R) -4- (4-chlorophenyl) piperazine-2-carboxylate.

(128-3) (2R) -4- (4-Chlorophenyl) -1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-2-carboxylate (Compound 128-3) Synthesis of 1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (143 mg), methyl (2R) -4- (4-chlorophenyl) piperazine-2-carboxylate (157 mg), EDC (153 mg) , HOBt (108 mg) and triethylamine (0.1 mL) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give (2R) -4- (4-chlorophenyl)- 290 mg (yield quant.) Of 1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-2-carboxylate was obtained.

Synthesis of (128-4) (2R) -4- (4-chlorophenyl) -1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-2-carboxylic acid (Compound 128) (2R) -4- (4-Chlorophenyl) -1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-2-carboxylate (290 mg) in tetrahydrofuran (2 mL) / methanol ( 2 mL) / water (2 ml) solution was added lithium hydroxide monohydrate (252 mg), and the mixture was stirred at 55 ° C. for 2 hours. Water was added to the reaction mixture, and the aqueous layer obtained by extraction with ethyl acetate was added with 10% aqueous citric acid solution, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-ethanol) to give (2R) -4- (4-chlorophenyl) -1 -22 mg (yield 8%) of [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-2-carboxylic acid was obtained.

<< Synthesis of 4-({4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} methyl) phenol (Compound 134) >>

  Compounds 83-1 to 83-3 were synthesized by the same procedure as (83-1) to (83-3) above.

Synthesis of (134-1) 3- {4-[(4-methoxyphenyl) methyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound 134-1) 1- ( Pyrimidin-2-yl) -1H-indole-3-carboxylic acid (92 mg), 1- (chloromethyl) -4-methoxybenzene (0.05 mL) and triethylamine (0.06 mL) were dissolved in dichloromethane (2 mL). And stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- {4-[(4-methoxyphenyl) 98 mg (yield 76%) of methyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole were obtained.

Synthesis of (134-2) 4-({4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} methyl) phenol (Compound 134) 3- {4- To a solution of [(4-methoxyphenyl) methyl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (15 mg) in dichloromethane, 1M boron tribromide / dichloromethane solution (0.1 mL) Was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-({4- [1- (pyrimidine- There were obtained 4 mg (29% yield) of 2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} methyl) phenol.

<< Synthesis of 3-[(2S) -2-methyl-4-pyrimidin-2-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 136) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

(136-1) of tert-butyl (3S) -3-methyl-4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxylate (Compound 136-1) Synthesis 1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (718 mg), tert-butyl (3S) -3-methylpiperazine-1-carboxylate (600 mg), EDC (747 mg), HOBt ( 527 mg) and triethylamine (0.5 mL) were dissolved in dichloromethane (6 mL) and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to remove tert-butyl (3S) -3-methyl-4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl]. 1.3 g of piperazine-1-carboxylate was obtained as a crude product.

Synthesis of (136-2) 3-[(2S) -2-methylpiperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 136-2) tert-Butyl (3S)- To a solution of 3-methyl-4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazine-1-carboxylate (1.3 g) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL). The mixture was further stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-ethanol) to give 3-[(2S) -2-methylpiperazine-1 -Carbonyl] -1- (pyrimidin-2-yl) -1H-indole 1.0 g (yield quant.) Was obtained.

Synthesis of (136-3) 3-[(2S) -2-methyl-4-pyrimidin-2-yl) piperazin-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 136) To a solution of 3-[(2S) -2-methylpiperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (96 mg) and 2-chloropyrimidine (34 mg) in ethanol (5 mL) is diisopropylethylamine. (0.1 mL) was added, and the mixture was stirred with heating under reflux for 23 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-[(2S) -2-methyl-4. -Pyrimidin-2-yl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (63 mg, yield 53%) was obtained. The obtained compound was recrystallized with ethanol.

  Compound 139 was synthesized by the same method as above.

<< Synthesis of 6-chloro-3- (4-phenylpiperazine-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound 137) >>

  Compounds 80-1, 80-2 and 116-1 were synthesized by the same procedure as in the above (80-1), (80-2) and (116-1).

Synthesis of (137-1) 6-chloro-3- (4-phenylpiperazine-1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole (Compound 137) 6-Chloro-1- (pyrimidine- 2-yl) -1H-indole-3-carboxylic acid (82 mg), 1-phenylpiperazine (49 mg), EDC (63 mg), HOBt (45 mg) and triethylamine (0.05 mL) were dissolved in dichloromethane (3 mL), Stir at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6-chloro-3- (4-phenylpiperazine- 106 mg (yield 85%) of 1-carbonyl) -1- (pyrimidin-2-yl) -1H-indole was obtained. The obtained compound was recrystallized from hexane-ethyl acetate.

  Compounds 138, 145, 150, 154 to 156, 161, 170, 178, 185, 211 and 214 were synthesized by the same method as described above.

<< Synthesis of N-benzyl-2- {4- [2-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} acetamide (Compound 141) >>

  Compounds 15-1, 15-2, and 124-1 to 124-3 were synthesized by the same procedure as the above (15-1), (15-2), and (124-1) to (124-3).

Synthesis of (141-1) N-benzyl-2- {4- [2-methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} acetamide (Compound 141) 2-Methyl-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (76 mg), N-benzyl-2- (piperazin-1-yl) acetamide (68 mg), EDC (75 mg), HOBt (53 mg) and triethylamine (0.05 mL) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-ethanol) to give N-benzyl-2- {4- [2- 99 mg (yield 71%) of methyl-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} acetamide was obtained.

  Compounds 71, 75, 142, 151, 152, 158, 159, 162 and 169 were synthesized by the same method as above.

«2- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} -N-[(4-chlorophenyl) methyl] acetamide (Compound 147 ) Synthesis >>

  Compounds 80-1, 80-2 and 116-1 were synthesized by the same procedure as in the above (80-1), (80-2) and (116-1).

Synthesis of (147-1) (4-chlorophenyl) methyl 2- (piperazin-1-yl) acetate (Compound 147-1) 2- {4-[(tert-Butoxy) carbonyl] piperazin-1-yl} acetic acid (500 mg ), (4-chlorophenyl) methanamine (0.27 mL), EDC (420 mg), and HOBt (297 mg) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 812 mg of tert-butyl 4- {2-[(4-chlorophenyl) methoxy] -2oxoethyl} piperazine-1-carboxylate as a crude product. Obtained. The obtained tert-butyl 4- {2-[(4-chlorophenyl) methoxy] -2oxoethyl} piperazine-1-carboxylate (812 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added dropwise. And stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 384 mg (yield 73%) of (4-chlorophenyl) methyl 2- (piperazin-1yl) acetate.

(147-2) 2- {4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} -N-[(4-chlorophenyl) methyl] Synthesis of Acetamide (Compound 147) 6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (83 mg), (4-Chlorophenyl) methyl 2- (piperazin-1-yl) acetate (80 mg ), EDC (75 mg), HOBt (53 mg) and triethylamine (0.05 mL) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 48 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- {4- [6-chloro-1- 129 mg (yield 82%) of (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} -N-[(4-chlorophenyl) methyl] acetamide was obtained. The obtained compound was recrystallized from hexane-ethyl acetate.

  Compound 157 was synthesized by the same method as above.

<< Synthesis of 3- [4- (4-hydroxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole-6-carbonitrile (Compound 153) >>

(153-1) Synthesis of 3- (2,2,2-trichloroacetyl) -1H-indole-6-carbonitrile (Compound 153-1) 6-Cyano-1H-indole (711 mg) in dioxane (20 mL) Were added trichloroacetyl chloride (2.8 mL) and pyridine (4 mL), and the mixture was stirred at 80 ° C. for 3.5 hours. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.4 g of 3- (2,2,2-trichloroacetyl) -1H-indole-6-carbonitrile as a crude product.

(153-2) Synthesis of methyl 6-cyano-1H-indole-3-carboxylate (compound 153-2) 3- (2,2,2-trichloroacetyl) -1H-indole-6-carbonitrile (1. 4 g) in methanol (30 mL) was added sodium hydroxide (96 mg) and stirred at 80 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of methyl 6-cyano-1H-indole-3-carboxylate as a crude product.

Synthesis of (153-3) methyl 6-cyano-1- (pyrimidin-2-yl) -1H-indole-3-carboxylate (Compound 153-3) 6-cyano-1H-indole-3-carboxylate (1 0.0 g) in DMF (30 mL) was slowly added 60% sodium hydride (220 mg), and the mixture was stirred at room temperature for 30 min, 2-chloropyrimidine (630 mg) was added, and the mixture was stirred at 120 ° C. for 4 hr. The reaction mixture is ice-cooled to 0 ° C., water (100 mL) and ethyl acetate (100 mL) are added, and the resulting solid is collected by filtration and washed with a mixed solution of ethyl acetate and hexane to give methyl 6-cyano- 845 mg (60% yield) of 1- (pyrimidin-2-yl) -1H-indole-3-carboxylate was obtained.

(153-4) Synthesis of 6-cyano-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (Compound 153-4) Methyl 6-cyano-1- (pyrimidin-2-yl)- Lithium hydroxide monohydrate (502 mg) was added to a solution of 1H-indole-3-carboxylate (845 mg) in THF (9 mL) / methanol (3 mL) / water (3 mL), and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added, and the mixture was extracted with ethyl acetate. The obtained aqueous layer was acidified with concentrated hydrochloric acid, and the obtained solid was collected by filtration and washed with water to give 600 mg of 6-cyano-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid. (Yield 76%) was obtained.

(153-5) Synthesis of 3- [4- (4-hydroxyphenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole-6-carbonitrile (Compound 153) -1- (Pyrimidin-2-yl) -1H-indole-3-carboxylic acid (132 mg), 1- (4-hydroxyphenyl) piperazine (89 mg) and DMT-MM (208 mg) were dissolved in DMF (5 mL). And stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [4- (4-hydroxyphenyl) piperazine. -1-Carbonyl] -1- (pyrimidin-2-yl) -1H-indole-6-carbonitrile (86 mg, yield 41%) was obtained. The obtained compound was recrystallized with ethanol and hexane.

<< Synthesis of 6- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-ol (Compound 166) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

Synthesis of (166-1) 5- (benzyloxy) -2-chloropyridine (Compound 166-1) 6-chloropyridin-3-ol (1.0 g), benzyl bromide (1.5 g), and potassium carbonate (2.4 g) was dissolved in DMF (40 mL) and stirred at 60 ° C. for 18 hours. After filtering the reaction solution, the residue obtained by distilling off the solvent of the obtained filtrate under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5- (benzyloxy) -2-chloro. 1.3 g (yield quant.) Of pyridine was obtained.

(166-2) Synthesis of 1- [5- (benzyloxy) pyridin-2-yl] piperazine (Compound 166-2) 5- (Benzyloxy) -2-chloropyridine (1.3 g), Piperazine (982 mg) Toluene (15 mL) was added to dipalladium (II) acetate (28 mg), BINAP (163 mg) and sodium tert-butoxide (876 mg) under a nitrogen stream, and the mixture was stirred at 100 ° C. for 20 hours. The reaction mixture was cooled to room temperature, filtered through celite with ethyl acetate, the obtained filtrate was acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The obtained aqueous layer was made basic with sodium hydroxide, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of 1- [5- (benzyloxy) pyridin-2-yl] piperazine (yield 85%).

Synthesis of (166-3) 3- {4- [5- (benzyloxy) pyridin-2-yl] piperazin-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (Compound 166-3) 1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (120 mg), 1- [5- (benzyloxy) pyridin-2-yl] piperazine (135 mg), EDC (105 mg), HOBt (74 mg ) And triethylamine (0.08 mL) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to give 3- {4- [5- (benzyloxy) pyridin-2-yl] piperazine-1-carbonyl} -1- (pyrimidin-2-yl ) -1H-indole 230 mg was obtained as a crude product.

(166-4) Synthesis of 6- {4- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-ol (Compound 166) 3- {4 -[5- (Benzyloxy) pyridin-2-yl] piperazin-1-carbonyl} -1- (pyrimidin-2-yl) -1H-indole (230 mg) in dichloromethane (3 mL) in trifluoroacetic acid (3 mL) Was added dropwise and stirred at 65 ° C. for 18 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6- {4- [1- (pyrimidine-2 150 mg (yield 75%) of -yl) -1H-indole-3-carbonyl] piperazin-1-yl} pyridin-3-ol were obtained. The obtained compound was recrystallized with ethanol.

  Compound 179 was synthesized by the same method as above.

<< Synthesis of 4- {4- [1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (Compound 171) >>

Synthesis of (171-1) 1- (pyrimidin-2-yl) -1H-indole-5-carboxylic acid (Compound 171-1) To a solution of 1H-indole-5-carboxylic acid (500 mg) in DMF (10 mL) was added 60 % Sodium hydride (273 mg) was added, and the mixture was stirred at room temperature for 20 min. Then, 2-chloropyrimidine (389 mg) was added, and the mixture was stirred at 120 ° C. for 4 hr. The reaction mixture is cooled to room temperature, water is added, and the mixture is extracted with ethyl acetate. The resulting aqueous layer is acidified with concentrated hydrochloric acid, stirred at room temperature for 30 minutes, and the resulting solid is collected by filtration and washed with water. Thus, 428 mg (yield 58%) of 1- (pyrimidin-2-yl) -1H-indole-5-carboxylic acid was obtained.

Synthesis of (171-2) 4- {4- [1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (Compound 171) 1- (Pyrimidin-2-yl ) -1H-indole-5-carboxylic acid (72 mg), 1- (4-hydroxyphenyl) piperazine (53 mg) and DMT-MM (125 mg) were dissolved in DMF (2 mL) and stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- {4- [1- (pyrimidine-2 114 mg (yield 95%) of -yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol were obtained. The obtained compound was recrystallized with ethanol.

  Compounds 110, 127, 172 and 183 were synthesized by the same method as described above.

<< Synthesis of 4- [4- (1-benzoyl-1H-indole-3-carbonyl) piperazin-1-yl] phenol (Compound 174) >>

(174-1) Synthesis of 1-benzoyl-1H-indole-3-carboxylic acid (Compound 174-1) To a solution of indole-3-carboxylic acid (500 mg) in DMF (6 mL) was added 60% sodium hydride (260 mg). After adding at 0 ° C. and stirring for 20 minutes, benzoyl chloride (0.72 mL) was added and stirred at room temperature for 16 hours. An aqueous phosphoric acid solution (1M) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-benzoyl-1H-indole-3-carboxylic acid. 416 mg (yield 51%) was obtained.

Synthesis of (174-2) 4- [4- (1-benzoyl-1H-indole-3-carbonyl) piperazin-1-yl] phenol (Compound 174) 1-Benzoyl-1H-indole-3-carboxylic acid (133 mg) ), 1- (4-hydroxyphenyl) piperazine (89 mg) and DMT-MM (208 mg) were dissolved in DMF (2.5 mL) and stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- [4- (1-benzoyl-1H- 142 mg (yield 67%) of indole-3-carbonyl) piperazin-1-yl] phenol were obtained.

  Compounds 76, 135, 148, 186 and 194 were synthesized by the same method as described above.

<< Synthesis of N-({1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] pyrrolidin-2-yl} methyl) aniline (Compound 175) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

(175-1) Synthesis of tert-butyl 2- (phenylcarbamoyl) pyrrolidine-1-carboxylate (Compound 175-1) 1- (tert-Butoxycarbonyl) pyrrolidine-2-carboxylic acid (0.50 g), aniline ( 0.24 g), HATU (1.06 g), and triethylamine (0.35 g) were dissolved in DMF (20 mL) and stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 2- (phenylcarbamoyl) pyrrolidine-1. -0.52 g (77% yield) of carboxylate was obtained.

(175-2) Synthesis of N-phenylpyrrolidine-2-carboxamide (Compound 175-2) tert-Butyl 2- (phenylcarbamoyl) pyrrolidine-1-carboxylate (0.50 g) in a dioxane (5 mL) solution Hydrochloric acid-dioxane solution (2N) was added and stirred at room temperature for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain 0.31 g (yield 95%) of N-phenylpyrrolidine-2-carboxamide.

(175-3) Synthesis of N-[(pyrrolidin-2-yl) methyl] aniline (Compound 175-3) To a solution of N-phenylpyrrolidine-2-carboxamide (0.31 g) in tetrahydrofuran (20 mL) was added borane- Tetrahydrofuran solution (3 mL) was added, and the mixture was stirred at 40 ° C. for 30 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-[(pyrrolidin-2-yl) methyl] aniline. 0.20 g (yield 70%) was obtained.

Synthesis of (175-4) N-({1- [1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] pyrrolidin-2-yl} methyl) aniline (Compound 175) 1- (Pyrimidine- 2-yl) -1H-indole-3-carboxylic acid (0.27 g), N-[(pyrrolidin-2-yl) methyl] aniline (0.20 g), HATU (0.52 g), and triethylamine (0. 21 g) was dissolved in DMF (10 mL) and stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by preparative HPLC to give N-({1- [1- (pyrimidin-2-yl) -1H. -Indol-3-carbonyl] pyrrolidin-2-yl} methyl) aniline (0.15 g, yield 33%) was obtained.

<< Synthesis of N- (1-phenylpyrrolidin-3-yl) -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound 176) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

Synthesis of (176-1) tert-butyl N-[(1-phenylpyrrolidin-2-yl) methyl] carbamate (Compound 176-1) tert-butyl pyrrolidin-3-ylcarbamate (0.8 g) and benzene bromide To a solution of (0.67 g) in dioxane (15 mL), BINAP (0.27 g), tris (dibenzylideneacetone) dipalladium (0) (0.22 g) and cesium carbonate (2.8 g) were added under a nitrogen atmosphere. , And stirred in a microwave (140 ° C., 100 W) for 3 hours. The reaction mixture was cooled to room temperature, filtered, washed with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate), and tert-butyl N- 0.35 g (yield 31%) of [(1-phenylpyrrolidin-2-yl) methyl] carbamate was obtained.

Synthesis of (176-2) (1-phenylpyrrolidin-2-yl) methanamine (compound 176-2) tert-butyl N-[(1-phenylpyrrolidin-2-yl) methyl] carbamate (0.35 g) dioxane To the (5 mL) solution was added hydrochloric acid-dioxane solution (2N), and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain 0.18 g (yield 82%) of (1-phenylpyrrolidin-2-yl) methanamine.

(176-3) Synthesis of N- (1-phenylpyrrolidin-3-yl) -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound 176) Yl) methanamine (0.18 g) and 1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (0.27 g) in DMF (5 mL) were added HATU (0.51 g) and triethylamine (0 .17 g) was added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by preparative HPLC, whereby N- (1-phenylpyrrolidin-3-yl) -1- (pyrimidine 0.10 g (24% yield) of 2-yl) -1H-indole-3-carboxamide was obtained.

<< Synthesis of 2-[(4-chlorophenyl) (2-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] formamido} ethyl) amino] acetic acid (Compound 184) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

(184-1) Synthesis of N- {2-[(4-chlorophenyl) amino] ethyl} -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound 184-1) 1- ( Pyrimidin-2-yl) -1H-indole-3-carboxylic acid (254 mg), N1- (4-chlorophenyl) ethane-1,2-dianamine (180 mg), EDC (222 mg), DMAP (142 mg) in dichloromethane (5 mL) ) And stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give N- {2-[(4-chlorophenyl) amino. Ethyl} -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide 160 mg (yield 39%) was obtained.

(184-2) tert-butyl 2-[(4-chlorophenyl) (2-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] formamido} ethyl) amino] acetate (Compound 184- Synthesis of 2) N- {2-[(4-chlorophenyl) amino] ethyl} -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (160 mg) in DMF (4 mL) solution 60% Sodium hydride (18 mg) was added, and the mixture was stirred at room temperature for 20 minutes. Then, tert-butyl 2-bromoacetate (0.07 mL) was added, and the mixture was stirred at room temperature for 48 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), and tert-butyl 2-[(4-chlorophenyl) ( 74 mg (yield 36%) of 2-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] formamido} ethyl) amino] acetate were obtained.

Synthesis of (184-3) 2-[(4-chlorophenyl) (2-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] formamido} ethyl) amino] acetic acid (Compound 184) tert -Butyl 2-[(4-chlorophenyl) (2-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] formamido} ethyl) amino] acetate (74 mg) in dichloromethane (1.5 mL) Trifluoroacetic acid (1 mL) was added to the solution and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and the resulting aqueous layer was neutralized with 10% aqueous citric acid solution and extracted with dichloromethane. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-ethanol). 36 mg (yield 56%) of (4-chlorophenyl) (2-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] formamido} ethyl) amino] acetic acid was obtained.

<< Synthesis of 4- {4- [3-chloro-1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (Compound 187) >>

  Compounds 171-1 and 171-2 were synthesized by the same procedure as (171-1) and (171-2) above.

Synthesis of (187-1) 4- {4- [3-Chloro-1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol (Compound 187) 4- {4 -A solution of [1- (pyrimidin-2-yl) -1H-indol-5-carbonyl] piperazin-1-yl} phenol (112 mg) in DMF (1 mL) was cooled to 0 ° C. with ice, and then N-chlorosuccinimide (42 mg). ) And stirred for 48 hours while raising the temperature to room temperature. The reaction mixture was ice-cooled again to 0 ° C., N-chlorosuccinimide (42 mg) was added, and the mixture was stirred for 17 hours while warming to room temperature. Ice water was added to the reaction solution, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer chromatography (hexane-ethyl acetate) to give 4- {4- [3-chloro- 1- (pyrimidin-2-yl) -1H-indole-5-carbonyl] piperazin-1-yl} phenol 12 mg (yield 10%) was obtained.

<< Synthesis of 4- (4-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] methyl} piperazin-1-yl) phenol (Compound 190) >>

Synthesis of (190-1) 1- (pyrimidin-2-yl) -1H-indole (Compound 190-1) To a solution of 1H-indole (468 mg) in DMF (8 mL) was added 60% sodium hydride (176 mg), After stirring at room temperature for 20 minutes, 2-chloropyrimidine (504 mg) was added, and the mixture was stirred at 120 ° C. for 18 hours. After cooling the reaction solution to room temperature, water was added and the resulting solid was collected by filtration and washed with water to give 578 mg (yield 74%) of 1- (pyrimidin-2-yl) -1H-indole.

Synthesis of (190-2) 1- (pyrimidin-2-yl) -1H-indole-3-carbaldehyde (Compound 190-2) 1- (Pyrimidin-2-yl) -1H-indole (195 mg) in DMF ( (2 mL) The solution was ice-cooled to 0 ° C., phosphoryl chloride (0.1 mL) was added, and the mixture was heated to 80 ° C. and stirred for 17 hours. The reaction mixture was ice-cooled again to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- (pyrimidin-2-yl) -1H- 98 mg (yield 44%) of indole-3-carbaldehyde was obtained.

Synthesis of (190-3) 4- (4-{[1- (pyrimidin-2-yl) -1H-indol-3-yl] methyl} piperazin-1-yl) phenol (Compound 190) 1- (Pyrimidine- 2-yl) -1H-indole-3-carbaldehyde (98 mg), 1- (4-hydroxyphenyl) piperazine (94 mg) and sodium triacetoxyborohydride (187 mg) in DCM (4 mL) and tetrahydrofuran (1 mL). Dissolved and stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- (4-{[1- (pyrimidine- 2-yl) -1H-indol-3-yl] methyl} piperazin-1-yl) phenol (64 mg, 38% yield) was obtained.

<< Synthesis of 2- {3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-indol-1-yl} -6-methylpyrimidine-4-carboxylic acid / hydrochloride (Compound 193) >>

Synthesis of (193-1) 3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-indole (Compound 193-1) 1H-indole-3-carboxylic acid (1.6 g), 1- ( 4-Chlorophenyl) piperazine monohydrochloride (2.6 g), EDC (2.5 g), HOBt (1.8 g) and triethylamine (3.2 mL) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 18 hours. . A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [4- (4-chlorophenyl) piperazine- 3.1 g (91% yield) of 1-carbonyl] -1H-indole was obtained.

(193) Synthesis of 2- {3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-indol-1-yl} -6-methylpyrimidine-4-carboxylic acid hydrochloride (Compound 193) To a solution of 3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-indole (340 mg) in DMF (2 mL) was slowly added 60% sodium hydride (44 mg), and the mixture was stirred at 0 ° C. for 20 minutes. Thereafter, methyl 2-chloro-6-methylpyrimidine-4-carboxylate (177 mg) was added, and the mixture was stirred at 100 ° C. for 18 hours. The reaction solution was cooled to room temperature, saturated sodium hydrogen carbonate rice solution was added, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give methyl 2- {3- [4- (4- Chlorophenyl) piperazine-1-carbonyl] -1H-indol-1-yl} -6-methylpyrimidine-4-carboxylate (138 mg, 28% yield) was obtained.
The resulting methyl 2- {3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-indol-1-yl} -6-methylpyrimidine-4-carboxylate (138 mg) was added to tetrahydrofuran (1 mL). And dissolved in water (0.3 mL), lithium hydroxide (13 mg) was added, and the mixture was stirred at room temperature for 20 hours. 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2- (3- [4- (4-chlorophenyl) piperazine-1-carbonyl] -1H-indol-1-yl} -6-methylpyrimidine-4-carboxylic acid / hydrochloric acid purified by chromatography (dichloromethane-ethanol) 33 mg (22% yield) of salt was obtained.

  Compound 192 was synthesized by the same method as above.

<< Synthesis of 5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 199) >>

  Compound 171-1 was synthesized by a procedure similar to that of (171-1) above.

Synthesis of (199-1) 5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 199) 1- (Pyrimidin-2-yl) ) -1H-indole-5-carboxylic acid (120 mg), 1- (4-fluorophenyl) piperazine (99 mg), EDC (105 mg), HOBt (74 mg), and triethylamine (0.08 mL) in dichloromethane (10 mL) Dissolved and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5- [4- (4-fluorophenyl) piperazine. 172 mg (yield 86%) of -1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole was obtained. The obtained compound was recrystallized from ethyl acetate-ethanol.

  Compounds 72, 73, 79, 100 to 105, 109, 112, 126, 163, 164, 177, 191, 195 to 198, 200, 201, 205, 210 and 212 were synthesized in the same manner as described above.

<< Synthesis of 3-fluoro-5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 202) >>

  Compounds 171-1 and 199 were synthesized by the same procedure as the above (171-1) and (199-1).

Synthesis of (202-1) 3-fluoro-5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (Compound 202) 5- [4 To a solution of-(4-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole (80 mg) in dimethyl sulfoxide (1 mL), 1-chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) (85 mg) was added, and the mixture was stirred at room temperature for 48 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate and the residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer chromatography (hexane-ethyl acetate) to give 3-fluoro-5- [4- ( 14 mg (17% yield) of 4-fluorophenyl) piperazine-1-carbonyl] -1- (pyrimidin-2-yl) -1H-indole were obtained.

<< Synthesis of N-[(1-phenylpyrrolidin-2-yl) methyl] -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound 206) >>

  Compound 108-1 was synthesized by the same procedure as in (108-1) above.

(206-1) Synthesis of tert-butyl N-[(1-phenylpyrrolidin-2-yl) methyl] carbamate (Compound 206-1) tert-butyl (pyrrolidin-2-yl) methylcarbamate (1.00 g) and Phenylboronic acid (0.73 g) was dissolved in dichloromethane (30 mL), and pyridine (2.37 g), copper acetate (2.72 g) and MS 4A (10 g) were added under an oxygen atmosphere, and the mixture was stirred overnight at room temperature. The residue obtained by filtering the reaction solution and distilling off the solvent of the resulting solution under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), and tert-butyl N-[(1-phenylpyrrolidine). There was obtained 0.45 g (yield 35%) of -2-yl) methyl] carbamate.

Synthesis of (206-2) (1-phenylpyrrolidin-2-yl) methanamine (compound 206-2) tert-butyl N-[(1-phenylpyrrolidin-2-yl) methyl] carbamate (0.45 g) dioxane To the (5 mL) solution was added hydrochloric acid-dioxane solution (2N), and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain 0.23 g (yield 80%) of (1-phenylpyrrolidin-2-yl) methanamine.

(206-3) Synthesis of N-[(1-phenylpyrrolidin-2-yl) methyl] -1- (pyrimidin-2-yl) -1H-indole-3-carboxamide (Compound 206) 1- (Pyrimidine- 2-yl) -1H-indole-3-carboxylic acid (0.23 g), (1-phenylpyrrolidin-2-yl) methanamine (0.31 g), HATU (0.59 g) and triethylamine (0.19 g). Dissolved in DMF (5 mL) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by preparative HPLC, whereby N-[(1-phenylpyrrolidin-2-yl) methyl] -1 0.05 g (yield 10%) of-(pyrimidin-2-yl) -1H-indole-3-carboxamide was obtained.

<< Synthesis of 4- [2- (aminoethyl) -4- [6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl] phenol (Compound 207) >>

  Compound 116-1 was synthesized by a procedure similar to that of (116-1) above.

Synthesis of (207-1) 2-chloro-N- (4-methoxyphenyl) acetamide (Compound 207-3) To a solution of 4-methoxyaniline (10.0 g) in DCM (70 mL), triethylamine (9.8 g) and chloro Acetyl chloride (10.9 g) was added and stirred at room temperature for 20 hours. After the solvent of the reaction solution was distilled off under reduced pressure, water (100 mL) was added, and the resulting solid was filtered and washed with water to give 14 g of 2-chloro-N- (4-methoxyphenyl) acetamide (yield 86). %).

(207-2) Synthesis of 2- (benzylamino) -N- (4-methoxyphenyl) acetamide (Compound 207-4) 2-Chloro-N- (4-methoxyphenyl) acetamide (2.0 g) in tetrahydrofuran ( 80 mL) solution was added benzylamine (1.28 g) and stirred at 98 ° C. for 18 hours. The reaction solution was cooled to room temperature, filtered, and washed with diethyl ether to obtain 1.35 g (yield 50%) of 2- (benzylamino) -N- (4-methoxyphenyl) acetamide.

(207-3) Synthesis of 2- [benzyl (3-chloro-2-hydroxypropyl) amino] -N- (4-methoxyphenyl) acetamide (Compound 207-5) 2- (Benzylamino) -N- (4 To a solution of -methoxyphenyl) acetamide (3.7 g) in dichloromethane (70 mL) / methanol (7 mL), magnesium sulfate (7.36 g) and epichlorohydrin (1.8 g) were slowly added and stirred at room temperature for 20 hours. did. Cold water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue obtained by evaporating the solvent of the organic layer under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- [benzyl (3-chloro-2-hydroxypropyl) amino] -N- ( 3.6 g (yield 73%) of 4-methoxyphenyl) acetamide was obtained.

Synthesis of (207-4) 4-benzyl-6- (hydroxymethyl) -1- (4-methoxyphenyl) piperazin-2-one (Compound 207-6) 2- [Benzyl (3-chloro-2-hydroxypropyl) ) Amino] -N- (4-methoxyphenyl) acetamide (3.6 g) in water (50 mL) / methanol (50 mL) was added with 5% aqueous sodium hydroxide (50 mL), and the mixture was stirred at room temperature for 18 hours. Cold water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-benzyl-6- (hydroxymethyl) -1 2.44 g (yield 75%) of-(4-methoxyphenyl) piperazin-2-one was obtained.

Synthesis of (207-5) [4-benzyl-1- (4-methoxyphenyl) piperazin-2-yl] methanol (Compound 207-7) 4-Benzyl-6- (hydroxymethyl) -1- (4-methoxy Borane-tetrahydrofuran complex (24 mL) was slowly added to a solution of (phenyl) piperazin-2-one (3.52 g) in tetrahydrofuran (40 mL), and the mixture was stirred at 40 ° C. for 12 hours. Methanol (10 mL) and hydrochloric acid (10 mL) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, cold water (20 mL) was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain [4-benzyl-1- (4-methoxyphenyl). ) Piperazin-2-yl] methanol 2.18g (70% yield).

(207-6) Synthesis of [4-benzyl-1- (4-methoxyphenyl) piperazin-2-yl] methyl methanesulfonate (Compound 207-8) [4-Benzyl-1- (4-methoxyphenyl) piperazine- To a solution of 2-yl] methanol (2.0 g) in dichloromethane (50 mL), triethylamine (1.3 g) and methanesulfonyl chloride (0.88 g) were slowly added and stirred at room temperature for 2 hours. Cold water (50 mL) was added to the reaction solution, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain [4-benzyl-1- (4-methoxyphenyl). ) Piperazin-2-yl] methyl methanesulfonate (2.25 g, yield 90%) was obtained.

Synthesis of (207-7) 2- (azidomethyl) -4-benzyl-1- (4-methoxyphenyl) piperazine (Compound 207-9) [4-Benzyl-1- (4-methoxyphenyl) piperazin-2-yl Sodium azide (0.34 g) was slowly added to a solution of methyl methanesulfonate (1.0 g) in DMF (20 mL), and the mixture was stirred at 90 ° C. for 2 hours. Cold water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2- (azidomethyl) -4-benzyl-1- 1.12 g (yield 86%) of (4-methoxyphenyl) piperazine was obtained.

Synthesis of (207-8) [4-benzyl-1- (4-methoxyphenyl) piperazin-2-yl] methanamine (Compound 207-10) 2- (azidomethyl) -4-benzyl-1- (4-methoxyphenyl) Triphenylphosphine (2.02 g) was added to a solution of piperazine (0.86 g) in tetrahydrofuran (160 mL), and the mixture was stirred at room temperature for 3 hours. Cold water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain [4-benzyl-1- (4-methoxyphenyl). ) Piperazin-2-yl] methanamine 0.64 g (yield 80%) was obtained.

Synthesis of (207-9) 4- [2- (aminoethyl) -4-benzylpiperazin-1-yl] phenol (Compound 207-11) [4-Benzyl-1- (4-methoxyphenyl) piperazine-2- Yl] methanamine (0.6 g) in dichloromethane (45 mL) was cooled to 0 ° C., boron tribromide (0.99 g) was slowly added, and the mixture was stirred at 0 ° C. for 1 hour. Cold water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4- [2- (aminoethyl) -4-benzylpiperazin-1-yl] phenol (0.6 g) as a crude product. .

Synthesis of (207-10) tert-butyl N-{[4-benzyl-1- (4-hydroxyphenyl) piperazin-2-yl] methyl} carbamate (compound 207-12) 4- [2- (aminoethyl) Di-4-tert-butyl dicarbonate (0.63 g) was added to a solution of (-4-benzylpiperazin-1-yl) phenol (0.6 g) in tetrahydrofuran (45 mL), and the mixture was stirred at room temperature overnight. Cold water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), and tert-butyl N-{[4-benzyl-1 0.5 g (yield 60%) of-(4-hydroxyphenyl) piperazin-2-yl] methyl} carbamate was obtained.

Synthesis of (207-11) tert-butyl N-{[1- (4-hydroxyphenyl) piperazin-2-yl] methyl} carbamate (compound 207-13) tert-butyl N-{[4-benzyl-1- To a solution of (4-hydroxyphenyl) piperazin-2-yl] methyl} carbamate (0.4 g) in methanol (15 mL) was added palladium carbon (0.5 g), and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. The reaction solution was filtered through celite and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate), and tert-butyl N-{[1- (4-hydroxyphenyl) piperazin-2-yl. ] 0.26 g (yield 85%) of methyl} carbamate was obtained.

(207-12) tert-Butyl N-({4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -1- (4-hydroxyphenyl) piperazine-2- Yl} methyl) carbamate (Compound 207-14) 6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid (0.13 g), tert-butyl N-{[1- HATU (0.24 g) was added to a solution of (4-hydroxyphenyl) piperazin-2-yl] methyl} carbamate (0.15 g) and triethylamine (0.1 g) in DMF (10 mL) and stirred at room temperature for 2.5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), and tert-butyl N-({4- [6- 50 mg (yield 30%) of chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -1- (4-hydroxyphenyl) piperazin-2-yl} methyl) carbamate were obtained.

(207-13) 4- [2- (Aminoethyl) -4- [6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl] phenol (Compound 207 ) Tert-butyl N-({4- [6-Chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] -1- (4-hydroxyphenyl) piperazin-2-yl} To a solution of (methyl) carbamate (50 mg) in dioxane (5 mL) was added hydrochloric acid-dioxane solution (2N), and the mixture was stirred at room temperature for 50 minutes. Sodium hydroxide aqueous solution (1N) was added to the reaction liquid, the residue obtained by adjusting to pH -7 and concentrating was refine | purified by preparative thin layer chromatography, 4- [2- (aminoethyl)- 25 mg (85% yield) of 4- [6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carbonyl] piperazin-1-yl] phenol was obtained.

<< Synthesis of 1- (2-fluorophenyl) -5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound 208) >>

Synthesis of (208-1) 5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound 208-1) 1H-indole-5-carboxylic acid (806 mg), 1- (4 -Fluorophenyl) piperazine (991 mg), EDC (1.1 g), HOBt (743 mg) and triethylamine (0.77 mL) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer washed with saturated brine was dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from hexane-ethyl acetate to give 1.5 g of 5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (yield). 91%).

Synthesis of (208-2) 1- (2-fluorophenyl) -5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound 208) 5- [4- (4-Fluoro) (Phenyl) piperazine-1-carbonyl] -1H-indole (323 mg), copper (I) iodide (38 mg) and tripotassium phosphate (446 mg) under a stream of nitrogen, toluene (3 mL), 1-fluoro-2- Iodobenzene (0.14 mL) and trans-1,2-cyclohexadiamine (0.025 mL) were added, and the mixture was stirred for 18 hours with heating under reflux. The reaction mixture was cooled to room temperature, filtered through celite with ethyl acetate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- (2-fluorophenyl). ) -5- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (418 mg, yield quant.) Was obtained.

  Compounds 111, 168, 180, 203 and 209 were synthesized by the same method as above.

<< Synthesis of 3-[(4-fluorophenyl) methyl] -6- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound 213) >>

(213-1) Synthesis of methyl 1H-indole-6-carboxylate (Compound 213-1) Concentrated sulfuric acid (0.1 mL) was added to a solution of 1H-indole-6-carboxylic acid (500 mg) in methanol (10 mL), The mixture was stirred for 16 hours under heating to reflux. The reaction solution was cooled to room temperature, neutralized with potassium carbonate, and stirred at room temperature for 1 hour. After evaporating the solvent of the reaction solution under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 462 mg of methyl 1H-indole-6-carboxylate (yield). 85%).

Synthesis of (213-2) methyl 3-[(4-fluorophenyl) methyl] -1H-indole-6-carboxylate (Compound 213-2) Methyl 1H-indole-6-carboxylate (175 mg) in dichloromethane (15 mL) ) 4-Fluorobenzaldehyde (0.1 mL) and trimethylsilyl trifluoromethanesulfonate (0.4 mL) were added to the solution. After ice cooling to 0 ° C., triethylsilane (0.52 mL) was added and the mixture was stirred at 0 ° C. for 3 hours. . Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 3-[(4-fluorophenyl) methyl]. 166 mg of -1H-indole-6-carboxylate (yield 59%) was obtained.

(213-3) Synthesis of 3-[(4-fluorophenyl) methyl] -1H-indole-6-carboxylic acid (Compound 213-3) Methyl 3-[(4-fluorophenyl) methyl] -1H-indole- To a solution of 6-carboxylate (166 mg) in tetrahydrofuran (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (99 mg), and the mixture was stirred at 50 ° C. for 3 hr. The reaction mixture was cooled to room temperature, acidified with 10% hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 111 mg of 3-[(4-fluorophenyl) methyl] -1H-indole-6-carboxylic acid as a crude product.

(213-4) Synthesis of 3-[(4-fluorophenyl) methyl] -6- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole (Compound 213) 3-[(4- Fluorophenyl) methyl] -1H-indole-6-carboxylic acid (75 mg), 1- (4-fluorophenyl) piperazine (75 mg), EDC (86 mg), HOBt (60 mg) and triethylamine (0.15 mL) in dichloromethane ( 5 mL) and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-[(4-fluorophenyl) methyl]- 124 mg (yield 72%) of 6- [4- (4-fluorophenyl) piperazine-1-carbonyl] -1H-indole was obtained.

Tables 2 and 3 show compounds 1-180, 182-188, 190-203 and 205-245.

<3. Evaluation of amyloid fibril formation inhibitory activity by thioflavin T (ThT) assay>
The inhibitory activity of the compounds 1-245 on GAβ-dependent amyloid fibril formation was evaluated by ThT assay.

(1) Preparation of Aβ solution Human Aβ1-40 (cat. # 4307-v, manufactured by Peptide Institute) was dissolved in 0.02% ammonia solution (400 μM), and centrifuged at 100,000 rpm for 3 hours (S110AT Rotor manufactured by Hitachi). About two thirds of the upper layer of the supernatant was collected and the protein concentration was measured. The Aβ solution was aliquoted and stored at −80 ° C. until use. Thawed immediately before use and diluted to 75 μM with phosphate buffer (PBS: cat. # 10010, Life Technologies).

(2) Preparation of GM1-containing liposome Using a chloroform / methanol mixture (1: 1) as a solvent, a mixed solution of 100 mM cholesterol and sphingomyelin (both manufactured by Sigma-Aldrich) was prepared. In this mixed solution, GM1 (cat. # 1061, manufactured by Matreya) was dissolved to a concentration of 50 mM. This lipid mixture solution was aliquoted into glass test tubes and stored at −20 ° C. until use. After melting before use, chloroform / methanol mixture (1: 1) was added and mixed, and then the solvent was removed by applying nitrogen gas to the suspension. The dried lipid mixture was resuspended in PBS so that the GM1 concentration was 2.5 mM, and freeze-thawed 5 times using liquid nitrogen. This lipid suspension was centrifuged at 15,000 rpm for 10 minutes, and the precipitate was resuspended in PBS so that GM1 was 2.5 mM. Using an ultrasonic crusher (XL-2000, manufactured by MISONIX) equipped with a microchip, sonication for 10 seconds was repeated on ice until this suspension became transparent to prepare GM1-containing liposomes. PBS was added immediately before use to dilute the GM1 concentration to 750 μM.

(3) Preparation of compound solution Compounds 1-180, 182-188, 190-203, and 205-245 prepared 10 mM and 2 mM solutions in DMSO, respectively. Immediately before use, it was diluted to 75 μM or 15 μM with PBS.

(4) GAβ-dependent amyloid fibril formation In a 96-well microplate, 75 μM of the Aβ solution prepared in (1) above and 5 μl of the compound solution prepared in (3) or 0.75% DMSO were mixed, Incubated for 10 minutes at room temperature. Next, 5 μl of 750 μM GM1-containing liposome prepared in (2) was added to each well and incubated at 37 ° C. for 18 hours.

(5) ThT assay ThT (manufactured by Sigma-Aldrich) was prepared to 5 μM using 50 mM glycine-NaOH buffer (pH 8.5). Immediately before the measurement, 10 μl from each well in (4) was transferred to a 96-well black plate. Using a multiplate reader (ARVO-HTS, manufactured by PerkinElmer), 50 μl of 5 μM ThT solution was added to each well from an injector, and then optimum fluorescence of ThT bound to amyloid fibrils (excitation wavelength: 430 nm, fluorescence wavelength) 490 nm).

  The fluorescence intensity of ThT indicates the degree of amyloid fibril formation. By determining the ratio of the ThT fluorescence intensity when the compound was added to the ThT fluorescence intensity when no compound was added, the inhibition rate of amyloid fibril formation by the compound was calculated. When the final concentration of the compound was 25 μM, the inhibition rate was evaluated as C, 40% or more and less than 80% as B, and 80% or more as A.

  In Table 3, ABC evaluation about the amyloid fibril formation inhibitory activity of compound 1-180, 182-188, 190-203, and 205-245 is shown. Compounds 1-180, 182-188, 190-203 and 205-245 were all confirmed to have inhibitory activity on amyloid fibril formation.

Claims (9)

Formula (I):

[Where:
R ₁ and R ₂ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group, or a C _1-20 hydroxyalkyl. Group, C _1-20 alkoxyalkyl group, carboxyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, cyano group, SO ₂ NH ₂ group, C _1-20 alkyl SO ₂ NH group or halogen Is an atom,
R ₃ and R ₄ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 hydroxyalkyl group, a C _1-20 alkoxyalkyl group, a C _1-20 alkylaminoalkyl group or a C _{1- A 20} aminoalkyl group, wherein R ₃ and R ₄ may together form a ring;
Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted C _5-14 aryl group, a substituted or unsubstituted C _1-14 heteroaryl group, or a hydrogen atom,
X and Y are each independently a single bond, —C (═O) —, —C (═O) — (CH ₂ ) _m —, —C (═O) NR _x —, —SO ₂ —, _{-SO 2 - (CH 2) m} -, - (CH 2) m -, - (CH 2) m -O-, or, _{- (CH} 2) m -NH-
(In the formula, m is an integer of 1 to 3, and R _x is a hydrogen atom, a C _1-20 alkyl group, a C _1-20 alkoxy group, a C _1-20 hydroxyalkyl group, or a C _1-20 alkoxyalkyl. Group, carboxyl group, C _1-20 alkylaminoalkyl group, C _1-20 aminoalkyl group, cyano group, C _1-20 alkyl SO ₂ NH group or halogen atom)
And
Z is an oxygen atom or CH ₂ ;
n is an integer of 1 to 3]
Or a pharmaceutically acceptable salt thereof or a solvate thereof, an amyloid fibril formation inhibitor. Said compound has the general formula (Ia):

[Where:
R ₁ and R ₂ are each independently a hydrogen atom, C _1-20 alkyl group, C _1-20 haloalkyl group, C _1-20 alkoxy group, C _1-20 haloalkoxy group, cyano group, C _{1- 20} alkyl SO ₂ NH group or a halogen atom,
Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted C _5-14 aryl group or a substituted or unsubstituted C _1-14 heteroaryl group;
X and Y are each independently a single bond, —C (═O) —, —C (═O) NR _x —, —SO ₂ —, or —CH ₂ —.
(Wherein R _x is a hydrogen atom, a C _1-20 alkyl group, a C _1-20 alkoxy group, a cyano group, a C _1-20 alkyl SO ₂ NH group or a halogen atom)
Is]
The amyloid fibril formation inhibitor of Claim 1 represented by these. Said compound has the general formula (Ia ′):

[Where:
R ₁ and R ₂ are each independently a hydrogen atom, a C _1-20 alkyl group, a C _1-20 haloalkyl group, a C _1-20 alkoxy group, a C _1-20 haloalkoxy group or a halogen atom,
Ar ₁ and Ar ₂ are each independently a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyrimidyl group or a substituted or unsubstituted pyridyl group,
X and Y are each independently a single bond or —CH ₂ —.
The amyloid fibril formation inhibitor of Claim 1 represented by these.   A compound selected from the group consisting of compounds Nos. 1-180, 182-188, 190-203 and 205-245 described in Table 1A to Table 1P, or a pharmaceutically acceptable salt thereof, or a solvate thereof An amyloid fibril formation inhibitor comprising:   The compound is compound numbers 1 to 3, 5, 15, 16, 20 to 22, 24 to 26, 30 to 35, 39, 41, 42, 51, 58 to 60, 67, 70 to 76, 78 to 84, 92-94, 96, 98-105, 107-126, 128, 129, 133-135, 137, 140, 143-161, 163-180, 182-188, 190, 192-194, 198-200, 203, The amyloid fibril formation inhibitor of Claim 4 selected from the group which consists of a compound of 205-218 and 232.   The compound has compound numbers 26, 73, 102, 103, 108, 110, 113, 114, 116-118, 133, 135, 140, 146-149, 154, 160, 161, 167-169, 173-175, The amyloid fibril formation inhibitor according to claim 4, which is selected from the group consisting of compounds of 178 to 180, 187, 190, 199, 200, 203, 207, 208, 210 and 213.   The therapeutic agent or preventive agent of a neurodegenerative disease containing the amyloid fibril formation inhibitor of any one of Claims 1-6.   The therapeutic or prophylactic agent according to claim 7, wherein the neurodegenerative disease is Alzheimer's disease.   A compound selected from the group consisting of compounds Nos. 1-180, 182-188, 190-203 and 205-245 described in Table 1A to Table 1P, or a pharmaceutically acceptable salt thereof, or a solvate thereof .