JP6790202B2 - Antiviral compound - Google Patents

Description

This application is U.S. Patent Application Nos. 13 / 100,827, 25, filed May 4, 2011, U.S. Patent Provisional Application Nos. 61 / 446,800, filed February 25, 2011, December 9, 2010. It claims priority from U.S. Patent Application No. 12 / 964,027 and U.S. Patent Application No. 12 / 903,822, filed October 13, 2010, both of which are in full by reference. Is incorporated herein by.

The present invention relates to compounds that are effective in inhibiting the replication of hepatitis C virus (“HCV”). The present invention also relates to compositions containing these compounds and how to use these compounds in treating HCV infections.

HCV is an RNA virus belonging to the genus Hepatitis virus of the Flaviviridae family. The enveloped HCV virion contains a positive-strand RNA genome encoding all known virus-specific proteins in a single uninterrupted reading frame. The reading frame contains about 9,500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. The polyproteins include core proteins, outer membrane proteins E1 and E2, membrane binding proteins p7 and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

The non-structural protein NS5A is basically a membrane-bound phosphoprotein that exists in both phosphorylated and hyperphosphorylated forms. It is an essential component of HCV replication and is thought to exert multiple functions at various stages of the viral life cycle. The full-length NS5A protein comprises three domains-ie, domain I, domain II and domain III. Domain I (residues 1-213) contains an amphipathic N-terminal helix that can promote zinc binding motifs and membrane binding. Domain II (residues 250-342) has regulatory functions such as interaction with protein kinases PKR and PI3K and NS5B, and also includes an interferon susceptibility determining region. Domain III (residues 356 to 447) plays a role in infectious virion assembly and can be regulated by phosphorylation within the domain. NS5A has been identified as a promising therapeutic target for treating HCV.

The present invention provides a compound of formula _{I, I A, I B,} I C, I D, I E, characterized acceptable salts compounds and their pharmaceutical _{I F} and _{I G.} These compounds and salts are useful in treating HCV infections because they can inhibit HCV replication.

The present invention also features compositions comprising the compounds or salts of the present invention. The composition also includes other therapeutic agents such as HCV helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors or internal ribosome entry site (IRES) inhibitors. Can include.

The present invention is further characterized by a method of using the compound or salt of the present invention to inhibit HCV replication. The method comprises contacting HCV virus-infected cells with a compound or salt of the invention to inhibit HCV virus replication in the cells.

Furthermore, the present invention is characterized by a method of using the compound or salt of the present invention or a composition containing the same in treating HCV infection. The method involves administering to a patient in need of treatment a compound or salt of the invention or a composition containing it to reduce blood or tissue levels of HCV virus in that patient. Have.

The present invention is also characterized by the use of the compounds or salts of the present invention in producing pharmaceuticals for the treatment of HCV infection. Furthermore, the present invention is characterized by a method for producing a compound or salt of the present invention.

Other features, objectives and advantages of the present invention will be apparent in the detailed description below. However, it should be understood that although the following detailed description shows preferred embodiments of the present invention, they are provided for purposes of illustration only and are not intended to limit the present invention. Various changes and modifications within the scope of the present invention will be apparent to those skilled in the art from detailed description.

Tellinghuisen et al. , Nature 435: 374-379 (2005) describes the crystal structure of an NS5A protein in which two NS5A monomers are packed as a dimer via contact near the N-terminus of the molecule. WO2006093867 envisages the design or selection of NS5A inhibitors using the crystal structure of the NS5A protein in combination with computer modeling.

To improve the interaction with the NS5A protein, many NS5A inhibitors are designed to have a dimeric or dimeric-like structure. For example, WO2006133326 (BMS) has the following formula:

を有する化合物が記載されており；ＷＯ２００８１４４３８０（ＢＭＳ）には、下記式：

Compounds have been described; WO2008144380 (BMS) has the following formula:

を有する化合物が描かれており；ＷＯ２００８０２１９２７（ＢＭＳ）には、下記式：

A compound having the following formula is drawn; WO2008021927 (BMS) has the following formula:

を有する化合物が示されており；ＷＯ２００８０２１９２７（ＢＭＳ）には、下記式：

Compounds are shown; WO2008021927 (BMS) has the following formula:

を有する化合物が示されており；ＵＳ２０１０００６８１７６（ＢＭＳ）には、下記式：

Compounds having the following formula are shown; in US20100068176 (BMS), the following formula:

を有する化合物が示されており、Ｌは、アリール類（例えば、

Compounds are shown in which L is an aryl (eg, for example).

）、ヘテロアリール類（例えば、

), Heteroaryls (eg)

）、脂肪族基（例えば、

), Aliphatic groups (eg

）、またはこれらの組み合わせ（例えば、

), Or a combination of these (eg,

）から選択される。

) Is selected.

Certain modifications to the above equation are also provided. For example, WO20100065681 (Presido) has the following formula:

が開示されており、式中、ＢはＱまたはＱ−Ｑであり、各Ｑは独立にシクロアルキル、シクロアルケニル、複素環、アリールまたはヘテロアリールから選択され、ただしＢがＱ−Ｑである場合、６員芳香環であるのは１個のＱのみであり、ただしＢがＱ−Ｑである場合、多環式であるいずれのＱもその多環の１個の環のみを介して分子のこの利の部分に連結されており；ＷＯ２０１００９６７７７（Ｐｒｅｓｉｄｉｏ）には類似の式：

Is disclosed, where in the formula B is Q or QQ, each Q is independently selected from cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl, provided that B is QQ. , A 6-membered aromatic ring is only one Q, but if B is a QQ, then any Q that is polycyclic is a molecule through only one ring of that polycycle. It is linked to this part of the interest; a formula similar to WO201096777 (Presidio):

が記載されており、式中、ＢはＷ−ＷまたはＷ−Ｘ″−Ｗであり、各Ｗは置換されていても良いアリールまたはヘテロアリールであり、Ｘ″は−Ｏ−、−Ｓ（Ｏ）_ｋ、−Ｎ（Ｒ^Ｎ）−および−ＣＲ′_２−から選択され；ＷＯ２０１００９１４１３（Ｅｎａｎｔａ）およびＵＳ２０１００２６６５４３（Ｅｎａｎｔａ）には下記式：

In the formula, B is W-W or W-X "-W, each W is an optionally substituted aryl or heteroaryl, and X" is -O-, -S ( ^{_{O) k, -N (R N}} ) - , and -CR _'2 - is selected from; WO2010091413 (Enanta) and US20100266543 (Enanta) in the following formula:

が示されており、式中、Ａは置換されたアリール、ヘテロアリール、複素環、Ｃ_３−Ｃ_８シクロアルキルまたはＣ_３−Ｃ_８シクロアルケニルであり、選択された置換基で置換されていても良く；ＵＳ２０１００２２１２１５（Ｅｎａｎｔａ）には下記式：

Is shown, in which A is a substituted aryl, heteroaryl, heterocycle, C _3- C ₈ cycloalkyl or C _3- C ₈ cycloalkenyl, substituted with the selected substituent. Also good; US201000221215 (Enanta) has the following formula:

が描かれており、式中、Ａはそれぞれ置換されていても良いアリール、ヘテロアリール、複素環、Ｃ_３−Ｃ_８シクロアルキルまたはＣ_３−Ｃ_８シクロアルケニルから選択され、Ｄは非存在であるか置換されていても良い脂肪族基であり、Ｔは非存在であるか置換されていても良い０から８個の炭素を含む直鎖脂肪族基であり、Ｅは非存在であるか独立に置換されていても良いアリールおよび置換されていても良いヘテロアリールから選択され、Ｄ、ＥおよびＴのうちの１個または２個が非存在である。

Is drawn, in which A is selected from optionally substituted aryl, heteroaryl, heterocycle, C _3- C ₈ cycloalkyl or C _3- C ₈ cycloalkenyl, and D is absent. Is it an aliphatic group that may be present or substituted, T is a linear aliphatic group containing 0 to 8 carbons that may be absent or substituted, and E is absent? Selected from optionally substituted aryls and optionally substituted heteroaryls, one or two of D, E and T are absent.

Tables 1 to 4 compare the antiviral activity of different NS5A compounds. As can be seen from these tables, some of the compounds generally included by WO20100065681 (Presidio) WO2010096777 (Presidio), WO2010096462 (Enanta), US20100266543 (Enanta), WO2010096462 (Enanta) and US201000266543 (Enanta). It appears to have comparable or lower anti-HCV activity compared to the corresponding compounds described in the application. WO20100065681 (Presidio), WO201096777 (Presidio), WO2010096462 (Enanta), US201000266543 (Enanta), WO2010096462 (Enanta) and US20100266543 (Enanta), but these compounds are not confirmed in the BMS application.

(BMS-7900052) uses a biphenyl linking group between the imidazole moieties. See WO2008021927 (BMS). The EC ₅₀ values of BMS-790052 for different HCV genotypes were found in Nettles et al. Infection: Results from a Proof-of-concept Study ", 59th Annual Meeting of the American Association for the Study of Liver Diseases (Oct 31-Nov 1 2008, San Francisco, CA; www.natap.org/2008/AASLD/AASLD_06 .Htm))). Specifically, Netorusu (Nettles) et al., HCV genotype 1a, 1b, 3a, _{EC 50} values of BMS-790052 is for 4a and 5a, respectively 0.05,0.009,0.127,0.012 , And 0.033 nM. Gao et al. , Nature 465: 96-100 (2010). The compounds in Table 1 use different linking groups between the imidazole moieties. Table 1 shows an EC ₅₀ values of these compounds when studied using individual replicon assay in the presence of 5% (by volume) fetal bovine serum (FBS). Compared with BMS-7900052, the activity of the compound against various HCV genotypes can be significantly reduced by replacing the biphenyl linking group with another linking group.

Table 2 compares compounds containing unsubstituted benzimidazoles with compounds containing halo-substituted benzimidazoles. Antiviral activity using replicons containing wild-type replicons (eg, 1bWT or 1aWT) and specific NS5A mutations (eg, 1bL28T, 1bY93H, 1aL31V, 1aY93C, 1aM28V, or 1aQ30E) in the absence of FBS. evaluated. Compared to reference compounds containing unsubstituted benzimidazoles, compounds containing substituted benzimidazoles generally showed comparable or lower activity against many of these HCV viruses.

Surprisingly in the present invention, compounds having halo-substituted benzimidazoles (eg, for example)

）がＮＳ５Ａ突然変異を含むある種のＨＣＶ変異株（例えば、１ａＬ３１Ｖ）に対してより良好な活性を有することができることが発見された。同様の試験によって、

) Can have better activity against certain HCV mutants containing the NS5A mutation (eg, 1aL31V). By a similar test

が、表２中の基準化合物と比較して、ＮＳ５Ａ突然変異Ｍ２８Ｔを含むＨＣＶ１ａ変異株に対して大幅に改善された活性を示すことも明らかになっている。これらの改善は、上記のＢＭＳ、ＰｒｅｓｉｄｉｏまたはＥｎａｎｔａの出願のいずれにおいても記載も示唆もされていない。従って、本発明は、ハロ置換されたベンズイミダゾールを含む化合物（例えば、

However, it has also been revealed that the activity is significantly improved against the HCV1a mutant strain containing the NS5A mutant M28T as compared with the reference compound in Table 2. These improvements are neither described nor suggested in any of the above BMS, Presido or Enanta applications. Therefore, the present invention relates to compounds containing halo-substituted benzimidazoles (eg, for example.

）を用いてＨＣＶ変異株（例えば、１ａＭ２８Ｔまたは１ａＬ３１Ｖ）を処理する方法を特徴とする。これらの方法は、そのようなＨＣＶ変異株（例えば、１ａＭ２８Ｔまたは１ａＬ３１Ｖ）に感染した患者に対して有効量のそのような化合物を投与することを含む。

) Is used to treat HCV mutant strains (eg, 1aM28T or 1aL31V). These methods include administering an effective amount of such compound to a patient infected with such an HCV mutant (eg, 1aM28T or 1aL31V).

The phenyl linking group between the benzimidazole moieties is pyrrolidinyl linked (eg,

で置き換えた場合に、ベンズイミダゾール部分にハロ置換を導入するためのプロセス化学極めて困難になったことも認められた。上記のＢＭＳ、ＰｒｅｓｉｄｉｏおよびＥｎａｎｔａの出願は、フェニル連結基が

It was also found that the process chemistry for introducing halo substitutions into the benzimidazole moiety became extremely difficult when replaced with. The above BMS, Presido and Enanta applications have a phenyl linking group.

で置き換わっている化合物におけるベンズイミダゾール部分上のハロ置換を可能とすると考えられる有効な開示を提供していない。図式ＸＸＩＶおよび本願の各種実施例（例えば、実施例２．１６、３．３５から３．４１、３．４６から３．５３、４．２６から４．３１、４．３７から４．４０、４．４２から４．４６、および４．５１から４．５７）は、置換されたピロリジニル連結基を有する化合物におけるそのような置換を可能とする有効な開示を提供する。

It does not provide a valid disclosure that would allow halo substitutions on the benzimidazole moiety in the compounds replaced by. Schematic XXIV and various examples of the present application (eg, Examples 2.16, 3.35 to 3.41, 3.46 to 3.53, 4.26 to 4.31, 4.37 to 4.40, 4 .42 to 4.46, and 4.51 to 4.57) provide effective disclosures that allow such substitutions in compounds with substituted pyrrolidinyl linking groups.

Table 3 compares compounds with different linking groups between the benzimidazole moieties. Antiviral activity was determined using the 1a and 1b replicon assays. "HP" refers to human plasma. Compounds containing pyrrolidinyl linking groups showed significantly lower anti-HCV activity compared to compounds containing pyrridinyl linking groups. Phenyl linking group used in US20100068176 (BMS)

）と比較して、ピリジニル連結基（

) Compared to the pyridinyl linking group (

）などの６員芳香族連結基は、同様または匹敵する抗ＨＣＶ活性を提供するものと予想される。

) And other 6-membered aromatic linking groups are expected to provide similar or comparable anti-HCV activity.

Table 4 further shows that the activity of the compound against HCV can be significantly reduced when the phenyl linking group is replaced with a pyrrolidinyl linking group. The compounds in Table 4, comprises a pyrrolidinyl linking group, having an _{EC 50} value of greater than 200 nM. By contrast, BMS-790,052 containing biphenyl linking group has the following _{The EC 50} values 0.2 nM. See the above literature by Nettles et al. Therefore, Tables 3 and 4 clearly show that the use of an unsubstituted pyrrolidinyl linking group in a dimeric or dimeric-like NS5A inhibitor can result in low anti-HCV activity.

Unexpectedly, it was discovered that the antiviral activity of the compound could be dramatically improved if the nitrogen atom in the pyrrolidinyl linking group was replaced with a carbocycle or heterocycle. Table 5 shows the anti-HCV activity of compounds in which the pyrrolidinyl linking group is substituted with a carbon ring or a heterocycle.

One thing to keep in mind

の抗ＨＣＶ活性が、

Anti-HCV activity of

より高いことは示されていない。

Not shown to be higher.

Table 5 also shows that another halo-substituted / heterocyclic substituent on the pyrrolidinyl linking group can significantly improve the anti-HCV activity of the compound (eg, Example 4.25). Compare with Example 3.20 or Example 5.1).

The present invention is characterized by a compound having formula I and a pharmaceutically acceptable salt thereof.

式中、
ＸはＣ_３−Ｃ_１２炭素環または３から１２員の複素環であり、１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く；
Ｌ_１およびＬ_２はそれぞれ独立に、結合；またはＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンまたはＣ_２−Ｃ_６アルキニレンから選択され、それらはそれぞれ、独立に各場合で、１以上のＲ_Ｌによって置換されていても良く；
Ｌ_３は、結合または−Ｌ_Ｓ−Ｋ−Ｌ_Ｓ′−であり、Ｋは結合、−Ｏ−、−Ｓ−、−Ｎ（Ｒ_Ｂ）−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）_２−、−Ｓ（Ｏ）−、−ＯＳ（Ｏ）−、−ＯＳ（Ｏ）_２−、−Ｓ（Ｏ）_２Ｏ−、−Ｓ（Ｏ）Ｏ−、−Ｃ（Ｏ）Ｏ−、−ＯＣ（Ｏ）−、−ＯＣ（Ｏ）Ｏ−、−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−、−ＯＣ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−、−Ｓ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｓ（Ｏ）_２Ｎ（Ｒ_Ｂ）−、−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｎ（Ｒ_Ｂ′）−、−Ｎ（Ｒ_Ｂ）ＳＯ_２Ｎ（Ｒ_Ｂ′）−または−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）Ｎ（Ｒ_Ｂ′）−から選択され；
ＡおよびＢはそれぞれ独立にＣ_３−Ｃ_１２炭素環または３から１２員の複素環であり、それぞれ独立に１以上のＲ_Ａで置換されていても良く；
Ｄは、Ｃ_３−Ｃ_１２炭素環または３から１２員の複素環であり、１以上のＲ_Ａで置換されていても良く；またはＤはＣ_３−Ｃ_１２炭素環または３から１２員の複素環であり、それはＪで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_１２炭素環または３から１２員の複素環であり、１以上のＲ_Ａで置換されていても良く、またはＪは−ＳＦ_５であり；またはＤは水素またはＲ_Ａであり；
Ｙは−Ｔ′−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄ、−Ｔ′−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄ、−Ｌ_Ｋ−Ｔ−Ｒ_Ｄ、または−Ｌ_Ｋ−Ｅから選択され；
Ｒ_１およびＲ_２はそれぞれ独立にＲ_Ｃであり、Ｒ_５はＲ_Ｂであり；またはＲ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって３から１２員の複素環を形成しており、それは１以上のＲ_Ａで置換されていても良く；
Ｒ_３、Ｒ_４、Ｒ_６およびＲ_７はそれぞれ独立にＲ_Ｃであり；またはＲ_３およびＲ_６がそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、３から１２員の炭素環または複素環を形成しており、それは１以上のＲ_Ａで置換されていても良く；
Ｚは−Ｔ′−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄ、−Ｔ′−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄ、−Ｌ_Ｋ−Ｔ−Ｒ_Ｄまたは−Ｌ_Ｋ−Ｅから選択され；
Ｒ_８およびＲ_９はそれぞれ独立にＲ_Ｃであり、Ｒ_１２はＲ_Ｂであり；またはＲ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって３から１２員の複素環を形成しており、それは１以上のＲ_Ａで置換されていても良く；
Ｒ_１０、Ｒ_１１、Ｒ_１３およびＲ_１４はそれぞれ独立にＲ_Ｃであり；またはＲ_１０およびＲ_１３がそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって３から１２員の炭素環または複素環を形成しており、それは１以上のＲ_Ａで置換されていても良く；
ＴおよびＴ′はそれぞれ独立に各場合で、結合、−Ｌ_Ｓ−、−Ｌ_Ｓ−Ｍ−Ｌ_Ｓ′−または−Ｌ_Ｓ−Ｍ−Ｌ_Ｓ′−Ｍ′−Ｌ_Ｓ″−から選択され、ＭおよびＭ′はそれぞれ独立に各場合で、結合、−Ｏ−、−Ｓ−、−Ｎ（Ｒ_Ｂ）−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）_２−、−Ｓ（Ｏ）−、−ＯＳ（Ｏ）−、−ＯＳ（Ｏ）_２−、−Ｓ（Ｏ）_２Ｏ−、−Ｓ（Ｏ）Ｏ−、−Ｃ（Ｏ）Ｏ−、−ＯＣ（Ｏ）−、−ＯＣ（Ｏ）Ｏ−、−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−、−ＯＣ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−、−Ｓ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｓ（Ｏ）_２Ｎ（Ｒ_Ｂ）−、−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｎ（Ｒ_Ｂ′）−、−Ｎ（Ｒ_Ｂ）ＳＯ_２Ｎ（Ｒ_Ｂ′）−、−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）Ｎ（Ｒ_Ｂ′）−、Ｃ_３−Ｃ_１２炭素環または３から１２員の複素環から選択され、前記Ｃ_３−Ｃ_１２炭素環および３から１２員の複素環はそれぞれ独立に各場合で、１以上のＲ_Ａによって置換されていても良く；
Ｌ_Ｋは独立に各場合で、結合、−Ｌ_Ｓ−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ′−または−Ｌ_Ｓ−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ′−；またはそれぞれ独立に各場合で１以上のＲ_Ｌによって置換されていても良いＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンまたはＣ_２−Ｃ_６アルキニレン；またはそれぞれ独立に各場合で１以上のＲ_Ａによって置換されていても良いＣ_３−Ｃ_１２炭素環または３から１２員の複素環から選択され；
Ｅは独立に各場合でＣ_３−Ｃ_１２炭素環または３から１２員の複素環から選択され、は独立に各場合で、１以上のＲ_Ａによって置換されていても良く；
Ｒ_Ｄはそれぞれ独立に各場合で、水素またはＲ_Ａから選択され；
Ｒ_Ａは独立に各場合で、ハロゲン、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、シアノまたは−Ｌ_Ｓ−Ｒ_Ｅから選択され、２個の隣接するＲ_Ａが、それらが結合している原子およびそれらが結合している原子間にある原子と一体となって、炭素環または複素環を形成していても良く；
Ｒ_ＢおよびＲ_Ｂ′はそれぞれ独立に各場合で、水素；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノまたは３から６員の炭素環または複素環から選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または３から６員の炭素環または複素環から選択され；Ｒ_ＢまたはＲ_Ｂ′における各３から６員の炭素環または複素環は独立に各場合で、ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良く；
Ｒ_Ｃは独立に各場合で、水素、ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノ；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノまたは３から６員の炭素環もしくは複素環から選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または３から６員の炭素環または複素環から選択され；Ｒ_Ｃにおける各３から６員の炭素環または複素環は独立に各場合で、ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良く；
Ｒ_Ｅは独立に各場合で、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓ、−Ｃ（Ｏ）Ｒ_Ｓ、−ＯＣ（Ｏ）Ｒ_Ｓ、−Ｃ（Ｏ）ＯＲ_Ｓ、−Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｓ（Ｏ）Ｒ_Ｓ、−ＳＯ_２Ｒ_Ｓ、−Ｃ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｒ_Ｓ′_、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｎ（Ｒ_Ｓ′Ｒ_Ｓ″）、−Ｎ（Ｒ_Ｓ）ＳＯ_２Ｒ_Ｓ′、−ＳＯ_２Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）ＳＯ_２Ｎ（Ｒ_Ｓ′Ｒ_Ｓ″）、−Ｎ（Ｒ_Ｓ）Ｓ（Ｏ）Ｎ（Ｒ_Ｓ′Ｒ_Ｓ″）、−ＯＳ（Ｏ）−Ｒ_Ｓ、−ＯＳ（Ｏ）_２−Ｒ_Ｓ、−Ｓ（Ｏ）_２ＯＲ_Ｓ、−Ｓ（Ｏ）ＯＲ_Ｓ、−ＯＣ（Ｏ）ＯＲ_Ｓ、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）ＯＲ_Ｓ′、−ＯＣ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）Ｓ（Ｏ）−Ｒ_Ｓ′、−Ｓ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｐ（Ｏ）（ＯＲ_Ｓ）_２、または−Ｃ（Ｏ）Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）−Ｒ_Ｓ′；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓ、または−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_６炭素環または３から６員の複素環から選択され；
Ｒ_Ｆは独立に各場合で、それぞれＯ、ＳまたはＮから選択される０、１、２、３、４もしくは５個のヘテロ原子を含み、独立に１以上のＲ_Ｌで置換されていても良いＣ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_１０アルケニルまたはＣ_２−Ｃ_１０アルキニル；または−（Ｒ_Ｘ−Ｒ_Ｙ）_Ｑ−（Ｒ_Ｘ−Ｒ_Ｙ′）から選択され、Ｑは０、１、２、３または４であり、各Ｒ_Ｘは独立にＯ、ＳまたはＮ（Ｒ_Ｂ）であり、各Ｒ_Ｙは独立Ｃ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンまたはＣ_２−Ｃ_６アルキニレンにであり、それらはそれぞれ独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基で置換されていても良く、各Ｒ_Ｙ′は独立にＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニルであり、それらはそれぞれ独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基で置換されていても良く；
Ｒ_Ｌは独立に各場合で、ハロゲン、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、シアノ、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓ、−Ｃ（Ｏ）Ｒ_Ｓ、−ＯＣ（Ｏ）Ｒ_Ｓ、−Ｃ（Ｏ）ＯＲ_Ｓ、−Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｓ（Ｏ）Ｒ_Ｓ、−ＳＯ_２Ｒ_Ｓ、−Ｃ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）または−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｒ_Ｓ′；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_６炭素環または３から６員の複素環から選択され；２個の隣接するＲ_Ｌが、それらが結合している原子およびそれらが結合している原子間にある原子と一体となって、炭素環または複素環を形成していても良く；
Ｌ_Ｓ、Ｌ_Ｓ′およびＬ_Ｓ″はそれぞれ独立に各場合で、結合；またはそれぞれ独立に各場合で１以上のＲ_Ｌによって置換されていても良いＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンまたはＣ_２−Ｃ_６アルキニレンから選択され；
Ｒ_Ｓ、Ｒ_Ｓ′およびＲ_Ｓ″はそれぞれ独立に各場合で、水素；それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_１−Ｃ_６アルキレン−Ｏ−Ｃ_１−Ｃ_６アルキルまたは３から６員の炭素環または複素環から選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または３から６員の炭素環または複素環から選択され；Ｒ_Ｓ、Ｒ_Ｓ′またはＲ_Ｓ′における各３から６員の炭素環または複素環は独立に各場合で、ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良い。

During the ceremony
X is a heterocycle 12 membered _C 3 _{-C 12} carbocyclic or 3, may be substituted by one or more _{R A} or _{R F;}
L ₁ and L ₂ are bound independently, respectively; or are selected from C _1- C ₆ alkylene, C _2- C ₆ alkenylene or C _2- C ₆ alkinylene, each independently one or more in each case. _May be replaced by _RL ;
L ₃ is a bond or _{-L S -K-L} S '- a and, K is _{bond, -O -, - S -,} - N (R B) -, - C (O) -, - S (O ) _2- , -S (O)-, -OS (O)-, -OS (O) _2- , -S (O) ₂ O-, -S (O) O-, -C (O) O- , -OC (O) -, - OC (O) O -, - C (O) N (R B) -, - N (R B) C (O) -, - N (R B) C (O) _{O -, - OC (O)} N (R B) -, - N (R B) S (O) -, - N (R B) S (O) 2 -, - S (O) N (R B) _{-, - S (O) 2} N (R B) -, - C (O) N (R B) C (O) -, - N (R B) C (O) N (R B ') -, - _{N (R B) SO 2 N} (R B ') - or _{-N (R B) S (O} ) N (R B') - is selected from;
A and B are each independently a C ₃ -C ₁₂ carbocyclic or 3-12 membered heterocyclic ring, optionally substituted with independently 1 or more R _A well;
D _is a C 3 _{-C 12} carbocyclic or 3-12 membered heterocyclic ring may be substituted by one or more _{R A;} or D is a _C 3 _{-C 12} carbocyclic or 3 12-membered heterocycle, which is substituted with J, may be substituted by one or more R _a, J is a heterocyclic ring from the C ₃ -C ₁₂ carbocyclic or 3 12-membered, one or more of R _May be substituted with _A , or J is -SF ₅ ; or D is hydrogen or _RA ;
Y is -T'-C (R ₁ R ₂ ) N (R ₅ ) -TR _D , -T'-C (R ₃ R ₄ ) C (R ₆ R ₇ ) -TR _D , -L Selected from _K- T-R _D or -L _K- E;
R ₁ and _{R 2} are each independently _{R C, R 5} is an _{R B;} or _{R 1} is _{R C, R 2} and _{R 5} together with the atom to which they are attached 3 from forms a 12-membered heterocyclic ring, which may be substituted by one or more R _a;
R ₃ , R ₄ , R ₆ and R ₇ are independently _RC ; or R ₃ and R ₆ are independently _RC , and R ₄ and R ₇ are integrated with the atom to which they are attached. becomes, it forms a carbocyclic or heterocyclic ring from 3 to 12-membered, which may be substituted by one or more R _a;
Z is -T'-C (R ₈ R ₉ ) N (R ₁₂ ) -TR _D , -T'-C (R ₁₀ R ₁₁ ) C (R ₁₃ R ₁₄ ) -TR _D , -L Selected from _K- T-R _D or -L _K- E;
R ₈ and _{R 9} are each independently _{R C, R 12} is an _{R B;} or _{R 8} is _{R C, R 9} and _{R 12} together with the atoms to which they are attached 3 from forms a 12-membered heterocyclic ring, which may be substituted by one or more R _a;
R ₁₀ , R ₁₁ , R ₁₃ and R ₁₄ are independently _RC ; or R ₁₀ and R ₁₃ are independently _RC , and R ₁₁ and R ₁₄ are integrated with the atom to which they are attached. and it turned and forms a carbocyclic or heterocyclic ring from 3 to 12-membered, which may be substituted by one or more R _a;
'In each case are each independently a _{bond, -L S -, - L S} -M-L S' - T and T or _{-L S -M-L S '-M'} -L S "- is selected from , _- - independently in each case, binding, -O, M and M 'S -, - N (R B ) -, - C (O) -, - S (O) 2 -, - S (O )-, -OS (O)-, -OS (O) _2- , -S (O) ₂ O-, -S (O) O-, -C (O) O-, -OC (O)-, _{-OC (O) O -, -} C (O) N (R B) -, - N (R B) C (O) -, - N (R B) C (O) O -, - OC (O) _{N (R B) -, -} N (R B) S (O) -, - N (R B) S (O) 2 -, - S (O) N (R B) -, - S (O) 2 _{N (R B) -, -} C (O) N (R B) C (O) -, - N (R B) C (O) N (R B ') -, - N (R B) SO 2 N _{(R B ') -, -} N (R B) S (O) N (R B') -, C 3 -C 12 is selected from carbocyclic or 3-12 membered heterocyclic ring, wherein the _C 3 _{-C 12} in each case independently heterocycle of 12-membered carbocyclic and 3, may be substituted by one or more R _a;
L _K in each case independently a _{bond, -L S -N (R B)} C (O) -L S '- or _{-L S -C (O) N (} R B) -L S'-; or each independently 1 or more _{R L} which may be _C 1 -C ₆ alkylene substituted by in each _case, C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene; or one or more R in each case independently Selected from C _3- C ₁₂ carbon rings or 3- to 12-membered heterocycles that may be substituted by _A ;
E is selected from heterocycles 12 membered C ₃ -C ₁₂ carbocyclic or 3 in each case independently, in each case independently, may be optionally substituted by one or more R _A;
R _D is independently selected from hydrogen or _RA in each case;
In each case R _A is independently halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, is selected from cyano or _-L S -R _E, 2 contiguous _{R A} is, atoms to which they are attached and They may be integrated with the atoms between the atoms to which they are bonded to form a carbocycle or heterocycle;
In R _B and R _{B 'are} in each case independently, hydrogen; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3 6 C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or 3- to 6-membered, which may be substituted with one or more substituents selected from member carbocycles or heterocycles. is selected from carbocyclic or heterocyclic ring; R _B or carbocyclic or heterocyclic ring each 3 to 6-membered in R _{B 'in} each case independently, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, Phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ halo It may be substituted with one or more substituents selected from alkynyl;
_RC independently in each case hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano; or independently in each case halogen, hydroxy, mercapto, amino, C _1- C ₆ alkyl, C which may be substituted with one or more substituents selected from carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3 to 6 membered carbocycles or heterocycles. _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or selected from 3 to 6 membered carbocycles or heterocycles; each 3 to 6 membered carbocycle or heterocycle in _RC is independently halogen in each case. , hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl It may be substituted by one or more substituents selected from _C 2 -C ₆ haloalkenyl or _C 2 -C ₆ haloalkynyl;
_RE is independently in each case, -OR _S , -S- _RS , -C (O) R _S , -OC (O) R _S , -C (O) OR _S , -N ( _RS). R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N ( _RS R _S '), -N ( _RS ) C (O) R _S ' _, -N ( R _S ) C (O) N ( _RS ′ R _S ″), -N ( _RS ) SO ₂ R _S ′, -SO ₂ N ( _RS R _S ′), -N ( _RS ) SO ₂ N _{(R S 'R S ")} , - N (R S) S (O) N (R S' R S"), - OS (O) -R S, -OS (O) 2 -R S, -S (O) ₂ OR _S , -S (O) OR _S , -OC (O) OR _S , -N ( _RS ) C (O) OR _S ', -OC (O) N ( _RS R _S ') _{, -N (R S) S (} O) -R S ', -S (O) N (R S R S'), - P (O) (oR S) 2 or -C, (O) N (R _{S) C (O) -R S} '; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, 1 or more substituents selected from formyl or cyano C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl which may be substituted by; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy. , Phosno, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ C _3- C ₆ carbocycles or 3- to 6-membered heterocycles that may be substituted with one or more substituents selected from haloalkynyl, C (O) OR _S , or -N ( _RS R _S '). Selected from the ring;
In each case R _F is independently, O, respectively, include 0,1,2,3,4 or 5 heteroatoms selected from S or N, optionally substituted with one or more _{R L} is independently good _C 1 _{-C 10 alkyl,} C 2 _{-C 10} alkenyl or _C 2 _{-C 10} alkynyl; or _{- (R X -R Y) Q} - is selected from _{(R X -R Y '),} Q is 0,1 , 2, 3 or 4, each _{R X} is independently O, S or N _{(R B),} each _{R Y} is independently _C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C _{6 to} alkynylene, each independently substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano. each _{R Y} 'is _C 1 -C ₆ alkyl is _{independently} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl, halogen each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, It may be substituted with one or more substituents selected from phosphonoxy, phosphono, tioxo, formyl or cyano;
_RL is independently in each case, halogen, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano, -O- _RS , -S- _RS , -C (O) R _S , -OC (O) R _S. , -C (O) OR _S , -N ( _RS R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N ( _RS R _S ') or -N ( R _S ) C (O) R _S '; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _{Even if} substituted with one or more substituents selected from _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl Selected from good C _3- C ₆ carbocycles or 3- to 6-membered heterocycles; two adjacent _RLs are integrated with the atom to which they are bonded and the atom between the atoms to which they are bonded. May form a carbocycle or a heterocycle;
L _{S, L S} 'and _{L S} "in each case independently, a bond; or independently to one or more _{R L} Good _C 1 -C be substituted by ₆ alkylene in each _case, C 2 -C It is selected from ₆ alkenylene or _C 2 -C ₆ alkynylene;
R _S , R _S ′ and R _S ″ are independently hydrogen in each case; halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, in each case independently. -OC ₁ -C ₆ Alkyne, -O-C _1- C ₆ alkylene-O-C _1- C ₆ Alkyne or substituted with one or more substituents selected from 3 to 6 membered carbocycles or heterocycles May be C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or selected from 3 to 6 membered carbocycles or heterocycles; _RS , _RS ′ or _RS Each 3- to 6-membered carbocycle or heterocycle in ′ is independent in each case, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyne. , _C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} optionally substituted by one or more substituents selected from C 2 -C ₆ haloalkenyl or _C 2 -C ₆ haloalkynyl You may.

A and B are preferably independently C ₅ -C ₆ carbocyclic (e.g., phenyl), 5-6 membered heterocyclic ring (e.g., pyridinyl or thiazolyl) or bicyclic compound of 8 to 12-membered, for example

から選択され、Ｚ_１は独立に各場合でＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｚ_２は独立に各場合でＮまたはＣＨから選択され、Ｚ_３は独立に各場合でＮまたはＣＨから選択され、Ｚ_４は独立に各場合でＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５およびＷ_６はそれぞれ独立に各場合でＣＨまたはＮから選択される。ＡおよびＢはそれぞれ独立に１以上のＲ_Ａで置換されていても良い。

Selected from, Z ₁ is independently selected from O, S, NH or CH ₂ in each case, Z ₂ is independently selected from N or CH in each case, and Z ₃ is independently selected from N or CH in each case. Selected from, Z ₄ is independently selected from O, S, NH or CH ₂ in each case, and W ₁ , W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are independently selected from CH or CH in each case. Selected from N. A and B may be substituted with one or more R _A independently.

More preferably, A is _C 5 -C ₆ carbocyclic ring, 5-6 membered heterocyclic ring,

から選択され、１以上のＲ_Ａで置換されていても良く；ＢはＣ_５−Ｃ_６炭素環、５から６員の複素環、

It is selected from one or more may be substituted by _{R A;} B is _C 5 -C ₆ carbocyclic ring, 5-6 membered heterocyclic ring,

から選択され、１以上のＲ_Ａで置換されていても良く；Ｚ_１、Ｚ_２、Ｚ_３、Ｚ_４、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５、Ｗ_６は上記で定義の通りである。好ましくは、Ｚ_３はＮであり、Ｚ_４はＮＨである。例えば、Ａはフェニル（例えば、

It is selected from may be substituted with one or more _{R A; Z 1, Z 2} , Z 3, Z 4, W 1, W 2, W 3, W 4, W 5, W 6 are defined above It is a street. Preferably, Z ₃ is N and Z ₄ is NH. For example, A is phenyl (eg,

）、ピリジニル（例えば、

), Pyrizinyl (eg

）、チアゾリル（例えば、

), Thiazolyl (eg

）、

),

（例えば、

(For example

）、または

), Or

（例えば、

(For example

）から選択することができ、１以上のＲ_Ａで置換されていても良く；Ｂはフェニル（例えば、

) Can be selected from, may be substituted by one or more R _A; B is phenyl (e.g.,

）、ピリジニル（例えば、

), Pyrizinyl (eg

）、チアゾリル（例えば、

), Thiazolyl (eg

）、

),

（例えば、

(For example

）、または

), Or

（例えば、

(For example

）から選択することができ、１以上のＲ_Ａで置換されていても良い。非常に好ましくは、ＡおよびＢの両方がフェニルである（例えば、ＡおよびＢの両方が

) From can be chosen, it may be substituted with one or more R _A. Very preferably, both A and B are phenyl (eg, both A and B are

）である。非常に好ましくは、Ａは

). Very preferably, A

であり、Ｂは

And B is

であり、；またはＡは

And; or A

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

であり；各ＡおよびＢは独立に１以上のＲ_Ａで置換されていても良い。

In it, each A and B may be substituted with 1 or more independently of R _A.

Preferably, A is

であり、Ｂは

And B is

であり、ＡおよびＢはＦまたはＣｌなどの１以上のハロゲンで置換されている。驚くべきことに、Ａおよび／またはＢがハロ置換されたベンズイミダゾールである場合（例えば、Ａが

And A and B are substituted with one or more halogens such as F or Cl. Surprisingly, if A and / or B is a halo-substituted benzimidazole (eg, A is

であり、Ｂが

And B is

である。）、式Ｉの化合物（ならびに下記に記載の式Ｉ_Ａ、Ｉ_Ｂ、Ｉ_Ｃ、Ｉ_Ｄ、Ｉ_Ｅ、Ｉ_ＦまたはＩ_Ｇ化合物、および下記で記載の各実施形態の化合物）が予想外に、置換されていないベンズイミダゾールを有する化合物と比較して大幅に改善された薬物動態特性を示すことが発見された。薬物動態における改善は、例えば、マウスでの経口投与から２４時間にわたる曲線下面積（ＡＵＣ）として測定されるより大きい総血漿レベル曝露として観察され得る（例については、下記を参照。）。驚くべきことに、ハロ置換されたベンズイミダゾールを有するこれら化合物が予想外に、ある種のＨＣＶ遺伝子型１ａ変異株（例えば、ＮＳ５Ａ突然変異Ｌ３１Ｍ、Ｙ９３Ｈ、またはＹ９３Ｎを含む変異株）に対する改善された阻害薬活性を示すことが発見された。従って、本発明は、ＨＣＶ遺伝子型１ａ変異株感染（例えば、Ｌ３１Ｍ、Ｙ９３Ｈ、またはＹ９３Ｎ１ａ変異株感染）を治療するためのそのような化合物の使用方法を想到するものである。これらの方法は、ＨＣＶ遺伝子型１ａ変異株（例えば、Ｌ３１Ｍ、Ｙ９３Ｈ、またはＹ９３Ｎ１ａ変異株）を有する患者に対してそのような化合物を投与することを含む。本発明はまた、遺伝子型１ａ変異株感染（例えば、Ｌ３１Ｍ、Ｙ９３Ｈ、またはＹ９３Ｎ１ａ変異株感染）の治療のための医薬製造におけるそのような化合物の使用を想到するものである。

Is. ), Formula _I A according the compounds of Formula I (as well as _{below, I B, I C, I} D, I E, I F , or _{I G} compounds, and compounds of the embodiments described below) is unexpectedly , It was found that they exhibit significantly improved pharmacokinetic properties compared to compounds with unsubstituted benzimidazoles. Improvements in pharmacokinetics can be observed, for example, as greater total plasma level exposure measured as area under the curve (AUC) over 24 hours from oral administration in mice (see below for examples). Surprisingly, these compounds with halo-substituted benzimidazoles were unexpectedly improved against certain HCV genotype 1a mutants (eg, mutants containing NS5A mutants L31M, Y93H, or Y93N). It was found to exhibit inhibitory activity. Therefore, the present invention conceives a method of using such a compound for treating HCV genotype 1a mutant infection (eg, L31M, Y93H, or Y93N1a mutant infection). These methods include administering such compounds to patients with HCV genotype 1a mutants (eg, L31M, Y93H, or Y93N1a mutants). The present invention also contemplates the use of such compounds in the manufacture of pharmaceuticals for the treatment of genotype 1a mutant infections (eg, L31M, Y93H, or Y93N1a mutant infections).

D is preferably, C ₅ -C ₆ carbocyclic ring, selected from the bicyclic compounds of the heterocyclic or 6 from 5 6 membered 12-membered, optionally substituted with one or more R _A. D is preferably _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ may be selected from alkynyl, optionally substituted with one or more substituents selected from _{R L} good. More preferably, D is _C 5 -C ₆ carbocyclic (e.g., phenyl), 6-membered heterocycle from 5 (e.g., pyridinyl, pyrimidinyl, thiazolyl), or 6 to 12 membered bicyclic compound (e.g., indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, a benzo [d] [1,3] dioxol-5-yl), optionally substituted with one or more _{R M} cage, is _{R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Preferably, D is phenyl, optionally substituted with one or more R _A. More preferably, D is phenyl, which is substituted with one or more R _M, is R _M is as defined above. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択されおよび好ましくは水素である。１以上のＲ_Ｎは好ましくは、Ｆなどのハロであることができる。

_RM is as defined above, and each _RN is independently selected from _RD and is preferably hydrogen. One or more _RNs can preferably be halos such as F.

D is preferably pyridinyl optionally substituted by one or more R _A, pyrimidinyl or thiazolyl. More preferably D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted with one or more R _M. Very preferably, D is

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくは、Ｆなどのハロであることができる。Ｄは好ましくは、インダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリルまたはインダゾリルであり、１以上のＲ_Ａで置換されていても良い。より好ましくはＤは、インダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリル、インダゾリルまたはベンゾ［ｄ］［１，３］ジオキソール−５−イルであり、１以上のＲ_Ｍで置換されている。非常に好ましくは、Ｄは、

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F. D is preferably, indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, optionally substituted with one or more _{R A.} More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, 1 or more. _Is replaced by RM. Very preferably, D is

であり、１以上のＲ_Ｍで置換されていても良い。

, And the optionally substituted with one or more R _M.

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from phosphonoxy, phosphono, tioxo, formyl or cyano; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C ₂ −C ₆ haloalkenyl or C ₂ −C ₆ haloalkynyl. It is a ring. More preferably, the _{R M} halogen, hydroxy, mercapto, amino, carboxy, or _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl, in each case in each of which independently, It may be substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Very preferably, R _M is C ₁ -C ₆ alkyl, which is halogen, hydroxy, mercapto, optionally substituted with one or more substituents selected from amino, or carboxy.

Preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, be thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond or _{C 1} -C ₆ alkylene, _{R E} is _{-N (R S R S ')} , - OR S, -C (O) R S, -C (O) OR S, -C (O) N (R _{S R S '), - N} (R S) C (O) R S', -N (R S) C (O) OR S ', -N (R S) SO 2 R S', -SO 2 R _S , -SR _S , or -P (O) (OR _S ) ₂ , where _RS and _RS ′ are, for example, independently in each case, (1) hydrogen or (2) one or more in each case. It can be selected from halogen, hydroxy, -OC _1- C ₆ alkyl or C _1- C ₆ alkyl, which may be substituted with a 3- to 6-membered heterocycle; or _RM is C ₁ -C ₆ alkyl, C _2- C ₆ alkynyl or C _2- C ₆ alkynyl, each independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo. , May be substituted with one or more substituents selected from alkyls or cyanos; or _RMs are C _3- C ₆ carbocycles or 3- to 6-membered heterocycles, each independently. In each case, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C. _{By one} or more substituents selected from _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, -C (O) OR _S , or -N ( _RS R _S ') It may be replaced. More preferably, _{R M} is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or _C 1 -C ₆ alkyl, (e.g., methyl, isopropyl, tert- butyl), _{C 2} -C ₆ alkenyl or C _2- C ₆ alkynyl, each independently substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy in each case. Is also good. For example _{R M is, CF 3, -C (CF 3} ) 2 -OH, -C (CH 3) 2 -CN, -C (CH 3) 2 -CH 2 OH or _{-C (CH} 3) 2 -CH, ₂ NH ₂ . Preferably, _{R M} is _{-L S} -R _{E, L} S is a bond, _{R E} is _{-N (R S R S ')} , - O-R S, -N (R S) C (O _{) oR S ', -N (R} S) SO 2 R S', a _-SO 2 _{R S,} or -SR _S. For example, if _{L S} is a bond, _{R E} is -N _(C 1 -C _{6 alkyl) 2 (e.g., -NMe 2); - N (} C 1 -C 6 alkylene _-O-C 1 -C ₆ alkyl) ₂ (eg -N (CH ₂ CH ₂ OMe) ₂ ); -N (C _1- C ₆ alkyl) (C _1- C ₆ alkylene-OC _1- C ₆ alkyl) (eg -N (CH ₃ )) (CH ₂ CH ₂ OMe)); -O-C _1- C ₆ alkyl (eg, -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -On-hexyl) ; _-O-C 1 -C ₆ haloalkyl _{(e.g., -OCF 3, -OCH 2 CF 3} ); - O-C 1 -C 6 alkylene - piperidine (e.g., _{-O-CH 2} CH ₂ -1- piperidyl) -N (C _1- C ₆ alkyl) C (O) OC _1- C ₆ alkyl (eg, -N (CH ₃ ) C (O) O-CH ₂ CH (CH ₃ ) ₂ ), -N (C) _1- C ₆ alkyl) SO ₂ C _1- C ₆ alkyl (eg -N (CH ₃ ) SO ₂ CH ₃ ); -SO ₂ C _1- C ₆ alkyl (eg -SO ₂ Me); -SO ₂ C _1- C ₆ haloalkyl (eg, -SO ₂ CF ₃ ); or -SC _1- C ₆ haloalkyl (eg, SCF ₃ ). Preferably, _{R M} is _{-L S} -R _{E, L} S is _C 1 -C ₆ alkylene _{(e.g., -CH 2 -, - C (} CH 3) 2 -, - C (CH 3) 2 -CH ₂ -), _and, R _E is the _{-O-R S, -C (O} ) oR S, -N (R S) C (O) oR S ' or _{-P (O) (oR S)} 2, .. For example _{R M} is _-C 1 -C ₆ alkylene _{-O-R S (e.g., -C (CH 3) 2 -CH} 2 -OMe); - C 1 -C 6 alkylene -C (O) OR _S (e.g., _{-C (CH 3) 2 -C (} O) OMe); - C 1 -C 6 alkylene _{-N (R S) C (O} ) OR S '( _{e.g., -C (CH 3) 2 -CH} 2 -NHC (O) OCH ₃ ); or -C _1- C ₆ alkylene-P (O) (OR _S ) ₂ (for example, -CH _2- P (O) (OEt) ₂ ). More preferably, the R _M is C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, each of which, in each case independently, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , Phosno, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') may be substituted by one or more substituents selected from,. For example, _RM is cycloalkyl (eg, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocycle (eg, morpholine-4-yl, 1,1-yl). Dioxide thiomorpholine-4-yl, 4-methylpiperazine-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidine-1-yl, piperidine-1-yl, 4-methylpiperidine-1-yl, 3 , 5-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridine-3-yl, 6- (dimethylamino) pyridine-3-yl). .. Very preferably, _{R M} is halogen, hydroxy, mercapto, amino or carboxy (e.g., tert- butyl, CF ₃₎ 1 or more may be substituted with a substituent _C 1 -C ₆ alkyl which is selected from Is.

More preferably, D is, C ₅ -C ₆ carbocyclic ring, a bicyclic compound of the heterocycle or 6 from 5 6 membered 12-membered, is substituted with J, substituted with one or more R _A even if well, J is C ₃ -C ₆ carbocycle, a bicyclic compound of the heterocycle or 6 from 3 6 membered to 12-membered, optionally substituted with one or more R _a. Preferably, J _is, C 3 -C ₆ is substituted with a carbon ring or 3 to 6-membered heterocyclic ring, wherein the _C 3 -C ₆ carbocycle or 3 to 6-membered heterocyclic ring independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl, _{C 2} -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J or It may be substituted with 1 or more _RA . Preferably, D is a heterocyclic 6-membered _C 5 -C ₆ carbocyclic ring or 5 is substituted with J, may be substituted by one or more _{R A,} J is _C 3 -C ₆ a heterocyclic 6-membered carbocyclic or 3, may be substituted by one or more R _a, and preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring They are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl. , C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C (O) OR _S or -N ( _RS R _S ') with one or more substituents It may be replaced. Preferably, D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring is substituted with J, it may be substituted by one or more R _A, J 6 to 12-membered bicyclic compounds (e.g., J 7 to 12 membered fused containing a nitrogen ring atom covalently attached to D, bridged or bicyclic compound spiro), and optionally substituted with one or more R _a You may. More preferably, D is phenyl, is substituted with J, may be substituted by one or more R _A, J from C ₃ -C ₆ carbocycle, 3-6 membered heterocyclic, or 6 bicyclic compounds of 12 members may be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, they Independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, optionally substituted with one or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') You may. Very preferably D

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。好ましくは、Ｄは、

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbon ring, a 3 to 6 member heterocycle or a 6 to 12 member bicyclic compound. , and the it may optionally be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, halogen them independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl, _{C 2} -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') with one or more substituents selected from optionally substituted. Preferably, D is

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、Ｃ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbocycle or a 3 to 6 member heterocycle and a C _3- C ₆ carbocycle. or 3 is substituted with from 6 membered heterocyclic ring, they are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or -N _{(R S} R S It may be substituted with one or more substituents selected from ′), and J may also be substituted with one or more _RA .

Preferably D is

であり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。

In it, J is a heterocyclic ring 6 membered _C 3 -C ₆ carbocycle or 3, may be substituted by one or more _{R A,} preferably J is at least _C 3 -C ₆ carbocycle or 3 is substituted with 6-membered heterocycle, they independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl, _{C 2} - C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ halo alkynyl, C (O) OR _S or -N ( _RS R _S ') It may be substituted with one or more substituents selected from.

Surprisingly, if D comprises a halo-substituted carbocycle or heterocycle (eg, a halo-substituted 5- to 6-membered carbocycle or heterocycle directly linked to X), the compound of formula I (eg, and formula _I a according to _{below, I B, I C, I} D, I E, I F , or _{I G} compounds, and compounds of the embodiments described below) HCV genotypes 2a, 2b, 3a or 4a It was discovered that significantly improved inhibitor activity and / or improved pharmacokinetic properties could be exhibited against. Therefore, the present invention conceives a method of using such compounds for treating HCV genotype 2a, 2b, 3a or 4a infections. These methods include administering such compounds to patients with HCV genotype 2a, 2b, 3a or 4a. The present invention also envisions the use of such compounds in the manufacture of pharmaceuticals for the treatment of HCV genotypes 2a, 2b, 3a or 4a. A suitable D for this purpose is, for example, the above.

であることができ、式中において、少なくとも１個のＲ_Ｎはフッ素などのハロである。好適なＤの具体例には、

It can be, in the formula, at least one R _N is halo such as fluorine. Specific examples of suitable D include

などがあるが、これらに限定されるものではなく、式中、Ｒ_Ｎ、Ｒ_ＭおよびＪは上記で記載の通りである。

However, the present invention is not limited to these, and _RN , _RM, and J are as described above.

X is preferably, C ₅ -C ₆ carbocyclic ring, a bicyclic compound of the heterocycle or 6 from 5 6 membered 12-membered, optionally substituted with one or more R _A or R _F. X is one or more R _A or can also be substituted with R _F is also a good C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring, two adjacent R _A on X is , They may be integrated with the ring atom to which they are bonded to form a 5- to 6-membered carbon ring or heterocycle. Preferably X is

であり、式中、Ｘ_３はＣ（Ｈ）であるか、好ましくはＮであり、−Ｌ_３−Ｄに直接結合しており；Ｘ_４はＣ_２−Ｃ_４アルキレン、Ｃ_２−Ｃ_４アルケニレンまたはＣ_２−Ｃ_４アルキニレン、それらはそれぞれＯ、ＳまたはＮから選択される１個もしくは２個のヘテロ原子を含んでいても良く；Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、Ｘ上の２個の隣接するＲ_Ａが、それらが結合している環原子と一体となって、５から６員の炭素環または複素環を形成していても良い。さらに、Ｘは

In the formula, X ₃ is C (H), preferably N, and is directly attached to −L _3- D; X ₄ is C _2- C ₄ alkylene, C _2- C ₄ alkenylene or C ₂ -C ₄ alkynylene, each of which O, can contain one or two heteroatoms selected from S or N well; X is optionally substituted with one or more R _a or R _F At best, two adjacent R _a on X is, they become the ring atom to which are attached, they may form a carbocyclic or heterocyclic ring 5-6 membered. Furthermore, X is

であることができ、式中、Ｘ_３はＣであり、−Ｌ_３−Ｄに直接連結されており、Ｘ_４はＣ_２−Ｃ_４アルキレン、Ｃ_２−Ｃ_４アルケニレンまたはＣ_２−Ｃ_４アルキニレンであり、それらはそれぞれＯ、ＳまたはＮから選択される１個もしくは２個のヘテロ原子を含んでいても良く、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、Ｘ上の２個の隣接するＲ_Ａが、それらが結合している環原子と一体となって、５から６員の炭素環または複素環を形成していても良い。さらに、Ｘは、

In the equation, X ₃ is C and is directly linked to -L _3- D, where X ₄ is C _2- C ₄ alkylene, C _2- C ₄ alkenylene or C _2- C ₄ alkynylene, each of which O, can contain one or two heteroatoms selected from S or N well, X is may be substituted by one or more R _a or R _F, X two adjacent R _a above is, they become the ring atom to which are attached, they may form a carbocyclic or heterocyclic ring 5-6 membered. Furthermore, X is

であることができ、式中、ＮはＬ_３−Ｄに直接連結されており、Ｘ_４はＣ_２−Ｃ_４アルキレン、Ｃ_２−Ｃ_４アルケニレンまたはＣ_２−Ｃ_４アルキニレンであり、それらはそれぞれＯ、ＳまたはＮから選択される１個もしくは２個のヘテロ原子を含んでいても良く、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、Ｘ上の２個の隣接するＲ_Ａが、それらが結合している環原子と一体となって、５から６員の炭素環または複素環を形成していても良い。

In the formula, N is directly linked to L _3- D and X ₄ is C _2- C ₄ alkylene, C _2- C ₄ alkenylene or C _2- C ₄ alkinylene, which they are. each O, may contain one or two heteroatoms selected from S or N, X may be substituted by one or more R _a or R _F, two adjacent on X _RA may be integrated with the ring atom to which they are bonded to form a 5- to 6-membered carbocycle or heterocycle.

For example, X is

であることができ、式中、Ｘ_１は独立に各場合でＣＨ_２、Ｏ、ＳまたはＮＨから選択され、Ｘ_２は独立に各場合でＣＨまたはＮから選択され、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘ_３′はＣであり、−Ｌ_３−Ｄに直接連結されており；Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、Ｘ上の２個の隣接するＲ_Ａが、それらが結合している環原子と一体となって、５から６員の炭素環または複素環を形成していても良い。別の例では、Ｘは、

In the equation, X ₁ is independently selected from CH ₂ , O, S or NH in each case, X ₂ is independently selected from CH or N in each case, and X ₃ is N. is coupled directly to _{-L 3} -D, _X 3 'is C, it is connected directly to _-L 3 -D; X may be substituted by one or more _{R a} or _{R F} two adjacent R _a on X is, they become the ring atom to which are attached, they may form a carbocyclic or heterocyclic ring 5-6 membered. In another example, X is

であり、式中、Ｘ_１は独立に各場合でＣＨ_２、Ｏ、ＳまたはＮＨから選択され、Ｘ_２は独立に各場合でＣＨまたはＮから選択され、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘ_３′はＣであり、−Ｌ_３−Ｄに直接連結されており；Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、Ｘ上の２個の隣接するＲ_Ａが、それらが結合している環原子と一体となって、５から６員の炭素環または複素環を形成していても良い。

In the equation, X ₁ is independently selected from CH ₂ , O, S or NH in each case, X ₂ is independently selected from CH or N in each case, X ₃ is N and -L. ₃ is connected directly to -D, _{X 3} 'is C, is connected directly to _-L 3 -D; X may be substituted by one or more _{R a} or _{R F,} the X two adjacent R _a of, they become a ring atom to which are attached, may form a carbocyclic or heterocyclic ring 5-6 membered.

Very preferably, X is

であり、式中、Ｘ_３はＣ（Ｈ）またはＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘ_３′はＣであり、−Ｌ_３−Ｄに直接連結されており、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、Ｘ上の２個の隣接するＲ_Ａが、それらが結合している環原子と一体となって、５から６員の炭素環または複素環を形成していても良い。より好ましくは、Ｘ_３はＮである。

In the equation, X ₃ is C (H) or N and is directly linked to −L ₃ −D, and X ₃ ′ is C and is directly linked to −L ₃ −D. X may be substituted by one or more R _a or R _F, 2 contiguous R _a on X is, they become the ring atom to which are bonded, carbon 5 to 6-membered It may form a ring or a heterocycle. More preferably, X ₃ is N.

In the example of X,

などがあるが、これらに限定されるものではなく、式中において「→」は−Ｌ_３−Ｄに対する共有結合連結を示している。各Ｘは、１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、Ｘ上の２個の隣接するＲ_Ａが、それらが結合している環原子と一体となって、５から６員の炭素環または複素環を形成していても良い。

There are like, is not limited to, "→" in the formula represents a covalent bond linkage to -L 3 _-D. Each X may be substituted by one or more R _A or R _F, 2 contiguous R _A on X, but they can become a ring atom to which are bonded, 6-membered 5 The carbon ring or heterocycle of the above may be formed.

Examples of preferred X include, but are not limited to, the pyrrolidine rings described below, each of which is one or more _RA or _RF :.

で置換されていても良い。

It may be replaced with.

As shown, the relative stereochemistry at the 2- and 5-positions of the pyrrolidine ring can be cis or trans. The stereochemistry of the appropriate substituent _RA at the 3- or 4-position of pyrrolidine can vary with respect to the substituent at any other position on the pyrrolidine ring. The stereochemistry in carbon can be (R) or (S), depending on the particular substituent attached to the pyrrolidine.

Examples of preferred X include, but are not limited to, pyrrole, triazole or thiomorpholine rings, each of which is one or more _RA or _RF :.

で置換されていても良い。

It may be replaced with.

As shown, the relative stereochemistry at the 3- and 5-positions of the thiomorpholine ring can be cis or trans. The stereochemistry on carbon can be (R) or (S), depending on the particular substituent attached to the thiomorpholine.

Preferably X is

であり、式中、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。好ましくは、Ｒ_ＦはＣ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_１０アルケニルまたはＣ_２−Ｃ_１０アルキニルであり、それらはそれぞれＯ、ＳまたはＮから選択される０、１、２、３、４もしくは５個のヘテロ原子を含み、独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基で置換されていても良い。好ましくは、Ｒ_ＦはＣ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_１０アルケニルまたはＣ_２−Ｃ_１０アルキニルであり、それらはそれぞれ０、１、２、３、４または５個のＯを含み、独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｒ_Ｆは−（Ｒ_Ｘ−Ｒ_Ｙ）_Ｑ−（Ｒ_Ｘ−Ｒ_Ｙ′）であり、Ｑは０、１、２、３または４であり；各Ｒ_Ｘは独立にＯ、ＳまたはＮ（Ｒ_Ｂ）であり；各Ｒ_Ｙは独立にＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンまたはＣ_２−Ｃ_６アルキニレンであり、それらはそれぞれ独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基で置換されていても良く；各Ｒ_Ｙ′は独立にＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニルであり、それらはそれぞれ独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基で置換されていても良い。好ましくは、各Ｒ_ＸはＯである。より好ましくは、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、各Ｒ_Ｆは独立にＣ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_１０アルケニルまたはＣ_２−Ｃ_１０アルキニルから選択され、それらはそれぞれ０、１、２または３個のＯを含み、独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基で置換されていても良い。好ましくは、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良く、各Ｒ_Ｆは独立に−（Ｏ−Ｃ_１−Ｃ_６アルキレン）_Ｑ−（Ｏ−Ｃ_１−Ｃ_６アルキル）から選択され、Ｑは好ましくは０、１、２または３である。

And a, wherein, _{X 3} is N, _-L 3 -D are connected directly to, X may be substituted with one or more _{R A} or _{R F.} Preferably, _{R F} is _C 1 _{-C 10 alkyl,} C 2 _{-C 10} alkenyl or _C 2 _{-C 10} alkynyl, each of which is selected from O, S or N 0,1,2,3,4 Alternatively, it may contain 5 heteroatoms and be independently substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano. .. Preferably, the _RF is C _1- C ₁₀ alkyl, C _2- C ₁₀ alkenyl or C _2- C ₁₀ alkynyl, each containing 0, 1, 2, 3, 4 or 5 O and independent. _May be replaced with 1 or more _RL . Preferably, the _{R F - (R X -R Y} ) Q - is _{(R X -R Y '),} Q is 0, 1, 2, 3 or 4; each _{R X} is independently O, S or be a N _{(R B);} each _{R Y} is _C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene independently halogen each of which independently, hydroxy, mercapto, amino , carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, may be substituted with one or more substituents selected from formyl or cyano; each R _{Y 'is} C ₁ -C ₆ alkyl independently, C ₂ - C ₆ alkenyl or C _2- C ₆ alkynyl, each independently one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano. It may be replaced with. Preferably, each _RX is O. Select More preferably, X may be substituted by one or more _{R A} or _{R F,} each _{R F} is _C 1 _{-C 10} alkyl _{independently} from C 2 _{-C 10} alkenyl or _C 2 _{-C 10} alkynyl And each contains 0, 1, 2 or 3 O's, one or more independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano. It may be substituted with a substituent. Preferably, X may be substituted by one or more _{R A} or _{R F,} each _{R F} is independently - _(O-C 1 -C _{6 alkylene) Q - (O-C 1} -C 6 alkyl) Selected from, Q is preferably 0, 1, 2 or 3.

L ₁ and L ₂ are preferably independently bonded or C _1- C ₆ alkylene, and L ₃ is preferably selected from bonded, C _1- C ₆ alkylene or -C (O)-, L ₁ , L ₂ And L ₃ may each be independently substituted with one or more _RL . More preferably, L ₁ , L ₂ and L ₃ are independently bound or C ₁ −C ₆ alkylene (eg, −CH _2- or − CH ₂ CH _2- ), respectively, and each independently has one or more _RLs. It may be replaced with. Very preferably, L ₁ , L ₂ and L ₃ are bonds.

Y is _{preferably, -L S -C (R 1 R} 2) N (R 5) -T-R D, -L S -C (R 3 R 4) C (R 6 R 7) -T-R D _{, -G-C (R 1 R} 2) N (R 5) -T-R D, -G-C (R 3 R 4) C (R 6 R 7) -T-R D, -N (R B _{) C (O) C (R} 1 R 2) N (R 5) -T-R D, -N (R B) C (O) C (R 3 R 4) C (R 6 R 7) -T- _{R D, -C (O) N} (R B) C (R 1 R 2) N (R 5) -T-R D, -C (O) N (R B) C (R 3 R 4) C ( _{R 6 R 7) -T-R} D, is selected from -N (R B) C (O ) -L S -E or _{-C (O) N (R B} ) -L S -E,. G is

などのＣ_５−Ｃ_６炭素環または５から６員の複素環であり、１以上のＲ_Ａ（例えば、１以上のクロロまたはブロモ）で置換されていても良い。Ｅは好ましくは、７から１２員の二環式化合物（例えば

A C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic rings such as 1 or more R _{A (e.g.,} one or more chloro or bromo) may be substituted with. E is preferably a 7 to 12 member bicyclic compound (eg,

であり、式中、Ｕは独立に各場合で、−（ＣＨ_２）−または−（ＮＨ）−から選択され；ＶおよびＺ_２０はそれぞれ独立に、Ｃ_１−Ｃ_４アルキレン、Ｃ_２−Ｃ_４アルケニレンまたはＣ_２−Ｃ_４アルキニレンから選択され、少なくとも１個の炭素原子が独立にＯ、ＳまたはＮで置き換わっていても良い。）であり、独立に１以上のＲ_Ａで置換されていても良い。より好ましくは、Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環または６から１２員の二環式化合物（例えば、

, And the formula, U is in each case independently, - (CH ₂₎ - or - (NH) - is selected from; each V and _{Z 20} are _{independently,} C 1 -C _{4 alkylene,} C 2 -C _It may be selected from ₄ alkenylene or C _2- C ₄ alquinylene, with at least one carbon atom independently replaced by O, S or N. ), And it may be substituted with one or more R _A independently. More preferably, R ₁ is _RC , with R ₂ and R ₅ being integrated with the atom to which they are attached to a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,). ,

）を形成しており、それは１以上のＲ_Ａ（ヒドロキシ、ハロ（例えば、フルオロ）、Ｃ_１−Ｃ_６アルキル（例えば、メチル）、またはＣ_２−Ｃ_６アルケニル（例えば、アリル）などがあるが、これらに限定されるものではない）で置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環／複素環または６から１２員の二環式化合物（例えば、

) Forms a, it one or more _{R A} (hydroxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl), or _C 2 -C ₆ alkenyl (e.g., allyl) and the like However, but is not limited to these; R ₃ and R ₆ are _RC independently, respectively, and R ₄ and R ₇ are integrated with the atom to which they are bonded. A 5- to 6-membered carbocycle / heterocycle or a 6 to 12-membered bicyclic compound (eg,

）を形成しており、それらは１以上のＲ_Ａ（ヒドロキシ、ハロ（例えば、フルオロ）、Ｃ_１−Ｃ_６アルキル（例えば、メチル）、またはＣ_２−Ｃ_６アルケニル（例えば、アリル）などがあるが、これらに限定されるものではない）で置換されていても良い。

) Forms a, they 1 or more _{R A} (hydroxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl), or _C 2 -C ₆ alkenyl (e.g., allyl) and the like However, it may be replaced by (but not limited to).

Y _{is, -M-C (R 1 R} 2) N (R 5) -C (O) -L Y '-M'-R D, -M-C (R 1 R 2) N (R 5) - _{L Y '-M'-R D,} -L S -C (R 1 R 2) N (R 5) -C (O) -L Y'-M'-R D, -L S -C (R 1 _{R 2) N (R 5)} -L Y '-M'-R D, -M-C (R 3 R 4) C (R 6 R 7) -C (O) -L Y'-M'-R _{D, -M-C (R 3} R 4) C (R 6 R 7) -L Y '-M'-R D, -L S -C (R 3 R 4) C (R 6 R 7) -C _(O) -L Y can also _{'-M'-R D} or _{-L S -C (R 3 R 4} ) C (R 6 R 7) -L Y,' is selected from _{-M'-R D} , M is preferably a _{bond, -C (O) N (R} B) - or _{-N (R B) C (O} ) - and is, M 'is preferably a _{bond, -C (O) N (R} B) _{-, - N (R B)} C (O) -, - N (R B) C (O) O-, N (R B) C (O) N (R B ') -, - N (R B) S (O) - or _{-N (R B) S (O} ) 2 - and is, _{L Y} 'is preferably 1 or more good _C 1 -C ₆ alkylene optionally substituted with _{R L. LY} ′ is, for example,

など（これらに限定されるものではない）のＣ_１−Ｃ_６アルキレンであり；適宜のＲ_Ｌはフェニル、−ＳＭｅまたはメトキシなど（これらに限定されるものではない）の置換基である。基Ｌ_Ｙ′内の炭素における立体化学は（Ｒ）または（Ｓ）であることができる。より好ましくは、Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環または６から１２員の二環式化合物（例えば、

Etc. (but not limited to) C _1- C ₆ alkylene; the appropriate _RL is a substituent such as (but not limited to) phenyl, -SMe or methoxy. The stereochemistry at the carbon in the group _LY ′ can be (R) or (S). More preferably, R ₁ is _RC , with R ₂ and R ₅ being integrated with the atom to which they are attached to a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,). ,

）を形成しており、それは１以上のＲ_Ａ（例えば、１以上のヒドロキシ）で置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環／複素環または６から１２員の二環式化合物（例えば、

) Forms a, it one or more _{R A} (e.g., may be substituted by one or more hydroxy); _{R 3} and _{R 6} are each independently _{R C, R 4} and _{R 7} are those A 5- to 6-membered carbocycle / heterocycle or a 6 to 12-membered bicyclic compound (eg, a 6 to 12 membered bicyclic compound) together with the atom

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。

) Forms a, it may be substituted by one or more R _A.

Preferably, Y is _{-N (R B) CO-C} (R 1 R 2) N (R 5) -C (O) -L Y '-N (R B) C (O) O-R D, - _{N (R B) CO-C} (R 1 R 2) N (R 5) -C (O) -L Y '-N (R B) C (O) -R D, -N (R B) CO- _{C (R 1 R 2) N} (R 5) -C (O) -L Y '-N (R B) S (O) 2 -R D, -N (R B) CO-C (R 1 R 2 _{) N (R 5) -C (} O) -L Y '-N (R B R B') -R D, -N (R B) CO-C (R 1 R 2) N (R 5) -C _{(O) -L Y '-O-} R D, -N (R B) CO-C (R 1 R 2) N (R 5) -C (O) -L Y' -R D, -N (R _{B) CO-C (R 1} R 2) N (R 5) -R D, -L S -C (R 1 R 2) N (R 5) -C (O) -L Y '-N (R B _{) C (O) O-R} D, -L S -C (R 1 R 2) N (R 5) -C (O) -L Y '-N (R B) C (O) -R D, - _{L S -C (R 1 R 2} ) N (R 5) -C (O) -L Y '-N (R B) S (O) 2 -R D, -L S -C (R 1 R 2) _{N (R 5) -C (O} ) -L Y '-N (R B R B') -R D, -L S -C (R 1 R 2) N (R 5) -C (O) -L _{Y '-O-R D, -L} S -C (R 1 R 2) N (R 5) -C (O) -L Y' -R D, -L S -C (R 1 R 2) N ( _{R 5) -R D, -N (} R B) CO-C (R 3 R 4) C (R 6 R 7) -C (O) -L Y '-N (R B) C (O) O- _{R D, -N (R B)} CO-C (R 3 R 4) C (R 6 R 7) -C (O) -L Y '-N (R B) C (O) -R D, -N _{(R B) CO-C (} R 3 R 4) C (R 6 R 7) -C (O) -L Y '-N (R B) S (O) 2 -R D, -N (R B) _{CO-C (R 3 R 4} ) C (R 6 R 7) -C (O) -L Y '-N (R B R B') -R D, -N (R B) CO-C (R 3 _{R 4) C (R 6 R} 7) -C (O) -L Y _{'-O-R D, -N (} R B) CO-C (R 3 R 4) C (R 6 R 7) -C (O) -L Y' -R D, -N (R B) CO- _{C (R 3 R 4) C} (R 6 R 7) -R D, -L S -C (R 3 R 4) C (R 6 R 7) -C (O) -L Y '-N (R B _{) C (O) O-R} D, -L S -C (R 3 R 4) C (R 6 R 7) -C (O) -L Y '-N (R B) C (O) -R D _{, -L S -C (R 3 R} 4) C (R 6 R 7) -C (O) -L Y '-N (R B) S (O) 2 -R D, -L S -C (R _{3 R 4) C (R 6} R 7) -C (O) -L Y '-N (R B R B') -R D, -L S -C (R 3 R 4) C (R 6 R 7 _{) -C (O) -L Y '} -O-R D, -L S -C (R 3 R 4) C (R 6 R 7) -C (O) -L Y' -R D or -L, _{S -C (R 3 R 4)} C (R 6 R 7) selected from -R _{D, L Y} 'is preferably 1 or more good _C 1 -C ₆ alkylene optionally substituted with _{R L.} R ₁ can be _RC , with R ₂ and R ₅ being integrated with the atom to which they are attached to a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg, for example.

）を形成していても良く、それは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであっても良く、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環／複素環または６から１２員の二環式化合物（例えば、

) May be in the form, it is 1 or more may be substituted by R _A; R ₃ and R ₆ are each independently be a R _C, R ₄ and R ₇ are bonded they A 5- to 6-membered carbocycle / heterocycle or a 6 to 12-membered bicyclic compound (eg,)

）を形成していても良く、それは１以上のＲ_Ａで置換されていても良い。

) May be in the form, it may be substituted with one or more R _A.

Highly preferably, Y is _{-N (R B ") CO-} C (R 1 R 2) N (R 5) -C (O) -L Y -N (R B") C (O) -L S It is selected from -R _E or _{-C (R 1 R 2) N} (R 5) -C (O) -L Y -N (R B ") C (O) -L S -R E, or Y is - _{G-C (R 1 R 2} ) N (R 5) -C (O) -L Y -N (R B ") is _{C (O) -L S -R E} , L Y is one or more _{R L} in an optionally substituted _C 1 -C ₆ alkylene, _{R B} "are each independently an _{R B} .R _B" each preferably and _{R 1} is hydrogen or _C 1 -C ₆ alkyl, R ₂ and R ₅ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocyclic ring or a 6 to 12-membered bicyclic compound (eg, a 6 to 12 membered bicyclic compound).

を形成しており、それは１以上のＲ_Ａ（ヒドロキシ、ハロ（例えば、フルオロ）、Ｃ_１−Ｃ_６アルキル（例えば、メチル）、またはＣ_２−Ｃ_６アルケニル（例えば、アリル）など（これらに限定されるものではない））で置換されていても良い。好ましくは、Ｌ_ＹはＣ_３−Ｃ_６炭素環または３から６員の複素環などの１以上のＲ_Ｌで置換されているＣ_１−Ｃ_６アルキレンであり、それは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基で置換されていても良い。非常に好ましくは、Ｌ_Ｙは、

Forms a, it one or more _{R A} (hydroxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl), or _C 2 -C ₆ alkenyl (e.g., allyl) and the like (in these It may be replaced with, but not limited to)). Preferably, _{L Y} is _C 1 -C ₆ alkylene substituted by one or more _{R L} such heterocycle 6-membered _C 3 -C ₆ carbocycle or 3, it is independently halogen, hydroxy, mercapto , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- It may be substituted with one or more substituents selected from C ₆ haloalkenyl or C _2- C ₆ haloalkynyl. Very preferably, _LY is

など（これらに限定されるものではない）（基Ｌ_Ｙ内の炭素における立体化学は（Ｒ）または（Ｓ）であることができる。）のＣ_１−Ｃ_６アルキレンであり、Ｌ_Ｙは独立に１以上のＲ_Ｌ（例えば、１以上のフェニルまたはメトキシ）で置換されていても良く、Ｇは好ましくは

_C 1 -C ₆ alkylene such as (but not limited to) (stereochemistry at the carbon in the group _{L Y} can be a (R) or (S).), _{L Y} is independently May be substituted with 1 or more _RLs (eg, 1 or more phenyls or methoxys), with G being preferred.

であり、Ｒ_Ｂ″は水素であり；−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−は

In and, _{R B} "is _{hydrogen; -C (R 1 R 2)} N (R 5) - is

であり；Ｌ_Ｓは結合であり；Ｒ_Ｅはメトキシである。

In it; _{L S} is a bond; _{R E} is methoxy.

A preferred example of Y is

などがあるが、これらに限定されるものではなく、式中、ＴおよびＲ_Ｄは本明細書で定義の通りである。Ｔは、例えば−Ｌ_Ｓ−Ｍ−Ｌ_Ｓ′−Ｍ′−Ｌ_Ｓ″−であることができ、Ｌ_Ｓは結合であり；ＭはＣ（Ｏ）であり；Ｌ_Ｓ′は

However, the present invention is not limited to these, and T and _RD are as defined herein. T, for example _{-L S -M-L S '-M'} -L S "- it can be, _{L S} is a bond; M is C (O); _{L S'} is

など（これらに限定されるものではない）のＣ_１−Ｃ_６アルキレンであり、式中、Ｌ_Ｓ′は独立に１以上のＲ_Ｌで置換されていても良く；Ｒ_Ｌはフェニルまたはメトキシなど（これらに限定されるものではない）の置換基であり；Ｍ′は−ＮＨＣ（Ｏ）−または−ＮＭｅＣ（Ｏ）−であり；Ｌ_Ｓ″は結合である。基Ｌ_Ｓ′内の炭素における立体化学は（Ｒ）または（Ｓ）であることができる。Ｒ_Ｄは例えばメトキシである。Ｔ−Ｒ_Ｄには、

C ₁ -C ₆ alkylene such as (but not limited to), wherein, L S _'may be substituted with 1 or more independently of R _L is; R _L is phenyl or methoxy such as a substituent of (these are not limited to); M 'is -NHC (O) - or -NMeC (O) - and is; _{L S} "is a bond group _{L S.'} carbons of the The steric chemistry in can be (R) or (S). _RD is, for example, methoxy. T- _RD is

などがあるが、これらに限定されるものではない。Ｔ−Ｒ_Ｄはある種の立体化学配置を含むこともできる、従ってＴ−Ｒ_Ｄには、

However, it is not limited to these. The T- _RD can also include certain stereochemical configurations, so the T- _RD can include

などがあるが、これらに限定されるものではない。

However, it is not limited to these.

A preferred example of Y is

などもあるが、これらに限定されるものではない。

However, it is not limited to these.

Z is _{preferably, -L S -C (R 8 R} 9) N (R 12) -T-R D, -L S -C (R 10 R 11) C (R 13 R 14) -T-R D _{, -G-C (R 8 R} 9) N (R 12) -T-R D, -G-C (R 10 R 11) C (R 13 R 14) -T-R D, -N (R B _{) C (O) C (R} 8 R 9) N (R 12) -T-R D, -N (R B) C (O) C (R 10 R 11) C (R 13 R 14) -T- _{R D, -C (O) N} (R B) C (R 8 R 9) N (R 12) -T-R D, -C (O) N (R B) C (R 10 R 11) C ( _{R 13 R 14) -T-R} D, it is selected from -N (R B) C (O ) -L S -E or _{-C (O) N (R B} ) -L S -E,. G is

などのＣ_５−Ｃ_６炭素環または５から６員の複素環であり、１以上のＲ_Ａ（例えば、１以上のクロロまたはブロモ）で置換されていても良い。Ｅは好ましくは、８から１２員の二環式化合物（例えば

A C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic rings such as 1 or more R _{A (e.g.,} one or more chloro or bromo) may be substituted with. E is preferably an 8- to 12-membered bicyclic compound (eg,

であり、Ｕは独立に各場合で−（ＣＨ_２）−または−（ＮＨ）−から選択され；ＶおよびＺ_２０はそれぞれ独立にＣ_１−Ｃ_４アルキレン、Ｃ_２−Ｃ_４アルケニレンまたはＣ_２−Ｃ_４アルキニレンから選択され、それらにおいて少なくとも１個の炭素原子が独立にＯ、ＳまたはＮで置き換わっていても良い。）、独立に１以上のＲ_Ａで置換されていても良い。より好ましくは、Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環または６から１２員の二環式化合物（例えば、

And U is independently selected from-(CH ₂ )-or-(NH)-in each case; V and Z ₂₀ are independently C _1- C ₄ alkylene, C _2- C ₄ alkenylene or C _{2 respectively.} is selected from -C ₄ alkynylene, at least one carbon atom in their independently O, it may be replaced by S or N. ), It may be independently substituted with 1 or more _RA . More preferably, R ₈ is _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are attached, a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,). ,

）を形成しており、それは１以上のＲ_Ａ（ヒドロキシ、ハロ（例えば、フルオロ）、Ｃ_１−Ｃ_６アルキル（例えば、メチル）、またはＣ_２−Ｃ_６アルケニル（例えば、アリル）など（これらに限定されるものではない））で置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環／複素環または６から１２員の二環式化合物（例えば、

) Forms a, it one or more _{R A} (hydroxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl), or _C 2 -C ₆ alkenyl (e.g., allyl) and the like (these (Not limited to))); R ₁₀ and R ₁₃ are _RC independently, respectively, and R ₁₁ and R ₁₄ are integrated with the atom to which they are attached. A 5- to 6-membered carbocycle / heterocycle or a 6 to 12-membered bicyclic compound (eg,

）を形成しており、それは１以上のＲ_Ａ（ヒドロキシ、ハロ（例えば、フルオロ）、Ｃ_１−Ｃ_６アルキル（例えば、メチル）またはＣ_２−Ｃ_６アルケニル（例えば、アリル）など（これらに限定されるものではない））で置換されていても良い。

) Forms a, it one or more _{R A} (hydroxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl) or _C 2 -C ₆ alkenyl (e.g., allyl) and the like (in these It may be replaced with, but not limited to)).

Z _{is, -M-C (R 8 R} 9) N (R 12) -C (O) -L Y '-M'-R D, -M-C (R 8 R 9) N (R 12) - _{L Y '-M'-R D,} -L S -C (R 8 R 9) N (R 12) -C (O) -L Y'-M'-R D, -L S -C (R 8 _{R 9) N (R 12)} -L Y '-M'-R D, -M-C (R 10 R 11) C (R 13 R 14) -C (O) -L Y'-M'-R _{D, -M-C (R 10} R 11) C (R 13 R 14) -L Y '-M'-R D, -L S -C (R 10 R 11) C (R 13 R 14) -C _{(O) -L Y '-M'-} R D or _{-L S -C (R 10 R 11} ) C (R 13 R 14) -L Y,' is selected from _{-M'-R D} is can, M is preferably _{coupled, -C (O) N (R} B) - or _{-N (R B) C (O} ) - is, M 'is preferably a _{bond, -C (O) N (R} B _{) -, - N (R B} ) C (O) -, - N (R B) C (O) O-, N (R B) C (O) N (R B ') -, - N (R B ) S (O) - or _{-N (R B) S (O} ) 2 - and is, _{L Y} 'is preferably _C 1 -C ₆ alkylene, which is optionally substituted with one or more independently of _{R L} Is also good. _LY ′ is, for example,

など（これらに限定されるものではない）のＣ_１−Ｃ_６アルキレンであり；前記適宜のＲ_Ｌはフェニル、−ＳＭｅまたはメトキシなど（これらに限定されるものではない）の置換基である。基Ｌ_Ｙ′内の炭素の立体化学は（Ｒ）または（Ｓ）であることができる。より好ましくは、Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環または６から１２員の二環式化合物（例えば、

Such as (but not limited to) C _1- C ₆ alkylene; the appropriate _RL is a substituent such as (but not limited to) phenyl, -SMe or methoxy. Stereochemistry of carbons in the radical L _{Y 'can} be a (R) or (S). More preferably, R ₈ is _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are attached, a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,). ,

）を形成しており、それは１以上のＲ_Ａ（例えば、１以上のヒドロキシ）で置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環／複素環または６から１２員の二環式化合物（例えば、

) Forms a, it one or more _{R A} (e.g., may be substituted by one or more _{hydroxy); R 10} and _{R 13} are each independently _{R C, R 11} and _{R 14} are those A 5- to 6-membered carbocycle / heterocycle or a 6 to 12-membered bicyclic compound (eg, a 5- to 12-membered bicyclic compound) together with the atom to which

）を形成しており、１以上のＲ_Ａで置換されていても良い。

) Forms a, optionally substituted with one or more R _A.

Preferably, Z is _{-N (R B) CO-C} (R 8 R 9) N (R 12) -C (O) -L Y '-N (R B) C (O) O-R D, - _{N (R B) CO-C} (R 8 R 9) N (R 12) -C (O) -L Y '-N (R B) C (O) -R D, -N (R B) CO- _{C (R 8 R 9) N} (R 12) -C (O) -L Y '-N (R B) S (O) 2 -R D, -N (R B) CO-C (R 8 R 9 _{) N (R 12) -C (} O) -L Y '-N (R B R B') -R D, -N (R B) CO-C (R 8 R 9) N (R 12) -C _{(O) -L Y '-O-} R D, -N (R B) CO-C (R 8 R 9) N (R 12) -C (O) -L Y' -R D, -N (R _{B) CO-C (R 8} R 9) N (R 12) -R D, -L S -C (R 8 R 9) N (R 12) -C (O) -L Y '-N (R B _{) C (O) O-R} D, -L S -C (R 8 R 9) N (R 12) -C (O) -L Y '-N (R B) C (O) -R D, - _{L S -C (R 8 R 9} ) N (R 12) -C (O) -L Y '-N (R B) S (O) 2 -R D, -L S -C (R 8 R 9) _{N (R 12) -C (O} ) -L Y '-N (R B R B') -R D, -L S -C (R 8 R 9) N (R 12) -C (O) -L _{Y '-O-R D, -L} S -C (R 8 R 9) N (R 12) -C (O) -L Y' -R D, -L S -C (R 8 R 9) N ( _{R 12) -R D, -N (} R B) CO-C (R 10 R 11) C (R 13 R 14) -C (O) -L Y '-N (R B) C (O) O- _{R D, -N (R B)} CO-C (R 10 R 11) C (R 13 R 14) -C (O) -L Y '-N (R B) C (O) -R D, -N _{(R B) CO-C (} R 10 R 11) C (R 13 R 14) -C (O) -L Y '-N (R B) S (O) 2 -R D, -N (R B) _{CO-C (R 10 R 11} ) C (R 13 R 14) -C (O) -L Y '-N (R B R B') -R D, -N (R B) CO-C _{(R 10 R 11) C (} R 13 R 14) -C (O) -L Y '-O-R D, -N (R B) CO-C (R 10 R 11) C (R 13 R 14) _{-C (O) -L Y '-R} D, -N (R B) CO-C (R 10 R 11) C (R 13 R 14) -R D, -L S -C (R 10 R 11) _{C (R 13 R 14) -C} (O) -L Y '-N (R B) C (O) O-R D, -L S -C (R 10 R 11) C (R 13 R 14) - _{C (O) -L Y '-N} (R B) C (O) -R D, -L S -C (R 10 R 11) C (R 13 R 14) -C (O) -L Y' - _{N (R B) S (O} ) 2 -R D, -L S -C (R 10 R 11) C (R 13 R 14) -C (O) -L Y '-N (R B R B') _{-R D, -L S -C (R} 10 R 11) C (R 13 R 14) -C (O) -L Y '-O-R D, -L S -C (R 10 R 11) C ( 'is selected from -R _D or _{-L S -C (R 10 R 11} ,) C (R 13 R 14) -R D, L Y' R 13 R 14) -C (O) -L Y is preferably is one or more _{R L} in an optionally substituted _C 1 -C ₆ alkylene independently. R ₈ can be _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are attached to a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg, for example.

）を形成していても良く、それは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであることができ、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環／複素環または６から１２員の二環式化合物（例えば、

) May be in the form, it may be substituted by one or more _{R A; R 10} and _{R 13} can each independently represents an _{R C, R 11} and _{R 14} are bonded they 5 to 6 membered carbocycles / heterocycles or 6 to 12 membered bicyclic compounds (eg, 6 to 12 membered bicyclic compounds) together with the atoms

）を形成していても良く、それは１以上のＲ_Ａで置換されていても良い。

) May be in the form, it may be substituted with one or more R _A.

Very preferably, Z is _{-N (R B ") CO-} C (R 8 R 9) N (R 12) -C (O) -L Y -N (R B") C (O) -L S -R _E or _{-C (R 8 R 9) N} (R 12) -C (O) -L Y -N (R B ") is selected from _{C (O) -L S -R E} , Z is -G _{-C (R 8 R 9) N} (R 12) -C (O) -L Y -N (R B ") is _{C (O) -L S -R E} , L Y is one or more _{R L} substituted a good _C 1 -C ₆ alkylene, _{R B} 'is .R _B is _{R B} independently "preferably each and _{R 8} is hydrogen or _C 1 -C ₆ alkyl, _{R 9} And R ₁₂ together with the atom to which they are attached, preferably a 5- to 6-membered heterocyclic ring or a 6 to 12-membered bicyclic compound (eg,

）を形成しており、それは１以上のＲ_Ａ（ヒドロキシ、ハロ（例えば、フルオロ）、Ｃ_１−Ｃ_６アルキル（例えば、メチル）、またはＣ_２−Ｃ_６アルケニル（例えば、アリル）など（これらに限定されるものではない））で置換されていても良い。好ましくは、Ｌ_ＹはＣ_３−Ｃ_６炭素環または３から６員の複素環などの１以上のＲ_Ｌで置換されているＣ_１−Ｃ_６アルキレンであり、それは独立にで置換されていても良くから選択される１以上の置換基ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニル．非常に好ましくは、Ｌ_Ｙは

) Forms a, it one or more _{R A} (hydroxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl), or _C 2 -C ₆ alkenyl (e.g., allyl) and the like (these It may be replaced with)). Preferably, L _Y is C ₁ -C ₆ alkylene substituted by one or more R _L such heterocycle 6-membered C ₃ -C ₆ carbocycle or 3, it is substituted with independently One or more substituents often selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl. Very preferably, _LY is

など（これらに限定されるものではない）のＣ_１−Ｃ_６アルキレン（基Ｌ_Ｙ内の炭素での立体化学は（Ｒ）または（Ｓ）であることができる。）であり；Ｌ_Ｙは独立に１以上のＲ_Ｌ（例えば、１以上のフェニルまたはメトキシ）で置換されていても良く；Ｇは好ましくは

Etc. be _C 1 -C ₆ alkylene (which are not limited to) (stereochemistry at the carbon in the group _{L Y} can be a (R) or (S).); _{L Y} is It may be independently substituted with one or more _RLs (eg, one or more phenyls or methoxys); G is preferably

であり；Ｒ_Ｂ″は水素であり；−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−は

By and; _{R B} "is _{hydrogen; -C (R 8 R 9)} N (R 12) - is

であり；Ｌ_Ｓは結合であり；Ｒ_Ｅはメトキシである。

In it; _{L S} is a bond; _{R E} is methoxy.

An example of a preferred Z is

などがあるが、これらに限定されるものではなく、式中、ＴおよびＲ_Ｄは上記で定義の通りである。Ｔは例えば、−Ｌ_Ｓ−Ｍ−Ｌ_Ｓ′−Ｍ′−Ｌ_Ｓ″−であることができ、Ｌ_Ｓは結合であり；ＭはＣ（Ｏ）であり；Ｌ_Ｓ′は

However, the present invention is not limited to these, and T and _RD are as defined above. T, for _{example, -L S -M-L S '} -M'-L S "- it can be, _{L S} is a bond; M is C (O); _{L S'} is

など（これらに限定されるものではない）のＣ_１−Ｃ_６アルキレンであり、Ｌ_Ｓ′は独立に１以上のＲ_Ｌで置換されていても良く；前記適宜のＲ_Ｌはフェニルまたはメトキシなど（これらに限定されるものではない）の置換基であり；Ｍ′は−ＮＨＣ（Ｏ）−または−ＮＭｅＣ（Ｏ）−であり；Ｌ_Ｓ″は結合である。基Ｌ_Ｓ′内の炭素の立体化学は（Ｒ）または（Ｓ）であることができる。Ｒ_Ｄは例えばメトキシである。Ｔ−Ｒ_Ｄには、

C ₁ -C ₆ alkylene such as (but not limited thereto), L S _'may be substituted with 1 or more independently of R _L; the appropriate R _L is phenyl or methoxy such as a substituent of (these are not limited to); M 'is -NHC (O) - or -NMeC (O) - and is; _{L S} "is a bond group _{L S.'} carbons of the The steric chemistry of can be (R) or (S). _RD is, for example, methoxy. For T- _RD ,

などがあるが、これらに限定されるものではない。Ｔ−Ｒ_Ｄは、ある種の立体化学配置を含むこともできることから、Ｔ−Ｒ_Ｄには、

However, it is not limited to these. Since T- _RD can also include certain stereochemical configurations, T- _RD may include.

などがあるが、これらに限定されるものではない。

However, it is not limited to these.

An example of a preferred Z is

などもあるが、これらに限定されるものではない。

However, it is not limited to these.

T is independently _{-C (O) -L S '-} , - C (O) O-L S' -, - C (O) -L S '-N (R B) C (O) -L S _{"-, - C (O)} -L S '-N (R B) C (O) O-L S" -, - N (R B) C (O) -L S' -N (R B) C _{(O) -L S "-,} - N (R B) C (O) -L S '-N (R B) C (O) O-L S" -, or -N _(R B) C _{(O ) -L S '-N (R B} ) -L S "-. can be selected from, but not limited thereto preferably, T is in each case independently, -C (O) _{-L S '-M'-L S "} - or _{-N (R B) C (O} ) -L S'-M'-LS" -. which is the more preferred selected from, T is in each case independently _{in, -C (O) -L S '} -N (R B) C (O) -L S "- or _{-C (O) -L S' -N} (R B) C (O) O-L S ″-Selected from.

T, for example _{-L S -M-L S '-M'} -L S "- can also be, _{L S} is a bond; M is C (O); _{L S'} is _{C 1} - C ₆ alkylene (eg,

）であり、Ｌ_Ｓ′は独立にＲ_Ｔで置換されていても良く；前記適宜のＲ_Ｔは−Ｃ_１−Ｃ_６アルキル、−Ｃ_２−Ｃ_６アルケニル、−Ｃ_１−Ｃ_６アルキル−ＯＨ、−Ｃ_１−Ｃ_６アルキル−Ｏ−Ｃ_１−Ｃ_６アルキル、３から６員の複素環（例えば、テトラヒドロフラニル）、またはＣ_３−Ｃ_６炭素環（例えば、フェニル、シクロヘキシル）から選択される置換基であり；Ｍ′は−ＮＨＣ（Ｏ）−、−Ｎ（Ｅｔ）Ｃ（Ｏ）−または−Ｎ（Ｍｅ）Ｃ（Ｏ）−であり；Ｌ_Ｓ″は結合である。Ｒ_Ｄは好ましくは、水素、−Ｃ_１−Ｃ_６アルキル（例えば、メチル）、−Ｏ−Ｃ_１−Ｃ_６アルキル（例えば、メトキシ、ｔｅｒｔ−ブトキシ）、メトキシメチル、または−Ｎ（Ｃ_１−Ｃ_６アルキル）_２（例えば、−ＮＭｅ_２）である。

), And _LS ′ may be independently substituted with _RT ; the appropriate _RT is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _1- C ₆ alkyl-. Select from OH, -C _1- C ₆ alkyl-OC _1- C ₆ alkyl, 3- to 6-membered heterocycle (eg, tetrahydrofuranyl), or C _3- C ₆ carbocycle (eg, phenyl, cyclohexyl) M'is -NHC (O)-, -N (Et) C (O)-or -N (Me) C (O)-; L _S "is a bond. _D is preferably hydrogen, -C _1- C ₆ alkyl (eg, methyl), -OC _1- C ₆ alkyl (eg, methoxy, tert-butoxy), methoxymethyl, or -N (C _1- C). ₆ Alkyl) ₂ (eg, −NMe ₂ ).

T- _RD is

であることができるが、これらに限定されるものではなく、基Ｔ−Ｒ_Ｄ内の炭素の立体化学は（Ｒ）または（Ｓ）であることができる。

However, but not limited to these, the stereochemistry of the carbon in the group T- _RD can be (R) or (S).

T is _{-L S -M-L} S '- can also be a, but is not limited thereto, wherein, _{L S} is a bond; M is C _{(O); L} S' _C 1 -C ₆ alkylene (e.g.,

）であり、Ｌ_Ｓ′は独立にＲ_Ｔで置換されていても良く；前記適宜のＲ_Ｔは−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル−ＯＨ、−Ｃ_１−Ｃ_６アルキル−Ｏ−Ｃ_１−Ｃ_６アルキルまたはＣ_３−Ｃ_６炭素環（例えば、フェニル、シクロヘキシル）から選択される置換基である。Ｒ_Ｄは例えば、−ＯＨ；−ＯＣ（Ｏ）Ｍｅ；−ＮＨ（Ｃ_１−Ｃ_６アルキル）（例えば、−ＮＨＭｅ、−ＮＨＥｔ）；−Ｎ（Ｃ_１−Ｃ_６アルキル）_２（例えば、−ＮＭｅ_２、−ＮＥｔ_２）；１以上のハロゲン、オキソで置換されていても良い３から１０員の複素環（例えば、ピロリジニル、イミダゾリジニル、ヘキサヒドロピリミジニル、モルホリニル、ピペリジニル）；−ＯＨで置換されていても良いＣ_３−Ｃ_１０炭素環（例えば、シクロペンチル）；−ＯＨで置換されていても良い−Ｃ_１−Ｃ_６アルキル（例えば、イソプロピル、３−ペンチル）；またはＮＨＲ_Ｔであり、Ｒ_Ｔは３から６員の複素環（例えば、チアゾリル、ピリミジニル）である。Ｔ−Ｒ_Ｄには、

), And, _{L S} 'may be substituted by _{R T} independently; the appropriate _{R T} is _-C 1 -C ₆ alkyl, _-C 1 -C ₆ alkyl -OH, _-C 1 _{-C 6} A substituent selected from alkyl-OC ₁ -C ₆ alkyl or C _3- C ₆ carbocycles (eg, phenyl, cyclohexyl). _RD is, for example, -OH; -OC (O) Me; -NH (C _1- C ₆ alkyl) (eg, -NH Me, -NHEt); -N (C _1- C ₆ alkyl) ₂ (eg,- NMe ₂ , -NET ₂ ); 3- to 10-membered heterocycles optionally substituted with one or more halogens, oxos (eg, pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, morpholinyl, piperidinyl); substituted with -OH. be good _C 3 _{-C 10} carbocycle (e.g., cyclopentyl); - may be substituted by OH _-C 1 -C ₆ alkyl (e.g., isopropyl, 3-pentyl); a or NHR _{T, R T} Is a 3- to 6-membered heterocycle (eg, thiazolyl, pyrimidinyl). For T- _RD ,

などがあるが、これらに限定されるものではなく、式中、基Ｔ−Ｒ_Ｄ内の炭素での立体化学は（Ｒ）または（Ｓ）であることができる。

However, the stereochemistry of carbon in the group T- _RD can be (R) or (S) in the formula.

In each compound of Formula I, _{L K} is a bond in each case _{independently; -L S '-N (R B} ) C (O) -L S -; - L S' -C (O) N (R B) -L _S -; or each independently represent a halogen in each _{case, R T, -O-R S} , -S-R S, -N (R S R S '), - OC (O) R S, -C ( O) C _1- C ₆ alkylene, C _2- C ₆ alkenylene, C ₂ which may be substituted with one or more substituents selected from OR _S , nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano. -C _{6 alkynylene,} C 3 _{-C 10} can also be selected from a carbon ring or a 3- to 10-membered heterocyclic _{ring, R T, R B, R} S, R S ', L S and _{L S'} is defined above It is a street.

Formula I and Formula _I A below including each and every embodiment described _below, I _{B, I} C, I _D, I E, the _{I F} or _{I G,} the _{R A} is preferably halogen, hydroxy, mercapto, Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano in each case. C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, Nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C ₂ -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl; or _-L a _-O-R S, - _{L A -S-R S, -L} A -C (O) R S, -L A -OC (O) R S, -L A -C (O) OR S, -L A -N (R S R _{S '), - L A -S} (O) R S, -L A -SO 2 R S, -L A -C (O) N (R S R S'), - L A -N (R S) _{C (O) R S ',} -L A -N (R S) C (O) N (R S' R S "), - L A -N (R S) SO 2 R S ', -L A - _{SO 2 N (R S R S} '), - L A -N (R S) SO 2 N (R S' R S "), - L A -N (R S) S (O) N (R S ' _{R S "), - L A} -OS (O) -R S, -L A -OS (O) 2 -R S, -L A -S (O) 2 OR S, -L A -S (O) _{OR S, -L A -OC (O} ) OR S, -L A -N (R S) C (O) OR S ', -L A -OC (O) N (R S R S'), - L _{A -N (R S) S (} O) -R S ', -L A -S (O) N (R S R S') or Is _{-L A -C (O) N (} R S) C (O) -R S '(L A bond _is a C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene. ).

More preferably, the _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo. , phosphonoxy, phosphono, thioxo, formyl or one or more which may be _C 1 -C ₆ alkyl substituted by a substituent selected from _cyano, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or each Independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, It may be substituted with one or more substituents selected from C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl C _3- C ₆ carbocycle or 3 to 6 members. It is a heterocycle of.

Very preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl which may be substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, tioxo, formyl or cyano.

L _S, with _{L S} 'and _{L S} "each case preferably each independently, a bond; or _C 1 -C _{6 alkylene,} is selected from C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene.

A and B can be the same or different. Similarly, L ₁ and L ₂ , or Y and Z, or YA- and Z-B-, or -A-L _1- and -B-L _2- can be the same or different. it can. In some cases, YA-L ₁ -is the same as Z-B-L _2- . In some other cases, YA-L _1- is different from Z-B-L _2- .

In one embodiment, A and B are independently 5- or 6-membered carbocycles or heterocycles (eg, for example.

などのフェニル）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い。Ｘは５員もしくは６員の炭素環または複素環または６から１２員の二環式化合物（例えば、

Phenyl), such as may be substituted with independently 1 or more R _A. X is a 5- or 6-membered carbocycle or heterocycle or a 6 to 12-membered bicyclic compound (eg,

であり、式中、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）、１以上のＲ_Ａで置換されていても良い。Ｘの具体例については上記で記載されている。ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であり、１以上のＲ_Ａで置換されていても良く、またはＪで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

In the equation, X ₃ is N and is directly linked to −L ₃₋ D. ), It may be substituted with 1 or more _RA . Specific examples of X are described above. D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl), and may be substituted with one or more R _A, or is substituted by J, one or more R It may be substituted with _A, where J is a C _3- C ₆ carbon ring, a 3- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound, even if substituted with 1 or more _RA. good. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl. , Cyan, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C (O) ) OR _S or −N ( _RS R _S ′) may be substituted with one or more substituents, and J may also be substituted with one or more _RA . Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。Ｙは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄ、または−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄであり、Ｚは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. Y is _{-N (R B) C (O} ) C (R 1 R 2) N (R 5) -T-R D or _{-N (R B) C (O} ) C (R 3 R 4), C ( R ₆ R ₇₎ is _{-T-R D,} Z is _{-N (R B) C (O} ) C (R 8 R 9) N (R 12) -T-R D or -N _(R B) C (O) C (R ₁₀ R ₁₁ ) C (R ₁₃ R ₁₄ ) -T- _RD . R ₁ is _RC , where R ₂ and R ₅ are integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, it one or more may be substituted by R _A; R ₃ and R ₆ are each independently R _C, together with the atom to which R ₄ and R ₇ are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, it may be substituted by one or more R _A. R ₈ is _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, it one or more may be substituted by _{R A; R 10} and _{R 13} are each independently _{R C,} together with the atoms _{to which R 11} and _{R 14} are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｔは好ましくは独立に、各場合で−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−から選択される。Ｌ_Ｙ′はそれぞれ独立にＬ_Ｓ′であり、好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

) Forms a, it may be substituted by one or more R _A. T is independently preferably, in each case _{-C (O) -L Y '-N} (R B) C (O) -L S "- or _{-C (O) -L Y' -N} (R B) It is selected from C (O) OL _S ″-. L _Y 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。Ｔは−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−から選択されることもできるが、これらに限定されるものではない。一部の場合、ＹおよびＺのうちの少なくとも一方、またはＹおよびＺの両方が独立に、

), And may be substituted with one or more substituents selected from _RL . T is _{-C (O) -L Y '-L} S "-, - C (O) -L Y' -O-L S" -, - C (O) -L Y '-N (R B) - L _S "-, or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - can also be selected from, but is not limited thereto. In some cases, at least one of Y and Z, or both Y and Z, independently.

であり、Ｒ_Ｄの例としては（１）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_３−Ｃ_６炭素環または３から６員の複素環から選択される１以上の置換基によって置換されていても良い−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または（２）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_６炭素環または３から６員の複素環などがあるが、これらに限定されるものではなく；Ｌ_Ｙ′の例としては、Ｃ_１−Ｃ_６アルキレンで置換されていても良いハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ホスホノキシ、−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニルまたは３から６員の炭素環または複素環などがあるが、これらに限定されるものではなく、前記３から６員の炭素環または複素環はハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基で置換されていても良い。

, And the examples of _{R D} is (1) a halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 3 -C ₆ carbocycle or May be substituted with one or more substituents selected from 3- to 6-membered heterocycles -OC _1- C ₆ alkyl, -OC _2- C ₆ alkyne, -OC _2- C ₆ alkynyl, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or (2) each independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, Phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ halo 1 or more substituted by substituent and the like may C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring selected from alkynyl, is not limited thereto; L Y _{'of examples,} C 1 -C ₆ good halogen substituted alkylene, hydroxy, mercapto, amino, carboxy, phosphonoxy, _-O-C 1 -C ₆ alkyl, _-O-C 2 -C ₆ alkenyl, - There are, but are not limited to, OC ₂ -C ₆ alkynyls or 3- to 6-membered carbocycles or heterocycles, and the 3- to 6-membered carbocycles or heterocycles are halogen, hydroxy, mercapto. , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C ₂ -C ₆ with one or more substituents selected from haloalkynyl may be substituted.

In another embodiment, A

であり、１以上のＲ_Ａで置換されていても良く；Ｂは

, And the may optionally be substituted with one or more R _A; B is

であり、１以上のＲ_Ａで置換されていても良い。Ｚ_１は独立に各場合で、Ｏ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は独立に各場合で、ＮまたはＣＨから選択される。好ましくは、Ａは

, And the optionally substituted with one or more R _A. Z ₁ is independently selected from O, S, NH or CH ₂ in each case; Z ₂ is independently selected from N or CH in each case. Preferably, A is

であり、Ｂは

And B is

であり、ＡおよびＢはＦまたはＣｌなどの１以上のハロゲンで置換されている。Ａおよび／またはＢがハロ置換されたベンズイミダゾール（例えば、Ａが

And A and B are substituted with one or more halogens such as F or Cl. Benzimidazole in which A and / or B is halo-substituted (eg, A

であり、Ｂが

And B is

である。）である場合、この実施形態の化合物は、置換されていないベンズイミダゾールを持たない同じ化合物と比較して、大幅に改善された薬物動態特性ならびにある種のＨＣＶ遺伝子型１ａ突然変異体に対する改善された阻害薬活性を有することができる。Ｘは５員もしくは６員の炭素環または複素環または６から１２員の二環式化合物（例えば、

Is. ), The compound of this embodiment has significantly improved pharmacokinetic properties as well as improved for certain HCV genotype 1a mutants as compared to the same compound without the unsubstituted benzimidazole. Can have inhibitory activity. X is a 5- or 6-membered carbocycle or heterocycle or a 6 to 12-membered bicyclic compound (eg,

であり、式中、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_Ａで置換されていても良い。Ｘの具体例は上記で記載されている。ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であり、１以上のＲ_Ａで置換されていても良く、またはＪで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

In the equation, X ₃ is N and is directly linked to −L ₃₋ D. ), And may be substituted with 1 or more _RA . Specific examples of X are described above. D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl), and may be substituted with one or more R _A, or is substituted by J, one or more R It may be substituted with _A, where J is a C _3- C ₆ carbon ring, a 3- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound, even if substituted with 1 or more _RA. good. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl. , Cyan, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C (O) ) OR _S or −N ( _RS R _S ′) may be substituted with one or more substituents, and J may also be substituted with one or more _RA . Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。Ｙは−Ｌ_Ｓ−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｌ_Ｓ−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄであり、Ｚは−Ｌ_Ｓ−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｌ_Ｓ−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、を形成しており５から６員の複素環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. Y is _{-L S -C (R 1 R 2} ) N (R 5) -T-R D or _{-L S -C (R 3 R 4} ) C (R 6 R 7) is _{-T-R D,} Z is _{-L S -C (R 8 R 9} ) N (R 12) -T-R D or _{-L S -C (R 10 R 11} ) C (R 13 R 14) -T-R D. R ₁ is _RC , and R ₂ and R ₅ are united with the atom to which they are bonded to form a 5- to 6-membered heterocycle (eg, for example.

それは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

It one or more R may be substituted by _A; a R ₃ and R ₆ are each independently R _C, R ₄ and R ₇ together with the atoms to which they are attached, 5-6 Member carbocycle or heterocycle (eg)

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, it may be substituted by one or more R _A. R ₈ is _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, it one or more may be substituted by _{R A; R 10} and _{R 13} are each independently _{R C,} together with the atoms _{to which R 11} and _{R 14} are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｔは好ましくは独立に各場合で−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−から選択される。Ｌ_Ｙ′はそれぞれ独立にＬ_Ｓ′であり、好ましくは、独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。Ｔは、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−から選択されることもできるが、これらに限定されるものではない。一部の場合において、少なくともＹおよびＺのうちの一方またはＹおよびＺの両方が独立に、

) Forms a, it may be substituted by one or more R _A. T is _-C in preferably each case independently _{(O) -L Y '-N (} R B) C (O) -L S "- or _{-C (O) -L Y' -N} (R B) C (O) Selected from OL _S ″-. L _Y 'is _{L S} independently' is, preferably, independently _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, optionally substituted with one or more substituents selected from _{R L} You may. T _{is, -C (O) -L Y '} -L S "-, - C (O) -L Y' -O-L S" -, - C (O) -L Y '-N (R B) -L _S "-, or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - can also be selected from, but is not limited thereto. In some cases, at least one of Y and Z or both Y and Z independently,

であり、Ｒ_Ｄの例としては、（１）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_３−Ｃ_６炭素環または３から６員の複素環から選択される１以上の置換基によって置換されていても良い−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または（２）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_６炭素環または３から６員の複素環などがあるが、これらに限定されるものではなく；Ｌ_Ｙ′の例としてはハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ホスホノキシ、−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニル、または３から６員の炭素環または複素環で置換されていても良いＣ_１−Ｃ_６アルキレンなどがあるが、これらに限定されるものではなく、前記３から６員の炭素環または複素環はハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基で置換されていても良い。

Examples of _RD are as follows: (1) In each case independently, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _3- C ₆ carbocycle. Alternatively, it may be substituted with one or more substituents selected from a 3- to 6-membered heterocycle: -OC _1- C ₆ alkyl, -O-C _2- C ₆ alkyne, -O-C _2- C ₆ alkynyl, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or (2) each independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more, etc. heterocyclic ring 6 membered good C ₃ -C ₆ carbocycle or 3 optionally substituted by a substituent selected from haloalkynyl, but is not limited thereto; L _Y ' Examples are halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-C _1- C ₆ alkyl, -O-C _2- C ₆ alkenyl, -O-C _2- C ₆ alkynyl, or 3 to 6 There are C _1- C ₆ alkylenes which may be substituted with a member carbocycle or a heterocycle, but the present invention is not limited to these, and the 3 to 6 member carbocycle or heterocycle may be halogen, hydroxy, Mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ with one or more substituents selected from haloalkynyl may be substituted.

In yet another embodiment, A and B are independently 5- or 6-membered carbocycles or heterocycles (eg, A and B are independent, respectively.

などのフェニルである。）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い。Ｘは５員もしくは６員の炭素環または複素環または６から１２員の二環式化合物（例えば、

Such as phenyl. ), And it may be substituted with independently 1 or more R _A. X is a 5- or 6-membered carbocycle or heterocycle or a 6 to 12-membered bicyclic compound (eg,

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_Ａで置換されていても良い。Ｘの具体例は上記で記載されている。Ｄは例えば、Ｃ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であることができ、１以上のＲ_Ａで置換されていても良く、Ｊで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

X ₃ is N and is directly connected to −L ₃₋ D. ), And may be substituted with 1 or more _RA . Specific examples of X are described above. D, for example, C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl) can be, may be substituted with one or more R _A, it is substituted with J, may be substituted with one or more R _a, J is a bicyclic compound of C ₃ -C ₆ carbocycle, a heterocycle or 6 from 3 6 membered to 12-membered, substituted with one or more R _a It may have been done. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl. , Cyan, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C (O) ) OR _S or −N ( _RS R _S ′) may be substituted with one or more substituents, and J may also be substituted with one or more _RA . Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。Ｙは−Ｇ−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄであり、Ｚは−Ｇ−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｇは独立に、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. Y is -G-C (R ₁ R ₂ ) N (R ₅ ) -T-R _D or -G-C (R ₃ R ₄ ) C (R ₆ R ₇ ) -T-R _D , where Z is -G-C (R ₈ R ₉ ) N (R ₁₂ ) -T-R _D or -G-C (R ₁₀ R ₁₁ ) C (R ₁₃ R ₁₄ ) -T-R _D. G independently,

などのＣ_５−Ｃ_６炭素環または５から６員の複素環であり、独立に１以上のＲ_Ａで置換されていても良い。Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

A C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic rings such as, may be substituted with one or more independently of R _A. R ₁ is _RC , where R ₂ and R ₅ are integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, it one or more may be substituted by R _A; R ₃ and R ₆ are each independently R _C, together with the atom to which R ₄ and R ₇ are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, it may be substituted by one or more R _A. R ₈ is _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, it one or more may be substituted by _{R A; R 10} and _{R 13} are each independently _{R C,} together with the atoms _{to which R 11} and _{R 14} are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｔは好ましくは独立に各場合で−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−から選択される。Ｌ_Ｙ′はそれぞれ独立にＬ_Ｓ′であり、好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

) Forms a, it may be substituted by one or more R _A. T is _-C in preferably each case independently _{(O) -L Y '-N (} R B) C (O) -L S "- or _{-C (O) -L Y' -N} (R B) C (O) Selected from OL _S ″-. L _Y 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、１以上の置換基Ｒ_Ｌで置換されていても良いから選択される。Ｔは、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−から選択されることもできるが、これらに限定されるものではない。一部の場合で、ＹおよびＺの少なくとも一方またはＹおよびＺの両方が独立に、

), Which may be substituted with one or more substituents _RL . T _{is, -C (O) -L Y '} -L S "-, - C (O) -L Y' -O-L S" -, - C (O) -L Y '-N (R B) -L _S "-, or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - can also be selected from, but is not limited thereto. In some cases, at least one of Y and Z or both Y and Z independently,

であり、Ｒ_Ｄの例には、（１）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_３−Ｃ_６炭素環または３から６員の複素環から選択される１以上の置換基によって置換されていても良い−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または（２）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_６炭素環または３から６員の複素環などがあるが、これらに限定されるものではなく；Ｌ_Ｙ′の例にはＣ_１−Ｃ_６アルキレンで置換されていても良いハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ホスホノキシ、−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニルまたは３から６員の炭素環または複素環などがあるが、これらに限定されるものではなく、前記３から６員の炭素環または複素環はハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基で置換されていても良い。

Examples of _RD include (1) each independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _3- C ₆ carbocycle. Alternatively, it may be substituted with one or more substituents selected from a 3- to 6-membered heterocycle: -OC _1- C ₆ alkyl, -O-C _2- C ₆ alkyne, -O-C _2- C ₆ alkynyl, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or (2) each independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more, etc. heterocyclic ring 6 membered good C ₃ -C ₆ carbocycle or 3 optionally substituted by a substituent selected from haloalkynyl, but is not limited thereto; L _Y ' also a good halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, _-O-C 1 -C ₆ alkyl, _-O-C 2 -C ₆ alkenyl, optionally substituted with _C 1 -C ₆ alkylene examples of - There are, but are not limited to, OC ₂ -C ₆ alkynyls or 3- to 6-membered carbocycles or heterocycles, and the 3- to 6-membered carbocycles or heterocycles are halogen, hydroxy, mercapto. , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C ₂ -C ₆ with one or more substituents selected from haloalkynyl may be substituted.

In yet another embodiment, A and B are independently 5- or 6-membered carbocycles or heterocycles (eg, A and B are independent, respectively).

などのフェニルである。）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い。Ｘは、５員もしくは６員の炭素環または複素環または６から１２員の二環式化合物（例えば、

Such as phenyl. ), And it may be substituted with independently 1 or more R _A. X is a 5- or 6-membered carbocycle or heterocycle or a 6 to 12-membered bicyclic compound (eg,

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_Ａで置換されていても良い。Ｘの具体例は上記で記載されている。Ｄは例えば、Ｃ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であることができ、１以上のＲ_Ａで置換されていても良く、Ｊで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

X ₃ is N and is directly connected to −L ₃₋ D. ), And may be substituted with 1 or more _RA . Specific examples of X are described above. D, for example, C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl) can be, may be substituted with one or more R _A, it is substituted with J, may be substituted with one or more R _a, J is a bicyclic compound of C ₃ -C ₆ carbocycle, a heterocycle or 6 from 3 6 membered to 12-membered, substituted with one or more R _a It may have been done. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, Formil, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C ( O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J may also be substituted with one or more _{R a.} Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。Ｙは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄであり、Ｚは−Ｇ−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄであり；またはＹは−Ｇ−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄであり、Ｚは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. Y is _{-N (R B) C (O} ) C (R 1 R 2) N (R 5) -T-R D or _{-N (R B) C (O} ) C (R 3 R 4) C (R ₆ R ₇ ) -TR _D , where Z is -GC (R ₈ R ₉ ) N (R ₁₂ ) -TR _D or -GC (R ₁₀ R ₁₁ ) C (R ₁₃ R) ₁₄ ) -T-R _D ; or Y is -G-C (R ₁ R ₂ ) N (R ₅ ) -T-R _D or -G-C (R ₃ R ₄ ) C (R ₆ R ₇₎ ) and _{-T-R D,} Z is _{-N (R B) C (O} ) C (R 8 R 9) N (R 12) -T-R D or _{-N (R B) C (O} ) C (R ₁₀ R ₁₁ ) C (R ₁₃ R ₁₄ ) -T- _RD . R ₁ is _RC , where R ₂ and R ₅ are integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, it one or more may be substituted by R _A; R ₃ and R ₆ are each independently R _C, together with the atom to which R ₄ and R ₇ are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、１以上のＲ_Ａで置換されていても良い。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, optionally substituted with one or more R _A. R ₈ is _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

Forms a, it one or more may be substituted by _{R A; R 10} and _{R 13} are each independently _{R C,} and together with the atoms _{to which R 11} and _{R 14} are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

を形成しており、１以上のＲ_Ａで置換されていても良い。Ｇは独立に

_May be substituted with one or more RAs. G independently

などのＣ_５−Ｃ_６炭素環または５から６員の複素環であり、独立に１以上のＲ_Ａで置換されていても良い。Ｔは好ましくは独立に各場合で−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−から選択される。Ｌ_Ｙ′はそれぞれ独立にＬ_Ｓ′であり、好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

A C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic rings such as, may be substituted with one or more independently of R _A. T is _-C in preferably each case independently _{(O) -L Y '-N (} R B) C (O) -L S "- or _{-C (O) -L Y' -N} (R B) C (O) Selected from OL _S ″-. L _Y 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。Ｔは、、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−から選択されることもできるが、これらに限定されるものではない。一部の場合で、Ｙは上記の

), And may be substituted with one or more substituents selected from _RL . T is _{,, - C (O) -L Y} '-L S "-, - C (O) -L Y' -O-L S" -, - C (O) -L Y '-N (R B ) _-L S "-, or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - can also be selected from, but not limited to .. In some cases, Y is above

であり、
Ｚは上記の

And
Z is the above

である。一部の場合で、Ｙは上記の

Is. In some cases, Y is above

であり、Ｚは上記の

And Z is above

である。

Is.

In yet another embodiment, A is a 5- or 6-membered carbocycle or heterocycle (eg, for example.

などのフェニル）であり、Ｂは

Phenyl), and B is

（例えば、

(For example

）であり；またはＡは

); Or A

（例えば、

(For example

）であり、Ｂは５員もしくは６員の炭素環または複素環（例えば、

), Where B is a 5- or 6-membered carbocycle or heterocycle (eg,

などのフェニル）である。ＡおよびＢはそれぞれ独立に１以上のＲ_Ａで置換されていても良い。Ｚ_１は独立に各場合で、Ｏ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は独立に各場合で、ＮまたはＣＨから選択される。Ｘは５員もしくは６員の炭素環または複素環または６から１２員の二環式化合物（例えば、

Phenyl) such as. A and B may be substituted with one or more R _A independently. Z ₁ is independently selected from O, S, NH or CH ₂ in each case; Z ₂ is independently selected from N or CH in each case. X is a 5- or 6-membered carbocycle or heterocycle or a 6 to 12-membered bicyclic compound (eg,

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_Ａで置換されていても良い。Ｘの具体例は上記で記載されている。ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であり、１以上のＲ_Ａで置換されていても良く、またはＪで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

X ₃ is N and is directly connected to −L ₃₋ D. ), And may be substituted with 1 or more _RA . Specific examples of X are described above. D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl), and may be substituted with one or more R _A, or is substituted by J, one or more R It may be substituted with _A, where J is a C _3- C ₆ carbon ring, a 3- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound, even if substituted with 1 or more _RA. good. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, Formil, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C ( O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J may also be substituted with one or more _{R a.} Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。Ａが５員もしくは６員の炭素環または複素環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. A 5- or 6-membered carbocycle or heterocycle (eg,

などのフェニル）である場合、Ｙは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄ、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄ、−Ｇ−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄであり、Ｚは−Ｌ_Ｓ−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｌ_Ｓ−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｂが５員もしくは６員の炭素環または複素環（例えば、

If phenyl), such as, Y is _{-N (R B) C (O} ) C (R 1 R 2) N (R 5) -T-R D, -N (R B) C (O) C ( R ₃ R ₄ ) C (R ₆ R ₇ ) -T-R _D , -G-C (R ₁ R ₂ ) N (R ₅ ) -T-R _D or -G-C (R ₃ R ₄ ) C _(R 6 _R 7) is _{-T-R D,} Z is _{-L S -C (R 8 R 9} ) N (R 12) -T-R D or _{-L S -C (R 10 R 11} ) C (R ₁₃ R ₁₄ ) -T- _RD . B is a 5- or 6-membered carbocycle or heterocycle (eg,

などのフェニル）である場合、Ｙは−Ｌ_Ｓ−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｌ_Ｓ−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄであり、Ｚは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄ、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄ、−Ｇ−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

If phenyl), such as, Y is _{-L S -C (R 1 R 2} ) N (R 5) -T-R D or _{-L S -C (R 3 R 4} ) C (R 6 R 7) a _{-T-R D,} Z is _{-N (R B) C (O} ) C (R 8 R 9) N (R 12) -T-R D, -N (R B) C (O) C ( R ₁₀ R ₁₁ ) C (R ₁₃ R ₁₄ ) -T-R _D , -G-C (R ₈ R ₉ ) N (R ₁₂ ) -T-R _D or -G-C (R ₁₀ R ₁₁ ) C (R ₁₃ R ₁₄ ) -T- _RD . R ₁ is _RC , where R ₂ and R ₅ are integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

Forms a, it one or more may be substituted by R _A; R ₃ and R ₆ are each independently R _C, and together with the atoms to which R ₄ and R ₇ are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, it may be substituted by one or more R _A. R ₈ is _RC , with R ₉ and R ₁₂ being integrated with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, it one or more may be substituted by _{R A; R 10} and _{R 13} are each independently _{R C,} together with the atoms _{to which R 11} and _{R 14} are attached they And a 5- to 6-membered carbocycle or heterocycle (eg,

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。Ｇは独立に

) Forms a, it may be substituted by one or more R _A. G independently

などのＣ_５−Ｃ_６炭素環または５から６員の複素環であり、独立に１以上のＲ_Ａで置換されていても良い。Ｔは好ましくは独立に各場合で−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−から選択される。Ｌ_Ｙ′はそれぞれ独立にＬ_Ｓ′であり、好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

A C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic rings such as, may be substituted with one or more independently of R _A. T is _-C in preferably each case independently _{(O) -L Y '-N (} R B) C (O) -L S "" - or _{-C (O) -L Y' -N} (R B) a .L is selected from _Y 'is _{L S} independently', preferably are each independently _C 1 -C ₆ alkylene _{(e.g., -CH 2 - - C (O} ) O-L S " or

ら選択される１以上の置換基で置換されていても良い。Ｔは−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−から選択されることもできるが、それらに限定されるものではない。一部の場合で、Ａが５員もしくは６員の炭素環または複素環（例えば、

It may be substituted with one or more substituents selected from the above. T is _{-C (O) -L Y '-L} S "-, - C (O) -L Y' -O-L S" -, - C (O) -L Y '-N (R B) - L _S "-, or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - can also be selected from, but is not limited to them. In some cases, A is a 5- or 6-membered carbocycle or heterocycle (eg,

などのフェニル）である場合、Ｙは上記の

If it is phenyl), Y is the above

であり、Ｚは上記の

And Z is above

である。一部の他の場合では、Ｂが５員もしくは６員の炭素環または複素環（例えば、

Is. In some other cases, B is a 5- or 6-membered carbocycle or heterocycle (eg,

などのフェニル）である場合、Ｙは上記の

If it is phenyl), Y is the above

であり、Ｚは上記の

And Z is above

である。

Is.

The present invention also
D is a _C 3 _{-C 12} carbocyclic or 3-12 membered heterocyclic ring, one or more may be substituted by _{R A;} or D is a _C 3 _{-C 12} carbocyclic or 3 12-membered heterocyclic a ring, is substituted with J, 1 or more may be substituted with R _a, J is C ₃ -C ₁₅ carbocyclic ring or 3 to 15 membered heterocyclic ring (e.g., isolated from 3 6 membered Cyclic compounds, 6-12 member fused, crosslinked or spiro bicyclic compounds, 10-15 membered tricyclic compounds containing fused, crosslinked or spiro rings, or 13-15 membered carbocycles or heterocycles. ), and it may be substituted by one or more _{R a,} or J is located in -SF _5; or D is hydrogen or _{R a;}
In each case R _A is independently, halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, is selected from cyano or _-L B -R _E; 2 contiguous _{R A} is, atoms to which they are attached and They may be integrated with the atoms between the atoms to which they are bonded to form a carbocycle or heterocycle;
In each case L _B is independently, _{L S;} or each independently O, it may have a S or N _{(R B)} replaced by that 1, 2, 3, 4 or 5 carbon atoms C ₁ -C _{10 alkylene,} C 2 _{-C 10} is selected from alkenylene or _C 2 _{-C 10} alkynylene, said _C 1 _{-C 10 alkylene,} C 2 _{-C 10} alkenylene or _C 2 _{-C 10} 1 each alkynylene are independently It may be replaced by the above _RL ;
In each case R _E is _{independently, -O-R S, -S-} R S, -C (O) R S, -OC (O) R S, -C (O) OR S, -N (R S R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N ( _RS R _S '), -N ( _RS ) C (O) R _S ' _, -N ( _{R S) C (O) N} (R S 'R S "), - N (R S) SO 2 R S', -SO 2 N (R S R S '), - N (R S) SO 2 N _{(R S 'R S ")} , - N (R S) S (O) N (R S' R S"), - OS (O) -R S, -OS (O) 2 -R S, -S (O) ₂ OR _S , -S (O) OR _S , -OC (O) OR _S , -N ( _RS ) C (O) OR _S ', -OC (O) N ( _RS R _S ') _{, -N (R S) S (} O) -R S ', -S (O) N (R S R S'), - P (O) (OR S) 2, = C (R S R S ') or _{-C (O) N (R S} ) C (O) -R S '; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , _C 3 _{-C 12} carbocycle or one or more may be substituted by a substituent _C 1 -C ₆ alkyl 3 is selected from the 12-membered _heterocycle, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, _{trimethylsilyl,} C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, C ₂ -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C _{6 haloalkynyl, -O-R S, -S-} R S, -C (O) R S, -C (O) oR _S, or _{-N (R S R S ')} 1 or more may be substituted by a substituent _C 3 _{-C 12} carbocyclic or 3-12 membered heterocyclic ring selected from (e.g. , 7-12 membered alkynes or heterocycles);
In each case of _RL independently, halogen, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano, -O- _RS , -S- _RS , -C (O) R _S , -OC (O) R _S , -C (O) OR _S , -N ( _RS R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N ( _RS R _S ') or -N ( R _S ) C (O) R _S '; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _{Even if} substituted with one or more substituents selected from _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl. Selected from good C _3- C ₁₂ carbocycles or 3-to 12-membered heterocycles (eg, C _3- C ₆ carbocycles or 3- to 6-membered heterocycles); two adjacent _RLs , they are bonded atoms and they together with the atoms to lie between atoms to which they are attached formula I according to herein that may be to form a carbocyclic or heterocyclic ring, I _a, I _B, It features compounds of _IC and _ID (including each of the embodiments described below) and pharmaceutically acceptable salts thereof.

In one embodiment, A and B are independently 5- or 6-membered carbocycles or heterocycles (preferably A and B are independent, respectively).

などのフェニルである。）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い（好ましくは、ＡおよびＢはそれぞれ独立に少なくとも１個のＦなどのハロで置換されている。）。Ｘは、５員もしくは６員の炭素環または複素環または６から１２員の二環式化合物（好ましくは、Ｘは、

Such as phenyl. ), And it is also a good (preferably substituted with independently one or more R _A, is substituted with halo, such as at least one of F A and B are each independently.). X is a 5- or 6-membered carbocycle or heterocycle or a 6 to 12-membered bicyclic compound (preferably X is

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_Ａで置換されていても良い。ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であり、Ｊで置換されており、１以上のＲ_Ａで置換されていても良い。ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物、１０から１５員の三環式化合物、または１３から１５員の炭素環／複素環であり、Ｊは１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物または７から１２員の炭素環／複素環で置換されており、それらは独立に（１）ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、−Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）、または（２）トリメチルシリル、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓ、−Ｃ（Ｏ）Ｒ_Ｓから選択される１以上の置換基で置換されていても良く；Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

X ₃ is N and is directly connected to −L ₃₋ D. ), And may be substituted with 1 or more _RA . D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl), and is substituted with J, it may be substituted with one or more R _A. J is a C _3- C _6- membered ring, a 3- to 6-membered heterocycle, a 6 to 12-membered bicyclic compound, a 10 to 15-membered tricyclic compound, or a 13 to 15-membered carbocycle / heterocycle. There, J may be substituted with one or more R _a. Preferably, J is substituted with a C _3- C ₆ alkyne, a 3 to 6 membered heterocycle, a 6 to 12 membered bicyclic compound or a 7 to 12 membered alkyne / heterocycle, which are independent. (1) Halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S R S ')} , or (2) trimethylsilyl, -O-R It may be substituted with one or more substituents selected from _S , -S- _RS , -C (O) _RS ; J may also be substituted with one or more _RA . Preferably D is

であり、Ｊは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはＦなどのハロである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。Ｙは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄ、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄ、−Ｇ−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄである。Ｚは−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄ、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄ、−Ｇ−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｇ−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｒ_１はＲ_Ｃであり；Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

And J is as defined above, and each _RN is independently selected from R _D , preferably a halo such as hydrogen or F. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. Y is _{-N (R B) C (O} ) C (R 1 R 2) N (R 5) -T-R D, -N (R B) C (O) C (R 3 R 4) C (R ₆ R ₇ ) -T-R _D , -G-C (R ₁ R ₂ ) N (R ₅ ) -T-R _D or -G-C (R ₃ R ₄ ) C (R ₆ R ₇ ) -T is a -R _D. Z is _{-N (R B) C (O} ) C (R 8 R 9) N (R 12) -T-R D, -N (R B) C (O) C (R 10 R 11) C (R ₁₃ R ₁₄ ) -T-R _D , -G-C (R ₈ R ₉ ) N (R ₁₂ ) -T-R _D or -G-C (R ₁₀ R ₁₁ ) C (R ₁₃ R ₁₄ ) -T is a -R _D. R ₁ is _RC ; R ₂ and R ₅ are united with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, they 1 or more may be substituted by R _A; is R ₃ and R ₆ are each independently R _C, and atoms of R ₄ and R ₇ are attached they Together, a 5- to 6-membered carbocycle or heterocycle (eg,

）または６から１２員の二環式化合物を形成しており、それらは１以上のＲ_Ａで置換されていても良い。Ｒ_８はＲ_Ｃであり；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Or forms a bicyclic compound of 6 to 12-membered, which may be substituted by one or more R _A. R ₈ is _RC ; R ₉ and R ₁₂ combine with the atom to which they are bonded to form a 5- to 6-membered heterocycle (eg, for example.

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, they 1 or more may be substituted by _{R A;} is _{R 10} and _{R 13} each independently _{R C,} and atoms _{of R 11} and _{R 14} are attached they Together, a 5- to 6-membered carbocycle or heterocycle (eg,

）または６から１２員の二環式化合物を形成しており、それらは１以上のＲ_Ａで置換されていても良い。Ｇは独立に

) Or forms a bicyclic compound of 6 to 12-membered, which may be substituted by one or more R _A. G independently

などのＣ_５−Ｃ_６炭素環または５から６員の複素環であり、それらは独立に１以上のＲ_Ａで置換されていても良い。Ｔは好ましくは独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−から選択される。Ｌ_Ｙ′はそれぞれ独立にＬ_Ｓ′であり、好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

A C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic rings such, they may be substituted with one or more independently of R _A. T is preferably in each case _{independently, -C (O) -L Y '} -N (R B) C (O) -L S "- or _{-C (O) -L Y' -N} (R B) It is selected from C (O) OL _S ″-. L _Y 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。Ｔは、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−から選択されることもできるが、これらに限定されるものではない。一部の場合で、Ｙは上記の

), And may be substituted with one or more substituents selected from _RL . T _{is, -C (O) -L Y '} -L S "-, - C (O) -L Y' -O-L S" -, - C (O) -L Y '-N (R B) -L _S "- or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - can also be selected from, but is not limited thereto. In some cases, Y is above

であり、Ｚは上記の

And Z is above

である。

Is.

In another embodiment, A

であり、１以上のＲ_Ａで置換されていても良く；Ｂは

, And the may optionally be substituted with one or more R _A; B is

であり、１以上のＲ_Ａで置換されていても良い。Ｚ_１は独立に各場合で、Ｏ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は独立に各場合で、ＮまたはＣＨから選択される。好ましくは、ＡおよびＢはそれぞれ独立に少なくとも１個のＦなどのハロで置換されている。好ましくは、Ａは

, And the optionally substituted with one or more R _A. Z ₁ is independently selected from O, S, NH or CH ₂ in each case; Z ₂ is independently selected from N or CH in each case. Preferably, A and B are each independently substituted with at least one halo such as F. Preferably, A is

であり、Ｂは

And B is

であり、ＡおよびＢはＦまたはＣｌなどの１以上のハロゲンで置換されている。Ａおよび／またはＢがハロ置換されたベンズイミダゾール（例えば、Ａが

And A and B are substituted with one or more halogens such as F or Cl. Benzimidazole in which A and / or B is halo-substituted (eg, A

であり、Ｂが

And B is

である。）である場合、この実施形態の化合物は、置換されていないベンズイミダゾールを有する同じ化合物と比較して、大幅に改善された薬物動態特性ならびにある種のＨＣＶ遺伝子型１ａ突然変異体に対する改善された阻害薬活性を有することができる。Ｘは５員もしくは６員の炭素環または複素環または６から１２員の二環式化合物（好ましくは、Ｘは

Is. ), The compound of this embodiment has significantly improved pharmacokinetic properties as well as improved for certain HCV genotype 1a mutants as compared to the same compound having benzimidazole intact. Can have inhibitory activity. X is a 5- or 6-membered carbocycle or heterocycle or a 6 to 12-membered bicyclic compound (preferably X is

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_Ａで置換されていても良い。ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であり、Ｊで置換されており、１以上のＲ_Ａで置換されていても良い。ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物、１０から１５員の三環式化合物または１３から１５員の炭素環／複素環であり、Ｊは１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物または７から１２員の炭素環／複素環で置換されており、それらは独立に（１）ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、−Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）、または（２）トリメチルシリル、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓ、または−Ｃ（Ｏ）Ｒ_Ｓから選択される１以上の置換基で置換されていても良く；Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

X ₃ is N and is directly connected to −L ₃₋ D. ), And may be substituted with 1 or more _RA . D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl), and is substituted with J, it may be substituted with one or more R _A. J is a C _3- C _6- membered ring, a 3- to 6-membered heterocycle, a 6 to 12-membered bicyclic compound, a 10 to 15-membered tricyclic compound, or a 13 to 15-membered carbocycle / heterocycle. , J may be substituted with 1 or more _RA . Preferably, J is substituted with a C _3- C ₆ alkyne, a 3 to 6 membered heterocycle, a 6 to 12 membered bicyclic compound or a 7 to 12 membered alkyne / heterocycle, which are independent. (1) Halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S R S ')} , or (2) trimethylsilyl, -O-R It may be substituted with one or more substituents selected from _S , -S- _RS , or -C (O) _RS ; J may also be substituted with one or more _RA . Preferably D is

であり、Ｊは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはＦなどのハロである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。Ｙは、−Ｌ_Ｓ−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄまたは−Ｌ_Ｓ−Ｃ（Ｒ_３Ｒ_４）Ｃ（Ｒ_６Ｒ_７）−Ｔ−Ｒ_Ｄである。Ｚは−Ｌ_Ｓ−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄまたは−Ｌ_Ｓ−Ｃ（Ｒ_１０Ｒ_１１）Ｃ（Ｒ_１３Ｒ_１４）−Ｔ−Ｒ_Ｄである。Ｒ_１はＲ_Ｃであり；Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

And J is as defined above, and each _RN is independently selected from R _D , preferably a halo such as hydrogen or F. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. Y _is a _{-L S -C (R 1 R 2} ) N (R 5) -T-R D or _{-L S -C (R 3 R 4} ) C (R 6 R 7) -T-R D .. Z is _{-L S -C (R 8 R 9} ) N (R 12) -T-R D or _{-L S -C (R 10 R 11} ) C (R 13 R 14) -T-R D. R ₁ is _RC ; R ₂ and R ₅ are united with the atom to which they are bonded to a 5- to 6-membered heterocycle (eg, for example.

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであり、Ｒ_４およびＲ_７がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, they 1 or more may be substituted by R _A; is R ₃ and R ₆ are each independently R _C, and atoms of R ₄ and R ₇ are attached they Together, a 5- to 6-membered carbocycle or heterocycle (eg,

）または６から１２員の二環式化合物を形成しており、それらは１以上のＲ_Ａで置換されていても良い。Ｒ_８はＲ_Ｃであり；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Or forms a bicyclic compound of 6 to 12-membered, which may be substituted by one or more R _A. R ₈ is _RC ; R ₉ and R ₁₂ combine with the atom to which they are bonded to form a 5- to 6-membered heterocycle (eg, for example.

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであり、Ｒ_１１およびＲ_１４がそれらが結合している原子と一体となって、５から６員の炭素環または複素環（例えば、

) Forms a, they 1 or more may be substituted by _{R A;} is _{R 10} and _{R 13} each independently _{R C,} and atoms _{of R 11} and _{R 14} are attached they Together, a 5- to 6-membered carbocycle or heterocycle (eg,

）または６から１２員の二環式化合物を形成しており、それらは１以上のＲ_Ａで置換されていても良い。Ｔは好ましくは独立に各場合で−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−から選択される。Ｌ_Ｙ′はそれぞれ独立にＬ_Ｓ′であり、好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

) Or forms a bicyclic compound of 6 to 12-membered, which may be substituted by one or more R _A. T is _-C in preferably each case independently _{(O) -L Y '-N (} R B) C (O) -L S "- or _{-C (O) -L Y' -N} (R B) C (O) Selected from OL _S ″-. L _Y 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。Ｔは、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−から選択されることもできるが、これらに限定されるものではない。一部の場合で、ＹおよびＺは独立に

), And may be substituted with one or more substituents selected from _RL . T _{is, -C (O) -L Y '} -L S "-, - C (O) -L Y' -O-L S" -, - C (O) -L Y '-N (R B) -L _S "-, or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - can also be selected from, but is not limited thereto. In some cases, Y and Z are independent

であり、Ｒ_Ｄの例としては、（１）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_３−Ｃ_６炭素環または３から６員の複素環から選択される１以上の置換基によって置換されていても良い−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または（２）それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_６炭素環または３から６員の複素環などがあるが、これらに限定されるものではなく；Ｌ_Ｙ′の例としてはハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ホスホノキシ、−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_２−Ｃ_６アルケニル、−Ｏ−Ｃ_２−Ｃ_６アルキニルで置換されていても良いＣ_１−Ｃ_６アルキレンまたは３から６員の炭素環または複素環などがあるが、これらに限定されるものではなく、前記３から６員の炭素環または複素環はハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基で置換されていても良い。

Examples of _RD are as follows: (1) In each case independently, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _3- C ₆ carbocycle. Alternatively, it may be substituted with one or more substituents selected from a 3- to 6-membered heterocycle: -OC _1- C ₆ alkyl, -O-C _2- C ₆ alkyne, -O-C _2- C ₆ alkynyl, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or (2) each independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more, etc. heterocyclic ring 6 membered good C ₃ -C ₆ carbocycle or 3 optionally substituted by a substituent selected from haloalkynyl, but is not limited thereto; L _Y ' Examples of are halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -OC _1- C ₆ alkyl, -OC _2- C ₆ alkenyl, -OC _2- C ₆ alkynyl substituted. Also good are C _1- C ₆ alkylene or 3- to 6-membered carbocycles or heterocycles, but are not limited to these, and the 3- to 6-membered carbocycles or heterocycles are halogen, hydroxy, mercapto. , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C ₂ -C ₆ with one or more substituents selected from haloalkynyl may be substituted.

In another aspect, the invention features acceptable salts compounds and pharmaceutical of formula I _A.

式中、
Ｒ_ＮＢはそれぞれ独立にＲ_Ｂから選択され；
Ｒ_Ｃ′はそれぞれ独立にＲ_Ｃから選択され；
Ｒ_Ｄ′はそれぞれ独立にＲ_Ｄから選択され；
Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ａ、Ｂ、Ｄ、Ｘ、Ｌ_１、Ｌ_２、Ｌ_３、Ｔ、Ｒ_Ａ、Ｒ_Ｂ、Ｒ_Ｃ、およびＲ_Ｄは式Ｉにおいて上記の通りである。

During the ceremony
R _NB is selected from _{R B} independently;
R _C 'is selected from _{R C} independently;
R _D' is independently selected from R _D ;
R ₂ and R ₅ together with the atom to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
R ₉ and R ₁₂ together with the atoms to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
_{A, B, D, X,} L 1, L 2, L 3, T, R A, R B, R C, and _{R D} are as described above for Formula I.

In this embodiment, A and B are preferably independently, C ₅ -C ₆ is selected from heterocyclic carbocyclic or 5-6 membered, optionally substituted with one or more R _A independently. More preferably, at least one of A and B is phenyl (eg,

であり、１以上のＲ_Ａで置換されていても良い。非常に好ましくは、ＡおよびＢの両方がそれぞれ独立にフェニル（例えば、

, And the optionally substituted with one or more R _A. Very preferably, both A and B are independently phenyl (eg, for example).

）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い。

), And it may be substituted with independently 1 or more R _A.

D is preferably, C ₅ -C ₆ carbocyclic ring, selected from the bicyclic compound from 6 membered heterocyclic rings from 5 or 8, 12-membered, optionally substituted with one or more R _A. D is _preferably, C 1 -C _{6 alkyl,} C 2 -C also ₆ alkenyl or _C 2 -C ₆ is selected from alkynyl, optionally substituted with one or more _{R L.} More preferably, D is _C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is optionally substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E,. Preferably, D is phenyl, optionally substituted with one or more R _A. More preferably, D is phenyl, which is substituted with one or more R _M, is R _M is as defined above. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F.

D preferably is pyridinyl, in pyrimidinyl or thiazolyl may be substituted with one or more R _A. More preferably D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted with one or more R _M. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。Ｄは好ましくはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリルまたはインダゾリルであり、１以上のＲ_Ａで置換されていても良い。より好ましくはＤはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリル、インダゾリルまたはベンゾ［ｄ］［１，３］ジオキソール−５−イルであり、１以上のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F. D is preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, optionally substituted with one or more _{R A.} More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, which is one or more. _Replaced by RM. Very preferably D

であり、１以上のＲ_Ｍで置換されていても良い。

, And the optionally substituted with one or more R _M.

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C ₆ alkyl selected from formyl or _cyano, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl Is. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, may or halogen in each case independently, hydroxy, mercapto, optionally substituted by one or more substituents selected from amino or carboxy C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl. Very preferably, R _M is independently a halogen, hydroxy, mercapto, one or more may be substituted with a substituent C ₁ -C ₆ alkyl is selected from amino or carboxy.

Preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, be thioxo or cyano; a or _{R M} is _{-L S} -R _{E, L} S is a bond or C a ₁ -C ₆ alkylene, _{R E} is _{-N (R S R S ')} , - OR S, -C (O) R S, -C (O) OR S, -C (O) N ( R _S R _S '), -N ( _RS ) C (O) R _S ' _, -N ( _RS ) C (O) OR _S ', -N ( _RS ) SO ₂ R _S ', -SO ₂ R _S , -SR _S , or -P (O) (OR _S ) ₂ , where R _S and R _S ′ are selected independently from each case, for example, (1) hydrogen or (2) in each case. one or more halogen, hydroxy, _-O-C 1 -C ₆ alkyl or 3 can be substituted with 6-membered heterocyclic ring is a good _C 1 -C ₆ alkyl; or _{R M} is _{C 1} - C ₆ alkyl, C _2- C ₆ alkynyl or C _2- C ₆ alkynyl, each independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or It may be substituted with one or more substituents selected from cyano; or _RMs are C _3- C ₆ carbocycles or 3-6 membered heterocycles, each independently halogen, in each case. Hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C ₂ -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S may be substituted or by one or more substituents selected from _{-N (R S R S ')} , .. More preferably, _{R M} is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or _C 1 -C ₆ alkyl, (e.g., methyl, isopropyl, tert- butyl), _{C 2} - They may be C ₆ alkenyl or C _2- C ₆ alkynyl, each independently substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy in each case. For example _{R M is, CF 3, -C (CF 3} ) 2 -OH, -C (CH 3) 2 -CN, -C (CH 3) 2 -CH 2 OH or _{-C (CH} 3) 2 -CH, ₂ NH ₂ . Preferably _{R M} is _{-L S} -R _{E, L} S is a bond, _{R E} is _{-N (R S R S ')} , - O-R S, -N (R S) C (O) _{oR S ', -N (R S} ) SO 2 R S', a _-SO 2 _{R S,} or -SR _S. For example, if _{L S} is a bond, _{R E} is -N _(C 1 -C _{6 alkyl) 2 (e.g., -NMe 2); - N (} C 1 -C 6 alkylene _-O-C 1 -C ₆ alkyl ) ₂ (eg -N (CH ₂ CH ₂ OME) ₂ ); -N (C _1- C ₆ alkyl) (C _1- C ₆ alkylene-OC _1- C ₆ alkyl) (eg -N (CH ₃₎ ) (CH ₂ CH ₂ OMe)); -O-C _1- C ₆ alkyl (eg, -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -On-hexyl _{); - O-C 1 -C} 6 haloalkyl _{(e.g., -OCF 3, -OCH 2 CF 3} ); - O-C 1 -C 6 alkylene - piperidine (e.g., _{-O-CH 2} CH ₂ -1- piperidyl ); -N (C _1- C ₆ alkyl) C (O) OC _1- C ₆ alkyl (for example, -N (CH ₃ ) C (O) O-CH ₂ CH (CH ₃ ) ₂ ), -N ( C _1- C ₆ alkyl) SO ₂ C _1- C ₆ alkyl (eg -N (CH ₃ ) SO ₂ CH ₃ ); -SO ₂ C _1- C ₆ alkyl (eg -SO ₂ Me); -SO ₂ C ₁ -C ₆ haloalkyl _(e.g., -SO 2 _CF 3); a or _-S-C 1 -C ₆ haloalkyl (e.g., SCF _3). Preferably _{R M} is _{-L S} -R _{E, L} S is _C 1 -C ₆ alkylene _{(e.g., -CH 2 -, - C (} CH 3) 2 -, - C (CH 3) 2 -CH 2 - _a), R _E is _{-O-R S, -C (O} ) oR S, -N (R S) C (O) oR S ' or _{-P, (O) (oR S} ) 2. For example _{R M} is _-C 1 -C ₆ alkylene _{-O-R S (e.g., -C (CH 3) 2 -CH} 2 -OMe); - C 1 -C 6 alkylene -C (O) OR _S (e.g., _{-C (CH 3) 2 -C (} O) OMe); - C 1 -C 6 alkylene _{-N (R S) C (O} ) OR S '( _{e.g., -C (CH 3) 2 -CH} 2 -NHC (O) OCH ₃ ); or -C _1- C ₆ alkylene-P (O) (OR _S ) ₂ (for example, -CH _2- P (O) (OEt) ₂ ). More preferably, R _M is a heterocyclic ring 6 membered C ₃ -C ₆ carbocycle or 3, halogens each case in each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , Thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl , -C (O) oR _S, or _{-N (R S} R _S ') may be substituted by one or more substituents selected from,. For example _{R M} is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-1-methylcyclopropyl pro-flops 1-yl, cyclohexyl), phenyl, heterocycle (e.g., morpholin-4-yl, 1,1-di Oxidethiomorpholine-4-yl, 4-methylpiperazine-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidine-1-yl, piperidine-1-yl, 4-methylpiperidine-1-yl, 3, 5-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridine-3-yl, 6- (dimethylamino) pyridine-3-yl). Very preferably, _{R M} is _C 1 -C ₆ alkyl, which is substituted with one or more substituents independently selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert- butyl, CF ₃₎ It may have been done.

More preferably, D is C ₅ -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is substituted with J, optionally substituted with one or more R _A at best, J is C ₃ -C ₆ carbocycle, a bicyclic compound of the heterocycle or 6 from 3 6 membered to 12-membered, optionally substituted with one or more R _a. Preferably, J is substituted with C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, wherein the C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring independently halogen, hydroxy, mercapto , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J is also 1 It may be replaced with the above _RA . Preferably, D is a heterocyclic 6-membered _C 5 -C ₆ carbocyclic ring or 5 is substituted with J, may be substituted by one or more _{R A,} J is _C 3 -C ₆ a heterocyclic 6-membered carbocyclic or 3, may be substituted by one or more R _a, and preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring cage, it is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, substituted by C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, 1 or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') It may have been done. Preferably, D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring is substituted with J, it may be substituted by one or more R _A, J 6 to 12-membered Bicyclic compounds (eg, 7-12 member condensed, crosslinked or spirobicyclic compounds containing a nitrogen ring atom intervening in J's covalent bond to D), one or more _RAs. It may be replaced with. More preferably, D is phenyl, is substituted with J, may be substituted by one or more R _A, J from C ₃ -C ₆ carbocycle, 3-6 membered heterocyclic, or 6 bicyclic compounds of 12 members may be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, they Independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, optionally substituted with one or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') You may. Very preferably D

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbon ring, a 3 to 6 member heterocycle or a 6 to 12 member bicyclic compound. , and the it may optionally be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, halogen them independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl, _{C 2} -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') with one or more substituents selected from optionally substituted. Preferably D is

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、Ｃ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbocycle or a 3 to 6 member heterocycle and a C _3- C ₆ carbocycle. or 3 is substituted with from 6 membered heterocyclic ring, they are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or -N _{(R S} R S It may be substituted with one or more substituents selected from ′), and J may also be substituted with one or more _RA . Preferably D is

であり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。

In it, J is a heterocyclic ring 6 membered _C 3 -C ₆ carbocycle or 3, may be substituted by one or more _{R A,} preferably J is at least _C 3 -C ₆ carbocycle or 3 is substituted with 6-membered heterocycle, they independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl, _{C 2} - C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ halo alkynyl, C (O) OR _S or -N ( _RS R _S ') It may be substituted with one or more substituents selected from.

X is _preferably, C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6-membered 12-membered (e.g.,

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｘの例は上記で記載されているが、それらに限定されるものではない。

X ₃ is N and is directly connected to −L ₃₋ D. ), And it may be substituted with one or more R _A or R _F. Examples of X are described above, but are not limited thereto.

L ₁ and L ₂ are preferably independently bonded or C _1- C ₆ alkylene, and L ₃ is preferably selected from bonded, C _1- C ₆ alkylene or -C (O)-, L ₁ , L ₂ And L ₃ may each be independently substituted with one or more _RL . More preferably, L ₁ , L ₂ and L ₃ are independently bound or C ₁ −C ₆ alkylene (eg, −CH _2- or − CH ₂ CH _2- ), respectively, and each independently has one or more _RLs. It may be replaced with. Very preferably, L ₁ , L ₂ and L ₃ are bonds.

R ₂ and R ₅ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。

) Forms a, they may be substituted by one or more R _A.

R ₉ and R ₁₂ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。

) Forms a, it may be substituted by one or more R _A.

_{-T-R D} 'is _-C in each case independently _{(O) -L Y' -,} - C (O) O-L Y '-R D', -C (O) -L Y '-N ( _{R B) C (O) -L} S "-R D ', -C (O) -L Y' -N (R B) C (O) O-L S" -R D ', -N (R B _{) C (O) -L Y '} -N (R B) C (O) -L S "-R D', -N (R B) C (O) -L Y '-N (R B) C ( _{O) O-L S "-R} D ', or _{-N (R B) C (O} ) -L Y' -N (R B) -L S" may be selected from -R _D ', the invention is not limited to, _{L Y} 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。より好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。非常に好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′は好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

), And may be substituted with one or more substituents selected from _RL . Preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -M'-L S "-R D ' or _{-N (R B) C (O} ) -L Y It is selected from the _{'-M'-L S "-R D} '. More preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) It is selected from _{-L Y '-N (R B)} C (O) O-L S "-R D'. Very preferably, _{-T-R D} 'is each case _{independently, -C (O) -L Y'} -N (R B) C (O) -R D ' or -C (O) -L _Y It is selected from the _{'-N (R B) C (} O) O-R D', L Y ' is _C 1 -C ₆ alkylene, preferably each independently (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。

), And may be substituted with one or more substituents selected from _RL .

R _NB and _{R C} 'is preferably hydrogen, _{R D'} is preferably in each case independently selected from _{R E.} More preferably, _RD ′ is independently in each case, and in each case independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _3- C ₆ carbon. C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from the ring or a 3- to 6-membered heterocycle; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl. Selected from the ring.

_RA is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or C _1- C ₆ alkyl, C _2- C ₆ alkyne or independently each case halogen. , hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, optionally substituted by one or more substituents selected from formyl or cyano C ₂ -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl ; or _{-L A -O-R S, -L} A -S-R S, -L A -C (O) R S, -L A -OC (O) R S, -L A -C (O) _{OR S, -L A -N (R} S R S '), - L A -S (O) R S, -L A -SO 2 R S, -L A -C (O) N (R S R S _{'), - L A -N (} R S) C (O) R S', -L A -N (R S) C (O) N (R S 'R S "), - L A -N (R _{S) SO 2 R S ',} -L A -SO 2 N (R S R S'), - L A -N (R S) SO 2 N (R S 'R S "), - L A -N ( _{R S) S (O) N} (R S 'R S "), - L A -OS (O) -R S, -L A -OS (O) 2 -R S, -L A -S (O) _{2 OR S, -L A -S (} O) OR S, -L A -OC (O) OR S, -L A -N (R S) C (O) OR S ', -L A -OC (O _{) N (R S R S '} ), - L A -N (R S) S (O) -R S', -L A -S (O) N (R S R S ') or _-L A -C _(O) a N (R S) C (O ) -R S ', L a is a _bond, C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or A C ₂ -C ₆ alkynylene.

More preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from phosphonoxy, phosphono, tioxo, formyl or cyano; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C ₂ −C ₆ haloalkenyl or C ₂ −C ₆ haloalkynyl. It is a ring.

Very preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo. a phosphonoxy, phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl selected from formyl or cyano.

L _S, with _{L S} 'and _{L S} "each case preferably each independently, a bond; or _C 1 -C _{6 alkylene,} is selected from C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene.

A and B can be the same or different. Similarly, L ₁ and L ₂ can be the same or different.

In one embodiment of this aspect, A and B are each independently a phenyl, it may be substituted with independently 1 or more R _A; D is phenyl, optionally substituted with one or more R _A and is substituted also good, or J, 1 or more may be substituted with R _a, J is C ₃ -C ₆ carbocycle, bicyclic heterocyclic, or 6 from 3 6-membered to 12-membered an expression compound may be substituted with one or more R _a. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, Formil, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C ( O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J may also be substituted with one or more _{R a.} Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。好ましくは、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D', or -C (O) -L _{Y '-N (R B) S} (O) 2 -L S "-R D' may also be selected from, but is not limited thereto. preferably, _{R 2} and _{R 5} are those Together with the bonded atom

を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、

The forms, which one or more may be substituted by R _A; is R ₉ and R ₁₂ are integral with the atoms to which they are attached,

を形成しており、それは１以上のＲ_Ａで置換されていても良い。

Forms a, it may be substituted by one or more R _A.

In another embodiment of this embodiment, A and B are independently phenyl (eg, eg).

）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い（好ましくは、ＡおよびＢはそれぞれ独立に少なくとも１個のＦなどのハロで置換されている。）。Ｘは、

), And it is also a good (preferably substituted with independently one or more R _A, is substituted with halo, such as at least one of F A and B are each independently.). X is

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｄはフェニルであり、Ｊで置換されており、１以上のＲ_Ａで置換されていても良い。ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物、１０から１５員の三環式化合物または１３から１５員の炭素環／複素環であり、Ｊは１以上のＲ_Ａで置換されていても良い。好ましくは、Ｊは、Ｃ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物または７から１２員の炭素環／複素環で置換されており、それらは独立に（１）ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、−Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）または（２）トリメチルシリル、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓまたは−Ｃ（Ｏ）Ｒ_Ｓから選択される１以上の置換基で置換されていても良く；Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは、

In and, _{X 3} is N, _-L 3 -D are connected directly to, X may be substituted with one or more _{R A} or _{R F.} D is phenyl, substituted with J, and may be substituted with 1 or more _RA . J is a C _3- C _6- membered ring, a 3- to 6-membered heterocycle, a 6 to 12-membered bicyclic compound, a 10 to 15-membered tricyclic compound, or a 13 to 15-membered carbocycle / heterocycle. , J may be substituted with 1 or more _RA . Preferably, J is substituted with a C _3- C ₆ alkyne, a 3 to 6 membered heterocycle, a 6 to 12 membered bicyclic compound or a 7 to 12 membered alkyne / heterocycle, which are substituted. independently (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') or (2) trimethylsilyl, -O-R It may be substituted with one or more substituents selected from _S , -S- _RS or -C (O) _RS ; J may also be substituted with one or more _RA . Preferably, D is

であり、Ｊは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはＦなどのハロである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′、または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

And J is as defined above, and each _RN is independently selected from R _D , preferably a halo such as hydrogen or F. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D', or -C (O) -L _{Y '-N (R B) S} (O) 2 -L S "-R D' may also be selected from, is .R ₂ and _{R 5} is not limited thereto by bonding them A 5- to 6-membered heterocycle (eg, for example)

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, they 1 or more may be substituted by R _A; becomes R ₉ and R ₁₂ together with the atom to which they are attached, 5-6 membered heterocyclic ring (e.g. ,

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。

) Forms a, they may be substituted by one or more R _A.

In yet another aspect, the invention features acceptable salts compounds and pharmaceutically formula I _B.

式中、
Ｒ_Ｃ′はそれぞれ独立にＲ_Ｃから選択され；
Ｒ_Ｄ′はそれぞれ独立にＲ_Ｄから選択され；
Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ａ、Ｂ、Ｄ、Ｘ、Ｌ_１、Ｌ_２、Ｌ_３、Ｔ、Ｒ_Ａ、Ｒ_ＣおよびＲ_Ｄは式Ｉにおいて上記の通りである。

During the ceremony
R _C 'is selected from _{R C} independently;
R _D' is independently selected from R _D ;
R ₂ and R ₅ together with the atom to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
R ₉ and R ₁₂ together with the atoms to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
A, B, D, X, L ₁ , L ₂ , L ₃ , T, _RA , _RC and R _D are as described above in Formula I.

In this embodiment, A and B are preferably independent.

などの８から１２員の二環式化合物から選択され、Ｚ_１は独立に各場合でＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｚ_２は独立に各場合でＮまたはＣＨから選択され、Ｚ_３は独立に各場合でＮまたはＣＨから選択され、Ｚ_４は独立に各場合でＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５およびＷ_６はそれぞれ独立に各場合で、ＣＨまたはＮから選択される。ＡおよびＢはそれぞれ独立に１以上のＲ_Ａで置換されていても良い。

Selected from 8- to 12-membered bicyclic compounds such as, Z ₁ is independently selected from O, S, NH or CH ₂ in each case, Z ₂ is independently selected from N or CH in each case. Z ₃ is independently selected from N or CH in each case, Z ₄ is independently selected from O, S, NH or CH ₂ in each case, W ₁ , W ₂ , W ₃ , W ₄ , W ₅ and W ₆ is independently selected from CH or N in each case. A and B may be substituted with one or more R _A independently.

More preferably, A is

から選択され、１以上のＲ_Ａで置換されていても良く；Ｂは

It is selected from, optionally substituted by one or more R _A well; B is

から選択され、１以上のＲ_Ａで置換されていても良く、Ｚ_１、Ｚ_２、Ｚ_３、Ｚ_４、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５、Ｗ_６は上記で定義の通りである。好ましくは、Ｚ_３はＮであり、Ｚ_４はＮＨである。例えば、Ａは

It is selected from may be substituted with one or more _{R A,} defined in _{Z 1, Z 2, Z 3} , Z 4, W 1, W 2, W 3, W 4, W 5, W 6 above It is a street. Preferably, Z ₃ is N and Z ₄ is NH. For example, A

（例えば、

(For example

）または

) Or

（例えば、

(For example

）から選択することができ、１以上のＲ_Ａで置換されていても良く；Ｂは、

) Can be selected from, it may be substituted by one or more R _A; B is

（例えば、

(For example

）または

) Or

（例えば、

(For example

）から選択することができ、１以上のＲ_Ａで置換されていても良い。

) From can be chosen, it may be substituted with one or more R _A.

Preferably, A is

（例えば、

(For example

であり、Ｂは

And B is

（例えば、

(For example

であり、Ａ′およびＢ′は独立にＣ_５−Ｃ_６炭素環または５から６員の複素環から選択され、ＡおよびＢは独立に１以上のＲ_Ａで置換されていても良い。

In and, A 'and B' are selected from heterocycle C ₅ -C ₆ carbocyclic ring or 5-6 membered independently, A and B may be substituted with 1 or more independently of R _A.

More preferably, A is

であり、Ｂは

And B is

であり、ＡおよびＢは１以上のＦまたはＣｌなどのハロゲンで置換されている。Ａおよび／またはＢがハロ置換されたベンズイミダゾール（例えば、Ａが

And A and B are substituted with one or more halogens such as F or Cl. Benzimidazole in which A and / or B is halo-substituted (eg, A

であり、Ｂが

And B is

である。）である場合、式Ｉ_Ｂの化合物は、置換されていないベンズイミダゾールを有する同じ化合物と比較して、大幅に改善された薬物動態特性ならびにある種のＨＣＶ遺伝子型１ａ突然変異体に対する改善された阻害薬活性を有することができる。

Is. If) A compound of formula I _B are compared to the same compound having a benzimidazole which is not substituted, improved for greatly improved pharmacokinetic properties as well as certain HCV genotypes 1a mutants Can have inhibitory activity.

D is preferably, C ₅ -C ₆ carbocyclic ring, selected from the bicyclic compounds of the heterocyclic or 6 from 5 6 membered 12-membered, optionally substituted with one or more R _A. D is _preferably, C 1 -C _{6 alkyl,} C 2 -C ₆ can also be selected from alkenyl, or _C 2 -C ₆ alkynyl, optionally substituted with one or more substituents selected from _{R L} good. More preferably, D is _C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is optionally substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Preferably, D is phenyl, optionally substituted with one or more R _A. More preferably, D is phenyl, which is substituted with one or more R _M, is R _M is as defined above. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F.

D preferably is pyridinyl, in pyrimidinyl or thiazolyl may be substituted with one or more R _A. More preferably D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted with one or more R _M. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。Ｄは好ましくはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリルまたはインダゾリルであり、１以上のＲ_Ａで置換されていても良い。より好ましくはＤはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリル、インダゾリルまたはベンゾ［ｄ］［１，３］ジオキソール−５−イルであり、１以上のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F. D is preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, optionally substituted with one or more _{R A.} More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, which is one or more. _Replaced by RM. Very preferably D

であり、１以上のＲ_Ｍで置換されていても良い。

, And the optionally substituted with one or more R _M.

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C ₆ alkyl selected from formyl or _cyano, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl Is. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, may or halogen in each case independently, hydroxy, mercapto, optionally substituted by one or more substituents selected from amino or carboxy C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl. Very preferably, _RM is a C _1- C ₆ alkyl which may be substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, be thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond or _{C 1} -C ₆ alkylene, _{R E} is _{-N (R S R S ')} , - OR S, -C (O) R S, -C (O) OR S, -C (O) N (R _{S R S '), - N} (R S) C (O) R S', -N (R S) C (O) OR S ', -N (R S) SO 2 R S', -SO 2 R _S , -SR _S or -P (O) (OR _S ) ₂ , where _RS and _RS ′ are independently selected from each case, for example, (1) hydrogen or (2) 1 or more in each case. halogen, hydroxy, _-O-C 1 -C ₆ alkyl or 3 can be substituted with 6-membered heterocyclic ring is a good _C 1 -C ₆ alkyl; or _{R M} is _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl, halogen in each case to each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano It may be substituted with one or more substituents of choice; or the _RM is a C _3- C ₆ carbocycle or a 3 to 6 membered heterocycle, which are independently halogen, hydroxy, in each case. Mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C ₂ -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') may be substituted by one or more substituents selected from. More preferably, the _{R M} halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or _C 1 -C ₆ alkyl (e.g., methyl, isopropyl, tert- _butyl), C 2 -C ₆ alkenyl or C ₂ -C ₆ alkynyl, halogen in each case to each of which independently, hydroxy, mercapto, amino, optionally substituted by one or more substituents selected from cyano or carboxy. For example _{R M is, CF 3, -C (CF 3} ) 2 -OH, -C (CH 3) 2 -CN, -C (CH 3) 2 -CH 2 OH or _{-C (CH} 3) 2 -CH ₂ It is NH ₂ . Preferably _{R M} is _{-L S} -R _{E, L} S is a bond, _{R E} is _{-N (R S R S ')} , - O-R S, -N (R S) C (O) _{oR S ', -N (R S} ) SO 2 R S', a _-SO 2 _{R S,} or -SR _S. For example, if _{L S} is a bond, _{R E} is -N _(C 1 -C _{6 alkyl) 2 (e.g., -NMe 2); - N (} C 1 -C 6 alkylene _-O-C 1 -C ₆ alkyl ) ₂ (eg -N (CH ₂ CH ₂ OME) ₂ ); -N (C _1- C ₆ alkyl) (C _1- C ₆ alkylene-OC _1- C ₆ alkyl) (eg -N (CH ₃₎ ) (CH ₂ CH ₂ OMe)); -O-C _1- C ₆ alkyl (eg, -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -On-hexyl _{); - O-C 1 -C} 6 haloalkyl _{(e.g., -OCF 3, -OCH 2 CF 3} ); - O-C 1 -C 6 alkylene - piperidine (e.g., _{-O-CH 2} CH ₂ -1- piperidyl ); -N (C _1- C ₆ alkyl) C (O) OC _1- C ₆ alkyl (for example, -N (CH ₃ ) C (O) O-CH ₂ CH (CH ₃ ) ₂ ), -N ( C _1- C ₆ alkyl) SO ₂ C _1- C ₆ alkyl (eg -N (CH ₃ ) SO ₂ CH ₃ ); -SO ₂ C _1- C ₆ alkyl (eg -SO ₂ Me); -SO ₂ C ₁ -C ₆ haloalkyl _(e.g., -SO 2 _CF 3); a or _-S-C 1 -C ₆ haloalkyl (e.g., SCF _3). Preferably _{R M} is _{-L S} -R _{E, L} S is _C 1 -C ₆ alkylene _{(e.g., -CH 2 -, - C (} CH 3) 2 -, - C (CH 3) 2 -CH 2 - _a), R _E is _{-O-R S, -C (O} ) oR S, -N (R S) C (O) oR S ' or _{-P (O) (oR S)} 2. For example _{R M} is _-C 1 -C ₆ alkylene _{-O-R S (e.g., -C (CH 3) 2 -CH} 2 -OMe); - C 1 -C 6 alkylene -C (O) OR _S (e.g., _{-C (CH 3) 2 -C (} O) OMe); - C 1 -C 6 alkylene _{-N (R S) C (O} ) OR S '( _{e.g., -C (CH 3) 2 -CH} 2 -NHC (O) OCH ₃ ); or -C _1- C ₆ alkylene-P (O) (OR _S ) ₂ (for example, -CH _2- P (O) (OEt) ₂ ). More preferably, R _M is a heterocyclic ring 6 membered C ₃ -C ₆ carbocycle or 3, halogens each case in each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , Thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl , -C (O) OR _S or -N ( _RS R _S ') may be substituted with one or more substituents selected from. For example _{R M} is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-1-methylcyclopropyl pro-flops 1-yl, cyclohexyl), phenyl, heterocycle (e.g., morpholin-4-yl, 1,1-di Oxidethiomorpholine-4-yl, 4-methylpiperazine-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidine-1-yl, piperidine-1-yl, 4-methylpiperidine-1-yl, 3, 5-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridine-3-yl, 6- (dimethylamino) pyridine-3-yl). Very preferably, _{R M} is _C 1 -C ₆ alkyl, which is halogen, hydroxy, mercapto, amino or carboxy (e.g., tert- butyl, CF ₃₎ optionally substituted with one or more substituents selected from You may.

More preferably, D is C ₅ -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is substituted with J, optionally substituted with one or more R _A at best, J is C ₃ -C ₆ carbocycle, a bicyclic compound of the heterocycle or 6 from 3 6 membered to 12-membered, optionally substituted with one or more R _a. Preferably, J is substituted with C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, wherein the C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring independently halogen, hydroxy, mercapto , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J is also 1 It may be replaced with the above _RA . Preferably, D is a heterocyclic 6-membered _C 5 -C ₆ carbocyclic ring or 5 is substituted with J, may be substituted by one or more _{R A,} J is _C 3 -C ₆ a heterocyclic 6-membered carbocyclic or 3, may be substituted by one or more R _a, and preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring cage, it is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, substituted by C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, 1 or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') It may have been done. Preferably, D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring is substituted with J, it may be substituted by one or more R _A, J 6 to 12-membered Bicyclic compounds (eg, 7-12 member condensed, crosslinked or spirobicyclic compounds containing a nitrogen ring atom intervening in J's covalent bond to D), one or more _RAs. It may be replaced with. More preferably, D is phenyl, is substituted with J, may be substituted by one or more R _A, J from C ₃ -C ₆ carbocycle, 3-6 membered heterocyclic, or 6 bicyclic compounds of 12 members may be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, they Independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, optionally substituted with one or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') You may. Very preferably D

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbon ring, a 3 to 6 member heterocycle or a 6 to 12 member bicyclic compound. , and the it may optionally be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, halogen them independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl, _{C 2} -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') with one or more substituents selected from optionally substituted. Preferably D is

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、Ｃ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbocycle or a 3 to 6 member heterocycle and a C _3- C ₆ carbocycle. or 3 is substituted with from 6 membered heterocyclic ring, they are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or -N _{(R S} R S It may be substituted with one or more substituents selected from ′), and J may also be substituted with one or more _RA . Preferably D is

であり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。

In it, J is a heterocyclic ring 6 membered _C 3 -C ₆ carbocycle or 3, may be substituted by one or more _{R A,} preferably J is at least _C 3 -C ₆ carbocycle or 3 is substituted with 6-membered heterocycle, they independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl, _{C 2} - C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ halo alkynyl, C (O) OR _S or -N ( _RS R _S ') It may be substituted with one or more substituents selected from.

X is _preferably, C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6-membered 12-membered (e.g.,

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｘの例は上記で記載されているが、それらに限定されるものではない。

X ₃ is N and is directly connected to −L ₃₋ D. ), And it may be substituted with one or more R _A or R _F. Examples of X are described above, but are not limited thereto.

L ₁ and L ₂ are preferably independently bonded or C _1- C ₆ alkylene, and L ₃ is preferably selected from bonded, C _1- C ₆ alkylene or -C (O)-, L ₁ , L ₂ And L ₃ may each be independently substituted with one or more _RL . More preferably, L ₁ , L ₂ and L ₃ are independently bound or C ₁ −C ₆ alkylene (eg, −CH _2- or − CH ₂ CH _2- ), respectively, and each independently has one or more _RLs. It may be replaced with. Very preferably, L ₁ , L ₂ and L ₃ are bonds.

R ₂ and R ₅ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。

) Forms a, they may be substituted by one or more R _A.

R ₉ and R ₁₂ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。

) Forms a, it may be substituted by one or more R _A.

_{-T-R D} 'is _-C in each case independently _{(O) -L Y' -R D} ', -C (O) O-L Y' -R D ', -C (O) -L Y' _{-N (R B) C (O} ) -L S "-R D ', -C (O) -L Y' -N (R B) C (O) O-L S" -R D ', -N _{(R B) C (O)} -L Y '-N (R B) C (O) -L S "-R D', -N (R B) C (O) -L Y '-N (R B _{) C (O) O-L} S "-R D ' or _{-N (R B) C (O} ) -L Y' -N (R B) -L S" may be selected from -R _D ' but not limited to, _{L Y} 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。より好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。非常に好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′は好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

), And may be substituted with one or more substituents selected from _RL . Preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -M'-L S "-R D ' or _{-N (R B) C (O} ) -L Y It is selected from the _{'-M'-L S "-R D} '. More preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) It is selected from _{-L Y '-N (R B)} C (O) O-L S "-R D'. Very preferably, _{-T-R D} 'is each case _{independently, -C (O) -L Y'} -N (R B) C (O) -R D ' or -C (O) -L _Y It is selected from the _{'-N (R B) C (} O) O-R D', L Y ' is _C 1 -C ₆ alkylene, preferably each independently (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。

), And may be substituted with one or more substituents selected from _RL .

_RC ′ is preferably hydrogen and _RD ′ is preferably independently selected from R _E in each case. More preferably, _RD ′ is independently in each case, and in each case independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _3- C ₆ carbon. C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from the ring or a 3- to 6-membered heterocycle; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl. Selected from the ring.

_RA is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or C _1- C ₆ alkyl, C _2- C ₆ alkyne or independently each case halogen. , hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, optionally substituted by one or more substituents selected from formyl or cyano C ₂ -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl ; or _{-L A -O-R S, -L} A -S-R S, -L A -C (O) R S, -L A -OC (O) R S, -L A -C (O) _{OR S, -L A -N (R} S R S '), - L A -S (O) R S, -L A -SO 2 R S, -L A -C (O) N (R S R S _{'), - L A -N (} R S) C (O) R S', -L A -N (R S) C (O) N (R S 'R S "), - L A -N (R _{S) SO 2 R S ',} -L A -SO 2 N (R S R S'), - L A -N (R S) SO 2 N (R S 'R S "), - L A -N ( _{R S) S (O) N} (R S 'R S "), - L A -OS (O) -R S, -L A -OS (O) 2 -R S, -L A -S (O) _{2 OR S, -L A -S (} O) OR S, -L A -OC (O) OR S, -L A -N (R S) C (O) OR S ', -L A -OC (O _{) N (R S R S '} ), - L A -N (R S) S (O) -R S', -L A -S (O) N (R S R S ') or _-L A -C _(O) a N (R S) C (O ) -R S ', L a is a _bond, C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or A C ₂ -C ₆ alkynylene.

More preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from phosphonoxy, phosphono, tioxo, formyl or cyano; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C ₂ −C ₆ haloalkenyl or C ₂ −C ₆ haloalkynyl. It is a ring.

Very preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo. a phosphonoxy, phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl selected from formyl or cyano.

L _S, with _{L S} 'and _{L S} "each case preferably each independently, a bond; or _C 1 -C _{6 alkylene,} is selected from C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene.

A and B can be the same or different. Similarly, L ₁ and L ₂ can be the same or different.

In one embodiment of this aspect, A

であり、１以上のＲ_Ａで置換されていても良く；Ｂは

, And the may optionally be substituted with one or more R _A; B is

であり、１以上のＲ_Ａで置換されていても良く；ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えばフェニル）であり、１以上のＲ_Ａで置換されていても良くまたはＪで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

, And the it may optionally be substituted with one or more R _A; D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g. phenyl), optionally substituted with one or more R _A is substituted with even better or J, may be substituted by one or more R _a, J is C ₃ -C ₆ carbocycle, bicyclic compound from 3 to 6-membered heterocyclic ring or 6-12 membered , and the optionally substituted with one or more R _a. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, Formil, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C ( O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J may also be substituted with one or more _{R a.} Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｚ_１は独立に各場合で、Ｏ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は独立に各場合で、ＮまたはＣＨから選択される。好ましくは、Ａは

And J and _RN are as defined above. Z ₁ is independently selected from O, S, NH or CH ₂ in each case; Z ₂ is independently selected from N or CH in each case. Preferably, A is

であり、Ｂは

And B is

であり、ＡおよびＢは１以上のＦまたはＣｌなどのハロゲンで置換されている。Ａおよび／またはＢがハロ置換されたベンズイミダゾール（例えば、Ａが

And A and B are substituted with one or more halogens such as F or Cl. Benzimidazole in which A and / or B is halo-substituted (eg, A

であり、Ｂが

And B is

である。）である場合、この実施形態の化合物置換されていないベンズイミダゾールを有する同じ化合物と比較して、大幅に改善された薬物動態特性ならびにある種のＨＣＶ遺伝子型１ａ突然変異体に対する改善された阻害薬活性を有することができる。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。

Is. ), Significantly improved pharmacokinetic properties as well as improved inhibitors for certain HCV genotype 1a mutants as compared to the same compound with unsubstituted benzimidazole in this embodiment. Can have activity. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D' or -C (O) -L _{Y '-N (R B) S (} O) 2 -L S "-R D' may also be selected from, but is not limited thereto.

In another embodiment of this aspect, A

であり、１以上のＲ_Ａ（例えば、ハロゲン）で置換されていても良く；Ｂは、

, And the one or more R _{A (e.g.,} halogen) may be substituted by; B is,

であり、１以上のＲ_Ａ（例えば、ハロゲン）で置換されていても良く；ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であり、１以上のＲ_Ａで置換されていても良くまたはＪで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

, And the one or more _{R A} (e.g., halogen) may be substituted with; is D is _C 5 -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl), one or more R substituted by _a is substituted by is good or J, may be substituted by one or more R _a, J from C ₃ -C ₆ carbocycle, 3-6 membered heterocyclic, or 6 12 bicyclic compounds of personnel, may be substituted with one or more R _a. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, Formil, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C ( O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J may also be substituted with one or more _{R a.} Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは、

And _RM and _RN are as defined above. Preferably, D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ａおよび／またはＢがハロ置換されたベンズイミダゾール（例えば、Ａが

And J and _RN are as defined above. Benzimidazole in which A and / or B is halo-substituted (eg, A

であり、Ｂが

And B is

である。）である場合、この実施形態の化合物は、置換されていないベンズイミダゾールを有する同じ化合物と比較して、大幅に改善された薬物動態特性ならびにある種のＨＣＶ遺伝子型１ａ突然変異体に対する改善された阻害薬活性を有することができる。Ｌ_１およびＬ_２はそれぞれ独立にであり結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、好ましくは５から６員の複素環または６から１２員の二環式化合物（例えば、

Is. ), The compound of this embodiment has significantly improved pharmacokinetic properties as well as improved for certain HCV genotype 1a mutants as compared to the same compound having benzimidazole intact. Can have inhibitory activity. L ₁ and L ₂ are independent and are bonded or C _1- C ₆ alkylene, respectively, and L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, L ₁ , L ₂ and L. Each of ₃ may be independently substituted with 1 or more _RL . Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D' or -C (O) -L _{Y '-N (R B) S (} O) 2 -L S "-R D' may also be selected from, is .R ₂ and _{R 5} are not limited to these are attached they Together with the atom, preferably a 5- to 6-membered heterocyclic ring or a 6 to 12-membered bicyclic compound (eg,

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、好ましくは５から６員の複素環または６から１２員の二環式化合物（例えば、

) Forms a, they may be substituted by one or more R _A. R ₉ and R ₁₂ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。より好ましくは、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、

) Forms a, they may be substituted by one or more R _A. More preferably, R ₂ and R ₅ are integrated with the atom to which they are bonded,

を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、

The forms, which one or more may be substituted by R _A; is R ₉ and R ₁₂ are integral with the atoms to which they are attached,

を形成しており、それは１以上のＲ_Ａで置換されていても良い。

Forms a, it may be substituted by one or more R _A.

In yet another embodiment of this aspect, A

であり、１以上のＲ_Ａで置換されていても良く（好ましくは、Ａは少なくとも１個のＦなどのハロゲンで置換されている。）；Ｂは

, And the it may optionally be substituted with one or more R _A (preferably, A is substituted by halogen, such as at least one of F.); B is

であり、１以上のＲ_Ａで置換されていても良い（好ましくは、Ｂは少なくとも１個のＦなどのハロゲンで置換されている。）。Ｘは

, And the optionally substituted with one or more R _A (preferably, B is substituted by halogen, such as at least one of F.). X is

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｄはフェニルであり、Ｊで置換されており、１以上のＲ_Ａで置換されていても良い。ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物、１０から１５員の三環式化合物または１３から１５員の炭素環／複素環であり、Ｊは１以上のＲ_Ａで置換されていても良い。好ましくは、Ｊは、Ｃ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物または７から１２員の炭素環／複素環で置換されており、それらは独立に（１）ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、−Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）または（２）トリメチルシリル、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓまたは−Ｃ（Ｏ）Ｒ_Ｓから選択される１以上の置換基で置換されていても良く；Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは、

In and, _{X 3} is N, _-L 3 -D are connected directly to, X may be substituted with one or more _{R A} or _{R F.} D is phenyl, substituted with J, and may be substituted with 1 or more _RA . J is a C _3- C _6- membered ring, a 3- to 6-membered heterocycle, a 6 to 12-membered bicyclic compound, a 10 to 15-membered tricyclic compound, or a 13 to 15-membered carbocycle / heterocycle. , J may be substituted with 1 or more _RA . Preferably, J is substituted with a C _3- C ₆ alkyne, a 3 to 6 membered heterocycle, a 6 to 12 membered bicyclic compound or a 7 to 12 membered alkyne / heterocycle, which are substituted. independently (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') or (2) trimethylsilyl, -O-R It may be substituted with one or more substituents selected from _S , -S- _RS or -C (O) _RS ; J may also be substituted with one or more _RA . Preferably, D is

であり、Ｊは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはＦなどのハロである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、好ましくは５から６員の複素環または６から１２員の二環式化合物（例えば、

And J is as defined above, and each _RN is independently selected from R _D , preferably a halo such as hydrogen or F. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D' or -C (O) -L _{Y '-N (R B) S (} O) 2 -L S "-R D' may also be selected from, is .R ₂ and _{R 5} are not limited to these are attached they Together with the atom, preferably a 5- to 6-membered heterocyclic ring or a 6 to 12-membered bicyclic compound (eg,

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く、Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、好ましくは５から６員の複素環または６から１２員の二環式化合物（例えば、

) Forms a, they may be substituted by one or more R _A, together with the atom to which R ₉ and R ₁₂ are attached they preferably 5-6 membered heterocyclic ring Or a 6 to 12 member bicyclic compound (eg,

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。より好ましくは、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、

) Forms a, they may be substituted by one or more R _A. More preferably, R ₂ and R ₅ are integrated with the atom to which they are bonded,

を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、

The forms, which one or more may be substituted by R _A; is R ₉ and R ₁₂ are integral with the atoms to which they are attached,

を形成しており、それは１以上のＲ_Ａで置換されていても良い。

Forms a, it may be substituted by one or more R _A.

Unexpectedly the present invention, the compounds according to aspect (preferably of the present invention there is provided a salt which is acceptable compound or a pharmaceutically formula I _B, A are

であり、Ｂが

And B is

であり、ＡおよびＢが独立に１以上のハロなどの１以上のＲ_Ａで置換されていても良いもの）が、異なるＨＣＶ遺伝子型および変異株に対する大幅に改善された活性を示すことが認められた。例えば、安定な細胞系における異なる遺伝子型のＨＣＶレプリコンに対して調べた場合に（５％ＦＢＳ存在下）、米国特許出願公開番号第２０１０／０３１７５６８号の実施例３７と比較して、実施例３．４８、３．５２、４．３８および５．１の化合物のＥＣ_５０値は、遺伝子型１ａに対しては実施例３７と比較して少なくとも約１／６であり、遺伝子型３ａに対しては少なくとも約１／３であり、遺伝子型６ａに対しては少なくとも約１／５０であり、遺伝子型２ａに対してはかなり低かった。さらに、一時トランスフェクションアッセイである種のＮＳ５Ａ突然変異を含むＨＣＶ遺伝子型１ａレプリコン二対して調べた場合に、そして米国特許出願公開番号第２０１０／０３１７５６８号の実施例３７と比較して、実施例３．４８、３．５２、４．３８および５．１の化合物のＥＣ_５０値は、Ｌ３１Ｖ変異株に対して実施例３７の少なくとも約１／１３０、Ｍ２８Ｔ変異株に対して少なくとも約１／７，５００、Ｍ２８Ｖ変異株に対して少なくとも約１／８０、Ｑ３０Ｅ変異株に対して少なくとも約１／５００、Ｑ３０Ｒ変異株に対して少なくとも約１／３００、Ｙ９３Ｃ変異株に対して少なくとも約１／８００、Ｙ９３Ｈ変異株に対して少なくとも約１／１，５００であり、Ｑ３０Ｈ変異株に対して大幅に低かった。同様に、一時トランスフェクションアッセイにおけるある種のＮＳ５Ａ突然変異を含むＨＣＶ遺伝子型１ｂレプリコンに対して試験を行う場合、そして米国特許出願公開番号第２０１０／０３１７５６８号の実施例３７と比較して、実施例５．１の化合物のＥＣ_５０値は、Ｙ９３Ｈ変異株に対して、実施例３７の少なくとも約１／１０であった。

In and, A and B are independently one or more halo, such as 1 or more of R _A may be substituted with a) is found to exhibit significantly improved activity against different HCV genotypes and mutant Was done. For example, when examined against different genotypes of HCV replicon in a stable cell line (in the presence of 5% FBS), Example 3 as compared to Example 37 of US Patent Application Publication No. 2010/0317568. The EC ₅₀ values of the compounds of .48, 3.52, 4.38 and 5.1 are at least about 1/6 for genotype 1a compared to Example 37 and for genotype 3a. Was at least about 1/3, at least about 1/50 for genotype 6a, and significantly lower for genotype 2a. In addition, when examined against HCV genotype 1a replicon containing certain NS5A mutations in a transient transfection assay, and in comparison to Example 37 of US Patent Application Publication No. 2010/0317568, Examples The EC ₅₀ values of the compounds of 3.48, 3.52, 4.38 and 5.1 were at least about 1/130 of Example 37 for the L31V mutant and at least about 1/7 for the M28T mutant. , 500, at least about 1/80 for the M28V mutant, at least about 1/500 for the Q30E mutant, at least about 1/300 for the Q30R mutant, at least about 1/800 for the Y93C mutant , At least about 1/1500 for the Y93H mutant, which was significantly lower for the Q30H mutant. Similarly, when testing against HCV genotype 1b replicon containing certain NS5A mutations in a transient transfection assay, and compared to Example 37 of US Patent Application Publication No. 2010/0317568. The EC ₅₀ value of the compound of Example 5.1 was at least about 1/10 of that of Example 37 with respect to the Y93H mutant.

Therefore, the present invention features methods of treating different HCV genotype or mutant strain infections. The method, HCV genotype 1a, 1b, 2a, 2b, 3a, 4a, for one to infected patients of 5a or 6a in infected patients or the mutant, the compounds of formula _{I B} or Includes administration of pharmaceutically acceptable salts thereof. Preferably, A is

であり、Ｂは

And B is

であり、ＡおよびＢは独立に１以上のハロなどの１以上のＲ_Ａで置換されていても良い。本発明のこの態様に記載の他の化合物または本態様下の実施形態、ならびに下記の実施例中の標題化合物も用いることができる。１実施形態において、治療を受ける患者はＨＣＶ遺伝子型１（１ａなど）に感染している。別の実施形態において、治療を受ける患者はＨＣＶ遺伝子型２（２ａなど）に感染している。さらに別の実施形態において、治療を受ける患者はＨＣＶ遺伝子型３（３ａなど）に感染している。別の実施形態において、治療を受ける患者はＨＣＶ遺伝子型４（４ａなど）に感染している。さらに別の実施形態において、治療を受ける患者はＨＣＶ遺伝子型５（５ａなど）に感染している。さらに別の実施形態において、治療を受ける患者はＨＣＶ遺伝子型６（６ａなど）に感染している。

In and, A and B may be substituted with one or more R _A, such as one or more independently halo. Other compounds described in this aspect of the invention or embodiments under this aspect, as well as the title compound in the Examples below, can also be used. In one embodiment, the patient being treated is infected with HCV genotype 1 (1a, etc.). In another embodiment, the patient being treated is infected with HCV genotype 2 (such as 2a). In yet another embodiment, the patient being treated is infected with HCV genotype 3 (such as 3a). In another embodiment, the patient being treated is infected with HCV genotype 4 (such as 4a). In yet another embodiment, the patient being treated is infected with HCV genotype 5 (eg, 5a). In yet another embodiment, the patient being treated is infected with HCV genotype 6 (such as 6a).

In yet another aspect, the present invention is further characterized acceptable salts compounds and their pharmaceutically formula I _C.

式中、
Ｒ_ＮＢはＲ_Ｂであり；
Ｒ_Ｃ′はそれぞれ独立にＲ_Ｃから選択され；
Ｒ_Ｄ′はそれぞれ独立にＲ_Ｄから選択され；
Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ａ、Ｂ、Ｄ、Ｘ、Ｌ_１、Ｌ_２、Ｌ_３、Ｔ、Ｒ_Ａ、Ｒ_Ｂ、Ｒ_ＣおよびＲ_Ｄは式Ｉにおいて上記の通りである。

During the ceremony
R _NB is an _{R B;}
R _C 'is selected from _{R C} independently;
R _D' is independently selected from R _D ;
R ₂ and R ₅ together with the atom to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
R ₉ and R ₁₂ together with the atoms to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
_{A, B, D, X,} L 1, L 2, L 3, T, R A, R B, is _{R C} and _{R D} are as described above for Formula I.

In this embodiment, A is preferably C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring may be substituted by one or more R _A, B is preferably a 12-membered to 8 bicyclic Formula compound (

など）であり、１以上のＲ_Ａで置換されていても良い。Ｚ_１は、Ｏ、Ｓ、ＮＨまたはＣＨ_２であり；Ｚ_２はＮまたはＣＨであり；Ｚ_３はＮまたはＣＨであり；Ｚ_４はＯ、Ｓ、ＮＨまたはＣＨ_２であり；Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５およびＷ_６はそれぞれ独立に、ＣＨまたはＮから選択される。

A, etc.), it may be substituted with one or more R _A. Z ₁ is O, S, NH or CH ₂ ; Z ₂ is N or CH; Z ₃ is N or CH; Z ₄ is O, S, NH or CH ₂ ; W ₁ , W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are independently selected from CH or N, respectively.

More preferably, A is phenyl (eg,

）であり、１以上のＲ_Ａで置換されていても良く；Ｂは

), And it may be substituted by one or more R _A; B is

であり、１以上のＲ_Ａで置換されていても良く、Ｚ_１、Ｚ_２、Ｚ_３、Ｚ_４、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５、Ｗ_６は上記で定義の通りである。好ましくは、Ｚ_３はＮであり、Ｚ_４はＮＨである。例えば、Ｂは

, And the may optionally be substituted with one or more _{R A,} of _{Z 1, Z 2, Z 3} , Z 4, W 1, W 2, W 3, W 4, W 5, W 6 are defined above It's a street. Preferably, Z ₃ is N and Z ₄ is NH. For example, B

（例えば、

(For example

）または

) Or

（例えば、

(For example

）であり、１以上のＲ_Ａで置換されていても良い。

), And may be substituted with 1 or more _RA .

Preferably, A is _C 5 -C ₆ carbocyclic (e.g.,

などのフェニル）または５から６員の複素環であり；Ｂは

Phenyl) or a 5- to 6-membered heterocycle; B is

（例えば、

(For example

）であり、Ｂ′はＣ_５−Ｃ_６炭素環または５から６員の複素環から選択される。ＡおよびＢは独立に１以上のＲ_Ａで置換されていても良い。

), And, B 'is selected from a heterocyclic 6-membered from _C 5 -C ₆ carbocyclic ring or 5. A and B may be substituted with 1 or more independently of R _A.

D is preferably, C ₅ -C ₆ carbocyclic ring, selected from the bicyclic compounds of the heterocyclic or 6 from 5 6 membered 12-membered, optionally substituted with one or more R _A. D is _preferably, C 1 -C _{6 alkyl,} C 2 -C ₆ can also be selected from alkenyl, or _C 2 -C ₆ alkynyl, optionally substituted with one or more substituents selected from _{R L} good. More preferably, D is _C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is optionally substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Preferably, D is phenyl, optionally substituted with one or more R _A. More preferably, D is phenyl, which is substituted with one or more R _M, is R _M is as defined above. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F.

D preferably is pyridinyl, in pyrimidinyl or thiazolyl may be substituted with one or more R _A. More preferably D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted with one or more R _M. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。Ｄは好ましくはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリルまたはインダゾリルであり、１以上のＲ_Ａで置換されていても良い。より好ましくはＤはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリル、インダゾリルまたはベンゾ［ｄ］［１，３］ジオキソール−５−イルであり、１以上のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F. D is preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, optionally substituted with one or more _{R A.} More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, which is one or more. _Replaced by RM. Very preferably D

であり、１以上のＲ_Ｍで置換されていても良い。

, And the optionally substituted with one or more R _M.

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C ₆ alkyl selected from formyl or _cyano, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl Is. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, may or halogen in each case independently, hydroxy, mercapto, optionally substituted by one or more substituents selected from amino or carboxy C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl. Very preferably, _RM is a C _1- C ₆ alkyl which may be substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, be thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond or _{C 1} -C ₆ alkylene, _{R E} is _{-N (R S R S ')} , - OR S, -C (O) R S, -C (O) OR S, -C (O) N (R _{S R S '), - N} (R S) C (O) R S', -N (R S) C (O) OR S ', -N (R S) SO 2 R S', -SO 2 R _S , -SR _S or -P (O) (OR _S ) ₂ , where _RS and _RS ′ are independently selected from each case, for example, (1) hydrogen or (2) 1 or more in each case. halogen, hydroxy, _-O-C 1 -C ₆ alkyl or 3 can be substituted with 6-membered heterocyclic ring is a good _C 1 -C ₆ alkyl; or _{R M} is _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl, halogen in each case to each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano It may be substituted with one or more substituents of choice; or the _RM is a C _3- C ₆ carbocycle or a 3 to 6 membered heterocycle, which are independently halogen, hydroxy, in each case. Mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C ₂ -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') may be substituted by one or more substituents selected from. More preferably, the _{R M} halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or _C 1 -C ₆ alkyl (e.g., methyl, isopropyl, tert- _butyl), C 2 -C ₆ alkenyl or C ₂ -C ₆ alkynyl, halogen in each case to each of which independently, hydroxy, mercapto, amino, optionally substituted by one or more substituents selected from cyano or carboxy. For example _{R M is, CF 3, -C (CF 3} ) 2 -OH, -C (CH 3) 2 -CN, -C (CH 3) 2 -CH 2 OH or _{-C (CH} 3) 2 -CH ₂ It is NH ₂ . Preferably _{R M} is _{-L S} -R _{E, L} S is a bond, _{R E} is _{-N (R S R S ')} , - O-R S, -N (R S) C (O) _{oR S ', -N (R S} ) SO 2 R S', a _-SO 2 _{R S,} or -SR _S. For example, if _{L S} is a bond, _{R E} is -N _(C 1 -C _{6 alkyl) 2 (e.g., -NMe 2); - N (} C 1 -C 6 alkylene _-O-C 1 -C ₆ alkyl ) ₂ (eg -N (CH ₂ CH ₂ OME) ₂ ); -N (C _1- C ₆ alkyl) (C _1- C ₆ alkylene-OC _1- C ₆ alkyl) (eg -N (CH ₃₎ ) (CH ₂ CH ₂ OMe)); -O-C _1- C ₆ alkyl (eg, -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -On-hexyl _{); - O-C 1 -C} 6 haloalkyl _{(e.g., -OCF 3, -OCH 2 CF 3} ); - O-C 1 -C 6 alkylene - piperidine (e.g., _{-O-CH 2} CH ₂ -1- piperidyl ); -N (C _1- C ₆ alkyl) C (O) OC _1- C ₆ alkyl (for example, -N (CH ₃ ) C (O) O-CH ₂ CH (CH ₃ ) ₂ ), -N ( C _1- C ₆ alkyl) SO ₂ C _1- C ₆ alkyl (eg -N (CH ₃ ) SO ₂ CH ₃ ); -SO ₂ C _1- C ₆ alkyl (eg -SO ₂ Me); -SO ₂ C ₁ -C ₆ haloalkyl _(e.g., -SO 2 _CF 3); a or _-S-C 1 -C ₆ haloalkyl (e.g., SCF _3). Preferably _{R M} is _{-L S} -R _{E, L} S is _C 1 -C ₆ alkylene _{(e.g., -CH 2 -, - C (} CH 3) 2 -, - C (CH 3) 2 -CH 2 - _a), R _E is _{-O-R S, -C (O} ) oR S, -N (R S) C (O) oR S ' or _{-P (O) (oR S)} 2. For example _{R M} is _-C 1 -C ₆ alkylene _{-O-R S (e.g., -C (CH 3) 2 -CH} 2 -OMe); - C 1 -C 6 alkylene -C (O) OR _S (e.g., _{-C (CH 3) 2 -C (} O) OMe); - C 1 -C 6 alkylene _{-N (R S) C (O} ) OR S '( _{e.g., -C (CH 3) 2 -CH} 2 -NHC (O) OCH ₃ ); or -C _1- C ₆ alkylene-P (O) (OR _S ) ₂ (for example, -CH _2- P (O) (OEt) ₂ ). More preferably, R _M is a heterocyclic ring 6 membered C ₃ -C ₆ carbocycle or 3, halogens each case in each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , Thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl , -C (O) OR _S or -N ( _RS R _S ') may be substituted with one or more substituents selected from. For example _{R M} is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-1-methylcyclopropyl pro-flops 1-yl, cyclohexyl), phenyl, heterocycle (e.g., morpholin-4-yl, 1,1-di Oxidethiomorpholine-4-yl, 4-methylpiperazine-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidine-1-yl, piperidine-1-yl, 4-methylpiperidine-1-yl, 3, 5-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridine-3-yl, 6- (dimethylamino) pyridine-3-yl). Very preferably, _{R M} is _C 1 -C ₆ alkyl, which is halogen, hydroxy, mercapto, amino or carboxy (e.g., tert- butyl, CF ₃₎ optionally substituted with one or more substituents selected from You may.

More preferably, D is C ₅ -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is substituted with J, optionally substituted with one or more R _A at best, J is C ₃ -C ₆ carbocycle, a bicyclic compound of the heterocycle or 6 from 3 6 membered to 12-membered, optionally substituted with one or more R _a. Preferably, J is substituted with C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, wherein the C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring independently halogen, hydroxy, mercapto , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J is also 1 It may be replaced with the above _RA . Preferably, D is a heterocyclic 6-membered _C 5 -C ₆ carbocyclic ring or 5 is substituted with J, may be substituted by one or more _{R A,} J is _C 3 -C ₆ a heterocyclic 6-membered carbocyclic or 3, may be substituted by one or more R _a, and preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring cage, it is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, substituted by C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, 1 or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') It may have been done. Preferably, D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring is substituted with J, it may be substituted by one or more R _A, J 6 to 12-membered Bicyclic compounds (eg, 7-12 member condensed, crosslinked or spirobicyclic compounds containing a nitrogen ring atom intervening in J's covalent bond to D), one or more _RAs. It may be replaced with. More preferably, D is phenyl, is substituted with J, may be substituted by one or more R _A, J from C ₃ -C ₆ carbocycle, 3-6 membered heterocyclic, or 6 bicyclic compounds of 12 members may be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, they Independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, optionally substituted with one or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') You may. Very preferably D

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbon ring, a 3 to 6 member heterocycle or a 6 to 12 member bicyclic compound. , and the it may optionally be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, halogen them independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl, _{C 2} -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') with one or more substituents selected from optionally substituted. Preferably D is

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、Ｃ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbocycle or a 3 to 6 member heterocycle and a C _3- C ₆ carbocycle. or 3 is substituted with from 6 membered heterocyclic ring, they are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or -N _{(R S} R S It may be substituted with one or more substituents selected from ′), and J may also be substituted with one or more _RA . Preferably D is

であり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。

In it, J is a heterocyclic ring 6 membered _C 3 -C ₆ carbocycle or 3, may be substituted by one or more _{R A,} preferably J is at least _C 3 -C ₆ carbocycle or 3 is substituted with 6-membered heterocycle, they independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl, _{C 2} - C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ halo alkynyl, C (O) OR _S or -N ( _RS R _S ') It may be substituted with one or more substituents selected from.

X is _preferably, C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6-membered 12-membered (e.g.,

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｘの例は上記で記載されているが、それらに限定されるものではない。

X ₃ is N and is directly connected to −L ₃₋ D. ), And it may be substituted with one or more R _A or R _F. Examples of X are described above, but are not limited thereto.

L ₁ and L ₂ are preferably independently bonded or C _1- C ₆ alkylene, and L ₃ is preferably selected from bonded, C _1- C ₆ alkylene or -C (O)-, L ₁ , L ₂ And L ₃ may each be independently substituted with one or more _RL . More preferably, L ₁ , L ₂ and L ₃ are independently bound or C ₁ −C ₆ alkylene (eg, −CH _2- or − CH ₂ CH _2- ), respectively, and each independently has one or more _RLs. It may be replaced with. Very preferably, L ₁ , L ₂ and L ₃ are bonds. L ₁ and L ₂ can be the same or different.

R ₂ and R ₅ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、好ましくは５から６員の複素環または６から１２員の二環式化合物（例えば、

) Forms a, they may be substituted by one or more R _A. R ₉ and R ₁₂ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。

) Forms a, it may be substituted by one or more R _A.

_{-T-R D} 'is _-C in each case independently _{(O) -L Y' -R D} ', -C (O) O-L Y' -R D ', -C (O) -L Y' _{-N (R B) C (O} ) -L S "-R D ', -C (O) -L Y' -N (R B) C (O) O-L S" -R D ', -N _{(R B) C (O)} -L Y '-N (R B) C (O) -L S "-R D', -N (R B) C (O) -L Y '-N (R B _{) C (O) O-L} S "-R D ' or _{-N (R B) C (O} ) -L Y' -N (R B) -L S" may be selected from -R _D ' but not limited to, _{L Y} 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。より好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。非常に好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′は好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

), And may be substituted with one or more substituents selected from _RL . Preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -M'-L S "-R D ' or _{-N (R B) C (O} ) -L Y It is selected from the _{'-M'-L S "-R D} '. More preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) It is selected from _{-L Y '-N (R B)} C (O) O-L S "-R D'. Very preferably, _{-T-R D} 'is each case _{independently, -C (O) -L Y'} -N (R B) C (O) -R D ' or -C (O) -L _Y It is selected from the _{'-N (R B) C (} O) O-R D', L Y ' is _C 1 -C ₆ alkylene, preferably each independently (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。

), And may be substituted with one or more substituents selected from _RL .

R _NB and _{R C} 'is preferably hydrogen, _{R D'} is preferably in each case independently selected from _{R E.} More preferably, _RD ′ is independently in each case, and in each case independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _3- C ₆ carbon. C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from the ring or a 3- to 6-membered heterocycle; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl. Selected from the ring.

_RA is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or C _1- C ₆ alkyl, C _2- C ₆ alkyne or independently each case halogen. , hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, optionally substituted by one or more substituents selected from formyl or cyano C ₂ -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl ; or _{-L A -O-R S, -L} A -S-R S, -L A -C (O) R S, -L A -OC (O) R S, -L A -C (O) _{OR S, -L A -N (R} S R S '), - L A -S (O) R S, -L A -SO 2 R S, -L A -C (O) N (R S R S _{'), - L A -N (} R S) C (O) R S', -L A -N (R S) C (O) N (R S 'R S "), - L A -N (R _{S) SO 2 R S ',} -L A -SO 2 N (R S R S'), - L A -N (R S) SO 2 N (R S 'R S "), - L A -N ( _{R S) S (O) N} (R S 'R S "), - L A -OS (O) -R S, -L A -OS (O) 2 -R S, -L A -S (O) _{2 OR S, -L A -S (} O) OR S, -L A -OC (O) OR S, -L A -N (R S) C (O) OR S ', -L A -OC (O _{) N (R S R S '} ), - L A -N (R S) S (O) -R S', -L A -S (O) N (R S R S ') or _-L A -C _(O) a N (R S) C (O ) -R S ', L a is a _bond, C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or A C ₂ -C ₆ alkynylene.

More preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from phosphonoxy, phosphono, tioxo, formyl or cyano; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C ₂ −C ₆ haloalkenyl or C ₂ −C ₆ haloalkynyl. It is a ring.

Very preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo. a phosphonoxy, phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl selected from formyl or cyano.

L _S, with _{L S} 'and _{L S} "each case preferably each independently, a bond; or _C 1 -C _{6 alkylene,} is selected from C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene.

In one embodiment of this aspect, A is phenyl, may be substituted by one or more R _A; B is

であり、１以上のＲ_Ａで置換されていても良く、Ｚ_１はＯ、Ｓ、ＮＨもしくはＣＨ_２であり；Ｚ_２はＮまたはＣＨである。ＤはＣ_５−Ｃ_６炭素環または５から６員の複素環（例えば、フェニル）であり、１以上のＲ_Ａで置換されていても良くまたはＪで置換されており、１以上のＲ_Ａで置換されていても良く、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良い。好ましくは、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

, And the may optionally be substituted with one or more _{R A, Z 1} is O, S, NH or CH _{2; Z 2} is N or CH. D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring (e.g., phenyl), and optionally substituted with one or more R _A is substituted with even better or J, one or more R _A J may be substituted with C _3- C ₆ carbocycle, 3 to 6 membered heterocycle or 6 to 12 membered bicyclic compound and may be substituted with 1 or more _RA. .. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, Formil, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C ( O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J may also be substituted with one or more _{R a.} Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。好ましくは、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D' or -C (O) -L _{Y '-N (R B) S (} O) 2 -L S "-R D' may also be selected from, but is not limited thereto. preferably, they are bonded _{R 2} and _{R 5} Together with the atom

を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、

The forms, which one or more may be substituted by R _A; is R ₉ and R ₁₂ are integral with the atoms to which they are attached,

を形成しており、それは１以上のＲ_Ａで置換されていても良い。

Forms a, it may be substituted by one or more R _A.

In another embodiment of this embodiment, A is phenyl (eg, for example.

）であり、１以上のＲ_Ａで置換されていても良く（好ましくは、Ａは少なくとも１個のＦなどのハロで置換されている。）；Ｂは

), And also may (preferably optionally substituted with one or more R _A, A is substituted with halo, such as at least one of F);. B is

であり、１以上のＲ_Ａで置換されていても良く（好ましくは、Ｂは少なくとも１個のＦなどのハロで置換されている。）。Ｘは、

, And the it may optionally be substituted with one or more R _A (preferably, B is substituted with halo, such as at least one of F.). X is

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｄはフェニルであり、Ｊで置換されており、１以上のＲ_Ａで置換されていても良い。ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物、１０から１５員の三環式化合物または１３から１５員の炭素環／複素環であり、Ｊは１以上のＲ_Ａで置換されていても良い。好ましくは、Ｊは、Ｃ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物または７から１２員の炭素環／複素環で置換されており、それらは独立に（１）ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、−Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）または（２）トリメチルシリル、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓまたは−Ｃ（Ｏ）Ｒ_Ｓから選択される１以上の置換基で置換されていても良く；Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは、

In and, _{X 3} is N, _-L 3 -D are connected directly to, X may be substituted with one or more _{R A} or _{R F.} D is phenyl, substituted with J, and may be substituted with 1 or more _RA . J is a C _3- C _6- membered ring, a 3- to 6-membered heterocycle, a 6 to 12-membered bicyclic compound, a 10 to 15-membered tricyclic compound, or a 13 to 15-membered carbocycle / heterocycle. , J may be substituted with 1 or more _RA . Preferably, J is substituted with a C _3- C ₆ alkyne, a 3 to 6 membered heterocycle, a 6 to 12 membered bicyclic compound or a 7 to 12 membered alkyne / heterocycle, which are substituted. independently (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') or (2) trimethylsilyl, -O-R It may be substituted with one or more substituents selected from _S , -S- _RS or -C (O) _RS ; J may also be substituted with one or more _RA . Preferably, D is

であり、Ｊは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはＦなどのハロである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。好ましくは、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

And J is as defined above, and each _RN is independently selected from R _D , preferably a halo such as hydrogen or F. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D' or -C (O) -L _{Y '-N (R B) S (} O) 2 -L S "-R D' may also be selected from, but is not limited thereto. preferably, they are bonded _{R 2} and _{R 5} A 5- to 6-membered heterocycle (eg, with the atom

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, they 1 or more may be substituted by R _A; becomes R ₉ and R ₁₂ together with the atom to which they are attached, 5-6 membered heterocyclic ring (e.g. ,

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。

) Forms a, they may be substituted by one or more R _A.

In yet another embodiment, the present invention features a compound of formula _ID below and a pharmaceutically acceptable salt thereof.

式中、
Ｇ_１およびＧ_２はそれぞれ独立に、Ｃ_５−Ｃ_６炭素環または５から６員の複素環から選択され、それぞれ独立に１以上のＲ_Ａで置換されていても良く；
Ｒ_Ｃ′はそれぞれ独立にＲ_Ｃから選択され；
Ｒ_Ｄ′はそれぞれ独立にＲ_Ｄから選択され；
Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、１以上のＲ_Ａで置換されていても良い３から１２員の複素環を形成しており；
Ａ、Ｂ、Ｄ、Ｘ、Ｌ_１、Ｌ_２、Ｌ_３、Ｔ、Ｒ_Ａ、Ｒ_ＣおよびＲ_Ｄは式Ｉにおいて上記の通りである。

During the ceremony
G ₁ and G ₂ are each independently, C ₅ -C ₆ is selected from heterocyclic carbocyclic or 5-6 membered, may be substituted by one or more R _A independently;
R _C 'is selected from _{R C} independently;
R _D' is independently selected from R _D ;
R ₂ and R ₅ together with the atom to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
R ₉ and R ₁₂ together with the atoms to which they are attached form one or more heterocyclic rings from R _A may be substituted with 3 12-membered;
A, B, D, X, L ₁ , L ₂ , L ₃ , T, _RA , _RC and R _D are as described above in Formula I.

In this embodiment, A and B are preferably independently, C ₅ -C ₆ is selected from heterocyclic carbocyclic or 5-6 membered, optionally substituted with one or more R _A independently. More preferably, at least one of A and B is phenyl (eg,

であり、１以上のＲ_Ａで置換されていても良い。非常に好ましくは、ＡおよびＢの両方がそれぞれ独立にフェニル（例えば、

, And the optionally substituted with one or more R _A. Very preferably, both A and B are independently phenyl (eg, for example).

）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い。

), And it may be substituted with independently 1 or more R _A.

D is preferably, C ₅ -C ₆ carbocyclic ring, selected from the bicyclic compound from 5 to 6 membered heterocyclic ring or 8-12 membered, optionally substituted with one or more R _A. D is _preferably, C 1 -C _{6 alkyl,} C 2 -C also ₆ alkenyl or _C 2 -C ₆ is selected from alkynyl, optionally substituted with one or more _{R L.} More preferably, D is _C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is optionally substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Preferably, D is phenyl, optionally substituted with one or more R _A. More preferably, D is phenyl, which is substituted with one or more R _M, is R _M is as defined above. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F.

D preferably is pyridinyl, in pyrimidinyl or thiazolyl may be substituted with one or more R _A. More preferably D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted with one or more R _M. Very preferably D

であり、Ｒ_Ｍは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素である。１以上のＲ_Ｎは好ましくはＦなどのハロであることもできる。Ｄは好ましくはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリルまたはインダゾリルであり、１以上のＲ_Ａで置換されていても良い。より好ましくはＤはインダニル、４，５，６，７−テトラヒドロベンゾ［ｄ］チアゾリル、ベンゾ［ｄ］チアゾリル、インダゾリルまたはベンゾ［ｄ］［１，３］ジオキソール−５−イルであり、１以上のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

_RM is as defined above, and each _RN is independently selected from _RD , preferably hydrogen. One or more _RNs can preferably be halos such as F. D is preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, optionally substituted with one or more _{R A.} More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, which is one or more. _Replaced by RM. Very preferably D

であり、１以上のＲ_Ｍで置換されていても良い。

, And the optionally substituted with one or more R _M.

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy , phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C ₆ alkyl selected from formyl or _cyano, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl Is. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, may or halogen in each case independently, hydroxy, mercapto, optionally substituted by one or more substituents selected from amino or carboxy C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl. Very preferably, _RM is a C _1- C ₆ alkyl which may be substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, be thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond or _{C 1} -C ₆ alkylene, _{R E} is _{-N (R S R S ')} , - OR S, -C (O) R S, -C (O) OR S, -C (O) N (R _{S R S '), - N} (R S) C (O) R S', -N (R S) C (O) OR S ', -N (R S) SO 2 R S', -SO 2 R _S , -SR _S or -P (O) (OR _S ) ₂ , where _RS and _RS ′ are independently selected from each case, for example, (1) hydrogen or (2) 1 or more in each case. halogen, hydroxy, _-O-C 1 -C ₆ alkyl or 3 can be substituted with 6-membered heterocyclic ring is a good _C 1 -C ₆ alkyl; or _{R M} is _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl, halogen in each case to each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano It may be substituted with one or more substituents of choice; or the _RM is a C _3- C ₆ carbocycle or a 3 to 6 membered heterocycle, which are independently halogen, hydroxy, in each case. Mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C ₂ -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') may be substituted by one or more substituents selected from. More preferably, the _{R M} halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or _C 1 -C ₆ alkyl (e.g., methyl, isopropyl, tert- _butyl), C 2 -C ₆ alkenyl or C ₂ -C ₆ alkynyl, halogen in each case to each of which independently, hydroxy, mercapto, amino, optionally substituted by one or more substituents selected from cyano or carboxy. For example _{R M is, CF 3, -C (CF 3} ) 2 -OH, -C (CH 3) 2 -CN, -C (CH 3) 2 -CH 2 OH or _{-C (CH} 3) 2 -CH ₂ It is NH ₂ . Preferably _{R M} is _{-L S} -R _{E, L} S is a bond, _{R E} is _{-N (R S R S ')} , - O-R S, -N (R S) C (O) _{oR S ', -N (R S} ) SO 2 R S', a _-SO 2 _{R S,} or -SR _S. For example, if _{L S} is a bond, _{R E} is -N _(C 1 -C _{6 alkyl) 2 (e.g., -NMe 2); - N (} C 1 -C 6 alkylene _-O-C 1 -C ₆ alkyl ) ₂ (eg -N (CH ₂ CH ₂ OME) ₂ ); -N (C _1- C ₆ alkyl) (C _1- C ₆ alkylene-OC _1- C ₆ alkyl) (eg -N (CH ₃₎ ) (CH ₂ CH ₂ OMe)); -O-C _1- C ₆ alkyl (eg, -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -On-hexyl _{); - O-C 1 -C} 6 haloalkyl _{(e.g., -OCF 3, -OCH 2 CF 3} ); - O-C 1 -C 6 alkylene - piperidine (e.g., _{-O-CH 2} CH ₂ -1- piperidyl ); -N (C _1- C ₆ alkyl) C (O) OC _1- C ₆ alkyl (for example, -N (CH ₃ ) C (O) O-CH ₂ CH (CH ₃ ) ₂ ), -N ( C _1- C ₆ alkyl) SO ₂ C _1- C ₆ alkyl (eg -N (CH ₃ ) SO ₂ CH ₃ ); -SO ₂ C _1- C ₆ alkyl (eg -SO ₂ Me); -SO ₂ C ₁ -C ₆ haloalkyl _(e.g., -SO 2 _CF 3); a or _-S-C 1 -C ₆ haloalkyl (e.g., SCF _3). Preferably _{R M} is _{-L S} -R _{E, L} S is _C 1 -C ₆ alkylene _{(e.g., -CH 2 -, - C (} CH 3) 2 -, - C (CH 3) 2 -CH 2 - _a), R _E is _{-O-R S, -C (O} ) oR S, -N (R S) C (O) oR S ' or _{-P (O) (oR S)} 2. For example _{R M} is _-C 1 -C ₆ alkylene _{-O-R S (e.g., -C (CH 3) 2 -CH} 2 -OMe); - C 1 -C 6 alkylene -C (O) OR _S (e.g., _{-C (CH 3) 2 -C (} O) OMe); - C 1 -C 6 alkylene _{-N (R S) C (O} ) OR S '( _{e.g., -C (CH 3) 2 -CH} 2 -NHC (O) OCH ₃ ); or -C _1- C ₆ alkylene-P (O) (OR _S ) ₂ (for example, -CH _2- P (O) (OEt) ₂ ). More preferably, R _M is a heterocyclic ring 6 membered C ₃ -C ₆ carbocycle or 3, halogens each case in each of which independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , Thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl , -C (O) OR _S or -N ( _RS R _S ') may be substituted with one or more substituents selected from. For example _{R M} is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-1-methylcyclopropyl pro-flops 1-yl, cyclohexyl), phenyl, heterocycle (e.g., morpholin-4-yl, 1,1-di Oxidethiomorpholine-4-yl, 4-methylpiperazine-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidine-1-yl, piperidine-1-yl, 4-methylpiperidine-1-yl, 3, 5-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridine-3-yl, 6- (dimethylamino) pyridine-3-yl). Very preferably, _{R M} is _C 1 -C ₆ alkyl, which is halogen, hydroxy, mercapto, amino or carboxy (e.g., tert- butyl, CF ₃₎ optionally substituted with one or more substituents selected from You may.

More preferably, D is C ₅ -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6 membered 12-membered, is substituted with J, optionally substituted with one or more R _A at best, J is C ₃ -C ₆ carbocycle, a bicyclic compound of the heterocycle or 6 from 3 6 membered to 12-membered, optionally substituted with one or more R _a. Preferably, J is substituted with C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, wherein the C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring independently halogen, hydroxy, mercapto , Amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') may be optionally substituted with one or more substituents selected from, J is also 1 It may be replaced with the above _RA . Preferably, D is a heterocyclic 6-membered _C 5 -C ₆ carbocyclic ring or 5 is substituted with J, may be substituted by one or more _{R A,} J is _C 3 -C ₆ a heterocyclic 6-membered carbocyclic or 3, may be substituted by one or more R _a, and preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring cage, it is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, substituted by C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, 1 or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') It may have been done. Preferably, D is C ₅ -C ₆ carbocyclic ring or 5 to 6 membered heterocyclic ring is substituted with J, it may be substituted by one or more R _A, J 6 to 12-membered Bicyclic compounds (eg, 7-12 member condensed, crosslinked or spirobicyclic compounds containing a nitrogen ring atom intervening in J's covalent bond to D), one or more _RAs. It may be replaced with. More preferably, D is phenyl, is substituted with J, may be substituted by one or more R _A, J from C ₃ -C ₆ carbocycle, 3-6 membered heterocyclic, or 6 bicyclic compounds of 12 members may be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, they Independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, optionally substituted with one or more substituents selected from C (O) oR _S, or _{-N (R S} R _S ') You may. Very preferably D

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環または６から１２員の二環式化合物であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbon ring, a 3 to 6 member heterocycle or a 6 to 12 member bicyclic compound. , and the it may optionally be substituted with one or more R _a, preferably J is substituted with at least C ₃ -C ₆ carbocycle or 3 to 6-membered heterocyclic ring, halogen them independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C ₆ haloalkyl, _{C 2} -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or _{-N (R S} R _S ') with one or more substituents selected from optionally substituted. Preferably D is

であり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはハロゲンであり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、Ｃ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良く、Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは

Each _RN is independently selected from the _RD , preferably hydrogen or halogen, where J is a C _3- C ₆ carbocycle or a 3 to 6 member heterocycle and a C _3- C ₆ carbocycle. or 3 is substituted with from 6 membered heterocyclic ring, they are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, C (O) oR _S, or -N _{(R S} R S It may be substituted with one or more substituents selected from ′), and J may also be substituted with one or more _RA . Preferably D is

であり、ＪはＣ_３−Ｃ_６炭素環または３から６員の複素環であり、１以上のＲ_Ａで置換されていても良く、好ましくはＪは少なくともＣ_３−Ｃ_６炭素環または３から６員の複素環で置換されており、それらは独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）から選択される１以上の置換基で置換されていても良い。

In it, J is a heterocyclic ring 6 membered _C 3 -C ₆ carbocycle or 3, may be substituted by one or more _{R A,} preferably J is at least _C 3 -C ₆ carbocycle or 3 is substituted with 6-membered heterocycle, they independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl, _{C 2} - C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ halo alkynyl, C (O) OR _S or -N ( _RS R _S ') It may be substituted with one or more substituents selected from.

X is _preferably, C 5 -C ₆ carbocyclic, bicyclic compounds of heterocyclic or 6 from 5 6-membered 12-membered (e.g.,

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されている。）であり、１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｘの例は上記で記載されているが、それらに限定されるものではない。

X ₃ is N and is directly connected to −L ₃₋ D. ), And it may be substituted with one or more R _A or R _F. Examples of X are described above, but are not limited thereto.

L ₁ and L ₂ are preferably independently bonded or C _1- C ₆ alkylene, and L ₃ is preferably selected from bonded, C _1- C ₆ alkylene or -C (O)-, L ₁ , L ₂ And L ₃ may each be independently substituted with one or more _RL . More preferably, L ₁ , L ₂ and L ₃ are independently bound or C ₁ −C ₆ alkylene (eg, −CH _2- or − CH ₂ CH _2- ), respectively, and each independently has one or more _RLs. It may be replaced with. Very preferably, L ₁ , L ₂ and L ₃ are bonds.

R ₂ and R ₅ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。

) Forms a, they may be substituted by one or more R _A.

R ₉ and R ₁₂ are integrated with the atom to which they are attached, preferably a 5- to 6-membered heterocycle or a 6 to 12-membered bicyclic compound (eg,).

）を形成しており、それは１以上のＲ_Ａで置換されていても良い。

) Forms a, it may be substituted by one or more R _A.

G ₁ and G ₂ are preferably independent of each other.

から選択され、それぞれ独立に１以上のＲ_Ａ（例えば、１以上のクロロまたはブロモ）で置換されていても良い。より好ましくは、Ｇ_１は

It is selected from, each independently 1 or more R _{A (e.g.,} one or more chloro or bromo) may be substituted with. More preferably, G ₁ is

（これの互変異体を含む）であり、Ｇ_２は

(Including tautomers of this), G ₂ is

（これの互変異体を含む）であり、各Ｇ_１およびＧ_２は独立に１以上のＲ_Ａ（例えば、１以上のクロロまたはブロモ）で置換されていても良い。

A (inclusive of tautomers), each of G ₁ and G ₂ are independently one or more R _{A (e.g.,} one or more chloro or bromo) may be substituted with.

_{-T-R D} 'is _-C in each case independently _{(O) -L Y' -,} - C (O) O-L Y '-R D', -C (O) -L Y '-N ( _{R B) C (O) -L} S "-R D ', -C (O) -L Y' -N (R B) C (O) O-L S" -R D ', -N (R B _{) C (O) -L Y '} -N (R B) C (O) -L S "-R D', -N (R B) C (O) -L Y '-N (R B) C ( _{O) O-L S "-R} D ' or _{-N (R B) C (O} ) -L Y' -N (R B) -L S" may be selected from -R _D ', these is not limited to, _{L Y} 'is _{L S} independently' is preferably independently _C 1 -C ₆ alkylene (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｙ′−Ｍ′−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。より好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択される。非常に好ましくは、−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′は好ましくはそれぞれ独立にＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−または

), And may be substituted with one or more substituents selected from _RL . Preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -M'-L S "-R D ' or _{-N (R B) C (O} ) -L Y It is selected from the _{'-M'-L S "-R D} '. More preferably, 'in the case each _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) It is selected from _{-L Y '-N (R B)} C (O) O-L S "-R D'. Very preferably, _{-T-R D} 'is each case _{independently, -C (O) -L Y'} -N (R B) C (O) -R D ' or -C (O) -L _Y It is selected from the _{'-N (R B) C (} O) O-R D', L Y ' is _C 1 -C ₆ alkylene, preferably each independently (e.g., -CH ₂ - or

）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良い。

), And may be substituted with one or more substituents selected from _RL .

_RC ′ is preferably hydrogen and _RD ′ is preferably independently selected from R _E in each case. More preferably, _RD ′ is independently in each case, and in each case independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _3- C ₆ carbon. C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from the ring or a 3- to 6-membered heterocycle; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl. Selected from the ring.

_RA is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or C _1- C ₆ alkyl, C _2- C ₆ alkyne or independently each case halogen. , hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, optionally substituted by one or more substituents selected from formyl or cyano C ₂ -C ₆ alkynyl; or independently each In some cases halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 or more heterocycle optionally substituted _C 3 -C ₆ carbocycle or 3 to 6-membered by substituents selected from haloalkynyl ; or _{-L A -O-R S, -L} A -S-R S, -L A -C (O) R S, -L A -OC (O) R S, -L A -C (O) _{OR S, -L A -N (R} S R S '), - L A -S (O) R S, -L A -SO 2 R S, -L A -C (O) N (R S R S _{'), - L A -N (} R S) C (O) R S', -L A -N (R S) C (O) N (R S 'R S "), - L A -N (R _{S) SO 2 R S ',} -L A -SO 2 N (R S R S'), - L A -N (R S) SO 2 N (R S 'R S "), - L A -N ( _{R S) S (O) N} (R S 'R S "), - L A -OS (O) -R S, -L A -OS (O) 2 -R S, -L A -S (O) _{2 OR S, -L A -S (} O) OR S, -L A -OC (O) OR S, -L A -N (R S) C (O) OR S ', -L A -OC (O _{) N (R S R S '} ), - L A -N (R S) S (O) -R S', -L A -S (O) N (R S R S ') or _-L A -C _(O) a N (R S) C (O ) -R S ', L a is a _bond, C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or A C ₂ -C ₆ alkynylene.

More preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from phosphonoxy, phosphono, tioxo, formyl or cyano; or independently. In each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C ₁ A C _3- C ₆ carbocyclic ring or a 3- to 6-membered complex that may be substituted with one or more substituents selected from −C ₆ haloalkyl, C ₂ −C ₆ haloalkenyl or C ₂ −C ₆ haloalkynyl. It is a ring.

Very preferably, _RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo. a phosphonoxy, phosphono, thioxo, one or more may be substituted by a substituent _C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl selected from formyl or cyano.

L _S, with _{L S} 'and _{L S} "each case preferably each independently, a bond; or _C 1 -C _{6 alkylene,} is selected from C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene.

A and B can be the same or different. Similarly, L ₁ and L ₂ can be the same or different.

In one embodiment of this aspect, A and B are each independently phenyl, each independently may be substituted with one or more R _A; is D is phenyl, substituted with one or more independent R _A is is substituted with even better or J have, may be substituted by one or more R _a, J is a 12-membered C ₃ -C ₆ carbocycle, 3 to 6-membered heterocyclic ring or 6 two a cyclic compound, may be substituted with one or more R _a. Preferably, J is substituted with a C _3- C ₆ carbocycle or a 3- to 6-membered heterocycle, which are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, Formil, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, C ( O) may be substituted with one or more substituents selected from OR _S or -N ( _RS R _S ′), J may also be substituted with one or more _RA ; G ₁

であり、Ｇ_２は

And G ₂ is

であり、各Ｇ_１およびＧ_２は独立に１以上のＲ_Ａ（例えば、１以上のクロロまたはブロモ）によって置換されていても良い。好ましくは、Ｄは

, And the may be substituted by each G ₁ and G ₂ are independently one or more R _{A (e.g.,} one or more chloro or bromo). Preferably D is

であり、Ｒ_ＭおよびＲ_Ｎは上記で定義の通りである。好ましくは、Ｄは

And _RM and _RN are as defined above. Preferably D is

であり、ＪおよびＲ_Ｎは上記で定義の通りである。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。好ましくは、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、

And J and _RN are as defined above. L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D' or -C (O) -L _{Y '-N (R B) S (} O) 2 -L S "-R D' may also be selected from, but is not limited thereto. preferably, they are bonded _{R 2} and _{R 5} Together with the atom

を形成しており、それは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、

The forms, which one or more may be substituted by R _A; is R ₉ and R ₁₂ are integral with the atoms to which they are attached,

を形成しており、それは１以上のＲ_Ａで置換されていても良い。

Forms a, it may be substituted by one or more R _A.

In another embodiment of this embodiment, A and B are independently phenyl (eg, eg).

）であり、それぞれ独立に１以上のＲ_Ａで置換されていても良い（好ましくは、ＡおよびＢはそれぞれ独立に少なくとも１個のＦなどのハロゲンで置換されている。）。Ｘは、

), And it is also good (preferably substituted with independently one or more R _A, A and B is substituted by halogen, such as at least one of F independently.). X is

であり、Ｘ_３はＮであり、−Ｌ_３−Ｄに直接連結されており、Ｘは１以上のＲ_ＡまたはＲ_Ｆで置換されていても良い。Ｄはフェニルであり、Ｊで置換されており、１以上のＲ_Ａで置換されていても良い。ＪはＣ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物、１０から１５員の三環式化合物または１３から１５員の炭素環／複素環であり、Ｊは１以上のＲ_Ａで置換されていても良い。好ましくは、Ｊは、Ｃ_３−Ｃ_６炭素環、３から６員の複素環、６から１２員の二環式化合物または７から１２員の炭素環／複素環で置換されており、それらは独立に（１）ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、−Ｃ（Ｏ）ＯＲ_Ｓまたは−Ｎ（Ｒ_ＳＲ_Ｓ′）または（２）トリメチルシリル、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓまたは−Ｃ（Ｏ）Ｒ_Ｓから選択される１以上の置換基で置換されていても良く；Ｊはまた１以上のＲ_Ａで置換されていても良い。好ましくは、Ｄは、

In and, _{X 3} is N, _-L 3 -D are connected directly to, X may be substituted with one or more _{R A} or _{R F.} D is phenyl, substituted with J, and may be substituted with 1 or more _RA . J is a C _3- C _6- membered ring, a 3- to 6-membered heterocycle, a 6 to 12-membered bicyclic compound, a 10 to 15-membered tricyclic compound, or a 13 to 15-membered carbocycle / heterocycle. , J may be substituted with 1 or more _RA . Preferably, J is substituted with a C _3- C ₆ alkyne, a 3 to 6 membered heterocycle, a 6 to 12 membered bicyclic compound or a 7 to 12 membered alkyne / heterocycle, which are substituted. independently (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, C ₁ -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) oR _S, or _{-N (R S} R _S ') or (2) trimethylsilyl, -O-R It may be substituted with one or more substituents selected from _S , -S- _RS or -C (O) _RS ; J may also be substituted with one or more _RA . Preferably, D is

であり、Ｊは上記で定義の通りであり、各Ｒ_Ｎは独立にＲ_Ｄから選択され、好ましくは水素またはＦなどのハロである。Ｇ_１は

And J is as defined above, and each _RN is independently selected from R _D , preferably a halo such as hydrogen or F. G ₁ is

であり、Ｇ_２は

And G ₂ is

であり、各Ｇ_１およびＧ_２は独立に１以上のＲ_Ａ（例えば、１以上のクロロまたはブロモ）によって置換されていても良い。Ｌ_１およびＬ_２はそれぞれ独立に結合またはＣ_１−Ｃ_６アルキレンであり、Ｌ_３は結合、Ｃ_１−Ｃ_６アルキレンまたは−Ｃ（Ｏ）−であり、Ｌ_１、Ｌ_２およびＬ_３はそれぞれ独立に１以上のＲ_Ｌで置換されていても良い。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ′は独立に各場合で、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′から選択され、Ｌ_Ｙ′はＣ_１−Ｃ_６アルキレン（例えば、−ＣＨ_２−）であり、Ｒ_Ｌから選択される１以上の置換基で置換されていても良く、Ｌ_Ｓ″は好ましくは結合である。−Ｔ−Ｒ_Ｄ′は−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｏ−Ｌ_Ｓ″−Ｒ_Ｄ′、−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ″−Ｒ_Ｄ′または−Ｃ（Ｏ）−Ｌ_Ｙ′−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ″−Ｒ_Ｄ′から選択されることもできるが、これらに限定されるものではない。好ましくは、Ｒ_２およびＲ_５がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

, And the may be substituted by each G ₁ and G ₂ are independently one or more R _{A (e.g.,} one or more chloro or bromo). L ₁ and L ₂ are independently bonded or C _1- C ₆ alkylene, L ₃ is bonded, C _1- C ₆ alkylene or -C (O)-, and L ₁ , L ₂ and L ₃ are bonded. independently may be substituted with one or more R _L. Preferably, L ₁ , L ₂ and L ₃ are bonds. 'In each case _{independently, -C (O) -L Y'} -T-R D -N (R B) C (O) -L S "-R D ' or -C (O) _-L Y''is selected _{from, L Y' -N (R B} ) C (O) O-L S "-R D is _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, is selected from _{R L} may be substituted with one or more substituents, _{L S} "is preferably a _{bond.-T-R D} 'is _{-C (O) -L Y' -L} S" -R D ', -C _{(O) -L Y '-O-} L S "-R D', -C (O) -L Y '-N (R B) -L S" -R D' or -C (O) -L _{Y '-N (R B) S (} O) 2 -L S "-R D' may also be selected from, but is not limited thereto. preferably, they are bonded _{R 2} and _{R 5} A 5- to 6-membered heterocycle (eg, with the atom

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良く；Ｒ_９およびＲ_１２がそれらが結合している原子と一体となって、５から６員の複素環（例えば、

) Forms a, they 1 or more may be substituted by R _A; becomes R ₉ and R ₁₂ together with the atom to which they are attached, 5-6 membered heterocyclic ring (e.g. ,

）または６から１２員の二環式化合物（例えば、

) Or 6 to 12 member bicyclic compounds (eg)

）を形成しており、それらは１以上のＲ_Ａで置換されていても良い。

) Forms a, they may be substituted by one or more R _A.

In another embodiment, the present invention features a compound having the formula _IE below and a pharmaceutically acceptable salt thereof.

式中、
Ｘは、４から８員の複素環であり、１以上のＲ_Ａで置換されていても良く；
Ｌ_１およびＬ_２はそれぞれ独立に、結合またはＣ_１−Ｃ_６アルキレンから選択され、それは独立に各場合で、１以上のハロ、ヒドロキシ、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルによって置換されていても良く；
Ｌ_３は結合またはＣ_１−Ｃ_６アルキレンであり；
ＡおよびＢはそれぞれ独立にフェニル、ピリジニル、チアゾリルまたは

During the ceremony
X is a 8-membered heterocyclic ring from 4 may be substituted by one or more R _A;
L ₁ and L ₂ are independently selected from the bond or C _1- C ₆ alkylene, which in each case are independently one or more halo, hydroxy, -OC _1- C ₆ alkyl or -OC. May be substituted with _1- C ₆ haloalkyl;
L ₃ is a bond or C _1- C ₆ alkylene;
A and B are independently phenyl, pyridinyl, thiazolyl or

であり、Ｚ_１は独立に各場合でＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｚ_３は独立に各場合でＮまたはＣＨから選択され、Ｗ_１、Ｗ_２およびＷ_３はそれぞれ独立に各場合でＣＨまたはＮから選択され；ＡおよびＢはそれぞれ独立に１以上のＲ_Ａで置換されていても良く；
ＤはＣ_６−Ｃ_１０炭素環または５から１２員の複素環であり、それらはそれぞれ１以上のＲ_Ｍで置換されていても良く；
Ｙは、−Ｔ′−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−Ｔ−Ｒ_Ｄであり；
Ｚは、−Ｔ′−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−Ｔ−Ｒ_Ｄであり；
Ｒ_１は、水素、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキルまたは３から６員の炭素環または複素環であり、各前記３から６員の炭素環または複素環は独立に各場合で、ハロゲン、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルから選択される１以上の置換基によって置換されていても良く；
Ｒ_２およびＲ_５はそれぞれ独立に水素、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキルまたは３から６員の炭素環または複素環であり、各前記３から６員の炭素環または複素環は独立に各場合で、ハロゲン、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルから選択される１以上の置換基によって置換されていても良く；またはＲ_２およびＲ_５がそれらが結合している原子と一体となって、３から１２員の複素環を形成しており、それは１以上のＲ_Ａ（例えば、１、２、３または４個のＲ_Ａ）で置換されていても良く；
Ｒ_８は、水素、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキルまたは３から６員の炭素環または複素環であり、各前記３から６員の炭素環または複素環は独立に各場合で、ハロゲン、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルから選択される１以上の置換基によって置換されていても良く；
Ｒ_９およびＲ_１２はそれぞれ独立に水素、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキルまたは３から６員の炭素環または複素環であり、各前記３から６員の炭素環または複素環は独立に各場合で、ハロゲン、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルから選択される１以上の置換基によって置換されていても良く；またはＲ_９およびＲ_１２がそれらが結合している原子と一体となって、１以上のＲ_Ａ（例えば、１、２、３もしくは４個のＲ_Ａ）で置換されていても良い３から１２員の複素環を形成しており；
Ｔは独立に各場合で、結合または−Ｃ（Ｏ）−Ｌ_Ｓ′−から選択され；
Ｔ′は独立に各場合で、結合、−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−または３から１２員の複素環から選択され、前記３から１２員の複素環は独立に各場合で１以上のＲ_Ａによって置換されていても良く；
Ｒ_Ｄはそれぞれ独立に各場合で、水素またはＲ_Ａから選択され；
Ｒ_Ａは独立に各場合で、ハロゲン、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、シアノまたは−Ｌ_Ｓ−Ｒ_Ｅから選択され；
Ｒ_ＢおよびＲ_Ｂ′はそれぞれ独立に各場合で、水素；または独立に各場合でハロゲンまたは３から６員の炭素環または複素環から選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル；または３から６員の炭素環または複素環から選択され；Ｒ_ＢまたはＲ_Ｂ′における各３から６員の炭素環または複素環は独立に各場合で、ハロゲン、ヒドロキシ、Ｃ_１−Ｃ_６アルキル、Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルから選択される１以上の置換基によって置換されていても良く；
Ｒ_Ｅは独立に各場合で、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓ、−Ｃ（Ｏ）Ｒ_Ｓ、−ＯＣ（Ｏ）Ｒ_Ｓ、−Ｃ（Ｏ）ＯＲ_Ｓ、−Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｓ（Ｏ）Ｒ_Ｓ、−ＳＯ_２Ｒ_Ｓ、−Ｃ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｒ_Ｓ′_、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｎ（Ｒ_Ｓ′Ｒ_Ｓ″″）、−Ｎ（Ｒ_Ｓ）ＳＯ_２Ｒ_Ｓ′、−ＳＯ_２Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）ＳＯ_２Ｎ（Ｒ_Ｓ′Ｒ_Ｓ″″）、−Ｎ（Ｒ_Ｓ）Ｓ（Ｏ）Ｎ（Ｒ_Ｓ′Ｒ_Ｓ″）、−ＯＳ（Ｏ）−Ｒ_Ｓ、−ＯＳ（Ｏ）_２−Ｒ_Ｓ、−Ｓ（Ｏ）_２ＯＲ_Ｓ、−Ｓ（Ｏ）ＯＲ_Ｓ、−ＯＣ（Ｏ）ＯＲ_Ｓ、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）ＯＲ_Ｓ′、−ＯＣ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）Ｓ（Ｏ）−Ｒ_Ｓ′、−Ｓ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｃ（Ｏ）Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）−Ｒ_Ｓ′または＝Ｃ（Ｒ_ＳＲ_Ｓ′）；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミルまたはシアノから選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_１２炭素環または３から１２員の複素環から選択され；
Ｒ_Ｌは独立に各場合で、ハロゲン、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、シアノ、−Ｏ−Ｒ_Ｓ、−Ｓ−Ｒ_Ｓ、−Ｃ（Ｏ）Ｒ_Ｓ、−ＯＣ（Ｏ）Ｒ_Ｓ、−Ｃ（Ｏ）ＯＲ_Ｓ、−Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｓ（Ｏ）Ｒ_Ｓ、−ＳＯ_２Ｒ_Ｓ、−Ｃ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）または−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｒ_Ｓ′；またはそれぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良いＣ_３−Ｃ_１２炭素環または３から１２員の複素環から選択され；
Ｌ_Ｓは独立に各場合で、結合；またはそれぞれ独立にハロゲンで置換されていても良いＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンまたはＣ_２−Ｃ_６アルキニレンから選択され；
Ｌ_Ｓ′は独立に各場合で、結合；またはＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンまたはそれぞれ独立に各場合で１以上のＲ_Ｌによって置換されていても良いＣ_２−Ｃ_６アルキニレンから選択され；
Ｒ_Ｓ、Ｒ_Ｓ′およびＲ_Ｓ″はそれぞれ独立に各場合で、水素；それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_１−Ｃ_６ハロアルキルまたは３から１２員の炭素環または複素環から選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または３から１２員の炭素環または複素環から選択され；Ｒ_Ｓ、Ｒ_Ｓ′またはＲ_Ｓ″における各３から１２員の炭素環または複素環は独立に各場合で、ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニルまたはＣ_２−Ｃ_６ハロアルキニルから選択される１以上の置換基によって置換されていても良く；
Ｒ_Ｍは独立に各場合で、
ハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、シアノ、ＳＦ_５、−Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｏ−Ｒ_Ｓ、−ＯＣ（Ｏ）Ｒ_Ｓ、−ＯＣ（Ｏ）ＯＲ_Ｓ、−ＯＣ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｃ（Ｏ）Ｒ_Ｓ、−Ｃ（Ｏ）ＯＲ_Ｓ、−Ｃ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｒ_Ｓ′_、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）ＯＲ_Ｓ′、−Ｎ（Ｒ_Ｓ）ＳＯ_２Ｒ_Ｓ′、−Ｓ（Ｏ）Ｒ_Ｓ、−ＳＯ_２Ｒ_Ｓ、−Ｓ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−ＳＲ_Ｓ、−Ｓｉ（Ｒ_Ｓ）_３または−Ｐ（Ｏ）（ＯＲ_Ｓ）_２；
それぞれ独立に各場合でハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、−Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｏ−Ｒ_Ｓ、−ＯＣ（Ｏ）Ｒ_Ｓ、−ＯＣ（Ｏ）ＯＲ_Ｓ、−ＯＣ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｃ（Ｏ）Ｒ_Ｓ、−Ｃ（Ｏ）ＯＲ_Ｓ、−Ｃ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｒ_Ｓ′_、−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）ＯＲ_Ｓ′、−Ｎ（Ｒ_Ｓ）ＳＯ_２Ｒ_Ｓ′、−Ｓ（Ｏ）Ｒ_Ｓ、−ＳＯ_２Ｒ_Ｓ、−Ｓ（Ｏ）Ｎ（Ｒ_ＳＲ_Ｓ′）、−ＳＲ_Ｓまたは−Ｐ（Ｏ）（ＯＲ_Ｓ）_２から選択される１以上の置換基によって置換されていても良いＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニル；または
Ｇ_２［Ｇ_２はＣ_３−Ｃ_１２炭素環または３から１２員の複素環であり、それらはそれぞれ独立に各場合で１以上のＲ_Ｇ２によって置換されていても良く、各Ｒ_Ｇ２は独立にハロゲン、ヒドロキシ、メルカプト、アミノ、カルボキシ、ニトロ、オキソ、ホスホノキシ、ホスホノ、チオキソ、ホルミル、シアノ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_１−Ｃ_６ハロアルキル、Ｃ_２−Ｃ_６ハロアルケニル、Ｃ_２−Ｃ_６ハロアルキニル、−Ｏ−Ｒ_Ｓ、−Ｃ（Ｏ）ＯＲ_Ｓ、−Ｃ（Ｏ）Ｒ_Ｓ、−Ｎ（Ｒ_ＳＲ_Ｓ′）または−Ｌ_４−Ｇ_３から選択される。］から選択され；
Ｌ_４は、結合、Ｃ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレン、Ｃ_２−Ｃ_６アルキニレン、−Ｏ−、−Ｓ−、−Ｎ（Ｒ_Ｂ）−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）_２−、−Ｓ（Ｏ）−、−Ｃ（Ｏ）Ｏ−、−ＯＣ（Ｏ）−、−ＯＣ（Ｏ）Ｏ−、−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｏ−、−ＯＣ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）−、−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−、−Ｓ（Ｏ）Ｎ（Ｒ_Ｂ）−、−Ｓ（Ｏ）_２Ｎ（Ｒ_Ｂ）−、−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）Ｎ（Ｒ_Ｂ′）−、−Ｎ（Ｒ_Ｂ）ＳＯ_２Ｎ（Ｒ_Ｂ′）−または−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）Ｎ（Ｒ_Ｂ′）−であり；
Ｇ_３は、Ｃ_３−Ｃ_１２炭素環または３から１２員の複素環であり、１以上のＲ_Ｇ３で置換されていても良く；
Ｒ_Ｇ３はそれぞれ独立に、各場合で、ハロゲン、−Ｃ_１−Ｃ_６アルキル、−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキル、−Ｏ−Ｃ_１−Ｃ_６ハロアルキル、Ｃ_３−Ｃ_６炭素環または３から６員の複素環である。

Z ₁ is independently selected from O, S, NH or CH ₂ in each case, Z ₃ is independently selected from N or CH in each case, and W ₁ , W ₂ and W ₃ are independently selected from each other. It may be substituted with one or more R _a, respectively a and B are independently, are selected from CH or N in each case;
D is a heterocycle of 12-membered _C 6 _{-C 10} carbocyclic ring or 5, they may be each substituted by 1 or more _{R M;}
Y is -T'-C (R ₁ R ₂ ) N (R ₅ ) -TR _D ;
Z is -T'-C (R ₈ R ₉ ) N (R ₁₂ ) -TR _D ;
R ₁ is hydrogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl or a 3 to 6 membered carbocycle or heterocycle, each of the above 3 to 6 membered carbocycles or heterocycles independently. Substituent with one or more substituents selected from halogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl. May;
R ₂ and R ₅ are independently hydrogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl or 3 to 6 membered carbocycles or heterocycles, respectively, the above 3 to 6 member carbocycles or heterocycles, respectively. Independently in each case, one or more substitutions selected from halogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl may be substituted by a group; or R ₂ and R ₅ together with the atom they are attached to form a heterocyclic ring of from 3 to 12-membered, it one or more R _{a (e.g.} May be replaced with 1, 2, 3 or 4 _RA );
R ₈ is hydrogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl or a 3- to 6-membered carbocycle or heterocycle, each of the above 3- to 6-membered carbocycles or heterocycles independently. Substituent with one or more substituents selected from halogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl. May;
R ₉ and R ₁₂ are independently hydrogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl or 3 to 6 membered carbocycles or heterocycles, respectively, the above 3 to 6 member carbocycles or heterocycles, respectively. Independently in each case, one or more substitutions selected from halogen, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl It may be substituted by a group; or _{R 9} and _{R 12} together with the atom to which they are attached, with one or more _{R a} (e.g., 1, 2, 3 or 4 _{R a)} It forms a 3- to 12-membered heterocycle that may be substituted;
T in each case independently a bond or -C (O) -L _S '- is selected from;
T 'is in each case independently a _{bond, -C (O) N (R} B) -, - N (R B) C (O) - or 3 is selected from the 12-membered heterocyclic ring, wherein from 3 to 12 It may be substituted by one or more R _a heterocycle may in each case independently of members;
R _D is independently selected from hydrogen or _RA in each case;
R _A is in each case independently selected from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E;
In R _B and R _{B 'are} in each case independently, hydrogen; may be substituted or independently by one or more substituents selected from carbocyclic or heterocyclic ring 6 membered halogen or 3 in each case C ₁ -C ₆ alkyl; or 3 is selected from the six-membered carbocyclic or heterocyclic ring; with R _B or R _B carbocyclic or heterocyclic ring each 3 to 6-membered in _'If each independently, halogen, hydroxy , C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl may be substituted with one or more substituents selected from. ;
_RE is independently in each case, -OR _S , -S- _RS , -C (O) R _S , -OC (O) R _S , -C (O) OR _S , -N ( _RS). R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N ( _RS R _S '), -N ( _RS ) C (O) R _S ' _, -N ( R _S ) C (O) N ( _RS ′ R _S ″ ″), -N ( _RS ) SO ₂ R _S ′, -SO ₂ N ( _RS R _S ′), -N ( _RS ) SO _{2 N (R S 'R S "} "), - N (R S) S (O) N (R S' R S "), - OS (O) -R S, -OS (O) 2 -R S, -S (O) ₂ OR _S , -S (O) OR _S , -OC (O) OR _S , -N ( _RS ) C (O) OR _S ', -OC (O) N ( _RS R _{S) '), - N (R S} ) S (O) -R S', -S (O) N (R S R S '), - C (O) N (R S) C (O) -R S' Or = C ( _RS R _S ′); or one or more substituents independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl or cyano in each case. C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl which may be substituted by; or independently each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy. , Phosno, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _2- C ₆ alkyne, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ Selected from C _3- C ₁₂ carbon rings or 3- to 12-membered heterocycles, which may be substituted with one or more substituents selected from haloalkynyl;
_RL is independently in each case, halogen, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano, -O- _RS , -S- _RS , -C (O) R _S , -OC (O) R _S. , -C (O) OR _S , -N ( _RS R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N ( _RS R _S ') or -N ( R _S ) C (O) R _S ′; or independently in each case halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _1- C ₆ alkyl, C _{Even if} substituted with one or more substituents selected from _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl Selected from good C _3- C ₁₂ carbocycles or 3 to 12 membered heterocycles;
L _S in the case each independently a bond; or are independently selected from optionally substituted with halogen _C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene;
L _S 'in each case independently a bond; or _C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or one or more _{R L} may be substituted by _C 2 -C in each case independently ₆ Selected from alkinilen;
R _S , R _S ′ and R _S ″ are independently hydrogen in each case; halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, in each case independently. _-O-C 1 -C ₆ alkyl, _-O-C 1 -C ₆ haloalkyl, or one or more good _C 1 -C be substituted with a substituent 3 is selected from the 12-membered carbocyclic or heterocyclic ring ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or selected from 3 to 12 membered carbon or heterocycles; 3 to 12 membered carbons in _RS , _RS ′ or _RS ″, respectively. Rings or heterocycles are independent in each case, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, C _1- C ₆ alkyne, C _2- C ₆ alkyne, C. It may be substituted with one or more substituents selected from _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl or C _2- C ₆ haloalkynyl;
_RM is independent in each case,
Halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, cyano, SF ₅ , -N ( _RS R _S '), -OR _S , -OC (O) R _S ,- OC (O) OR _S , -OC (O) N ( _RS R _S '), -C (O) R _S , -C (O) OR _S , -C (O) N ( _RS R _S ') , -N ( _RS ) C (O) R _S ' _, -N ( _RS ) C (O) OR _S ', -N ( _RS ) SO ₂ R _S ', -S (O) R _S ,- SO ₂ R _S , -S (O) N ( _RS R _S '), -SR _S , -Si ( _RS ) ₃ or -P (O) (OR _S ) ₂ ;
Halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, -N ( _RS R _S '), -OR _S , -OC (O) independently in each case. ) R _S , -OC (O) OR _S , -OC (O) N ( _RS R _S '), -C (O) R _S , -C (O) OR _S , -C (O) N (R) _{S R S '), - N} (R S) C (O) R S', -N (R S) C (O) OR S ', -N (R S) SO 2 R S', -S (O ) R _S , -SO ₂ R _S , -S (O) N ( _RS R _S '), -SR _S or -P (O) (OR _S ) Replaced by one or more substituents selected from _2. May be C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl; or G ₂ [G ₂ is a C _3- C ₁₂ carbocycle or a 3- to 12-membered heterocycle. they may be optionally substituted by one or more R _G2 in each case independently, each R _G2 are independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , C _1- C ₆ alkyl, C _2- C ₆ alkynyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl, C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, -OR _S , -C (O) OR _S , -C (O) R _S , -N ( _RS R _S ') or -L _4- G ₃ . ] Is selected;
L ₄ is a _bond, C 1 -C _{6 alkylene,} C 2 -C _{6 alkenylene,} C 2 -C ₆ alkynylene, -O -, - S -, - N (R B) -, - C (O) -, _{-S (O) 2 -, -} S (O) -, - C (O) O -, - OC (O) -, - OC (O) O -, - C (O) N (R B) -, _{-N (R B) C (O} ) -, - N (R B) C (O) O -, - OC (O) N (R B) -, - N (R B) S (O) -, - _{N (R B) S (O} ) 2 -, - S (O) N (R B) -, - S (O) 2 N (R B) -, - N (R B) C (O) N (R _{B ') -, - N (} R B) SO 2 N (R B') - or _{-N (R B) S (O} ) N (R B ') - a and;
G ₃ are _a C 3 _{-C 12} carbocyclic or 3-12 membered heterocyclic ring may be substituted by one or more _{R G3;}
R _G3 is independent of each other, in each case halogen, -C _1- C ₆ alkyl, -C (O) C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl. , -O-C ₁ -C ₆ haloalkyl, C _3- C ₆ carbocycles or 3- to 6-membered heterocycles.

As described herein above for compounds of formula _IE , A and B are phenyl, pyridinyl, thiazolyl or, respectively.

であり、Ｚ_１は独立に各場合でＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｚ_３は独立に各場合でＮまたはＣＨから選択され、Ｗ_１、Ｗ_２およびＷ_３はそれぞれ独立に各場合でＣＨまたはＮから選択され；ＡおよびＢはそれぞれ独立に１以上のＲ_Ａで置換されていても良い。

Z ₁ is independently selected from O, S, NH or CH ₂ in each case, Z ₃ is independently selected from N or CH in each case, and W ₁ , W ₂ and W ₃ are independently selected from each other. It is selected from CH or N in each case; a and B may be substituted with one or more R _a independently.

Preferably, A is phenyl (eg,

）、ピリジニル（例えば、

), Pyrizinyl (eg

）、チアゾリル（例えば、

), Thiazolyl (eg

）または

) Or

（例えば、

(For example

）から選択され、１以上のＲ_Ａで置換されていても良い。

) Is selected from, optionally substituted with one or more R _A.

Preferably B is phenyl (eg,

）、ピリジニル（例えば、

), Pyrizinyl (eg

）、チアゾリル（例えば、

), Thiazolyl (eg

）または

) Or

（例えば、

(For example

）から選択され、１以上のＲ_Ａで置換されていても良い。

) Is selected from, optionally substituted with one or more R _A.

Very preferably both A and B are phenyl (eg, both A and B are

である。）；またはＡは

Is. ); Or A

であり、Ｂは

And B is

であり；またはＡは、

Is; or A is

であり、Ｂは

And B is

であり；またはＡは、

Is; or A is

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

であり；各ＡおよびＢは独立に１以上のＲ_Ａで置換されていても良い。

In it, each A and B may be substituted with 1 or more independently of R _A.

In certain embodiments of this aspect of the present invention, A and B is substituted by one or more _{R A,} each _{R A} independently halogen (e.g., fluoro, _chloro), L S _-R E (L _S is a bond and _RE is -C _1- C ₆ alkyl (eg, methyl), -O- _RS (eg, -O-C _1- C ₆ alkyl, -OCH ₃ ) or one or more halogens. optionally substituted _-C 1 -C ₆ alkyl (e.g., -CF ₃₎ is selected from.) or _{L S -R} E _(L S is _C 1 -C ₆ alkylene, _{R E} is -O -R _S (e.g., _-C 1 -C ₆ alkyl _-O-C 1 -C _{6 alkyl,} -CH 2 OCH ₃₎ is a.). For example, in certain embodiments, A is

であり、Ｂは本明細書で上記で定義の通りである。ある種の他の実施形態において、Ｂは

And B is as defined above herein. In certain other embodiments, B

であり、Ａは本明細書で上記で定義の通りである。さらに別の実施形態において、Ａは

And A is as defined above herein. In yet another embodiment, A

であり；Ｂは

And B is

である。

Is.

As described above for the compounds of formula I _E, D is one or more -C C ₆ optionally substituted by R _{M 10} carbocyclic or 3-12 membered heterocyclic ring. Preferably, D is a C _6- C ₁₀ aryl (eg, phenyl, naphthyl, indanyl) or a 5 to 10 member heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [ d] thiazolyl, indazolyl, a benzo [d] [1,3] dioxol-5-yl), D is optionally substituted with one or more _{R M.} For example, in certain embodiments, D is preferably substituted by one or more _{R M} phenyl, each _{R M} is independently halogen (e.g., fluoro, chloro, _bromo); C 1 -C ₆ alkyl ( for example, tert- butyl); one or more _C 1 -C ₆ alkyl substituted by halogen _{(e.g., CF 3); - O-} C 1 -C such _{alkyl -O-R S} (e.g., -O -CH ₂ CH ₃ ); or -O-C _1- C ₆ alkyl (eg, -O-CF ₃ , -O-CH ₂ CHF ₂ ) or -OC substituted with one or more halogens in each case. _1- C ₆ alkyl (eg, -O-CH ₂ CH ₂ OCH ₃ ); replaced with a 3- to 12-membered heterocycle (eg, 3-ethyloxetane-3-yl, 1,3-dioxolane-4-yl) -O- _RS (eg, -OC _1- C ₆ alkyl, such as -O-CH ₂ ); -O- _RS [ _RS may be substituted 3 to 12 members. It is a carbocycle or a heterocycle (eg, cyclopentyl, cyclohexyl, phenyl, 1,3-dioxane-5-yl). ]; -N ( _RS ) C (O) R _S '[ _RS and R _S'are independently C _1- C ₆ alkyls (eg, -N (t-Bu) C (O) Me). .. _{]; SF 5; -SO 2 R} S [R S is _C 1 -C ₆ alkyl (e.g., _-SO 2 Me). ]; Or _C 3 _{-C 12} carbocycle (e.g., cyclopropyl, cyclohexyl, phenyl).

In certain embodiments of this aspect of the present invention, D is preferably phenyl or pyridyl is substituted by one or more R _M, 1 single R _M is G _2. In certain embodiments D is phenyl or pyridyl, D is substituted by G _2, G ₂ is a 3 to 12 membered heterocyclic ring (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl), One or more halogens (eg fluoro, chloro), hydroxy, oxo, cyano, C _1- C ₆ alkyl (eg methyl), C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C ₆ haloalkyl (For example, CF ₃ ), C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, -OC _1- C ₆ alkyl (eg -O-CH ₃ ), -C (O) OR _S (eg, -O-CH ₃ ) For example, it may be replaced with -C (O) OCH ₃ ), -C (O) R _S (eg, -C (O) CH ₃ ) or -N ( _RS R _S '); D is 1 It may be further substituted by the above _{R M,} is _{R M} halogen (e.g., fluoro, _chloro), C 1 -C ₆ alkyl (e.g., _methyl), C 1 -C ₆ haloalkyl (e.g., CF _3), or -O-C ₁ -C ₆ alkyl (eg, -O-CH ₃ ). In certain other embodiments, D is phenyl or pyridyl, G _2, for example L ₄ -G ₃ 8-membered carbocyclic monocyclic 3 substituted with ring or a monocyclic 4 to 8 membered heterocyclic a ring may be optionally substituted with one or more _{R G2,} L _{4, G 3} and _{R G2} are as defined herein. L ₄ is, for example, a bond, C _1- C ₆ alkylene (eg, -CH _2- , -CH ₂ CH _2- , -CH ₂ CH ₂ CH _2-, etc.), -O- or -S (O) _2- Is. G ₃ is, for example, a C _3- C ₁₂ carbon ring that may be substituted with one or more _RG3s . _RG2 and _RG3 are independent in each case halogen, -C (O) C _1- C ₆ alkyl, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ It is alkyl or -OC _1- C ₆ haloalkyl. In certain embodiments, G ₂ is

であり、

And

は、窒素原子を介して親分子部分に結合している単環式４から８員窒素含有複素環（例えば、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル）であり、１個もしくは２個のＬ_４−Ｇ_３で置換されており、１以上のＲ_Ｇ２で置換されていても良い。従って、Ｌ_４が結合であるある種の実施形態において、Ｇ_２は

Is a monocyclic 4 to 8 membered nitrogen-containing heterocyclic ring attached to the parent molecular moiety through a nitrogen atom (for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl), one or two L ₄ -G ₃ is substituted with may be substituted with one or more R _G2. Thus, in certain embodiments _{L 4} is a bond, _{G 2} is

であり、

And

はＲ_Ｇ２で置換されていても良く、Ｇ_３はＲ_Ｇ３で置換されていても良い。従って、

May be substituted with R _G2, G ₃ may be substituted by R _G3. Therefore,

は、例えば３−フェニルアゼチジン−１−イル、３−フェニルピロリジン−１−イル、４−フェニルピペラジン−１−イル、４−フェニルピペリジン−１−イル、４−フェニル−３，６−ジヒドロピリジン−１（２Ｈ）−イル、４，４−ジフェニルピペリジン−１−イル、４−アセチル−４−フェニルピペリジン−１−イル、４−（４−メトキシフェニル）ピペリジン−１−イル、４−（４−フルオロフェニル）ピペリジン−１−イルまたは３−フェニルピペリジン−１−イルであることができ、Ｄは１以上のＲ_Ｍ（例えば、フルオロ、クロロ、メチル、メトキシ）でさらに置換されていても良い。

For example, 3-phenylazetidine-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperidine-1-yl, 4-phenylpiperidine-1-yl, 4-phenyl-3,6-dihydropyridine- 1 (2H) -yl, 4,4-diphenylpiperidine-1-yl, 4-acetyl-4-phenylpiperidine-1-yl, 4- (4-methoxyphenyl) piperidin-1-yl, 4- (4- (4-methoxyphenyl) It can be fluorophenyl) piperidine-1-yl or 3-phenylpiperidine-1-yl, where D may be further substituted with one or more _RMs (eg, fluoro, chloro, methyl, methoxy).

In certain other embodiments of this aspect of the invention, L ₄ is C _1- C ₆ alkylene, -O- or -S (O) _2- , and G ₂ is.

であり、

And

は上記で定義の通りであり、Ｒ_Ｇ２で置換されていても良く、Ｇ_３は上記で定義の通りであり、Ｒ_Ｇ３で置換されていても良い。従って、

Is as defined above, may be substituted with R _G2, G ₃ are as defined above, it may be substituted with R _G3. Therefore,

は、例えば４−トシルピペラジン−１−イル、４−フェノキシピペリジン−１−イル、３−フェノキシピロリジン−１−イル、４−ベンジルピペリジン−１−イル、４−フェネチルピペリジン−１−イルまたは３−フェニルプロピル）ピペリジン−１−イルであることができる。

For example, 4-tosylpiperazin-1-yl, 4-phenoxypiperidine-1-yl, 3-phenoxypyrrolidine-1-yl, 4-benzylpiperidine-1-yl, 4-phenethylpiperidin-1-yl or 3-yl. It can be phenylpropyl) piperidine-1-yl.

In certain other embodiments of this aspect of the present invention, D is phenyl or pyridyl, D is is substituted by G _2, G ₂ is substituted with L ₄ -G ₃ and 1 or more R _G2 which may be a spiro, a bridged or fused bicyclic carbon ring or heterocyclic ring, D is may be substituted by one or more _{R M, R M, L 4} , G 3 and R _G2 are hereby As defined in the book. In certain embodiments, G ₂ is

であり、

And

は、窒素原子を介して親分子部分に結合しているスピロ、架橋もしくは縮合の二環式窒素含有複素環（例えば、３−アザビシクロ［３．２．０］ヘプト−３−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イル、１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イル）であり、Ｇ_３および１以上のＲ_Ｇ２で置換されていても良い。従って、Ｇ_２は３−アザビシクロ［３．２．０］ヘプト−３−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イルまたは１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イルであり；Ｌ_４は結合であり、Ｄは１以上のＲ_Ｍ（例えば、フルオロ、クロロ、メチル、メトキシ）で置換されていても良い。

Is a spiro, cross-linked or condensed bicyclic nitrogen-containing heterocycle (eg, 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo) attached to the parent molecule via a nitrogen atom. [2.2.2] Oct-2-yl, 6-azaspiro [2.5] Oct-6-yl, Octahydro-2H-isoindole-2-yl, 3-azaspiro [5.5] Undec-3- yl, 1,3-dihydro -2H- isoindol-2-yl, 1,4-dioxa-8-azaspiro [4.5] dec-8-yl), optionally substituted with _{G 3,} and 1 or more _{R G2} It may have been done. Therefore, G ₂ is 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] octo-2-yl, 6-azaspiro [2.5] octo-6-yl. , Octahydro-2H-isoindole-2-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindole-2-yl or 1,4-dioxa-8-azaspiro [4.5] Dec-8-yl; L ₄ is a bond and D may be substituted with one or more _RMs (eg, fluoro, chloro, methyl, methoxy).

In certain embodiments of this aspect of the invention, D

であり、Ｒ_Ｍは式Ｉ_Ｅとの関連で上記で定義の通りであり、Ｄは１以上の別のＲ_Ｍによって置換されていても良い。例えば、Ｄが

In and, R _M is as defined above in connection with formula I _E, D may be substituted by one or more different R _M. For example, D

である場合、Ｒ_Ｍはフルオロ、クロロ、ｔｅｒｔ−ブチル、−Ｏ−ＣＨ_２ＣＨ_３、−Ｏ−ＣＦ_３、−Ｏ−ＣＨ_２ＣＨＦ_２、−Ｏ−ＣＨ_２ＣＨ_２ＯＣＨ_３、−Ｏ−ＣＨ_２−（３−エチルオキセタン−３−イル）、−Ｏ−ＣＨ_２−（１，３−ジオキソラン−４−イル）、−Ｏ−シクロペンチル、−Ｏ−シクロヘキシル、−Ｏ−フェニル、−Ｏ−（１，３−ジオキサン−５−イル）、シクロプロピル、シクロヘキシル、フェニル、ＳＦ_５、−ＳＯ_２Ｍｅまたは−Ｎ（ｔ−Ｂｕ）Ｃ（Ｏ）Ｍｅであることができ、Ｄはハロゲン（例えば、フルオロ、クロロ）およびＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。

If, _RM is fluoro, chloro, tert-butyl, -O-CH ₂ CH ₃ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -O-CH ₂ CH ₂ OCH ₃ , -O- CH _2- (3-ethyloxetane-3-yl), -O-CH _2- (1,3-dioxolane-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -O- It can be (1,3-dioxane-5-yl), cyclopropyl, cyclohexyl, phenyl, SF ₅ , -SO ₂ Me or -N (t-Bu) C (O) Me, where D is halogen (eg, halogen (eg). , fluoro, chloro) and C ₁ -C ₆ alkyl (e.g., optionally substituted by one or more different R _M is selected from the group consisting of methyl).

In certain embodiments, D is

であり、Ｒ_Ｍはフルオロ、クロロ、ｔｅｒｔ−ブチル、−Ｏ−ＣＨ_２ＣＨ_３、−Ｏ−ＣＦ_３、−Ｏ−ＣＨ_２ＣＨＦ_２、−Ｏ−ＣＨ_２ＣＨ_２ＯＣＨ_３、ＳＦ_５、−ＳＯ_２Ｍｅまたは−Ｎ（ｔ−Ｂｕ）Ｃ（Ｏ）Ｍｅであり、Ｄはハロゲン（例えば、フルオロ、クロロ）およびＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。

_RM is fluoro, chloro, tert-butyl, -O-CH ₂ CH ₃ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -O-CH ₂ CH ₂ OCH ₃ , SF ₅ ,- a SO ₂ Me, or -N (t-Bu) C ( O) Me, D is a halogen (e.g., fluoro, chloro) and _C 1 -C ₆ alkyl (e.g., methyl) one or more selected from the group consisting of by another R _M of which may be substituted.

In certain embodiments, D is

であり、Ｒ_Ｍはシクロプロピル、シクロヘキシルまたはフェニルであり、Ｄはハロゲン（例えば、フルオロ、クロロ）およびＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。

In and, R _M is cyclopropyl, cyclohexyl or phenyl, D is a halogen (e.g., fluoro, chloro) and C ₁ -C ₆ alkyl (e.g., methyl) another one or more selected from the group consisting of R _It may be replaced by _M.

In certain embodiments, D is

であり、Ｒ_Ｍは−Ｏ−ＣＨ_２−（３−エチルオキセタン−３−イル）、−Ｏ−ＣＨ_２−（１，３−ジオキソラン−４−イル）、−Ｏ−シクロペンチル、−Ｏ−シクロヘキシル、−Ｏ−フェニルまたは−Ｏ−（１，３−ジオキサン−５−イル）であり、Ｄはハロゲン（例えば、フルオロ、クロロ）およびＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。

And a, _{R M} is _-O-CH 2 - (3- _{ethyloxetan-3-yl), - O-CH 2 -} (1,3- dioxolan-4-yl), - O-cyclopentyl, -O- cyclohexyl is -O- phenyl or -O- (1,3-dioxan-5-yl), D is selected from the group consisting of halogen (e.g., fluoro, chloro) and _C 1 -C ₆ alkyl (e.g., methyl) it may be substituted by one or more different R _M being.

In certain embodiments, D is

であり、Ｇ_２はピリジニル（例えば、ピリジン−２−イル）、ピペリジン−１−イル、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イル、３，３−ジメチルアゼチジン−１−イルまたはオキサゾリル（例えば、１，３−オキサゾール−２−イル）であり、Ｄはハロゲン（例えば、フルオロ、クロロ）およびＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。

G ₂ is pyridinyl (eg, pyridine-2-yl), piperidine-1-yl, 4,4-dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, 2,6-dimethyl Piperidine-1-yl, 4- (propan-2-yl) piperidine-1-yl, 4-fluoropiperidine-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine- 1-yl, 4-methylpiperidine-1-yl, 4-tert-butylpiperidine-1-yl, 2-oxopiperidine-1-yl, 3,3-dimethylazetidine-1-yl or oxazolyl (eg, 1) , 3-oxazol-2-yl), and, D is a halogen (e.g. substitution, fluoro, chloro) and _C 1 -C ₆ alkyl (e.g., by one or more different _{R M} is selected from the group consisting of methyl) It may have been done.

In another embodiment of this aspect of the invention, D

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

In and, _{G 1} is N, be a C-H or _{C-R M; G 2} is

であり、

And

は窒素原子を介して親分子部分に結合している単環式４から８員窒素含有複素環（例えば、アゼチジニル、ピロリジニル、ピペリジニル）であり、Ｌ_４−Ｇ_３によって置換されており、１以上のＲ_Ｇ２で置換されていても良く；Ｌ_４は結合、Ｃ_１−Ｃ_６アルキレン、−Ｏ−または−Ｓ（Ｏ）_２−であり；Ｇ_３はアリール（例えば、フェニル）、シクロアルキル（例えば、シクロヘキシル）または複素環（例えばチエニル）であり、各Ｇ_３は１以上のＲ_Ｇ３で置換されていても良く；Ｒ_Ｇ２およびＲ_Ｇ３は各場合でそれぞれ独立にハロゲン、−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルであり；ｇは０、１、２または３であり；Ｒ_Ｍは式Ｉ_Ｅとの関連で上記で定義の通りである、この実施形態による化合物の１群においてＤは

Bonded to are monocyclic 4 to 8 membered nitrogen-containing heterocyclic ring (e.g., azetidinyl, pyrrolidinyl, piperidinyl) to the parent molecular moiety through a nitrogen atom is, is substituted by L ₄ -G _3, 1 or more may be substituted by the _{R G2; L 4} is a _bond, C 1 -C ₆ alkylene, -O- or -S _{(O) 2} - a and; _{G 3} is aryl (e.g., phenyl), cycloalkyl ( for example, cyclohexyl) or a heterocyclic (e.g. thienyl), each _{G 3} are may be substituted by one or more _{R G3; R G2} and halogen _{R G3} is independently at each occurrence, -C (O) C _1- C ₆ alkyl, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl; g is 0, 1 , 2 or 3; _RM is as defined above in the context of formula _IE , in a group of compounds according to this embodiment D is

であり、Ｇ_３は１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

In and, G ₃ is 1 or two phenyl optionally substituted with R _G3; g is 0, 1 or 2; R _M is independently fluoro, chloro, methyl, methoxy, tri Fluoromethyl or trifluoromethoxy;

およびＲ_Ｇ３は上記で定義の通りである。この実施形態の化合物の別の下位群において、Ｄは、

And _RG3 are as defined above. In another subgroup of compounds of this embodiment, D

であり、Ｇ_３は１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；Ｒ_Ｍ１はそれぞれ独立に水素、フルオロ、クロロまたはメチルであり；Ｒ_Ｇ２は本明細書で記載の適宜の置換基である。この実施形態による化合物の別の群では、Ｄは

In and, G ₃ is 1 or two phenyl optionally substituted with R _G3; R _M1 are each independently hydrogen, fluoro, chloro or methyl; R _G2 is described herein It is an appropriate substituent. In another group of compounds according to this embodiment, D

であり、Ｌ_４はＣ_１−Ｃ_６アルキレン、−Ｏ−または−Ｓ（Ｏ）_２−であり；Ｇ_３は１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

L ₄ is C _1- C ₆ alkylene, -O- or -S (O) _2- ; G ₃ is a phenyl that may be substituted with one or two RG _3s ; g. is 0, 1 or 2; R _M are each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

であり、Ｒ_Ｇ３は上記で定義の通りである。

And _RG3 is as defined above.

In yet another embodiment of this aspect of the invention, D

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

In and, _{G 1} is N, be a C-H or _{C-R M; G 2} is

であり、

And

は、窒素原子を介して親分子部分に結合しているスピロ、架橋もしくは縮合の二環式窒素含有複素環（例えば、３−アザビシクロ［３．２．０］ヘプト−３−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イル、１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イル）であり、Ｌ_４−Ｇ_３および１以上のＲ_Ｇ２で置換されていても良く；Ｌ_４は結合、Ｃ_１−Ｃ_６アルキレン、−Ｏ−または−Ｓ（Ｏ）_２−であり；Ｇ_３はアリール（例えば、フェニル）、シクロアルキル（例えば、シクロヘキシル）または複素環（例えば、チエニル）であり、各Ｇ_３は１以上のＲ_Ｇ３で置換されていても良く；Ｒ_Ｇ２およびＲ_Ｇ３は各場合でそれぞれ独立にハロゲン、−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルであり；ｇは０、１、２または３であり；Ｒ_Ｍは式Ｉ_Ｅとの関連で上記で定義の通りである。この実施形態による化合物の１群において、Ｄは

Is a spiro, cross-linked or condensed bicyclic nitrogen-containing heterocycle (eg, 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo) attached to the parent molecule via a nitrogen atom. [2.2.2] Oct-2-yl, 6-azaspiro [2.5] Oct-6-yl, octahydro-2H-isoindole-2-yl, 3-azaspiro [5.5] Undec-3- Il, 1,3-dihydro-2H-isoindole-2-yl, 1,4-dioxa-8-azaspiro [4.5] deku-8-yl), L _4- G ₃ and R of 1 or more. _May be substituted with _G2 ; L ₄ is a bond, C _1- C ₆ alkylene, -O- or -S (O) _2- ; G ₃ is aryl (eg, phenyl), cycloalkyl (eg, eg). cyclohexyl) or a heterocyclic (e.g., thienyl), each _{G 3} are may be substituted by one or more _{R G3; R G2} and halogen _{R G3} is independently at each occurrence, -C (O) C _1- C ₆ alkyl, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl; g is 0, 1, 2 or 3; _RM is as defined above in the context of the formula _IE . In one group of compounds according to this embodiment, D

であり、ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

And g is 0, 1 or 2; _RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

は上記で定義の通りである。化合物のさらに別の下位群において、Ｄは

Is as defined above. In yet another subgroup of compounds, D

であり、Ｒ_Ｍ１はそれぞれ独立に水素、フルオロ、クロロまたはメチルであり、

And _RM1 are independently hydrogen, fluoro, chloro or methyl, respectively.

は上記で定義の通りである（例えば、３−アザビシクロ［３．２．０］ヘプト−３−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イル、１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イル）。

Is as defined above (eg, 3-azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindole-2-yl, 2-azabicyclo [2.2.2] octo- 2-yl, 6-azaspiro [2.5] octo-6-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindole-2-yl, 1,4 -Dioxa-8-azaspiro [4.5] deku-8-yl).

In yet another embodiment of this aspect of the invention, D

であり、

And

は、１以上のＲ_Ｇ２で置換されている単環式４から８員窒素含有複素環（例えば、アゼチジニル、ピロリジニル、ピペリジニル）であり、Ｒ_Ｇ２は各場合でそれぞれ独立にハロゲン、−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルであり；Ｒ_Ｍはそれぞれ独立にハロゲン、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルである。この実施形態による化合物の１群において、

Is one or more R _G2 monocyclic 4 to 8 membered nitrogen-containing heterocyclic ring substituted with (e.g., azetidinyl, pyrrolidinyl, piperidinyl), R _G2 halogen is independently at each occurrence, -C (O ) _C 1 -C ₆ alkyl, _-C 1 -C ₆ alkyl, _-C 1 -C ₆ haloalkyl, it is a _-O-C 1 -C ₆ alkyl, or _-O-C 1 -C ₆ haloalkyl; _{R M} are each Independently halogen, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl. In one group of compounds according to this embodiment

は１個もしくは２個のＲ_Ｇ２で置換されているアゼチジニル、ピロリジニルまたはピペリジニルであり、Ｒ_Ｇ２は各場合でそれぞれ独立にメチル、エチル、イソプロピル、ｔｅｒｔ−ブチル、フルオロ、クロロまたはトリフルオロメチルであり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロまたはメチルである。例えば

Is azetidinyl substituted with one or two R _G2, pyrrolidinyl or piperidinyl, methyl R _G2 are independently at each occurrence, ethyl, isopropyl, tert- butyl, fluoro, chloro or trifluoromethyl ; R _M are each independently fluoro, chloro or methyl. For example

は、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イルまたは３，３−ジメチルアゼチジン−１−イルである。

4,4-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, 2,6-dimethylpiperidine-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-Fluoropiperidin-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine-1-yl, 4-methylpiperidine-1-yl, 4-tert-butylpiperidine-1 -Il, 2-oxopiperidine-1-yl or 3,3-dimethylazetidine-1-yl.

Compounds of the following formula _IE :

において、分子の残りの部分へのＸの結合は、略した構造式Ｘ′によって簡便に描くことができ、そこではＸに結合した基は式Ｉ_Ｅに描かれているものと同じ相対空間的方向を維持している。理解すべき点として、可変要素基Ｘをその後に描く場合には、Ｘの置換基は式Ｉ_Ｅおよび式Ｘ′と同じ相対的位置および方向を補助することになる。

In, the bond of X to the rest of the molecule can be conveniently depicted by the abbreviated structural formula X', where the group attached to X is the same relative spatial as that depicted in formula _IE. Maintaining direction. It should be understood that when the variable element group X is subsequently drawn, the substituents of X will assist in the same relative positions and orientations as in formulas _IE and X'.

式Ｉ_Ｅの化合物には、可変要素ＸがＸ−１、Ｘ−２、Ｘ−３およびＸ−４からなる群から選択され、Ｘ−１、Ｘ−２、Ｘ−３およびＸ−４が分子の残り部分に対して構造Ｘ′と同じ方向を保持しており；Ｘ−１、Ｘ−２およびＸ−３における

In the compounds of formula _IE , the variable element X is selected from the group consisting of X-1, X-2, X-3 and X-4, with X-1, X-2, X-3 and X-4 It holds the same orientation as structure X'with respect to the rest of the molecule; at X-1, X-2 and X-3.

の存在が、単結合もしくは二重結合を表し、Ｘ_１がＣ_１−Ｃ_２アルキレンまたはＣ_２アルケニレンであり、Ｘ_２およびＸ_３がそれぞれＣ_１−Ｃ_２アルキレンまたはＣ_２アルケニレンであり、Ｘ_４がＣ_１−Ｃ_２アルキレンであるものなどがある。

The presence of represents a single or double bond, where X ₁ is C _1- C ₂ alkylene or C ₂ alkenylene, X ₂ and X ₃ are C _1- C ₂ alkylene or C ₂ alkenylene, respectively, and X. _In some cases, ₄ is C _1- C ₂ alkylene.

According to the above description, in certain embodiments of this aspect of the present invention, X is pyrrolyl, wherein X _A:

に示したように分子の残りの部分に結合している。ある種の実施形態において、Ｘはピロリジニルであり、式Ｘ_Ｂ：

It is bound to the rest of the molecule as shown in. In certain embodiments, X is pyrrolidinyl and formula X _B :

に示したように分子の残りの部分に結合している。式Ｘ_Ｂによる実施形態は、シス（Ｘ_Ｂ１）型またはトランス（Ｘ_Ｂ２）型：

It is bound to the rest of the molecule as shown in. The embodiment according to the formula X _B is: cis (X _B1 ) type or trans (X _B2 ) type:

で存在していることができる。Ｘ_Ｂ、Ｘ_Ｂ１およびＸ_Ｂ２におけるキラル炭素原子は、（Ｒ）または（Ｓ）の絶対立体化学を有することができる。

Can exist in. The chiral carbon atoms at X _B , X _B1 and X _B2 can have the absolute stereochemistry of (R) or (S).

In yet another embodiment of this aspect of the invention, X is pyrrolyl and formula X _C1 or X _C2 :.

に示したように分子の残りの部分に結合している。ある種の実施形態において、Ｘはピロリジニルであり、式Ｘ_Ｄ１またはＸ_Ｄ２：

It is bound to the rest of the molecule as shown in. In certain embodiments, X is pyrrolidinyl and formula X _D1 or X _D2 :.

に示したように分子の残りの部分に結合している。式Ｘ_Ｄ１またはＸ_Ｄ２による実施形態は、シス型またはトランス型で存在することができ、Ｘ_Ｄ１およびＸ_Ｄ２におけるキラル炭素原子は（Ｒ）または（Ｓ）の絶対立体化学を有することができる。ある種の実施形態において、Ｘはアゼチジニルであり、式Ｘ_Ｅ１またはＸ_Ｅ２：

It is bound to the rest of the molecule as shown in. The embodiment according to the formula X _D1 or X _D2 can exist in the cis or trans form, and the chiral carbon atoms in X _D1 and X _D2 can have the absolute stereochemistry of (R) or (S). In certain embodiments, X is azetidinyl and formula X _E1 or X _E2 :.

に示したように分子の残りの部分に結合している。Ｘ_Ｅ１およびＸ_Ｅ２におけるキラル炭素原子は、独立に（Ｒ）または（Ｓ）の絶対立体化学を有することができる。

It is bound to the rest of the molecule as shown in. The chiral carbon atoms in X _E1 and X _E2 can independently have (R) or (S) absolute stereochemistry.

In certain preferred embodiments of this aspect of the present invention, X is _{X A, X B, X B1} , X B2, X C1 or _{X C2} and _L 1, _{L 2} and _{L 3} are each a bond. In certain other embodiments, X is X _D1 , X _D2 , X _E1 or X _{E 2} , and L ₁ , L ₂ and L ₃ are bonds, respectively. In another embodiment, X is X _E1 , L ₁ and L ₂ are methylene (that is, -CH _2- ), respectively, and L ₃ is a bond.

In the compounds of formula _{I E,} Y is _{-T'-C (R 1 R 2} ) N (R 5) -T-R D, Z is _{-T'-C (R 8 R 9} ) N (R 12 ) -T- _RD ; T', R ₁ , R ₂ , R ₅ , R ₈ , R ₉ , R ₁₂ , T and R _D are as defined herein.

Preferably R ₁ , R ₂ , R ₅ , R ₈ , R ₉ and R ₁₂ are independently hydrogen; C _1- C ₆ alkyl; or 3 to 6 membered carbocycles or heterocycles, 3 to 6 respectively. carbocycle or heterocycle each case independently of personnel, one or more substituted with a substituent may be selected from halogen or C ₁ -C ₆ alkyl; R ₂ and R ₅ are bonded to them together are atom, may form a heterocyclic ring of 3 to 12-membered substituted with 0, 1, 2, 3 or 4 _{R a, atoms R 9} and _{R 12} are attached they together, may form a heterocyclic ring of 3 to 12-membered substituted with 0, 1, 2, 3 or 4 R _a, R _a is as defined herein.

In certain embodiments of this aspect of the present invention, _{R 1} is hydrogen, together with the atoms _{to which R 2} and _{R 5} are attached they, substituted with 0, 1, 2, 3 or 4 _{R A} 3 to 12 membered heterocycles (eg,

）を形成しており、Ｒ_Ａはハロゲン（例えば、フルオロ、クロロ）；シアノ；Ｌ_Ｓが単結合でありＲ_ＥがＣ_１−Ｃ_６アルキル（例えば、メチル、エチル）、−Ｏ−Ｃ_１−Ｃ_６アルキル（例えば、メトキシ）または−Ｏ−Ｃ_１−Ｃ_６ハロアルキル（例えば、トリフルオロメトキシ）であるＬ_Ｓ−Ｒ_Ｅ；またはＬ_Ｓが二重結合でありＲ_Ｅが＝Ｃ（Ｒ_ＳＲ_Ｓ′）（例えば、

) Forms a, _{R A} is a halogen (e.g., fluoro, chloro), cyano; _{L S} is a bond _{R E} is _C 1 -C ₆ alkyl (e.g., methyl, ethyl), - _{O-C 1} -C ₆ alkyl (e.g., methoxy) or _-O-C 1 -C ₆ haloalkyl (e.g., trifluoromethoxy) which is _L S -R _E; or _{L S} is a double bond _{R E} is = C (R _S R _S ') (for example,

）であるＬ_Ｓ−Ｒ_Ｅである。好ましい実施形態において、Ｒ_２およびＲ_５がそれらが結合している原子とともに、０個もしくは１個のＲ_Ａで置換されているピロリジン環（すなわち、

) Is an _L S -R _E is. In a preferred embodiment, the pyrrolidine ring (i.e.,) in which R ₂ and R ₅ are substituted with 0 or 1 _RA with the atom to which they are attached

）を形成しており、Ｒ_Ａはフルオロ、メトキシ、メチル、エチルまたはシアノである。別の好ましい実施形態において、Ｒ_２およびＲ_５がそれらが結合している原子とともに、ピロリジン環（すなわち、

), And _RA is fluoro, methoxy, methyl, ethyl or cyano. In another preferred embodiment, R ₂ and R ₅ together with the atom to which they are attached are pyrrolidine rings (ie, ie).

）を形成している。

) Is formed.

In certain other embodiments of this aspect of the present invention, _{R 8} is hydrogen, together with the atoms _{to which R 9} and _{R 12} are attached they, 0,1,2,3 or 4 _{R A} A 3- to 12-membered heterocycle substituted with (eg,

）を形成しており、Ｒ_Ａはハロゲン（例えば、フルオロ、クロロ）；シアノ；Ｌ_Ｓが単結合でありＲ_ＥがＣ_１−Ｃ_６アルキル（例えば、メチル、エチル）、−Ｏ−Ｃ_１−Ｃ_６アルキル（例えば、メトキシ）または−Ｏ−Ｃ_１−Ｃ_６ハロアルキル（例えば、トリフルオロメトキシ）であるＬ_Ｓ−Ｒ_Ｅ；またはＬ_Ｓが二重結合でありＲ_Ｅが＝Ｃ（Ｒ_ＳＲ_Ｓ′）（例えば、

) Forms a, _{R A} is a halogen (e.g., fluoro, chloro), cyano; _{L S} is a bond _{R E} is _C 1 -C ₆ alkyl (e.g., methyl, ethyl), - _{O-C 1} -C ₆ alkyl (e.g., methoxy) or _-O-C 1 -C ₆ haloalkyl (e.g., trifluoromethoxy) which is _L S -R _E; or _{L S} is a double bond _{R E} is = C (R _S R _S ') (for example,

）であるＬ_Ｓ−Ｒ_Ｅである。好ましい実施形態において、Ｒ_９およびＲ_１２がそれらが結合している原子とともに、０個もしくは１個のＲ_Ａで置換されているピロリジン環（すなわち、

) Is an _L S -R _E is. In a preferred embodiment, the pyrrolidine ring (i.e.,) in which R ₉ and R ₁₂ are substituted with 0 or 1 _RA , together with the atom to which they are attached.

）を形成しており、Ｒ_Ａはフルオロ、メトキシ、メチル、エチルまたはシアノである。別の好ましい実施形態において、Ｒ_９およびＲ_１２がそれらが結合している原子とともに、ピロリジン環（すなわち、

), And _RA is fluoro, methoxy, methyl, ethyl or cyano. In another preferred embodiment, R ₉ and R ₁₂ together with the atom to which they are attached, together with the pyrrolidine ring (ie, ie.

）を形成している。

) Is formed.

As used herein, the chiral carbon in the ring formed by combining R ₂ and R ₅ or R ₉ and R ₁₂ can have the stereochemistry of (R) or (S). A pyrrolidine ring formed from R ₂ and R ₅ or R ₉ and R ₁₂ (ie,

）は好ましくは、（Ｓ）立体化学（すなわち、

) Is preferably (S) stereochemistry (ie,

）を有する。

).

In this aspect of the present invention, T 'in each case independently a _{bond, -C (O) N (R} B) -, - or from 3 to 12-membered heterocycle _{- N (R B) C (} O) is selected, heterocycle 12 membered from the 3 may be substituted by one or more R _a independently at each occurrence, R _a and R _B are as described herein. In particular, T 'is -C (O) N _{(R B)} - if it is, it is possible _{R B} is hydrogen (i.e., T' is -C (O) N (H) - and is). In certain embodiments, T 'is optionally substituted with one or more R _A in each case imidazolyl (i.e.,

）であり、Ｒ_Ａはハロゲン（例えば、フルオロ、クロロ）、Ｃ_１−Ｃ_６アルキル（例えば、メチル、エチル）またはＣ_１−Ｃ_６ハロアルキル（例えば、トリフルオロメチル）である。ある種の実施形態において、Ｔ′はイミダゾリル（すなわち、

), And _RA is a halogen (eg, fluoro, chloro), C _1- C ₆ alkyl (eg, methyl, ethyl) or C _1- C ₆ haloalkyl (eg, trifluoromethyl). In certain embodiments, T'is imidazolyl (ie, i.e.).

）である。

).

This aspect of the invention envisions specific combinations of A and Y and B and Z. A is _C 5 -C ₆ carbocyclic (e.g., phenyl) or 5 to 6 membered heterocyclic ring (e.g., pyridinyl or thiazolyl) preferably Y and B are _C 5 -C ₆ carbocyclic ring when it is (e.g., phenyl) Or a preferred example of Z in the case of a 5- to 6-membered heterocycle (eg, pyridinyl or thiazolyl) is

などがあるが、これらに限定されるものではなく、ＴおよびＲ_Ｄは本明細書で定義の通りである。

However, but not limited to these, T and _RD are as defined herein.

In certain embodiments of this aspect of the present invention, A may be substituted with one or more R _A described herein

であり、またはＹ−Ａは

Or YA is

であり、Ｔ′が結合である場合の好ましいＹの例としては、

As a preferred example of Y when T'is a bond,

などがあるが、これらに限定されるものではなく、ＴおよびＲ_Ｄは本明細書で定義の通りである。

However, but not limited to these, T and _RD are as defined herein.

In certain embodiments of this aspect of the present invention, B may be substituted with one or more R _A described herein

であり、Ｂ−Ｚは

And BZ is

であり、Ｔ′が結合である場合の好ましいＺの例には、

A preferred example of Z when T'is a bond is

などがあるが、これらに限定されるものではなく、ＴおよびＲ_Ｄは本明細書で定義の通りである。

However, but not limited to these, T and _RD are as defined herein.

T is independently at each occurrence a bond or -C (O) -L _S '- a and, _{L S'} are as defined herein. L _S ′

などがあるが、これらに限定されるものではなく、Ｌ_Ｓ′は１以上のＲ_Ｌで置換されていても良く；Ｒ_Ｌは炭素環（例えば、シクロヘキシル、シクロペンチル、シクロブチル、シクロプロピル、フェニル）、メトキシまたは複素環（例えば、テトラヒドロフラニル、テトラヒドロピラニル）など（これらに限定されるものではない）の置換基である。

There are like, but the invention is not limited to, L S _'may be substituted by one or more R _L; R _L is carbocyclic (e.g., cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl) , Methoxy or heterocycles (eg, tetrahydrofuranyl, tetrahydropyranyl), etc. (but not limited to these).

R _D is hydrogen or _{R A, R A} is as defined herein. Therefore, the _{R D,} it is like _{R A,} is not limited thereto, _{R A} is _{L S} -R _{E, L} S and _{R E} are as defined herein. Therefore, _LS is a bond to R _D , and _RE is -N ( _RS R _S '), -N ( _RS ) C (O) R _S ' _, -N ( _RS ) C (O). _{N (R S 'R S "} ), - N (R S) SO 2 R S', -N (R S) SO 2 N (R S 'R S"), - N (R S) S (O) _{N (R S 'R S "} ), - N (R S) C (O) oR S' is or _{-N (R S) S (O} ) -R S 'L S -R E; or each independently halogen in each case, hydroxy, _cyano, C 1 -C _{6 alkyl,} and C 2 -C _{6 alkenyl,} optionally substituted by one or more substituents selected from C 2 -C ₆ alkynyl or _C 1 -C ₆ haloalkyl There are also good C _3- C ₁₂ carbocycles or 3- to 12-membered heterocycles, but are not limited to these.

In one embodiment of this aspect of the present invention, _{R D} is the _{L S} -R _{E, L} S is a bond, _{R E} is _{-N (R S) C (O} ) OR S ' or 3 to 12-membered Heterocycles of (eg, pyrrolidine, piperidine, azepanyl), _RS and _RS ′ are as defined herein. For example _{R D} is preferably _{L S} -R _{E, L} S is a bond, _{R E} is -N (H) C (O) OMe.

Therefore, according to the above description, T- _RD

などがあるが、これらに限定されるものではない。Ｔ−Ｒ_Ｄは特定の立体化学配置を含んでいても良く；従って、Ｔ−Ｒ_Ｄには、

However, it is not limited to these. The T- _RD may contain a specific stereochemical configuration; therefore, the T- _RD may include.

などがあるが、これらに限定されるものではない。

However, it is not limited to these.

According to this aspect of the invention, A is C ₅ -C ₆ carbocyclic (e.g., phenyl) or 5 to 6 membered heterocyclic ring (e.g., pyridinyl or thiazolyl) preferably Y and B when it is the C ₅ - C ₆ carbocycle (e.g., phenyl) preferred examples of Z when it is or 5 to 6 membered heterocyclic ring (e.g., pyridinyl or thiazolyl) is

などがあるが、これらに限定されるものではない。

However, it is not limited to these.

A may be substituted by one or more R _A described herein

であり、Ｙ−Ａが

And YA

である場合の好ましいＹの例としては、

As a preferable example of Y in the case of

などがあるが、これらに限定されるものではない。

However, it is not limited to these.

B may be substituted with one or more R _A described herein

であり、Ｂ−Ｚが

And BZ

である好ましいＺの例としては、

An example of a preferred Z is

などがあるが、これらに限定されるものではない。

However, it is not limited to these.

In yet another aspect, the invention features acceptable salts compounds and pharmaceutical of formula I _F.

式中、
Ｘは

During the ceremony
X is

であり、Ｘは１以上のＲ_Ａで置換されていても良く；
Ａは

In it, X is may be substituted by one or more R _A;
A is

であり、Ａは１以上のＲ_Ａで置換されていても良く；
Ｂは

In it, A is may be substituted by one or more R _A;
B is

であり、Ｂは１以上のＲ_Ａで置換されていても良く；
Ｙ、Ｚ、Ｒ_ＡおよびＤは本明細書で上記で記載の通りである（例えば、式Ｉ、Ｉ_Ａ、Ｉ_Ｂ、Ｉ_Ｃ、Ｉ_ＤまたはＩ_Ｅについて記載の、好ましくは式Ｉ_Ｅについて記載のＹ、Ｚ、Ｒ_ＡおよびＤ）。

In it, B may be substituted by one or more R _A;
Y, Z, _{R A} and D are as described hereinabove (e.g., Formula _{I, I} A, I _B, described for I C, _{I D} or _{I E,} preferably for Formula _{I E} Y, Z, _RA and D) described.

In one embodiment of this aspect of the invention, X is

であり；Ａは

Is; A is

であり、Ａは１以上のＲ_Ａで置換されていても良く；Ｂは

In it, A is may be substituted by one or more R _A; B is

であり、Ｂは１以上のＲ_Ａで置換されていても良く；Ｙは

In it, B may be substituted by one or more R _A; Y is

であり；Ｚは

Is; Z is

であり；およびＤ、Ｒ_Ａ、ＴおよびＲ_Ｄは本明細書で上記で定義の通りである（例えば、式Ｉ、Ｉ_Ａ、Ｉ_Ｂ、Ｉ_Ｃ、Ｉ_ＤまたはＩ_Ｅに記載の通りであり、好ましくは式Ｉ_Ｅに記載の通りである。）。

In it, and _{D, R} A, T and _{R D} are as defined hereinabove (e.g., Formula _{I, I} A, I _B, were as described in I C, _{I D} or _{I E} Yes, preferably as described in Formula _IE ).

In another embodiment of this aspect of the invention, A or B is _RA [ _RA is each independently halogen (eg, fluoro, chloro). _{]; L S -R E [L} S is a bond, _{R E} is _-C 1 -C ₆ alkyl (e.g., methyl), - _{O-R S} (e.g., _-O-C 1 -C ₆ alkyl, -OCH ₃ ) or -C _1- C ₆ alkyl (eg, -CF ₃ ) which may be substituted with one or more halogens. ]; Or _{L S -R} E _[L S is _C 1 -C ₆ alkylene, _{R E} is _{-O-R S} (e.g., _-C 1 -C ₆ alkyl _-O-C 1 -C ₆ alkyl, - CH ₂ OCH ₃ ). ], It may be substituted with one or more substituents selected from. This embodiment, A and B compounds are replaced by are both one R _A; by A is one R _A; compound substituted A and B are both the zero of R _A is substituted, B is a compound which is substituted by 0 for R _a; is substituted by and a 0 of R _a, B is and compounds which are substituted by one R _a. Preferably, A is

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

であり；またはＡは

Is; or A is

であり、Ｂは

And B is

である。

Is.

In yet another embodiment of this aspect of the invention, T- _RD is independently in each case.

からなる群から選択され；（Ｓ）立体化学を有する化合物（例えば、

Selected from the group consisting of; (S) compounds having stereochemistry (eg,

）が好ましく、Ｄは本明細書において上記で定義の通りである。

) Is preferred, and D is as defined above herein.

In another embodiment, in this aspect of the invention, X

であり；Ａが

And A is

であり、Ａが１以上のＲ_Ａで置換されていても良く；Ｂが

And a, A is may be substituted by one or more R _A; B is

であり、Ｂが１以上のＲ_Ａで置換されていても良く；Ｙが

And B may be replaced by 1 or more _RA ; Y is

であり；Ｚが、

And Z is

であり；Ｄ、Ｒ_Ａ、ＴおよびＲ_Ｄが本明細書で上記で定義の通りである式Ｉ_Ｆの化合物およびその医薬として許容される塩を特徴とする。この実施形態による特定の下位群には、Ａが

By and; D, R A, and wherein the _{salt T} and R _D are acceptable compounds and their pharmaceutically formula I _F are as defined hereinabove. A is included in the specific subgroup according to this embodiment.

であり；Ｂが

And B is

であり；Ｙが

And Y is

であり；Ｚが

Is; Z is

であり；Ｔ−Ｒ_Ｄがそれぞれ独立に

And each T- _RD is independent

であり；およびＤが本明細書で上記で定義の通りである化合物などがある。

And some compounds where D is as defined above herein.

In yet another embodiment, this aspect of the invention is described by X.

であり；ＡおよびＢがそれぞれ

And A and B respectively

であり；ＹおよびＺがそれぞれ独立に

And Y and Z are independent of each other

であり；Ｄ、ＴおよびＲ_Ｄが本明細書で上記で定義の通りである式Ｉ_Ｆの化合物およびその医薬として許容される塩を特徴とする。この実施形態による特定の下位群には、Ｔ−Ｒ_Ｄがそれぞれ独立に

By and; D, and wherein the salt T and R _D are acceptable compounds and their pharmaceutically formula I _F are as defined hereinabove. Independent subgroups of T- _RD according to this embodiment

から選択され；Ｄが本明細書で上記で定義の通りである化合物などがある。

Selected from; such as compounds where D is as defined above herein.

According to description of this embodiment of the present invention in respective embodiments and Formula I _F above, a group and subgroup of compounds having a particular value for D. Included in each of the embodiments are a group of compounds and a subgroup having the following specific values for D.

In the description of aspects of embodiments and the present invention certain group and the compound according to formula I _F, D is

であり、Ｒ_Ｍはフルオロ、クロロ、ｔｅｒｔ−ブチル、−Ｏ−ＣＨ_２ＣＨ_３、−Ｏ−ＣＦ_３、−Ｏ−ＣＨ_２ＣＨＦ_２、−Ｏ−ＣＨ_２ＣＨ_２ＯＣＨ_３、−Ｏ−ＣＨ_２−（３−エチルオキセタン−３−イル）、−Ｏ−ＣＨ_２−（１，３−ジオキソラン−４−イル）、−Ｏ−シクロペンチル、−Ｏ−シクロヘキシル、−Ｏ−フェニル、−Ｏ−（１，３−ジオキサン−５−イル）、シクロプロピル、シクロヘキシル、フェニル、ＳＦ_５、−ＳＯ_２Ｍｅまたは−Ｎ（ｔ−Ｂｕ）Ｃ（Ｏ）Ｍｅであり、Ｄはハロゲン（例えば、フルオロ、クロロ）またはＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。

_RM is fluoro, chloro, tert-butyl, -O-CH ₂ CH ₃ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -O-CH ₂ CH ₂ OCH ₃ , -O-CH. _2- (3-Ethyloxetane-3-yl), -O-CH _2- (1,3-dioxolane-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -O- ( 1,3-dioxane-5-yl), cyclopropyl, cyclohexyl, phenyl, SF ₅ , -SO ₂ Me or -N (t-Bu) C (O) Me, where D is halogen (eg, fluoro, chloro). ) or C ₁ -C ₆ alkyl (e.g., optionally substituted by one or more different R _M is selected from the group consisting of methyl).

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _F, D is

であり、Ｇ_２はピリジニル（例えば、ピリジン−２−イル）、ピペリジン−１−イル、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イル、３，３−ジメチルアゼチジン−１−イルまたはオキサゾリル（例えば、１，３−オキサゾール−２−イル）であり、Ｄはハロゲン（例えば、フルオロ、クロロ）またはＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。特に、これらの群によれば、Ｄが

G ₂ is pyridinyl (eg, pyridine-2-yl), piperidine-1-yl, 4,4-dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, 2,6-dimethyl Piperidine-1-yl, 4- (propan-2-yl) piperidine-1-yl, 4-fluoropiperidine-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine- 1-yl, 4-methylpiperidine-1-yl, 4-tert-butylpiperidine-1-yl, 2-oxopiperidine-1-yl, 3,3-dimethylazetidine-1-yl or oxazolyl (eg, 1) , 3-oxazol-2-yl), and, D is a halogen (e.g. substitution, fluoro, chloro) or _C 1 -C ₆ alkyl (e.g., by one or more different _{R M} is selected from the group consisting of methyl) It may have been done. In particular, according to these groups, D

であり；Ｇ_２がピペリジン−１−イル、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イルまたは３，３−ジメチルアゼチジン−１−イルであり；Ｒ_Ｍ１がそれぞれ独立に水素、フルオロ、クロロまたはメチルである化合物である。

By and; _{G 2} is piperidin-1-yl, 4,4-dimethyl-1-yl, 4,4-difluoro-1-yl, 2,6-dimethyl-piperidin-1-yl, 4- (propane - 2-Il) piperidine-1-yl, 4-fluoropiperidine-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine-1-yl, 4-methylpiperidine-1-yl Il, 4-tert-butylpiperidine-1-yl, 2-oxopiperidine-1-yl or 3,3-dimethylazetidine-1-yl; _RM1 is independently hydrogen, fluoro, chloro or methyl, respectively. It is a compound.

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _F, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

In and, _{G 1} is N, be a C-H or _{C-R M; G 2} is

であり、

And

であり、Ｒ_Ｍおよびｇは本明細書で上記で定義の通りである。特に、これらの群によれば、Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２であり；

And _RM and g are as defined above herein. In particular, according to these groups, R _M are each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2;

は本明細書で上記で定義の通りである。さらに別の下位群では、Ｌ_４は結合であり；Ｇ_２は

Is as defined above herein. In yet another subgroup, L ₄ is a bond; G ₂ is

であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。特定の下位群では、

_RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In certain subgroups

は３−フェニルアゼチジン−１−イル、３−フェニルピロリジン−１−イル、４−フェニルピペラジン−１−イル、４−フェニルピペリジン−１−イル、４−フェニル−３，６−ジヒドロピリジン−１（２Ｈ）−イル、４，４−ジフェニルピペリジン−１−イル、４−アセチル−４−フェニルピペリジン−１−イル、４−（４−メトキシフェニル）ピペリジン−１−イル、４−（４−フルオロフェニル）ピペリジン−１−イルまたは３−フェニルピペリジン−１−イルであり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。他の下位群において、Ｌ_４はＣ_１−Ｃ_６アルキレン、−Ｏ−または−Ｓ（Ｏ）_２−であり；Ｇ_２は

3-Phenylazetidine-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperazine-1-yl, 4-phenylpiperidine-1-yl, 4-phenyl-3,6-dihydropyridine-1 ( 2H) -yl, 4,4-diphenylpiperidine-1-yl, 4-acetyl-4-phenylpiperidine-1-yl, 4- (4-methoxyphenyl) piperidin-1-yl, 4- (4-fluorophenyl) ) be piperidin-1-yl or 3-phenyl-piperidin-1-yl; _{R M} is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2 is there. In the other subgroups, L ₄ is C _1- C ₆ alkylene, -O- or -S (O) _2- ; G ₂ is

であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。特定の下位群において、

_RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In a particular subgroup

は４−トシルピペラジン−１−イル、４−フェノキシピペリジン−１−イル、３−フェノキシピロリジン−１−イル、４−ベンジルピペリジン−１−イル、４−フェネチルピペリジン−１−イルまたは３−フェニルプロピル）ピペリジン−１−イルであり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。化合物のさらに別の下位群では、Ｄは

Is 4-tosylpiperazin-1-yl, 4-phenoxypiperidine-1-yl, 3-phenoxypyrrolidine-1-yl, 4-benzylpiperidine-1-yl, 4-phenethylpiperidin-1-yl or 3-phenylpropyl ) be piperidin-1-yl; _{R M} is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In yet another subgroup of compounds, D is

であり、Ｇ_３は１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

In and, G ₃ is 1 or two phenyl optionally substituted with R _G3; g is 0, 1 or 2; R _M is independently fluoro, chloro, methyl, methoxy, tri Fluoromethyl or trifluoromethoxy;

およびＲ_Ｇ３は上記で定義の通りである。化合物の他の群では、Ｄは

And _RG3 are as defined above. In the other group of compounds, D

であり、Ｌ_４はＣ_１−Ｃ_６アルキレン、−Ｏ−または−Ｓ（Ｏ）_２−であり；Ｇ_３は１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

L ₄ is C _1- C ₆ alkylene, -O- or -S (O) _2- ; G ₃ is a phenyl that may be substituted with one or two RG _3s ; g. is 0, 1 or 2; R _M are each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

およびＲ_Ｇ３は上記で定義の通りである。化合物のさらに別の下位群では、Ｄは

And _RG3 are as defined above. In yet another subgroup of compounds, D is

であり、Ｇ_３は１個もしくは２個の本明細書において上記で定義のＲ_Ｇ３で置換されていても良いフェニルであり；Ｒ_Ｍ１はそれぞれ独立に水素、フルオロ、クロロまたはメチルであり；Ｒ_Ｇ２は−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルおよび−Ｏ−Ｃ_１−Ｃ_６ハロアルキルからなる群から選択される上記の適宜の置換基である。

And G ₃ is one or two _phenyls that may be substituted with RG _{3 as} defined above herein; _{RM 1} is independently hydrogen, fluoro, chloro or methyl; R. _G2 is derived from -C (O) C _1- C ₆ alkyl, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl and -O-C _1- C ₆ haloalkyl. The above-mentioned appropriate substituent selected from the group.

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _F, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

In and, _{G 1} is N, be a C-H or _{C-R M; G 2} is

であり、

And

、Ｒ_Ｍおよびｇは本明細書で上記で定義の通りである。特に、これらの下位群において、Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２であり；

, _RM and g are as defined above herein. In particular, in these subgroups, fluoro each R _M independently, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2;

は３−アザビシクロ［３．２．０］ヘプト−３−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イルまたは１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イルである。化合物のさらに別の下位群において、Ｄは

Is 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] octo-2-yl, 6-azaspiro [2.5] octo-6-yl, octahydro-2H -Isoindole-2-yl, 3-azaspiro [5.5] Undec-3-yl, 1,3-dihydro-2H-isoindole-2-yl or 1,4-dioxa-8-azaspiro [4.5] ] Dec-8-ile. In yet another subgroup of compounds, D

であり、ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

And g is 0, 1 or 2; _RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

は上記で定義の通りである。化合物のさらに別の下位群では、Ｄは

Is as defined above. In yet another subgroup of compounds, D is

であり、Ｒ_Ｍ１はそれぞれ独立に水素、フルオロ、クロロまたはメチルであり、

And _RM1 are independently hydrogen, fluoro, chloro or methyl, respectively.

は上記で定義の通りである（例えば、３−アザビシクロ［３．２．０］ヘプト−３−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イル、１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イル）。

Is as defined above (eg, 3-azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindole-2-yl, 2-azabicyclo [2.2.2] octo- 2-yl, 6-azaspiro [2.5] octo-6-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindole-2-yl, 1,4 -Dioxa-8-azaspiro [4.5] deku-8-yl).

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _F, D is

であり、

And

は１以上のＲ_Ｇ２で置換されている単環式４から８員窒素含有複素環（例えば、アゼチジニル、ピロリジニル、ピペリジニル）であり、Ｒ_Ｇ２各場合でそれぞれ独立にハロゲン、−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルであり；Ｒ_Ｍはそれぞれ独立にハロゲン、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルである。前記実施形態による化合物の各群において、

1 or more R _G2 substituted by by being monocyclic 4 to 8 membered nitrogen-containing heterocyclic ring (e.g., azetidinyl, pyrrolidinyl, piperidinyl) are halogen each case independently R _G2 each, -C (O) C ₁ -C ₆ alkyl, _-C 1 -C ₆ alkyl, _-C 1 -C ₆ haloalkyl, be a _-O-C 1 -C ₆ alkyl, or _-O-C 1 -C ₆ haloalkyl; _{R M} are each independently Halogen, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl. In each group of compounds according to the embodiment,

は、１個もしくは２個のＲ_Ｇ２で置換されているアゼチジニル、ピロリジニルまたはピペリジニルであり、Ｒ_Ｇ２は各場合で、それぞれメチル、エチル、イソプロピル、ｔｅｒｔ−ブチル、フルオロ、クロロまたはトリフルオロメチルであり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロまたはメチルである。例えば

Is one or azetidinyl substituted with two R _G2, pyrrolidinyl or piperidinyl, in case R _G2 each represent methyl, ethyl, isopropyl, tert- butyl, fluoro, chloro or trifluoromethyl _RM is independently fluoro, chloro or methyl, respectively. For example

は、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イルまたは３，３−ジメチルアゼチジン−１−イルである。

4,4-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, 2,6-dimethylpiperidine-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-Fluoropiperidin-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine-1-yl, 4-methylpiperidine-1-yl, 4-tert-butylpiperidine-1 -Il, 2-oxopiperidine-1-yl or 3,3-dimethylazetidine-1-yl.

In yet another aspect, the invention features acceptable salts compounds and pharmaceutically formula I _G.

式中、
Ｘは

During the ceremony
X is

であり、Ｘは１以上のＲ_Ａで置換されていても良く；
Ａは

In it, X is may be substituted by one or more R _A;
A is

であり、Ａは１以上のＲ_Ａで置換されていても良く；
Ｂは

In it, A is may be substituted by one or more R _A;
B is

であり、Ｂは１以上のＲ_Ａで置換されていても良く；
Ｙ、Ｚ、Ｒ_ＡおよびＤは本明細書で上記で記載の通りである（例えば、式Ｉ、Ｉ_Ａ、Ｉ_Ｂ、Ｉ_Ｃ、Ｉ_Ｄ、Ｉ_ＥまたはＩ_Ｆについて記載の通りであり、好ましくは式Ｉ_Ｅについて記載の通りである。）。

In it, B may be substituted by one or more R _A;
Y, Z, _{R A} and D are as described hereinabove (for example, as described for Formula _{I, I A, I B,} I C, I D, I E or _{I F,} Preferably, the formula _{IE is} as described).

In one embodiment, in this aspect of the invention, X

であり；Ａが

And A is

であり、Ａが１個のＲ_Ａで置換されていても良く；Ｂが

And A may be replaced by one _RA ; B is

であり、Ｂが１個のＲ_Ａで置換されていても良く；Ｒ_Ａがハロゲン（例えば、フルオロ、クロロ）、Ｌ_Ｓ−Ｒ_Ｅ［Ｌ_Ｓは単結合であり、Ｒ_Ｅは−Ｃ_１−Ｃ_６アルキル（例えば、メチル）、−Ｏ−Ｒ_Ｓ（例えば、−Ｏ−Ｃ_１−Ｃ_６アルキル、−ＯＣＨ_３）または１以上のハロゲンで置換されていても良い−Ｃ_１−Ｃ_６アルキル（例えば、−ＣＦ_３）である。］またはＬ_Ｓ−Ｒ_Ｅ［Ｌ_ＳはＣ_１−Ｃ_６アルキレンであり、Ｒ_Ｅは−Ｏ−Ｒ_Ｓ（例えば、−Ｃ_１−Ｃ_６アルキル−Ｏ−Ｃ_１−Ｃ_６アルキル、−ＣＨ_２ＯＣＨ_３）である。］であり；ＹおよびＺがそれぞれ独立に

In it, B can be substituted with one _{R A; R A} is a halogen (e.g., fluoro, _{chloro), L S -R E [L} S is a bond, _{R E} is -C ₁ May be substituted with -C ₆ alkyl (eg, methyl), -O- _RS (eg, -O-C _1- C ₆ alkyl, -OCH ₃ ) or one or more halogens -C _1- C ₆ Alkyl (eg, -CF ₃ ). Or _{L S -R} E _[L S is _C 1 -C ₆ alkylene, _{R E} is _{-O-R S} (e.g., _-C 1 -C ₆ alkyl _-O-C 1 -C ₆ alkyl, -CH ₂ OCH ₃ ). ]; Y and Z are independent

であり；Ｔ−Ｒ_Ｄがそれぞれ独立に

And each T- _RD is independent

であり；Ｄが本明細書で上記で定義の通りである式Ｉ_Ｇの化合物およびその医薬として許容される塩を特徴とする。

In it; D is characterized acceptable salts compounds and pharmaceutically formula I _G are as defined hereinabove.

In another embodiment, this aspect of the invention is
X is

であり；Ａが

And A is

であり、Ａが１個のＲ_Ａで置換されていても良く；Ｂが

And A may be replaced by one _RA ; B is

であり、Ｂが１個のＲ_Ａで置換されていても良く；Ｒ_Ａがハロゲン（例えば、フルオロ、クロロ）、Ｌ_Ｓ−Ｒ_Ｅ［Ｌ_Ｓは単結合であり、Ｒ_Ｅは−Ｃ_１−Ｃ_６アルキル（例えば、メチル）、−Ｏ−Ｒ_Ｓ（例えば、−Ｏ−Ｃ_１−Ｃ_６アルキル、−ＯＣＨ_３）または１以上のハロゲンで置換されていても良い−Ｃ_１−Ｃ_６アルキル（例えば、−ＣＦ_３）である。］またはＬ_Ｓ−Ｒ_Ｅ［Ｌ_ＳはＣ_１−Ｃ_６アルキレンであり、Ｒ_Ｅは−Ｏ−Ｒ_Ｓ（例えば、−Ｃ_１−Ｃ_６アルキル−Ｏ−Ｃ_１−Ｃ_６アルキル、−ＣＨ_２ＯＣＨ_３）である。］であり；ＹおよびＺがそれぞれ独立に

In it, B can be substituted with one _{R A; R A} is a halogen (e.g., fluoro, _{chloro), L S -R E [L} S is a bond, _{R E} is -C ₁ May be substituted with -C ₆ alkyl (eg, methyl), -O- _RS (eg, -O-C _1- C ₆ alkyl, -OCH ₃ ) or one or more halogens -C _1- C ₆ Alkyl (eg, -CF ₃ ). Or _{L S -R} E _[L S is _C 1 -C ₆ alkylene, _{R E} is _{-O-R S} (e.g., _-C 1 -C ₆ alkyl _-O-C 1 -C ₆ alkyl, -CH ₂ OCH ₃ ). ]; Y and Z are independent

であり、Ｔ−Ｒ_Ｄがそれぞれ独立に

And each T- _RD is independent

であり、（Ｓ）立体化学を有する化合物（例えば、

And (S) a compound having stereochemistry (eg,

）が特に想到され；Ｄが本明細書で上記で定義の通りである式Ｉ_Ｇの化合物およびその医薬として許容される塩を特徴とする。この下位群には、ＡおよびＢが両方とも１個のＲ_Ａによって置換されている化合物；ＡおよびＢが両方とも０個のＲ_Ａによって置換されている化合物；Ａが１個のＲ_Ａによって置換されており、Ｂが０個のＲ_Ａによって置換されている化合物；およびＡが０個のＲ_Ａによって置換されており、Ｂが１個のＲ_Ａによって置換されている化合物などがある。特に、この下位群によれば、Ａが

) It is particularly is contemplated; D is characterized acceptable salts compounds and pharmaceutically formula I _G are as defined hereinabove. This subgroup, compounds are replaced by A and B are both 1 R _A; A and B are both compounds are replaced by zero of R _A; A is by a single R _A is substituted, B is a compound which is substituted by 0 for R _a; is substituted by and a 0 of R _a, B is and compounds which are substituted by one R _a. In particular, according to this subgroup, A

であり、Ｂが

And B is

である化合物；またはＡが

Compound; or A is

であり、Ｂが

And B is

である化合物；またはＡが

Compound; or A is

であり、Ｂが

And B is

である化合物；またはＡが

Compound; or A is

であり、Ｂが

And B is

である化合物などがある。

There are compounds that are.

According to the description of this aspect of the present invention, respectively and Formula I _G of the embodiment, there are groups and subgroups of compounds having a particular value for D. Included in each of the embodiments are a group of compounds and a subgroup having the following specific values for D.

In the group of compounds according to this aspect of the invention, D is C _6- C ₁₀ aryl (eg, phenyl, naphthyl, indanyl) or 5 to 10 member heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydro). benzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, a benzo [d] [1,3] dioxol-5-yl), D is and compounds substituted with one or more _{R M.} Particular subgroups according to this aspect and their embodiments, _{R M} is halogen (e.g., fluoro, chloro, _bromo); C 1 -C ₆ alkyl (e.g., tert- butyl); optionally substituted with one or more halogens C _1- C ₆ alkyl (eg, CF ₃ ); -O-C _1- C ₆ alkyl (eg, -O-CH ₂ CH ₃ ); 1 or more halogens in each case (eg, -O-CF ₃₎ , _{-O-CH 2} CHF 2) or _-O-C 1 -C ₆ alkyl substituted with _-O-C 1 -C ₆ alkyl _{(-O-CH 2 CH 2 OCH} 3); optionally substituted -OC _1- C ₆ alkyl (eg, -O-CH) substituted with a 3- to 12-membered heterocycle (eg, 3-ethyloxetane-3-yl, 1,3-dioxolan-4-yl) ₂ ); -O- _RS [ _RS is a 3- to 12-membered carbocycle or heterocycle which may be substituted (eg, cyclopentyl, cyclohexyl, phenyl, 1,3-dioxane-5-yl). _{]; - N (R S)} C (O) R S '[R S and _{R S'} are each _C 1 -C ₆ alkyl independently (e.g., -N (t-Bu) C (O) Me ); SF ₅ ; -SO _{2 RS} [ _RS is C _1- C ₆ alkyl] (eg, -SO ₂ Me); or C _3- C ₁₂ carbon ring (eg, cyclopropyl, cyclohexyl, phenyl) There are compounds that are. Other subgroup of this embodiment, D is substituted by G _2, a phenyl optionally substituted by one or more R _M, heterocyclic from G ₂ is 3 12 membered (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl), the heterocyclic ring is halogen, hydroxy, oxo, _cyano, C 1 -C ₆ alkyl (e.g., _methyl), C 2 -C _{6 alkenyl,} C 2 -C ₆ alkynyl, C _1- C ₆ haloalkyl (eg CF ₃ ), C _2- C ₆ haloalkenyl, C _2- C ₆ haloalkynyl, -OC _1- C ₆ alkyl (eg -O-CH ₃ ), -C ( O) OR _S (eg, -C (O) OCH ₃ ), -C (O) R _S (eg, -C (O) CH ₃ ), -N ( _RS R _S ') or L _4- G _{3 RM} is selected from halogen (eg fluoro, chloro), alkyl (eg methyl), haloalkyl (eg CF ₃ ) or -OC _1- C ₆ alkyl (eg -O-CH ₃ ). It may be substituted with one or more substituents; such as compounds in which L ₄ , G ₃ , _RS and _RS ′ are as defined above herein.

In the description of aspects of embodiments and the present invention certain group and the compound according to formula I _G, D is

であり、Ｒ_Ｍはフルオロ、クロロ、ｔｅｒｔ−ブチル、−Ｏ−ＣＨ_２ＣＨ_３、−Ｏ−ＣＦ_３、−Ｏ−ＣＨ_２ＣＨＦ_２、−Ｏ−ＣＨ_２ＣＨ_２ＯＣＨ_３、−Ｏ−ＣＨ_２−（３−エチルオキセタン−３−イル）、−Ｏ−ＣＨ_２−（１，３−ジオキソラン−４−イル）、−Ｏ−シクロペンチル、−Ｏ−シクロヘキシル、−Ｏ−フェニル、−Ｏ−（１，３−ジオキサン−５−イル）、シクロプロピル、シクロヘキシル、フェニル、ＳＦ_５、−ＳＯ_２Ｍｅまたは−Ｎ（ｔ−Ｂｕ）Ｃ（Ｏ）Ｍｅであり、Ｄはハロゲン（例えば、フルオロ、クロロ）またはＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。

_RM is fluoro, chloro, tert-butyl, -O-CH ₂ CH ₃ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -O-CH ₂ CH ₂ OCH ₃ , -O-CH. _2- (3-Ethyloxetane-3-yl), -O-CH _2- (1,3-dioxolane-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -O- ( 1,3-dioxane-5-yl), cyclopropyl, cyclohexyl, phenyl, SF ₅ , -SO ₂ Me or -N (t-Bu) C (O) Me, where D is halogen (eg, fluoro, chloro). ) or C ₁ -C ₆ alkyl (e.g., optionally substituted by one or more different R _M is selected from the group consisting of methyl).

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _G, D is

であり、Ｇ_２はピリジニル（例えば、ピリジン−２−イル）、ピペリジン−１−イル、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イル、３，３−ジメチルアゼチジン−１−イルまたはオキサゾリル（例えば、１，３−オキサゾール−２−イル）であり、Ｄはハロゲン（例えば、フルオロ、クロロ）またはＣ_１−Ｃ_６アルキル（例えば、メチル）からなる群から選択される１以上の別のＲ_Ｍによって置換されていても良い。特に、これらの群によれば、Ｄが

G ₂ is pyridinyl (eg, pyridine-2-yl), piperidine-1-yl, 4,4-dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, 2,6-dimethyl Piperidine-1-yl, 4- (propan-2-yl) piperidine-1-yl, 4-fluoropiperidine-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine- 1-yl, 4-methylpiperidine-1-yl, 4-tert-butylpiperidine-1-yl, 2-oxopiperidine-1-yl, 3,3-dimethylazetidine-1-yl or oxazolyl (eg, 1) , 3-oxazol-2-yl), and, D is a halogen (e.g. substitution, fluoro, chloro) or _C 1 -C ₆ alkyl (e.g., by one or more different _{R M} is selected from the group consisting of methyl) It may have been done. In particular, according to these groups, D

であり；Ｇ_２がピペリジン−１−イル、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イルまたは３，３−ジメチルアゼチジン−１−イルであり；Ｒ_Ｍ１がそれぞれ独立に水素、フルオロ、クロロまたはメチルである化合物である。

By and; _{G 2} is piperidin-1-yl, 4,4-dimethyl-1-yl, 4,4-difluoro-1-yl, 2,6-dimethyl-piperidin-1-yl, 4- (propane - 2-Il) piperidine-1-yl, 4-fluoropiperidine-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine-1-yl, 4-methylpiperidine-1-yl Il, 4-tert-butylpiperidine-1-yl, 2-oxopiperidine-1-yl or 3,3-dimethylazetidine-1-yl; _RM1 is independently hydrogen, fluoro, chloro or methyl, respectively. It is a compound.

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _G, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

In and, _{G 1} is N, be a C-H or _{C-R M; G 2} is

であり、

And

、Ｒ_Ｍおよびｇは本明細書で上記で定義の通りである。特に、これらの群によれば、Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２であり；

, _RM and g are as defined above herein. In particular, according to these groups, R _M are each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2;

は本明細書で上記で定義の通りである。さらに別の下位群において、Ｌ_４は結合であり；Ｇ_２は

Is as defined above herein. In yet another subgroup, _{L 4} is a bond; _{G 2} is

であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。特定の下位群において、

_RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In a particular subgroup

は、３−フェニルアゼチジン−１−イル、３−フェニルピロリジン−１−イル、４−フェニルピペラジン−１−イル、４−フェニルピペリジン−１−イル、４−フェニル−３，６−ジヒドロピリジン−１（２Ｈ）−イル、４，４−ジフェニルピペリジン−１−イル、４−アセチル−４−フェニルピペリジン−１−イル、４−（４−メトキシフェニル）ピペリジン−１−イル、４−（４−フルオロフェニル）ピペリジン−１−イルまたは３−フェニルピペリジン−１−イルであり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。他の下位群において、Ｌ_４はＣ_１−Ｃ_６アルキレン、−Ｏ−または−Ｓ（Ｏ）_２−であり；Ｇ_２は

3-Phenylazetidine-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperazine-1-yl, 4-phenylpiperidine-1-yl, 4-phenyl-3,6-dihydropyridine-1 (2H) -yl, 4,4-diphenylpiperidine-1-yl, 4-acetyl-4-phenylpiperidine-1-yl, 4- (4-methoxyphenyl) piperidin-1-yl, 4- (4-fluoro) Phenyl) piperidine-1-yl or 3-phenylpiperidine-1-yl; _RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2 Is. In the other subgroups, L ₄ is C _1- C ₆ alkylene, -O- or -S (O) _2- ; G ₂ is

であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。特定の下位群において、

_RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In a particular subgroup

は、４−トシルピペラジン−１−イル、４−フェノキシピペリジン−１−イル、３−フェノキシピロリジン−１−イル、４−ベンジルピペリジン−１−イル、４−フェネチルピペリジン−１−イルまたは３−フェニルプロピル）ピペリジン−１−イルであり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２である。化合物のさらに別の下位群において、Ｄは

4-Tosylpiperazin-1-yl, 4-phenoxypiperidine-1-yl, 3-phenoxypyrrolidine-1-yl, 4-benzylpiperidine-1-yl, 4-phenethylpiperidin-1-yl or 3-phenylpropi Le) be piperidin-1-yl; R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In yet another subgroup of compounds, D

であり、Ｇ_３は１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

In and, G ₃ is 1 or two phenyl optionally substituted with R _G3; g is 0, 1 or 2; R _M is independently fluoro, chloro, methyl, methoxy, tri Fluoromethyl or trifluoromethoxy;

およびＲ_Ｇ３は上記で定義の通りである。化合物の他の群において、Ｄは

And _RG3 are as defined above. In the other group of compounds, D

であり、Ｌ_４はＣ_１−Ｃ_６アルキレン、−Ｏ−または−Ｓ（Ｏ）_２−であり；Ｇ_３は１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

L ₄ is C _1- C ₆ alkylene, -O- or -S (O) _2- ; G ₃ is a phenyl that may be substituted with one or two RG _3s ; g. is 0, 1 or 2; R _M are each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

およびＲ_Ｇ３は上記で定義の通りである。化合物のさらに別の下位群では、Ｄは

And _RG3 are as defined above. In yet another subgroup of compounds, D is

であり、Ｇ_３は本明細書において上記で定義の１個もしくは２個のＲ_Ｇ３で置換されていても良いフェニルであり；Ｒ_Ｍ１はそれぞれ独立に水素、フルオロ、クロロまたはメチルであり；Ｒ_Ｇ２は−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルおよび−Ｏ−Ｃ_１−Ｃ_６ハロアルキルからなる群から選択される上記で記載の適宜の置換基である。

In and, G ₃ is 1 or two phenyl optionally substituted with R _G3 as defined herein above; R _M1 are each independently hydrogen, fluoro, chloro or methyl; R _G2 is derived from -C (O) C _1- C ₆ alkyl, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl and -O-C _1- C ₆ haloalkyl. The appropriate substituents described above selected from the group.

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _G, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

In and, _{G 1} is N, be a C-H or _{C-R M; G 2} is

であり、

And

、Ｒ_Ｍおよびｇは本明細書で上記で定義の通りである。特に、これらの下位群によれば、Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；ｇは０、１または２であり；

, _RM and g are as defined above herein. In particular, according to these subgroups, R _M are each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2;

は３−アザビシクロ［３．２．０］ヘプト−３−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イルまたは１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イルである。化合物のさらに別の下位群において、Ｄは

Is 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] octo-2-yl, 6-azaspiro [2.5] octo-6-yl, octahydro-2H -Isoindole-2-yl, 3-azaspiro [5.5] Undec-3-yl, 1,3-dihydro-2H-isoindole-2-yl or 1,4-dioxa-8-azaspiro [4.5] ] Dec-8-ile. In yet another subgroup of compounds, D

であり、ｇは０、１または２であり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロ、メチル、メトキシ、トリフルオロメチルまたはトリフルオロメトキシであり；

And g is 0, 1 or 2; _RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

は上記で定義の通りである。化合物のさらに別の下位群において、Ｄは

Is as defined above. In yet another subgroup of compounds, D

であり、Ｒ_Ｍ１はそれぞれ独立に水素、フルオロ、クロロまたはメチルであり、

And _RM1 are independently hydrogen, fluoro, chloro or methyl, respectively.

は上記で定義の通りである（例えば、３−アザビシクロ［３．２．０］ヘプト−３−イル、オクタヒドロ−２Ｈ−イソインドール−２−イル、２−アザビシクロ［２．２．２］オクト−２−イル、６−アザスピロ［２．５］オクト−６−イル、３−アザスピロ［５．５］ウンデク−３−イル、１，３−ジヒドロ−２Ｈ−イソインドール−２−イル、１，４−ジオキサ−８−アザスピロ［４．５］デク−８−イル）。

Is as defined above (eg, 3-azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindole-2-yl, 2-azabicyclo [2.2.2] octo- 2-yl, 6-azaspiro [2.5] octo-6-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindole-2-yl, 1,4 -Dioxa-8-azaspiro [4.5] deku-8-yl).

In the description of this embodiment other groups and the embodiments and the present invention compounds according to formula I _G, D is

であり、

And

は１以上のＲ_Ｇ２で置換されている単環式４から８員窒素含有複素環（例えば、アゼチジニル、ピロリジニル、ピペリジニル）であり、Ｒ_Ｇ２は各場合でそれぞれ独立にハロゲン、−Ｃ（Ｏ）Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルであり；Ｒ_Ｍはそれぞれ独立にハロゲン、−Ｃ_１−Ｃ_６アルキル、−Ｃ_１−Ｃ_６ハロアルキル、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルである。前記実施形態による化合物の各群において、

1 or more R _G2 monocyclic 4 to 8 membered nitrogen-containing heterocyclic ring substituted with the (for example, azetidinyl, pyrrolidinyl, piperidinyl), and halogen R _G2 are independently at each occurrence, -C (O) C ₁ -C ₆ alkyl, _-C 1 -C ₆ alkyl, _-C 1 -C ₆ haloalkyl, be a _-O-C 1 -C ₆ alkyl, or _-O-C 1 -C ₆ haloalkyl; _{R M} are each independently Halogen, -C _1- C ₆ alkyl, -C _1- C ₆ haloalkyl, -O-C _1- C ₆ alkyl or -O-C _1- C ₆ haloalkyl. In each group of compounds according to the embodiment,

は１個もしくは２個のＲ_Ｇ２で置換されているアゼチジニル、ピロリジニルまたはピペリジニルであり、Ｒ_Ｇ２は各場合でそれぞれメチル、エチル、イソプロピル、ｔｅｒｔ−ブチル、フルオロ、クロロまたはトリフルオロメチルであり；Ｒ_Ｍはそれぞれ独立にフルオロ、クロロまたはメチルである。例えば

Is azetidinyl substituted with one or two R _G2, pyrrolidinyl or piperidinyl, each methyl when the R _G2 each, ethyl, isopropyl, tert- butyl, fluoro, chloro or trifluoromethyl; R _M is independently fluoro, chloro or methyl, respectively. For example

は、４，４−ジメチルピペリジン−１−イル、４，４−ジフルオロピペリジン−１−イル、２，６−ジメチルピペリジン−１−イル、４−（プロパン−２−イル）ピペリジン−１−イル、４−フルオロピペリジン−１−イル、３，５−ジメチルピペリジン−１−イル、４−（トリフルオロメチル）ピペリジン−１−イル、４−メチルピペリジン−１−イル、４−ｔｅｒｔ−ブチルピペリジン−１−イル、２−オキソピペリジン−１−イルまたは３，３−ジメチルアゼチジン−１−イルである。

4,4-Dimethylpiperidine-1-yl, 4,4-difluoropiperidine-1-yl, 2,6-dimethylpiperidine-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-Fluoropiperidin-1-yl, 3,5-dimethylpiperidine-1-yl, 4- (trifluoromethyl) piperidine-1-yl, 4-methylpiperidine-1-yl, 4-tert-butylpiperidine-1 -Il, 2-oxopiperidine-1-yl or 3,3-dimethylazetidine-1-yl.

The present invention also provides, in each case _{R E} is _{independently, -O-R S, -S-} R S, -C (O) R S, -OC (O) R S, -C (O) OR S, -N ( _RS R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N ( _RS R _S '), -N ( _RS ) C (O) R _{S ', -N (R S) C} (O) N (R S' R S "), - N (R S) SO 2 R S ', -SO 2 N (R S R S'), - N (R _{S) SO 2 N (R S} 'R S "), - N (R S) S (O) N (R S' R S"), - OS (O) -R S, -OS (O) 2 - _RS , -S (O) ₂ OR _S , -S (O) OR _S , -OC (O) OR _S , -N ( _RS ) C (O) OR _S ′, -OC (O) N (R) _{S R S '), - N} (R S) S (O) -R S', -S (O) N (R S R S '), - P (O) (OR S) 2, = C (R _S R _S ') or _{-C (O) N (R S} ) C (O) -R S'; or halogen in each case independently, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, C _1- C ₆ alkyl, C _2- C ₆ alkenyl or C _2- C ₆ alkynyl, which may be substituted with one or more substituents selected from thioxo, formyl or cyano; or halogen in each case independently. , Hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, tioxo, formyl, cyano, trimethylsilyl, C _1- C ₆ alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, C _1- C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C _{6 haloalkynyl, -O-R S, -S-} R S, -C (O) R S, -C (O) oR S or -N ( R _S R _S ′) may be substituted with one or more substituents selected from C _3- C ₁₂ carbocycles or 3- to 12-membered heterocycles of the formula _IE described herein. characterized acceptable salts (each of including forms described below) and its pharmaceutical compounds I _F and I _G.

The compounds of the present invention can be used in the form of salts. Depending on the particular compound, the salt of the compound is advantageous because of one or more of the physical properties of the salt, such as improved drug stability under certain conditions or desired solubility in water or oil. there is a possibility. In some cases, salts of a compound may be useful in isolating or purifying the compound.

When attempting to administer a salt to a patient, the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, base addition salts and alkali metal salts.

Pharmaceutically acceptable acid addition salts can be made from inorganic or organic acids. Examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Examples of suitable organic acids include, but are not limited to, aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acids and sulfonic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartrate, Citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, asparagate, glutamate, benzoate, anthranyl acid, mesylate, stearate, salicylate, p. -Hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-Hydroxyethane sulfonate, sufanilate, cyclohexylamino sulfonate, algenic acid, b-hydroxybutyrate, galactalate, galacturonate, adipate, alginate, bicarbonate Salt, butyrate, cerebrate, camphor sulfonate, cyclopentanepropionate, dodecyl sulfate, glycoheptanate, glycerophosphate, hemisulfate, heptaneate, hexanate, nicotinate, 2 -Naphthale sulfonate, oxalate, palmate, pectinate, persulfate, 3-phenylpropionate, picphosphate, pivalate, thiocyanate, tosylic acid Includes salts and undecanoates.

Pharmaceutically acceptable base addition salts include, but are not limited to, metal salts and organic salts. Examples of suitable metal salts include, but are not limited to, alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other pharmaceutically acceptable metal salts. Such salts can be made from, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc. Examples of suitable organic salts are from tertiary and quaternary amines such as tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and prokine. It can be manufactured, but is not limited to these. Basic nitrogen-containing groups include alkyl halides (eg, methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl and stearyl chloride / bromide / iodide), dialkyl sulfates (eg, dimethyl sulfate, diethyl, dibutyl and diamyl), aralkyl. It can be quaternized with agents such as halides (eg, benzyl and phenethyl bromide) and others.

The compounds or salts of the invention form solvates with water (ie, hydrates) or solvates with organic solvents (eg, methanol, ethanol or acetonitrile) to form metanolates, ethanolates or acetonitrilates, respectively. ) Can exist.

The compounds or salts of the invention can also be used in the form of prodrugs. Some prodrugs are aliphatic or aromatic esters derived from acidic groups on the compounds of the invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of the invention. Phosphate prodrugs of hydroxyl groups are preferred prodrugs.

The compounds of the present invention can contain asymmetrically substituted carbon atoms called chiral centers. These compounds are present as a single stereoisomer (eg, a single enantiomer or a single diastereomer), a mixture of stereoisomers (eg, a mixture of enantiomers or diastereomers) or a racemic mixture. However, it is not limited to these. Compounds identified herein as single stereoisomers are compounds that are present in a form that is substantially free of other stereoisomers (eg, substantially free of other enantiomers or diastereomers). Means to explain. "Substantially free" means that at least 80% of the compound in the composition is the stereoisomer described; preferably at least 90% of the compound in the composition is the stereoisomer described. Being; more preferably, it means that at least 95%, 96%, 97%, 98% or 99% of the compound in the composition is the stereoisomer described. If the chemical structure of a compound does not specify the stereochemistry of chiral carbon, the chemical structure includes compounds that also contain any stereoisomer of the chiral center.

The individual stereoisomers of the compounds of the invention can be prepared using a variety of methods known in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic division of enantiomers, conversion of enantiomers to diastereomers in enantiomeric mixtures and subsequent chromatographic separation of diastereomers and individual. Regeneration of enantiomers, as well as enzymatic division, but are not limited to these.

Stereospecific synthesis typically involves suitable optically pure (enantiomerically pure) or substantially optically pure materials as well as synthetic reactions that do not cause racemization or stereochemical inversion at the chiral center. Is used. Mixtures of stereoisomers of compounds, such as racemic mixtures resulting from synthetic reactions, can be separated, for example, by chromatographic techniques understood by those skilled in the art. The chromatographic division of the enantiomer can be performed by using a chiral chromatography resin, which is often commercially available. To give a non-limiting example, a racemate is used as a solution and loaded on a column containing a chiral stationary phase. The enantiomer can then be separated by HPLC. Division of the enantiomers can also be performed by converting the enantiomers in the mixture to diastereomers by reaction with a chiral auxiliary. The resulting diastereomers can be separated by column chromatography or crystallization / recrystallization. This technique is useful when the compound to be separated contains a carboxyl, amino or hydroxyl group that forms a salt or covalent bond with the chiral auxiliary. Examples of, but not limited to, chiral auxiliary are chirally pure amino acids, organic carboxylic acids, organic sulfonic acids, and the like. Once the diastereomers have been chromatographically separated, the individual enantiomers can be regenerated. Very often, the chiral auxiliary can be recovered and reused.

Enzymes such as esterases, phosphatases or lipases can be useful in splitting enantiomer derivatives in enantiomer mixtures. For example, the ester derivative of the carboxyl group in the compound to be separated can be treated with an enzyme that selectively hydrolyzes only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.

Alternatively, a suitable method known in the art such as treatment of the carboxylic acid with a suitable optically pure base such as an alkaloid or phenethylamine followed by precipitation or crystallization / recrystallization of an enantiomerically pure salt may be used. It can be used to make salts of enantiomers in the mixture. Suitable methods for the division / recrystallization of stereoisomeric mixtures such as racemic mixtures are described in the work of Jakes et al. (ENANTIOMERS, RACEMATES, AND RESOLUTIONS; Jacques et al., 1981, John Willey and Sons, New York, NY). is there.

The compounds of the present invention may have one or more unsaturated carbon-carbon double bonds. Unless otherwise noted, all double bond isomers such as cis (Z) and trans (E) isomers and mixtures thereof shall be included in the scope of the described compounds. Furthermore, when the compounds are present in various tautomers, the compounds described are not limited to any specific tautomer, but include all tautomers.

Certain compounds of the invention may exist in different, distinct, stable conformations that are separable. For example, twist asymmetry due to restricted rotation around an asymmetric single bond due to steric hindrance or ring strain may allow the separation of different conformers. The present invention includes each conformer isomer of these compounds and a mixture thereof.

Certain compounds of the invention may also be present in the zwitterionic form, and the present invention includes each zwitterionic form of these compounds and mixtures thereof.

The compounds of the invention are described herein using standard nomenclature. In the case of the described compounds having an asymmetric center, it should be understood that all stereoisomers of the compound and mixtures thereof are included in the present invention unless otherwise specified. Examples of stereoisomers include, but are not limited to, enantiomers, diastereomers and cis-trans isomers. If the compound described is present in various tautomers, the compound is inclusive of all tautomers. In this specification, certain compounds, variables _{(e.g., A, B, D, X} , L 1, L 2, L 3, Y, Z, T, R A or _{R B)} a general formula that includes Described using. Unless otherwise noted, each variable element in such an expression is defined independently of any other variable element, and variable elements used multiple times in an expression are defined independently in each case. To. If the parts are described as being selected "independently" from a group, the parts are selected independently of each other. Thus, each part can be the same as or different from the other parts or parts.

Number of carbon atoms in the hydrocarbyl moiety may be indicated by the prefix "C _x -C _y", x in the case is the minimum number of carbon atoms in the moiety, y is the maximum number. So, for example, "C _1- C ₆ alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. More specifically, C _3- C ₆ cycloalkyl means a saturated hydrocarbyl ring containing 3 to 6 carbon ring atoms. The prefix attached to the substituent of a plurality of components applies only to the first component immediately following the prefix. To explain, the term "carbon ring alkyl" includes two components, the carbocycle and the alkyl. Thus, for _example, C 3 -C ₆ carbocycle _C 1 -C ₆ alkyl _refers to a _C 3 -C ₆ carbocycle via a C 1 -C ₆ alkyl group attached to the parent molecular moiety.

Unless otherwise noted, if a connecting element connects two other elements in a drawn structure, the leftmost component of that connecting element is on the left side of the drawn structure. It is connected to an element, and the component described on the far right of the connecting element is connected to the right element in the drawn structure. To illustrate, the chemical structure is _{-L S -M-L} S '- a and, M is _{-N (R B) S (O} ) - if it is, the chemical structure is _-L S -N _(R B) S (O) -L _S '- is.

When the connecting element in the drawn structure is a bond, the element on the left side of the connecting element is directly connected to the element on the right side of the connecting element via a covalent bond. For example, there chemical structure _{-L S -M-L} S '- painted and, if M is selected as the binding, its chemical structure is _{-L S -L} S' - a. If two or more adjacent connecting elements in the drawn structure are joins, the element to the left of these connecting elements is directly linked to the element to the right of these connecting elements via a covalent bond. .. For example, there chemical structure _{-L S -M-L S '-M'} -L S "- depicted as, M and _{L S'} If is selected as the binding, its chemical structure is _-L S -M ' -L _S "- to become. Similarly, the chemical structure is _{-L S -M-L S '-M'} -L S "- drawn as, M, _{L S'} and when M 'is a bond, its chemical structure is -L _S - It becomes L _S ″-.

When a chemical formula is used to describe a part, the dotted line indicates part of the part with free valence.

When a part is described as "may be replaced", the part may or may not be replaced. If it is stated that a portion may be substituted with a specific number or less of non-hydrogen groups, that portion is not substituted or is the maximum by or at that specific number of non-hydrogen groups. Depending on the number of replaceable positions or less, it can be replaced by the smaller number. Therefore, for example, when a part is described as a heterocycle which may be substituted with 3 or less non-hydrogen groups, the heterocycle having less than 3 substitutable positions can be substituted with the heterocycle. It can be substituted with only a few non-hydrogen groups that have a number of positions. To explain, tetrazolyl (which has only one substitutable position) may be substituted with one or less non-hydrogen groups. More specifically, when it is stated that amino nitrogen may be substituted with 2 or less non-hydrogen groups, primary amino nitrogen may be substituted with 2 or less non-hydrogen groups. This means that amino nitrogen may be substituted with one or less non-hydrogen groups.

If a moiety is substituted with oxo or thioxo, it contains a carbon atom covalently attached to at least two hydrogens (eg CH ₂ ), the two hydrogen groups being oxo or By being substituted with thioxo, it means that C = O or C = S, respectively.

The term "alkenyl" means a linear or branched hydrocarbyl chain containing one or more double bonds. Each carbon-carbon double bond can have either cis or trans geometry within the alkenyl moiety with respect to the group substituted on the double bond carbon. Examples of alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl. It is not limited.

The term "alkenylene" refers to a divalent unsaturated hydrocarbyl chain that can be linear or branched and has at least one carbon-carbon double bond. Examples of alkenylene groups include -C (H) = C (H)-, -C (H) = C (H) -CH _2- , -C (H) = C (H) -CH _2- CH ₂ -, -CH _2- C (H) = C (H) -CH _2- , -C (H) = C (H) -CH (CH ₃ )-and -CH _2- C (H) = C (H) ) -CH (CH ₂ CH ₃ )-etc., But are not limited to these.

The term "alkyl" means a linear or branched saturated hydrocarbyl chain. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, iso-amyl and hexyl. ..

The term "alkylene" refers to a divalent saturated hydrocarbyl chain that can be linear or branched. Representative examples of _{alkylene, -CH 2 -, - CH 2} CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 - and _{-CH 2 CH (CH 3) CH} 2 - However, it is not limited to these.

The term "alkynyl" means a linear or branched hydrocarbyl chain containing one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl and 3-butynyl.

The term "alkynylene" refers to a divalent unsaturated hydrocarbon group that can be linear or branched and has at least one carbon-carbon triple bond. Representative alkynylene groups, and _{examples, -C≡C -, - C≡C-CH} 2 -, - C≡C-CH 2 -CH 2 -, - CH 2 -C≡C-CH 2 -, - C≡C-CH (CH 3) - and _{-CH 2 -C≡C-CH (CH 2} CH 3) - , and the like.

The terms "carbon ring" or "carbon ring system" or "carbon ring system" are saturated with zero heteroatom atoms (eg, "cycloalkyl"), partially saturated (eg, "cycloalkenyl" or "cycloalkenyl". Cycloalkynyl ") or completely unsaturated (eg," aryl ") ring system. A "ring atom" or "ring member" is an atom that is combined together to form a ring or a plurality of rings. The carbon ring can be, but is not limited to, a monocycle, two fused rings or a crosslinked or spiro ring. The substituted carbocycles can have cis or trans geometry. Typical examples of carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl. , Naftyl, Indanyl, 1,2,3,4-tetrahydro-naphthyl, Indenyl, Isoindenyl, Decalinyl, Norpinanyl and the like, but are not limited thereto. The carbocyclic group can be attached to the parent molecule moiety via a substitutable carbocyclic atom. If the carbocyclic group is a divalent portion connecting two other elements in the drawn chemical structure (such as A in formula I), then the carbocyclic group can be substituted with any two. It can be bonded to two other elements via a ring atom. Similarly, if the carbocyclic group is a trivalent portion (such as X in Formula I) that connects three other elements in the drawn chemical structure, the carbocyclic group is any three of them. It can be attached to three other elements via a substitutable ring atom of.

The term "carbon ring alkyl" refers to a carbocyclic group attached to a parent molecule moiety via an alkylene group. For example, C _3- C ₆ carbocyclic ring C _1- C ₆ alkyl refers to a C _3- C ₆ carbocyclic ring group attached to the parent molecule moiety via a C _1- C ₆ alkylene.

The term "cycloalkenyl" refers to a non-aromatic partially unsaturated carbocyclic moiety having zero heteroatom ring members. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and octahydronaphthalenyl.

The term "cycloalkyl" refers to a saturated carbocyclic group containing zero heteroatom ring members. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalynyl and norpinanyl.

The prefix "halo" indicates that the substituent with that prefix is substituted with one or more independently selected halogen groups. For example, "C _1- C ₆ haloalkyl" means a C _1- C ₆ alkyl substituent in which one or more hydrogen atoms are replaced by independently selected halogen groups. Examples of C _1- C ₆ haloalkyl include, but are not limited to, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl. It should be understood that if a substituent is substituted by a plurality of halogen groups, the halogen groups may be the same or different (unless otherwise noted).

The term "heterocycle" or "heterocyclic" or "heterocyclic" means that at least one of the ring atoms is a heteroatom (ie nitrogen, oxygen or sulfur) and the remaining ring atoms are independently carbon. Saturated (eg, "heterocycloalkyl"), partially unsaturated (eg, "heterocycloalkenyl" or "heterocycloalkynyl") or completely unsaturated (eg, "heterocycloalkynyl") selected from the group consisting of nitrogen, oxygen and sulfur. Heteroaryl ") refers to the ring system. The heterocycle can be, but is not limited to, a monocycle, two fused rings or a crosslinked or spiro ring. The heterocyclic group can be linked to the parent molecule moiety via any substitutable carbon or nitrogen atom in the group. If the heterocyclic group is a divalent portion connecting two other elements in the drawn chemical structure (such as A in Formula I), then the heterocyclic group can be replaced by any two. It can be bonded to two other elements via a heterocyclic atom. Similarly, if the heterocyclic group is a trivalent portion (such as X in Formula I) that connects three other elements in the drawn chemical structure, then the heterocyclic group is any three of them. It can be attached to three other elements via a substitutable ring atom of.

The heterocycle can be, but is not limited to, a monocyclic ring containing one ring. Examples of monocyclic rings include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolydinyl, triazolyl, tetrazolyl, dithiolyl, oxalyl. , Isooxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also referred to as "azoximyl"), , 2,5-oxadiazolyl (also referred to as "frazanyl") and 1,3,4-oxadiazolyl), oxatriazolyl (1,2,3,4-oxatriazolyl and 1,2,3 5-oxatriazolyl, etc.), dioxazolyl (1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl and 1,3,4-dioxazolyl, etc.), oxathiolanyl, pyranyl (1) , 2-pyranyl and 1,4-pyranyl, etc.), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (pyridazinyl (also referred to as "1,2-diazinyl"), pyrimidinyl (also referred to as "1,3-diazinyl") , Etc. (also referred to as "1,4-diazinyl"), piperazinyl, triazinyl (s-triazinyl (also referred to as "1,3,5-triazinyl"), etc.), as-triazinyl (1) , 2,4-Triazinyl) and v-triazinyl (also referred to as "1,2,3-triazinyl"), oxadinyl (1,2,3-oxadinyl, 1,3,2-oxadinyl, 1, , 3,6-oxazinyl (also referred to as "pentoxazolyl"), 1,2,6-oxazinyl and 1,4-oxazinyl, isooxadinyl (such as o-isooxadinyl and p-isooxazinyl), oxazolidinyl, isooxazolidini Lu, oxathiadinyl (such as 1,2,5-oxathiadinyl or 1,2,6-oxathiadinyl), oxadiazinyl (such as 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl , Oxepinyl, thiepinyl, thiomorpholinyl and diazepinyl, among others Not limited.

Heterocycles include, for example, naphthilidinyl (such as [1,8] naphthilidinyl and [1,6] naphthilidinyl), thiazole pyrimidinyl, thienopyrimidineyl, pyrimidopyrimidinenyl, pyridopyrimidinyl, pyrazoropyrimidinyl, indridinyl, pyrindinyl, pyranopyrrolidyl, 4H-quinolinidinyl. , Prinyl, pyridopyridinyl (such as pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl and pyrido [4,3-b] -pyridinyl), pyridopyrimidine and pteridinyl, etc. It may be a bicyclic ring containing a fused ring, but is not limited thereto. Other examples of fused ring heterocycles include indolyl, isoindrill, indolinyl (also referred to as "psoid indrill"), isoindazolyl (also referred to as "benzopyrazolyl" or indazolyl), benzoazinyl (quinolinyl ("1-"). (Also referred to as "benzoazinyl") and isoquinolinyl (also referred to as "2-benzoazinyl"), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (sinnolinyl (also referred to as "1,2-benzodiazinyl") and quinazolinyl ("1,2-benzodiazinyl") (Also known as 1,3-benzodiazinyl)), benzopyranyl (such as “chromenyl” and “isochromenyl”), benzothiopyranyl (also referred to as “thiochromenyl”), benzoxazolyl, indooxadinyl (also referred to as “thiochromenyl”), etc. (Also known as "benzoisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also referred to as "chromalonyl"), isobenzofuranyl, benzothienyl ("" Benzothiophenyl "," thionaphthenyl "and" benzothiofuranyl "), isobenzothienyl (also referred to as" isobenzothiophenyl "," isothionaphthenyl "and" isobenzothiofuranyl ") , Benzothiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzothiasiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (1,3,2-benzoxazinyl, 1,4) , 2-benzoxazine, 2,3,1-benzoxazine and 3,1,4-benzoxazinyl, etc.), benzoisooxadinyl (1,2-benzoisooxadinyl and 1, There are, but are not limited to, benzo-fused heterocycles such as 4-benzoisooxadinyl) and tetrahydroisoquinolinyl.

The heterocycle can be, for example, a spirocyclic system such as 1,4-dioxa-8-azaspiro [4.5] decanyl, but is not limited thereto.

Heterocycles can contain one or more sulfur atoms as ring members, and in some cases the sulfur atoms are oxidized to SO or SO ₂ . The nitrogen heteroatom in the heterocycle may or may not be quaternized and may or may not be oxidized to N-oxide. In addition, nitrogen heteroatoms may or may not be N-protected.

The heterocycle or carbocycle may be further substituted. Unless otherwise noted, the term "substituted" means that one, two, or three or more of the hydrogen atoms are -F, -Cl, -Br, -I, hydroxy, protected hydroxy. , -NO ₂ , -N ₃ , -CN, -NH ₂ , Protected Amino, Oxo, Thioxo, -NH-C _1- C ₁₂ -alkyl, -NH-C _2- C ₈ -alkenyl, -NH- C _2- C ₈ -alkynyl, -NH-C _3- C ₁₂ -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroaryl Amino, -OC ₁ -C ₁₂ -alkyl, -O-C _2- C ₈ -alkenyl, -O-C _2- C ₈ -alkynyl, -O-C _3- C ₁₂ -cycloalkyl, -O- Aryl, -O-heteroaryl, -O-heterocycloalkyl, -C (O) -C _1- C ₁₂ -alkyl, -C (O) -C _2- C ₈ -alkenyl, -C (O) -C _2- C ₈ -alkynyl, -C (O) -C _3- C ₁₂ -cycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) -heterocycloalkyl,- CONH ₂ , -CONH-C _1- C ₁₂ -alkyl, -CONH-C _2- C ₈ -alkenyl, -CONH-C _2- C ₈ -alkynyl, -CONH-C _3- C ₁₂ -cycloalkyl, -CONH -Aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO _2- C _1- C ₁₂ -alkyl, -OCO _2- C _2- C ₈ -alkenyl, -OCO _2- C _2- C _8- C 8- Alkinyl, -OCO _2- C _3- C ₁₂ -cycloalkyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocycloalkyl, -OCONH ₂ , -OCONH-C _1- C ₁₂ -alkyl , -OCONH-C ₂ -C ₈ -alkenyl, -OCONH-C _2- C ₈ -alkynyl, -OCONH-C _3- C ₁₂ -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-hetero Cycloalkyl, -NHC (O) -C _1- C ₁₂ -alkyl, -NHC (O) -C _2- C ₈ -a Lucenyl, -NHC (O) -C _2- C ₈ -alkynyl, -NHC (O) -C _3- C ₁₂ -cycloalkyl, -NHC (O) -aryl, -NHC (O) -heteroaryl, -NHC (O) -Heterocycloalkyl, -NHCO _2- C _1- C ₁₂ -alkyl, -NHCO _2- C _2- C ₈ -alkenyl, -NHCO _2- C _2- C ₈ -alkynyl, -NHCO ₂ -C _3- C ₁₂ -cycloalkyl, -NHCO ₂ -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -heterocycloalkyl, -NHC (O) NH ₂ , -NHC (O) NH-C _1- C ₁₂ -alkyl, -NHC (O) NH-C _2- C ₈ -alkenyl, -NHC (O) NH-C _2- C ₈ -alkynyl, -NHC (O) NH-C _3- C ₁₂ -cycloalkyl, -NHC (O) NH- aryl, -NHC (O) NH- heteroaryl, -NHC (O) NH- _{heterocycloalkyl, NHC (S) NH 2,} -NHC (S) NHC 1 -C 12 - Alkyl, -NHC (S) NH-C _2- C ₈ -alkenyl, -NHC (S) NH-C _2- C ₈ -alkynyl, -NHC (S) NH-C _3- C ₁₂ -cycloalkyl, -NHC (S) NH-aryl, -NHC (S) NH-heteroaryl, -NHC (S) NH-heterocycloalkyl, -NHC (NH) NH ₂ , -NHC (NH) NH-C _1- C ₁₂ -alkyl , -NHC (NH) NH-C _2- C ₈ -alkenyl, -NHC (NH) NH-C _2- C ₈ -alkynyl, -NHC (NH) NH-C _3- C ₁₂ -cycloalkyl, -NHC ( NH) NH-aryl, -NHC (NH) NH-heteroaryl, -NHC (NH) NH-heterocycloalkyl, -NHC (NH) -C _1- C ₁₂ -alkyl, -NHC (NH) -C _2- C ₈ -alkenyl, -NHC (NH) -C _2- C ₈ -alkynyl, -NHC (NH) -C _3- C ₁₂ -cycloalkyl, -NHC (NH) -aryl, -NHC (NH) -heteroaryl , -NHC (NH) -heterocycloalkyl, -C (NH) NH-C _1- C ₁₂ -alkyl, -C (NH) NH-C _2- C ₈ -alkenyl , -C (NH) NH-C _2- C ₈ -alkynyl, -C (NH) NH-C _3- C ₁₂ -cycloalkyl, -C (NH) NH-aryl, -C (NH) NH-heteroaryl , -C (NH) NH-heterocycloalkyl, -S (O) -C _1- C ₁₂ -alkyl, -S (O) -C _2- C ₈ -alkenyl, -S (O) -C _2- C ₈ -alkynyl, -S (O) -C _3- C ₁₂ -cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) -heterocycloalkyl, -SO ₂ NH ₂ , -SO ₂ NH-C _1- C ₁₂ -alkyl, -SO ₂ NH-C _2- C ₈ -alkenyl, -SO ₂ NH-C _2- C ₈ -alkynyl, -SO ₂ NH-C _3- C ₁₂ -Cycloalkyl, -SO ₂ NH-aryl, -SO ₂ NH-heteroaryl, -SO ₂ NH-heterocycloalkyl, -NHSO _2- C _1- C ₁₂ -alkyl, -NHSO _2- C _2- C ₈ -Alkenyl, -NHSO _2- C _2- C ₈ -alkynyl, -NHSO _2- C _3- C ₁₂ -cycloalkyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocycloalkyl,- CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C _3- C ₁₂ -cycloalkyl, polyalkoxyalkyl, polyalkoxy , -Methoxymethoxy, -methoxyethoxy, -SH, -SC _1- C ₁₂ -alkyl, -SC _2- C ₈ -alkenyl, -SC _2- C ₈ -alkynyl, -SC ₃ Refers to substitution by independent replacement by -C ₁₂ -cycloalkyl, -S-aryl, -heteroaryl, -S-heterocycloalkyl, methylthiomethyl, etc. (but not limited to these). It should be understood that aryls, heteroaryls, alkyls, etc. can be further substituted.

An "aliphatic" group is a non-aromatic moiety consisting of a combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen and other atoms, with one or more unsaturated units such as double and / or triple bonds. It may be included. Examples of aliphatic groups include O, OH, NH, NH ₂ , C (O), S (O) ₂ , C (O) O, C (O) NH, OC (O) O, OC (O). NH, OC (O) NH ₂ , S (O) ₂ NH, S (O) ₂ NH ₂ , NHC (O) NH ₂ , NHC (O) C (O) NH, NHS (O) ₂ NH, NHS ( Contains functional groups such as O) ₂ NH ₂ , C (O) NHS (O) ₂ , C (O) NHS (O) ₂ NH or C (O) NHS (O) ₂ NH ₂ , and one or more functional groups. There are groups in which one or more carbons of non-aromatic hydrocarbons (which may be substituted) and non-aromatic hydrocarbons (which may be substituted) are replaced by functional groups. The carbon atom of the aliphatic group may be oxo-substituted. Aliphatic groups can be linear, branched or cyclic and preferably contain from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups clearly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines and polyimines. The aliphatic group may be substituted. The linear aliphatic group is a non-cyclic aliphatic group. It should be understood that when a linear aliphatic group is said to "contain" or "contain" or "contain" one or more designated functional groups, the linear aliphatic group is said to contain that designation. One or more of the functional groups or combinations thereof or one or more carbons of non-aromatic hydrocarbons (which may be substituted) can be selected from the groups replaced by the specified functional group. Exemplary linear aliphatic groups include alkyl, alkenyl or alkynyl, each of which may be substituted, with a functional group in the middle or at the end.

In the chemical formula

は、単結合または二重結合を指す。

Refers to a single bond or a double bond.

The term "pharmaceutically acceptable" is used adjectively to mean that a modified noun is suitable for use in a drug or as part of a drug.

The term "therapeutically effective amount" refers to the total amount of each active substance sufficient to show meaningful patient benefit, such as reduced viral load.

The term "prodrug" refers to the present invention as a compound of the invention that has a chemically or metabolically cleaving group and is pharmacologically active in vivo by solvolysis or under physiological conditions. Refers to a derivative of the compound of. Prodrugs of a compound can be formed by conventional methods by reaction of functional groups of the compound (such as amino, hydroxy, carboxy or phosphate groups). Prodrugs often provide the benefits of solubility, histocompatibility or delayed release in mammals (Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam, See 1985). Prodrugs include acid derivatives known to those skilled in the art, such as esters produced by reaction of a polyacidic compound with a suitable alcohol or amides produced by reaction of an acid compound with a suitable amine. Examples of prodrugs include acetates, formates, benzoic acid esters and other acylated derivatives or amine functional groups of alcohols within the compounds of the invention, or phosphate esters of the compounds of the invention. It is not limited.

The term "solvate" refers to the physical association of one or more solvents, organic or inorganic, with the compounds of the invention. This physical association often involves hydrogen bonds. In some cases, the solvate is isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. A "solvate" includes both a solution phase and an isolating solvate. Examples of solvates include, but are not limited to, hydrates, etanolates and metanolates.

The term "N-protecting group" or "N-protecting" refers to a group capable of protecting an amino group against undesired reactions. Commonly used N-protecting groups are described in the work of Green et al. (Greene and Wuts, PROTECTING GROUPSINCHEMICALSYNTHESIS (3rd ed., John Wiley & Sons, NY (1999)). Examples of N-protecting groups include. Formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl or Acyl groups such as 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulphenyl groups such as phenylsulphenyl (phenyl-S-) or triphenylmethylsulphenyl (trityl-S-); p- Sulfinyl groups such as methylphenylsulfinyl (p-methylphenyl-S (O)-) or t-butylsulfinyl (t-Bu-S (O)-); benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxy Benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxy Carbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, dimethyl- 3,5-Dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl Carbamate-forming groups such as phenoxycarbonyl, 4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl or phenylthiocarbonyl; benzyl, p-methoxybenzyl, triphenylmethyl or benzyloxymethyl; p-methoxy Feni There are, but are not limited to, alkyl groups such as, and silyl groups such as trimethylsilyl. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The abbreviations used in the diagrams, intermediates and description of the examples below are: Ac: Acetyl; APCI: Atmospheric Pressure Chemical Ionization; aq or aq. : Aqueous system; atm: atmospheric pressure; Boc: t-butoxycarbonyl; Bu: butyl; t-Bu or tert-butyl: tert-butyl; Cbz: benzyloxycarbonyl; dba: dibenzylidineacetone; DCI: desorption chemical ionization; DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone; DEPBT: 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 (3H) -one; DIBAL: aluminum hydride Diisobutyl; DMA: N, N-dimethylacetamide; DME: 1,2-dimethoxyethane; DMF: N, N-dimethylformamide; DMSO: Dimethyl sulfoxide; DMPU: 1,3-dimethyl-3,4,5,6- Tetrahydro-2 (1H) -pyrimidinone; dppf: 1,1'-bis (diphenylphosphino) ferrocene; EDC, EDAC or EDCI: N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; e. e. : Enantiomeric excess; ELSD: Evaporative Light Scattering Detector; ESI: Electrospray-ionization; Et: ethyl; _Et 3 N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; _Et 2 O: diethyl ether; eq or equiv: equivalent Fmoc: 9-fluorenylmethoxycarbonyl; HATU: O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate; HOBt: 1-hydroxy Benzotriazole; HPLC: High Performance Liquid Chromatography; HOBt: 1-Hydroxybenzotriazole; LCMS: Liquid Chromatography / Mass Analysis; mCPBA: m-Chloroperbenzoic Acid; Me: Methyl; MeOH: Methanol; OAc: Acetate; Ms: Methanolsulfonyl; OTF: triflate or trifluoromethanesulfonate; PDC: pyridinium dichromate; i-Pr: isopropyl; Ph: phenyl; PPh ₃ : triphenylphosphine; psi or pisi: pounds / square inch (gas); PTFE: poly Tetrafluoroethylene; PXPd: [(t-Bu) ₂ PCl] ₂ PdCl ₂ , PyBOP: (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; SEM: 2- (trimethylsilyl) ethoxymethyl; T3P: propane Phosphonate anhydride; Tf: trifluorosulfonyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography; Troc: 2,2,2-trichloroethoxycarbonyl; v / v: volume / volume; wt% : Weight percent; w / v: Weight / volume; w / w: Weight / weight; XantPhos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene.

The compound of the present invention can be produced by using various methods. Non-limiting examples include compounds of the present invention, the compound of formula II (e.g., from n = 0 8), the compound of formula V _{(X 4} can be, for example, O or NR _{A, R A} is As described above herein, preferably H or C _1- C ₆ alkyl, 3- to 12-membered carbocycles or heterocycles, -C (O) _RS , -C (O) OR _S , -C (O) N ( _RS R _S '), -SO ₂ N ( _RS R _S '), -S (O) ₂ OR _S , -S (O) OR _S , -S (O) N ( R _S R _S ') is a suitable protecting group such as described above in the definition of _{R E} or Boc or Fmoc and the like.) or a compound of formula VIII (E are, for example, 3 to 7-membered carbocyclic or heterocyclic ring it can be optionally substituted with one or more R _a.) a can be prepared according to Scheme I as a starting material, a, B, D, Y, Z and R _a are as described above .. The 1,4-diketones II, V and VIII can be reduced to 1,4-diols using the methods described below and the resulting racemic, enantiomer-rich or meso-form 1,4-diols. The species can be converted to dimesylates III, VI or IX by the methods described below, or can be converted to ditriflates, ditosilates or dihalides. Dimesylates III, VI and IX, ditrifurates, ditocillates or dihalides are aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline, 3-fluoroaniline under the conditions described below. , 4-Trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines or allylamines, etc. (but not limited to) The compound of the present invention can be obtained. L ₁ and L ₂ can be readily introduced into formulas II, V and VIII in view of the present invention as will be appreciated by those skilled in the art. Similarly, DL _3- NH ₂ can be used in place of D-NH ₂ , as will be appreciated by those skilled in the art.

As another non-limiting example, compounds of the invention can be prepared from compounds of formulas II and III according to the methods shown in Diagram II. 1,4-Diketones such as Formula IV are known such as the reaction of α-bromoketones such as Formula II with methylketones such as Formula III in the presence of suitable Lewis acids such as ZnCl ₂ or Ti (OiPr) ₄ . It can be produced using the method (see Never, et al., Synthesis: 1259-1262 (2000)). For example, II (1 eq) III (1 eq) in the presence of ZnCl ₂ (2 eq), diethylamine (1.5 eq) and tert-butanol (1.5 eq) in a solvent such as benzene at approximately room temperature. The diketones IV can be obtained by reacting with (0.5 equivalents). The 1,4-diketone IV can be reduced to 1,4-diols such as V by the action of NaBH ₄ , LiAlH ₄ or DIBAL. Alternatively, the enantiomer-selective reduction of 1,4-diketones, such as formula IV, can be reduced by camhair chloroborane (DIP-chloride) of (-) or (+)-diisopi, by borane and oxoazaborolidine catalysts. Reduction or [RuCl ₂ {(R) -BINAP} {(R, R) -DPEN}] (BINAP = 2,2'-bis (diarylphosphino) -1,1'-binaphthyl; DPN = 1,2 -Reporting methods such as reduction by asymmetric hydrogenation in the presence of a suitable ruthenium (II) catalyst such as (diphenylethylenediamine) (Chong, et al., Terahedron: Asymmetry 6: 409-418 (1995), Li, et. al., Tetrahedron 63: 8046-8053 (2007), Aldous, et al., Tetrahedron: Asymmetric 11: 2455-2462 (2000), Masui, et al., Synlett: 273-274 (1997), et al. , Adv. Synth. Catal. 347: 1193-1197 (2005), Sato, et al., Synthesis: 1434-1438 (2004)). The diketones IV (1 eq) can be reduced with NaBH ₄ (3 eq) in a solvent such as tetrahydrofuran while heating to about 50 ° C. Diketone IV (1 eq) in a solvent such as THF at a temperature in the range of about 10 ° C to about 30 ℃, N, N-diethylaniline borane (about 2 eq), trimethylborate (about 0.2 eq) and It can be selectively reduced enantiomer by addition to a mixture obtained from α, α-diphenyl-2-pyrrolidinmethanol (about 0.17 eq) of (S) or (R) (Synthesis 2507-2510 (2003)). ). The obtained racemic, enantiomer-rich or meso-form 1,4-diols V can be reacted with methanesulfonyl chloride or methanesulfonic acid anhydride to obtain a dimesylate VI. For example, diisopropylethylamine (about 4 equivalents) in a solvent such as tetrahydrofuran or 2-methyltetrahydrofuran or the like is prepared by raising the temperature of diols V (1 equivalent) from about -15 ° C to -25 ° C to about room temperature. Can be reacted with methanesulfonic acid anhydride (about 2.5 equivalents) in the presence of the base. Alternatively, Formula V, p- toluenesulfonyl chloride or can be converted chloride or by the action of triflic anhydride in Jitorifureto or ditosylate, CCl ₄ or CBr ₄ or SOCl ₂ in the presence in the action of PPh _3, POCl ₃ or It can be converted to dihalide such as dibromide or dichloride by the action of PBr ₃ . Dimesylate, ditriflate, ditosylate or dihalide is reacted with an amine such as 4-fluoroaniline at room temperature to 100 ° C. in the presence or absence of a co-solvent such as DMF (according to the method shown for explanation in Diagram II). , Pyrrolidines such as Formula VII can be obtained. Dimesylate VI (1 eq) (or otherwise, ditrifurate, ditocillate or dihalide) in the presence or absence of a co-solvent such as DMF at approximately room temperature to about 100 ° C. in a solvent such as tetrahydrofuran or 2-methyltetrahydrofuran. Among them, pyrrolidines such as formula VII can be obtained by reacting with 1 to 20 equivalents of amine D-NH ₂ such as substituted aniline. When a relatively small equivalent of amine D-NH ₂ is used (ie, 1 to 2 equivalents), a base such as diisopropylethylamine can be added to accelerate the reaction. In some cases, amines can be used in large excesses (ie, as reaction solvents). For example, the reaction of dimesylate (1 eq) with excess aniline (about 6.5 eq) can be carried out by heating to 65 ° C. in 2-methyltetrahydrofuran until the reaction is complete. Many substituted aniline can be reacted with the dimesylate of formula VI, including 3-fluoro-4- (piperidine-1-yl) aniline, 3,5-difluoro-4- (piperidine-1-yl). Aniline, 3,5-difluoro-4- (4-phenylpiperidine-1-yl) aniline, 3-difluoro-4- (4-phenylpiperidine-1-yl) aniline, 4- (4-phenylpiperidine-1-yl) Il) aniline, 4-cyclopropylaniline, 4-cyclopropyl-2-fluoroaniline, 4-cyclopropyl-3,5-difluoroaniline, 4-cyclohexyl-3-fluoroaniline, biphenyl-4-amine, 4-( Pyridin-2-yl) aniline, 3,5-dichloro-4- (piperidine-1-yl) aniline, 4- (4,4-dimethylpiperidine-1-yl) -3,5-difluoroaniline, 4-( 4,4-Fluoropiperidin-1-yl) -3,5-difluoroaniline, 3-methyl-4- (piperidine-1-yl) aniline, 2,5-difluoro-4- (piperidine-1-yl) aniline , 4- (3,5-dimethylpiperidine-1-yl) -3,5-difluoroaniline, 4- (2,6-dimethylpiperidine-1-yl) -3,5-difluoroaniline, 2,3,5 -Trifluoro-4- (piperidine-1-yl) aniline, 3,5-difluoro-4- (4-isopropylpiperidine-1-yl) aniline, 3,5-difluoro-4- (4-methylpiperidine-1) -Il) aniline, 3,5-difluoro-4- (4- (trifluoromethyl) piperidine-1-yl) aniline, 4- (4-tert-butylpiperidine-1-yl) -3,5-difluoroaniline , 3,5-Difluoro-4- (6-azaspiro [2.5] octane-6-yl) aniline, 4- (2-azabicyclo [2.2.2] octane-2-yl) -3,5- Difluoroaniline, 4- (3,3-dimethylazetidine-1-yl) -3,5-difluoroaniline, 4-tert-butylaniline, 4-ethoxyaniline, 4-phenoxyaniline, 1- (4-aminophenyl) ) Piperidine-2-one, 4- (cyclopentyloxy) -3-fluoroaniline, 3-chloro-4- (trifluoromethoxy) aniline, 2,5-difluoro-4- (trifluoromethyl) aniline, 4-( 2,2-Difluoroethoxy) aniline, 4-chloroa Nirin, 4- (2-methoxyethoxy) aniline, 4- (oxazole-2-yl) aniline, 4- (2-fluoropyridine-4-yl) aniline, 3,4-difluoroaniline, 4-chloro-3- Fluoroaniline, 3-fluoro-4- (methylsulfonyl) aniline, 4- (3-azabicyclo [3.2.0] heptane-3-yl) -3,5-difluoroaniline, 4-((3-ethyloxetane) -3-yl) methoxy) aniline, 4-cyclopropyl-3,5-difluoroaniline, 4- (1,3-dioxan-5-yloxy) aniline, 3,5-difluoro-4- (octahydroisoindole-) 2-yl) aniline, 4-((1,3-dioxolan-4-yl) methoxy) aniline, 4-((3-ethyloxetane-3-yl) methoxy) -3,5-difluoroaniline, 4-( Pentafluorosulfanyl) aniline, N1-tert-butyl-2-fluorobenzene-1,4-diamine, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines, allylamines or general procedure 1, There are, but are not limited to, anilines listed in 1.1 or 1.2 or which can be produced using them. The dinitro formula VII is treated with Fe in the presence of NH ₄ Cl, HCl or acetic acid, or with a hydride reducing agent such as sodium borohydride in a solvent such as ethanol or THF (BiCl ₃ , SbCl _3). , NiCl ₂ , Cu ₂ Cl ₂ or CoCl ₂ with or without transition metal salts), can be reduced to the formula VIII of diamino. For example, in a 1: 1 mixture of THF and ethanol, compound VII (1 eq) is reduced to VIII by reaction with iron powder (about 6 eq) and ammonium chloride while heating to about 60-80 ° C. Can be done. Alternatively, hydrogenation in the presence of a suitable catalyst such as palladium or platinum catalyst or Raney nickel can reduce Formula VII to the product Formula VIII. For example, the reduction of VII to VIII can be carried out by exposure to hydrogen gas at about 0.21 MPa (30 psig) in the presence of Raney nickel Grace2800 while shaking in a solvent such as tetrahydrofuran. N-methylmorpholine, Hunig base, pyridine, 2 in a solvent such as THF, DMF, dichloromethane, ethyl acetate or DMSO in the presence of peptide coupling reagents such as EDAC / HOBT, PyBOP, HATU, T3P or DEPBT. Prophosphoric acid (Boc is shown, but Cbz, Troc or Fmoc may be substituted) with or without the addition of amine bases such as 6-lutidine or triethylamine. ) To obtain the formula IX. For example, VIII (1 eq) 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (2.5 eq) and HATU (2 eq) in the presence of diisopropylethylamine (3 eq) in DMSO at about room temperature. The product IX can be provided by reaction with (5 equivalents). Acquisition of X by elimination of the Boc protecting group can be performed by treatment with an acid such as TFA, HCl or formic acid. For example, compound X can be obtained by reacting IX (1 equivalent) with TFA: CH ₂ Cl ₂ (1: 1) at room temperature. Compound XI can be prepared by coupling Formula X with the acid of choice using the standard peptide coupling reagents and conditions described above. For example, X (1 equivalent) is divided into 2- (methoxycarbonylamino) -3-methylbutanoic acid, 2- (methoxycarbonylamino) -3,3-dimethylbutanoic acid, 2-cyclohexyl-2- (methoxycarbonylamino) acetic acid. , 2- (Methoxycarbonylamino) -2- (tetrahydro-2H-pyran-4-yl) acetic acid or acids such as, but not limited to, the acids listed under General Procedure 19 (2 equivalents). Can be reacted with. Alternatively, N-methylmorpholin, Hunig base, pyridine, 2,6-lutidine in a solvent such as THF, DMF, dichloromethane or DMSO in the presence of a peptide coupling reagent such as EDAC / HOBT, PyBOP, HATU, T3P or DEPBT. Alternatively, compound XI can be obtained directly by reacting diamine VIII directly with appropriately N-substituted proline with or without the addition of amine bases such as triethylamine. For example, in the presence of diisopropylethylamine (about 5.5 equivalents) in a solvent such as ethyl acetate at a temperature of about 0 ° C. to about room temperature, VIII (1 equivalent) was added to 1- (2- (methoxycarbonylamino) -3-. XI can be obtained by direct reaction with methylbutanoyl) pyrrolidine-2-carboxylic acid (about 2 equivalents) and T3P (about 2.8 equivalents). The above procedure has shown the synthesis of specific compounds XI of the invention having proline groups substituted with Y and Z (ie, R ₂ and R ₅ with the atom to which they are attached, and R ₉ and R ₁₂ each form a 5-membered heterocycle with the atom to which they are bonded.) It should be understood that similar synthetic procedures are used to produce compounds of the invention in which Y, Z, R ₂ , R ₅ , R ₉ and R ₁₂ are other than those shown and described in Diagram II. be able to. In each equation in Diagram II

を、

,

（Ｄは上記で定義されている）で置き換えることができ、そのような化合物は、図式ＩＩに記載の方法に従って容易に製造することができる（化合物ＶＩＩＩからの直接の化合物ＸＩの製造を含む）。同様に、式ＸＩＩの化合物を、式Ｘの化合物から製造することができるか、式ＶＩＩＩの化合物から直接製造することができる。

Can be replaced with (D is defined above), such compounds can be readily prepared according to the method set forth in Schema II (including the production of compound XI directly from compound VIII). .. Similarly, a compound of formula XII can be prepared from a compound of formula X or directly from a compound of formula VIII.

As yet another non-limiting example, the compounds of Formula II and Formula III (A, B, D, Y and Z) shown in Scheme III, using the same conditions as described above for the production of IV in Scheme II. Can be produced from (as described above) to produce the compounds of the present invention. Similarly, the obtained 1,4-diketone IV can be reduced to 1,4-diol V using the method described above for Diagram II. By the above method, the racemic, enantiomer-rich or meso-form 1,4-diol V obtained can be converted to dimesylate VI, or ditriflate, ditocillate or dihalide. Under the above conditions, dimesylate VI, ditriflate, ditosylate or dihalide, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4 -Reacts with amines such as, but not limited to, chloroaniline, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines or allylamines to give the compounds of the invention. be able to. Alternatively, a compound such as VIII in which R is a group such as allyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl can be used as a useful reagent for elimination of the R group (Rh (Ph ₃ P) in the case of R = allyl). _{3 With} a rhodium catalyst such as Cl, treatment with an acid such as TFA or HCl in the case of R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, and hydrogenation decomposition by a Pd catalyst in the case of R = substituted benzyl). The treatment can give a compound such as IX. Palladium catalyst (Pd _(OAc) such as ₂ or _Pd 2 _{(dba) 3)} and phosphine ligand (such as triphenylphosphine or XantPhos) and a base (sodium bis (trimethylsilyl) amide, potassium tert- butoxide or the like _K 3 PO ₄ ), The Buchwald-Hartwig reaction can be used to react amine IX with aryl halides or trifrates (shown iodide for illustration) such as X to give the compounds of the invention. .. Alternatively, a reductive amination in a solvent such as ethanol, toluene, THF or dichloromethane in the presence of a hydride reducing agent such as sodium borohydride or sodium cyanoborohydride (with or without an acid such as acetic acid). The compound of the present invention can be obtained by reacting IX with an aldehyde or a ketone by conversion. Alternatively, reductive amination can be carried out by using hydrogenation in the presence of a suitable catalyst such as palladium or platinum catalyst or Raney nickel. Alternatively, amine IX can be reacted with a nucleophile such as alkyl halides or with an aryl electrophile (preferably electron-deficient aryl and heteroaryl halides and trifurates) by a nucleophilic aromatic substitution reaction. The reaction can give the compound of the present invention.

As a further non-limiting example, starting from compounds of formula II and III as shown in Scheme IV, it is possible to prepare compounds of XIII, the X ₅ in Formula II and Formula III halogen (e.g., Represents a Cl, Br or F) or nitro group. Moreover, each phenyl ring may be substituted with _{X 13, X 13} is an _X 5, H, alkyl, haloalkyl, alkoxy or haloalkoxy. 1,4-Diketones such as IV can be produced using the known methods described above for the production of IV for Diagram II. By the action of NaBH ₄ , LiAlH ₄ or DIBAL, 1,4-diketones IV can be reduced to 1,4-diols such as V. Alternatively, the enantiomeric selective reduction of 1,4-diketones such as IV can be carried out by the method described above for the production of V in Scheme II. As described for Intermediate 20D, there is another substituent X ₁₃ on the phenyl ring, it is possible to perform chiral reduction at lower stereoselectivity. The racemic, enantiomer-rich or meso-form 1,4-diols V can be reacted with methanesulfonyl chloride or methanesulfonic anhydride to give dimesylate VI. Alternatively, V can be converted to ditriflate or ditosylate by the method described above for Diagram II. Similar to Schema II, dimesylate, ditriflate, ditocilate or dihalide is reacted with amine D-NH ₂ of the amines (but not limited to) described or mentioned in Schema II to give VII. Can be done. When X ₅ in formula VII is nitro, with Fe in the presence of NH ₄ Cl, HCl or acetic acid, or with a hydride reducing agent such as sodium borohydride in a solvent such as ethanol or THF (BiCl ₃ , SbCl). _3. Transition metal salts such as NiCl ₂ , Cu ₂ Cl ₂ or CoCl ₂ are added or not added), and Fe can be used to reduce the nitro group to the tetraamino product IX. Alternatively, VII (X ₅ = nitro) can be reduced to product IX by hydrogenation in the presence of a suitable catalyst such as palladium or platinum catalyst or Raney nickel. Alternatively, the compound VII, which is X ₅ = halogen, has ammonia (R = H) or a suitable protecting group (substituted benzyl or R = allyl such as R = 4-methoxybenzyl or 2,4-dimethoxybenzyl). Can be reacted with amines. R protecting group (Rh (Ph ₃ P) ₃ Cl or other rhodium catalyst in the case of R = allyl, treatment with an acid such as TFA or HCl in the case of R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, Product IX can be obtained by treating the resulting product VIII with a reagent useful for the elimination of R = substituted benzyl, which is Pd-catalyzed hydrocracking). In the presence of peptide coupling reagents such as EDAC / HOBT, PyBOP, HATU, T3P or DEPBT, in solvents such as THF, DMF, dichloromethane or DMSO, N-methylmorpholin, Hunig base, pyridine, 2,6-lutidin or With or without an amine base such as triethylamine, the formula IX is reacted with a suitably protected prophosphate (Boc is shown, but Cbz, Troc or Fmoc may be substituted) to amide. X can be obtained as a mixture of products. Formula X describes a reaction that occurs on a particular NH ₂ group, but the reaction can occur on any NH ₂ . Conversion to the benzimidazole compound XI can be carried out by heating X in acetic acid (50-100 ° C.). Alternatively, XI can be produced by reacting IX with an aldehyde and then treating with an oxidizing agent such as Cu (OAc) ₂ or MnO ₂ (Penning, et al., Bioorg. Med. Chem. 2008). , 16, 6965-6975.). After removing the Boc protecting group from XI (performed by treatment with an acid such as TFA, HCl or formic acid), the diamine obtained using the standard peptide coupling reagents and conditions described above for Scheme II. By coupling XII with the selected acid, the compounds of the invention can be prepared to give XIII. In each scheme in Diagram IV

は、

Is

（Ｄは上記で定義されている）で置き換えることができ、そのような化合物は、図式ＩＶに記載の方法に従って容易に製造することができる。同様に、式ＸＩＶの化合物を、式ＸＩＩの化合物から製造することができる。図式ＩＶにおける合成方法に従う場合、エナンチオマー豊富ジオールＶから、多様な量の立体異性シスおよびトランスのピロリジン類ＶＩＩを含む混合物を得ることができる。立体異性ピロリジン類は、標準的なクロマトグラフィー技術に従って分離することができる。あるいは、そのような分離は、図式ＸＩＩＩおよびＸＩＶの段階を含む合成方法における後の段階で、または最終段階後に行うことができる。

(D is defined above) can be replaced and such compounds can be readily prepared according to the method described in Schematic IV. Similarly, compounds of formula XIV can be prepared from compounds of formula XII. Mixtures containing varying amounts of steric isomer cis and trans pyrrolidines VII can be obtained from the enantiomer-rich diol V when the synthetic method in Scheme IV is followed. The stereoisomeric pyrrolidines can be separated according to standard chromatographic techniques. Alternatively, such separation can be performed at a later stage in the synthetic method, including the stages of Schematic XIII and XIV, or after the final stage.

Alternatively, IX in Schema IV can be prepared from the compound of Formula II according to the method shown in Schema V. Compound VIII from Scheme II can be treated with an acylating agent such as acetyl chloride or acetic anhydride to give Compound II (Scheme V). The provision of III by nitration of Compound II can be carried out using known methods such as treatment with nitric acid or potassium nitrate in the presence of an acid such as sulfuric acid or treatment with NO ₂ BF ₄ . Treatment with Boc anhydride in the presence of DMAP to give IV, then sequentially treating IV with hydroxide (NaOH, KOH, LiOH, etc.) to remove acetyl groups and strong acids such as TFA or HCl. By removing the Boc protecting group by treatment with, the acetamide protecting group can be removed to obtain V. The nitro group in V can be reduced to an amino group for Schematic IV using the method described above to give IX. In each scheme in Diagram V

を、

,

（Ｄは上記で定義されている）で置き換えることができ、そのような化合物は、図式Ｖに記載の方法に従って容易に製造することができる。

(D is defined above) can be replaced and such compounds can be readily prepared according to the method described in Diagram V.

As yet another non-limiting example, the compounds of the invention can be prepared starting from the compounds of formula II according to the method shown in Schematic VI, A, B, D, Y and Z described above. It is a street. Under acid catalytic conditions such as acetic acid, TFA, formic acid or HCl, the 1,4-diketone compound of formula II (manufactured according to the method set forth in formula III) is aniline, 3,5-difluoroaniline, 3,4-difluoroaniline. , 4-Fluoroaniline, 3-Fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines or allylamines, etc. (limited to these) The compounds of the present invention can be obtained by reacting with amines (which are not).

As yet another non-limiting example, the compounds of the invention can be prepared from the compounds of formula II according to the method shown in Schematic VII. Starting from, for example, 1- (4-bromophenyl) ethanone and 2-bromo-1- (4-bromophenyl) ethanone, using a chemistry similar to that of scheme II for producing VII (in scheme II). as can be R _X is bromo, a compound of formula II is a halogen or triflate or nonaflate, such as chloro or iodo, to provide boronic acid or ester, such as formula III. R _X is bromo, halogen or triflate or a compound of formula II is nonaflate, R is hydrogen, boronic acid or ester of formula III is methyl, ethyl or cyclic pinacolate esters such as chloro or iodo (e.g., cyclic pinacolato It can be converted to rate ester). For example, in the presence of a catalyst such as tris (dibenzilidenacetone) palladium (0) and a ligand such as tri-t-butylphosphine, in a solvent such as tetrahydrofuran, dioxane or toluene, from ambient temperature about 130. Treatment with pinacol-borane at temperatures in the ° C range can convert compounds of formula II to compounds of formula III. Alternatively, in the presence of a catalyst such as, for example, Combiphos-Pd6 (CombiPhos Catalysts, Inc. (NJ, USA), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct or palladium acetate. In the presence of a ligand such as, for example 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl (XPhos) and a base such as potassium acetate, for example toluene, dioxane, tetrahydrofuran, dimethylformamide or Compound II can be reacted with bis (pinacolato) diboron in a solvent such as dimethyl sulfoxide at a temperature of about 60 to about 130 ° C. to give compound III, or the compound of formula II can be expressed in n-BuLi, The compound of formula III can be obtained by reacting with an organic lithium reagent such as sec-BuLi or t-BuLi and then with trimethylborate or triethylborate.

The compound of formula III in the diagram VII can be coupled with a compound of formula IV in which _RY is a halogen such as bromo, chloro or iodo under Suzuki reaction conditions to obtain a compound of formula V. Such conditions include, for example, tris (dibenzilidenacetone) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) palladium or dichloro [1,1'-. Bis (diphenylphosphino) ferrocene] Palladium catalysts such as palladium (II) dichloromethane adducts; bases such as potassium carbonate, potassium phosphate, potassium t-butoxide, sodium carbonate, cesium carbonate or cesium fluoride; and about 40 There is the use of solvents such as toluene, ethanol, water or tetrahydrofuran or mixtures thereof, which are heated in a temperature range of about 130 ° C. to.

Elimination of the Boc protecting group from V can be performed by treatment with an acid such as TFA, HCl or formic acid. Certain compounds of the invention, such as VI, use standard peptide coupling reagents such as EDAC / HOBT, PyBOP, HATU or DEPBT in solvents such as THF, DMF, dichloromethane or DMSO, and N-methylmorpholin, It can be prepared by coupling the resulting amino compound with a selected acid with or without the addition of amine bases such as Hunig base, pyridine, 2,6-lutidine or triethylamine. Each _{R Z} is independently _-L Y _{'-M'-R D (e.g., -L Y -N (R B "} ) C (O) -L S -R E) _{is, D,} L 3, _{R 1 , R 2, R 5, L} Y, R B ", L S, R E, the L Y ', M' and _{R D} are as defined above. Alternatively, a compound of formula VII can be obtained by similarly introducing a functional group of T- _RD after elimination of the Boc protecting group in V.

As another non-limiting example, the compounds of the present invention are prepared according to the formula VIII by first cleaving the diol by an oxidative method and then performing acid hydrolysis of acetonide using the compound of the formula II as a raw material. Can be manufactured. The dialdehyde intermediates are then mixed with aryl or arylboronic acid boronate (Compound IV or Compound VII where A and Y are as described above) and Aniline III (W is _RM or J, _RM and J is as defined above) to form formula V or formula VIII, respectively. Formula V can be derivatized by deprotonation of the hydroxyl group with a strong base such as sodium hydride, butyllithium or potassium hydride, and then alkylation with _RS -halogen. Alternatively, formula VIII can be deprotonated with a strong base (eg, sodium hydride), alkylated with _RS -halogen, and then acid hydrolyzed with a phenol protecting group. The compounds of formula IX are obtained by sulfonylating the phenols with nonafluorobutylsulfonylfluoride in the presence of a neutralizing agent such as potassium carbonate in a polar aprotic solvent such as DMF and then heating. By heating the formula IX with bis (pinacolato) diboron in the presence of a palladium catalyst such as X-phos and Pd ₂ (dba) ₃ and a base such as potassium acetate in an organic solvent such as dioxane, the boronate of the formula X can be obtained. Manufactured. Formula X is further derivatized by heating a suitably substituted heteroaryl halide in the presence of a palladium catalyst such as PdCl ₂ (dppf) and a base such as sodium carbonate in a mixture of toluene and ethanol. Let it be the final product. _RS is as defined above. In each scheme in Diagram VIII

を、

,

（Ｄは上記で定義されている）で置き換えることができ、そのような化合物は、図式ＶＩＩＩに記載の方法に従って容易に製造することができる

(D is defined above) can be replaced and such compounds can be readily prepared according to the method described in Schematic VIII.

As yet another non-limiting example, the compounds of the present invention can be prepared from the compounds of Formula II and Formula III as raw materials according to Schematic IX. The carboxylic acid of formula III is activated for coupling using a reagent such as isobutyl chlorite, DCC, EDAC or HATU in the presence of an organic base such as diisopropylethylamine. Once activated, dianiline of formula II is added to the reaction to isolate the intermediate amide and heated in acetic acid, preferably at 60 ° C., to give the compound of formula IV. The benzimidazole of formula IV is treated with SEM-Cl in the presence of a base in an aprotic solvent such as THF to obtain two protected benzimidazole positional isomers V. By heating Formula V with bis (pinacolato) diboron in the presence of a palladium catalyst such as PdCl ₂ (dppf), X-Phos and a base such as potassium acetate in an organic solvent such as dioxane, the boronate ester VI Manufactured. Heating gives both benzimidazole positional isomers VI. The diol VII is oxidatively cleaved and then acid hydrolysis of acetonide is performed. The dialdehyde intermediate is then treated with arylboronate VI and aniline VIII (W is _RM or J, _RM and J are as defined above) to treat the three types of formula IX. A benzimidazole positional isomer is produced. The hydroxyl group is deprotonated with a strong base such as sodium hydride, butyl lithium or potassium hydride, then alkylated with _RS -halogen, then preferably a mineral acid such as hydrochloric acid in an alcohol solvent such as methanol. The formula X is produced by acid hydrolysis of pyrrolidine and benzimidazole protecting groups by treatment with. Isobutyl chloroformate in the presence of an organic base such as diisopropylethylamine, DCC, using a reagent such as EDAC, or HATU, with a carboxylic acid _R Z -COOH, activated against the coupling. Once activated, formula X is added to the reaction to isolate formula XI. In each scheme in Diagram IX

を、

,

（Ｄは上記で定義されている）で置き換えることができ、そのような化合物は、図式ＩＸに記載の方法に従って容易に製造することができる。

It can be replaced with (D is defined above) and such compounds can be readily prepared according to the method described in Schematic IX.

R ₂₀ is _{-L S '-M'-L S "} -R D, certain compounds of the invention of the general formula D are as described above (8), prepared according to the method of Scheme X The diaryldiketone (3) can be obtained by reacting the bromoalkylketone (1) with the arylalkylketone (2) using the conditions mediated by the Lewis acid described above in Diagram II. Bis (pinacolato) in the presence of a base such as potassium acetate and a catalyst such as PdCl ₂ (dppf) -CH ₂ Cl _{2 in} a solvent such as DMSO, dimethoxyethane or dioxane while heating from 60 to 100 ° C. The diketone (3) can be converted to bisboronate (4) by reacting with diborane. By the Suzuki reaction using the Suzuki conditions described in Schematic VII, bisboronate (4) is converted to intermediate (5) in the same manner. The intermediate (5) can be converted to (6) by reacting with amine D-NH ₂ under similar conditions as described in Schematic VI, for example, toluene and the like (these). (5) is reacted with D-NH _{2 in} the presence of an acid such as TFA (not limited to these) while heating to 110 ° C. in a solvent (not limited to). The intermediate of the general structure (6) can be obtained by converting the compound (6) into the compound of the general formula (7) and then the compound of the general formula (8) in the same manner as described in the diagram VII. Alternatively, the compound of formula (X-1) can be obtained by introducing the functional group of T- _RD into the compound of formula (7) in the same manner.

Intermediate (6) can also be manufactured using the pathway depicted in Schematic XI. Using the conditions described in Diagram VI and X in the same manner, Intermediate (3) can be reacted with Amine D-NH ₂ to obtain Intermediate (9), which is described in Diagram X above. Can be converted to (10) in the same manner, and then (10) can be converted to compound (6) using the Suzuki reaction conditions described in Schematic VII.

As yet another non-limiting _{example, R 20} is _{-L S '-M'-L S "} -R D, a compound of general formula (15) of the present invention D is is as described above , Can be produced according to the method shown in Schematic XII. Under acid catalytic conditions such as acetic acid, TFA, formic acid or HCl, 1,4-diketone compound (3) is reacted with amine D-NH ₂ to compound. (11) can be obtained, for example, diketone (3) (1 equivalent) with aniline (1.2 equivalent) and TFA (2 equivalent) while heating to approximately 80 to 120 ° C. in a solvent such as toluene. Reaction can be carried out to obtain compound (11), or diketone (3) is reacted with aniline (about 10 equivalents) while heating to about 70 ° C. in acetic acid to give compound (11). Examples of amines that can be reacted according to the above description include, but are limited to, amines described or mentioned in Scheme II as suitable for the reaction with intermediate (5). Not. By reducing with iron in the presence of ammonium chloride, the compound of formula (11) can be converted to the compound of formula (12), for example, ethanol: THF: water (1: 1: 0. Compound (12) is obtained by reacting compound (11) (1 equivalent) with iron powder (about 6 equivalents) in the presence of ammonium chloride (about 3 equivalents) under reflux in the mixed solvent of 25). The conversion from (11) to (12) can also be carried out in Scheme II by the other methods described above, eg, by catalytic hydrogenation, to convert VII to VIII. From VIII to IX in Diagram II. Conversion of compound (12) (1 equivalent) to compound (13) using peptide coupling conditions, eg, EDAC / HOBt (2 equivalents) and a suitable acid in a solvent such as DMF at approximately room temperature. About the conversion from IX to X in Diagram II The TFA / CH ₂ Cl ₂ described above can be used to convert compound (13) to compound (14) from (12) to (13). The compound (14) can be converted to the compound (15) by using the same procedure as the procedure in the diagram II for converting from X to XI, such as a coupling procedure for converting to compound (15). similar functional groups -R _D, is introduced into the compound of formula (14), to give a compound of formula (XII-1).

The compound of general formula (19), wherein D is as described above, can be prepared according to the method of diagram XIII. A Buchwald reaction with tert-butyl 2-carbamoylpyrrolidine-1-carboxylate can be used to convert a compound of general formula (16) to a compound of general formula (17). In this Buchwald reaction, a base (for example, cesium carbonate), a palladium catalyst (for example, tris (dibenzylideneacetone) dipalladium (0)), and a phosphine are arranged while heating to about 80 to 120 ° C. in a solvent such as dioxane. It can be performed in the presence of a ligand (eg, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene). The conditions outlined in Diagram IV can be used in a similar manner to reduce the intermediate (17) to (18) and cyclize to (19). Compound (19) can be further reacted according to the method shown in Diagram IV to give compound of the present invention. Each phenyl ring in the above structure can be substituted with X _13, X ₁₃ is H, halogen, alkyl, haloalkyl, alkoxy or haloalkoxy. The mixture of cis and trans-stereoisomeric pyrrolidines in Schematic XIII can be separated into cis and trans isomers using standard chromatographic methods.

Certain compounds of the invention of the general formula (23), wherein D is as described above, can be prepared according to the method of Schematic XIV. Compound (21) can be obtained by reacting compound (16) with compound (20) using the Buchwald reaction outlined in Diagram XIII. Compound (21) can be reduced to compound (22) and cyclized to (23) using the same conditions outlined in the above scheme.

R ₂₀ is _{-L S '-M'-L S "} -R D, certain compounds of general formula (29) of the present invention D is is as described above, prepared according to the method of Scheme XV The compounds of formula (24) can be trimethylsilylacetylene, palladium catalysts (eg, bis (triphenylphosphine) palladium (II) chloride), copper catalysts (eg, copper (I) iodide) and bases (eg, copper (I)). , Triethylamine) can be converted to the compound of formula (25) (Sonogashira reaction), and an amine base can also be used as a solvent. The compound (25) can be used as a fluoride source (for example, in a solvent such as THF). It can be desilylated to compound (26) by reaction with tetrabutylammonium fluoride) to form the dianion of (26) with n-butyllithium, followed by wine revamide (eg, N- (tert)). -Butoxycarbonyl) -L-proline-N'-methoxy-N'methylamide) can be used to convert compound (26) to compound (27), such as THF or dimethoxyethane. It can be carried out in a suitable solvent. Compound (27) can be converted to compound (28) by reacting with hydrazine in a solvent such as ethanol, using the method outlined in the diagram above. , Compound (28) can be converted to compound (29), or the functional group of T- _RD can be similarly introduced into compound of formula (28) to give compound of formula (XV-1). be able to.

R ₂₀ is _{-L S '-M'-L S "} -R D, D are certain compounds of general formula (34) of the present invention is as described above, prepared according to the method of Scheme XVI In methanol as a solvent, while heating to about 100 ° C., in the presence of a palladium catalyst (eg, PdCl ₂ (dppf)), under pressure (about 0.41 MPa (about 60 psi)), (. Compound (24) can be converted to compound (30) by reacting 24) with CO (gas). Reacting with hydrazine in a solvent such as methanol while heating to about 60-80 ° C. The compound (30) can be converted to the compound (31) in a solvent such as butanol, heated to about 150 ° C., and irradiated in a microwave reactor while the base (for example, potassium carbonate). Compound (31) can be converted to compound (32) by reacting with N-Boc-2-cyano-pyrrolidin in the presence. The conditions outlined in the diagram above can be used in a similar manner. , Compound (32) can be deprotected to compound (33) and acylated to (34), or the functional group of T- _RD can be similarly introduced into compound of formula (33). , Compound of formula (XVI-1) can be obtained.

R ₂₀ is _{-L S '-M'-L S "} -R D, D are certain compounds of general formula (38) of the present invention is as described above, prepared according to the method of Scheme XVII The compound of formula (24) can be converted to compound (35) by reacting with CuCN while heating to about 160 ° C. while irradiating with microwaves in a solvent such as DMF. Compound (35) can be converted to compound (36) by reacting with HCl (gas) in anhydrous methanol at ° C. and raising the temperature to room temperature. NH ₃ (NH ₃ ) in anhydrous methanol at 0 ° C. Compound (36) can be converted to compound (37) by reacting with (gas) and raising the temperature to room temperature. In the presence of a base (eg, potassium carbonate), in THF (41). By reacting, compound (37) can be converted to compound (38), or by similarly introducing a functional group of T- _RD into compound of formula (33), formula (XVII-1). ) Compound can be obtained.

Compounds of formula (41) R ₂₀ is _{-L S '-M'-L S "} -R D is chloroformate at .THF in 0 ℃ which can be produced using the methods of Scheme XVIII (39) Compound (39) can be converted to compound (40) by reacting with isobutyl acid acid and then with diazomethane. Compound (40) is converted to compound (41) by reaction with HBr in acetate. can be. Similarly, converting a compound of formula (XVIII-1) to the compound of formula (XVIII-2), then it can be converted to (XVIII-3), T- R D in the above As defined.

R ₂₀ is _{-L S '-M'-L S "} -R D, certain compounds of general formula (48) of the present invention D is is as described above, prepared according to the method of Scheme XIX Compound (44) can be obtained by reacting compound (42) with compound (43) using the above-mentioned Lewis acid-mediated conditions in Scheme II in the same manner. Can be used in a similar manner to sequentially convert compound (44) to diol (45), mesylate (46) and cyclic intermediate (47). Conditions referred to in Schematic XIV and described in Schematic XIII. Compound (47) can be converted to compound (48) by reacting with (20) under backwald conditions such as, or TR with T and _RD as defined above. The functional group of _D can be similarly introduced into the compound of formula (47) to obtain the compound of formula (XIX-1).

R ₂₀ is _{-L S '-M'-L S "} -R D, D are certain compounds of general formula (55) of the present invention is as described above, prepared according to the method of Scheme XX Diethyl meso-2,5-dibromoadipate (49) is reacted with amine D-NH _{2 in} a solvent such as THF, dioxane or dimethoxyethane while heating at 50-100 ° C. Compound (50) can be obtained. Compound (50) is hydrolyzed with a base (eg, NaOH, KOH) in a mixture of alcohol (eg, methanol, ethanol) as a solvent and water to give compound (50) (51). ). By first reacting with oxalyl chloride and treating the intermediate acid chloride with diazomethane at 0 ° C., compound (51) can be converted to (52). Reaction with HBr aqueous solution. The compound (52) can be converted to the compound (53) by the reaction. The compound (53) can be converted to the compound (54) by the reaction with thiourea in a solvent such as ethanol. used in the same manner above conditions in, can be converted compound (54) into the compound (55). Similarly, T and R _D is a functional group of the T-R _D are as defined above The compound of formula (XX-1) can be obtained by introducing into the compound of formula (54).

R ₂₀ is _{-L S '-M'-L S "} -R D, D are certain compounds of general formula (60) of the present invention is as described above, prepared according to the method of Scheme XXI In pyridine, compound (56) can be reacted with compound (57) while heating to about 135 ° C. to form compound (58). Amin D-NH ₂ with POCl ₃ . Compound (58) can be converted to compound (59) by reacting, then adding (58) and heating in 1,2-dichlorobenzene at about 200 ° C. as described above in Schematic VII. used in the same manner conditions, can be converted compound (59) into the compound (60). Similarly, T and R _D is formula a functional group T-R _D are as defined above (59 ) Can be introduced into the compound of the formula (XXI-1).

R ₂₀ is _{-L S '-M'-L S "} -R D, D are certain compounds of general formula (66) of the present invention is as described above, prepared according to the method of Scheme XXII The compound (62) can be obtained by reacting the compound of the general formula (61) with boron tribromide at 0 ° C. in dichloromethane, and hydrogenation conditions for which platinum (II) oxide is used. Compound (63) was obtained as a compound (63). Coupling between compound (63) and a proline derivative (64) was performed using the standard coupling conditions described above to obtain compound (65). Can be converted to (66) in THF by the action of diethylazodicarboxylate and triphenylphosphine.

R ₂₀ is _{-L S '-M'-L S "} -R D, D are certain compounds of general formula (74) of the present invention is as described above, prepared according to the method of Scheme XXIII Compound (67) can be converted to (68) by reducing the nitro group with tin (II) chloride in ethanol. Peptide coupling with Boc-proline and then The compound (69) can be produced from (68) by heating the amide obtained in the above in acetic acid at 80 ° C., and the compound (69) is reacted with SEM-Cl and diisopropylethylamine in dichloromethane. (70) can be obtained by using a base such as cesium fluoride at 100 ° C. in a solvent such as N, N-dimethylformamide, and using a palladium catalyst such as PXPd (71). Coupling can give (72). Reaction with Selectfluor in a mixture of THF and water, then hydrogenation in ethyl acetate with 3% Pt / carbon, then hydrogenation in methanol. Compound (72) can be converted to (73) by reduction with sodium boron. Compound (73) can be reacted with methanesulfonyl chloride and triethylamine in dichloromethane at −10 ° C. , and then give an intermediate in the addition of amine _(H 2 N-D), deprotected using 4N HCl / 1,4-dioxane, then using a peptide coupling procedure described above R be to ₂₀ CO ₂ H and a coupling, it is possible to convert it into (74). Similarly, T and _{R D} is a functional group of the _{T-R D} are as defined above, the formula (73 ) Can be introduced into the compound of the formula (XXIII-1).

R ₂₀ is _{-L S '-M'-L S "} -R D, D are certain compounds of general formula (81) of the present invention is as described above, prepared according to the method of Scheme XXIV In ethanol, SnCl ₂ can be used to convert compound (75) to (76). In addition, the phenyl ring of compound (75) is X at a position where it is substituted with hydrogen or fluorine. can be substituted with _13, X ₁₃ is H, alkyl, haloalkyl, alkoxy or haloalkoxy, using the compound in the subsequent steps. using the above peptide coupling procedure (76) (64 ) To give the amide and heat it in acetic acid at 100 ° C. to give (77) the compound (77) in SEM-Cl and diisopropylethylamine in dichloromethane. (78) can be obtained by reacting with. For brief explanation, the SEM protective group on benzimidazole is shown bound to the specific nitrogen of benzimidazole. The actual substitution of the SEM group. The position may be any nitrogen (ie, (78) can be a mixture of position isomers). In subsequent compounds (79) to (80), depending on the position isomer of the SEM group. Mixtures of SEM position isomers are produced and they are separable or inseparable. In practice, SEM position isomers can be used as a mixture. Compound (78) is prepared according to the method described above (71). (79) can be obtained by reacting with. Using Selectfluor in a mixture of THF and water, then hydrogenating with Pt / carbon in ethyl acetate and reducing with sodium boron hydride in methanol. Alternatively, compound (79) can be converted to (80) as a chiral reduction condition using α, α-diphenyl-2-pyrrolidin methanol, diethylanilineborane and trimethylborane of (S) or (R). mesylated with methanesulfonyl chloride and triethylamine at a lower temperature, then reacted with a primary amine H _{2 N-D,} by deprotection with 4N HCl / 1,4-dioxane, compound (80) can be converted into compound (81). Similarly, functional groups T and R _D are as defined above T-R _D is introduced to the compound of formula (77), after synthesis procedure ends Obtain the compound of formula (XXIV-1) Can be

Certain amines D-NH ₂ in the Scheme is represented by the formula (84) can be prepared according to the general method shown in Scheme XXV, R _N is as defined above (e.g., halogen, alkyl, haloalkyl), _{R M} is _{-N (R S R S ')} ( e.g., -NEt _2), heterocyclic (e.g., pyrrolidin-1-yl, piperidin-1-yl,

など。Ｇ_３は上記で定義されており、

Such. G ₃ are are defined above,

はＧ_３で置換されている窒素含有複素環であり、

Is a nitrogen-containing heterocyclic ring substituted with G _3,

は窒素含有架橋二環式複素環である。）または−ＯＲ_Ｓ（例えば、−Ｏ−ｔ−ブチル、−Ｏ−イソプロピルなど）である。フルオロニトロベンゼン類（８２）を、ＤＭＳＯなどの溶媒中、適宜に加熱しながら、リン酸水素二カリウムの存在下に適切なアミンと反応させて、Ｒ_Ｍが−Ｎ（Ｒ_ＳＲ_Ｓ′）（例えば、−ＮＥｔ_２）または複素環（例えば、ピロリジン−１−イル、ピペリジン−１−イルである中間体（８３）を得ることができる。

Is a nitrogen-containing crosslinked bicyclic heterocycle. ) Or -OR _S (eg, -OT-butyl, -O-isopropyl, etc.). Fluoro nitrobenzenes (82), in a solvent such as DMSO, with heating as appropriate, is reacted with an appropriate amine in the presence of dipotassium hydrogen phosphate, _{R M} is _{-N (R S R S ')} ( For example, an intermediate (83) that is -NET ₂ ) or a heterocycle (eg, pyrrolidine-1-yl, piperidine-1-yl) can be obtained.

など）である。フルオロニトロベンゼン類（８２）をアルカリ金属アルコキシド（例えば、カリウムｔｅｒｔ−ブトキシド）と反応させて、Ｒ_Ｍが−ＯＲ_Ｓ（例えば、−Ｏ−ｔ−ブチル、−Ｏ−イソプロピルなど）である中間体（８３）を得ることもできる。公知のニトロ還元条件を用いて、中間体（８３）を（８４）に変換することができる。例えば、パラジウム／炭素を用いる接触水素化によって、（８３）を（８４）に変換することができる。あるいは、溶媒としてのＴＨＦ／メタノール／水中での鉄／塩化アンモニウムとの反応によって、（８３）を（８４）に変換することができる。ニトロ還元を行うための他の条件には、前記の図式に記載の条件および当業者に公知条件などがある。

Etc.). Fluoro nitrobenzenes (82) an alkali metal alkoxide (e.g., potassium tert- butoxide) to give the intermediate _{R M} is -OR _S (e.g., -O-t-butyl, -O- isopropyl, etc.) ( 83) can also be obtained. The intermediate (83) can be converted to (84) using known nitro-reduction conditions. For example, catalytic hydrogenation with palladium / carbon can convert (83) to (84). Alternatively, (83) can be converted to (84) by reaction with iron / ammonium chloride in THF / methanol / water as a solvent. Other conditions for performing nitro reduction include the conditions described in the above scheme and conditions known to those skilled in the art.

Certain compounds of the invention (XXVI-10) can be prepared according to the methods outlined in Schematic XXVI, where D, T and _RD are as described above. The diketone compound (XXVI-1) can be obtained by reacting compound (1) with compound (III) using the conditions outlined in Diagram II for the production of compound (IV). Compound (XXVI-1) can be converted to compound (XXVI-2) using the general conditions of Diagram II for conversion of (IV) to (V). Compound (XXVI-2) can be converted to compound (XXVI-3) using the general conditions of Diagram II for conversion of (V) to (VI). Compound (XXVI-3) can be converted to compound (XXVI-4) using the general conditions of Diagram II for conversion of (VI) to (VII). Schematic VII for conversion of (II) to (III) The compound of formula (XXVI-4) can be converted to compound (XXVI-5) using the general conditions of VII. The general conditions of Schematic VII for the conversion of (III) to (IV) can be used to convert compound (XXVI-5) to compound (XXVI-6). Compound (XXVI-6) can be converted to compound (XXVI-7) using the general conditions of Diagram II for conversion of (VII) to (VIII). For example, the compound (XXVI-6) (1 equivalent) can be reduced with hydrogen gas (1 atm) in the presence of PtO ₂ (about 0.2 equivalent) in a solvent such as ethanol: THF (1: 1). .. Compound (XXVI-7) can be converted to compound (XXVI-8) using the method outlined in Diagram II for conversion of (VIII) to (IX). For example, in DMSO at about room temperature, in the presence of diisopropylethylamine (3 eq), (XXVI-7) (1 eq) 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (from 1.5). Compound (XXVI-8) can be obtained by reacting with 3 equivalents) and HATU (about 1.6 equivalents). Compound (XXVI-8) can be converted to compound (XXVI-9) using the method outlined in Diagram II for conversion of (IX) to (X). For example, compound (XXVI-9) can be obtained by reacting (XXVI-8) (1 eq) with HCl / dioxane at about room temperature. Compound (XXVI-9) can be converted to compound (XXVI-10) using the method outlined in Diagram II for conversion of (X) to (XI). For example, (XXVI-9) (1 equivalent) in a solvent such as DMSO, 2- (methoxycarbonylamino) -3-methylbutanoic acid (about 2-3 equivalents), HATU (about 2.5 to 3.5 equivalents). ) And diisopropylethylamine (about 10 equivalents) to give the product (XXVI-10).

Certain compounds of the invention (XXVII-7) can be prepared according to the methods outlined in Schematic XXVII, with D, T and _RD as described above. Compound (XXVI-1) can be converted to compound (XXVII-1) using the general conditions of Schematic XII for conversion of (3) to (11). Compound (XXVII-1) can be converted to compound (XXVII-2) by reduction using the conditions outlined above in Diagram II. For example, in ethanol: THF: water (1: 1: 0.25), with iron powder (about 6 equivalents) and ammonium chloride (about 3 equivalents) while heating to reflux temperature (XXVII-1) (1 equivalent). Can be reduced to give (XXVII-2). Use the conditions described above for the conversion of VIII to IX in Schematic II, the conversion of (12) to (13) in Schematic XII, or the conversion of (XXVI-7) to (XXVI-8) in Schematic XXVI. The compound (XXVII-2) can be converted into the compound (XXVII-3). Compound (XXVII-3) was sequentially compounded with compound (XXVII-4) and (XXVII-) using the methods and conditions outlined in Schematic VII for the conversion from (II) to (III) and to (V). It can be converted to 5). Compounds (XXVII-5) were sequentially compounded using the methods and conditions outlined above, eg, using the method for converting (IX) to (X) and then to (XI) in Schematic II. It can be converted to XXVII-6) and (XXVII-7).

Compounds of certain general formulas (XXVIII-7) of the invention, wherein D, T and _RD are as described above, can be prepared according to the procedure of Schematic XXVIII. 2-Bromo-1- (4-nitrophenyl) according to the method described above for the production of compound (VII) in Scheme II, the production of (XXVI-4) in Schematic XXVI and the production of (VII) in Schematic IV. ) Compound (XXVIII-1) can be prepared from etanone, 1- (4-chloro-3-nitrophenyl) etanone and amine D-NH ₂ . Convert compound (XXVIII-1) (1 eq) to compound (XXVIII-2) by reacting with undiluted 4-methoxybenzylamine (about 4-6 equivalents) while heating to about 140-150 ° C. can do. Compound (XXVIII-2) can be converted to compound (XXVIII-3) by reducing according to the conditions outlined in Diagram II for the production of compound (VIII). For example, react (XXVIII-2) (1 eq) with PtO ₂ (about 0.4 to 0.5 eq) in a solvent such as ethanol: THF (1: 1) under a hydrogen atmosphere (1 to 4 ohms). By allowing the compound (XXVIII-3) to be obtained. Compound (XXVIII-3) can be converted to compound (XXVIII-4) according to the conditions outlined in Diagram II for the production of compound (IX). For example, at room temperature in a solvent such as DMSO, (XXVIII-3) (1 eq) 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (about 2 to 3 eq), HATU (about 2 to 3 eq). Compound (XXVIII-4) can be obtained by reacting with (equivalent) and diisopropylethylamine (about 3 equivalents). CH ₂ Cl ₂ : Compound (XXVIII-4) (1 eq) is compounded (XXVIII-5) by reacting with DDQ (approximately 1.2 eq) at room temperature in a solvent mixture of water (20: 1). ) Can be converted. Compound (XXVIII-5) can be converted to compound (XXVIII-6) according to the general method described in Schematic IV for compound (XI) (eg, heating to about 60-70 ° C. in acetic acid). Compound (XXVIII-6) is further converted to Compound (XXVIII-7) by using the standard deprotection and coupling methods referred to in Schematic IV for producing compound (XIII) or (XIV). Can be converted.

Certain compounds of the invention (XXIX-9), wherein D, T and _RD are as described above, can be prepared according to the procedure of Schematic XXIX. For the production of compound (VII) in Diagram II, the production of (XXVI-4) in Diagram XXVI and the production of (VII) in Diagram IV, compound (XXIX-1) was 2-bromo- according to the method described above. It can be prepared from 1- (4-bromophenyl) etanone, 1- (4-chloro-3-nitrophenyl) etanone and amine D-NH ₂ . Converting compound (XXIX-1) (1 equivalent) to compound (XXIX-2) by reacting with undiluted 3,4-dimethoxybenzylamine (about 10 equivalents) while heating to about 140-150 ° C. can do. Compound (XXIX-2) can be converted to compound (XXIX-3) according to the conditions outlined in Diagram II for the production of compound (VIII). For example, by reacting (XXIX-2) (1 eq) with PtO ₂ (about 0.1 eq) in a solvent such as ethanol: THF: EtOAc (1: 1) under a hydrogen atmosphere (eg, 1 atm). , Compound (XXIX-3) can be obtained. Compound (XXIX-3) can be converted to compound (XXIX-4) according to the conditions outlined in Diagram II for producing compound (IX). For example, (XXIX-3) (1 equivalent) in a solvent such as DMF at room temperature (S) -1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2. -Substituted proline such as carboxylic acid (about 1.2 to 1.5 eq), HOBt (about 1.2 to 1.5 eq), EDAC (about 1.2 to 1.5 eq) and N-methyl The compound (XXIX-4) can be obtained by reacting with morpholin (about 5 to 6 equivalents). The compound (XXIX-4) can be deprotected to the compound (XXIX-5) by reacting with excess TFA in a solvent such as methylene chloride at about room temperature. Convert compound (XXIX-5) to compound (XXIX-6) according to the general method described in Schematic IV (eg, heating to about 60-80 ° C. in acetic acid) to produce compound (XI). can do. Compound (XXIX-6) can be converted to compound (XXIX-7) according to the general conditions of Schematic VII for producing compound (III). For example, in a solvent such as toluene, while heating to 80-100 ° C., (XXIX-6) (1 eq) was added to PdCl ₂ (dppf) (about 0.1 eq), potassium acetate (about 3 to 5 eq) and The compound (XXIX-7) can be obtained by reacting with bis (pinacolato) diborone (about 3 equivalents). Compound (XXIX-7) can be converted to compound (XXIX-8) according to the general conditions of Schematic VII for producing compound (V). For example, in a solvent such as toluene, at about 80-100 ° C., compound (XXIX-7) (1 eq) is mixed with intermediate 1D (about 2 eq), 1M sodium carbonate (about 3 eq) and PdCl ₂ (dppf) (. The compound (XXIX-8) can be obtained by reacting with (about 0.1 equivalent). The standard deprotection methods (eg, HCl / dioxane) and coupling methods (eg, carboxylic acid, HOBt, EDAC and N-methylmorpholine) referred to in Scheme IV for producing compound (XIV) are used. As a result, the compound (XXIX-8) can be further converted into the compound (XXIX-9).

Certain compounds of the invention (XXX-8) can be prepared according to the method shown in Schematic XXX. The ester (XXX-1) is reacted with a suitable reducing agent such as DIBAL-H in a solvent such as THF, dichloromethane or diethyl ether to give the corresponding alcohol, which is then subjected to a solvent such as dichloromethane, THF or diethyl ether. It can be oxidized to aldehyde (XXX-2) by using a suitable oxidizing agent such as PDC. By reacting (XXX-3) (available from aniline, aldehyde and KCN using Strecker reaction) with aldehyde (XXX-2) in a solvent such as ethanol with a base such as potassium hydroxide, the formula (XXX-3) Pyrrole of XXX-4) can be produced (Synlett, 2003, pp1427-1430). By using the palladium-catalyzed reaction described above in Schematic VII, the bromine atom in the pyrrole compound (XXX-4) can be converted to the bis-borane compound (XXX-5). Phenylimidazole (XXX-6) can be obtained by reacting the pyrrole compound (XXX-5) with bromoimidazole such as Intermediate 1D using Suzuki reaction conditions. It is known to those skilled in the art that various reaction conditions are effective in mediating the Suzuki reaction. In particular, a reaction for producing (XXX-6) can be carried out using a Pd (dppf) Cl ₂ catalyst and potassium carbonate in a mixture of toluene and water while heating to about 100 ° C. Acquisition of (XXX-7) by elimination of the Boc protecting group can be performed by treatment with an acid such as TFA, HCl or formic acid. Certain compounds of the invention (XXX-8) in which T, _RD and D are as described above were selected (XXX-7) using the standard peptide coupling reagents and conditions described above. It can be produced by coupling with a reagent.

The present invention also conceives of the schematic XXXI-XXXIII for producing the compounds of the present invention. For example, the compound of the invention (XXXI-5) can be prepared using a series of steps outlined in Schematic XXXI. This procedure corresponds to that of Schematic XXX. The compound (XXXI-1) can be converted to the compound (XXXI-2) by sequentially performing a Heck reaction with ethyl acrylate and then a reduction to an aldehyde (XXXI-2). The compound (XXXI-3) can be obtained by reacting an aldehyde such as (XXXI-2) with the compound (XXX-3) in the same manner as in the conditions of the diagram XXX. The compound (XXXI-3) can then be converted to the boronate compound (XXXI-4) using the conditions outlined above in Schematic VII. Compound (XXXI-4) can be converted to compound (XXXI-5) by performing several steps such as Suzuki reaction, deprotection and coupling outlined in the above scheme.

Meyer et al. Synthesis, 2005, pp. 945-956 and Meyer et al Synlett, 2003, pp. Substituted α-aminonitriles can be reacted with α, β-unsaturated carbonyl compounds to give substituted hydroxy-cyanopyrrolidines according to the method described in 1427-1430. Similarly, the compound (XXXII-1) can be reacted with an α, β-unsaturated aldehyde (XXXII-2) to give pyrrolidine (XXXII-3). Hydroxy and cyano groups of compounds such as (XXXII-3) have been added to Synthesis, 2005, pp. According to the method described in 945-956, reduction can be carried out with FeSO ₄ using a reagent such as NaBH ₃ CN or NaBH ₃ CN. The nitro group of a compound such as (XXXII-3) can be reduced using standard conditions such as catalytic hydrogenation or reduction with iron powder and ammonium chloride. Typical nitro reduction conditions are described elsewhere herein. The Boc group of a compound such as (XXXII-3) can be eliminated using standard conditions such as TFA / CH ₂ Cl ₂ or HCl / dioxane. Compound (XXXII-5) can be obtained by reacting a compound such as (XXXII-4) with a suitable N-protected proline acid under the standard conditions described elsewhere herein. Compounds for which T, _RD and D are as described herein by deprotecting a compound such as (XXXII-5) and coupling it with a selected acid according to the methods described herein. (XXXII-6) can be obtained.

Yet another compound of the invention can be prepared according to the method outlined in Schematic XXXIII. Compounds such as (XXXIII-1) by acylation with protected proline acid (see Tetrahedron 2003, pp2701-2712), cyclization (see Tet. Lett. 2003, 5807-5810), SEM protection and nitroreduction. It can be prepared from -nitro-o-phenylenediamine. Compounds such as (XXXIII-1) can be converted to the Strecker product (XXXIII-2) by reacting with the aldehydes D-CHO and KCN in a manner similar to that referred to in Schematic XXX. A compound such as (XXXIII-2) can be condensed with a compound such as (XXXI-2) and then reduced to obtain a compound such as (XXXIII-3) (eg, Meyer et al. Synthesis, 2005, pp. 945-956 and Meyer et al Synlett, 2003, pp. 1427-1430). Compounds such as (XXXIII-3) were deprotected using standard conditions for elimination of Boc and SEM groups (see General Procedure 23), and the resulting amino compounds were subjected to conventional amide bond formation. Reactions with the appropriate acid under the conditions can give the compound (XXXIII-4) whose T, _RD and D are as described herein.

Certain compounds of the invention can also be prepared using the methods outlined in Schematic XXXIV. The ketone XXXIV-1 (reference: US200900760776; p19, [0146]) can be homologized in two steps to the aldehyde XXXIV-3. In the first step, the ketone can be reacted with dimethylsulfonium methylide in dimethyl sulfoxide to produce epoxide XXXIV-2. The epoxide can be rearranged to an aldehyde by treating it with an acid such as p-toluenesulfonic acid while heating it in toluene at a temperature of about 80 to 110 ° C. (Reference: J. Am. Chem). Soc. (1965) 1353, 1358; J. Org. Chem. (1972) 4075, 4076, 4077; Bioorg. Med. Chem. Lett. (2009) 5864, 5686). J. Am. Chem. Soc. , 1951, 73, 5171 and US5095153 Example 3a can be used to convert aldehyde XXXIV-3 to diol XXXIV-4 by potassium carbonate and formaldehyde in ethanol. The diol can be converted to bismesylate XXXIV-5 by reacting with excess methanesulfonyl chloride and triethylamine in dichloromethane from 0 ° C. to room temperature. Bismesylate can be converted to azide XXXIV-6 by reacting with sodium azide (about 1 equivalent) while heating to about 110 ° C. in DMPU. The azide can be converted to phosphoruimidate XXXIV-7 by reacting with freshly distilled triethylphosphite (about 1 equivalent) in dehydrated toluene / tetrahydrofuran at room temperature. By heating in o-xylene to about 150 ° C., phospholuimidate can be converted to azetidine-phosphonate XXXIV-8. Azetidine-phosphonate can be converted to azetidine XXXIV-9 by reacting with trifluoroacetic acid in dichloromethane at room temperature. Azetidine can be reacted with a suitable aryl halide (eg, iodide) using the Buchwald reaction to give N-aryl azetidine XXXIV-10. Under appropriate conditions, the mixture is heated to 80 to 100 ° C. in a solvent such as dioxane, and while subjected to appropriate microwave irradiation, aryl iodide (about 2 equivalents), Pd ₂ (dba) ₃ (about 0.025 equivalents). ), 4,5-Bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos; about 0.1 equivalent) and sodium tert-butoxide (about 1.2 equivalent). Bisbromide can be converted to bisboronate XXXIV-11 by reacting with bis (pinacolato) diborane, potassium acetate and PdCl ₂ (dppf) in a solvent such as DME, dioxane or DMSO at about 85 ° C. it can. Suitable such as methyl (S) -1-((S) -2- (5-bromo-1H-imidazol-2-yl) pyrrolidine-1-yl) -3-methyl-1-oxobutane-2-ylcarbamate By reacting with halide (ie, Suzuki reaction), bisboronate can be converted to the compound XXXIV-12 of the present invention.

Certain compounds of the invention can also be prepared using the methods outlined in Schema XXXV. Compounds such as XXXV-1 can be prepared using known methods by alkylating malonic acid esters with benzyl halides. Compound XXXV-1 can be converted to compound XXXV-2 by reduction with lithium aluminum hydride. By reaction with a base such as ms ₂ O and diisopropylethylamine, can be converted to compound XXXV-2 to compound XXXV-3. Compound XXXV-3 can be converted to compound XXXV-4 using a method similar to the method for converting XXXIV-5 to XXXIV-9 (see diagram XXXIV). Similarly, compound XXXV-4 can be converted to compound XXXV-5 using a Buchwald reaction similar to the reaction of diagram XXXIV. Compound XXXV-5 can then be converted to XXXV-6 by demethylation (eg by BBr ₃ ) and triflate formation by Tf ₂ O. Compound XXXV-6 can be converted to compound XXXV-7 in the same manner as conversion of XXXIV-10 to XXXIV-11. Finally, the Suzuki coupling of diagram XXXIV can be used to convert compound XXXV-7 to compound XXXV-8.

The above scheme (schematic I-XXXV) shows compounds in which the aromatic ring (eg, phenyl) is substituted with a group in a particular position chemistry (eg, para). Raw materials or intermediates with para-substitution provide the final product with para-substitution in the above diagram. It will be apparent to those skilled in the art that substitutions in the above scheme of raw materials or intermediates with different position chemistry (eg, meta) will provide the final product with different position chemistry. For example, replacement of a para-substituted raw material or intermediate in the above diagram with a meta-substituted raw material or intermediate is believed to yield a meta-substituted product.

If the portion described herein (eg, -NH ₂ or -OH) is incompatible with the synthetic method, the moiety is protected with a suitable protecting group that is stable to the reaction conditions used in that method. be able to. The protecting group can be eliminated at a suitable location in the reaction procedure to give the desired intermediate or target compound. Suitable protecting groups and methods for protecting or deprotecting parts are known to those of skill in the art, examples of which are described in the aforementioned Greene and Wuts works. The optimum reaction conditions and reaction times for each individual step can be determined by the particular reactant used and the substituents present in the reactant used. Solvents, temperatures and other reaction conditions can be readily selected by those skilled in the art based on the present invention.

As will be apparent to those skilled in the art, other compounds of the invention can be similarly prepared according to the above scheme and the procedures described in the intermediates, general procedures and examples below. It should be understood that the above embodiments and diagrams and the following intermediates, general procedures and examples are provided for illustration purposes only and are not intended to limit the invention. Various changes and modifications within the scope of the present invention will be apparent to those skilled in the art from the description herein.

The following Example compounds were named using ACD Name version 12 (ACD Name v12). Other compounds were named using ChemDraw version 9.0 (v9) and ACD Name v12 unless otherwise noted. Both naming programs can provide chemical names according to the tautomer structure selected for naming. The structure is shown as a chemically distinct tautomer and can be named.

For example, tautomer structure:

は、下記の名称：
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−フェニルピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（Ｃｈｅｍｄｒａｗ ｖ９）；
６，６′−［（２Ｒ，５Ｒ）−１−フェニルピロリジン−２，５−ジイル］ビス｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール｝（ＡＣＤ Ｎａｍｅ ｖ１２）を有する。

Is the following name:
(S) -6,6'-((2R, 5R) -1-phenylpyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-2-yl) -1H-benzo [d] imidazole) ) (Chemdraw v9);
6,6'-[(2R, 5R) -1-phenylpyrrolidine-2,5-diyl] bis {2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazole} (ACD Name v12) Have.

Tautomer structure:

は、下記の名称：
（Ｓ）−５，５′−（（２Ｒ，５Ｒ）−１−フェニルピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（Ｃｈｅｍｄｒａｗ ｖ９）；
５，５′−［（２Ｒ，５Ｒ）−１−フェニルピロリジン−２，５−ジイル］ビス｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール｝（ＡＣＤ Ｎａｍｅ ｖ１２）を有する。

Is the following name:
(S) -5,5'-((2R, 5R) -1-phenylpyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) ) (Chemdraw v9);
5,5'-[(2R, 5R) -1-phenylpyrrolidine-2,5-diyl] bis {2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazole} (ACD Name v12) Have.

Tautomer structure:

は、下記の名称：
（Ｓ）−５，５′−（（２Ｒ，５Ｒ）−１−フェニルピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（Ｃｈｅｍｄｒａｗ ｖ９）；
５−［（２Ｒ，５Ｒ）−１−フェニル−５−｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール（ＡＣＤ Ｎａｍｅ ｖ１２）を有する。

Is the following name:
(S) -5,5'-((2R, 5R) -1-phenylpyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) ) (Chemdraw v9);
5-[(2R, 5R) -1-phenyl-5-{2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazol-6-yl} pyrrolidine-2-yl] -2-[( 2S) -pyrrolidine-2-yl] -1H-benzimidazole (ACD Name v12).

Certain compounds in the examples below can be purified using reverse phase HPLC. Purification can be performed using a C18 or C8 reverse phase column. Compounds are eluted with a gradient of about 10% to 100% acetonitrile / 0.1% TFA aqueous solution; about 60% to 100% methanol / 10 mM ammonium acetate aqueous solution; or about 10% to 95% methanol / 10 mM ammonium acetate aqueous solution. can do. In the case of purification performed with TFA, the product thus obtained can be in the form of a TFA salt. Compounds can be characterized as TFA salts or free bases after neutralization, extraction and isolation.

Certain compounds in the examples below are in normal phase, such as conventional flash chromatography or automated purification systems using prepack silica gel columns (55 or 35 μm silica gel, Isco gold columns) (eg, Isco Combi-Flash, Analogix Intellifelash). It can be purified using silica gel chromatography. The compound can also be purified by preparative TLC.

Typical solvents for silica gel chromatography include ethyl acetate / hexane, diethyl ether / hexane, THF / hexane, ethyl acetate / methylene chloride, methanol / methylene chloride, NH ₄ OH-containing methanol / methylene chloride, acetone / hexane and There are methylene chloride / hexane and so on.

Intermediate synthesis

Intermediate 1
(S) -2- (4-Bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl

Intermediate 1A
(S) Oxalyl chloride (5.32 mL, 60.8 mmol) and dehydrated dichloromethane (125 mL) in a 500 mL trineck flask dried in a dryer purged with tert-butyl nitrogen -2-formylpyrrolidin-1-carboxylic acid. In addition, the solution was cooled to −78 ° C. A solution of dehydrated DMSO (7.30 mL, 103 mmol) in dehydrated dichloromethane (25 mL) was added dropwise from a constant pressure dropping funnel over 20 minutes. A solution of tert-butyl (9.41 g, 46.8 mmol) of (S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate in dehydrated dichloromethane (50 mL) was added dropwise from a constant pressure dropping funnel over 20 minutes to the reaction mixture. Was stirred at −78 ° C. for 30 minutes. Triethylamine (32.6 mL, 234 mmol) was added dropwise with a syringe over 5 minutes and the viscous white mixture was stirred in an ice-water bath for 30 minutes. The reaction was stopped with a 10% (w / v) aqueous citric acid solution (30 mL). The mixture was partitioned between Et ₂ O (550 mL) and 10% (w / v) aqueous citric acid solution in a separatory funnel. The layers were separated and the organic phase was washed with water and brine. The organic phase was dehydrated with anhydrous Na ₂ SO ₄ , filtered and concentrated to give a yellow oil (9.4 g), which was used directly in the next reaction.

Intermediate 1B
(S) The product (20 g, 100 mmol) from tert-butyl intermediate 1A of -2- (1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid was dissolved in methanol (50.2 mL) and ammonium hydroxide (50.2 mL) 50.2 mL) was added. Glyoxal (40% aqueous solution; 24.08 mL, 211 mmol) was added dropwise to this solution over 10 minutes. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with 50 mL of water, and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated (Na ₂ SO ₄ ) and concentrated to give a tan solid. The solid was treated with ether and concentrated. The solid was ground with 2: 1 diethyl ether: hexane (150 mL) to give 17 g of the solid, which was used directly in the next reaction. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.14 / 1.40 (s, 9H), 1.81-2.12 (m, 4H), 3.32-3.33 (m, 1H), 3.35-3.50 (m, 1H), 4.72-4.81 (m, 1H), 6.84 (s, 1H), 11.68 (s, 1H).

Intermediate 1C
Dichloromethane (200 mL) of the product (12.05 g, 50.8 mmol) from tert-butyl intermediate 1B of (S) -2- (4,5-dibromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid The medium solution was cooled (0 ° C.) and N-bromosuccinimide (108 mmol) was added thereto. The mixture is stirred in an ice bath for 2 hours, concentrated, dissolved in ethyl acetate (250 mL), washed with water (3 times at 150 mL) and brine (1 time at 100 mL), dehydrated (0054 ₄ ) and concentrated. , Obtained a very dark residue. The residue was mixed with dichloromethane / hexane (1: 1) and then concentrated to give a brown solid (about 19 g). The solid was ground with ether (about 100 mL) and filtered to isolate a tan solid (13.23 g, 65% yield). ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 1.49 (s, 9H) 1.86-2.17 (m, 3H) 2.80-2.95 (m, 1H) 3.30-3. 44 (m, 2H), 4.85 (dd, J = 7.54, 2.55Hz, 1H), 10.82 (s, 1H); MS (DCI +) m / z 394/396/398 (M + H) ⁺ ..

Intermediate 1D
(S) -2- (4-Bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl Product from intermediate 1C in a 1 liter round bottom flask equipped with a condenser and a glass stopper. (6.25 g, 15.82 mmol) was dissolved in dioxane (200 mL) and water (200 mL). A solution of sodium sulfite (22.38 g, 174 mmol) in water (200 mL) was added and the mixture was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and dioxane and a small amount of water were removed by rotary evaporator. The residue was extracted with dichloromethane. The combined organic phases were washed with brine (50 mL), dehydrated with anhydrous Na ₂ SO ₄ , filtered, concentrated on a rotary evaporator and co-distilled with 2: 1 hexane / dichloromethane (100 mL) to create a beige foam. (4.38 g) was obtained. The foam is dissolved in dichloromethane (2 mL), hexane (2 mL) is added, the resulting solution is loaded onto a column and purified by silica gel flash chromatography eluting with 30% to 80% ethyl acetate / hexane. The compound was obtained as a white solid (3.48 g). ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 1.48 (s, 9H) 1.83-2.33 (m, 3H) 2.79-3.02 (m, 1H) 3.37 (dd, J = 7.10, 5.37Hz, 2H), 4.88 (dd, J = 7.59, 2.49Hz, 1H), 6.92 (s, 1H), 10.70 (brs, 1H); MS (ESI +) m / z 316/318 (M + H) ⁺ .

中間体２
（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸
ジオキサン（２７７ｍＬ）に溶かした（Ｓ）−２−アミノ−３−メチルブタン酸（５７ｇ、４８７ｍｍｏｌ）に、２Ｎ水酸化ナトリウム水溶液（８０３ｍＬ、１６０６ｍｍｏｌ）、次にクロルギ酸メチル（７５ｍＬ、９７３ｍｍｏｌ）を１時間かけて滴下し、それによって溶液は昇温した。添加後、混合物を６０℃で２２時間加熱し、冷却し、ジクロロメタン（４００ｍＬ）で抽出した。得られた水層を氷浴で冷却し、ｐＨが２となるまで１２Ｎ塩酸を滴下した。得られた混合物を０℃で２時間撹拌し、得られた固体を減圧濾過によって回収し、真空乾燥機で乾燥して、標題化合物８０ｇ（９４％）を無色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．５０（ｂｓ、１Ｈ）、７．３４（ｄ、Ｊ＝８．６Ｈｚ、１Ｈ）、３．８４（ｄｄ、Ｊ＝８．６、６．０Ｈｚ、１Ｈ）、３．５４（ｓ、３Ｈ）、２．０３（ｍ、１Ｈ）、０．８６（ｔ、Ｊ＝７．０Ｈｚ、６Ｈ）。

Intermediate 2
In (S) -2- amino-3-methylbutanoic acid (57 g, 487 mmol) dissolved in (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid dioxane (277 mL), a 2N sodium hydroxide aqueous solution (803 mL, 1606 mmol), then methyl chlorobutanoate (75 mL, 973 mmol) was added dropwise over 1 hour, thereby warming the solution. After the addition, the mixture was heated at 60 ° C. for 22 hours, cooled and extracted with dichloromethane (400 mL). The obtained aqueous layer was cooled in an ice bath, and 12N hydrochloric acid was added dropwise until the pH reached 2. The obtained mixture was stirred at 0 ° C. for 2 hours, the obtained solid was recovered by vacuum filtration and dried in a vacuum dryer to give 80 g (94%) of the title compound as a colorless solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.50 (bs, 1H), 7.34 (d, J = 8.6 Hz, 1H), 3.84 (dd, J = 8.6, 6.0 Hz) , 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.86 (t, J = 7.0Hz, 6H).

Intermediate 3
Methyl (S) -1-((S) -2-carbamoylpyrrolidine-1-yl) -3-methyl-1-oxobutane-2-ylcarbamate

Intermediate 3A
Obtained by adding 4N HCl / dioxane solution (209 mL, 836 mmol) to tert-butyl (29.8 g, 139 mmol) of (S) -pyrrolidin-2-carboxamide hydrochloride (S) -2-carbamoylpyrrolidin-1-carboxylate. The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated, ground with diethyl ether, filtered under reduced pressure and dried in vacuo to give 21.6 g (104%) of the title product as a colorless solid.

Intermediate 3B
Methyl (S) -1-((S) -2-carbamoylpyrrolidine-1-yl) -3-methyl-1-oxobutane-2- ylcarbamate intermediate 3A (21.6 g, 144 mmol), intermediate 2 (29) . 1 g, 166 mmol), 1H-benzo [d] [1,2,3] triazole-1-ol hydrate (27.6 g, 180 mmol), N ¹ -((ethylimino) methylene) -N ³ , N ³ -Dimethylpropane-1,3-diamine hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL, 578 mmol) were dissolved in dichloromethane (960 mL) and stirred at room temperature for 18 hours. The resulting solution was concentrated to give a residue, water was added and the solution was extracted with a 25% isopropanol / chloroform solution (2000 mL twice). The organic layer is washed with brine, the organic extract is dehydrated with sulfonyl ₄ and concentrated to give a yellow oil, which is purified by column chromatography eluting with a gradient of 0% to 10% methanol / dichloromethane. As a result, 25 g (64%) of the title compound was obtained as a colorless solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 7.28 (m, 2H), 6.81 (s, 1H), 4.24 (dd, J = 8.1, 4.4 Hz, 1H), 4. 00 (t, J = 8.4Hz, 1H), 3.75 (m, 1H), 3.55 (m, 1H), 3.50 (s, 3H), 2.02 (m, 1H), 1 .97 (m, 2H), 1.80 (m, 2H), 0.92 (d, J = 6.7Hz, 3H), 0.86 (d, J = 8.6Hz, 3H).

Intermediate 4
Methyl (S) -1-((S) -2- (5-bromo-1H-imidazol-2-yl) pyrrolidine-1-yl) -3-methyl-1-oxobutane-2-ylcarbamate

Intermediate 4A
The mixture of (S) -5-bromo-2- (pyrrolidin-2-yl) -1H-imidazole hydrochloride intermediate 1D (5.0 g, 15.8 mmol) in 4M HCl / dioxane (40 mL) was stirred for 1 hour. .. The mixture was concentrated to give 3.99 g (100%) of the title compound. MS (ESI) m / z 217 (M + H) ⁺ .

Intermediate 4B
Methyl (S) -1-((S) -2- (5-bromo-1H-imidazol-2-yl) pyrrolidine-1-yl) -3-methyl-1-oxobutane-2-ylcarbamate intermediate 4A ( 3.99 g, 15.8 mmol), Intermediate 2 (2.77 g, 15.8 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (3.63 g, 19.0 mmol), 1 A mixture of -hydroxy-benzotriazole hydrate (2.90 g, 19.0 mmol) and N-methylmorpholine (12.2 mL, 111.0 mmol) in DMF (150 mL) was stirred overnight. The mixture was diluted with _{H 2} O, and extracted with EtOAc (3 x 300 mL). The organic layer was washed with H _{2 O} and brine. The organic phase was dehydrated (sulfate ₄ ), filtered and concentrated. Purification by chromatography (silica gel, 75% EtOAc / Hexanes) gave 5.2 g (88%) of the title compound. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.79 (dd, J = 6.67, 3.63 Hz, 6H), 1.84-1.96 (m, 3H), 2.02-2.14 (M, 2H), 3.51 (s, 3H), 3.66-3.80 (m, 2H), 3.96-4.03 (m, 1H), 4.91-4.99 (m) , 1H), 7.06 (d, J = 1.52Hz, 1H), 7.26 (d, J = 8.46Hz, 1H), 12.01 (s, 1H); MS (ESI) m / z373 (M + H) ⁺ .

Intermediate 5
Dimethanesulfonic acid (1S, 4S) -1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-diyl

Intermediate 5A
2-Bromo-1- (4-chloro-3-nitrophenyl) etanone
Method A
Under _{N 2} atmosphere in a flask fitted with a magnetic stir bar, was added 4'-chloro-3'-nitroacetophenone (10.0 g, 50.1 mmol) and THF (100 mL). Phenyltrimethylammonium tribromide (19.78 g, 52.6 mmol) was added to the stirred mixture in small portions over a period of 15 minutes. The resulting mixture was stirred via LCMS with hourly monitoring. After 3 hours, the mixture was filtered and the resulting solid was washed with EtOAc. The organic solution was concentrated and the _{H 2} O and 10% NaHCO ₃ aqueous solution was added, the mixture was washed with EtOAc (2 x 300 mL). The combined organic layers were washed with brine, dehydrated (sulfonyl ₄ ), filtered and concentrated. The residue was purified by crystallization. The residue was dissolved in EtOAc (100 mL) and hexane was added slowly until the mixture became turbid. After standing for several hours, 2-bromo-1- (4-chloro-3-nitrophenyl) etanone (9.81 g, 70%) was recovered as an off-white solid product. ^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δppm 5.00 (s, 2H) 7.98 (d, J = 8.54 Hz, 1H) 8.24 (dd, J = 8.54, 2.14 Hz, 1H) ) 8.61 (d, J = 1.98Hz, 1H).

Method B
To a 500 ml round bottom flask, 1- (4-chloro-3-nitrophenyl) etanone (11.98 g, 60 mmol) in benzene (75 mL) was added to obtain a white suspension. Bromine (9.59 g, 60.0 mmol) was added dropwise over 5 minutes to give a deep red solution. The mixture was stirred for 1 hour to give a yellow solution and concentrated under reduced pressure to give a yellow solid. Recrystallization from 9: 1 hexane / ethyl acetate gave 2-bromo-1- (4-chloro-3-nitrophenyl) etanone as a yellow needle.

Intermediate 5B
Add 1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-dione zinc chloride (II) (14.68 g, 108 mmol) to toluene (81 mL), then diethylamine (8.35 mL, 81 mmol) and tert-butanol (7.73 mL, 81 mmol) were added. The resulting heterogeneous solution was stirred at room temperature for about 2 hours. The intermediate 5A (15.0 g, 53.9 mmol) and 4'-chloro-3'-nitroacetophenone (16.13 g, 81 mmol) were then added to the solution in one dose and the resulting mixture was stirred at room temperature for 42 hours. did. The reaction was stopped with a 5% aqueous sulfuric acid solution (500 mL), and high stirring was performed to induce solid formation. The obtained solid was collected by vacuum filtration and washed in the order of toluene, water and methanol. The solid was then added to the hot ethyl acetate solution and the resulting heterogeneous solution was stirred for 30 minutes. The solid was recovered and dried overnight in a vacuum dryer to give 16.6 g (78%) of the title compound. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ8.61 (d, J = 1.9 Hz, 2H), 8.27 (dd, J = 8.4, 1.9 Hz, 2H), 7.96 (d) , J = 8.3Hz, 2H), 3.48 (s, 4H).

Intermediate 5C
(1S, 4S) -1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-diol in a dry flask under nitrogen at ambient temperature, (R)-(+)-α, α-Diphenyl-2-pyrrolidinmethanol (1.08 g, 4.28 mmol) was dissolved in 70 mL of THF, and trimethylborate (650 μL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hour. When the solution was cooled in a cooling bath to about 10 ° C. and N, N-diethylaniline borane (9.18 mL, 51.6 mmol) was added dropwise, slight foaming was observed. After 15 minutes, the solution was transferred to a dropping funnel and suspended in 200 mL of THF 1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-dione (intermediate 5B) (10.0 g). , 25.2 mmol) and cooled to about 10 ° C. Foaming was observed. After the addition, the mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath, 30 mL of methanol was added dropwise until foaming stopped and the mixture was stirred at ambient temperature for 30 minutes. The mixture was filtered to remove trace amounts of insoluble unreacted material. The filtrate was concentrated, poured into 1M HCl, extracted with ethyl acetate, dehydrated with sodium sulfate and concentrated to give the title compound (9.9 g, 99%) as a yellow waxy solid. Chiral HPLC e. e. > 99.9% (RR diol could not be detected). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 7.94 (d, J = 1.9 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.60 (dd, J = 8) .4, 1.9Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).

Intermediate 5D
1 liter round containing dimethanesulfonic acid (1S, 4S) -1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-diyl intermediate 5C (20.0 g, 49.9 mmol) 310 mL of dichloromethane was added in the bottom flask with stirring and cooling in an ice bath. Triethylamine (20.84 mL, 150 mmol) was added to the slurry, and the mixture was stirred in an ice bath for 10 minutes, and then a solution of methanesulfonyl chloride (8.5 mL, 110 mmol) in dichloromethane (10 mL) was added dropwise to the reaction solution. After the addition was complete, the flask was removed from the ice bath and stirred at room temperature for 3 hours. Water (400 mL) was added to the reaction solution with high stirring, and the mixture was allowed to elapse for 20 minutes. The solid was collected by filtration and washed thoroughly with water dichloromethane and diethyl ether. The solid was dried overnight in a vacuum dryer at 60 ° C. to give a white solid (20.49 g, 73.7% yield). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.81-1.91 (m, 2H) 2.06 (m, 2H) 3.18 (s, 6H) 5.73-5.84 (m, 2H) ) 7.71-7.77 (m, 2H) 7.80-7.85 (m, 2H) 8.13 (d, J = 1.74Hz, 2H).

中間体５．１
（１Ｒ，４Ｒ）−１，４−ビス（４−クロロ−３−ニトロフェニル）ブタン−１，４−ジオール
（Ｓ）−（−）−α，α−ジフェニル−２−ピロリジンメタノールおよび中間体５Ｃの方法を用いて、（１Ｒ，４Ｒ）−１，４−ビス（４−クロロ−３−ニトロフェニル）ブタン−１，４−ジオールを製造することができる。

Intermediate 5.1
(1R, 4R) -1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-diol (S)-(-)-α, α-diphenyl-2-pyrrolidinmethanol and intermediate 5C (1R, 4R) -1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-diol can be produced by the method of.

中間体５．２
ジメタンスルホン酸（１Ｒ，４Ｒ）−１，４−ビス（４−クロロ−３−ニトロフェニル）ブタン−１，４−ジイル
中間体５Ｄ下に記載の方法に従って、（１Ｒ，４Ｒ）−１，４−ビス（４−クロロ−３−ニトロフェニル）ブタン−１，４−ジオールをジメタンスルホン酸（１Ｒ，４Ｒ）−１，４−ビス（４−クロロ−３−ニトロフェニル）ブタン−１，４−ジイルに変換することができる。

Intermediate 5.2
Dimethanesulfonic acid (1R, 4R) -1,4-bis (4-chloro-3-nitrophenyl) butane-1,4-diyl intermediate 5D According to the method described below, (1R, 4R) -1, 4-bis (4-chloro-3-nitrophenyl) butane-1,4-diol to dimethanesulfonic acid (1R, 4R) -1,4-bis (4-chloro-3-nitrophenyl) butane-1, It can be converted to 4-giyl.

Intermediate 6
Dimethanesulfonic acid (1R, 4R) -1,4-bis (4-nitrophenyl) butane-1,4-diyl

Intermediate 6A
Diethylamine (1.558 mL) while stirring 1,4-bis (4-nitrophenyl) butane-1,4-dione anhydrous zinc chloride (II) (2.73 g, 20.00 mmol) in dehydrated benzene (15 mL). , 15.00 mmol) and t-butanol (1.435 mL, 15.00 mmol) were added and the resulting mixture was stirred at room temperature for 90 minutes to give a turbid solution. To this mixture was added 2-bromo-1- (4-nitrophenyl) etanone (2.44 g, 10.00 mmol) and 1- (4-nitrophenyl) etanone (2.477 g, 15.00 mmol). The mixture was stirred at room temperature overnight. The mixture was added to water (50 mL) and extracted with ethyl acetate (3 times at 50 mL). The combined organic layers were dehydrated with Na ₂ SO ₄ , filtered and concentrated. The resulting residue was ground with dichloromethane to give an orange-red solid, which was collected by filtration and dried to give the title compound (2.0 g, 61% yield).

Intermediate 6B
(1R, 4R) -1,4-bis (4-nitrophenyl) butane-1,4-diol (S)-(-)-α, α-diphenyl-2-pyrrolidinmethanol (2.71 g, 10.70 mmol) ), THF (80 mL) was added at 23 ° C. The resulting very dilute suspension was treated with trimethylborate (1.44 g, 13.86 mmol) over 30 seconds and the resulting solution was mixed at 23 ° C. for 1 hour. The solution was cooled to 16-19 ° C. and N, N-diethylaniline borane (21.45 g, 132 mmol) was added dropwise by syringe over 3-5 minutes while maintaining the internal temperature at 16-19 ° C. (Note: vigorous _{H 2} evolution). After 15 minutes, _{H 2} generation had stopped. The product from Example 6A (22.04 g, 95 wt%, 63.8 mmol) and then THF (80 mL) were added to another container to give an orange-red slurry. After cooling the slurry to 11 ° C., the borane solution was transferred to the dione slurry over 3 to 5 minutes via a cannula. During that time, the internal temperature of the slurry increased to 16 ° C. After the addition was complete, the reaction was maintained at 20-27 ° C. for an additional 2.5 hours. After completion of the reaction, the mixture was a to 5 ° C. cooling, was added dropwise over methanol (16.7 g, 521 mmol) 5 to 10 minutes while maintaining the internal temperature <20 ° C. (NOTE: vigorous _{H 2} evolution). After the exotherm stopped (about 10 minutes), the temperature was adjusted to 23 ° C. and the reaction solution was mixed until the solid was completely dissolved. Ethyl acetate (300 mL) and 1M HCl (120 mL) were added and the phases were separated. The organic phase (2 x 120 _mL) 1M HCl, and washed sequentially with H 2 O (65 mL) and aqueous 10% NaCl solution (65 mL). The organic layer was dehydrated with sulfonyl ₄ , filtered and concentrated under reduced pressure. Upon concentration, crystallization of the product occurred. The temperature of the slurry was raised to 50 ° C., and heptane (250 mL) was added over 15 minutes. The slurry was mixed at 23 ° C. for 30 minutes and filtered. The moist cake was washed with 3: 1 heptane: ethyl acetate (75 mL) and the orange-red crystalline solid was dried at 45 ° C. for 24 hours to impurities 11% mesoisomer (relative to dl isomer). The title compound (15.35 g, 99.3% ee, yield 61%) was obtained.

Intermediate 6C
The product (5.01 g, 13.39 mmol) from dimethanesulfonic acid (1R, 4R) -1,4-bis (4-nitrophenyl) butane-1,4-diyl intermediate 6B was added to 2-methyltetrahydrofuran (5.01 g, 13.39 mmol). It was combined with 70 mL), cooled to −5 ° C., and N, N-diisopropylethylamine (6.81 g, 52.7 mmol) was added over 30 seconds. Separately, a solution of methanesulfonic acid anhydride (6.01 g, 34.5 mmol) in 2-methyltetrahydrofuran (30 mL) was prepared and placed in a diol slurry for 3 minutes while maintaining the internal temperature from -15 ° C to -25 ° C. I added it over. After stirring at −15 ° C. for 5 minutes, the cooling bath was removed, and the reaction solution was slowly heated to 23 ° C. and mixed for 30 minutes. After completion of the reaction, the crude slurry is used directly without purification or isolation.

Intermediate 7
Dimethanesulfonic acid ((1R, 4R) -1,4-bis (4-bromophenyl) butane-1,4-diyl)

Intermediate 7A
Diethylamine (11.16 mL, 108 mmol) and 2- in a solution of 1,4-bis (4-bromophenyl) butane-1,4-dione zinc chloride (II) (19.62 g, 144 mmol) in benzene (108 mL). Methylpropan-2-ol (10.32 mL, 108 mmol) was added and the mixture was stirred at room temperature for 2 hours. 2-Bromo-1- (4-bromophenyl) ethanone (20.0 g, (72 mmol) and 1- (4-bromophenyl) etanone (21.48 g, 108 mmol) were added in one portion and the mixture was stirred overnight ( 18 hours). The reaction mixture was stopped at 5% H ₂ SO ₄ (500 mL) and stirred with high agitation to induce precipitation of the product, which was recovered by vacuum filtration, benzene, water, methanol and then. The product was washed in the order of dichloromethane. The product was vacuum dried to give the title compound as a white solid (11.15 g, yield 39.1%).

Intermediate 7B
(1R, 4R) -1,4-bis (4-bromophenyl) butane-1,4-diol (S)-(-)-α, α-diphenyl-2-pyrrolidinmethanol (3.81 g, 15.04 mmol) ), THF (140 mL) was added at 23 ° C. The resulting thin slurry was treated with trimethylborate (2.189 mL, 19.63 mmol) to give a clear solution. After stirring for 1.5 hours, the solution was cooled to 10-15 ° C. and N, N-diethylaniline borane (33.1 mL, 186 mmol) was added by syringe over 5-10 minutes. Slight fever and H ₂ evolution was observed. Intermediate 7A (35.045 g, 88 mmol) and then THF (140 mL) were placed in a separate container to give a slurry. The slurry was cooled to 10 ° C. The cooled borane solution was transferred to the dione slurry via a cannula over about 5 minutes while maintaining the internal temperature at <25 ° C. After the transfer was complete, the slurry was maintained at 15 ° C. for 5 minutes and the temperature was maintained at 23 ° C. for 3 hours. After completion of the reaction, the solution was cooled to 5 ° C. and methanol (31.6 mL, 780 mmol) was slowly added to maintain the temperature at <20 ° C. (Note: intense hydrogen generation). The hazy solution was mixed for an additional hour to complete the reaction termination. The hazy solution was diluted with EtOAc (500 mL) and 1M HCl (220 mL). The phases were separated, (2 x 220 _mL) The organic phase 1M HCl, and washed sequentially with H 2 O (110 mL) and 25% NaCl solution (110 mL). The organic layer was concentrated under reduced pressure, then the residue was dissolved in EtOAc, filtered, concentrated and crystallized from EtOAc / Hexanes to give the title compound (16.92 g; 100% ee; isolation yield). 47%).

Intermediate 7C
Intermediate 7B (0.60 g, 1.500 mmol) in dimethanesulfonic acid (1R, 4R) -1,4-bis (4-bromophenyl) butane-1,4-diyl dehydrated CH ₂ Cl ₂ (15 mL) in at _{0 ℃, Et 3 N (0.627mL} , 4.50mmol) was added and the resulting mixture until a homogeneous solution was obtained and stirred for 10 min at 0 ° C.. Methanesulfonyl chloride (0.292 mL, 3.75 mmol) was added dropwise to the cooled solution, and the mixture obtained as measured by TLC (1: 1 EtOAc: Hexanes) was stirred at 0 ° C. for 1.5 hours. did. The solvent was removed under reduced pressure to give a solid, which was vacuum dried.

中間体８
（２Ｓ，４Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）−４−（ｔｅｒｔ−ブチルジメチルシリルオキシ）ピロリジン−２−カルボン酸
（２Ｓ，４Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）−４−ヒドロキシピロリジン−２−カルボン酸（５．３１ｇ、２２．９６ｍｍｏｌ）およびイミダゾール（７．８２ｇ、１１５ｍｍｏｌ）を環境温度でジクロロメタン（１０６ｍＬ）およびジメチルホルムアミド（２２ｍＬ）中で合わせ、ｔｅｒｔ−ブチルクロロジメチルシラン（７．６１ｇ、５０．５ｍｍｏｌ）を少量ずつ加えた。混合物を１８時間撹拌し、水で希釈し、酢酸エチルで抽出し、濃縮して標題化合物を得た。

Intermediate 8
(2S, 4S) -1- (tert-butoxycarbonyl) -4- (tert-butyldimethylsilyloxy) pyrrolidine-2-carboxylic acid (2S, 4S) -1- (tert-butoxycarbonyl) -4-hydroxypyrrolidin -2-Carboxylic acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined in dichloromethane (106 mL) and dimethylformamide (22 mL) at ambient temperature and tert-butylchlorodimethylsilane (7. 61 g, 50.5 mmol) was added little by little. The mixture was stirred for 18 hours, diluted with water, extracted with ethyl acetate and concentrated to give the title compound.

中間体９
（Ｓ）−１−（（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタノイル）ピロリジン−２−カルボン酸
中間体２（１５０ｇ、８５６ｍｍｏｌ）、ＨＯＢｔ水和物（１３８ｇ、８９９ｍｍｏｌ）およびＤＭＦ（１５００ｍＬ）をフラスコに入れた。混合物を１５分間撹拌して透明溶液を得た。ＥＤＣ塩酸塩（１７２ｇ、８９９ｍｍｏｌ）を入れ、２０分間混合した。混合物を冷却して１３℃とし、（Ｌ）−プロリンベンジルエステル塩酸塩（２０７ｇ、８５６ｍｍｏｌ）を入れた。トリエチルアミン（１０９ｇ、１０７９ｍｍｏｌ）を３０分以内で入れた。得られた懸濁液を室温で１．５時間混合した。反応混合物を冷却して１５℃とし、６．７％ＮａＨＣＯ_３ １５００ｍＬを１．５時間入れ、次に水１２００ｍＬを６０分間かけて加えた。混合物を室温で３０分間撹拌し、それを濾過し、水／ＤＭＦ混合物（１：２、２５０ｍＬ）と次に水（１５００ｍＬ）で洗浄した。湿ったケーキを５５℃で２４時間乾燥して、生成物（Ｓ）−１−（（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタノイル）ピロリジン−２−カルボン酸ベンジル２８２ｇを白色固体として得た（９０％）。

Intermediate 9
(S) -1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylic acid intermediate 2 (150 g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF (1500 mL) was placed in a flask. The mixture was stirred for 15 minutes to give a clear solution. EDC hydrochloride (172 g, 899 mmol) was added and mixed for 20 minutes. The mixture was cooled to 13 ° C. and (L) -proline benzyl ester hydrochloride (207 g, 856 mmol) was added. Triethylamine (109 g, 1079 mmol) was added within 30 minutes. The resulting suspension was mixed at room temperature for 1.5 hours. The reaction mixture was cooled to 15 ° C., 1500 mL of 6.7% NaHCO ₃ was added for 1.5 hours, then 1200 mL of water was added over 60 minutes. The mixture was stirred at room temperature for 30 minutes, filtered and washed with water / DMF mixture (1: 2, 250 mL) followed by water (1500 mL). The moist cake was dried at 55 ° C. for 24 hours to whiten 282 g of the product (S) -1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylate benzyl. Obtained as a solid (90%).

Benzyl (40 g) of (S) -1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylate and 5% Pd / alumina were placed in a pearl reactor and then THF (160 mL) was added. The reactor was sealed, purged with nitrogen (6 times at about 0.18 MPa (20 psi)) and then hydrogen purged (6 times at about 0.21 MPa (about 0.21 MPa (30 psi) g)). The reactor was pressurized with hydrogen to about 0.21 MPa (about 0.21 MPa (30 psi) g) and stirred at room temperature for about 15 hours. The obtained slurry was filtered through a GF / F filter and concentrated to obtain about 135 g of a solution. Heptane (120 mL) was added and the solution was stirred until a solid was formed. After 2-3 hours from the addition, additional heptane (240 mL) was added dropwise and the slurry was stirred for about 1 hour and filtered. The solid was dried to give the title compound (S) -1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylic acid.

Intermediate 10
4-Cyclohexyl-3-fluoroaniline hydrochloride

Intermediate 10A
3-Fluoro-4-iodoanilin in 1: 1 methanol-dichloromethane (20 mL) of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol). A solution of benzyltrimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) was added to the suspension at 0 ° C. over 30 minutes. The temperature of the mixture was raised to room temperature for 1 hour. The reaction was stopped by adding water and the organic layer was extracted with water (twice). The oil was obtained by dehydration (Na ₂ SO ₄ ) and concentration under reduced pressure and chromatographically purified on a 100 g silica gel cartridge eluting with 10% to 100% ethyl acetate / hexane. These procedures gave the title compound (2.20 g, 89%) as a pink solid. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 7.41 (dd, J = 8.3, 7.3 Hz, 1H), 6.42 (dd, J = 9.9, 2.5 Hz, 1H), 6.27 (Dd, J = 8.5, 2.5 Hz, 1H), 3.81 (s, 2H); MS + ESIm / z (relative abundance ratio) 238 (100, M + H).

Intermediate 10B
The procedure for producing the 4- (cyclohexene-1-yl) -3-fluoroaniline title compound is described in General Procedure 1.2A.

Intermediate 10C
4-Cyclohexyl-3-fluoroaniline hydrochloride 4- (cyclohexene-1-yl) -3-fluoroaniline (general procedure 1.2A) (1.16 g, 6.07 mmol) in ethanol (30 mL) 10% solution It was treated with palladium / carbon (300 mg) and then hydrogenated at 1 atm for 18 hours. The mixture was filtered through diatomaceous earth, concentrated to about 1/4 volume and treated with hydrogen chloride / dioxane solution (4N, 10 mL). The mixture was partially concentrated under reduced pressure to about 1/4 volume, diluted with ether (about 100 mL) and the solid was collected by filtration. After drying in a vacuum dryer at 50 ° C. for 3 hours, these procedures gave the title compound (1.13 g, 81%) as a light gray solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 7.35 (t, J = 8.1 Hz, 1H), 7.03 (d, J = 9.4 Hz, 2H), 2.76 (dd, J = 15) 6.6, 6.9 Hz, 1H), 1.74 (m, 5H), 1.40 (m, 4H), 1.21 (m, 1H). MS (DCI +) m / z (relative abundance ratio) 194 (100, M + H), 211 (67, M + NH ₄ ).

Intermediate 11A
Add to a flask containing N- (4-bromo-5-fluoro-2-nitrophenyl) -2,2,2 -trifluoroacetamidotrifluoroacetic anhydride (10.0 mL, 70.5 mmol) at 0 ° C. 4-Bromo-3-fluoroaniline (2.0 g, 10.5 mmol) and stirring continued for 30 minutes (Charifson, PS; et al. J. Med. Chem. 2008, 51, 5243-5263). Potassium nitrate (1.3 g, 12.6 mmol) was added and the solution was heated to 25 ° C. The solution was concentrated, the residue was dissolved in EtOAc, washed with 10% NaHCO ₃ , brine, dehydrated (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated to give the title compound (3.5 g, 10.5 mmol, 100%).

Intermediate 11B
4-Bromo-5-fluoro-2-nitroaniline N- (4-bromo-5-fluoro-2-nitrophenyl) -2,2,2-trifluoroacetamide (3.5 g, 10.5 mmol), CH ₃ OH (30 mL) followed by 1.0 MK ₂ CO ₃ (10.5 mL, 10.5 mmol) was added and the solution was stirred for 30 minutes (Charifson, PS; et al. J. Med. MeOH 2008). , 51, 5243-5263). The solution was diluted with _{H 2} O and stirred for 1 hour. The obtained orange-red solid was collected by filtration and dried in a vacuum dryer to give the title compound (2.1 g, 8.8 mmol, 84%).

Intermediate 11C
4-Bromo-5-fluorobenzene-1,2-diamine 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and H ₂ O (3mL) was added to iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol) was added and the mixture was heated for 4 hours at 95 ° C.. The cooled mixture was diluted with EtOH, filtered through a filter with diatomaceous earth until no color appeared and concentrated. The residue was dissolved in _EtOAc, washed with _H 2 O, brine, dried _(Na 2 _SO 4), filtered, and concentrated. Hexane was added and the resulting solid was collected by filtration to give the title compound (710 mg, 3.5 mmol, 81%).

Intermediate 12
4-Bromo-3-chlorobenzene-1,2-diamine

Intermediate 12A
4-Bromo-3-chloro-2-nitroaniline 3-Chloro-2-nitroaniline (5.00 g, 29.0 mmol) was dissolved in glacial acetic acid (258 mL). Imide N-bromosuccinate (5.06 g, 28.4 mmol) was added and the resulting mixture was refluxed for 1 hour. The reaction was cooled to room temperature and poured into water to give a precipitate, which was filtered, washed with water and dried to constant weight to give the title compound (4.78 g, 67%). ^{1 1} H NMR (400 MHz, CDCL ₃ ) δppm 7.46 (d, J = 9.0, 1H), 6.64 (d, J = 9.0, 1H), 4.74 (s, 2H).

Intermediate 12B
4-Bromo-3-chlorobenzene-1,2-diamine 4-bromo-3-chloro-2-nitroaniline (4.78 g, 19.01 mmol) was dissolved in ethanol (112 mL). Tin (II) chloride (14.42 g, 76 mmol) was added and the resulting mixture was refluxed and stirred for 12 hours. The mixture was cooled to room temperature and adjusted to pH 5 with water and a saturated sodium bicarbonate solution. The resulting solid was filtered and washed thoroughly with ethyl acetate. The filtrate was washed with water and brine, dehydrated with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with a solvent gradient of 0% to 50% EtOAc / Hexanes to give the title compound (3.32 g, 79%). ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 6.94 (d, 1H), 6.51 (d, J = 7.0, 1H), 3.87 (brs, 2H), 3.46 (brs, 2H) ..

Intermediate 13
4-Bromo-3-methylbenzene-1,2-diamine

Intermediate 13A
CH ₂ Cl ₂ (4) of N- (3-bromo-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide 3-bromo-2-methylaniline (1.0 g, 5.37 mmol) Trifluoroacetic anhydride (2.0 mL, 14.2 mmol) was added to the solution in (0.0 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes and solid potassium nitrate (0.679 g, 6.72 mmol) was added. The cooling bath was removed and the mixture was stirred at room temperature overnight. LCMS showed that a single product was produced. The mixture was concentrated under reduced pressure and the residue was partitioned between water and CH ₂ Cl ₂ (twice). The organic layers were combined and dehydrated with Na ₂ SO ₄ . The desiccant was removed by filtration and the crude product was purified by crystallization from aqueous EtOH to give the title compound (1.3 g, 74%).

Intermediate 13B
CH _{3 of} 3-bromo-2-methyl-6-nitroaniline N- (3-bromo-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide (1.3 g, 3.97 mmol) The solution in OH (30 mL) was treated with potassium carbonate (1.099 g, 7.95 mmol) and the mixture was stirred at 50 ° C. overnight. The mixture was cooled to room temperature, poured into water, adjusted to pH 6 by adding 1N HCl aqueous solution, and the mixture was extracted with CH ₂ Cl ₂ (3 times). The combined extracts were dehydrated with Na ₂ SO ₄ , the desiccant was filtered off and the solvent was removed under reduced pressure to give the title compound as a yellow solid (0.57 g, 62%).

Intermediate 13C
Tin (II) chloride (1) in a solution of 4-bromo-3-methylbenzene-1,2-diamine- 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL). .48 g, 7.8 mmol) was added and the resulting solution was stirred at 70 ° C. for 4 hours. The mixture was cooled to room temperature, poured into water, and 1N NaOH aqueous solution was added to adjust the pH to> 7. The resulting mixture was extracted with CH ₂ Cl ₂ (twice) and the combined extracts were dehydrated with Na ₂ SO ₄ . The desiccant was removed by filtration and the solvent was removed under reduced pressure to give the title compound as an oil (0.34 g, 88%).

Intermediate 14
5-Bromo-3-fluorobenzene-1,2-diamine 4-bromo-2-fluoro-6-nitroaniline (0.5 g, 2.1 mmol) in THF (4.6 mL), EtOH (4.6 mL) and in H ₂ O (1.5mL) was added iron powder (0.6 g, 10.6 mmol) and ammonium chloride (0.17 g, 3.2 mmol) KaTae. The resulting mixture was stirred at 95 ° C. for 22 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was filtered and washed with EtOH until no color appeared. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with _{H 2} O and brine, dried over _Na 2 SO _4, filtered and concentrated to give the title compound (0.43 g, 99%) of the shaped brown wax Obtained as a solid.

Intermediate 15
4-Bromo-3-fluorobenzene-1,2-diamine

Intermediate 15A
To the 3-fluoro-2-nitroaniline pressure tube, 1,3-difluoro-2-nitrobenzene (2.8 mL, 26.4 mmol) and 7N NH ₃ / CH ₃ OH (10 mL, 70 mmol) were added. The tube was sealed and the mixture was stirred at room temperature for 5 days. The solution was diluted with H ₂ O, extracted with CH ₂ Cl ₂ , and the combined extracts were washed with brine, dehydrated with Na ₂ SO ₄ , filtered and concentrated to give an oil. The oil was ground with hexane and the resulting orange-red solid was collected by filtration to give the title compound (2.1 g, 51%).

Intermediate 15B
4-Bromo-3-fluoro-2-nitroaniline 3-Fluoro-2-nitroaniline (2.1 g, 13.4 mmol) in a solution in DMF (30 mL) at 0 ° C., N-bromosuccinimide (2.4 g) , 13.4 mmol) in DMF (20 mL) was added. The obtained solution was stirred at 0 ° C. for 30 minutes and heated to room temperature over 1 hour. The solution was diluted with EtOAc, washed with _{H 2} O and brine, dried over MgSO _4, filtered and concentrated to give the title compound (3.1g, 97%).

Intermediate 15C
EtOH (30 mL) and H in a solution of 4-bromo-3-fluorobenzene-1,2-diamine 4-bromo-3-fluoro-2-nitroaniline (3.0 g, 12.8 mmol) in THF (30 mL). ₂ O (10 mL) was added, then iron powder (3.6 g, 63.8 mmol) and ammonium chloride (1.0 g, 19.2 mmol) were added. The resulting mixture was stirred at 80 ° C. for 16 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was washed with EtOH until it passed through the filter and no color appeared. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel with a solvent gradient of 0% to 40% EtOAc / Hexanes to give the title compound (2.2 g, 84%).

Intermediate 16
4-Cyclopropyl-2-fluoroaniline 4-cyclopropyl-2-fluoro-1-nitrobenzene (produced according to the method described in General Procedure 1.2C) (2.2 g, 12.14 mmol) in ethanol: THF: water 3 It was dissolved in 7 mL of a 3: 1 (volume ratio) mixture. To this was added ammonium chloride (1.02 g, 19.07 mmol) and then iron powder (3.50 g, 62.7 mmol). The obtained mixture was heated in a 90 ° C. oil bath under a nitrogen atmosphere with high stirring for 1 hour. The reaction mixture was filtered under reduced pressure through a sand and diatomaceous earth layer. The filtrate was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dehydrated (sulfonyl ₄ ) and concentrated under reduced pressure to give an orange-red oil (1.90 g).

Intermediate 17
2- (Methoxycarbonylamino) -3-methylbut-2-enoic acid

中間体１７Ａ
２−（メトキシカルボニルアミノ）−３−メチルブト−２−エン酸エチル
ディーン−スタークトラップおよび還流冷却管を取り付けた丸底フラスコで、エチル−３−メチル−２−オキソブタノエート（４．０３ｇ、２８．０ｍｍｏｌ）、メチルカーバメート（２．０９８ｇ、２８．０ｍｍｏｌ）およびピリジン４−メチルベンゼンスルホネート（０．７０ｇ、２．８０ｍｍｏｌ）のベンゼン溶液（９０ｍＬ）を加熱還流した。４４時間の加熱後、混合物を冷却し、酢酸エチル（５０ｍＬ）とブライン（５０ｍＬ）との間で分配した。有機相をブラインで洗浄し（５０ｍＬで２回）、脱水し（ＭｇＳＯ_４）、減圧下に濃縮した。粗生成物を、シリカゲルでのクロマトグラフィー（酢酸エチル−ヘキサン）によって精製して、標題化合物をオフホワイト結晶固体として得た（１．４８７ｇ、２６％）。

Intermediate 17A
In a round-bottom flask equipped with an ethyldeen-stark trap of 2- (methoxycarbonylamino) -3-methylbut-2-enoate and a reflux condenser, ethyl-3-methyl-2-oxobutanoate (4.03 g, A benzene solution (90 mL) of 28.0 mmol), methyl carbamate (2.098 g, 28.0 mmol) and pyridine4-methylbenzenesulfonate (0.70 g, 2.80 mmol) was heated to reflux. After heating for 44 hours, the mixture was cooled and partitioned between ethyl acetate (50 mL) and brine (50 mL). The organic phase was washed with brine (twice at 50 mL), dehydrated (marriage ₄ ) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate-hexane) to give the title compound as an off-white crystalline solid (1.487 g, 26%).

中間体１７Ｂ
２−（メトキシカルボニルアミノ）−３−メチルブト−２−エン酸
中間体１７Ａからの生成物（０．３７３ｇ、１．８５ｍｍｏｌ）を室温で１：１（体積比）エタノール：水混合物２ｍＬに溶かした。これに、水酸化リチウム（０．０９５ｇ、３．９９ｍｍｏｌ）を１回で加えた。終夜撹拌後、反応混合物を酢酸エチル（２５ｍＬ）と１Ｎ ＨＣｌ（５ｍＬ）との間で分配し、それに固体ＮａＣｌを加えた。水相を酢酸エチルで１回抽出し、合わせた有機層をブラインで洗浄し（５ｍＬで３回）、脱水し（ＭｇＳＯ_４）、濃縮して、標題化合物（０．２８９ｇ、９０％）を、単離物として用いるのに十分な純度のオフホワイト固体として得た。

Intermediate 17B
The product (0.373 g, 1.85 mmol) from 2- (methoxycarbonylamino) -3-methylbut-2-enoic acid intermediate 17A was dissolved in 2 mL of a 1: 1 (volume ratio) ethanol: water mixture at room temperature. .. To this was added lithium hydroxide (0.095 g, 3.99 mmol) in a single dose. After stirring overnight, the reaction mixture was partitioned between ethyl acetate (25 mL) and 1N HCl (5 mL), to which solid NaCl was added. The aqueous phase was extracted once with ethyl acetate, the combined organic layers were washed with brine (3 times at 5 mL), dehydrated (sulfonyl ₄ ) and concentrated to give the title compound (0.289 g, 90%). It was obtained as an off-white solid of sufficient purity for use as an isolate.

Intermediate 18
(2S, 3aS, 6aS) -2-carbamoylhexahydrocyclopenta [b] pyrrole-1 (2H) -tert-butyl carboxylate

中間体１８Ａ
（２Ｓ，３ａＳ，６ｂａＳ）−ヘキサヒドロシクロペンタ［ｂ］ピロール−１，２（２Ｈ）−ジカルボン酸２−ベンジル１−ｔｅｒｔ−ブチル
（２Ｓ，３ａＳ，６ａＳ）−オクタヒドロシクロペンタ［ｂ］ピロール−２−カルボン酸ベンジル塩酸塩（２．０ｇ、７．１０ｍｍｏｌ）のジクロロメタン（３６ｍＬ）中懸濁液に室温でジ−ｔｅｒｔ−ブチルジカーボネート（１．７０ｇ、７．８１ｍｍｏｌ）を加え次にトリエチルアミン（２．１８ｍＬ、１５．６２ｍｍｏｌ）を加えた。激しいガス発生を伴って溶液は急速に均一となり、発泡はすでに停止する。２時間後、混合物をジクロロメタンで希釈し、ブラインで洗浄し（６０ｍＬで３回）、脱水し（ＭｇＳＯ_４）、濃縮した。粗生成物を、シリカゲルでのクロマトグラフィーによって精製して（酢酸エチル−ヘキサン）、標題化合物（２．５８ｇ、定量的）を透明油状物として得た。

Intermediate 18A
(2S, 3aS, 6baS) -Hexahydrocyclopenta [b] pyrrole-1,2 (2H) -dicarboxylic acid 2- benzyl1 -tert-butyl (2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole To a suspension of benzyl -2-carboxylic acid hydrochloride (2.0 g, 7.10 mmol) in dichloromethane (36 mL), di-tert-butyl dicarbonate (1.70 g, 7.81 mmol) was added at room temperature, and then triethylamine. (2.18 mL, 15.62 mmol) was added. The solution rapidly homogenizes with vigorous gas generation and foaming has already stopped. After 2 hours, the mixture was diluted with dichloromethane, washed with brine (3 times at 60 mL), dehydrated (Then ₄ ) and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate-hexane) to give the title compound (2.58 g, quantitative) as a clear oil.

中間体１８Ｂ
（２Ｓ，３ａＳ，６ａＳ）−１−（ｔｅｒｔ−ブトキシカルボニル）オクタヒドロシクロペンタ［ｂ］ピロール−２−カルボン酸
中間体１８Ａからの生成物（２．４５ｇ、７．１ｍｍｏｌ）を室温でメタノール（３５ｍＬ）に溶かした。これにパールマン触媒（０．１５３ｇ）を加え、次に減圧下に脱気し（３回）、水素を加えた（風船）。１時間後、反応混合物を減圧珪藻土で濾過し、濾液を濃縮して透明粘稠油状物を得た（１．８９ｇ、定量的）、それは単離物として使用する上で十分な純度のものであった。

Intermediate 18B
A product (2.45 g, 7.1 mmol) from (2S, 3aS, 6aS) -1- (tert-butoxycarbonyl) octahydrocyclopenta [b] pyrrole-2-carboxylic acid intermediate 18A was added to methanol (2.45 g, 7.1 mmol) at room temperature. It was dissolved in 35 mL). A Pearlman catalyst (0.153 g) was added thereto, then degassed under reduced pressure (3 times), and hydrogen was added (balloon). After 1 hour, the reaction mixture was filtered through vacuum diatomaceous earth and the filtrate was concentrated to give a clear viscous oil (1.89 g, quantitative), of sufficient purity for use as an isolate. there were.

中間体１８Ｃ
（２Ｓ，３ａＳ，６ａＳ）−２−カルバモイルヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−カルボン酸ｔｅｒｔ−ブチル
窒素下に室温で、中間体１８Ｂからの生成物（１．８１ｇ、７．１ｍｍｏｌ）をＴＨＦ（４０ｍＬ）に溶かした。これにＮ−メチルモルホリン（１．０ｍＬ、９．０９ｍｍｏｌ）を加え、得られた溶液を冷却して−１５℃とした。その冷溶液に、クロルギ酸イソブチル（１．０３ｍＬ、７．８１ｍｍｏｌ）を注射器によって滴下した。白色沈殿が直ちに生成する。添加完了したら、混合物を低温下で２０分間撹拌した。アンモニアガスを、さらに冷却しながら２分間混合物に吹き込むことで導入した。添加完了したら、反応液を昇温させて氷浴温度とし、半時間撹拌し、昇温させて室温とした。室温で１５分後、混合物をブライン（４５０ｍＬ）に投入し、ジクロロメタンで抽出した（５０ｍＬで６回）。合わせた抽出液を脱水し（ＭｇＳＯ_４）、濃縮した。粗生成物を、シリカゲルでのクロマトグラフィーによって精製して（酢酸エチル−ヘキサン）、標題化合物（１．６８ｇ、９３％）を粘稠白色泡状物として得た。

Intermediate 18C
(2S, 3aS, 6aS) -2-Carbamoyl Hexahydrocyclopenta [b] Pyrrole-1 (2H) -tert-butyl carboxylate At room temperature, the product from intermediate 18B (1.81 g, 7. 1 mmol) was dissolved in THF (40 mL). N-Methylmorpholine (1.0 mL, 9.09 mmol) was added thereto, and the obtained solution was cooled to −15 ° C. Isobutyl chlorgiate (1.03 mL, 7.81 mmol) was added dropwise to the cold solution by syringe. A white precipitate is formed immediately. When the addition was complete, the mixture was stirred at low temperature for 20 minutes. Ammonia gas was introduced by blowing into the mixture for 2 minutes with further cooling. When the addition was completed, the temperature of the reaction solution was raised to the ice bath temperature, and the mixture was stirred for half an hour and raised to room temperature. After 15 minutes at room temperature, the mixture was added to brine (450 mL) and extracted with dichloromethane (6 times at 50 mL). The combined extracts were dehydrated (sulfate ₄ ) and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate-hexane) to give the title compound (1.68 g, 93%) as a viscous white foam.

Intermediate 19
(S, E) -2- (5- (3-oxoprop-1-enyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1 -Tert-butyl carboxylate

Intermediate 19A
(S, E) -2- (5- (3-ethoxy-3-oxoprop-1-eneyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl ) Pyrrolidine-1-carboxylic acid tert-butyl THF (18 mL) dissolved in (S) -2- (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole- 2-Il) Pyrrolidine-1-carboxylate tert-butyl (2.973 g, 5.99 mmol), ethyl acrylate (0.714 mL, 6.59 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.104 g, 0.359 mmol), N, N-dicyclohexylmethylamine (1.461 mL, 6.89 mmol) and tris (dibenzilidenacetone) dipalladium (0) (0.164 g, 0.18 mmol) with nitrogen in solution for 15 minutes. It was blown to remove oxygen and the mixture was heated at 60 ° C. for 2 hours. After cooling to room temperature, the solution was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to give a residue, then the residue was dissolved in dichloromethane and extracted with water. The organic layer was dehydrated and concentrated. The residue was purified by chromatography (silica gel, hexane / ethyl acetate) to give the title compound 2.56 g (83%). MS (ESI) m / z 516 (M + H) ⁺ .

Intermediate 19B
(S, E) -2- (5- (3-Hydroxyprop-1-eneyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine- Tert-Butyl 1-carboxylic acid intermediate 19A (2.56 g, 4.97 mmol) was dissolved in THF (17 mL) and the mixture was cooled in a dry ice acetone bath to -78 ° C. Next, a solution of aluminum hydride diisobutyl (solution in 1.0 N THF, 22.75 mL, 24.75 mmol) was added dropwise. The temperature of the obtained mixture was slowly raised overnight to room temperature, and the reaction was stopped with a 1N aqueous sodium hydroxide solution. The mixture was added to ethyl acetate and extracted with an aqueous solution of Rochelle salt (potassium sodium tartrate). The organic layers were combined, dehydrated and concentrated. The residue was purified by chromatography (silica gel, hexane / ethyl acetate), thereby giving 0.93 g, (40%) of the title compound. MS (ESI) m / z 474 (M + H) ⁺ .

Intermediate 19C
(S, E) -2- (5- (3-oxoprop-1-enyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1 The product of tert-butyl intermediate 19B (0.93 g, 1.96 mmol) was dissolved in dichloromethane (7.5 mL), pyridinium dichromate (1.11 g, 2.95 mmol) was added, and the resulting mixture was obtained. Was stirred overnight at room temperature. Hexane was added to the solution and it was filtered through diatomaceous earth. The filtrate was concentrated to give a residue, which was dissolved in dichloromethane and extracted with water. The organic layer was dehydrated and concentrated, and the residue was purified by chromatography (silica gel, hexane / ethyl acetate) to give 0.3 g (32%) of the title compound. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 9.65 (d, J = 7.8 Hz, 1H), 8.05 (m, 1H), 7.82 (d, J = 15.8 Hz, 1H), 7.70 (m, 2H), 6.87 (dd, J = 15.8, 7.8Hz, 1H), 5.70 (s, 2H), 5.14 (m, 1H), 3.57 ( m, 2H), 3.42 (m, 1H), 2.40 (m, 5H), 1.30 (s, 4H), 0.95 (s, 5H), 0.80 (m, 2H), -0.10 (s, 9H); MS (ESI) m / z 472 (M + H) ⁺ .

中間体２０Ａ
１−（４−クロロ−２−フルオロ−５−ニトロフェニル）エタノン
４−クロロ−２−フルオロ−５−ニトロ安息香酸（１６．０ｇ、７２．９ｍｍｏｌ）の脱水ＣＨ_２Ｃｌ_２（４００ｍＬ）中溶液に、オキサリルクロライド（９．５７ｍＬ、１０９ｍｍｏｌ）およびＤＭＦ（２滴）を加え、得られた混合物を室温でガス発生が停止するまで撹拌した。混合物を濃縮し、真空乾燥した。別の加熱乾燥した反応フラスコ中、−７８℃のＺｎＢｒ_２（２４．６ｇ、１０９ｍｍｏｌ）の脱水ＴＨＦ（３００ｍＬ）中混合物を、ＣＨ_３ＭｇＢｒ溶液（２９．１ｍＬ、３．０Ｍ Ｅｔ_２Ｏ中溶液、８７ｍｍｏｌ）を滴下した。得られた混合物を−７８℃で１５分間撹拌し、反応混合物を昇温させて室温とし、３０分間撹拌した。混合物を冷却して−７８℃とし、酸クロライドの脱水ＴＨＦ中溶液（１００ｍＬ）を滴下し、次にＰｄ（ＰＰｈ_３）_４（１．６８ｇ、１．４６ｍｍｏｌ）を加えた。得られた混合物を−７８℃で１０分間撹拌し、昇温させて環境温度とし、さらに１６時間撹拌した。１Ｍ ＨＣｌ水溶液を加えることで混合物を反応停止し、Ｈ_２Ｏ（１００ｍＬ）で希釈し、ＣＨ_２Ｃｌ_２で抽出した（３００ｍＬで３回）。合わせた有機抽出液を脱水し（ＭｇＳＯ_４）、濾過し、濃縮した。粗生成物をカラムクロマトグラフィー（シリカゲル、５％ＥｔＯＡｃ／ヘキサン）によって精製して、標題化合物を得た（１１．７９ｇ、７４％）。

Intermediate 20A
Solution of 1- (4-chloro-2-fluoro-5-nitrophenyl) ethanone 4-chloro-2-fluoro-5-nitrobenzoic acid (16.0 g, 72.9 mmol) in dehydrated CH ₂ Cl ₂ (400 mL) Oxalyl chloride (9.57 mL, 109 mmol) and DMF (2 drops) were added to the mixture, and the resulting mixture was stirred at room temperature until gas generation stopped. The mixture was concentrated and vacuum dried. In another heat-dried reaction flask, a mixture of ZnBr ₂ (24.6 g, 109 mmol) at −78 ° C. in dehydrated THF (300 mL) was added to CH ₃ MgBr solution (29.1 mL, 3.0 M Et ₂ O solution). 87 mmol) was added dropwise. The resulting mixture was stirred at −78 ° C. for 15 minutes, the reaction mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled to −78 ° C., a solution of acid chloride in dehydrated THF (100 mL) was added dropwise, then Pd (PPh ₃ ) ₄ (1.68 g, 1.46 mmol) was added. The obtained mixture was stirred at −78 ° C. for 10 minutes, heated to an environmental temperature, and further stirred for 16 hours. The mixture was quenched by addition of aqueous 1M _HCl, diluted with H 2 O (100mL), and extracted with _CH 2 Cl ₂ (3 x 300 mL). The combined organic extracts were dehydrated (sulfonyl ₄ ), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 5% EtOAc / Hexanes) to give the title compound (11.79 g, 74%).

Intermediate 20A can also be produced by reacting intermediate acid chloride with dimethyl malonate, MgCl ₂ and triethylamine in methylene chloride, followed by acid hydrolysis and decarboxylation.

中間体２０Ｂ
２−ブロモ−１−（４−クロロ−２−フルオロ−５−ニトロフェニル）エタノン
ＴＨＦ（１００ｍＬ）に溶かした中間体２０Ａの生成物（３．０ｇ、１３．７９ｍｍｏｌ）に、臭化ピリジニウムパーブロマイド（４．６３ｇ、１４．４８ｍｍｏｌ）を数分間かけて少量ずつ加えた。得られた混合物を環境温度で２時間撹拌し、濾過した。濾過した固体をＥｔＯＡｃで洗い、濾液を減圧下に濃縮した。粗生成物を、カラムクロマトグラフィー（シリカゲル、２０％ＥｔＯＡｃ／ヘキサン）によって精製して、標題化合物を得た（３．８ｇ、９３％）。

Intermediate 20B
2-Bromo-1- (4-chloro-2-fluoro-5-nitrophenyl) Etanone In the product of Intermediate 20A dissolved in THF (100 mL) (3.0 g, 13.79 mmol), pyridinium bromide per bromide. (4.63 g, 14.48 mmol) was added in small portions over several minutes. The resulting mixture was stirred at ambient temperature for 2 hours and filtered. The filtered solid was washed with EtOAc and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc / Hexanes) to give the title compound (3.8 g, 93%).

中間体２０Ｃ
１，４−ビス（４−クロロ−２−フルオロ−５−ニトロフェニル）ブタン−１，４−ジオン
中間体２０Ａ（４．９２ｇ、２２．６２ｍｍｏｌ）および中間体２０Ｂ（４．４７ｇ、１５．０８ｍｍｏｌ）を、中間体５Ｂに記載の方法を用いて処理して標題化合物を得た（４．７４ｇ、７３％）。

Intermediate 20C
1,4-Bis (4-chloro-2-fluoro-5-nitrophenyl) butane-1,4-dione intermediate 20A (4.92 g, 22.62 mmol) and intermediate 20B (4.47 g, 15.08 mmol) ) Was treated using the method described for Intermediate 5B to give the title compound (4.74 g, 73%).

中間体２０Ｄ
（１Ｓ，４Ｓ）−１，４−ビス（４−クロロ−２−フルオロ−５−ニトロフェニル）ブタン−１，４−ジオール
中間体２０Ｃの生成物（１．０ｇ、２．３０９ｍｍｏｌ）を、中間体５Ｃで記載の方法を用いて処理して標題化合物（０．９６ｇ、９５％）を得た。中間体２０Ｄを形成するためのキラル還元において、反応は、中間体５Ｃの場合より低い立体選択性で進行する。

Intermediate 20D
(1S, 4S) -1,4-bis (4-chloro-2-fluoro-5-nitrophenyl) butane-1,4-diol intermediate 20C product (1.0 g, 2.309 mmol) was added in the middle. Treatment with body 5C using the method described gave the title compound (0.96 g, 95%). In chiral reduction to form Intermediate 20D, the reaction proceeds with lower stereoselectivity than in Intermediate 5C.

中間体２０Ｅ
ジメタンスルホン酸（１Ｓ，４Ｓ）−１，４−ビス（４−クロロ−２−フルオロ−５−ニトロフェニル）ブタン−１，４−ジイル
中間体２０Ｄ（０．９５ｇ、２．１７ｍｍｏｌ）の脱水ＣＨ_２Ｃｌ_２（２０ｍＬ）中溶液に０℃で、メタンスルホニルクロライド（０．４２ｍＬ、５．４３ｍｍｏｌ）を加え、次にトリエチルアミン（０．９１ｍＬ、６．５２ｍｍｏｌ）を滴下した。得られた混合物を室温で９０分間撹拌し、減圧下に濃縮した。ヘキサンを加え、得られた固体を濾過によって回収し、Ｈ_２Ｏで洗浄し、真空乾燥して、標題化合物を得た（１．２９ｇ、１００％）。

Intermediate 20E
Dehydration of dimethanesulfonic acid (1S, 4S) -1,4-bis (4-chloro-2-fluoro-5-nitrophenyl) butane-1,4-diyl intermediate 20D (0.95 g, 2.17 mmol) Methanesulfonyl chloride (0.42 mL, 5.43 mmol) was added to the solution in CH ₂ Cl ₂ (20 mL) at 0 ° C., and then triethylamine (0.91 mL, 6.52 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 90 minutes and concentrated under reduced pressure. Hexane was added and the resulting solid was collected by filtration, washed with _{H 2} O, and dried in vacuo to give the title compound (1.29g, 100%).

中間体２１
ジメタンスルホン酸（１Ｓ，４Ｓ）−１−（４−クロロ−２−フルオロ−５−ニトロフェニル）−４−（４−クロロ−３−ニトロフェニル）ブタン−１，４−ジイル
中間体２１は、中間体２０Ｅを製造するための一般法に従って中間体２０Ｂおよび１−（４−クロロ−３−ニトロフェニル）エタノン（から市販Ａｌｄｒｉｃｈ）から製造することができる。

Intermediate 21
Dimethanesulfonic acid (1S, 4S) -1- (4-chloro-2-fluoro-5-nitrophenyl) -4- (4-chloro-3-nitrophenyl) butane-1,4-diyl intermediate 21 , Can be made from Intermediate 20B and 1- (4-chloro-3-nitrophenyl) ethanone (from Aldrich, commercially available) according to the general method for making Intermediate 20E.

中間体２２Ａ
１−ベンジル−４−（４−メトキシフェニル）ピペリジン−４−オール
１−ベンジルピペリジン−４−オン（５．４ｍＬ、３０．２ｍｍｏｌ）のＴＨＦ（６０ｍＬ）中溶液を冷却し（０℃）、それに（４−メトキシフェニル）マグネシウムブロマイド（０．５Ｍ ＴＨＦ中溶液、９０ｍＬ、４５．０ｍｍｏｌ）をカニューレを介してゆっくり（約２５分間）加えた。反応液を０℃で窒素下に２時間撹拌した。飽和ＮＨ_４Ｃｌ水溶液で反応停止し、エーテルで希釈した。有機分画を飽和ＮＨ_４Ｃｌ水溶液（２回）、ブライン（１回）で洗浄し、濃縮した。フラッシュクロマトグラフィー（５％から１００％ＥｔＯＡｃ／ヘキサン）を用いる精製によって、標題化合物４．０２ｇ（４４％）を得た。ＭＳ（ＤＣＩ）ｍ／ｚ２９８（Ｍ＋Ｈ）^＋。

Intermediate 22A
A solution of 1-benzyl-4- (4-methoxyphenyl) piperidine-4-ol 1-benzylpiperidine-4-one (5.4 mL, 30.2 mmol) in THF (60 mL) was cooled (0 ° C.) into it. (4-Methoxyphenyl) magnesium bromide (solution in 0.5 M THF, 90 mL, 45.0 mmol) was added slowly (about 25 minutes) via a cannula. The reaction was stirred at 0 ° C. under nitrogen for 2 hours. The reaction was quenched with saturated aqueous _NH 4 Cl and diluted with ether. The organic fraction saturated aqueous _NH 4 Cl (2 times), washed with brine (1 ×), and concentrated. Purification using flash chromatography (5% to 100% EtOAc / Hexanes) gave 4.02 g (44%) of the title compound. MS (DCI) m / z 298 (M + H) ⁺ .

中間体２２Ｂ
１−ベンジル−４−（４−メトキシフェニル）−１，２，３，６−テトラヒドロピリジン
１−ベンジル−４−（４−メトキシフェニル）ピペリジン−４−オール（１２．３１ｇ、４１．３６ｍｍｏｌ）のジオキサン（５０ｍＬ）中溶液に６Ｍ ＨＣｌ（１００ｍＬ、水溶液）を加え、反応液を強く加熱還流した（１１０℃）。２時間後、反応は完結していなかった。加熱を止め、反応液を環境温度で２日間撹拌状態とした。反応は進行していたが、完了しなかったので、それを加熱して１１０℃とした。１時間後、反応液を冷却し、体積を約１／３に減じた。溶液を氷浴で冷却し、ＮａＯＨペレットで中和した。粘稠懸濁液を濾過した。沈殿を水で洗い、７０℃で真空乾燥して、標題化合物６．２ｇ（４７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ２．７４−２．６２（ｍ、１Ｈ）、３．３０−３．０６（ｍ、２Ｈ）、３．５０（ｄ、Ｊ＝１８．５、１Ｈ）、３．６７−３．５６（ｍ、１Ｈ）、３．８２（ｓ、３Ｈ）、４．０３−３．９０（ｍ、１Ｈ）、４．２１（ｄｄ、Ｊ＝５．７、１３．０、１Ｈ）、４．３４（ｄｄ、Ｊ＝５．１、１３．０、１Ｈ）、５．８８（ｓ、１Ｈ）、６．８８（ｄ、Ｊ＝８．７、２Ｈ）、７．３２（ｄ、Ｊ＝８．７、２Ｈ）、７．５１−７．４３（ｍ、３Ｈ）、７．７１（ｄｄ、Ｊ＝２．７、６．３、２Ｈ）、１２．８５（ｓ、１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ２８０（Ｍ＋Ｈ）^＋；ＭＳ（ＤＣＩ）ｍ／ｚ２８０（Ｍ＋Ｈ）^＋。

Intermediate 22B
1-Benzyl-4- (4-Methoxyphenyl) -1,2,3,6-tetrahydropyridine 1-benzyl-4- (4-methoxyphenyl) piperidin-4-ol (12.31 g, 41.36 mmol) 6M HCl (100 mL, aqueous solution) was added to the solution in dioxane (50 mL), and the reaction solution was strongly heated and refluxed (110 ° C.). After 2 hours, the reaction was not complete. The heating was stopped and the reaction solution was stirred at the ambient temperature for 2 days. The reaction was proceeding but not completed, so it was heated to 110 ° C. After 1 hour, the reaction was cooled and the volume was reduced to about 1/3. The solution was cooled in an ice bath and neutralized with NaOH pellets. The viscous suspension was filtered. The precipitate was washed with water and dried in vacuo at 70 ° C. to give 6.2 g (47%) of the title compound. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 2.74-2.62 (m, 1H), 3.30-3.06 (m, 2H), 3.50 (d, J = 18.5, 1H), 3.67-3.56 (m, 1H), 3.82 (s, 3H), 4.03-3.90 (m, 1H), 4.21 (dd, J = 5.7, 13.0) , 1H), 4.34 (dd, J = 5.1, 13.0, 1H), 5.88 (s, 1H), 6.88 (d, J = 8.7, 2H), 7.32 (D, J = 8.7, 2H), 7.51-7.43 (m, 3H), 7.71 (dd, J = 2.7, 6.3, 2H), 12.85 (s, 1H); MS (ESI) m / z 280 (M + H) ⁺ ; MS (DCI) m / z 280 (M + H) ⁺ .

中間体２２Ｃ
４−（４−メトキシフェニル）ピペリジン
２５０ｍＬステンレス製圧力瓶中にてトリフルオロエタノール（６０ｍＬ）中の中間体２２Ｂからの生成物（６．２ｇ）を２０％Ｐｄ（ＯＨ）_２−Ｃ（含水）（１．２４０ｇ、８．８３ｍｍｏｌ）に加えた。混合物を約０．２１ＭＰａ（約０．２１ＭＰａ（３０ｐｓｉ））の水素下に５０℃で２３時間振盪した。混合物をＰＴＦＥ膜によって濾過し、濃縮し、真空乾燥して、所望の生成物４．３３ｇをＨＣｌ塩として得た。（ＨＣｌ塩）^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ２．０３（ｄ、Ｊ＝１３．１、２Ｈ）、２．２８−２．１１（ｍ、２Ｈ）、２．７２（ｔ、Ｊ＝１０．２、１Ｈ）、３．０８−２．９１（ｍ、２Ｈ）、３．６２（ｄ、Ｊ＝８．３、２Ｈ）、３．７９（ｓ、３Ｈ）、６．８６（ｄ、Ｊ＝８．３、２Ｈ）、７．１６（ｄ、Ｊ＝８．５、２Ｈ）、９．６５（ｄ、Ｊ＝８３．１、２Ｈ）；ＭＳ（ＤＣＩ）ｍ／ｚ１９２（Ｍ＋Ｈ）^＋。

Intermediate 22C
20% Pd (OH) _2- C (water content) of the product (6.2 g) from intermediate 22B in trifluoroethanol (60 mL) in a 4- (4-methoxyphenyl) piperidine 250 mL stainless steel pressure bottle. It was added to (1.240 g, 8.83 mmol). The mixture was shaken under hydrogen at about 0.21 MPa (about 0.21 MPa (30 psi)) at 50 ° C. for 23 hours. The mixture was filtered through a PTFE membrane, concentrated and dried in vacuo to give 4.33 g of the desired product as an HCl salt. (HCl salt) ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 2.03 (d, J = 13.1, 2H) 2.28-2.11 (m, 2H) 2.72 (t, J = 10) .2, 1H), 3.08-2.91 (m, 2H), 3.62 (d, J = 8.3, 2H), 3.79 (s, 3H), 6.86 (d, J) = 8.3, 2H), 7.16 (d, J = 8.5, 2H), 9.65 (d, J = 83.1, 2H); MS (DCI) m / z192 (M + H) ⁺ .

Intermediates 23, 24 and 25 can be produced using the methods used to produce Intermediate 22C.

Intermediate 23
4- (4-fluorophenyl) piperidine

Intermediate 24
4- (2,4-difluorophenyl) piperidine

Intermediate 25
4- (3,5-difluorophenyl) piperidine

中間体２６Ａ
４−フルオロ−４−フェニルピペリジン−１−カルボン酸ｔｅｒｔ−ブチル
冷却した（−７８℃；ドライアイス／アセトン浴）４−ヒドロキシ−４−フェニルピペリジン−１−カルボン酸ｔｅｒｔ−ブチル（８．０５ｇ、２９．０ｍｍｏｌ）のジクロロメタン（１００ｍＬ）中溶液に窒素下に、ジエチルアミノ硫黄トリフルオリド（４ｍＬ、３２．７ｍｍｏｌ）のジクロロメタン（１０ｍＬ）中溶液を加えた。反応液を−７８℃で約１時間撹拌した。反応液を浴から外し、昇温させて環境温度としさらに３０分間撹拌した。飽和ＮａＨＣＯ_３水溶液（１００ｍＬ）で反応停止した。有機分画をブライン（約５０ｍＬ）で洗浄した。次に、３−クロロ過安息香酸（１．０９９５ｇ、６．３７ｍｍｏｌ）を反応液に加え、環境温度で３０分間撹拌した。この段階を飽和ＮａＨＣＯ_３水溶液（１００ｍＬ）で反応停止した。有機分画を飽和ＮａＨＣＯ_３水溶液（１００ｍＬで１回）、水（１００ｍＬで１回）およびブライン（１００ｍＬで１回）で洗浄し、脱水し（ＭｇＳＯ_４）、過酸化物について調べ（３から１０ｐｐｍ）、濃縮して明黄色油状物を得た。油状物を真空乾燥して、標題化合物８．２７ｇ（１００％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．４２（ｄ、Ｊ＝５．７、９Ｈ）、１．９６−１．８５（ｍ、３．５Ｈ）、２．０３（ｄｄｄ、Ｊ＝５．２、１３．３、１７．８、１．５Ｈ）、３．０６（ｓ、２Ｈ）、３．９８（ｄ、Ｊ＝１２．０、２Ｈ）、７．３３（ｄ、Ｊ＝７．１、１Ｈ）、７．４６−７．３６（ｍ、４Ｈ）；ＭＳ（ＤＣＩ）ｍ／ｚ２８０（Ｍ＋Ｈ^＋、６０％）、２９７（Ｍ＋ＮＨ_４ ^＋、１００％）。

Intermediate 26A
4-Fluoro-4-phenylpiperidin-1-carboxylic acid tert-butyl Cooled (-78 ° C; dry ice / acetone bath) 4-Hydroxy-4-phenylpiperidin-1-carboxylic acid tert-butyl (8.05 g, A solution of diethylaminosulfur trifluoride (4 mL, 32.7 mmol) in dichloromethane (10 mL) was added to a solution of 29.0 mmol) in dichloromethane (100 mL) under nitrogen. The reaction was stirred at −78 ° C. for about 1 hour. The reaction solution was removed from the bath, heated to the ambient temperature, and stirred for another 30 minutes. The reaction was stopped with a saturated aqueous solution of NaHCO ₃ (100 mL). The organic fraction was washed with brine (about 50 mL). Next, 3-chloroperbenzoic acid (1.0995 g, 6.37 mmol) was added to the reaction mixture, and the mixture was stirred at the ambient temperature for 30 minutes. This step was terminated with saturated aqueous NaHCO ₃ solution (100 mL). The organic fraction was washed with saturated aqueous NaHCO ₃ solution (1 time at 100 mL), water (1 time at 100 mL) and brine (1 time at 100 mL), dehydrated (sulfonyl ₄ ) and examined for peroxides (3 to 10 ppm). ), Concentrated to obtain a bright yellow oil. The oil was vacuum dried to give 8.27 g (100%) of the title compound. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.42 (d, J = 5.7, 9H), 1.96-1.85 (m, 3.5H), 2.03 (ddd, J = 5) .2, 13.3, 17.8, 1.5H), 3.06 (s, 2H), 3.98 (d, J = 12.0, 2H), 7.33 (d, J = 7. 1, 1H), 7.46-7.36 (m, 4H); MS (DCI) m / z 280 (M + H ⁺ , 60%), 297 (M + NH ₄ ⁺ , 100%).

中間体２６Ｂ
４−フルオロ−４−フェニルピペリジン
４−フルオロ−４−フェニルピペリジン−１−カルボン酸ｔｅｒｔ−ブチル（８．２７ｇ、２９．６ｍｍｏｌ）のジオキサン（１０ｍＬ）中溶液に、塩酸（４Ｍジオキサン中溶液、２０ｍＬ、８０ｍｍｏｌ）を加えた。反応液を環境温度で４時間撹拌した。反応液を濃縮して油状物を得た。エーテルを加え、得られた固体を超音波処理し、終夜高撹拌して黄褐色固体を得た。固体を濾過し、エーテルで洗い、６０℃で３時間真空乾燥して、標題生成物５．５６ｇ（８７％）を得た。ＭＳ（ＤＣＩ）ｍ／ｚ１８０（Ｍ＋Ｈ）^＋。

Intermediate 26B
4-Fluoro-4-phenylpiperidine 4-fluoro-4-phenylpiperidine-1-carboxylic acid tert-butyl (8.27 g, 29.6 mmol) in dioxane (10 mL) in dioxane (10 mL) with hydrochloric acid (solution in 4M dioxane, 20 mL) , 80 mmol) was added. The reaction was stirred at ambient temperature for 4 hours. The reaction solution was concentrated to obtain an oil. Ether was added and the resulting solid was sonicated and stirred overnight to give a tan solid. The solid was filtered, washed with ether and vacuum dried at 60 ° C. for 3 hours to give 5.56 g (87%) of the title product. MS (DCI) m / z180 (M + H) ⁺ .

中間体２７Ａ
４−（ヒドロキシジフェニルメチル）ピペリジン−１−カルボン酸ｔｅｒｔ−ブチル
ジ−ｔｅｒｔ−ブチルジカーボネート（８．４３ｍＬ、３６．７ｍｍｏｌ）のジクロロメタン（１５ｍＬ）中溶液をジフェニル（ピペリジン−４−イル）メタノール（８．０７２１ｇ、３０．２ｍｍｏｌ）のジクロロメタン（１００ｍＬ）中溶液に加え、トリエチルアミン（５．１ｍＬ、３６．６ｍｍｏｌ）を加え、反応液を環境温度で２時間撹拌した。反応液をジクロロメタンで希釈し、飽和ＮａＨＣＯ_３水溶液（２回）、水（１回）およびブライン（１回）で洗浄し、脱水し（ＭｇＳＯ_４）、濃縮して標題化合物１１．６３ｇ（１０５％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ３６７（Ｍ＋Ｈ）^＋、３６６（Ｍ−Ｈ）^＋。

Intermediate 27A
4- (hydroxydiphenyl methyl) piperidine-1-carboxylic acid tert- butyl di -tert- butyl dicarbonate (8.43mL, 36.7mmol) in dichloromethane (15 mL) was treated with diphenyl (piperidin-4-yl) methanol ( To a solution of 8.0721 g, 30.2 mmol) in dichloromethane (100 mL), triethylamine (5.1 mL, 36.6 mmol) was added, and the reaction solution was stirred at ambient temperature for 2 hours. The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO ₃ solution (2 times), water (1 time) and brine (1 time), dehydrated (0054 ₄ ) and concentrated to 11.63 g (105%) of the title compound. ) Was obtained. MS (ESI) m / z 367 (M + H) ⁺ 366 (MH) ⁺ .

中間体２７Ｂ
４−（フルオロジフェニルメチル）ピペリジン
中間体２６Ａおよび２６Ｂの一般的方法を用い、４−（ヒドロキシジフェニルメチル）ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルから標題化合物３．３７ｇ（１００％）をＨＣｌ塩として製造した。ＭＳ（ＤＣＩ）ｍ／ｚ２７０（Ｍ＋Ｈ）^＋。

Intermediate 27B
Using the general method of 4- (fluorodiphenylmethyl) piperidine intermediates 26A and 26B, 3.37 g (100%) of the title compound from tert-butyl 4- (hydroxydiphenylmethyl) piperidine-1-carboxylate as an HCl salt. Manufactured. MS (DCI) m / z 270 (M + H) ⁺ .

General procedure
General procedure 1.4-Synthesis of amino-substituted anilines

Intermediate aniline, which has a para-amino group relative to aniline, can be prepared using a two-step procedure. Fluoronitrobenzenes, fluoronitropyridines or fluoronitropyrimidines are appropriately heated and microwave-irradiated appropriately in step 1, and potassium dihydrogen phosphate (equivalent) or potassium carbonate is present in a solvent such as DMSO. Suitable amines below:

と反応させることができる（

Can react with (

はＲ_Ｍ中に存在していることができ、窒素を介して結合しているアミン基を表す。）。段階２は、パラジウム／炭素またはラネーニッケルを用いる接触水素化などの標準的なニトロ還元条件によって行うことができる。あるいは、その還元は、溶媒としてのＴＨＦ／メタノール／水中にて鉄／塩化アンモニウムを用いて行うことができる。基：

Can be present in the R _M, it represents an amine group attached through a nitrogen. ). Step 2 can be performed under standard nitro-reduction conditions such as catalytic hydrogenation with palladium / carbon or Raney nickel. Alternatively, the reduction can be carried out using iron / ammonium chloride in THF / methanol / water as a solvent. Group:

が置換されていても良い環状アミン（例えば、ピペリジン、ピロリジン）である場合、置換されていても良い環状アミンは、本明細書に記載の方法に従ってまたは公知の方法を用いて得ることができる。例えば、Ｐａｔｅｌ ｅｔ ａｌ． Ｊ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ ４９（２５） ７４５０（２００６）に示されている方法を参照する。

Where is a optionally substituted cyclic amine (eg, piperidine, pyrrolidine), the optionally substituted cyclic amine can be obtained according to the methods described herein or by using known methods. For example, Patel et al. See the method shown in J Medicinal Chemistry 49 (25) 7450 (2006).

Explanation of general procedure 1: General procedure 1A
Stage 1
1. (2,6-difluoro-4-nitrophenyl) -4-phenylpiperidine In a 100 mL round bottom flask, 3,4,5-trifluoronitrobenzene (1.751 mL, 15 mmol) and potassium dihydrogen phosphate (5. 23 g, 30.0 mmol) was mixed in DMSO (15.00 mL) to give a yellow suspension. 4-Phenylpiperidine (2.419 g, 15.00 mmol) was added as a solid in small portions over 10 minutes to give a deep yellow suspension with some exotherm. The mixture was stirred for 1 hour and partitioned between EtOAc and water. The EtOAc layers were washed twice with 50 mL of water and brine, respectively, dehydrated (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as a yellow solid (4.53 g, 95% yield).

Stage 2
3,5-Difluoro-4- (4-phenylpiperidine-1-yl) aniline in a 500 mL round bottom flask, 1- (2,6) in a solvent mixture of EtOH (60 mL) / THF (60 mL) / water (20 mL) -Difluoro-4-nitrophenyl) -4-phenylpiperidine (4.53 g, 14.23 mmol), iron (3.97 g, 71.2 mmol) and ammonium chloride (1.142 g, 21.35 mmol) were added. The mixture was refluxed with high stirring for 3 hours, cooled, filtered through diatomaceous earth and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dehydrated (Na ₂ SO ₄ ), filtered and solvent evaporated to give the title compound as a yellow solid (3.93 g, 96% yield). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.63-1.81 (m, 4H) 2.54-2.64 (m, 1H) 2.95-3.03 (m, 2H) 3.09 (T, J = 10.57Hz, 2H) 5.42 (s, 2H) 6.10-6.21 (m, 2H) 7.15-7.22 (m, 1H) 7.25-7.34 (M, 4H); MS (ESI +) m / z 289 (M + H) ⁺ .

Explanation of general procedure 1: General procedure 1B
Stage 1
5-Nitro-2- (Pyrrolidine-1-yl) Pyridine To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100 mL), pyrrolidine (15.72 mL, 189 mmol) was added at room temperature. The mixture was heated at 70 ° C. for 18 hours. The cooled solution was concentrated under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ and 1M NaOH. The organic layer was dehydrated (Na ₂ SO ₄ ), filtered and the solvent removed under reduced pressure to give the title compound (9.52 g, 78%). MS (ESI) m / z 194 (M + H) ⁺ .

Stage 2
6- (Pyrrolidine-1-yl) Pyridine-3-amine 5-Nitro-2- (Pyrrolidine-1-yl) Pyridine (9.52 g, 49.3 mmol) was dissolved in THF (50 mL) and DMF (40 mL). Raney nickel 2800 was added to a pressure bottle containing an aqueous slurry (45%) (9.52 g, 162 mmol). The mixture was stirred for 2 hours at about 0.21 MPa (30 psi) under _{H 2} gas. The solution was filtered through a nylon membrane, washed with CH ₃ OH and the filtrate was concentrated under reduced pressure to give the title compound (7.78 g, 97%). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.81-1.91 (m, 4H) 3.17-3.29 (m, 4H) 4.30 (s, 2H) 6.25 (d, J) = 8.7, 1H), 6.90 (dd, J = 2.8, 8.7, 1H), 7.55 (d, J = 2.6, 1H); MS (ESI) m / z 164 ( M + H) ⁺ .

Explanation of general procedure 1 step 2: general procedure 1C
4- (3,5-Dimethylpiperidine-1-yl) -3,5-difluoroaniline 500 mL in a stainless steel pressure bottle, 1- (2,6-difluoro-4-nitrophenyl) -3,5-dimethylpiperidine ( 14.01 g, 51.8 mmol) and THF (240 mL) were added to an aqueous slurry of Raney nickel 2800 (14.01 g, 239 mmol). The mixture was stirred at about 0.21 MPa (30 psi) and room temperature for 8 hours. The mixture was filtered through a nylon membrane and concentrated to give the title compound.

Explanation of general procedure 1 step 2: general procedure 1D
3-Methyl-4- (piperidin-1-yl) aniline 1- (2-methyl-4-nitrophenyl) piperidine (6.75 g, 30.6 mmol) in ethyl acetate (50 mL) in 10% palladium / Carbon (0.033 g, 0.306 mmol) was added and the mixture was hydrogenated at room temperature for 20 hours (hydrogen balloon). The mixture was filtered through diatomaceous earth, washed with ethyl acetate and the filtrate was concentrated to give 5.5 g (94%) of the title compound. MS (ESI) m / z 191 (M + H) ⁺ .

Explanation of general procedure 1 step 1: General procedure 1E
4-Fluoronitrobenzene (0.752 mL, 7.02 mmol), 4-phenylpiperidine (1.) in a 20 mL microwave tube dried in a 1- (4-nitrophenyl) -4-phenylpiperidine dryer under nitrogen. Add 166 g, 7.02 mmol) and potassium carbonate (0.970 g, 7.02 mmol), add dehydrated DMSO (7 mL), seal the tube with an aluminum crimp cap, microwave reactor (Personal Chemistry, 300 W, 2.4). It was heated in bar) at 190 ° C. for 10 minutes. TLC (SiO ₂ , 5% EtOAc / Hexanes) showed completion of the reaction. The reaction mixture was added to water (50 mL), stirred for 5 minutes, and filtered under reduced pressure using a Büchner funnel. The recovered yellow solid was washed with water (twice at 10 mL) and Et ₂ O (5 mL) and the bright yellow solid was vacuum dried to give the title compound (1.712 g, 6.06 mmol, 86%). ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 1.73-1.90 (m, 2H), 2.00 (d, J = 13.34 Hz, 2H), 2.73-2.86 (m, 1H), 3.02-3.17 (m, 2H), 4.10 (d, J = 13.23Hz, 2H), 6.87 (d, J = 9.43Hz, 2H), 7.23 (t, J) = 7.75Hz, 3H), 7.33 (t, J = 7.43Hz, 2H), 8.14 (d, J = 9.33Hz, 2H); MS (ESI +) m / z 283 (M + H) ⁺ .

The following amines can be produced by using the method shown in General Procedure 1 above.
4- (4,4-Dimethylpiperidine-1-yl) -3,5-difluoroaniline;
4- (2-azabicyclo [2.2.2] octane-2-yl) -3,5-difluoroaniline;
3,5-Difluoro-4- (4-isopropylpiperidine-1-yl) aniline;
3,5-Difluoro-4- (4- (trifluoromethyl) piperidine-1-yl) aniline;
4- (4-tert-Butylpiperidin-1-yl) -3,5-difluoroaniline;
3,5-Difluoro-4- (6-azaspiro [2.5] octane-6-yl) aniline;
4- (3,3-Dimethylazetidine-1-yl) -3,5-difluoroaniline;
4- (4,4-difluoropiperidine-1-yl) -3,5-difluoroaniline;
3,5-Difluoro-4- (4-fluoropiperidine-1-yl) aniline;
3,5-Difluoro-4- (piperidine-1-yl) aniline;
2,3,5,6-tetrafluoro-4- (piperidine-1-yl) aniline;
3-Methyl-4- (piperidine-1-yl) aniline;
3,5-Difluoro-4-((3aR, 7aS) -1H-isoindole-2 (3H, 3aH, 4H, 5H, 6H, 7H, 7aH) -yl) aniline;
N ¹ -tert-Butyl-2-fluorobenzene-1,4-diamine;
3,5-Difluoro-4- (4-methylpiperidin-1-yl) aniline;
3,5-Dichloro-4- (piperidine-1-yl) aniline;
2,5-Difluoro-4- (piperidine-1-yl) aniline;
4-((2R, 6S) -2,6-dimethylpiperidine-1-yl) -3,5-difluoroaniline;
2,3,5-trifluoro-4- (piperidine-1-yl) aniline;
4-((1R, 5S) -3-azabicyclo [3.2.0] heptane-3-yl) -3,5-difluoroaniline;
3-Fluoro-4- (piperidine-1-yl) aniline;
3,5-Difluoro-4- (3-azaspiro [5.5] undecane-3-yl) aniline;
3,5-Difluoro-4- (isoindoline-2-yl) aniline;
3,5-Difluoro-4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) aniline;
4- (4-Phenyl-5,6-dihydropyridine-1 (2H) -yl) aniline;
3-Fluoro-4- (4-phenylpiperidine-1-yl) aniline;
4- (4,4-diphenylpiperidin-1-yl) -3,5-difluoroaniline;
4- (4-Phenylpiperidine-1-yl) aniline;
1- (1- (4-Amino-2,6-difluorophenyl) -4-phenylpiperidine-4-yl) etanone;
3,5-Difluoro-4- (4- (3-phenylpropyl) piperidine-1-yl) aniline;
3,5-Difluoro-4- (8-azaspiro [4.5] decane-8-yl) aniline;
3,5-Difluoro-4- (3-phenylpiperidine-1-yl) aniline;
3,5-Difluoro-4- (3-phenylpyrrolidine-1-yl) aniline;
3,5-Difluoro-4- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) aniline;
3,5-Difluoro-4- (4-phenylpiperazine-1-yl) aniline;
4- (4- (2,6-difluorophenyl) piperazine-1-yl) -3,5-difluoroaniline;
3,5-Difluoro-4- (4- (pyrimidine-2-yl) piperazine-1-yl) aniline;
3,5-Difluoro-4- (2-phenylmorpholino) aniline;
(S) -3,5-difluoro-4- (2-phenylmorpholino) aniline;
3,5-Difluoro-4- (2-phenylpiperidine-1-yl) aniline;
4-((2S, 6R) -2,6-dimethylmorpholine) -3,5-difluoroaniline;
4- (4-Cyclohexylpiperidin-1-yl) -3,5-difluoroaniline;
4- (4-Benzylpiperidin-1-yl) -3,5-difluoroaniline;
3,5-Difluoro-4- (4- (4-methoxyphenyl) piperidine-1-yl) aniline;
3,5-Difluoro-4- (4- (4-fluorophenyl) piperidine-1-yl) aniline;
4- (4- (3,4-difluorophenyl) piperidine-1-yl) -3,5-difluoroaniline;
4- (4- (3,5-difluorophenyl) piperidine-1-yl) -3,5-difluoroaniline;
3,5-Difluoro-4- (4-fluoro-4-phenylpiperidine-1-yl) aniline;
3,5-Difluoro-4- (4- (fluorodiphenylmethyl) piperidine-1-yl) aniline;
4- (4-Fluoro-4-phenylpiperidine-1-yl) aniline;
3,5-Difluoro-4- (4- (pyridin-2-yl) piperidine-1-yl) aniline;
3,5-Difluoro-4- (4- (naphthalene-2-yl) piperidine-1-yl) aniline;
3,5-Difluoro-4- (4- (naphthalene-1-yl) piperidine-1-yl) aniline; and 3,5-difluoro-4- (4- (4- (trimethylsilyl) phenyl) piperidine-1- Il) Aniline.

General procedure 1.1.4- Alkoxy-substituted aniline

The intermediate anilines having an alkoxy substituent para to the aniline can be prepared by a two step _{procedure, G 10} is -OR _S (e.g., -O-t-butyl, -O- isopropyl, -O- CH _2- (3-ethyloxetane-3-yl), -O-CH _2- (1,3-dioxolane-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O- (1,3-yl) Dioxane-5-yl)). In step 1, fluoronitrobenzenes can be reacted with suitable alcohols and bases (eg, Cs ₂ CO ₃ , potassium tert-butoxide) in a solvent such as MSO while heating to 50-100 ° C. .. Step 2 can be performed under standard nitro-reduction conditions such as catalytic hydrogenation with palladium / carbon or Raney nickel described elsewhere herein. Alternatively, the reduction can be carried out using iron / ammonium chloride in THF / methanol / water as a solvent.

Explanation of general procedure 1.1: General procedure 1.1A
Stage 1
Cesium carbonate (7.09 mL, 89.0 mmol) in a solution of 3-ethyl-3-((4-nitrophenoxy) methyl) oxetane 4-fluoronitrobenzene (3.76 mL, 35.4 mmol) in DMSO (35 mL) at room temperature. And then 3-ethyl-3-oxetanemethanol (4.48 mL, 42.5 mmol) was added. The mixture was heated to 70 ° C. for 2 hours. After cooling, water was added, the resulting precipitate was filtered, washed with water and dried in a vacuum dryer to give the title compound (8.28 g, 98% yield).

Stage 2
4-((3-Ethyloxetane-3-yl) methoxy) aniline 3-ethyl-3-((4-nitrophenoxy) methyl) oxetane (8.28 g, 34.9 mmol) THF: EtOH: water (140 mL) Ammonium chloride (2.80 g, 52.3 mmol) and then iron powder (9.74 g, 174 mmol) were added to the solution in the 3: 3: 1 mixture at room temperature. The mixture was heated to 90 ° C. for 1 hour and then hot filtered through diatomaceous earth using a THF wash solution to complete the transfer. The filtrate was concentrated under reduced pressure, the residue was taken up in ethyl acetate, washed with brine, dehydrated (Na ₂ SO ₄ ) and concentrated to give the title compound without further purification (7.12 g, Yield 98%).

The following amines can be produced by using the method shown in General Procedure 1 above.
4-((3-Ethyloxetane-3-yl) methoxy) -3,5-difluoroaniline;
4-((1,3-Dioxolane-4-yl) methoxy) aniline;
4- (1,3-dioxane-5-yloxy) aniline.

General procedure 1.2. Aniline formation by Suzuki-type reaction

Produce certain intermediate anilines from bromide, iodide or triflate (ie, X _1.2 = Br, I or OTf) by carbon-carbon bond formation reactions mediated by Suzuki, Still and other similar transition metals. Compounds in which _RM1.2 is cycloalkyl, aryl, heteroaryl or cycloalkenyl can be formed. The above is a description of the method carried out for aniline, but the method can also be carried out with other functional groups, which functional groups can be converted to aniline (eg, nitro groups).

Explanation of general procedure 1.2, general procedure 1.2A
4- (Cyclohexene-1-yl) -3-fluoroaniline in a pressure tube, 3-fluoro-4-iodoaniline (2.29 g, 9.66 mmol) and potassium carbonate (1.74 g, 12.58 mmol) 4: The solution in 1 dimethoxyethane-water (33 mL) was degassed by nitrogen blowing for 40 minutes, then 1-cyclohexenylboronic acid pinacol ester (2.7 mL, 2.61 g, 12.56 mmol) was added. Next, 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added, and then degassed for an additional 5 minutes. The pressure tube was sealed and the temperature was raised at 100 ° C. for 18 hours. The mixture was cooled, diluted with ethyl acetate and then extracted with water and saturated sodium chloride solution. The solution was dehydrated (Na ₂ SO ₄ ) and stirred with 3- (mercaptopropyl) silica gel for 1 hour. A brown oil was obtained by concentration under reduced pressure and chromatographically purified on a 340 g silica gel cartridge eluting with 10% to 100% ethyl acetate / hexane. These procedures gave the title compound (1.16 g, 63%) as a light brown oil. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 7.00 (m, 1H), 6.37 (m, 2H), 5.84 (s, 1H), 3.71 (brs, 2H), 2.32 (m) , 2H), 2.17 (m, 2H), 1.73 (m, 2H), 1.65 (m, 2H); MS (+ DCI) m / z (relative abundance ratio) 192 (100, M + H) ..

Explanation of general procedure 1.2, general procedure 1.2B
In a 4-cyclopropyl-3,5-difluoroaniline pressure tube, 4-bromo-3,5-difluoroaniline (1.0 g, 4.8 mmol), cesium carbonate (4.7 g, 14.4 mmol), toluene (10 mL). ) And water (1 mL) were added. The solution was degassed for 30 minutes with _{N 2} gas, followed cyclopropyl-trifluoro - borate · potassium salt (0.8 g, 5.3 mmol), di (1-adamantyl)-n-butylphosphine hydroiodide ( 0.07 g, 0.14 mmol) and palladium (II) acetate (0.02 g, 0.096 mmol) were added. Degassing was continued for 5 minutes, the tube was sealed and heated at 100 ° C. for 18 hours. The cooled solution was diluted with EtOAc, washed with _{H 2} O and brine, dried _(Na 2 _SO 4), and filtered. The filtrate was treated with 3-mercaptopropyl silica gel for 1 hour. The mixture was filtered and concentrated to give the crude product, which was purified by flash chromatography (0% to 30% EtOAc / Hexanes) to give the title compound (0.67 g, 4.0 mmol, 82). %).

Explanation of general procedure 1.2, general procedure 1.2C
4-Cyclopropyl-2-fluoro-1-nitrobenzene 4-bromo-2-fluoronitrobenzene (0.5 g, 2.27 mmol), cyclopropylboronic acid (0.293 g, 3.41 mmol), potassium trihydrogen phosphate (0.5 g, 3.41 mmol) Toluene-water mixture of 0.965 g, 4.55 mmol), tricyclohexylphosphonium tetrafluoroborate (0.021 g, 0.057 mmol) and palladium (II) acetate (6.12 mg 0.027 mmol) 10: 1 (volume ratio) ( The solution in (11 mL) was purged with nitrogen and degassed in vacuum three times. The reaction mixture was heated in an oil bath at 85 ° C. for 4 hours. The reaction mixture was partitioned with ethyl acetate, the organic phase was washed with water, dehydrated (Na ₂ SO ₄ ) and concentrated. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dehydrated (Na ₂ SO ₄ ) and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate-hexane) to give the title compound (0.382 g, 88%) as a yellow oil.

General procedure 1.3

Certain intermediate anilines can be prepared using the general procedures described above and below. The procedure is the reaction of fluoronitrobenzene with the cyclic amine moiety (step 1); conversion to vinyl coupling partners (steps 2 and 3); coupling of vinyl coupling partners with another suitable partner (step 4). ; And the reduction of nitro groups and olefins (step 5). Alternatively, this pathway can be used to produce aniline with unchanged olefins by selective reduction of nitro groups. Carbon-carbon bond reactions that can be suitable for step 4 include, for example, Suzuki reaction, Still reaction or Negishi reaction.

Explanation of general procedure 1.3: General procedure 1.3A
Stage 1
8- (2,6-difluoro-4-nitrophenyl) -1,4-dioxa-8-azaspiro [4.5] Decane 1,2,3-trifluoro-5-nitrobenzene ( 4.0 mL, 34.3 mmol) ), 1,4-Dioxa-8-azaspiro [4.5] decane (6.59 mL, 51.4 mmol) and potassium carbonate (5.68 g, 41.1 mmol) in DMSO (35 mL) at 100 ° C. 3 It was heated for hours and cooled to room temperature. The mixture was partitioned between water and EtOAc and the organic layer was dehydrated with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with a solvent gradient of 0% to 20% EtOAc / Hexanes to give a yellow oil.

Stage 2

１−（２，６−ジフルオロ−４−ニトロフェニル）ピペリジン−４−オン
前記手順からの粗８−（２，６−ジフルオロ−４−ニトロフェニル）−１，４−ジオキサ−８−アザスピロ［４．５］デカンを４：１アセトン：水（１００ｍＬ）に溶かした。濃ＨＣｌ（５ｍＬ）を加え、得られた混合物を５０℃で８時間撹拌し、冷却して室温とした。混合物を減圧下に濃縮して約２０ｍＬとし、それを濃ＮａＨＣＯ_３水溶液（１００ｍＬ）に注意深く加え、ＥｔＯＡｃで抽出した（１００ｍＬで２回）。合わせた有機抽出液をＮａ_２ＳＯ_４で脱水し、濾過し、減圧下に濃縮した。粗生成物をＥｔ_２Ｏおよびヘキサンで磨砕して明黄色固体を得て、それを回収し、乾燥させて、標題化合物を得た（７．１３ｇ、８１％）。

1- (2,6-difluoro-4-nitrophenyl) piperidine-4-one Crude 8- (2,6-difluoro-4-nitrophenyl) -1,4-dioxa-8-azaspiro [4] from the above procedure .5] Decane was dissolved in 4: 1 acetone: water (100 mL). Concentrated HCl (5 mL) was added and the resulting mixture was stirred at 50 ° C. for 8 hours and cooled to room temperature. The mixture was concentrated under reduced pressure to about 20 mL, which was carefully added to concentrated aqueous NaHCO ₃ solution (100 mL) and extracted with EtOAc (twice at 100 mL). The combined organic extracts were dehydrated with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was ground with Et ₂ O and hexane to give a bright yellow solid, which was recovered and dried to give the title compound (7.13 g, 81%).

Stage 3

トリフルオロメタンスルホン酸１−（２，６−ジフルオロ−４−ニトロフェニル）−１，２，３，６−テトラヒドロピリジン−４−イル
１−（２，６−ジフルオロ−４−ニトロフェニル）ピペリジン−４−オン（５．０ｇ、１９．５２ｍｍｏｌ）の脱水ＴＨＦ（５０ｍＬ）中溶液に−７８℃で乾燥Ｎ_２雰囲気下にて、１Ｍリチウムビス（トリエチルシリル）アミドのＴＨＦ中溶液（２９．３ｍＬ、２９．３ｍｍｏｌ）を１０分間かけて滴下した。得られた深赤色溶液を−７８℃で５分間撹拌し、１，１，１−トリフルオロ−Ｎ−フェニル−Ｎ−（トリフルオロメチルスルホニル）メタンスルホンアミド（７．６７ｇ、２１．４７ｍｍｏｌ）を加えた。得られた混合物を−７８℃で１時間撹拌し、混合物を昇温させて室温とした。混合物をＥｔＯＡｃ（１００ｍＬ）で希釈し、１Ｎ ＮａＯＨ水溶液（５０ｍＬ）および水（５０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で脱水した。乾燥剤を濾去し、溶媒を減圧下に除去して粗生成物を得て、それを０％から４０％ＥｔＯＡｃ／ヘキサンの溶媒勾配を用いるシリカゲルでのカラムクロマトグラフィーによって精製した。標題化合物を黄色油状物として得て、それは減圧下に結晶化した（６．１２ｇ、８１％）。

Trifluoromethanesulfonic acid 1- (2,6-difluoro-4-nitrophenyl) -1,2,3,6-tetrahydropyridine-4-yl- 1- (2,6-difluoro-4-nitrophenyl) piperidin-4 - one (5.0g, 19.52mmol) in dehydrated THF (50 mL) in a dry _{N 2} atmosphere at -78 ° C. was added a solution, 1M lithium bis (triethylsilyl) THF solution of the amide (29.3 mL, 29 .3 mmol) was added dropwise over 10 minutes. The resulting deep red solution was stirred at −78 ° C. for 5 minutes to add 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (7.67 g, 21.47 mmol). added. The resulting mixture was stirred at −78 ° C. for 1 hour and the mixture was warmed to room temperature. The mixture was diluted with EtOAc (100 mL), washed with 1N aqueous NaOH solution (50 mL) and water (50 mL) and dehydrated with Na ₂ SO ₄ . The desiccant was removed by filtration and the solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography on silica gel with a solvent gradient of 0% to 40% EtOAc / Hexanes. The title compound was obtained as a yellow oil, which crystallized under reduced pressure (6.12 g, 81%).

Stage 4 (Suzuki reaction)

１−（２，６−ジフルオロ−４−ニトロフェニル）−４−（３，４−ジフルオロフェニル）−１，２，３，６−テトラヒドロピリジン
Ｎ_２ガスを２０分間吹き込みながら、トリフルオロメタンスルホン酸１−（２，６−ジフルオロ−４−ニトロフェニル）−１，２，３，６−テトラヒドロピリジン−４−イル（１．１８ｇ、３．０４ｍｍｏｌ）、２−（３，４−ジフルオロフェニル）−４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（１．０２ｇ、４．２５ｍｍｏｌ）、塩化リチウム（０．３８７ｇ、９．１２ｍｍｏｌ）および２．０Ｍ炭酸ナトリウム水溶液（４．５６ｍＬ、９．１２ｍｍｏｌ）の脱水ＤＭＥ（１５ｍＬ）中混合物を高撹拌した。テトラキス（トリフェニルホスフィン）パラジウム（０）（０．１７６ｇ、０．１５２ｍｍｏｌ）を加え、得られた混合物をさらに５分間脱気した。反応フラスコに冷却管を取り付け、１００℃油浴に入れた。暗色混合物を乾燥Ｎ_２雰囲気下に１００℃で１６時間撹拌し、冷却して室温とし、水（５０ｍＬ）とＥｔＯＡｃ（５０ｍＬで２回）との間で分配した。合わせた有機層をＮａ_２ＳＯ_４で脱水し、濾過し、減圧下に濃縮し、粗生成物を０％から４０％ＥｔＯＡｃ／ヘキサンの溶媒勾配を用いるシリカゲルでのカラムクロマトグラフィーによって精製して黄色油状物を得て、それは静置していると固化した。固体をＥｔ_２Ｏおよびヘキサンで磨砕し、濾過し、乾燥して、標題化合物を得た（０．６７ｇ、６３％）。

Trifluoromethanesulfonic acid 1 while blowing 1- (2,6-difluoro-4-nitrophenyl) -4- (3,4-difluorophenyl) -1,2,3,6-tetrahydropyridine N ₂ gas for 20 minutes. -(2,6-difluoro-4-nitrophenyl) -1,2,3,6-tetrahydropyridine-4-yl (1.18 g, 3.04 mmol), 2- (3,4-difluorophenyl) -4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.02 g, 4.25 mmol), lithium chloride (0.387 g, 9.12 mmol) and 2.0 M aqueous sodium carbonate solution (4.56 mL, The mixture in 9.12 mmol) dehydrated DME (15 mL) was highly stirred. Tetrakis (triphenylphosphine) palladium (0) (0.176 g, 0.152 mmol) was added and the resulting mixture was degassed for an additional 5 minutes. A cooling tube was attached to the reaction flask and placed in a 100 ° C. oil bath. The dark mixture was stirred dry _N 16 hours at 100 ° C. under ₂ atmosphere, cooled to room temperature, water (50 mL) and was partitioned between EtOAc (2 x 50 mL). The combined organic layers are dehydrated with Na ₂ SO ₄ , filtered, concentrated under reduced pressure and the crude product purified by column chromatography on silica gel with a solvent gradient of 0% -40% EtOAc / Hexanes to yellow. Obtaining an oil, it solidified when left to stand. The solid was ground with Et ₂ O and hexane, filtered and dried to give the title compound (0.67 g, 63%).

Stage 5

（４−（４−（３，４−ジフルオロフェニル）ピペリジン−１−イル）−３，５−ジフルオロアニリン
１−（２，６−ジフルオロ−４−ニトロフェニル）−４−（３，４−ジフルオロフェニル）−１，２，３，６−テトラヒドロピリジン（０．６７ｇ、１．９０ｍｍｏｌ）のＴＨＦ（２０ｍＬ）中溶液に１０％Ｐｄ／炭素（５０ｍｇ）を加えた。反応フラスコにＮ_２ガスを流し、得られた混合物を１ａｔｍＨ_２ガス下に２４時間高撹拌した。混合物を珪藻土によって濾過し、減圧下に濃縮して、標題化合物を固体として得た（０．６２ｇ、１００％）。

(4- (4- (3,4-difluorophenyl) piperidine-1-yl) -3,5-difluoroaniline 1- (2,6-difluoro-4-nitrophenyl) -4- (3,4-difluorophenyl) phenyl) -1,2,3,6-tetrahydropyridine (0.67g, 10% Pd / carbon THF (20 mL) a solution of 1.90 mmol) of (50 mg) was added. the reaction flask flushed with _{N 2} gas The resulting mixture was stirred under 1 atmosphere ₂ gas for 24 hours. The mixture was filtered through diatomaceous soil and concentrated under reduced pressure to give the title compound as a solid (0.62 g, 100%).

The following amines can be produced using the method shown in General Procedure 1.3 above.
3,5-Difluoro-4- (4- (4-fluorophenyl) piperidine-1-yl) aniline;
3,5-Difluoro-4- (4- (3- (trimethylsilyl) phenyl) piperidine-1-yl) aniline; and 3,5-difluoro-4- (4- (5-methylthiophen-2-yl) piperidine) -1-Il) Aniline.

General procedure 2. Pyrrolidine formation from amines and dimesylates (5)

Dimesylate (5) (1 eq) as a single steric isomer or mixture of isomers, with or without a co-solvent such as DMF, undiluted or in a solvent such as tetrahydrofuran or 2-methyltetrahydrofuran. Pyrrolidine according to the formula (6) can be obtained by reacting with 1 to 20 equivalents of amine D-NH ₂ at about 100 ° C. from room temperature. When a small equivalent of amine D-NH ₂ is used (ie 1 to 2 equivalents), a base such as diisopropylethylamine can be added to accelerate the reaction. For example, the reaction with excess aniline D-NH ₂ (about 5 to 10 eq) of dimesylate (1 eq) can be performed by heating in 2-methyltetrahydrofuran or DMF to 50 to 65 ° C. until the reaction is complete. it can. Alternatively, dimesylate (1 eq) can be reacted with undiluted excess aniline D-NH ₂ (about 15-20 eq) at room temperature or while heating to about 65 ° C. The reaction solution is partitioned between an organic solvent (eg, ethyl acetate) and a dilute aqueous HCl solution, then the organic layer is separated, the organic layer is appropriately washed with water, and the organic layer is dried (eg, sulfonyl _4). , Na ₂ SO ₄ ), can be filtered, and the solvent distilled off. The product can be purified by column chromatography on silica gel eluting with a standard solvent such as a mixture of ethyl acetate and hexane, or the product can be purified by grinding or recrystallization.

Explanation of general procedure 2: General procedure 2A
(2S, 5S) -1- (4-tert-butylphenyl) -2,5-bis (4-nitrophenyl) pyrrolidine intermediate 6C in a crude product solution (7.35 g, 13.39 mmol) at 23 ° C. 4-tert-Butylaniline (13.4 g, 90 mmol) was added over 1 minute. The reaction solution was heated to 65 ° C. for 2 hours. Upon completion, the reaction mixture was cooled to 23 ° C. and diluted with 2-methyltetrahydrofuric acid (100 mL) and 1M HCl (150 mL). After partitioning the phase, the organic phase was treated with 1M HCl (140 mL), 2-methyltetrahydrofuran (50 mL) and 25 wt% NaCl aqueous solution (100 mL) to partition the phase. The organic phase was washed with 25 wt% NaCl aqueous solution (50 mL), dehydrated with sulfonyl ₄ , filtered and concentrated under reduced pressure to about 20 mL. Crystallization was induced by adding heptane (30 mL) and additional 2-methyltetrahydrofuran. The slurry was further concentrated, additional heptane (40 mL) was added slowly, the slurry was filtered and washed with 2-methyltetrahydrofuran: heptane (1: 4, 20 mL). The solid was suspended in CH ₃ OH (46 mL) for 3 hours, filtered and the hydrous solid was washed with additional CH ₃ OH (18 mL). The solid was dried in a vacuum dryer at 45 ° C. for 16 hours to give the title compound (3.08 g).

General procedure 3. Pyrrolidine formation from amines and bisbromophenyl dimesylates

The general procedure 3 can be performed using substantially the same conditions as those of the general procedure 2.

Explanation of general procedure 3: General procedure 3A
(2S, 5S) -2,5-bis (4-bromophenyl) -1- (4-tert-butylphenyl) pyrrolidine intermediate 7C was dissolved in dehydrated DMF (5 mL) and 4-tert-butylaniline (2. 39 mL, 15 mmol) was added. The resulting mixture was stirred at 40 ° C. for 4 hours and it was partitioned between 1N aqueous HCl (30 mL) and EtOAc (30 mL). The organic layer was washed with H ₂ O and dehydrated with Na ₂ SO ₄ . The desiccant was removed by filtration, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel with a solvent gradient of 0% to 20% EtOAc / Hexanes. The title compound was obtained as a colorless solid (0.71 g, 92%). ^{1 1} H NMR showed that this acquisition was an 87:13 mixture of trans: cispyrrolidine isomers.

General procedure 4. Pyrrolidine formation from amines and dimesylates (52)

The general procedure 4 can be performed using substantially the same conditions as the condition of the general procedure 2. For example, undiluted or in a solvent such as ethanol, acetonitrile, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, DMF or DMA or in a solvent mixture at about room temperature to about 100 ° C., a single steric isomer or mixture of isomers. Dimesylate (52) (1 equivalent) as is reacted with 1 to 20 equivalents of amine D-NH ₂ to obtain pyrrolidines such as in formula (53). Alternatively, dimesylate (3-10 equivalents) in a solvent or solvent mixture such as methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, DMF or DMA at a temperature of about room temperature to about 70 ° C. in the presence of a base such as diisopropylethylamine (3-10 equivalents). 52) (1 equivalent) can be reacted with amine D-NH ₂ (1 to 4 equivalents). When amine D-NH ₂ is used in low equivalents (ie, 1 to 2 equivalents), a larger amount of base such as diisopropylethylamine (about 8 to 10 equivalents) can be added to accelerate the reaction. If the amine is less reactive (eg, 2,5-difluoro-4- (trifluoromethyl) aniline, 2-fluoropyridine-4-amine), a reaction time of several days may be required. The reaction is carried out by partitioning between an organic solvent (eg ethyl acetate) and water or dilute aqueous HCl solution, then separating the organic layer and appropriately washing the organic layer with water and / or brine to remove the organic layer. It can be dehydrated with a desiccant (eg, transferase ₄ , Na ₂ SO ₄ ), filtered and solvent distilled off. The product (53) can be purified by column chromatography on silica gel eluting with a standard solvent such as ethyl acetate and hexane or a mixture of hexane or methylene chloride / hexane. The residual amine can be removed using a methylene chloride / hexane system, in which case the reaction is stopped with water instead of the aqueous HCl solution. In such cases, a second chromatography using an ethyl acetate / hexane system may be required to separate the cispyrrolidine product from the transpyrrolidine product. Alternatively, the product can be purified by grinding or recrystallization.

Explanation of general procedure 4: General procedure 4A
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-cyclohexylphenyl) pyrrolidinedimethylformamide (8 mL) in intermediate 5D (4.99 mmol), 4 -Cyclohexylaniline (5.24 g, 29.9 mmol) was added and the solution was heated at 65 ° C. for 2 hours. The reaction mixture was charged into 1M HCl and extracted with dichloromethane. The organic phase was concentrated and purified on a CombiFlash® 80 g silica column eluting with 0% to 20% ethyl acetate / hexane to give 1.38 g (51%) of the title compound.

Explanation of general procedure 4: General procedure 4B
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidine in a 250 mL flask, 3,5-Difluoro-4- (4-phenylpiperidine-1-yl) aniline (3.1 g, 10.76 mmol), intermediate 5D (5.0 g, 8.97 mmol), DMF (15 mL) and diisopropylethylamine (3.1 g, 10.76 mmol) 15.7 mL, 90 mmol) was added. The obtained slurry was placed in an oil bath at 60 ° C. and heated under N ₂ for 18 hours. The amber solution was cooled, diluted with 300 mL of ethyl acetate, washed twice with 100 mL of water twice with 100 mL of 2 × 1N HCl with brine, dehydrated (Na ₂ SO ₄ ), filtered and concentrated. The crude product was flash chromatographically purified on a 330 g silica cartridge eluting with 50% to 80% dichloromethane / hexane to give unreacted aniline. The column fractions containing the products were combined and concentrated to give an orange-red solid, which was dissolved in 20 mL of hot ethyl acetate, treated with 15 mL of hexane and stirred overnight at ambient temperature to give a precipitate (cispyrrolidine). , It was removed by filtration. The filtrate is concentrated and chromatographed again on a 330 g silica cartridge eluting with 40% to 70% methylene chloride / hexane to 1-(4-((2R, 5R) -2,5-bis (4-chloro)). -3-Nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidine was obtained as an orange-red foam (2.26 g, 36%). MS (ESI +) m / z 653 (M + H) ⁺ .

Explanation of general procedure 4: General procedure 4C
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2-fluorophenyl) -4-phenylpiperidine intermediate 5D (6. 0 g, 10.76 mmol), 3-fluoro-4- (4-phenylpiperidine-1-yl) aniline (4.37 g, 16.15 mmol) and diisopropylethylamine (15.04 mL, 86 mmol) in N, N-dimethylacetamide. They were combined in (15 mL) and heated at 60 ° C. for 3 hours. The solution was diluted with water, extracted with dichloromethane and washed with brine. The organic layer was concentrated and purified by chromatography eluting with 30% to 100% dichloromethane / hexane to give 5.05 g (74%) of a yellow solid.

Explanation of general procedure 4: General procedure 4D
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-ethoxyphenyl) pyrrolidine intermediate 5D (2.5805 g, 4.63 mmol) and 4-ethoxyaniline (2) .4 mL, 18.60 mmol) were combined in DMF (30 mL) and stirred overnight at room temperature. The reaction was diluted with EtOAc / ether, washed with water (twice) and brine (once) and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc) to give 1.8 g (77%) of the title compound.

Explanation of general procedure 4: General procedure 4E
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine dimethanesulfonic acid Solution of (1S, 4S) -1,4-bis (4-chloro-2-fluoro-5-nitrophenyl) butane-1,4-diyl (500 mg, 0.843 mmol) in CH ₃ CN (4.5 mL) Was added 3,5-difluoro-4- (piperidine-1-yl) aniline (358 mg, 1.685 mmol) and Hunig base (0.736 mL, 4.21 mmol). The suspension was heated at 75 ° C. for 24 hours. The solvent was removed by rotary evaporation and the residue was dissolved in EtOAc, washed with 1N _{HCl, H} 2 O, brine, dried (MgSO _4), filtered, and concentrated. The crude product was chromatographed on an ISCO 24g silica gel cartridge eluting with 20% to 70% CH ₂ Cl ₂ / hexanes to give the title compound containing a small amount of the corresponding cis-pyrrolidine isomer.

The following substituted pyrrolidines can be produced using the general method.
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4,4-dimethylpiperidine;
2-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-azabicyclo [2.2. 2] Octane;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-isopropylpiperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (trifluoromethyl) piperidine ;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-tert-butylpiperidin;
6-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -6-azaspiro [2.5] Octane;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4,4-dimethylpiperidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4- (3,3-dimethylazetidine-1-yl) -3,5-difluorophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-phenoxyphenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) Pyridine-2 (1H) -one;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (2,5-difluoro-4- (trifluoromethyl) phenyl) pyrrolidine;
2-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) oxazole;
4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2-fluoropyridine;
(2R, 5R) -1- (4-chloro-3-fluorophenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4,4-difluoropiperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-fluoropiperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-fluorophenyl) pyrrolidine;
(2R, 5R) -1- (4-tert-butylphenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-cyclopropyl-3,5-difluorophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-cyclohexyl-3-fluorophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (3,4-difluorophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4- (2,2-difluoroethoxy) phenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3,5-dimethylpiperidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] pyrrolidine (ACD Name v12);
2-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) pyridine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4- (2-methoxyethoxy) -3-methylphenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-chlorophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1-(4-((3-ethyloxetane-3-yl) methoxy) phenyl) pyrrolidine;
(2R, 5R) -1- (biphenyl-4-yl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
(2R, 5R) -1- (4- (1,3-dioxane-5-yloxy) phenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
(2R, 5R) -1- (4-((1,3-dioxolane-4-yl) methoxy) phenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1-(4-((3-ethyloxetane-3-yl) methoxy) -3,5-difluorophenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,3,5,6-tetrafluorophenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2-methylphenyl) piperidine;
(3aR, 7aS) -2-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) Octahydro-1H -Isoindole;
4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -N-tert-butyl-2-fluoroaniline;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-methylpiperidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4- (cyclopentyloxy) -3-fluorophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (3-fluoro-4- (methylthio) phenyl) pyrrolidine 1-(4-((2R, 5R) -2) , 5-Bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-dichlorophenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,5-difluorophenyl) piperidine;
(2R, 6S) -1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2, 6-Dimethylpiperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,3,6-trifluorophenyl) piperidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-cyclopropylphenyl) pyrrolidine;
(1R, 5S) -3- (4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3- Azabicyclo [3.2.0] heptane;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-cyclopropyl-2-fluorophenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2-fluorophenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) -4-phenylpiperidine;
3-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3-azaspiro [5.5] Undecane;
2-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) isoindoline;
8-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -1,4-dioxa-8- Azaspiro [4.5] Decane;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenyl-1,2, 3,6-tetrahydropyridine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4,4-diphenylpiperidin;
1-(1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidine- 4-Il) Etanon;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine;
1- (4- (2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (3-phenylpropyl) Piperidine;
8-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -8-azaspiro [4.5] Decane;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (naphthalene-2-yl) ) Piperidine;
2- (1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine-4-yl) Pyridine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4- (trimethylsilyl)) Phenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (naphthalene-1-yl) ) Piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (3 -Phenylpropyl) piperidine;
6-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -6-azaspiro [ 2.5] Octane;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-tert- Butyl piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (naphthalene) -2-yl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3,5- Dimethylpiperidine;
1'-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2,3 -Dihydrospiro [Inden-1,4'-piperidine];
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3-phenylpiperidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (3,5-difluoro-4- (3-phenylpyrrolidin-1-yl) phenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4-methoxyphenyl) Piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-fluoro-4-phenylpiperidine ;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) -4-fluoro-4-phenylpiperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (fluoro) Diphenylmethyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidine ;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4-fluorophenyl) Piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (3,4-difluorophenyl) Phenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (3,5-difluorophenyl) Phenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (3- (trimethylsilyl) Phenyl) piperidine;
(2R, 5R) -1- (4- (benzyloxy) phenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4) -(Trifluoromethyl) phenyl) piperazin;
1-(4-((2R, 5R) -2- (4-chloro-2-fluoro-5-nitrophenyl) -5- (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2, 6-difluorophenyl) piperidine;
4-Benzyl-1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine ;
4-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-phenylmorpholine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-phenylpiperidine;
(2S, 6R) -4- (4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) ) -2,6-Dimethylmorpholine;
3-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3-azaspiro [ 5.5] Undecane;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-cyclohexylpiperidin ;
(S) -4- (4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-phenylmorpholine ;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (2) , 4-Difluorophenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4) -Fluorophenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperazine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4- (trifluorophenyl) Methyl) phenyl) piperazin;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (2) , 6-Difluorophenyl) piperazine;
2- (4-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperazine- 1-Il) Pyrimidine;
5-((2S, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2- (4-phenylpiperidine-1-yl) pyrimidine;
5-((2S, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2- (piperidine-1-yl) pyrimidine;
1-(4-((2S, 5S) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (2) , 6-Difluorophenyl) piperazine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (5) -Methylthiophen-2-yl) piperidine; and 1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2 , 6-Difluorophenyl) -4-fluoro-4-phenylpiperidine.

General procedure 5. Nitro reduction

Compound (about 6 equivalents) and ammonium chloride (about 3 equivalents) by reaction with iron powder (about 6 equivalents) in a solvent of THF: ethanol: water (1: 1: 0.2) at about 60-80 ° C. 6) (1 equivalent) can be reduced to (7). The reaction solution can be post-treated by cooling, filtering through diatomaceous earth, washing with ethanol and concentrating under reduced pressure. Alternatively, hydrogenation (about 0.21 MPa (30 psi) H ₂ ) in the presence of PtO ₂ (about 0.4 equivalents) in a solvent of ethanol: THF (about 1: 1) causes (6) (1). Equivalent) can be reduced to (7). Post-treatment of the reaction can be carried out by filtration and solvent distillation. Alternatively, by exposing to about 0.21 MPa (30 psig) hydrogen gas in the presence of Raney nickel Grace2800 (50% by weight of the reaction product) in a solvent such as tetrahydrofuran with shaking, (6) (1 equivalent) (7). ) Can be reduced. Post-treatment of the reaction can be carried out by filtration and solvent distillation. The product (7) can be purified by chromatography on silica gel using a typical organic solvent such as a mixture of ethyl acetate and hexane.

General procedure 5.1. Nitro reduction of pyrrole

Compound (11) can be converted to (12) using the conditions outlined for General Procedure 5, especially by the iron reduction method.

Explanation of general procedure 5.1: General procedure 5.1A

４，４′−（１−（４−フルオロフェニル）−１Ｈ−ピロール−２，５−ジイル）ジアニリン
１−（４−フルオロフェニル）−２，５−ビス（４−ニトロフェニル）−１Ｈ−ピロール（１．０１７ｇ、２．４９６ｍｍｏｌ）のエタノール（１５ｍＬ）およびＴＨＦ（１５ｍＬ）中溶液に、鉄粉（０．８３６ｇ、１４．９８ｍｍｏｌ）を加え、次に塩化アンモニウム（０．４０１ｇ、７．４９ｍｍｏｌ）および水（３．７５ｍＬ）を加えた。反応混合物を４５分間還流させた。反応混合物を珪藻土でスラリー濾過し、エタノールで洗浄した。合わせた濾液を濃縮し、残留物をカラムクロマトグラフィー（３０％から５０％ＥｔＯＡｃ：ヘキサンの勾配溶離）によって精製して、標題化合物１．０９ｇ（７７％）を得た。

4,4'-(1- (4-fluorophenyl) -1H-pyrrole-2,5-diyl) dianiline 1- (4-fluorophenyl) -2,5-bis (4-nitrophenyl) -1H-pyrrole Iron powder (0.836 g, 14.98 mmol) was added to a solution of (1.017 g, 2.496 mmol) in ethanol (15 mL) and THF (15 mL), followed by ammonium chloride (0.401 g, 7.49 mmol). And water (3.75 mL) was added. The reaction mixture was refluxed for 45 minutes. The reaction mixture was slurry filtered through diatomaceous earth and washed with ethanol. The combined filtrates were concentrated and the residue was purified by column chromatography (30% to 50% EtOAc: gradient elution of hexanes) to give 1.09 g (77%) of the title compound.

General procedure 6. Amide coupling

In DMSO at about room temperature, in the presence of diisopropylethylamine (3-4 eq), with 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (about 2.5 eq) and HATU (about 2 to 3 eq). By reacting, compound (7) (1 equivalent) can be converted to compound (8). Instead of using HATU, T3P or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / 1-hydroxybenzotriazole can be used to facilitate this reaction. The reaction can also be carried out in a solvent such as tetrahydrofuran, ethyl acetate or DMF. It is partitioned between an organic solvent (eg ethyl acetate) and water or dilute HCl aqueous solution, then the organic layer is separated, the organic layer is appropriately washed with water and / or brine, and the organic layer is desiccanted (eg). , Ethyl ₄ , Na ₂ SO ₄ ), the reaction can be post-treated by filtering and distilling off the solvent. The product (8) can be purified by column chromatography on silica gel eluting with a standard organic solvent such as a mixture of ethyl acetate and hexane.

General procedure 6.1. Amide coupling of pyrroles

The aniline compound (12) can be converted to an amide (13) using the conditions outlined above in General Procedure 6.

Explanation of general procedure 6.1: General procedure 6.1A

（２Ｓ，２′Ｓ）−２，２′−（４，４′−（１−（４−ｔｅｒｔ−ブチルフェニル）−１Ｈ−ピロール−２，５−ジイル）ビス（４，１−フェニレン）ビス（アザネジル）ビス（オキソメチレン））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
４，４′−（１−（４−ｔｅｒｔ−ブチルフェニル）−１Ｈ−ピロール−２，５−ジイル）ジアニリン（０．３１０ｇ、０．８１３ｍｍｏｌ）のＤＭＦ（５ｍＬ）中溶液に、（Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピロリジン−２−カルボン酸（０．３８５ｇ、１．７９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール水和物（０．２７４ｇ；１．７９ｍｍｏｌ）およびＮ−（３−ジメチルアミノプロピル）−Ｎ′−エチルカルボジイミド塩酸塩（０．３４３ｇ、１．７９ｍｍｏｌ）を加え、混合物を終夜撹拌した。混合物を水に投入し、ＣＨ_２Ｃｌ_２で抽出した。有機抽出液を脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮して粗生成物を得て、それをエーテルでの磨砕によって精製して、標題化合物３２５ｍｇ（５１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．２５（ｓ、２４Ｈ）１．８３（ｓ、６Ｈ）２．１５（ｓ、２Ｈ）３．４５（ｍ、４Ｈ）４．１８（ｓ、２Ｈ）６．４０（ｓ、２Ｈ）６．９８（ｓ、６Ｈ）７．３７（ｓ、６Ｈ）９．９８（ｓ、２Ｈ）。

(2S, 2'S) -2,2'-(4,4'-(1- (4-tert-butylphenyl) -1H-pyrrole-2,5-diyl) bis (4,1-phenylene) bis (Azanesil) Bis (oxomethylene)) Dipyrrolidine-1-carboxylate tert-butyl 4,4'-(1- (4-tert-butylphenyl) -1H-pyrrole-2,5-diyl) dianiline (0.310 g) , 0.813 mmol) in solution in DMF (5 mL), (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (0.385 g, 1.79 mmol), 1-hydroxybenzotriazole hydrate (0.274 g; 1.79 mmol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.343 g; 1.79 mmol) were added and the mixture was stirred overnight. The mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic extract was dehydrated (Na ₂ SO ₄ ), filtered and concentrated to give the crude product, which was purified by grinding with ether to give 325 mg (51%) of the title compound. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.25 (s, 24H) 1.83 (s, 6H) 2.15 (s, 2H) 3.45 (m, 4H) 4.18 (s, 2H) ) 6.40 (s, 2H) 6.98 (s, 6H) 7.37 (s, 6H) 9.98 (s, 2H).

General procedure 7. Suzuki coupling

Bis (pinacolato) diborane (about 2 to 4 equivalents), potassium acetate (about 4 to 8 equivalents) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) chloride in solvents such as DME, dioxane or DMSO. Dibromo compound (34.1) (1) by mixing with a dichloromethane complex (PdCl ₂ (dppf)) (about 0.1 to 0.2 eq), degassing the mixture and heating to about 85 ° C. Equivalent) can be converted to dichloromethane compound (35.1). Allow to cool to room temperature, dilute with methylene chloride, wash the organic layer appropriately with water and / or brine, dehydrate the organic layer with a desiccant (eg, sulfonyl ₄ , Na ₂ SO ₄ ), filter and solvent. By distilling off, the reaction can be post-treated. Intermediate 1D (about 1-2 equivalents), aqueous sodium carbonate solution (about 1-3.5 equivalents) and PdCl ₂ (dppf) (about 0.2 equivalents) in a solvent such as dimethoxyethane or toluene: ethanol (1: 1). Compound (35.1) can be converted to compound (36.1) by mixing with (03 to 0.2 eq), degassing, and heating the reaction to about 80 to 100 ° C. Cooled to room temperature, an organic solvent (e.g., ethyl acetate) and partitioned between water, washed appropriately organic layer was washed with water and / or brine, the organic layer dried agent (e.g., MgSO _4, Na ₂ The post-treatment of the reaction can be carried out by dehydrating with SO ₄ ), filtering and distilling off the solvent. Alternatively, the reaction can be post-treated by concentrating under reduced pressure, partitioning between 25% isopropyl alcohol / chloroform, dehydrating the organic layer (eg Na ₂ SO ₄ ), filtering and distilling off the solvent. it can. Compounds (35.1) and (36.1) can be purified by column chromatography on silica gel eluting with a standard organic solvent such as a mixture of ethyl acetate and hexane, or ground or recrystallized. Can be purified by.

Explanation of general procedure 7: General procedure 7A

ラセミ体トランス−１−（４−ｔｅｒｔ−ブチルフェニル）−２，５−ビス（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）ピロリジン
ラセミ体のトランス−２，５−ビス（４−ブロモフェニル）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン（３．８８ｇ、７．５６ｍｍｏｌ）、４，４，４′，４′，５，５，５′，５′−オクタメチル−２，２′−ビ（１，３，２−ジオキサボロラン）（６．７２ｇ、２６．５ｍｍｏｌ）、［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）（０．６１７ｇ、０．７５６ｍｍｏｌ）および酢酸カリウム（３．３４ｇ、３４．０ｍｍｏｌ）をジメトキシエタン（７０ｍＬ）中で合わせ、窒素ガスを溶液に１０分間吹き込んだ。反応混合物を８５℃で１時間加熱した。反応溶液を冷却して室温とし、珪藻土で濾過し、酢酸エチル（２０ｍＬ）で洗浄した。濾液を脱水し、濃縮し、残留物を０％から１０％酢酸エチル／ヘキサンの溶媒勾配で溶離を行うシリカゲルでのカラムクロマトグラフィーで精製し、次に得られた固体をジエチルエーテルで磨砕することで、標題化合物（１．１４ｇ、２５％）をトランス立体異性体の１／１混合物として得た。

Lasemi-form trans-1- (4-tert-butylphenyl) -2,5-bis (4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) pyrrolidine Lasemi-form trans-2,5-bis (4-bromophenyl) -1- (4-tert-butylphenyl) pyrrolidine (3.88 g, 7.56 mmol), 4,4,4', 4', 5, 5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (6.72 g, 26.5 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloro Phenyl (II) (0.617 g, 0.756 mmol) and potassium acetate (3.34 g, 34.0 mmol) were combined in dimethoxyethane (70 mL) and nitrogen gas was blown into the solution for 10 minutes. The reaction mixture was heated at 85 ° C. for 1 hour. The reaction solution was cooled to room temperature, filtered through diatomaceous earth and washed with ethyl acetate (20 mL). The filtrate is dehydrated and concentrated, the residue is purified by column chromatography on silica gel eluting with a solvent gradient of 0% to 10% ethyl acetate / hexane, and the resulting solid is then ground with diethyl ether. This gave the title compound (1.14 g, 25%) as a 1/1 mixture of trans steric isomers.

（２Ｓ，２′Ｓ）−２，２′−（５，５′−（４，４′−（１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ビス（１Ｈ−イミダゾール−５，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
ラセミ体トランス−１−（４−ｔｅｒｔ−ブチルフェニル）−２，５−ビス（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）ピロリジン（０．９１５ｇ、１．５０６ｍｍｏｌ）、中間体１Ｄ（１．４２９ｇ、４．５２ｍｍｏｌ）および［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）（０．１２３ｇ、０．１５１ｍｍｏｌ）を、トルエン（７ｍＬ）、エタノール（７ｍＬ）および２Ｎ重炭酸ナトリウム水溶液（２．６４ｍＬ、５．２８ｍｍｏｌ）の混合物に溶かした。窒素ガスを溶液に１０分間吹き込み、反応混合物を１００℃で３時間加熱した。反応溶液を冷却して室温とし、水（２０ｍＬ）を加えた。次に、反応混合物をジクロロメタン（５０ｍＬ）で抽出し、脱水し、濃縮した。残留物を、０％から８０％酢酸エチル／ヘキサンの溶媒勾配で溶離を行うシリカゲルでのカラムクロマトグラフィーによって精製して、標題化合物（０．９３ｇ、７５％）をトランス立体異性体の１／１混合物として得た。

(2S, 2'S) -2,2'-(5,5'-(4,4'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (4,1-) phenylene)) bis (1H-imidazole-5,2-diyl)) Jipirorijin 1-carboxylic acid tert- butyl racemic trans-1- (4-tert- butylphenyl) -2,5-bis (4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) pyrrolidine (0.915 g, 1.506 mmol), intermediate 1D (1.429 g, 4.52 mmol) and [1 , 1'-bis (diphenylphosphino) phenylene] dichloropalladium (II) (0.123 g, 0.151 mmol) in toluene (7 mL), ethanol (7 mL) and 2N sodium bicarbonate aqueous solution (2.64 mL, 5. It was dissolved in a mixture of 28 mmol). Nitrogen gas was blown into the solution for 10 minutes and the reaction mixture was heated at 100 ° C. for 3 hours. The reaction solution was cooled to room temperature and water (20 mL) was added. The reaction mixture was then extracted with dichloromethane (50 mL), dehydrated and concentrated. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of 0% to 80% ethyl acetate / hexane to give the title compound (0.93 g, 75%) 1/1 of the trans stereoisomer. Obtained as a mixture.

General procedure 7.1. Suzuki coupling about pyrroles

一般手順７で上記に概要を記載した条件を用いて、ジブロモ化合物（４６）を順次、化合物（４７）および（４３）に変換することができる。

The dibromo compound (46) can be sequentially converted to compounds (47) and (43) using the conditions outlined above in General Procedure 7.

Explanation of general procedure 7.1: General procedure 7.1B

１−（４−ｔｅｒｔ−ブチルフェニル）−２，５−ビス（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）−１Ｈ−ピロール
２，５−ビス（４−ブロモフェニル）−１−（４−ｔｅｒｔ−ブチルフェニル）−１Ｈ−ピロール（２．３２ｇ、４．５６ｍｍｏｌ）のＤＭＳＯ（２６ｍＬ）中溶液に室温で、ビス（ピナコラト）ジボラン（２．５４ｇ、１０．０２ｍｍｏｌ）、酢酸カリウム（５．００ｇ、３６．４ｍｍｏｌ）およびＰｄＣｌ_２（ｄｐｐｆ）（７４４ｍｇ、０．９１ｍｍｏｌ）を加えた。混合物を脱気し、加熱して８５℃とした。４時間後、混合物を冷却して室温とし、ジクロロメタンで希釈し、水と次にブラインで洗浄した。有機相を脱水し（Ｎａ_２ＳＯ_４）、濃縮した。残留物を２０％酢酸エチル／ヘキサンに取り、短いシリカゲル層（２０％酢酸エチル：ヘキサンで溶離）で濾過し、濃縮し、標題化合物を明黄色固体として得た（１．６２ｇ；収率５９％）。

1- (4-tert-Butylphenyl) -2,5-bis (4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -1H-pyrrole 2 , 5-Bis (4-bromophenyl) -1- (4-tert-Butylphenyl) -1H-pyrrole (2.32 g, 4.56 mmol) in DMSO (26 mL) at room temperature, bis (pinacolato) diborane (2.54 g, 10.02 mmol), potassium acetate (5.00 g, 36.4 mmol) and PdCl ₂ (dppf) (744 mg, 0.91 mmol) were added. The mixture was degassed and heated to 85 ° C. After 4 hours, the mixture was cooled to room temperature, diluted with dichloromethane and washed with water and then brine. The organic phase was dehydrated (Na ₂ SO ₄ ) and concentrated. The residue was taken on 20% ethyl acetate / hexane, filtered through a short silica gel layer (20% ethyl acetate: eluted with hexane) and concentrated to give the title compound as a bright yellow solid (1.62 g; 59% yield). ).

（２Ｓ，２′Ｓ）−２，２′−（４，４′−（４，４′−（１−（４−ｔｅｒｔ−ブチルフェニル）−１Ｈ−ピロール−２，５−ジイル）ビス（４，１−フェニレン））ビス（１Ｈ−イミダゾール−４，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
中間体１Ｄ（６６４ｍｇ、２．１０ｍｍｏｌ）、１−（４−ｔｅｒｔ−ブチルフェニル）−２，５−ビス（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）−１Ｈ−ピロール（１．４８ｇ、２．４５ｍｍｏｌ）、２Ｍ炭酸ナトリウム（１４００μＬ、２．８０ｍｍｏｌ）およびＰｄ（ｄｐｐｆ）Ｃｌ_２（５１．２ｍｇ、０．０７０ｍｍｏｌ）のＤＭＥ（２８００μＬ）中混合物について、１４０℃で２０分間マイクロ波照射を行った。混合物を酢酸エチルで希釈し、水およびブラインで洗浄し、Ｎａ_２ＳＯ_４で脱水した。生成物を、３０から７０％酢酸エチル：ヘキサンで溶離を行うシリカゲルで精製して、標題化合物を得た（１４０ｍｇ；収率２４％）。

(2S, 2'S) -2,2'-(4,4'-(4,4'-(1- (4-tert-butylphenyl) -1H-pyrrole-2,5-diyl) bis (4) , 1-Phenylene)) Bis (1H-imidazol-4,2-diyl)) tert-butyl intermediate dipyrrolidine-1-carboxylate 1D (664 mg, 2.10 mmol), 1- (4-tert-butylphenyl)- 2,5-Bis (4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -1H-pyrrole (1.48 g, 2.45 mmol), 2M carbonate A mixture of sodium (1400 μL, 2.80 mmol) and Pd (dppf) Cl ₂ (51.2 mg, 0.070 mmol) in DME (2800 μL) was irradiated with microwaves at 140 ° C. for 20 minutes. The mixture was diluted with ethyl acetate, washed with water and brine and dehydrated with Na ₂ SO ₄ . The product was purified on silica gel eluting with 30-70% ethyl acetate: hexane to give the title compound (140 mg; 24% yield).

General procedure 8. Buchwald reaction

In dioxane, tert-butyl 2-carbamoylpyrrolidin-1-carboxylate (about 3 equivalents), cesium carbonate (about 3 equivalents), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (about 0. Mix with 05 to 0.3 eq) and tris (dibenzylideneacetone) dipalladium (0) (about 0.05 to 0.2 eq) to degas the mixture and bring to about 100 ° C. for about 1 to 8 hours. By heating, compound (64) (1 equivalent) can be converted to compound (65). Alternatively, the reaction is potassium carbonate (about 3 equivalents), Pd (OAc) ₂ (about 0.02 equivalents) and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (about 0.04 equivalents). ) Can be used. The reaction can be carried out in a flask equipped with a reflux condenser in an inert atmosphere or in a sealed tube. The product (65) can be purified by silica gel chromatography eluting with standard solvents such as ethyl acetate and methylene chloride.

Explanation of general procedure 8: General procedure 8A

（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−シクロヘキシルフェニル）ピロリジン−２，５−ジイル）ビス（２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−３−ニトロフェニル）−１−（４−シクロヘキシルフェニル）ピロリジン（一般手順４Ａ）（１．２９ｇ、２．３９ｍｍｏｌ）、（Ｓ）−２−カルバモイルピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（１．５３ｇ、７．１６ｍｍｏｌ）、炭酸セシウム（２．３３ｇ、７．１６ｍｍｏｌ）、４，５−ビス（ジフェニルホスフィノ）−９，９−ジメチルキサンテン（０．３３ｇ、０．５７３ｍｍｏｌ）およびトリス（ジベンジリデンアセトン）ジパラジウム（０）（０．３２８ｇ、０．３５８ｍｍｏｌ）をジオキサン（１８ｍＬ）中で合わせ、窒素を溶液に１５分間に吹き込んだ。次に、フラスコに還流冷却管でキャップを施し、溶液を１００℃で８時間加熱した。珪藻土での濾過および濃縮後、残留物を０％から２０％酢酸エチル／ジクロロメタンで溶離を行うＣｏｍｂｉＦｌａｓｈ（登録商標）８０ｇシリカカラムで精製して、標題化合物１．７１ｇ（８０％）を得た。

(2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (4-cyclohexylphenyl) pyrrolidine-2,5-diyl) bis (2-nitro-4, 1-Phenylene)) Bis (Azaneyl) Bis (oxomethylene) Dipyrrolidine-1-carboxylate tert-butyl (2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-) Cyclohexylphenyl) pyrrolidine (general procedure 4A) (1.29 g, 2.39 mmol), (S) -2-carbamoylpyrrolidin-1-carboxylate tert-butyl (1.53 g, 7.16 mmol), cesium carbonate (2. 33 g, 7.16 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.33 g, 0.573 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.328 g, 0.358 mmol) was combined in dioxane (18 mL) and nitrogen was blown into the solution for 15 minutes. The flask was then capped with a reflux condenser and the solution heated at 100 ° C. for 8 hours. After filtration and concentration on diatomaceous earth, the residue was purified on a CombiFlash® 80 g silica column eluting with 0% to 20% ethyl acetate / dichloromethane to give 1.71 g (80%) of the title compound.

Description of General Procedure 8: General Procedure 8B, Example 1A

（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
１００ｍリットル丸底フラスコに、ジオキサン（３４．６ｍＬ）中の１−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−３−ニトロフェニル）ピロリジン−１−イル）−２，６−ジフルオロフェニル）−４−フェニルピペリジン（２．２６ｇ、３．４６ｍｍｏｌ）、（Ｓ）−２−カルバモイルピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（２．２２３ｇ、１０．３７ｍｍｏｌ）、炭酸セシウム（３．３８ｇ、１０．３７ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（０．１９０ｇ、０．２０７ｍｍｏｌ）および（９，９−ジメチル−９Ｈ−キサンテン−４，５−ジイル）ビス（ジフェニルホスフィン）（０．３００ｇ、０．５１９ｍｍｏｌ）を加えて紫色懸濁液を得た。混合物にＮ_２を２０分間吹き込み、Ｎ_２下に１００℃で３時間加熱し、冷却し、ＥｔＯＡｃびに投入した。ＥｔＯＡｃ層をＨ_２Ｏ ５０ｍＬで２回、次に飽和ＮａＣｌで洗浄した。ＥｔＯＡｃ層を３−メルカプトプロピルシリカおよびＮａ_２ＳＯ_４で同時に１時間処理し、濾過し、濃縮した。１％から３％メタノール／メチレンクロライドで溶離を行う１２０ｇシリカカートリッジでのクロマトグラフィーを用いる精製によって取得物を得て、それはＨＰＬＣによって純度９０％であった。１５％から５０％ＥｔＯＡｃ／ヘキサンで溶離を行う１２０ｇシリカカートリッジでの第２のカラムによって、標題化合物を橙赤色泡状物として得た（２．６ｇ、７２％、ＨＰＬＣによる純度９７％）。ＭＳ（ＥＳＩ＋）ｍ／ｚ１００９（Ｍ＋Ｈ）^＋。

(2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine) -2,5-diyl) bis (2-nitro-4,1-phenylene)) bis (azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylate tert-butyl 100 ml round bottom flask with dioxane (34.6 mL) 1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidine ( 2.26 g, 3.46 mmol), (S) -2-carbamoylpyrrolidine-1-carboxylate tert-butyl (2.223 g, 10.37 mmol), cesium carbonate (3.38 g, 10.37 mmol), tris (di) Bendylideneacetone) dipalladium (0) (0.190 g, 0.207 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphine) (0.300 g, 0.519 mmol) In addition, a purple suspension was obtained. N ₂ was blown into the mixture for 20 minutes, heated under N ₂ at 100 ° C. for 3 hours, cooled and charged into EtOAc. Twice EtOAc layer _H 2 O 50 mL, then washed with saturated NaCl. The EtOAc layer was simultaneously treated with 3-mercaptopropyl silica and Na ₂ SO ₄ for 1 hour, filtered and concentrated. The acquisition was obtained by purification using chromatography on a 120 g silica cartridge eluting with 1% to 3% methanol / methylene chloride, which was 90% pure by HPLC. A second column on a 120 g silica cartridge eluting with 15% to 50% EtOAc / Hexanes gave the title compound as an orange-red foam (2.6 g, 72%, purity 97% by HPLC). MS (ESI +) m / z 1009 (M + H) ⁺ .

一般手順８の説明：一般手順８Ｂ、実施例１Ｂ（モノ置換）
メチル（Ｓ）−１−（（Ｓ）−２−（４−（（２Ｒ，５Ｒ）−５−（４−クロロ−３−ニトロフェニル）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２−イル）−２−ニトロフェニルカルバモイル）ピロリジン−１−イル）−３−メチル−１−オキソブタン−２−イルカーバメート
管中において１−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−３−ニトロフェニル）ピロリジン−１−イル）−２，６−ジフルオロフェニル）−４−フェニルピペリジン（０．７４５ｇ、１．１４ｍｍｏｌ）をジオキサン（１２ｍＬ）に溶かし、メチル（Ｓ）−１−（（Ｓ）−２−カルバモイルピロリジン−１−イル）−３−メチル−１−オキソブタン−２−イルカーバメート（０．３０９ｇ、１．１４ｍｍｏｌ）、炭酸セシウム（０．４０９ｇ、１．２５ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（０．０６６ｇ、０．１１ｍｍｏｌ）およびトリス（ジベンジリデンアセトン）ジパラジウム（０）（０．０５２ｇ、０．０５７ｍｍｏｌ）で処理した。窒素をこの混合物に１５分間吹き込み、管を密閉し、１００℃で２時間加熱した。混合物を水で希釈し、ジクロロメタンで抽出し、濃縮し、０％から５％メタノール／ジクロロメタンで溶離を行うクロマトグラフィーによって精製して、暗黄色固体０．４４ｇ（４３％）を得た。

Description of General Procedure 8: General Procedure 8B, Example 1B (Mono Replacement)
Methyl (S) -1-((S) -2-(4-((2R, 5R) -5- (4-chloro-3-nitrophenyl) -1- (3,5-difluoro-4- (4) −Phenylpiperidin-1-yl) phenyl) pyrrolidine-2-yl) -2-nitrophenylcarbamoyl) pyrrolidine-1-yl) -3-methyl-1-oxobutane-2-ylcarbamate In a tube 1- (4- ( 4-4-yl) ((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidin (0.745 g, 1.14 mmol) Methyl (S) -1-((S) -2-carbamoylpyrrolidin-1-yl) -3-methyl-1-oxobutane-2-ylcarbamate (0.309 g, 1.14 mmol) was dissolved in dioxane (12 mL). ), Cesium carbonate (0.409 g, 1.25 mmol), Xantphos (0.066 g, 0.11 mmol) and tris (dibenzilidenacetone) dipalladium (0) (0.052 g, 0.057 mmol). Nitrogen was blown into the mixture for 15 minutes, the tubes were sealed and heated at 100 ° C. for 2 hours. The mixture was diluted with water, extracted with dichloromethane, concentrated and purified by chromatography eluting with 0% to 5% methanol / dichloromethane to give 0.44 g (43%) of a dark yellow solid.

Description of General Procedure 8: General Procedure 8B, Example 2

２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（５−フルオロ−２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
丸底フラスコに、１−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−２−フルオロ−５−ニトロフェニル）ピロリジン−１−イル）−２，６−ジフルオロフェニル）ピペリジン（４．１ｇ、６．６８ｍｍｏｌ）、（Ｓ）２−カルバモイルピロリジン−１−カルボン酸−ｔｅｒｔ−ブチル（４．３０ｇ、２０．０５ｍｍｏｌ）、炭酸セシウム（６．１ｇ、１８．７２ｍｍｏｌ）およびＸａｎｔＰｈｏｓ（０．６９６ｇ、１．２０３ｍｍｏｌ）と次にジオキサン（３０ｍＬ）を入れ、溶液をＮ_２ガスで３０分間脱気した。溶液を高撹拌して固体の混合を維持し、Ｎ_２ガスの流量を高く維持して、混合物の完全な脱気が確保されるようにした。トリス（ジベンジリデンアセトン）ジパラジウム（０．３６７ｇ、０．４０１ｍｍｏｌ）を加え、溶液をＮ_２ガス下に１００℃で２時間加熱した。溶液を冷却し、ＥｔＯＡｃで希釈し、珪藻土で濾過し、Ｈ_２Ｏおよびブラインで洗浄し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、３−メルカプトプロピル官能化シリカゲルで３０分間処理し、濾過し、濃縮して粗生成物を得た。３０分間かけての０％から４０％ＥｔＯＡｃ／ヘキサンで溶離を行うＩＳＣＯ１２０ｇシリカゲルカートリッジで精製を行って、標題化合物を得た（４．５２ｇ、４．６６ｍｍｏｌ、６９．８％）。

2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5-) Fluor-2-nitro-4,1-phenylene)) bis (azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylic acid tert-butyl Round bottom flask in 1-(4-((2R, 5R) -2, 5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine (4.1 g, 6.68 mmol), (S) 2-carbamoylpyrrolidine- Add 1-carboxylic acid-tert-butyl (4.30 g, 20.05 mmol), cesium carbonate (6.1 g, 18.72 mmol) and XantPhos (0.696 g, 1.203 mmol) and then dioxane (30 mL). the solution was degassed for 30 minutes with _{N 2} gas. The solution was agitated to maintain a solid mixture and a high N ₂ gas flow rate was maintained to ensure complete degassing of the mixture. Tris (dibenzylideneacetone) dipalladium (0.367 g, 0.401 mmol) was added and the solution was heated at 100 ° C. under a _{N 2} gas. The solution was cooled, diluted with EtOAc, filtered through diatomaceous earth, washed with _{H 2} O and brine, dried _(Na 2 _SO 4), filtered, and treated for 30 minutes with 3-mercaptopropyl functionalized silica gel, filtered And concentrated to obtain a crude product. Purification on an ISCO 120 g silica gel cartridge eluting with 0% to 40% EtOAc / Hexanes over 30 minutes gave the title compound (4.52 g, 4.66 mmol, 69.8%).

General procedure 8.1. Buchwald with dipeptides

ジメチル（２Ｒ，２′Ｒ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３−フルオロ−４−モルホリノフェニル）ピロリジン−２，５−ジイル）ビス（２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート
マイクロ波管中、４−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−３−ニトロフェニル）ピロリジン−１−イル）−２−フルオロフェニル）モルホリン（１．３９ｇ、２．４８ｍｍｏｌ）、中間体３Ｂ（２．０２ｇ、７．４３ｍｍｏｌ）、ＸａｎｔＰｈｏｓ（１２９ｍｇ、０．２２ｍｍｏｌ）および炭酸セシウム（２．４２ｇ、７．４３ｍｍｏｌ）のジオキサン（１４ｍＬ）中懸濁液を３０分間の窒素吹き込みによって脱気した。混合物をトリス（ジベンジリデンアセトン）ジパラジウム（０）（６８ｍｇ、０．０７４ｍｍｏｌ）で処理し、次にさらに５分間脱気した。マイクロ波管を密閉し、混合物を昇温して１００℃として２時間経過させた。混合物を冷却し、酢酸エチルで希釈し、水（３回）および飽和塩化ナトリウム溶液で抽出した。溶液を脱水し（Ｎａ_２ＳＯ_４）、３−（メルカプトプロピル）シリカゲルとともに終夜撹拌した。濾過および減圧下での濃縮によって固体を得て、それを０％から１０％メタノール／ジクロロメタンで溶離を行う３４０ｇシリカゲルカートリッジでクロマトグラフィー精製した。これらの手順によって、標題化合物を橙赤色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０−０．９０（ｍ、１２Ｈ）１．７４（ｂｒｓ、２Ｈ）１．８２−２．０３（ｍ、１０Ｈ）２．０８−２．２０（ｍ、２Ｈ）２．７１−２．８１（ｍ、４Ｈ）３．５２（ｓ、６Ｈ）３．６２（ｍ、４Ｈ）３．７６（ｓ、２Ｈ）４．０２（ｍ、２Ｈ）４．５０（ｄ、Ｊ＝４．４Ｈｚ、２Ｈ）５．３９（ｓ、２Ｈ）６．０４−６．１９（ｍ、２Ｈ）６．７４−６．８１（ｍ、１Ｈ）７．３２（ｄ、Ｊ＝８．４Ｈｚ、２Ｈ）７．４７−７．６０（ｍ、４Ｈ）７．８０（ｄ、Ｊ＝１．５Ｈｚ、２Ｈ）１０．４１（ｓ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０３１（Ｍ＋Ｈ）^＋。

Dimethyl (2R, 2'R) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (3-fluoro-4-) Morpholine phenyl) pyrrolidine-2,5-diyl) bis (2-nitro-4,1-phenylene)) bis (azaneyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl- 4-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) in a 1-oxobutane-2,1-diyl) dicarbamate microwave tube -2-Fluorophenyl) Morpholine (1.39 g, 2.48 mmol), Intermediate 3B (2.02 g, 7.43 mmol), XantPhos (129 mg, 0.22 mmol) and Cesium carbonate (2.42 g, 7.43 mmol) The suspension in dioxane (14 mL) was degassed by blowing nitrogen for 30 minutes. The mixture was treated with tris (dibenzylideneacetone) dipalladium (0) (68 mg, 0.074 mmol) and then degassed for an additional 5 minutes. The microwave tube was sealed and the mixture was heated to 100 ° C. for 2 hours. The mixture was cooled, diluted with ethyl acetate and extracted with water (3 times) and saturated sodium chloride solution. The solution was dehydrated (Na ₂ SO ₄ ) and stirred with 3- (mercaptopropyl) silica gel overnight. A solid was obtained by filtration and concentration under reduced pressure and chromatographically purified on a 340 g silica gel cartridge eluting with 0% to 10% methanol / dichloromethane. These procedures gave the title compound as an orange-red solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80-0.90 (m, 12H) 1.74 (brs, 2H) 1.82-2.03 (m, 10H) 2.08-2.20 (M, 2H) 2.71-2.81 (m, 4H) 3.52 (s, 6H) 3.62 (m, 4H) 3.76 (s, 2H) 4.02 (m, 2H) 4 .50 (d, J = 4.4Hz, 2H) 5.39 (s, 2H) 6.04-6.19 (m, 2H) 6.74-6.81 (m, 1H) 7.32 (d) , J = 8.4Hz, 2H) 7.47-7.60 (m, 4H) 7.80 (d, J = 1.5Hz, 2H) 10.41 (s, 2H); MS (ESI) m / z1031 (M + H) ⁺ .

General procedure 9. Nitro reduction

Hydrogen gas (1-4 eq) in a solvent such as tetrahydrofuran, ethanol or a mixture thereof, with a catalyst such as PtO ₂ (about 0.2 to 0.3 eq) or Raney nickel (eg, 50% hydrous; 1 eq). ) Can convert compound (65) (1 equivalent) to compound (66). The reaction was post-treated by filtration through diatomaceous earth or silica gel and concentrated in filtrate to give compound (66). By reaction with iron powder (about 6 eq) and ammonium chloride (about 3 eq) in a solvent of THF: ethanol: water (1: 1: 0.2) while heating to about 60-100 ° C. (65). ) (1 equivalent) can also be reduced.

Description of General Procedure 9: General Procedure 9A, Example 1

（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
２５０ｍＬステンレス製圧力瓶中で（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（２．２８７ｇ、２．３５０ｍｍｏｌ）のＴＨＦ（６０ｍＬ）中溶液を、ＰｔＯ_２（０．４５７ｇ、２．０１４ｍｍｏｌ）に加え、約０．２１ＭＰａ（３０ｐｓｉ）水素圧下に室温で４時間撹拌した。混合物をナイロン膜で濾過し、濾液をロータリーエバポレータによって濃縮し、真空乾燥して、標題化合物を褐色固体として得た（２．０２ｇ、９４％）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．３０−１．４４（ｍ、１８Ｈ）、１．５３−１．９８（ｍ、１１Ｈ）、２．０８−２．２９（ｍ、１Ｈ）、２．４３−２．６０（ｍ、３Ｈ）、３．３５−３．５０（ｍ、４Ｈ）、４．１６−４．２９（ｍ、２Ｈ）、４．７９（ｄ、Ｊ＝３５．４６Ｈｚ、４Ｈ）、４．９７（ｓ、２Ｈ）、６．２１（ｄ、Ｊ＝８．８９Ｈｚ、２Ｈ）、６．４１（ｄｄ、Ｊ＝２０．６６、７．８６Ｈｚ、２Ｈ）、６．５３−６．６１（ｍ、２Ｈ）、６．６６（ｄ、Ｊ＝８．８９Ｈｚ、２Ｈ）、６．９３−７．０６（ｍ、２Ｈ）、７．１７（ｔ、Ｊ＝６．８９Ｈｚ、１Ｈ）、７．２１−７．３２（ｍ、４Ｈ）、９．１８（ｄ、Ｊ＝３９．２５Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９１３（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ９１１（Ｍ−Ｈ）⁻。

(2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (2-amino-4,1-phenylene)) Bis (azaneyl) Bis (oxomethylene) dipyrrolidine-1-carboxylic acid tert-butyl 250 mL In a stainless steel pressure bottle (2S, 2'S) -2,2 ′-(4,4′-((2R, 5R) -1- (4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-nitro-4,1-) A solution of tert-butyl (2.287 g, 2.350 mmol) of bis (azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylate in THF (60 mL) was added to PtO ₂ (0.457 g, 2.014 mmol). In addition, the mixture was stirred at room temperature for 4 hours under a hydrogen pressure of about 0.21 MPa (30 psi). The mixture was filtered through a nylon membrane, the filtrate was concentrated on a rotary evaporator and dried in vacuo to give the title compound as a brown solid (2.02 g, 94%). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.30-1.44 (m, 18H), 1.53-1.98 (m, 11H), 2.08-2.29 (m, 1H), 2.43-2.60 (m, 3H), 3.35-3.50 (m, 4H), 4.16-4.29 (m, 2H), 4.79 (d, J = 35.46Hz) 4,97 (s, 2H), 6.21 (d, J = 8.89Hz, 2H), 6.41 (dd, J = 20.66, 7.86Hz, 2H), 6.53 -6.61 (m, 2H), 6.66 (d, J = 8.89Hz, 2H), 6.93-7.06 (m, 2H), 7.17 (t, J = 6.89Hz, 1H), 7.21-7.32 (m, 4H), 9.18 (d, J = 39.25Hz, 2H); MS (ESI +) m / z 913 (M + H) ⁺ ; MS (ESI-) m / z911 (MH) ^- .

Description of General Procedure 9: General Procedure 9A, Example 2
2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- Amino-5-fluoro-4,1-phenylene)) Bis (azaneyl) Bis (oxomethylene) dipyrrolidine-1-carboxylate tert-butyl 250 mL In a stainless steel pressure bottle, 2,2'-(4,4'-(4,4'-( (2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-nitro-4,1-phenylene) ) Bis (azaneil) Bis (oxomethylene) dipyrrolidine-1-carboxylate tert-butyl (4.5 g, 4.64 mmol) and THF (100 mL) are added to PtO ₂ (0.900 g, 3.96 mmol) to create a hydrogen atmosphere. It was stirred at room temperature for 22 hours under (about 0.21 MPa (30 psi)). The mixture was filtered through a nylon membrane and concentrated to give a yellow-orange-red foam.

Explanation of general procedure 9: General procedure 9B

（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
２５０ｍＬ圧力瓶中、ＴＨＦ（４０ｍＬ）中で（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（一般手順８Ｂ）（２．６ｇ、２．５８ｍｍｏｌ）およびラネーニッケル２８００（４５重量％含水品、２．６ｇ、４４ｍｍｏｌ）を合わせた。容器を密閉し、約０．２１ＭＰａ（３０ｐｓｉ）Ｈ_２下に５時間撹拌した。溶液をナイロン膜によって濾過し、濾液を濃縮して標題化合物を黄褐色泡状物として得て（２．４４ｇ、定量的収率）、それを精製せずに用いた。ＭＳ（ＥＳＩ＋）ｍ／ｚ９４９（Ｍ＋Ｈ）^＋。

(2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine) -2,5-diyl) bis (2-amino-4,1-phenylene)) bis (azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylate tert-butyl 250 mL in a pressure bottle, in THF (40 mL) ( 2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine- 2,5-diyl) bis (2-nitro-4,1-phenylene)) bis (azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylate tert-butyl (general procedure 8B) (2.6 g, 2.58 mmol) ) And lane nickel 2800 (45 wt% hydrous product, 2.6 g, 44 mmol) were combined. The container was sealed and stirred under about 0.21 MPa (30 psi) H ₂ for 5 hours. The solution was filtered through a nylon membrane and the filtrate was concentrated to give the title compound as a tan foam (2.44 g, quantitative yield), which was used unpurified. MS (ESI +) m / z 949 (M + H) ⁺ .

Explanation of general procedure 9: General procedure 9C

ジメチル（［（２Ｒ，５Ｒ）−１−（４，５，６，７−テトラヒドロ−１，３−ベンゾチアゾール−２−イル）ピロリジン−２，５−ジイル］ビス｛（２−アミノベンゼン−４，１−ジイル）カルバモイル（２Ｓ）ピロリジン−２，１−ジイル［（２Ｓ）−３−メチル−１−オキソブタン−１，２−ジイル］｝）ビスカーバメート（ＡＣＤ Ｎａｍｅ ｖ１２））
ジメチル（［（２Ｒ，５Ｒ）−１−（４，５，６，７−テトラヒドロ−１，３−ベンゾチアゾール−２−イル）ピロリジン−２，５−ジイル］ビス｛（２−ニトロベンゼン−４，１−ジイル）カルバモイル（２Ｓ）ピロリジン−２，１−ジイル［（２Ｓ）−３−メチル−１−オキソブタン−１，２−ジイル］｝）ビスカーバメート（ＡＣＤ Ｎａｍｅ ｖ１２））（０．５９ｇ、０．５９６ｍｍｏｌ）をテトラヒドロフラン（１５ｍＬ）に溶かし、ラネーニッケルスラリー／水（０．２５ｍＬ）で処理した。フラスコを排気し、水素風船に対して開放し、環境温度で１時間撹拌した。溶液をシリカ層によって濾過し、濃縮乾固して、標題化合物を得た。

Dimethyl ([(2R, 5R) -1- (4,5,6,7-tetrahydro-1,3-benzothiazole-2-yl) pyrrolidine-2,5-diyl] bis {(2-aminobenzene-4) , 1-diyl) carbamoyl (2S) pyrrolidine-2,1-diyl [(2S) -3-methyl-1-oxobutane-1,2-diyl]}) biscarbamate (ACD Name v12))
Dimethyl ([(2R, 5R) -1- (4,5,6,7-tetrahydro-1,3-benzothiazole-2-yl) pyrrolidine-2,5-diyl] bis {(2-nitrobenzene-4,, 1-diyl) Carbamoyl (2S) pyrrolidine-2,1-diyl [(2S) -3-methyl-1-oxobutane-1,2-diyl]}) biscarbamate (ACD Name v12)) (0.59 g, 0 .596 mmol) was dissolved in tetrahydrofuran (15 mL) and treated with Raney nickel slurry / water (0.25 mL). The flask was evacuated, opened against a hydrogen balloon and stirred at ambient temperature for 1 hour. The solution was filtered through a silica layer and concentrated to dryness to give the title compound.

Explanation of general procedure 9: General procedure 9D

ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−クロロ−３−フルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート
圧力瓶中にて、ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−クロロ−３−フルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート（１．０ｇ、１．０２ｍｍｏｌ）およびテトラヒドロフラン（２５ｍＬ）を酸化白金（０．２０ｇ、０．８８ｍｍｏｌ）に加え、環境温度で約０．２１ＭＰａ（３０ｐｓｉ）で水素下に１．５時間撹拌した。溶液をナイロン膜によって濾過し、濃縮乾固して、１００％収率の褐色残留物を得て、それを精製せずに用いた。

Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (4-chloro-3-) Fluorophenyl) pyrrolidine-2,5-diyl) bis (2-amino-4,1-phenylene)) bis (azanesil) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl- In a 1-oxobutane-2,1-diyl) dicarbamate pressure bottle, dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4) ′-((2R, 5R) -1- (4-chloro-3-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-nitro-4,1-phenylene)) bis (azanesil) bis (oxomethyl) ) Bis (pyrrolidine-2,1-diyl)) Bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate (1.0 g, 1.02 mmol) and tetrahydrofuran (25 mL) platinum oxide (0. In addition to 20 g (0.88 mmol), the mixture was stirred under hydrogen at an ambient temperature of about 0.21 MPa (30 psi) for 1.5 hours. The solution was filtered through a nylon membrane and concentrated to dryness to give a 100% yield brown residue, which was used unpurified.

Explanation of general procedure 9: General procedure 9E

ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニル−５，６−ジヒドロピリジン−１（２Ｈ）−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート
ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニル−５，６−ジヒドロピリジン−１（２Ｈ）−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−ニトロ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート（１５０ｍｇ、０．１３４ｍｍｏｌ）を、窒素下にＴＨＦ（１ｍＬ）および純粋ＥｔＯＨ（１ｍＬ）の混合物に溶かした。塩化アンモニウム（１０．７３ｍｇ、０．２０１ｍｍｏｌ）の水溶液（水０．３３３ｍＬ）、次に鉄粉（３７．４ｍｇ、０．６６９ｍｍｏｌ）を加え、混合物を還流冷却管下に油浴にて９０℃で加熱した。１時間後、反応混合物を冷却して室温とし、セライト５４５の床で減圧濾過し、ＥｔＯＡｃで十分に洗浄した。濾液をロータリーエバポレータによって濃縮して、有機溶媒を除去した。残留物をＥｔＯＡｃ（５０ｍＬ）に溶かし、水（２５ｍＬで２回）およびブライン（２５ｍＬ）で洗浄し、無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮した。残留物を、３％から４％メタノール／ＣＨ_２Ｃｌ_２の段階的勾配で溶離を行うＳｉＯ_２フラッシュクロマトグラフィー（Ａｌｌｔｅｃｈ Ｅｘｔｒａｃｔ−Ｃｌｅａｎカラム、１０ｇ床）によって精製して、生成物を黄色固体として得た（７７ｍｇ、０．０７３ｍｍｏｌ、５４％）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９２（ｄｄ、Ｊ＝１３．０７、６．５６Ｈｚ、１２Ｈ）、１．５８−１．７５（ｍ、２Ｈ）、１．８３−２．０９（ｍ、８Ｈ）、２．１３−２．２８（ｍ、１Ｈ）、３．１７（ｓ、２Ｈ）、３．３８−３．６８（ｍ、８Ｈ）、３．５５（ｓ、６Ｈ）、３．８４（ｓ、２Ｈ）、４．０５（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）、４．３７−４．４７（ｍ、２Ｈ）、４．９３（ｓ、４Ｈ）、５．０１（ｄ、Ｊ＝５．１０Ｈｚ、２Ｈ）、５．８５−６．００（ｍ、２Ｈ）、６．１４（ｓ、１Ｈ）、６．４４（ｄ、Ｊ＝８．０２Ｈｚ、２Ｈ）、６．５５−６．６６（ｍ、２Ｈ）、７．０２（ｄ、Ｊ＝７．８１Ｈｚ、２Ｈ）、７．２１−７．４９（ｍ、８Ｈ）、９．２８（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６１（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０５９（Ｍ−Ｈ）⁻。

Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-) 4- (4-Phenyl-5,6-dihydropyridine-1 (2H) -yl) phenyl) pyrrolidine-2,5-diyl) bis (2-amino-4,1-phenylene)) bis (azanesil) bis (oxo Methylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamatedimethyl (2S, 2'S) -1,1'-((2S, 2) 'S) -2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenyl-5,6-dihydropyridine-1 (2H) -yl) ) Phenyl) pyrrolidine-2,5-diyl) bis (2-nitro-4,1-phenylene)) bis (azanesil) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl- 1-Oxobutane-2,1-diyl) dicarbamate (150 mg, 0.134 mmol) was dissolved in a mixture of THF (1 mL) and pure EtOH (1 mL) under nitrogen. An aqueous solution of ammonium chloride (10.73 mg, 0.201 mmol) (0.333 mL of water), then iron powder (37.4 mg, 0.669 mmol) was added, and the mixture was placed in an oil bath under a reflux condenser at 90 ° C. It was heated. After 1 hour, the reaction mixture was cooled to room temperature, filtered under reduced pressure on a bed of Celite 545 and washed thoroughly with EtOAc. The filtrate was concentrated on a rotary evaporator to remove the organic solvent. The residue was dissolved in EtOAc (50 mL), washed with water (twice at 25 mL) and brine (25 mL), dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated by rotary evaporator. The residue is purified by SiO ₂ flash chromatography (Alltech Extract-Clean column, 10 g bed) eluting with a stepwise gradient of 3% to 4% methanol / CH ₂ Cl ₂ to give the product as a yellow solid. (77 mg, 0.073 mmol, 54%). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.92 (dd, J = 13.07, 6.56 Hz, 12H), 1.58-1.75 (m, 2H), 1.83-2.09 (M, 8H), 2.13-2.28 (m, 1H), 3.17 (s, 2H), 3.38-3.68 (m, 8H), 3.55 (s, 6H), 3.84 (s, 2H), 4.05 (t, J = 8.35Hz, 2H), 4.37-4.47 (m, 2H), 4.93 (s, 4H), 5.01 ( d, J = 5.10Hz, 2H) 5.85-6.00 (m, 2H), 6.14 (s, 1H), 6.44 (d, J = 8.02Hz, 2H), 6. 55-6.66 (m, 2H), 7.02 (d, J = 7.81Hz, 2H), 7.21-7.49 (m, 8H), 9.28 (s, 2H); MS ( ESI +) m / z 1061 (M + H) ⁺ ; MS (ESI-) m / z 1059 (MH) ⁻ .

General procedure 10. Benzimidazole formation

Compound (66) can be converted to compound (57) by heating to 50-80 ° C with acetic acid in acetic acid or in toluene or dioxane. The solution is concentrated, neutralized with aqueous sodium bicarbonate solution, extracted with an organic solvent (eg, dichloromethane), the organic solvent mixture (eg, sulfonyl ₄ , Na ₂ SO ₄ ) is dehydrated, filtered and concentrated under reduced pressure. By doing so, the reaction can be post-processed. The reaction can also be carried out in toluene as a solvent with the addition of acetic acid (about 3 to 5 eq) and heating to 50-80 ° C. The post-treatment can consist of simple solvent distillation and addition of toluene and removal of residual acetic acid by distillation. Compound (57) can be purified by chromatography on silica gel eluting with ethyl acetate / dichloromethane or methanol / dichloromethane. The cyclization depicted above is shown with the binding of the t-butoxycarbonyl (Boc) group, but the reaction can also be carried out with the binding of the group -T- _RD, where T and _RD are described herein. As defined in.

Description of General Procedure 10: General Procedure 10A; Example 1

（２Ｓ，２′Ｓ）−２，２′−（５，５′−（１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
トランスジアステレオマーの混合物として、（２Ｓ，２′Ｓ）−２，２′−（５，５′−（１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−５，１−フェニレン）ビス（アザネジル）ビス（オキソメチレン））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（０．３５５ｇ）を無希釈で酢酸（３ｍＬ）に溶かし、７２℃で加熱して２時間経過させた。溶液を濃縮し、水に投入し、重炭酸ナトリウムでｐＨを約７から８に調節した。生成物をジクロロメタンで抽出し、濃縮し、０％から５％メタノール／ジクロロメタンで溶離を行う４０ｇカラムを用いるシリカゲルでのクロマトグラフィーによって精製して、標題化合物０．１８５ｇ（５５％）を明黄色固体として得た。

(2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (1H-benzo [d] imidazole-5, 5) 2-Diyl)) Dipyrrolidine-1-carboxylic acid tert-butyl transdiastereomeric as a mixture (2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butyl) Phenyl) pyrrolidine-2,5-diyl) bis (2-amino-5,1-phenylene) bis (azaneyl) bis (oxomethylene)) tert-butyl dipyrrolidine-1-carboxylate (0.355 g) undiluted It was dissolved in acetic acid (3 mL) and heated at 72 ° C. for 2 hours. The solution was concentrated, poured into water and the pH was adjusted to about 7-8 with sodium bicarbonate. The product was extracted with dichloromethane, concentrated and purified by chromatography on silica gel using a 40 g column eluting with 0% to 5% methanol / dichloromethane to give 0.185 g (55%) of the title compound as a bright yellow solid. Obtained as.

Description of General Procedure 10: General Procedure 10A; Example 2

（２Ｓ，２′Ｓ）−２，２′−（６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−６，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（２．４ｇ、２．５７ｍｍｏｌ）および酢酸（１．５４ｇ、２５．７ｍｍｏｌ）のトルエン（５０ｍＬ）中溶液を、７０℃で２時間加熱し、冷却し、濃縮した。残留物をトルエン１５ｍＬと３回共沸させ、真空乾燥して黄色泡状物（２．３４ｇ、定量的収率）を得て、それを精製せずに用いた。ＭＳ（ＥＳＩ＋）ｍ／ｚ９１３（Ｍ＋Ｈ）^＋。

(2S, 2'S) -2,2'-(6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine) -2,5-diyl) bis (1H-benzo [d] imidazole-6,2-diyl)) dipyrrolidine-1-carboxylate tert-butyl (2S, 2'S) -2,2'-(4,4) ′-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-amino-4,1- A solution of tert-butyl (2.4 g, 2.57 mmol) of bis (azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylate and acetic acid (1.54 g, 25.7 mmol) in toluene (50 mL). It was heated at 70 ° C. for 2 hours, cooled and concentrated. The residue was azeotroped with 15 mL of toluene three times and dried in vacuo to give a yellow foam (2.34 g, quantitative yield), which was used unpurified. MS (ESI +) m / z 913 (M + H) ⁺ .

Description of General Procedure 10: General Procedure 10A; Example 3
(2S, 2'S) -2,2'-(6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2, 5-diyl) bis (5-fluoro-1H-benzo [d] imidazole-6,2-diyl)) dipyrrolidine-1-carboxylic acid tert-butyl crude 2,2'-(4,4'-((2R, 2R,) 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-amino-5-fluoro-4,1-phenylene)) bis ( To tert-butyl azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylate (general procedure 9A from Example 2), add toluene (45 mL) and then acetic acid (2.66 mL, 46.4 mmol) to make 50 solutions. The mixture was stirred at ° C. for 16 hours. The cooled solution was concentrated, azeotroped twice with toluene and the crude residue was purified with an ISCO 40 g silica gel cartridge eluting with 0% to 5% CH ₃ OH / CH ₂ Cl ₂ to give the title compound ( 2.85 g).

Description of General Procedure 10: General Procedure 10B, Example 1

メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−クロロ−３−フルオロフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート（ＡＣＤ Ｎａｍｅ ｖ１２）
ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−クロロ−３−フルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート（一般手順９Ｄ）（０．９８ｇ、１．０１ｍｍｏｌ）をトルエン（１２ｍＬ）に溶かし、氷酢酸（１．１６ｍＬ、２０．２ｍｍｏｌ）で処理し、６５℃で１．５時間加熱した。混合物を濃縮し、ジクロロメタンに溶かし、重炭酸ナトリウム溶液で洗浄した。有機反応混合物を濃縮し、０％から６％メタノール／ジクロロメタンで溶離を行うクロマトグラフィーによって精製して、標題化合物０．１７ｇ（１９％）を暗黄色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７７−０．９０（ｍ、１２Ｈ）１．６６−１．７８（ｍ、２Ｈ）１．８８−１．９５（ｍ、２Ｈ）１．９６−２．０６（ｍ、４Ｈ）２．１５−２．２４（ｍ、４Ｈ）２．５４−２．６０（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．７９−３．８６（ｍ、４Ｈ）４．０６（ｔ、Ｊ＝８．４６Ｈｚ、２Ｈ）５．１０−５．１８（ｍ、２Ｈ）５．３７−５．４５（ｍ、２Ｈ）６．１６（ｄｄ、Ｊ＝９．４９、２．０１Ｈｚ、１Ｈ）６．２２（ｄｄ、Ｊ＝１３．５５、２．０６Ｈｚ、１Ｈ）７．００−７．１１（ｍ、３Ｈ）７．２２（ｓ、１Ｈ）７．２８（ｄ、Ｊ＝８．５７Ｈｚ、２Ｈ）７．３２（ｓ、１Ｈ）７．４０（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．４７（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）１２．０７（ｄ、Ｊ＝２．９３Ｈｚ、２Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ８８４（Ｍ＋Ｈ）^＋。

Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-chloro-3-fluorophenyl) -5- {2-[(2S) -1-] {(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazole-2 -Il} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate (ACD Name v12)
Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (4-chloro-3-) Fluorophenyl) pyrrolidine-2,5-diyl) bis (2-amino-4,1-phenylene)) bis (azanesil) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl- 1-oxobutane-2,1-diyl) dicarbamate (general procedure 9D) (0.98 g, 1.01 mmol) was dissolved in toluene (12 mL) and treated with glacial acetic acid (1.16 mL, 20.2 mmol), 65. It was heated at ° C. for 1.5 hours. The mixture was concentrated, dissolved in dichloromethane and washed with sodium bicarbonate solution. The organic reaction mixture was concentrated and purified by chromatography eluting with 0% to 6% methanol / dichloromethane to give 0.17 g (19%) of the title compound as a dark yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.77-0.90 (m, 12H) 1.66-1.78 (m, 2H) 1.88-1.95 (m, 2H) 1.96 -2.06 (m, 4H) 2.15-2.24 (m, 4H) 2.54-2.60 (m, 2H) 3.54 (s, 6H) 3.79-3.86 (m) , 4H) 4.06 (t, J = 8.46Hz, 2H) 5.10-5.18 (m, 2H) 5.37-5.45 (m, 2H) 6.16 (dd, J = 9) .49, 2.01Hz, 1H) 6.22 (dd, J = 13.55, 2.06Hz, 1H) 7.00-7.11 (m, 3H) 7.22 (s, 1H) 7.28 (D, J = 8.57Hz, 2H) 7.32 (s, 1H) 7.40 (d, J = 8.24Hz, 1H) 7.47 (d, J = 8.13Hz, 1H) 12.07 (D, J = 2.93Hz, 2H); MS (APCI +) m / z 884 (M + H) ⁺ .

Description of General Procedure 10: General Procedure 10B; Example 2

メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［３−フルオロ−４−（メチルスルホニル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート（ＡＣＤ Ｎａｍｅ ｖ１２）
ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（３−フルオロ−４−（メチルスルホニル）フェニル）ピロリジン−２，５−ジイル）ビス（２−アミノ−４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート（０．１９０ｇ、０．１９７ｍｍｏｌ）のトルエン（２ｍＬ）中懸濁液に酢酸（１ｍＬ、１７．４８ｍｍｏｌ）を加え、反応混合物を６０℃で終夜撹拌した。ＬＣＭＳは反応完結を示している。反応混合物を酢酸エチルで希釈し、飽和ＮａＨＣＯ_３溶液で洗浄した。有機抽出液を分離し、無水硫酸ナトリウムで脱水し、濾過し、ロータリーエバポレータで濃縮し、５％から１００％アセトニトリル／水（ＴＦＡ）を用いる逆相ＨＰＬＣによって精製した。純粋な分画を合わせ、飽和ＮａＨＣＯ_３溶液で中和し、濃縮した。残留物をＣＨ_２Ｃｌ_２で抽出した。有機抽出液を分離し、無水硫酸ナトリウムで脱水し、濾過し、濃縮して、標題化合物（３０ｍｇ）を白色固体として得た。

Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [3-fluoro-4- (methylsulfonyl) phenyl] -5- {2-[(2S)) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate (ACD Name v12)
Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1- (3-fluoro-4-) (Methylsulfonyl) Phenyl) Pyrrolidine-2,5-diyl) Bis (2-amino-4,1-phenylene)) Bis (Azanesil) Bis (oxomethylene) Bis (Pyrrolidine-2,1-Diyl)) Bis (3 Add acetic acid (1 mL, 17.48 mmol) to a suspension of −methyl-1-oxobutane-2,1-diyl) dicarbamate (0.190 g, 0.197 mmol) in toluene (2 mL) and bring the reaction mixture to 60 ° C. Stirred overnight. LCMS indicates that the reaction is complete. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ solution. The organic extract was separated, dehydrated over anhydrous sodium sulfate, filtered, concentrated on a rotary evaporator and purified by reverse phase HPLC using 5% to 100% acetonitrile / water (TFA). The pure fractions were combined, neutralized with saturated NaHCO ₃ solution and concentrated. The residue was extracted with CH ₂ Cl ₂ . The organic extract was separated, dehydrated with anhydrous sodium sulfate, filtered and concentrated to give the title compound (30 mg) as a white solid.

General procedure 11. Procedure for eliminating the t-butoxycarbonyl protecting group

Elimination of the t-butoxycarbonyl (Boc) protecting group as described above can be carried out using standard conditions such as treatment with an acid such as TFA, HCl or formic acid. For example, the chloride protecting group can be removed by reacting with TFA / CH ₂ Cl ₂ or HCl in dioxane at room temperature. The compound can be used or isolated as a salt or free base.

After removing the Boc-protecting group, and cispyrrolidine:

およびトランスピロリジン：

And transpyrrolidine:

の混合物として化合物が処理された場合、シスおよびトランスジアステレオマーについて、標準的なクロマトグラフィー法（例えば、順相シリカゲルまたは逆相）を用いる分離を行うことができる。例えば、一般型１１−１および１１−２の化合をこのようにして分離することができる。

When the compound is treated as a mixture of, the cis and transdiastereomers can be separated using standard chromatographic methods (eg, normal phase silica gel or reverse phase). For example, the combinations of general types 11-1 and 11-2 can be separated in this way.

Explanation of general procedure 11. General procedure 11A (HCl-dioxane), Example 1

（Ｓ）−５，５′−（１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）
（２Ｓ，２′Ｓ）−２，２′−（５，５′−（１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（０．２０４ｇ、０．２６４ｍｍｏｌ）を室温でＴＨＦ（２ｍＬ）に溶かし、４Ｍ ＨＣｌ／ジオキサン（２ｍＬ）で処理した。反応完了後、混合物を濃縮乾固して粗標題化合物を得た。

(S) -5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] Imidazole)
(2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (1H-benzo [d] imidazole-5, 5) 2-Diyl)) tert-butyl dipyrrolidine-1-carboxylate (0.204 g, 0.264 mmol) was dissolved in THF (2 mL) at room temperature and treated with 4M HCl / dioxane (2 mL). After completion of the reaction, the mixture was concentrated to dryness to give a crude title compound.

Explanation of general procedure 11. General procedure 11A (HCl-dioxane), Example 2
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole)
(2S, 2'S) -2,2'-(6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine) A solution of tert-butyl (2.34 g, 2.57 mmol) of -2,5-diyl) bis (1H-benzo [d] imidazol-6,2-diyl) dipyrrolidine-1-carboxylate in dioxane (25 mL). Treatment with 4M hydrogen chloride / dioxane (16.06 mL, 64.3 mmol) gave a yellowish brown suspension. The mixture was sonicated for 10 minutes to break the solid into a fine suspension, stirred for 2 hours and concentrated. The residue was azeotroped with 30 mL of toluene three times and dried to give the HCl salt of the title compound as a tan powder, which was used unpurified (assuming quantitative yield, 2.57 mmol). MS (ESI +) m / z 713 (M + H) ⁺ .

Explanation of general procedure 11. General procedure 11A (HCl-dioxane), Example 3
6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[( 2S) -Pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12)
(2S, 2'S) -2,2'-(6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2, Solution of 5-diyl) bis (5-fluoro-1H-benzo [d] imidazol-6,2-diyl)) tert-butyl dipyrrolidine-1-carboxylate (2.85 g, 3.26 mmol) in dioxane (10 mL) 4M HCl / dioxane (10.0 mL, 40.0 mmol) was added to the solution, and the solution was stirred at room temperature for 1 hour. The solution was concentrated, dissolved in a small amount of H ₂ O, placed on an ISCO 130 g C18 cartridge and eluted with 0% to 100% CH ₃ CN / (0.1% TFA / H ₂ O). The desired fractions were combined, basified with 10% NaHCO ₃ solution and extracted with EtOAc. The combined extracts were dehydrated (sulfonyl ₄ ), filtered and concentrated to give the title compound (932.5 mg, 1.386 mmol, 42.5%).

Explanation of general procedure 11. General procedure 11B (TFA-CH) ₂ Cl ₂ )

（Ｓ）−５，５′−（１−（４−フルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）
（２Ｓ，２′Ｓ）−２，２′−（５，５′−（１−（４−フルオロフェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（０．１２０ｇ、０．１６３ｍｍｏｌ）を室温でジクロロメタン（２ｍＬ）に溶かし、ＴＦＡ（１ｍＬ）で処理した。混合物を濃縮乾固し、２５％イソプロパノール／ジクロロメタンに溶かし、重炭酸ナトリウム溶液で洗浄した。得られた固体を濾去し、乾燥させた。有機濾液を濃縮し、乾燥して、追加の標題化合物を得た。オフホワイト固体のバッチを合わせて標題化合物を得た（０．０６２ｇ、７２％収率）。

(S) -5,5'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole)
(2S, 2'S) -2,2'-(5,5'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (1H-benzo [d] imidazol-5,2- Diyl)) tert-butyl dipyrrolidine-1-carboxylate (0.120 g, 0.163 mmol) was dissolved in dichloromethane (2 mL) at room temperature and treated with TFA (1 mL). The mixture was concentrated to dryness, dissolved in 25% isopropanol / dichloromethane and washed with sodium bicarbonate solution. The obtained solid was filtered off and dried. The organic filtrate was concentrated and dried to give additional title compound. Batches of off-white solids were combined to give the title compound (0.062 g, 72% yield).

The following compounds as free bases or salts can be prepared using General Procedure 8, General Procedure 9A (PtO ₂ ), General Procedure 10 / 10A and General Procedure 11 / 11A.
(S) -6,6'-((2R, 5R) -1- (4- (pyridin-2-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-2) -Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine) -2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (2-methoxyethoxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-2-) Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-chlorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [D] Imidazole);
(S) -6,6'-((2R, 5R) -1- (3-methyl-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5S) -1- (4-cyclopropyl-3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5S) -1- (4-cyclopropyl-2-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-2-) Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3-fluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (trifluoromethyl) piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4,4-dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (6-azaspiro [2.5] octane-6-yl) phenyl) pyrrolidine-2,5- Diyl) bis (2-((S) -pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (isoindoline-2-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-( (S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
2- (4-((2R, 5R) -2,5-bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazol-6-yl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-azabicyclo [2.2.2] octane;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-isopropylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (3,3-dimethylazetidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) Bis (2-((S) -pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)-)- Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[( 2S) -Pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12);
(S) -6,6'-((2S, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-) 2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis ( 5-Fluoro-2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis ( 2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (2,3-dihydrospiro [indene-1,4'-piperidine] -1'-yl) -3,5-difluoro) Phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4-methoxyphenyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-fluoro-4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-fluoro-4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-( (S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (fluorodiphenylmethyl) piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5) -Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4-fluorophenyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (3- (trimethylsilyl) phenyl) piperidine-1-yl) phenyl) pyrrolidine-2, 5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (3,4-difluorophenyl) piperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (3,5-difluorophenyl) piperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) phenyl) pyrrolidine- 2,5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
6-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) -5-(2-((S) -pyrrolidin-2-yl) -1H-benzo [D] Imidazole-6-yl) pyrrolidine-2-yl) -5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole;
(S) -6,6'-((2R, 5R) -1- (4- (4-benzylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (5) -Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-benzylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
4- (4-((2R, 5R) -2,5-bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazol-6-yl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-phenylmorpholine;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (2-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(2S, 6R) -4- (4-((2R, 5R) -2,5-bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole- 6-yl) Pyrrolidine-1-yl) -2,6-difluorophenyl) -2,6-dimethylmorpholine;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (3-azaspiro [5.5] undecane-3-yl) phenyl) pyrrolidine-2,5- Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-cyclohexylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (5) -Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -4- (4-((2R, 5R) -2,5-bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole-6- Il) Pyrrolidine-1-yl) -2,6-difluorophenyl) -2-phenylmorpholine;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperazine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, R) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- ((2S, 4R) -4-fluoropyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (2,6-difluorophenyl) piperazine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (2,4-difluorophenyl) piperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4-fluorophenyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5S) -1-(4- (4- (2,6-difluorophenyl) piperazine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (5-methylthiophen-2-yl) piperidine-1-yl) phenyl) pyrrolidine- 2,5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole); and (S) -6,6'-((2R, 5R) ) -1- (3,5-difluoro-4- (4-fluoro-4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S)-)- Pyrrolidine-2-yl) -1H-benzo [d] imidazole).

The following compounds as free bases or salts can be prepared using General Procedure 8, General Procedure 9B (Raney Nickel), General Procedure 10 / 10A and General Procedure 11 / 11A.
(S) -6,6'-((2R, 5R) -1- (biphenyl-4-yl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H -Benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (cyclopentyloxy) -3-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4-((3aR, 7aS) -1H-isoindole-2 (3H, 3aH, 4H, 5H, 6H) , 7H, 7aH) -yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-dichloro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (2,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4-((2R, 6S) -2,6-dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2 , 5-Diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (2,3,5-trifluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-cyclohexyl-3-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) ) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,4-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl)- 1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-ethoxyphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H- Benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (2,2-difluoroethoxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (3,5-dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
6,6'-{(2R, 5R) -1- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] pyrrolidine-2,5-diyl} bis {2-[(2S) -pyrrolidin-2-yl) ] -1H-benzimidazole} (ACD Name v12);
(S) -6,6'-((2S, 5S) -1- (4-cyclopropylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H -Benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl)- 1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- ((2S, 4S) -4-methoxypyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- ((2S, 4S) -4-fluoropyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 4S) -4-fluoropyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 4S) -4-methoxypyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -5,5-dimethylpyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 4S) -4-fluoro) Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() 3S) -2-azabicyclo [2.2.1] heptane-3-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Indoline-2-yl) -1H-benzo [d] imidazole);
(S, R) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- ((2S, 4R) -4-methoxypyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -4-methylenepyrrolidine-2-) Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4,4-diphenylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
1-(1-(4-((2R, 5R) -2,5-bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazol-6-yl) pyrrolidine-1) -Il) -2,6-difluorophenyl) -4-phenylpiperidine-4-yl) etanone;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis ( 2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 3aS, 6aS)) -Octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (3-azaspiro [5.5] undecane-3-yl) phenyl) pyrrolidine-2,5- Diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3-fluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-( (S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (3-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (3-phenylpyrrolidin-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (pyrimidine-2-yl) piperazin-1-yl) phenyl) pyrrolidine-2,5 -Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5R) -1- (2- (4-phenylpiperidin-1-yl) pyrimidin-5-yl) pyrrolidine-2,5-diyl) bis (5-fluoro) -2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole); and (S) -6,6'-((2S, 5R) -1- (2- (piperidine-1) -Il) pyrimidin-5-yl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole).

The following compounds as free bases or salts can be produced using General Procedure 8, General Procedure 9E (Fe / NH ₄ Cl), General Procedure 10 / 10A and General Procedure 11 / 11A.
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (3-phenylpropyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (6-azaspiro [2.5] octane-6-yl) phenyl) pyrrolidine-2,5- Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (5-Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (naphthalen-2-yl) piperidine-1-yl) phenyl) pyrrolidine-2,5 -Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole); and (S) -6,6'-((2R, 5R) -1 -(4- (benzyloxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole).

Explanation of general procedure 11. General procedure 11C (mono-deprotection)

（２Ｓ，３ａＳ，６ａＳ）−２−（５−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル）−５−（２−（（２Ｓ，３ａＳ，６ａＳ）−オクタヒドロシクロペンタ［ｂ］ピロール−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−５−イル）ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−カルボン酸ｔｅｒｔ−ブチル
原料のジ−Ｂｏｃ保護アミン（１．２４ｇ、１．３６ｍｍｏｌ）を環境温度でジクロロメタン（１２ｍＬ）に溶かし、１．５時間にわたり３０分ごとに少量ずつのトリフルオロ酢酸（０．１０ｍＬ、１．３５ｍｍｏｌ）で処理した。溶液を濃縮乾固し、ジクロロメタンに再溶解させ、重炭酸ナトリウム溶液で洗浄した。濃縮後、残留物を０％から２０％メタノール／ジクロロメタンで溶離を行うクロマトグラフィーによって精製して、標題のモノ脱保護アミン４２５ｍｇ（３８％）を黄色粉末として得た。

(2S, 3aS, 6aS) -2-(5-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl))-5-(2-((2S, 2S,) 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazol-5-yl) pyrrolidine-2-yl) -1H-benzo [d] imidazol-2-yl) Hexahydrocyclopenta [b] pyrrole-1 (2H) -tert -butyl carboxylic acid raw material di-Boc protected amine (1.24 g, 1.36 mmol) was dissolved in dichloromethane (12 mL) at ambient temperature for 1.5 hours. It was treated with a small amount of trifluoroacetic acid (0.10 mL, 1.35 mmol) every 30 minutes. The solution was concentrated to dryness, redissolved in dichloromethane and washed with sodium bicarbonate solution. After concentration, the residue was purified by chromatography eluting with 0% to 20% methanol / dichloromethane to give the title monodeprotected amine 425 mg (38%) as a yellow powder.

General procedure 12. End cap added

The formation of the amide by the reaction of the amines depicted above with the acid can be carried out according to the method outlined in Diagram 1 and other above diagrams. EDAC / HOBT, PyBOP with or without amine bases such as Hunig bases, N-methylmorpholin, pyridine, 2,6-lutidine or triethylamine in solvents such as THF, DMF, dichloromethane, ethyl acetate or DMSO. , HATU, T3P or DEPBT can be used to accelerate the reaction to give the amide product. For example, amine (1 equivalent), 2- (methoxycarbonylamino) -3-methylbutanoic acid, 2- (methoxycarbonylamino) -3,3-dimethylbutanoic acid, 2-cyclohexyl-2- (methoxycarbonylamino) acetic acid , 2- (Methoxycarbonylamino) -2- (tetrahydro-2H-pyran-4-yl) acetic acid or acids (2 equivalents) such as, but not limited to, those listed below under General Procedure 19. ) Can be reacted. The final coupling product can contain varying amounts of stereoisomers with respect to the pyrrolidine ring. For fluorosubstituted benzimidazole-containing products (eg, Example 6.1, Example 6.12, Example 6.16), to perform final purification to remove the rest of another stereoisomer, The following chiral chromatography may be required in general procedure 12C.

Explanation of general procedure 12. General procedure 12A

ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（５，５′−（（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメートおよびジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（５，５′−（（２Ｓ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート
（Ｓ）−５，５′−（１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（０．１５０ｇ、０．２６１ｍｍｏｌ）およびジイソプロピルエチルアミン（０．３６５ｍＬ、２．０９ｍｍｏｌ）を室温でＤＭＳＯ（３ｍＬ）に溶かし、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（０．１０５ｇ、０．６０１ｍｍｏｌ）と次にＨＡＴＵ（０．２０４ｇ、０．５３６ｍｍｏｌ）で処理した。溶液を室温で１時間撹拌し、水で希釈した。固体生成物を濾去し、０％から８％メタノール／ジクロロメタンで溶離を行う１２ｇカラムを用いるシリカゲルでのクロマトグラフィーによって精製して、黄色固体０．１４３ｇ（６０％）をトランスジアステレオマーの混合物として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７５−０．９２（ｍ、１２Ｈ）１．０７（ｓ、９Ｈ）１．６４−１．７６（ｍ、２Ｈ）１．８５−２．０４（ｍ、６Ｈ）２．１２−２．２６（ｍ、４Ｈ）２．４３（ｄｄ、Ｊ＝７．７５、４．０７Ｈｚ、２Ｈ）３．５３（ｓ、６Ｈ）３．７６−３．８７（ｍ、４Ｈ）４．０４（ｄｄ、Ｊ＝１１．４９、６．５１Ｈｚ、２Ｈ）５．１２（ｔ、Ｊ＝７．５９Ｈｚ、２Ｈ）５．３５（ｄ、Ｊ＝３．２５Ｈｚ、２Ｈ）６．２５（ｄ、Ｊ＝８．４６Ｈｚ、２Ｈ）６．８５−６．９６（ｍ、２Ｈ）７．０７（ｔ、Ｊ＝７．９７Ｈｚ、２Ｈ）７．１９（ｓ、１Ｈ）７．２８（ｄ、Ｊ＝８．３５Ｈｚ、３Ｈ）７．３８（ｄｄ、Ｊ＝８．１９、１．９０Ｈｚ、１Ｈ）７．４６（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）１１．９７−１２．０９（ｍ、２Ｈ）。

Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(5,5'-((2R, 5R) -1- (4-tert-butylphenyl) ) Pyrrolidine-2,5-diyl) bis (1H-benzo [d] imidazol-5,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1 -Diyl) dicarbamate and dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(5,5'-((2S, 5S) -1-( 4-tert-Butylphenyl) pyrrolidine-2,5-diyl) bis (1H-benzo [d] imidazole-5,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1 -Oxobutane-2,1-diyl) dicarbamate (S) -5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-) 2-Il) -1H-benzo [d] imidazole) (0.150 g, 0.261 mmol) and diisopropylethylamine (0.365 mL, 2.09 mmol) were dissolved in DMSO (3 mL) at room temperature and (S) -2- It was treated with (methoxycarbonylamino) -3-methylbutanoic acid (0.105 g, 0.601 mmol) and then HATU (0.204 g, 0.536 mmol). The solution was stirred at room temperature for 1 hour and diluted with water. The solid product is filtered off and purified by chromatography on silica gel with a 12 g column eluting with 0% to 8% methanol / dichloromethane to give 0.143 g (60%) of the yellow solid a mixture of transdiastereomers. Got as. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.75-0.92 (m, 12H) 1.07 (s, 9H) 1.64-1.76 (m, 2H) 1.85-2.04 (M, 6H) 2.12-2.26 (m, 4H) 2.43 (dd, J = 7.75, 4.07Hz, 2H) 3.53 (s, 6H) 3.76-3.87 (M, 4H) 4.04 (dd, J = 11.49, 6.51Hz, 2H) 5.12 (t, J = 7.59Hz, 2H) 5.35 (d, J = 3.25Hz, 2H) ) 6.25 (d, J = 8.46Hz, 2H) 6.85-6.96 (m, 2H) 7.07 (t, J = 7.97Hz, 2H) 7.19 (s, 1H) 7 .28 (d, J = 8.35Hz, 3H) 7.38 (dd, J = 8.19, 1.90Hz, 1H) 7.46 (d, J = 8.13Hz, 1H) 11.97-12 .09 (m, 2H).

Explanation of general procedure 12. General procedure 12B

ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｓ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメートおよびジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート
（２Ｓ，２′Ｓ）−Ｎ，Ｎ′−（４，４′−（（２Ｓ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ジピロリジン−２−カルボキサミドおよび（２Ｓ，２′Ｓ）−Ｎ，Ｎ′−（４，４′−（（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ジピロリジン−２−カルボキサミド（２９．０ｍｇ、０．０５０ｍｍｏｌ）、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１９．２７ｍｇ、０．１１０ｍｍｏｌ）、ＥＤＡＣ（２１．０９ｍｇ、０．１１０ｍｍｏｌ）、ＨＯＢＴ（１６．８５ｍｇ、０．１１０ｍｍｏｌ）およびＮ−メチルモルホリン（０．０２７ｍＬ、０．２５０ｍｍｏｌ）をＤＭＦ（２ｍＬ）中で合わせた。反応混合物を室温で３時間撹拌した。混合物を酢酸エチルと水との間で分配した。有機層をブラインで２回洗浄し、硫酸ナトリウムで脱水し、濾過し、溶媒留去した。残留物を、酢酸エチル／ヘキサン（５０％から８０％）で溶離を行うシリカゲルでのクロマトグラフィーによって精製して固体を得た。固体を酢酸エチル／ヘキサンで磨砕して、標題化合物（１３ｍｇ、２９％）をトランスジアステレオマーの混合物として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８５−０．９５（ｍ、１２Ｈ）１．１１（ｓ、９Ｈ）１．５９−１．６５（ｍ、２Ｈ）１．７９−２．０４（ｍ、８Ｈ）２．１０−２．１８（ｍ、２Ｈ）２．４１−２．４６（ｍ、２Ｈ）３．５２（ｓ、６Ｈ）３．５７−３．６７（ｍ、２Ｈ）３．７６−３．８６（ｍ、２Ｈ）４．００（ｔ、Ｊ＝７．５６Ｈｚ、２Ｈ）４．３９−４．４６（ｍ、２Ｈ）５．１５（ｄ、Ｊ＝７．００Ｈｚ、２Ｈ）６．１７（ｄ、Ｊ＝７．７０Ｈｚ、２Ｈ）６．９４（ｄ、Ｊ＝８．７８Ｈｚ、２Ｈ）７．１３（ｄ、Ｊ＝７．３７Ｈｚ、４Ｈ）７．３０（ｄ、Ｊ＝８．２０Ｈｚ、２Ｈ）７．５０（ｄ、Ｊ＝８．２４Ｈｚ、４Ｈ）９．９８（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８９５（Ｍ＋Ｈ）^＋。

Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2S, 5S) -1- (4-tert-butylphenyl) ) Pyrrolidine-2,5-diyl) bis (4,5-phenylene)) bis (azaneyl) bis (oxomethylene) bis (pyrrolidin-2,1-diyl)) bis (3-methyl-1-oxobutane-2, 1-diyl) dicarbamate and dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R, 5R) -1-) (4-tert-Butylphenyl) Pyrrolidine-2,5-diyl) Bis (4,1-phenylene)) Bis (Azanyl) Bis (oxomethylene) Bis (Pyrrolidine-2,1-Diyl)) Bis (3-Methyl) -1-oxobutane-2,1-diyl) dicarbamate (2S, 2'S) -N, N'-(4,4'-((2S, 5S) -1- (4-tert-butylphenyl) pyrrolidine) -2,5-diyl) bis (4,1-phenylene)) dipyrrolidine-2-carboxamide and (2S, 2'S) -N, N'-(4,4'-((2R, 5R) -1- (4-tert-Butylphenyl) pyrrolidine-2,5-diyl) bis (4,1-phenylene)) dipyrrolidine-2-carboxamide (29.0 mg, 0.050 mmol), (S) -2- (methoxycarbonylamino) ) -3-Methylbutanoic acid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg, 0.110 mmol) and N-methylmorphylene (0.027 mL, 0.250 mmol). ) Was combined in DMF (2 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with brine, dehydrated with sodium sulfate, filtered and solvent evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane (50% -80%) to give a solid. The solid was ground with ethyl acetate / hexane to give the title compound (13 mg, 29%) as a mixture of transdiastereomers. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.85-0.95 (m, 12H) 1.11 (s, 9H) 1.59-1.65 (m, 2H) 1.79-2.04 (M, 8H) 2.10-2.18 (m, 2H) 2.41-2.46 (m, 2H) 3.52 (s, 6H) 3.57-3.67 (m, 2H) 3 .76-3.86 (m, 2H) 4.00 (t, J = 7.56Hz, 2H) 4.39-4.46 (m, 2H) 5.15 (d, J = 7.00Hz, 2H) ) 6.17 (d, J = 7.70Hz, 2H) 6.94 (d, J = 8.78Hz, 2H) 7.13 (d, J = 7.37Hz, 4H) 7.30 (d, J) = 8.20Hz, 2H) 7.50 (d, J = 8.24Hz, 4H) 9.98 (s, 2H); MS (ESI +) m / z 895 (M + H) ⁺ .

Explanation of general procedure 12. General procedure 12C

メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１１６ｍｇ、０．６６０ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１．０ｍＬ）中溶液に、ＥＤＣ（１２７ｍｇ、０．６６０ｍｍｏｌ）を加え、溶液を室温で２０分間撹拌した。この溶液を６，６′−｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛５−フルオロ−２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール｝（ＡＣＤ Ｎａｍｅ ｖ１２）（１４８ｍｇ、０．２２０ｍｍｏｌ）およびヒューニッヒ塩基（０．２３１ｍＬ、１．３２０ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１．０００ｍＬ）中溶液にカニューレで加え、次にＨＯＢＴ（１０１ｍｇ、０．６６０ｍｍｏｌ）を加え、溶液を室温で１時間撹拌した。溶液をＣＨ_２Ｃｌ_２で希釈し、Ｈ_２Ｏで洗浄し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。生成物はさらに精製することができる。

Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5-{6 −Fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine -2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate (S) -2- (methoxycarbonylamino) EDC (127 mg, 0.660 mmol) was added to a solution of -3-methylbutanoic acid (116 mg, 0.660 mmol) in CH ₂ Cl ₂ (1.0 mL), and the solution was stirred at room temperature for 20 minutes. This solution was added to 6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2. -[(2S) -Pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12) (148 mg, 0.220 mmol) and CH ₂ Cl ₂ (1.) of Hunig base (0.231 mL, 1.320 mmol). 000 mL) was added to the solution by cannula, then HOBT (101 mg, 0.660 mmol) was added and the solution was stirred at room temperature for 1 hour. The solution was diluted with CH ₂ Cl ₂ , washed with H ₂ O, dehydrated (Na ₂ SO ₄ ), filtered and concentrated. The product can be further purified.

From another experiment using the coupling procedure above, Teledyne / ISCO CombiFlash (registered) using a C18 cartridge that elutes at 0% to 30% CH ₃ CN / (0.1% TFA / H ₂ O) over 30 minutes. The crude product (approximately 4 mmol) was purified with the Trademark) Rf system. The desired fraction was basified with a 10% NaHCO ₃ solution and extracted with EtOAc. The combined extracts were dehydrated (Na ₂ SO ₄ ), filtered and concentrated to give a white solid (545 mg). The acquisition was repurified and mostly on a Waters preparative HPLC system using a C18 column elution with 0% to 95% CH ₃ CN / (0.1% TFA / H ₂ O) over 40 minutes. A obtained product (195 mg) containing the title compound and a residual amount of diastereomeric product was obtained. To remove residual diastereomers, 55/30/15 hexane / THF / [CH ₃ OH / EtOH 8:] were used for this sample using a Chiralpac® IA column (5 cm x 15 cm, 20 mL / min). The title compound was obtained by performing chiral chromatography eluting in 2] (116 mg, 0.118 mmol). ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.51-10.60 (m, 1H) 10.33-10.41 (m, 1H) 7.43-7.50 (m, 1H) 7.32 (t) , 1H) 7.13 (d, 1H) 6.93 (t, 1H) 5.82 (d, 2H) 5.28-5.48 (m, 6H) 4.26-4.39 (m, 2H) ) 3.78-3.90 (m, 2H) 3.70-3.71 (d, 6H) 3.57-3.67 (m, 2H) 3.44-3.57 (m, 1H) 2 .99-3.12 (m, 2H) 2.79-2.98 (m, 4H) 1.78-2.58 (m, 12H) 1.41-1.51 (m, 2H) 0.80 −0.95 (m, 12H); MS (ESI) m / z987 (M + H) ⁺ .

General procedure 14. Chiral separation

ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（５，５′−（（２Ｓ，５Ｓ）−１−（４−フルオロフェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート
トランスジアステレオマーの混合物を、ヘキサン／ＥｔＯＨ／ＣＨ_３ＯＨ／１，２−ジクロロエタン／ジエチルアミン（２５／２５／２５／２５／０．１）の混合物で溶離を行うＣｈｉｒａｌｐａｋＩＡカラムでのキラルクロマトグラフィーによってクロマトグラフィー精製して、２種類の別個の異性体を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７５−０．８９（ｍ、１２Ｈ）１．６４−１．７３（ｍ、２Ｈ）１．８５−２．０３（ｍ、６Ｈ）２．１２−２．２４（ｍ、４Ｈ）２．８１−２．９０（ｍ、２Ｈ）３．５２（ｓ、６Ｈ）３．７６−３．８７（ｍ、４Ｈ）４．０１−４．０９（ｍ、２Ｈ）５．０８−５．１６（ｍ、２Ｈ）５．３４（ｑ、Ｊ＝６．６５Ｈｚ、２Ｈ）６．２６（ｄｄ、Ｊ＝９．０５、４．５０Ｈｚ、２Ｈ）６．６７−６．７８（ｍ、２Ｈ）７．０３（ｔ、Ｊ＝８．０２Ｈｚ、２Ｈ）７．２０（ｓ、１Ｈ）７．２４−７．３２（ｍ、３Ｈ）７．３６（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４４（ｄ、Ｊ＝７．９２Ｈｚ、１Ｈ）１２．０１−１２．０７（ｍ、２Ｈ）。
および

Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(5,5'-((2S, 5S) -1- (4-fluorophenyl) pyrrolidine) -2,5-diyl) bis (1H-benzo [d] imidazole-5,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) ) Chiral on a ChiralpacIA column where the mixture of dikerbamate transdiastereomers is eluted with a mixture of hexane / EtOH / CH ₃ OH / 1,2-dichloroethane / diethylamine (25/25/25/25 / 0.1). Chromatographic purification by chromatography gave two distinct isomers. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.75-0.89 (m, 12H) 1.64-1.73 (m, 2H) 1.85-2.03 (m, 6H) 2.12 -2.24 (m, 4H) 2.81-2.90 (m, 2H) 3.52 (s, 6H) 3.76-3.87 (m, 4H) 4.01-4.09 (m) , 2H) 5.08-5.16 (m, 2H) 5.34 (q, J = 6.65Hz, 2H) 6.26 (dd, J = 9.05, 4.50Hz, 2H) 6.67 -6.78 (m, 2H) 7.03 (t, J = 8.02Hz, 2H) 7.20 (s, 1H) 7.24-7.32 (m, 3H) 7.36 (d, J) = 8.13Hz, 1H) 7.44 (d, J = 7.92Hz, 1H) 12.01-12.07 (m, 2H).
and

ジメチル（２Ｓ，２′Ｓ）−１，１′−（（２Ｓ，２′Ｓ）−２，２′−（５，５′−（（２Ｒ，５Ｒ）−１−（４−フルオロフェニル）ピロリジン−２，５−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ビス（ピロリジン−２，１−ジイル））ビス（３−メチル−１−オキソブタン−２，１−ジイル）ジカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９３（ｍ、１２Ｈ）１．６９（ｔ、Ｊ＝９．６５Ｈｚ、２Ｈ）１．８２−２．０６（ｍ、６Ｈ）２．０９−２．２６（ｍ、４Ｈ）３．０４−３．２３（ｍ、２Ｈ）３．５２（ｓ、６Ｈ）３．７３−３．９０（ｍ、４Ｈ）４．０６（ｔ、Ｊ＝８．４６Ｈｚ、２Ｈ）５．０５−５．２１（ｍ、２Ｈ）５．２９−５．４４（ｍ、２Ｈ）６．２１−６．３２（ｍ、２Ｈ）６．６７−６．８６（ｍ、２Ｈ）７．０５（ｔ、Ｊ＝８．７８Ｈｚ、２Ｈ）７．１８（ｓ、１Ｈ）７．２３−７．３３（ｍ、３Ｈ）７．３７（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４５（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）１２．０４（ｄ、Ｊ＝１４．９６Ｈｚ、２Ｈ）。

Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(5,5'-((2R, 5R) -1- (4-fluorophenyl) pyrrolidine) -2,5-diyl) Bis (1H-benzo [d] imidazol-5,2-diyl)) Bis (pyrrolidine-2,1-diyl)) Bis (3-methyl-1-oxobutane-2,1-diyl) ) Jikabamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.93 (m, 12H) 1.69 (t, J = 9.65 Hz, 2H) 1.82-2.06 (m, 6H) 2 .09-2.26 (m, 4H) 3.04-3.23 (m, 2H) 3.52 (s, 6H) 3.73-3.90 (m, 4H) 4.06 (t, J) = 8.46Hz, 2H) 5.05-5.21 (m, 2H) 5.29-5.44 (m, 2H) 6.21-6.32 (m, 2H) 6.67-6.86 (M, 2H) 7.05 (t, J = 8.78Hz, 2H) 7.18 (s, 1H) 7.23-7.33 (m, 3H) 7.37 (d, J = 8.13Hz) , 1H) 7.45 (d, J = 8.02Hz, 1H) 12.04 (d, J = 14.96Hz, 2H).

General procedure 15. The benzimidazole synthesis diagram VIII by the methoxybenzylamine substitution route I shows the method for producing certain compounds (57) and (59). General procedure 15A shows a representative synthesis of (57) where D is 4-tert-butylphenyl.

Explanation of general procedure 15. General procedure 15A

The five steps shown above will be described by the following experimental procedure.

4,4'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (N- (4-methoxybenzyl) -2-nitroaniline)
1- (4-tert-Butylphenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine (4.41 g, 8.57 mmol) undiluted with p-methoxybenzylamine (8.93 mL, 68.6 mmol) and heated at 145 ° C. for 1 hour. The mixture was diluted with dichloromethane and filtered. The filtrate was washed with 0.5 M HCl, a solution of NaHCO ₃ and then brine. The organic phase was concentrated and purified by chromatography on silica gel using an 80 g column eluting with 0% to 50% ethyl acetate / hexane to give 4.13 g (67%) of an orange-red foam solid.

4,4'-(1- (4-tert-Butylphenyl) pyrrolidine-2,5-diyl) bis (N1- (4-methoxybenzyl) benzene-1,2-diamine)
4,4'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (N- (4-methoxybenzyl) -2-nitroaniline) (2 g, 2.79 mmol) in THF ( 15 mL), dissolved in a mixture of ethanol (15 mL) and ethyl acetate (5 mL). Next, platinum oxide (0.254 g, 1.12 mmol) was added as a THF slurry. The flask was evacuated, purged twice with nitrogen, evacuated and opened against a hydrogen balloon. The mixture is stirred at room temperature for 20 hours, filtered through diatomaceous earth, concentrated and purified by chromatography on silica gel using an 80 g column eluting with 0% -40% ethyl acetate / dichloromethane to trans of the first peak. The product was obtained (0.508 g, 28%).

(2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2- (4-methoxybenzylamino)-) 5,1-phenylene) bis (azaneyl) bis (oxomethylene)) dipyrrolidine-1-carboxylic acid tert-butyl 4,4'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (N1- (4-methoxybenzyl) benzene-1,2-diamine) (0.422 g, 0.643 mmol) and diisopropylethylamine (0.674 mL, 3.86 mmol) were dissolved in DMSO (6 mL) at room temperature and S- It was treated with Boc-proline (0.319 g, 1.48 mmol) and then HATU (0.514 g, 1.35 mmol). The solution was stirred at room temperature for 1 hour and diluted with water. The solid product is filtered off and purified by chromatography on silica gel using a 40 g column elution with 0% to 50% ethyl acetate / dichloromethane to give the title compound (0.565 g, 84%) as a yellow solid. It was.

(2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-amino-5,1-phenylene) Bis (azaneyl) bis (oxomethylene)) tert-butyl dipyrrolidine-1-carboxylate (2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butylphenyl) pyrrolidine) -2,5-diyl) bis (2- (4-methoxybenzylamino) -5,1-phenylene) bis (azaneyl) bis (oxomethylene)) tert-butyl dipyrrolidine-1-carboxylate (0.565 g, 0) .538 mmol) was dissolved in dichloromethane (5 mL) and water (0.25 mL) at room temperature and treated with DDQ (0.244 g, 1.076 mmol) over 2 minutes. The mixture is diluted with sodium bicarbonate solution, extracted in small portions with dichloromethane, concentrated and purified by chromatography on silica gel with a 40 g column eluting with 0% to 15% methanol / dichloromethane to give the title compound (0). .355 g, 81%) was obtained as a yellow solid.

(2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (1H-benzo [d] imidazole-5, 5) 2-Diyl)) tert-butyl dipyrrolidine-1-carboxylate (2S, 2'S) -2,2'-(5,5'-(1- (4-tert-butylphenyl) pyrrolidine-2,5- Diyl) bis (2-amino-5,1-phenylene) bis (azaneyl) bis (oxomethylene)) tert-butyl dipyrrolidine-1-carboxylate is dissolved in undiluted acetic acid (3 mL) and heated at 72 ° C for 2 hours. did. The solution was concentrated and poured into water. The pH was adjusted from about 7 to 8 with sodium bicarbonate. The product is extracted with dichloromethane, concentrated and purified by chromatography on silica gel with a 40 g column eluting with 0% to 5% methanol / dichloromethane to give the title compound (0.185 g, 55%) a bright yellow color. Obtained as a solid.

General procedure 16. The benzimidazole synthesis diagram VIII by the methoxybenzylamine substitution route II outlines the methods for producing certain compounds (57) and (59). A representative synthesis of (57), where D is 4-fluorophenyl, is shown in General Procedure 16A below.

Explanation of general procedure 16. General procedure 16A

The five steps shown above will be described by the experimental procedure below.

4,4'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (N- (4-methoxybenzyl) -2-nitroaniline)
In a microwave reactor, 2,5-bis (4-chloro-3-nitrophenyl) -1- (4-fluorophenyl) pyrrolidine (0.88 g, 1.86 mmol) was added to 4-methoxybenzylamine (3. Combined with 64 mL, 28.0 mmol) and heated at 145 ° C. for 1 hour. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated and purified by chromatography on silica gel using a 330 g column eluting with 0% to 60% ethyl acetate / hexane to give 0.79 g (62%) of an orange-red foam solid.

4,4'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-nitroaniline)
4,4'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (N- (4-methoxybenzyl) -2-nitroaniline) (0.78 g, 1.15 mmol) at room temperature It was dissolved in dichloromethane (10 mL) and treated with TFA (1.8 mL, 23.0 mmol) for 3 hours. The residue was concentrated and partitioned between dichloromethane and sodium bicarbonate solution. The organic layer was concentrated and purified by chromatography on silica gel using a 40 g column eluting with dichloromethane to give 0.218 g (43%) of trans isomers.

4,4'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) dibenzene-1,2-diamine 4,4'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) ) Bis (2-nitroaniline) (0.218 g, 0.50 mmol) was dissolved in DMF (5 mL) and platinum oxide (0.226 g, 0.99 mmol) was added as a THF slurry. The flask was evacuated, purged twice with nitrogen, evacuated and opened against a hydrogen balloon. The mixture was stirred at room temperature for 20 hours. The solution was used in the next step without purification.

(2S, 2'S) -2,2'-(5,5'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-amino-5,1-phenylene)) bis Crude DMF solution of (azaneil) bis (oxomethylene) dipyrrolidine-1-carboxylate tert-butyl 4,4'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) dibenzene-1,2-diamine Was treated with diisopropylethylamine (0.296 mL, 1.70 mmol) and S-Boc-proline (0.192 g, 0.89 mmol), followed by HATU (0.322 g, 0.85 mmol). The solution was stirred at room temperature for 1.5 hours and the reaction mixture was diluted with water. The solid product is filtered off and purified by chromatography on silica gel with a 12 g column eluting with 0% to 3% methanol / dichloromethane to give 0.235 g (72%) of a yellow solid, for which. , The stereochemistry of acylation was optionally assigned to the reaction at the meta-amino group.

(2S, 2'S) -2,2'-(5,5'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (1H-benzo [d] imidazole-5,2- Diyl)) tert-butyl dipyrrolidine-1-carboxylic acid (2S, 2'S) -2,2'-(5,5'-(1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis ( 2-Amino-5,1-phenylene)) bis (azaneyl) bis (oxomethylene) tert-butyl dipyrrolidine-1-carboxylate was dissolved in undiluted acetic acid (2 mL) and heated at 60 ° C. for 1 hour. The solution was concentrated, poured into water and the pH was adjusted to about 7-8 with sodium bicarbonate. The product is extracted with dichloromethane, concentrated and purified by chromatography on silica gel with a 12 g column eluting with 0% to 20% ethyl acetate / dichloromethane to reveal the title compound (0.124 g, 55%). Obtained as a yellow solid.

General procedure 17. Suzuki coupling of N-aryl group

With the appropriate boronic acid or ester, an additional 2,5-bis (4-chloro-3-nitrophenyl) -1- (4-iodophenyl) pyrrolidine (or equivalent triflate, nonafrate or) was subjected to the Suzuki reaction shown. Intermediate compounds such as bromide) can be further made ( _RSuz represents a suitable cycloalkyl, aryl, cycloalkenyl or heteroaryl group). Suitable conditions for carrying out this Suzuki reaction include those described in Diagram V for the synthesis of compound (37).

Explanation of general procedure 17: General procedure 17A

４−（５−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−３−ニトロフェニル）ピロリジン−１−イル）フェニル）ピリジン−２−イル）モルホリン
（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−３−ニトロフェニル）−１−（４−ヨードフェニル）ピロリジン（１．８６９ｇ、３．２ｍｍｏｌ）、４−（５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピリジン−２−イル）モルホリン（０．９２９ｇ、３．２０ｍｍｏｌ）、リン酸カリウム（１．３５９ｇ、６．４０ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（０．０２９ｇ、０．０３２ｍｍｏｌ）および１，３，５，７−テトラメチル−６−フェニル−２，４，８−トリオキサ−６−ホスファアダマンテ（０．０２８ｇ、０．０９６ｍｍｏｌ）をＴＨＦ（１８ｍＬ）／水（６ｍＬ）中で合わせた。混合物を窒素で１５分間パージし、室温で２４時間撹拌した。反応混合物を酢酸エチルと飽和重炭酸ナトリウムとの間で分配した。有機層をブラインで洗浄し、硫酸ナトリウムで脱水し、濾過し、溶媒留去した。残留物を、酢酸エチル／ヘキサン（２０％から４０％）で溶離を行うシリカゲルでのクロマトグラフィーによって精製して標題化合物（１．０１ｇ、５１％）を固体として得た。

4- (5-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) pyridin-2-yl) morpholine (2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-iodophenyl) pyrrolidine (1.869 g, 3.2 mmol), 4- (5- (4,5,5,5-) Tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) morpholine (0.929 g, 3.20 mmol), potassium phosphate (1.359 g, 6.40 mmol), tris (dibenzylideneacetone) ) Dipalladium (0) (0.029 g, 0.032 mmol) and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.028 g, 0.096 mmol) was combined in THF (18 mL) / water (6 mL). The mixture was purged with nitrogen for 15 minutes and stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dehydrated with sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane (20% -40%) to give the title compound (1.01 g, 51%) as a solid.

General procedure 18. Proline Amide Synthesis A particular substituted proline amide can be produced using methods such as those shown in General Procedures 18A-18C.

Explanation of general procedure 18. General procedure 18A

メチル（２Ｓ）−１−（（３Ｓ）−３−カルバモイル−２−アザビシクロ［２．２．１］ヘプタン−２−イル）−３−メチル−１−オキソブタン−２−イルカーバメート
（３Ｓ）−２−（（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタノイル）−２−アザビシクロ［２．２．１］ヘプタン−３−カルボン酸（１．７８ｇ、５．９７ｍｍｏｌ）、２−（３Ｈ−［１，２，３］トリアゾロ［４，５−ｂ］ピリジン−３−イル）−１，１，３，３−テトラメチルイソウロニウムヘキサフルオロホスフェート（２．４９ｇ、５．５６ｍｍｏｌ）およびジイソプロピルエチルアミン（２．６１ｍＬ、１４．９２ｍｍｏｌ）を環境温度でアセトニトリル（３０ｍＬ）に溶かし、２８％水酸化アンモニウム溶液（２．４９ｇ、１７．９８ｍｍｏｌ）を滴下することで処理した。得られた混合物を１時間撹拌し、水で希釈し、ジクロロメタンで抽出した。有機層をブラインで洗浄し、硫酸ナトリウムで脱水し、濾過し、濃縮して、メチル（２Ｓ）−１−（（３Ｓ）−３−カルバモイル−２−アザビシクロ［２．２．１］ヘプタン−２−イル）−３−メチル−１−オキソブタン−２−イルカーバメートを白色ロウ状固体として得た。

Methyl (2S) -1-((3S) -3-carbamoyl-2-azabicyclo [2.2.1] heptane-2-yl) -3-methyl-1-oxobutane-2-ylcarbamate (3S) -2 -((S) -2- (Methoxycarbonylamino) -3-methylbutanoyl) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid (1.78 g, 5.97 mmol), 2-( 3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) -1,1,3,3-tetramethylisouronium hexafluorophosphate (2.49 g, 5.56 mmol) and Diisopropylethylamine (2.61 mL, 14.92 mmol) was dissolved in acetonitrile (30 mL) at ambient temperature and treated with a 28% ammonium hydroxide solution (2.49 g, 17.98 mmol) dropwise. The resulting mixture was stirred for 1 hour, diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dehydrated with sodium sulphate, filtered and concentrated to concentrate methyl (2S) -1-((3S) -3-carbamoyl-2-azabicyclo [2.2.1] heptane-2. -Il) -3-methyl-1-oxobutane-2-ylcarbamate was obtained as a white waxy solid.

Explanation of general procedure 18. General procedure 18B

（２Ｓ，４Ｓ）−２−カルバモイル−４−メトキシピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
（２Ｓ，４Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）−４−メトキシピロリジン−２−カルボン酸（２．９ｇ、１１．８２ｍｍｏｌ）をアセトニトリル（１５０ｍＬ）に溶かし、氷浴で冷却した。Ｎ^１−（（エチルイミノ）メチレン）−Ｎ^３，Ｎ^３−ジメチルプロパン−１，３−ジアミン塩酸塩（２．７２ｇ、１４．１９ｍｍｏｌ）および１Ｈ−ベンゾ［ｄ］［１，２，３］トリアゾール−１−オール水和物（２．１７ｇ、１４．１９ｍｍｏｌ）を加え、混合物を環境温度で１５時間撹拌したところ透明となった。２８％水酸化アンモニウム（４．９３ｍＬ、３５．５ｍｍｏｌ）を滴下して、沈殿を得た。２時間撹拌後、混合物を濃縮し、水で希釈し、酢酸エチルで抽出した。有機層をブラインで洗浄し、硫酸ナトリウムで脱水し、濾過し、濃縮して、１００％収率の（２Ｓ，４Ｓ）−２−カルバモイル−４−メトキシピロリジン−１−カルボン酸ｔｅｒｔ−ブチルを白色ロウ状固体として得た。

(2S, 4S) -2-carbamoyl-4-methoxypyrrolidine-1-carboxylic acid tert-butyl (2S, 4S) -1- (tert-butoxycarbonyl) -4-methoxypyrrolidine-2-carboxylic acid (2.9 g) , 11.82 mmol) was dissolved in acetonitrile (150 mL) and cooled in an ice bath. N ¹ -((ethylimino) methylene) -N ³ , N ³ -dimethylpropane-1,3-diamine hydrochloride (2.72 g, 14.19 mmol) and 1H-benzo [d] [1,2,3] triazole -1-All hydrate (2.17 g, 14.19 mmol) was added and the mixture was stirred at ambient temperature for 15 hours and became clear. 28% ammonium hydroxide (4.93 mL, 35.5 mmol) was added dropwise to give a precipitate. After stirring for 2 hours, the mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated with sodium sulphate, filtered and concentrated to whiten 100% yield of (2S, 4S) -2-carbamoyl-4-methoxypyrrolidine-1-carboxylate tert-butyl. Obtained as a waxy solid.

Other amides that can be prepared using General Procedure 18B include
(2S, 4R) -2-carbamoyl-4-methoxypyrrolidine-1-carboxylate tert-butyl;
(2S, 4S) -2-carbamoyl-4-fluoropyrrolidine-1-carboxylate tert-butyl; and (S) -5-carbamoyl-2,2-dimethylpyrrolidine-1-carboxylate tert-butyl.

Explanation of general procedure 18. General procedure 18C

（Ｓ）−２−カルバモイル−４−メチレンピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
（Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）−４−メチレンピロリジン−２−カルボン酸（１．０５ｇ、４．４８ｍｍｏｌ）およびＮ−メチルモルホリン（０．６４ｍＬ、５．８３ｍｍｏｌ）をテトラヒドロフラン（２５ｍＬ）に溶かし、ドライアイス／アセトン浴で冷却して−１５℃とした。クロルギ酸イソブチル（０．６５ｍＬ、４．９３ｍｍｏｌ）を滴下し、溶液を１５分間撹拌した。内部温度を低下させて−２５℃とし、アンモニア（ガス）を溶液に２分間吹き込み、フラスコを氷浴に移し、さらに２０分間撹拌した。溶液をブラインに投入し、酢酸エチルで抽出し、硫酸マグネシウムで脱水し、濾過し、濃縮した。この残留物をエーテル／ヘキサンで磨砕し、濾過し、乾燥させて、（Ｓ）−２−カルバモイル−４−メチレンピロリジン−１−カルボン酸ｔｅｒｔ−ブチル０．９７ｇ（８１％）を白色固体として得た。

(S) -2-Carbamoyl-4-methylenepyrrolidine-1-carboxylic acid tert-butyl (S) -1- (tert-butoxycarbonyl) -4-methylenepyrrolidine-2-carboxylic acid (1.05 g, 4.48 mmol) ) And N-methylmorpholine (0.64 mL, 5.83 mmol) were dissolved in tetrahydrofuran (25 mL) and cooled in a dry ice / acetone bath to -15 ° C. Isobutyl chlorite (0.65 mL, 4.93 mmol) was added dropwise and the solution was stirred for 15 minutes. The internal temperature was lowered to -25 ° C., ammonia (gas) was blown into the solution for 2 minutes, the flask was transferred to an ice bath and stirred for an additional 20 minutes. The solution was poured into brine, extracted with ethyl acetate, dehydrated with magnesium sulfate, filtered and concentrated. The residue was ground with ether / hexane, filtered and dried to give 0.97 g (81%) of tert-butyl (S) -2-carbamoyl-4-methylenepyrrolidine-1-carboxylate as a white solid. Obtained.

General procedure 19

Amino acid carbamate intermediates can be made using the methods and outlines shown above to make Intermediate 2.

The following compounds can be produced from the appropriate amino acids according to General Procedure 19.
(S) -2- (Methoxycarbonylamino) -2- (Tetrahydro-2H-pyran-4-yl) acetic acid;
(S) -2-cyclohexyl-2- (methoxycarbonylamino) acetic acid;
(S) -2-Cyclopentyl-2- (methoxycarbonylamino) acetic acid;
(S) -2-Cyclobutyl-2- (methoxycarbonylamino) acetic acid;
(S) -2-Cyclopropyl-2- (methoxycarbonylamino) acetic acid;
(S) -2- (Methoxycarbonylamino) -3,3-dimethylbutane acid;
(2S, 3R) -3-methoxy-2- (methoxycarbonylamino) butanoic acid;
(2S, 3S) -3-methoxy-2- (methoxycarbonylamino) butanoic acid;
(S) -2- (Methoxycarbonylamino) -2-((R) -tetrahydrofuran-3-yl) acetic acid;
(S) -2- (Methoxycarbonylamino) -2-((S) -tetrahydrofuran-3-yl) acetic acid;
(S) -2- (2,3-dihydro-1H-indene-2-yl) -2- (methoxycarbonylamino) acetic acid.
(S) -3-ethyl-2- (methoxycarbonylamino) pentanoic acid; and (S) -2- (ethoxycarbonylamino) -3-methylbutanoic acid.

General procedure 20

Diamines (79) can be converted to benzimidazoles (81) in two steps, as outlined above in Schematic XIII.

Explanation of general procedure 20. General procedure 20A
(S) -2- (6-bromo-5-fluoro-1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl 4-bromo-5-fluorobenzene-1,2-diamine In a solution in DMSO (42 mL) of (1.7 g, 8.4 mmol), (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.8 g, 8.4 mmol) and then HATU ( 3.5 g, 9.3 mmol) and N, N-diisopropyl-N-ethylamine (3.7 mL, 21.1 mmol) were added and the solution was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with _{H 2} O and brine, dried _(Na 2 _SO 4), filtered, and concentrated. Acetic acid (40 mL) was added and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was then cooled and concentrated. The residue was azeotroped with toluene twice to give the crude product, which was purified by flash chromatography (0% to 50% EtOAc / Hexanes) to give the title compound (2.5 g, 6. 4 mmol, 77%).

(S) -2- (5-Bromo-6-fluoro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl (S) -2- (6-bromo-5-fluoro-1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl (2.5 g, 6.4 mmol) in THF (32 mL) Sodium hydride (0.27 g, 6.8 mmol) was added to the medium solution and stirring was continued for 30 minutes. 2- (Trimethylsilyl) -ethoxymethyl chloride (1.2 mL, 6.8 mmol) was added and stirring was continued for 30 minutes. Water was added and the reaction was stopped. The mixture was diluted with EtOAc, washed with 1N HCl, _{H 2} O and brine, dried _(Na 2 _SO 4), filtered, and concentrated to an oil. The oil was purified by flash chromatography (0% to 30% EtOAc / Hexanes) to give the title compound (2.9 g, 5.7 mmol, 89%).

The compound of the following general formula (81) can be produced according to the general procedure 20 using an appropriate diamine as a raw material.
(S) -2- (5-Bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl;
(S) -2- (5-Bromo-4-methyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl ;
(S) -2- (5-Bromo-4-chloro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl ;
(S) -2- (5-Bromo-4-fluoro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl ;
(S) -2- (6-bromo-3-((2- (trimethylsilyl) ethoxy) methyl) -3H-imidazole [4,5-b] pyridin-2-yl) pyrrolidine-1-carboxylate tert-butyl ;
(S) -2- (5-Bromo-7-methyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl ;
(S) -2- (5-Bromo-6-methyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl ;
(S) -2- (5-Bromo-6- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylic acid Tert-butyl acid;
(S) -2- (5-Bromo-7- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylic acid Tert-butyl acid;
(S) -2- (5-Bromo-6-methoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl ;
(S) -2- (5-Bromo-7-methoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl And (S) -5-bromo-2- (1- (tert-butoxycarbonyl) pyrrolidine-2-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole- Methyl 7-carboxylate.

General procedure 21
Compound (81) can be converted to compound (82.2), as outlined above in Diagram XIII. Compounds representative synthesis of (82.2) described in General Procedure 21A _{below, X 13} is a 6-position of the fluorine benzimidazole moiety. For simplicity of explanation, the SEM protecting group on benzimidazole is shown bound to the specific nitrogen of benzimidazole. In the general procedures 21A and 22A, the actual substitution position of the SEM group has not been determined, and any nitrogen may be used.

Explanation of general procedure 21. General procedure 21A

（２Ｓ，２′Ｓ）−２，２′−（５，５′−（フラン−２，５−ジイル）ビス（６−フルオロ−１−（（２−（トリメチルシリル）エトキシ）メチル）−１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
圧力管中、（Ｓ）−２−（５−ブロモ−６−フルオロ−１−（（２−（トリメチルシリル）エトキシ）メチル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）ピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（６００ｍｇ、１．２ｍｍｏｌ）、２，５−ビス（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フラン（１８６ｍｇ、０．６ｍｍｏｌ）、フッ化セシウム（３５３ｍｇ、２．３ｍｍｏｌ）およびＤＭＦ（４ｍＬ）を合わせ、混合物をＮ_２ガスで３０分間脱気した。この混合物に［（ｔ−Ｂｕ）_２ＰＣｌ］_２ＰｄＣｌ_２（ＰＸＰｄ）（１５．７ｍｇ、０．０３ｍｍｏｌ）を加え、管を密閉し、１００℃で１８時間加熱した。冷却した溶液をＥｔＯＡｃで希釈し、珪藻土で濾過した。濾液をＨ_２Ｏおよびブラインで洗浄し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、３−メルカプトプロピルシリカゲルで３０分間処理した。混合物を濾過し、濾液を濃縮して粗生成物を得て、それをフラッシュクロマトグラフィー（０−５０％ＥｔＯＡｃ／ヘキサン）によって精製して、標題化合物を得た（２６９ｍｇ、０．２９ｍｍｏｌ、５０％）。

(2S, 2'S) -2,2'-(5,5'-(Fran-2,5-diyl) bis (6-fluoro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H- Benzo [d] imidazol-5,2-diyl)) dipyrrolidine-1-carboxylic acid tert-butyl In a pressure tube, (S) -2- (5-bromo-6-fluoro-1-) ((2- (trimethylsilyl)) Ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl (600 mg, 1.2 mmol), 2,5-bis (4,5,5-tetramethyl) 1,3,2-dioxaborolan-2-yl) furan (186 mg, 0.6 mmol), cesium fluoride (353 mg, 2.3 mmol) and DMF combined (4 mL), degassed mixture _N 30 min ₂ gas did. [(T-Bu) ₂ PCl] ₂ PdCl ₂ (PXPd) (15.7 mg, 0.03 mmol) was added to the mixture, the tube was sealed, and the mixture was heated at 100 ° C. for 18 hours. The cooled solution was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with H ₂ O and brine, dehydrated (Na ₂ SO ₄ ), filtered and treated with 3-mercaptopropyl silica gel for 30 minutes. The mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by flash chromatography (0-50% EtOAc / Hexanes) to give the title compound (269 mg, 0.29 mmol, 50%). ).

（２Ｓ，２′Ｓ）−２，２′−｛［（２Ｅ）−１，４−ジオキソブト−２−エン−１，４−ジイル］ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）｝ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（ＡＣＤ Ｎａｍｅ ｖ１２）
（２Ｓ，２′Ｓ）−２，２′−（５，５′−（フラン−２，５−ジイル）ビス（６−フルオロ−１−（（２−（トリメチルシリル）エトキシ）メチル）−１Ｈ−ベンゾ［ｄ］イミダゾール−５，２−ジイル）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（３４０ｍｇ、．３６ｍｍｏｌ）のＴＨＦ（８ｍＬ）中溶液に、Ｓｅｌｅｃｔｆｌｕｏｒ（登録商標）（１−クロロメチル−４−フルオロ−１，４−ジアゾニアビシクロ［２．２．２］オクタンビス（テトラフルオロボレート））（２５８ｍｇ、０．７３ｍｍｏｌ）と次にＨ_２Ｏ（１ｍＬ）を加えた。溶液を１時間撹拌し、ＥｔＯＡｃで希釈し、Ｈ_２Ｏおよびブラインで洗浄し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮して標題化合物を得た。

(2S, 2'S) -2,2'-{[(2E) -1,4-dioxobut-2-ene-1,4-diyl] bis (6-fluoro-1-{[2- (trimethylsilyl)) Ethoxy] methyl} -1H-benzimidazole-5,2-diyl)} di-tert-butyl dipyrrolidine-1-carboxylate (ACD Name v12)
(2S, 2'S) -2,2'-(5,5'-(Fran-2,5-diyl) bis (6-fluoro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H- Selectfluor® (1-chloromethyl-4-fluoro) in a solution of tert-butyl (340 mg, .36 mmol) benzo [d] imidazol-5,2-diyl) dipyrrolidine-1-carboxylate in THF (8 mL). -1,4-Diazoniabicyclo [2.2.2] octambis (tetrafluoroborate)) (258 mg, 0.73 mmol) and then H ₂ O (1 mL) were added. The solution was stirred for 1 hour and EtOAc. in diluted, washed with _{H 2} O and brine, dried _(Na 2 _SO 4), filtered, and concentrated to give the title compound.

（２Ｓ，２′Ｓ）−２，２′−［（１，４−ジオキソブタン−１，４−ジイル）ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）］ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（ＡＣＤ Ｎａｍｅ ｖ１２）
（２Ｓ，２′Ｓ）−２，２′−｛［（２Ｅ）−１，４−ジオキソブト−２−エン−１，４−ジイル］ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）｝ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（３４６ｍｇ、０．３６ｍｍｏｌ）のＥｔＯＡｃ（７ｍＬ）中溶液に、白金（３％炭素担持品）（７１ｍｇ、０．３６ｍｍｏｌ）を加え、溶液を１ａｔｍのＨ_２ガス下に２時間撹拌した。溶液を濾過し、ＥｔＯＡｃで洗浄し、濾液を濃縮して残留物を得て、それをフラッシュクロマトグラフィー（０％から５０％ＥｔＯＡｃ／ヘキサン）によって精製して、標題化合物を得た（２６９ｍｇ、０．２８ｍｍｏｌ、７８％）。

(2S, 2'S) -2,2'-[(1,4-dioxobutane-1,4-diyl) bis (6-fluoro-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-benz Imidazole-5,2-diyl)] di-tert-butyl dipyrrolidine-1-carboxylate (ACD Name v12)
(2S, 2'S) -2,2'-{[(2E) -1,4-dioxobut-2-ene-1,4-diyl] bis (6-fluoro-1-{[2- (trimethylsilyl)) Ethoxy] methyl} -1H-benzimidazole-5,2-diyl)} di-tert-butyl dipyrrolidine-1-carboxylate (346 mg, 0.36 mmol) in EtOAc (7 mL) solution with platinum (3% carbon bearing) goods) (71 mg, 0.36 mmol) was added and the solution was stirred for 2 hours in _{H 2} gas under 1 atm. The solution was filtered, washed with EtOAc, the filtrate was concentrated to give a residue and purified by flash chromatography (0% to 50% EtOAc / Hexanes) to give the title compound (269 mg, 0). .28 mmol, 78%).

General procedure 22
Compound (82.2) can be converted to compound (84), as outlined above in Diagram XIII. The general procedure 22A below shows the representative synthesis of compound (84), where D is 4-tert-butylphenyl and both stereochemistry of the alcohol on the butane-1,4-diyl group is (S). ), And X ₁₃ is 6-fluoro. Pyrrolidine formation by cyclization allows the formation of trans-pyrrolidine with varying amounts of cis-pyrrolidine. The cis-pyrrolidine can be separated either after deprotection (see General Procedure 23) or after any step after deprotection.

Explanation of general procedure 22. General procedure 22A

（２Ｓ，２′Ｓ）−２，２′−｛［（１Ｓ，４Ｓ）−１，４−ジヒドロキシブタン−１，４−ジイル］ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）｝ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（ＡＣＤ Ｎａｍｅ ｖ１２）
（Ｒ）−（＋）−α，α−ジフェニル−２−ピロリジンメタノール（５９．９ｍｇ、０．２４ｍｍｏｌ）のＴＨＦ（２．８ｍＬ）中溶液に、トリメチルボレート（０．０３４ｍＬ、０．３１ｍｍｏｌ）を加え、得られた溶液を９０分間撹拌した。溶液を冷却して０℃とし、０℃で撹拌を続けながら３０分間かけてＮ，Ｎ−ジエチルアニリンボラン（０．４ｍＬ、２．２ｍｍｏｌ）を少量ずつ加えた。（２Ｓ，２′Ｓ）−２，２′−［（１，４−ジオキソブタン−１，４−ジイル）ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）］ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（２６５ｍｇ、．２８ｍｍｏｌ）のＴＨＦ（２．８ｍＬ）中溶液を０℃とし、それに、この溶液をカニューレを介して加え、昇温させて室温とし、１６時間撹拌した。溶液を冷却して０℃とし、ＣＨ_３ＯＨ（０．０９ｍＬ、２．２ｍｍｏｌ）を加え、溶液を昇温させて室温とし、２時間撹拌した。１Ｎ ＨＣｌを加え、その水溶液をＥｔＯＡｃで抽出した。合わせた抽出液をブラインで洗浄し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。フラッシュクロマトグラフィー（０％から３％ＣＨ_３ＯＨ／ＣＨ_２Ｃｌ_２）によって精製を行って、標題化合物を得た（２４８ｍｇ、０．２６ｍｍｏｌ、９３％）。

(2S, 2'S) -2,2'-{[(1S, 4S) -1,4-dihydroxybutane-1,4-diyl] bis (6-fluoro-1-{[2- (trimethylsilyl) ethoxy] ] Methyl} -1H-benzimidazole-5,2-diyl)} di-tert-butyl dipyrrolidine-1-carboxylate (ACD Name v12)
(R)-(+)-Α, α-diphenyl-2-pyrrolidin Methanol (59.9 mg, 0.24 mmol) in THF (2.8 mL) with trimethylbolate (0.034 mL, 0.31 mmol). In addition, the resulting solution was stirred for 90 minutes. The solution was cooled to 0 ° C., and N, N-diethylaniline borane (0.4 mL, 2.2 mmol) was added little by little over 30 minutes while continuing stirring at 0 ° C. (2S, 2'S) -2,2'-[(1,4-dioxobutane-1,4-diyl) bis (6-fluoro-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-benz Imidazole-5,2-diyl)] A solution of di-tert-butyl dipyrrolidine-1-carboxylate (265 mg, .28 mmol) in THF (2.8 mL) was brought to 0 ° C. and this solution was added via a cannula. The temperature was raised to room temperature, and the mixture was stirred for 16 hours. The solution was cooled to 0 ° C., CH ₃ OH (0.09 mL, 2.2 mmol) was added, the solution was heated to room temperature, and the mixture was stirred for 2 hours. 1N HCl was added and the aqueous solution was extracted with EtOAc. The combined extracts were washed with brine, dehydrated (Na ₂ SO ₄ ), filtered and concentrated. Purification by flash chromatography (0% to 3% CH ₃ OH / CH ₂ Cl ₂ ) gave the title compound (248 mg, 0.26 mmol, 93%).

（２Ｓ，２′Ｓ）−２，２′−｛［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル］ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）｝ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（ＡＣＤ Ｎａｍｅ ｖ１２）
（２Ｓ，２′Ｓ）−２，２′−｛［（１Ｓ，４Ｓ）−１，４−ジヒドロキシブタン−１，４−ジイル］ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）｝ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（１００ｍｇ、．１０ｍｍｏｌ）のＣＨ_２Ｃｌ_２（１ｍＬ）中溶液に−２０℃で、トリエチルアミン（０．０４４ｍＬ、０．３１ｍｍｏｌ）と次にメシルクロライド（０．０１８ｍＬ、０．２３ｍｍｏｌ）を加え、溶液を−２０℃で１時間撹拌した。４−ｔｅｒｔ−ブチルアニリン（０．０８３ｍＬ、０．５２ｍｍｏｌ）を１回で加え、溶液を撹拌しながら昇温させて室温として終夜経過させた。溶液をＥｔＯＡｃで希釈し、１Ｎ ＨＣｌ、Ｈ_２Ｏおよびブラインで洗浄し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。フラッシュクロマトグラフィー（０％から５０％ＥｔＯＡｃ／ヘキサン）による精製によって、標題化合物を得た（４６ｍｇ、０．０４ｍｍｏｌ、４１％）。

(2S, 2'S) -2,2'-{[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis (6-fluoro-1-{[2 -(Trimethylsilyl) ethoxy] methyl} -1H-benzimidazole-5,2-diyl)} di-tert-butyl dipyrrolidine-1-carboxylate (ACD Name v12)
(2S, 2'S) -2,2'-{[(1S, 4S) -1,4-dihydroxybutane-1,4-diyl] bis (6-fluoro-1-{[2- (trimethylsilyl) ethoxy] ] Methyl} -1H-benzimidazole-5,2-diyl)} di-tert-butyl dipyrrolidine-1-carboxylate (100 mg, .10 mmol) in CH ₂ Cl ₂ (1 mL) at -20 ° C, triethylamine. (0.044 mL, 0.31 mmol) followed by meshyl chloride (0.018 mL, 0.23 mmol) and the solution was stirred at −20 ° C. for 1 hour. 4-tert-Butylaniline (0.083 mL, 0.52 mmol) was added in one portion, and the solution was heated to room temperature with stirring and allowed to elapse overnight. The solution was diluted with EtOAc, washed with 1N HCl, _{H 2} O and brine, dried _(Na 2 _SO 4), filtered, and concentrated. Purification by flash chromatography (0% to 50% EtOAc / Hexanes) gave the title compound (46 mg, 0.04 mmol, 41%).

General procedure 23. De-book / de-SEM procedure

Simultaneous removal of Boc and SEM protecting groups as described above using standard conditions such as treatment with an acid such as HCl in a solvent such as dioxane or methanol or a mixture thereof at a temperature of about room temperature to about 60 ° C. Can be carried out. The compound obtained by deprotection may consist of a mixture of stereoisomers that can be separated by reverse phase HPLC. The resulting deprotected compound can be isolated as a free base directly from the reaction or reverse phase HPLC, or after neutralization, extraction with an organic solvent and standard isolation.

Explanation of general procedure 23. General procedure 23A

６，６′−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル］ビス｛５−フルオロ−２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール｝（ＡＣＤ Ｎａｍｅ ｖ１２）
（２Ｓ，２′Ｒ）−２，２′−｛［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル］ビス（６−フルオロ−１−｛［２−（トリメチルシリル）エトキシ］メチル｝−１Ｈ−ベンズイミダゾール−５，２−ジイル）｝ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（４４ｍｇ、０．０４ｍｍｏｌ）のジオキサン（１ｍＬ）中溶液に、４Ｍ ＨＣｌ／ジオキサン（１ｍＬ、４．０ｍｍｏｌ）を加え、溶液を５０℃で２時間撹拌した。冷却した溶液を濃縮し、減圧下に１時間置いて粗標題化合物を得て、それを精製せずに用いた。

6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {5-fluoro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12)
(2S, 2'R) -2,2'-{[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis (6-fluoro-1-{[2 -(Trimethylsilyl) ethoxy] methyl} -1H-benzimidazole-5,2-diyl)} di-tert-butyl dipyrrolidine-1-carboxylate (44 mg, 0.04 mmol) in dioxane (1 mL) in 4M HCl / Dioxane (1 mL, 4.0 mmol) was added and the solution was stirred at 50 ° C. for 2 hours. The cooled solution was concentrated and placed under reduced pressure for 1 hour to give the crude title compound, which was used unpurified.

Diamines listed below:
4-Bromo-3-methylbenzene-1,2-diamine;
5-Bromo-3-fluorobenzene-1,2-diamine;
4-Bromo-3-fluorobenzene-1,2-diamine;
For 4-bromo-3-chlorobenzene-1,2-diamine; and 4-bromo-5-fluorobenzene-1,2-diamine, a series of general procedures 20 / 20A, 21 / 21A, 22 / 22A, 23 / 23A. The following compound can be obtained.
6,6'-[1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {4-fluoro-2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazole} ( ACD Name v12);
6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-fluoro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-fluoro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-chloro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-chloro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-methyl-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-methyl-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-{(2R, 5R) -1- [3-fluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[(2S)) -Pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12);
6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[( 2S) -pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12); and 6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine) -1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazole} (ACD Name v12).

The following Example compounds 1.1 to 1.8 can be prepared from the substituted pyrrolidines listed appropriately according to the methods of General Procedure 8.1, General Procedure 9C (Raney Nickel) and General Procedure 10B.

Pyrrolidines (2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (4-phenoxyphenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) Pyridine-2 (1H) -one;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1- (2,5-difluoro-4- (trifluoromethyl) phenyl) pyrrolidine;
4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2-fluoropyridine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4,4-difluoropiperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-fluoropiperidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1-(4-((3-ethyloxetane-3-yl) methoxy) phenyl) pyrrolidine; and (1R, 5S) -3- (4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3-azabicyclo [3.2 .0] Heptane.

実施例１．１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−（４−フェノキシフェニル）ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７８−０．９１（ｍ、１２Ｈ）１．７０（ｄ、Ｊ＝６．８３Ｈｚ、２Ｈ）１．８６−１．９６（ｍ、２Ｈ）１．９９（ｄ、Ｊ＝２．１７Ｈｚ、４Ｈ）２．１５−２．２５（ｍ、４Ｈ）２．５５−２．６１（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０６（ｔ、Ｊ＝８．４０Ｈｚ、２Ｈ）５．１３（ｔ、Ｊ＝７．２６Ｈｚ、２Ｈ）５．３５−５．４３（ｍ、２Ｈ）６．３５（ｄ、Ｊ＝９．１１Ｈｚ、２Ｈ）６．６２−６．６９（ｍ、２Ｈ）６．７１（ｄ、Ｊ＝８．０２Ｈｚ、２Ｈ）６．９３（ｔ、Ｊ＝７．４３Ｈｚ、１Ｈ）７．０８（ｔ、Ｊ＝９．４３Ｈｚ、２Ｈ）７．１８−７．２５（ｍ、３Ｈ）７．２７−７．３４（ｍ、３Ｈ）７．３９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４７（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）１２．０５（ｄ、Ｊ＝１２．０４Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９２４．４（Ｍ＋Ｈ）^＋。

Example 1.1
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- (4-phenoxyphenyl) pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine -1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 0.78-0.91 (m, 12H) 1.70 (d, J = 6.83 Hz, 2H) 1.86-1.96 (m, 2H) 1 .99 (d, J = 2.17Hz, 4H) 2.15-2.25 (m, 4H) 2.55-2.61 (m, 2H) 3.54 (s, 6H) 3.82 (s) , 4H) 4.06 (t, J = 8.40Hz, 2H) 5.13 (t, J = 7.26Hz, 2H) 5.35-5.43 (m, 2H) 6.35 (d, J) = 9.11Hz, 2H) 6.62-6.69 (m, 2H) 6.71 (d, J = 8.02Hz, 2H) 6.93 (t, J = 7.43Hz, 1H) 7.08 (T, J = 9.43Hz, 2H) 7.18-7.25 (m, 3H) 7.27-7.34 (m, 3H) 7.39 (d, J = 8.13Hz, 1H) 7 .47 (d, J = 8.02Hz, 1H) 12.05 (d, J = 12.04Hz, 2H); MS (ESI +) m / z 924.4 (M + H) ⁺ .

実施例１．２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［４−（２−オキソピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９２（ｍ、１２Ｈ）１．６６−１．７６（ｍ、６Ｈ）１．９１（ｄｄ、Ｊ＝１３．６１、７．５４Ｈｚ、２Ｈ）１．９５−２．０４（ｍ、４Ｈ）２．２０（ｄｄ、Ｊ＝１６．２６、３．８０Ｈｚ、６Ｈ）２．５８−２．６４（ｍ、２Ｈ）３．３９−３．４５（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０２−４．０９（ｍ、２Ｈ）５．０９−５．１９（ｍ、２Ｈ）５．３５−５．４３（ｍ、２Ｈ）６．２９（ｄ、Ｊ＝８．８９Ｈｚ、２Ｈ）６．７０−６．７８（ｍ、２Ｈ）７．０７（ｄ、Ｊ＝８．１３Ｈｚ、２Ｈ）７．２２（ｓ、１Ｈ）７．２９（ｄ、Ｊ＝８．３５Ｈｚ、２Ｈ）７．３３（ｓ、１Ｈ）７．３８（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）７．４７（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）１２．０４（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９２９．５（Ｍ＋Ｈ）^＋。

Example 1.2
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [4- (2-oxopiperidine-1-yl) phenyl] pyrrolidine-2-yl} -1H -Benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.92 (m, 12H) 1.66-1.76 (m, 6H) 1.91 (dd, J = 13.61, 7.54 Hz) , 2H) 1.95-2.04 (m, 4H) 2.20 (dd, J = 16.26, 3.80Hz, 6H) 2.58-2.64 (m, 2H) 3.39-3 .45 (m, 2H) 3.54 (s, 6H) 3.82 (s, 4H) 4.02-4.09 (m, 2H) 5.09-5.19 (m, 2H) 5.35 -5.43 (m, 2H) 6.29 (d, J = 8.89Hz, 2H) 6.70-6.78 (m, 2H) 7.07 (d, J = 8.13Hz, 2H) 7 .22 (s, 1H) 7.29 (d, J = 8.35Hz, 2H) 7.33 (s, 1H) 7.38 (d, J = 8.35Hz, 1H) 7.47 (d, J) = 8.13Hz, 1H) 12.04 (s, 2H); MS (ESI +) m / z 929.5 (M + H) ⁺ .

実施例１．３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｒ）−１−［２，５−ジフルオロ−４−（トリフルオロメチル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９４（ｍ、１２Ｈ）１．８３−２．０７（ｍ、８Ｈ）２．１４−２．２８（ｍ、４Ｈ）２．３５−２．４５（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．７５−３．９４（ｍ、４Ｈ）４．０７（ｄｄ、Ｊ＝８．１９、４．９３Ｈｚ、２Ｈ）５．１９（ｄｄ、Ｊ＝３１．５０、３．７４Ｈｚ、４Ｈ）６．４８−６．６１（ｍ、１Ｈ）７．２０−７．３５（ｍ、５Ｈ）７．４０−７．４６（ｍ、１Ｈ）７．４９−７．５６（ｍ、２Ｈ）７．５８−７．６５（ｍ、１Ｈ）１２．１２（ｄ、Ｊ＝４．６６Ｈｚ、２Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ９３６．２４（Ｍ＋Ｈ）^＋。

Example 1.3
Methyl {(2S) -1-[(2S) -2-{5-[(2S, 5R) -1- [2,5-difluoro-4- (trifluoromethyl) phenyl] -5-{2- [ (2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl]- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.94 (m, 12H) 1.83-2.07 (m, 8H) 2.14-2.28 (m, 4H) 2.35 -2.45 (m, 2H) 3.54 (s, 6H) 3.75-3.94 (m, 4H) 4.07 (dd, J = 8.19, 4.93Hz, 2H) 5.19 (Dd, J = 31.50, 3.74Hz, 4H) 6.48-6.61 (m, 1H) 7.20-7.35 (m, 5H) 7.40-7.46 (m, 1H) ) 7.49-7.56 (m, 2H) 7.58-7.65 (m, 1H) 12.12 (d, J = 4.66Hz, 2H); MS (APCI +) m / z 936.24 ( M + H) ⁺ .

実施例１．４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（２−フルオロピリジン−４−イル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７７−０．９１（ｍ、１２Ｈ）１．３２（ｔｄ、Ｊ＝１４．９９、７．４３Ｈｚ、１Ｈ）１．５３（ｄｔ、Ｊ＝２１．２３、６．６３Ｈｚ、１Ｈ）１．７４（ｄｄ、Ｊ＝１１．９３、６．０７Ｈｚ、２Ｈ）１．８６−２．０５（ｍ、６Ｈ）２．１４−２．２３（ｍ、４Ｈ）３．５４（ｓ、６Ｈ）３．７７−３．８６（ｍ、４Ｈ）４．０５−４．１０（ｍ、２Ｈ）５．１１−５．１８（ｍ、２Ｈ）５．４５−５．５９（ｍ、２Ｈ）５．７９（ｓ、１Ｈ）６．１８−６．２３（ｍ、１Ｈ）７．０３−７．１３（ｍ、２Ｈ）７．２３（ｓ、１Ｈ）７．２９（ｄ、Ｊ＝８．３５Ｈｚ、２Ｈ）７．３４（ｄ、Ｊ＝１．５２Ｈｚ、１Ｈ）７．４２（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）７．４７−７．５６（ｍ、２Ｈ）１２．１１（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８５１．３（Ｍ＋Ｈ）^＋。

Example 1.4
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (2-fluoropyridin-4-yl) -5- {2-[(2S) -1- {(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazole-2 -Il} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.77-0.91 (m, 12H) 1.32 (td, J = 14.99, 7.43 Hz, 1H) 1.53 (dt, J = 21) .23, 6.63Hz, 1H) 1.74 (dd, J = 11.93, 6.07Hz, 2H) 1.86-2.05 (m, 6H) 2.14.2.23 (m, 4H) ) 3.54 (s, 6H) 3.77-3.86 (m, 4H) 4.05-4.10 (m, 2H) 5.11-5.18 (m, 2H) 5.45-5 .59 (m, 2H) 5.79 (s, 1H) 6.18-6.23 (m, 1H) 7.03-7.13 (m, 2H) 7.23 (s, 1H) 7.29 (D, J = 8.35Hz, 2H) 7.34 (d, J = 1.52Hz, 1H) 7.42 (d, J = 8.35Hz, 1H) 7.47-7.56 (m, 2H) ) 12.11 (s, 2H); MS (ESI +) m / z 851.3 (M + H) ⁺ .

実施例１．５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４，４−ジフルオロピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）dｐｐｍ０．７４−０．９３（ｍ、１２Ｈ）１．６３−１．７４（ｍ、２Ｈ）１．８５−２．０６（ｍ、１２Ｈ）２．１９（ｄｄ、Ｊ＝９．４９、５．３７Ｈｚ、４Ｈ）２．８６−２．９６（ｍ、４Ｈ）３．５４（ｓ、６Ｈ）３．７６−３．８６（ｍ、４Ｈ）４．０７（ｔ、Ｊ＝８．２４Ｈｚ、２Ｈ）５．０９−５．２０（ｍ、２Ｈ）５．３３−５．４２（ｍ、２Ｈ）５．９２（ｄ、Ｊ＝１２．９０Ｈｚ、２Ｈ）７．０７（ｔ、Ｊ＝７．３７Ｈｚ、２Ｈ）７．２１（ｓ、１Ｈ）７．２６−７．３３（ｍ、３Ｈ）７．４１（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）１２．０８（ｄ、Ｊ＝１２．９０Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９８７．５（Ｍ＋Ｈ）^＋。

Example 1.5
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4,5-difluoropiperidin-1-yl) -3,5-difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) dppm 0.74-0.93 (m, 12H) 1.63-1.74 (m, 2H) 1.85-2.06 (m, 12H) 2.19 (Dd, J = 9.49, 5.37Hz, 4H) 2.86-2.96 (m, 4H) 3.54 (s, 6H) 3.76-3.86 (m, 4H) 4.07 (T, J = 8.24Hz, 2H) 5.09-5.20 (m, 2H) 5.33-5.42 (m, 2H) 5.92 (d, J = 12.90Hz, 2H) 7 .07 (t, J = 7.37Hz, 2H) 7.21 (s, 1H) 7.26-7.33 (m, 3H) 7.41 (d, J = 8.13Hz, 1H) 7.49 (D, J = 8.13Hz, 1H) 12.08 (d, J = 12.90Hz, 2H); MS (ESI +) m / z987.5 (M + H) ⁺ .

実施例１．６
メチル｛１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フルオロピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９１（ｍ、１２Ｈ）１．６３−１．７１（ｍ、６Ｈ）１．７６−１．９７（ｍ、４Ｈ）１．９８−２．０７（ｍ、４Ｈ）２．１４−２．２３（ｍ、４Ｈ）２．７１−２．７８（ｍ、２Ｈ）２．９０−３．００（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０６（ｔ、Ｊ＝８．７３Ｈｚ、２Ｈ）４．５８−４．７８（ｍ、１Ｈ）５．１１−５．１８（ｍ、２Ｈ）５．３３−５．４３（ｍ、２Ｈ）５．９０（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）７．０７（ｔ、Ｊ＝７．３７Ｈｚ、２Ｈ）７．２０（ｓ、１Ｈ）７．２６−７．３２（ｍ、３Ｈ）７．４１（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．４９（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）１２．０７（ｄ、Ｊ＝１６．４８Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９６９．５（Ｍ＋Ｈ）
^＋。

Example 1.6
Methyl {1-[(2S) -2- {5-[(2R, 5R) -1- [3,5-difluoro-4- (4-fluoropiperidin-1-yl) phenyl] -5- {2- [(2S) -1- {2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.91 (m, 12H) 1.63-1.71 (m, 6H) 1.76-1.97 (m, 4H) 1.98 -2.07 (m, 4H) 2.14-2.23 (m, 4H) 2.71-2.78 (m, 2H) 2.90-3.00 (m, 2H) 3.54 (s) , 6H) 3.82 (s, 4H) 4.06 (t, J = 8.73Hz, 2H) 4.58-4.78 (m, 1H) 5.11-5.18 (m, 2H) 5 .33-5.43 (m, 2H) 5.90 (d, J = 12.69Hz, 2H) 7.07 (t, J = 7.37Hz, 2H) 7.20 (s, 1H) 7.26 -7.32 (m, 3H) 7.41 (d, J = 8.24Hz, 1H) 7.49 (d, J = 8.24Hz, 1H) 12.07 (d, J = 16.48Hz, 2H) ); MS (ESI +) m / z 969.5 (M + H)
⁺ .

実施例１．７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛４−［（３−エチルオキセタン−３−イル）メトキシ］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ１２．２６−１１．９８（ｍ、２Ｈ）、７．４４（ｄ、Ｊ＝８．２、１Ｈ）、７．３７（ｄ、Ｊ＝８．２、１Ｈ）、７．３３−７．１８（ｍ、４Ｈ）、７．０５（ｔ、Ｊ＝８．１、２Ｈ）、６．６２−６．５３（ｍ、２Ｈ）、６．２６（ｄ、Ｊ＝８．８、２Ｈ）、５．４０−５．３０（ｍ、２Ｈ）、５．１７−５．０８（ｍ、２Ｈ）、４．２９（ｄ、Ｊ＝５．７、２Ｈ）、４．２２（ｄ、Ｊ＝５．８、２Ｈ）、４．０６（ｔ、Ｊ＝８．３、２Ｈ）、３．８６−３．７５（ｍ、６Ｈ）、３．５３（ｓ、６Ｈ）、２．５４（ｓ、２Ｈ）、２．２４−２．１２（ｍ、４Ｈ）、２．０６−１．８３（ｍ、６Ｈ）、１．７５−１．６２（ｍ、４Ｈ）、０．９１−０．７４（ｍ、１５Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９４６．５（Ｍ＋Ｈ）^＋。

Example 1.7
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {4-[(3-ethyloxetane-3-yl) methoxy] phenyl} -5- {2 -[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl ] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ12.26-11.98 (m, 2H), 7.44 (d, J = 8.2, 1H), 7.37 (d, J = 8.2) , 1H), 7.33-7.18 (m, 4H), 7.05 (t, J = 8.1, 2H), 6.62-6.53 (m, 2H), 6.26 (d) , J = 8.8, 2H), 5.40-5.30 (m, 2H), 5.17-5.08 (m, 2H), 4.29 (d, J = 5.7, 2H) 4.22 (d, J = 5.8, 2H), 4.06 (t, J = 8.3, 2H), 3.86-3.75 (m, 6H), 3.53 (s, 6H), 2.54 (s, 2H), 2.24-2.12 (m, 4H), 2.06-1.83 (m, 6H), 1.75-1.62 (m, 4H) , 0.91-0.74 (m, 15H); MS (ESI +) m / z 946.5 (M + H) ⁺ .

実施例１．８
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛４−［（１Ｒ，５Ｓ）−３−アザビシクロ［３．２．０］ヘプト−３−イル］−３，５−ジフルオロフェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８２（ｓ、１２Ｈ）１．６１（ｓ、３Ｈ）１．７１（ｄ、２Ｈ）１．９７（ｍ、９Ｈ）２．２０（ｓ、２Ｈ）２．７４−２．７８（ｍ、２Ｈ）２．８５（ｓ、５Ｈ）３．５３（ｓ、６Ｈ）３．８２（ｓ、３Ｈ）４．０６（ｓ、２Ｈ）５．１４（ｓ、２Ｈ）５．３８（ｓ、２Ｈ）５．９１（ｓ、２Ｈ）７．０９（ｓ、１Ｈ）７．３７（ｍ、６Ｈ）７．６３（ｓ、１Ｈ）７．８８（ｓ、１Ｈ）１２．０５（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９６３．５（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９６１．４（Ｍ−Ｈ）⁻。

Example 1.8
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {4-[(1R, 5S) -3-azabicyclo [3.2.0] hepto-3] -Il] -3,5-difluorophenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl ] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.82 (s, 12H) 1.61 (s, 3H) 1.71 (d, 2H) 1.97 (m, 9H) 2.20 (s, 2H) ) 2.74-2.78 (m, 2H) 2.85 (s, 5H) 3.53 (s, 6H) 3.82 (s, 3H) 4.06 (s, 2H) 5.14 (s) , 2H) 5.38 (s, 2H) 5.91 (s, 2H) 7.09 (s, 1H) 7.37 (m, 6H) 7.63 (s, 1H) 7.88 (s, 1H) ) 12.05 (s, 2H); MS (ESI +) m / z 963.5 (M + H) ⁺ , (ESI-) m / z 961.4 (MH) ⁻ .

The following Example compounds 2.1 to 2.17 can be prepared from the substituted pyrrolidines listed appropriately according to the methods of General Procedure 8.1, General Procedure 9D (PtO ₂ ) and General Procedure 10B.

Pyrrolidines 2- (4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) phenyl) oxazole;
(2R, 5R) -1- (4-chloro-3-fluorophenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
(2R, 5R) -1- (4- (1,3-dioxane-5-yloxy) phenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
(2R, 5R) -1- (4-((1,3-dioxolane-4-yl) methoxy) phenyl) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine;
(2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) -1-(4-((3-ethyloxetane-3-yl) methoxy) -3,5-difluorophenyl) pyrrolidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,3,5,6-tetrafluorophenyl) piperidine;
(2R, 5R) -2.5-bis (4-chloro-3-nitrophenyl) -1- (3-fluoro-4- (methylsulfonyl) phenyl) pyrrolidine ((2R, 5R) -2.5-bis (4-Chloro-3-nitrophenyl) -1- (obtained by mCPBA oxidation of 3-fluoro-4- (methylthio) phenyl) pyrrolidine);
4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -N-tert-butyl-2-fluoroaniline;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-methylpiperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (3-phenylpropyl) Piperidine;
8-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -8-azaspiro [4.5] Decane;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (naphthalene-2-yl) ) Piperidine;
2- (1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) piperidine-4-yl) Pyridine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4- (trimethylsilyl)) Phenyl) piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (naphthalene-1-yl) ) Piperidine;
1-(4-((2R, 5R) -2,5-bis (4-chloro-2-fluoro-5-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -3,5- Dimethylpiperidine; and 1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4- (4) -(Trifluoromethyl) phenyl) piperidine.

実施例２．１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［４−（１，３−オキサゾール−２−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９１（ｍ、１２Ｈ）１．７０−１．７９（ｍ、２Ｈ）１．８９（ｄｄｄ、Ｊ＝１４．２０、７．０５、６．９４Ｈｚ、２Ｈ）１．９５−２．０４（ｍ、４Ｈ）２．１３−２．２３（ｍ、４Ｈ）２．５５−２．６１（ｍ、２Ｈ）３．５３（ｓ、６Ｈ）３．７７−３．８４（ｍ、４Ｈ）４．０５（ｔ、Ｊ＝８．６７Ｈｚ、２Ｈ）５．０９−５．１８（ｍ、２Ｈ）５．４６−５．５４（ｍ、２Ｈ）６．４５（ｄ、Ｊ＝８．８９Ｈｚ、２Ｈ）７．０８（ｔ、Ｊ＝７．７５Ｈｚ、２Ｈ）７．１３（ｓ、１Ｈ）７．２３（ｓ、１Ｈ）７．２８（ｄ、Ｊ＝８．２４Ｈｚ、２Ｈ）７．３３（ｓ、１Ｈ）７．３９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４５−７．５６（ｍ、３Ｈ）７．９４（ｓ、１Ｈ）１２．０６（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８９９．４（Ｍ＋Ｈ）^＋。

Example 2.1
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [4- (1,3-oxazol-2-yl) phenyl] pyrrolidine-2-yl}- 1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.91 (m, 12H) 1.70-1.79 (m, 2H) 1.89 (ddd, J = 14.20, 7.05) , 6.94Hz, 2H) 1.95-2.04 (m, 4H) 2.13-2.23 (m, 4H) 2.55-2.61 (m, 2H) 3.53 (s, 6H) ) 3.77-3.84 (m, 4H) 4.05 (t, J = 8.67Hz, 2H) 5.09-5.18 (m, 2H) 5.46-5.54 (m, 2H) ) 6.45 (d, J = 8.89Hz, 2H) 7.08 (t, J = 7.75Hz, 2H) 7.13 (s, 1H) 7.23 (s, 1H) 7.28 (d) , J = 8.24Hz, 2H) 7.33 (s, 1H) 7.39 (d, J = 8.13Hz, 1H) 7.45-7.56 (m, 3H) 7.94 (s, 1H) ) 12.06 (s, 2H); MS (ESI +) m / z 899.4 (M + H) ⁺ .

実施例２．２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−クロロ−３−フルオロフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７７−０．９０（ｍ、１２Ｈ）１．６６−１．７８（ｍ、２Ｈ）１．８８−１．９５（ｍ、２Ｈ）１．９６−２．０６（ｍ、４Ｈ）２．１５−２．２４（ｍ、４Ｈ）２．５４−２．６０（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．７９−３．８６（ｍ、４Ｈ）４．０６（ｔ、Ｊ＝８．４６Ｈｚ、２Ｈ）５．１０−５．１８（ｍ、２Ｈ）５．３７−５．４５（ｍ、２Ｈ）６．１６（ｄｄ、Ｊ＝９．４９、２．０１Ｈｚ、１Ｈ）６．２２（ｄｄ、Ｊ＝１３．５５、２．０６Ｈｚ、１Ｈ）７．００−７．１１（ｍ、３Ｈ）７．２２（ｓ、１Ｈ）７．２８（ｄ、Ｊ＝８．５７Ｈｚ、２Ｈ）７．３２（ｓ、１Ｈ）７．４０（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．４７（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）１２．０７（ｄ、Ｊ＝２．９３Ｈｚ、２Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ８８４（Ｍ＋Ｈ）^＋。

Example 2.2
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-chloro-3-fluorophenyl) -5- {2-[(2S) -1-] {(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazole-2 -Il} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.77-0.90 (m, 12H) 1.66-1.78 (m, 2H) 1.88-1.95 (m, 2H) 1.96 -2.06 (m, 4H) 2.15-2.24 (m, 4H) 2.54-2.60 (m, 2H) 3.54 (s, 6H) 3.79-3.86 (m) , 4H) 4.06 (t, J = 8.46Hz, 2H) 5.10-5.18 (m, 2H) 5.37-5.45 (m, 2H) 6.16 (dd, J = 9) .49, 2.01Hz, 1H) 6.22 (dd, J = 13.55, 2.06Hz, 1H) 7.00-7.11 (m, 3H) 7.22 (s, 1H) 7.28 (D, J = 8.57Hz, 2H) 7.32 (s, 1H) 7.40 (d, J = 8.24Hz, 1H) 7.47 (d, J = 8.13Hz, 1H) 12.07 (D, J = 2.93Hz, 2H); MS (APCI +) m / z 884 (M + H) ⁺ .

実施例２．３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（１，３−ジオキサン−５−イルオキシ）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．２８−１１．９８（ｍ、２Ｈ）、７．４５（ｄ、Ｊ＝８．１、１Ｈ）、７．３７（ｄ、Ｊ＝８．２、１Ｈ）、７．３２−７．２３（ｍ、３Ｈ）、７．２１（ｓ、１Ｈ）、７．１２−７．０１（ｍ、２Ｈ）、６．６２−６．５１（ｍ、２Ｈ）、６．２４（ｄ、Ｊ＝８．９、２Ｈ）、５．４０−５．２７（ｍ、２Ｈ）、５．１８−５．０９（ｍ、２Ｈ）、４．７２（ｄ、Ｊ＝６．１、１Ｈ）、４．６７（ｄ、Ｊ＝６．２、１Ｈ）、４．０６（ｔ、Ｊ＝８．４、２Ｈ）、４．０１−３．７５（ｍ、７Ｈ）、３．６８−３．５８（ｍ、２Ｈ）、３．５２（ｄ、Ｊ＝１５．９、６Ｈ）、２．２８−１．８３（ｍ、１２Ｈ）、１．７４−１．６２（ｍ、２Ｈ）、０．９３−０．７３（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９３４．５（Ｍ＋Ｈ）^＋。

Example 2.3
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (1,3-dioxan-5-yloxy) phenyl] -5-{2- [ (2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl]- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.28-11.98 (m, 2H), 7.45 (d, J = 8.1, 1H), 7.37 (d, J = 8.2) , 1H), 7.32-7.23 (m, 3H), 7.21 (s, 1H), 7.12-7.01 (m, 2H), 6.62-6.51 (m, 2H) ), 6.24 (d, J = 8.9, 2H), 5.40-5.27 (m, 2H), 5.18-5.09 (m, 2H), 4.72 (d, J) = 6.1, 1H), 4.67 (d, J = 6.2, 1H), 4.06 (t, J = 8.4, 2H), 4.01-3.75 (m, 7H) 3.68-3.58 (m, 2H), 3.52 (d, J = 15.9, 6H), 2.28-1.83 (m, 12H), 1.74-1.62 ( m, 2H), 0.93-0.73 (m, 12H); MS (ESI +) m / z934.5 (M + H) ⁺ .

実施例２．４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（１，３−ジオキソラン−４−イルメトキシ）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．２７−１１．９５（ｍ、２Ｈ）、７．４３（ｄ、Ｊ＝８．１、１Ｈ）、７．３５（ｄ、Ｊ＝８．２、１Ｈ）、７．３２−７．２２（ｍ、３Ｈ）、７．１９（ｓ、１Ｈ）、７．０３（ｔ、Ｊ＝７．４、２Ｈ）、６．５９−６．４７（ｍ、２Ｈ）、６．２３（ｄ、Ｊ＝８．８、２Ｈ）、５．３９−５．２７（ｍ、２Ｈ）、５．１６−５．０４（ｍ、２Ｈ）、４．８３（ｄ、Ｊ＝２．６、１Ｈ）、４．７４（ｓ、１Ｈ）、４．２２−４．１２（ｍ、１Ｈ）、４．０４（ｔ、Ｊ＝８．３、２Ｈ）、３．８８（ｔ、Ｊ＝７．５、１Ｈ）、３．８３−３．６７（ｍ、６Ｈ）、３．５７−３．４７（ｍ、７Ｈ）、２．２９−１．８０（ｍ、１２Ｈ）、１．７４−１．６０（ｍ、２Ｈ）、０．９３−０．７１（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９３４．４（Ｍ＋Ｈ）^＋。

Example 2.4
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (1,3-dioxolan-4-ylmethoxy) phenyl] -5-{2- [ (2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl]- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.27-11.95 (m, 2H), 7.43 (d, J = 8.1, 1H), 7.35 (d, J = 8.2) , 1H), 7.32-7.22 (m, 3H), 7.19 (s, 1H), 7.03 (t, J = 7.4, 2H), 6.59-6.47 (m) , 2H), 6.23 (d, J = 8.8, 2H), 5.39-5.27 (m, 2H), 5.16-5.04 (m, 2H), 4.83 (d) , J = 2.6, 1H), 4.74 (s, 1H), 4.22-4.12 (m, 1H), 4.04 (t, J = 8.3, 2H), 3.88 (T, J = 7.5, 1H), 3.83-3.67 (m, 6H), 3.57-3.47 (m, 7H), 2.29-1.80 (m, 12H) 1.74-1.60 (m, 2H), 0.93-0.71 (m, 12H); MS (ESI +) m / z 934.4 (M + H) ⁺ .

実施例２．５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−｛４−［（３−エチルオキセタン−３−イル）メトキシ］−３，５−ジフルオロフェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ１２．３０−１２．０２（ｍ、２Ｈ）、７．４７（ｄ、Ｊ＝８．３、１Ｈ）、７．４０（ｄ、Ｊ＝８．３、１Ｈ）、７．３４−７．１６（ｍ、４Ｈ）、７．０６（ｔ、Ｊ＝７．０、２Ｈ）、５．９８（ｄ、Ｊ＝１２．３、２Ｈ）、５．４６−５．３０（ｍ、２Ｈ）、５．２４−５．０５（ｍ、２Ｈ）、４．２９（ｄ、Ｊ＝５．５、２Ｈ）、４．２１（ｄ、Ｊ＝５．８、２Ｈ）、４．０５（ｔ、Ｊ＝８．２、２Ｈ）、３．９０−３．７２（ｍ、６Ｈ）、３．５２（ｓ、６Ｈ）、２．２７−１．８１（ｍ、１２Ｈ）、１．７３−１．６０（ｍ、４Ｈ）、０．９１−０．６９（ｍ、１５Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９８２．４（Ｍ＋Ｈ）^＋。

Example 2.5
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- {4-[(3-ethyloxetane-3-yl) methoxy] -3,5-difluorophenyl] } -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl } Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ12.30-12.02 (m, 2H), 7.47 (d, J = 8.3, 1H), 7.40 (d, J = 8.3) , 1H), 7.34-7.16 (m, 4H), 7.06 (t, J = 7.0, 2H), 5.98 (d, J = 12.3, 2H), 5.46 -5.30 (m, 2H), 5.24-5.05 (m, 2H), 4.29 (d, J = 5.5, 2H), 4.21 (d, J = 5.8, 2H), 4.05 (t, J = 8.2, 2H), 3.90-3.72 (m, 6H), 3.52 (s, 6H), 2.27-1.81 (m, 12H), 1.73-1.60 (m, 4H), 0.91-0.69 (m, 15H); MS (ESI +) m / z982.4 (M + H) ⁺ .

実施例２．６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（６−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝−１−［２，３，５，６−テトラフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ１２．１０（ｄｄ、Ｊ＝５８．０、３７．７、２Ｈ）、７．５２−７．２１（ｍ、６Ｈ）、７．０７（ｔ、Ｊ＝８．１、２Ｈ）、５．５２−５．２９（ｍ、２Ｈ）、５．１７−５．０３（ｍ、２Ｈ）、４．１２−３．９３（ｍ、２Ｈ）、３．８８−３．６６（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、２．８７−２．７１（ｍ、４Ｈ）、２．２７−１．７６（ｍ、１４Ｈ）、１．５０−１．３２（ｍ、６Ｈ）、０．９３−０．７０（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９８７．３（Ｍ＋Ｈ）^＋。

Example 2.6
Methyl {(2S) -1-[(2S) -2-(6-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} -1- [2,3,5,6-tetrafluoro-4- (piperidine-1-yl) phenyl] Pyrrolidine-2-yl} -1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ12.10 (dd, J = 58.0, 37.7, 2H), 7.52-7.21 (m, 6H), 7.07 (t, J) = 8.1, 2H), 5.52-5.29 (m, 2H), 5.17-5.03 (m, 2H), 4.12-3.93 (m, 2H), 3.88 -3.66 (m, 4H), 3.53 (s, 6H), 2.87-2.71 (m, 4H), 2.27-1.76 (m, 14H), 1.501-1 .32 (m, 6H), 0.93-0.70 (m, 12H); MS (ESI +) m / z987.3 (M + H) ⁺ .

実施例２．７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［３−フルオロ−４−（メチルスルホニル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）dｐｐｍ０．８１−０．９７（ｍ、１２Ｈ）、１．３０（ｓ、２Ｈ）、１．８２（ｄ、Ｊ＝４．２Ｈｚ、２Ｈ）、１．９０−２．３５（ｍ、１２Ｈ）、３．６０（ｓ、６Ｈ）、３．８８（ｓ、３Ｈ）、４．１３（ｔ、Ｊ＝８．３Ｈｚ、２Ｈ）、５．２０（ｔ、Ｊ＝７．３Ｈｚ、２Ｈ）、５．６２（ｓ、２Ｈ）、６．２６−６．４０（ｍ、Ｊ＝９．５Ｈｚ、２Ｈ）、７．１５（ｄ、Ｊ＝７．０Ｈｚ、２Ｈ）、７．３０（ｓ、１Ｈ）、７．３２−７．４５（ｍ、４Ｈ）、７．４９（ｄ、Ｊ＝８．２Ｈｚ、１Ｈ）、７．５６（ｄ、Ｊ＝８．１Ｈｚ、１Ｈ）、１２．１６（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９２８．４（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９２６．３（Ｍ−Ｈ）⁻。

Example 2.7
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [3-fluoro-4- (methylsulfonyl) phenyl] -5- {2-[(2S)) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) dppm 0.81-0.97 (m, 12H), 1.30 (s, 2H), 1.82 (d, J = 4.2Hz, 2H), 1. 90-2.35 (m, 12H), 3.60 (s, 6H), 3.88 (s, 3H), 4.13 (t, J = 8.3Hz, 2H), 5.20 (t, J = 7.3Hz, 2H), 5.62 (s, 2H), 6.26-6.40 (m, J = 9.5Hz, 2H), 7.15 (d, J = 7.0Hz, 2H) ), 7.30 (s, 1H), 7.32-7.45 (m, 4H), 7.49 (d, J = 8.2Hz, 1H), 7.56 (d, J = 8.1Hz) , 1H), 12.16 (s, 2H); MS (ESI +) m / z 928.4 (M + H) ⁺ , (ESI-) m / z 926.3 (MH) ⁻ .

実施例２．８
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−｛４−［アセチル（ｔｅｒｔ−ブチル）アミノ］−３−フルオロフェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
４−（（２Ｒ，５Ｒ）−２，５−ビス（４−クロロ−３−ニトロフェニル）ピロリジン−１−イル）−Ｎ−ｔｅｒｔ−ブチル−２−フルオロアニリンを原料として、上記で示した手順の最初の生成物は、メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（ｔｅｒｔ−ブチルアミノ）−３−フルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート（ＡＣＤ Ｎａｍｅ ｖ１２）であった。無水酢酸／ピリジンとの反応によってＮ−アセチル基を付加して、標題化合物を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７３−０．９０（ｍ、１２Ｈ）、１．１３（ｄ、Ｊ＝５．２０Ｈｚ、９Ｈ）、１．３７−１．４４（ｍ、４Ｈ）、１．６２−１．７２（ｍ、２Ｈ）、１．９２−２．０２（ｍ、９Ｈ）、２．１０−２．２６（ｍ、５Ｈ）、２．５１−２．５８（ｍ、２Ｈ）、３．５２（ｓ、６Ｈ）、３．７３−３．８５（ｍ、４Ｈ）、３．９８−４．１２（ｍ、２Ｈ）、５．０９−５．１７（ｍ、２Ｈ）、５．３６−５．４８（ｍ、３Ｈ）、６．０８−６．１８（ｍ、３Ｈ）、６．７４−６．８７（ｍ、１Ｈ）、７．０８（ｄｄ、Ｊ＝１３．７２、８．２９Ｈｚ、３Ｈ）、７．２０（ｓ、１Ｈ）、７．２４−７．３１（ｍ、４Ｈ）、７．４０（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４８（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、１２．０１（ｓ、１Ｈ）、１２．１７（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９６４（Ｍ＋Ｈ）^＋。

Example 2.8
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- {4- [acetyl (tert-butyl) amino] -3-fluorophenyl} -5- {2 -[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-6-yl} pyrrolidine-2-yl ] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate 4-((2R, 5R) -2,5-bis (4-chloro-) Using 3-nitrophenyl) pyrrolidine-1-yl) -N-tert-butyl-2-fluoroaniline as a raw material, the first product of the procedure shown above is methyl {(2S) -1-[(2S)). -2- {6-[(2R, 5R) -1- [4- (tert-butylamino) -3-fluorophenyl] -5- {2-[(2S) -1-{(2S) -2- [(Methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1- Il] -3-methyl-1-oxobutan-2-yl} carbamate (ACD Name v12). An N-acetyl group was added by reaction with acetic anhydride / pyridine to give the title compound. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.73-0.90 (m, 12H), 1.13 (d, J = 5.20 Hz, 9H), 1.37-1.44 (m, 4H) ), 1.62-1.72 (m, 2H), 1.92-2.02 (m, 9H), 2.10-2.26 (m, 5H), 2.51-2.58 (m) , 2H), 3.52 (s, 6H), 3.73-3.85 (m, 4H), 3.98-4.12 (m, 2H), 5.09-5.17 (m, 2H) ), 5.36-5.48 (m, 3H), 6.08-6.18 (m, 3H), 6.74-6.87 (m, 1H), 7.08 (dd, J = 13) .72, 8.29Hz, 3H), 7.20 (s, 1H), 7.24-7.31 (m, 4H), 7.40 (d, J = 8.24Hz, 1H), 7.48 (D, J = 8.13Hz, 1H), 12.01 (s, 1H), 12.17 (s, 1H); MS (ESI +) m / z 964 (M + H) ⁺ .

実施例２．９
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−メチルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７５−０．９０（ｍ、１２Ｈ）、１．０５−１．１８（ｍ、２Ｈ）、１．２４−１．３７（ｍ、２Ｈ）、１．４５−１．５４（ｍ、２Ｈ）、１．６２−１．７３（ｍ、２Ｈ）、１．８４−２．０５（ｍ、７Ｈ）、２．１２−２．２５（ｍ、５Ｈ）、２．６９−２．８１（ｍ、４Ｈ）、３．５２（ｓ、６Ｈ）、３．７７−３．８６（ｍ、４Ｈ）、４．０５（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）、５．１０−５．１８（ｍ、２Ｈ）、５．３５（ｑ、Ｊ＝７．３４Ｈｚ、２Ｈ）、５．８７（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）、７．０２−７．１０（ｍ、２Ｈ）、７．１９（ｓ、１Ｈ）、７．２４−７．３２（ｍ、３Ｈ）、７．３９（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４７（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、１２．０６（ｄ、Ｊ＝２０．９３Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９６６（Ｍ＋Ｈ）^＋。

Example 2.9
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [3,5-difluoro-4- (4-methylpyrrolidine-1-yl) phenyl] -5] -5 -{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.75-0.90 (m, 12H), 1.05-1.18 (m, 2H), 1.24-1.37 (m, 2H), 1.45-1.54 (m, 2H), 1.62-1.73 (m, 2H), 1.84-2.05 (m, 7H), 2.12-2.25 (m, 5H) ) 2.69-2.81 (m, 4H), 3.52 (s, 6H), 3.77-3.86 (m, 4H), 4.05 (t, J = 8.35Hz, 2H) ), 5.10-5.18 (m, 2H), 5.35 (q, J = 7.34Hz, 2H), 5.87 (d, J = 12.69Hz, 2H), 7.02-7 .10 (m, 2H), 7.19 (s, 1H), 7.24-7.32 (m, 3H), 7.39 (d, J = 8.24Hz, 1H), 7.47 (d) , J = 8.13Hz, 1H) 12.06 (d, J = 20.93Hz, 2H); MS (ESI +) m / z 966 (M + H) ⁺ .

実施例２．１０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（３−フェニルプロピル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７２−０．９５（ｍ、１２Ｈ）、１．００−１．３１（ｍ、９Ｈ）、１．４６−１．５９（ｍ、４Ｈ）、１．６１−１．７９（ｍ、２Ｈ）、１．８３−２．０８（ｍ、６Ｈ）、２．１１−２．２７（ｍ、４Ｈ）、２．７７（ｓ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．４６Ｈｚ、２Ｈ）、５．０８−５．１９（ｍ、２Ｈ）、５．２８−５．４６（ｍ、２Ｈ）、５．８８（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）、７．０１−７．１０（ｍ、２Ｈ）、７．１０−７．３３（ｍ、９Ｈ）、７．４０（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、７．４８（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、１１．７１−１２．５１（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６９（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０６７（Ｍ−Ｈ）⁻。

Example 2.10
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (3-phenylpropyl) piperidine-1-yl) ] Phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.72-0.95 (m, 12H), 1.00-1.31 (m, 9H), 1.46-1.59 (m, 4H), 1.61-1.79 (m, 2H), 1.83-2.08 (m, 6H), 2.11-2.27 (m, 4H), 2.77 (s, 4H), 3. 54 (s, 6H), 3.82 (s, 4H), 4.06 (t, J = 8.46Hz, 2H), 5.08-5.19 (m, 2H), 5.28-5. 46 (m, 2H), 5.88 (d, J = 12.79Hz, 2H), 7.01-7.10 (m, 2H), 7.10-7.33 (m, 9H), 7. 40 (d, J = 8.13Hz, 1H), 7.48 (d, J = 8.13Hz, 1H), 11.71-12.51 (m, 2H); MS (ESI +) m / z 1069 (M + H) ) ⁺ ; MS (ESI-) m / z 1067 (MH) ^- .

実施例２．１１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（８−アザスピロ［４．５］デク−８−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７３−０．９３（ｍ、１２Ｈ）、１．２９−１．４３（ｍ、９Ｈ）、１．５２（ｔ、Ｊ＝６．８３Ｈｚ、５Ｈ）、１．６８（ｓ、２Ｈ）、１．８１−２．０８（ｍ、６Ｈ）、２．１０−２．２６（ｍ、４Ｈ）、２．７５（ｓ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．４０Ｈｚ、２Ｈ）、５．０９−５．１９（ｍ、２Ｈ）、５．２９−５．４６（ｍ、２Ｈ）、５．８８（ｄ、Ｊ＝１２．５８Ｈｚ、２Ｈ）、７．０３−７．１１（ｍ、２Ｈ）、７．２０（ｓ、１Ｈ）、７．２５−７．３３（ｍ、３Ｈ）、７．４０（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、１１．６３−１２．５７（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１００５（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１００３（Ｍ−Ｈ）⁻。

Example 2.11.
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (8-azaspiro [4.5] dex-8-yl) -3,5- Difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.73-0.93 (m, 12H), 1.29-1.43 (m, 9H), 1.52 (t, J = 6.83Hz, 5H) ), 1.68 (s, 2H), 1.81-2.08 (m, 6H), 2.10-2.26 (m, 4H), 2.75 (s, 4H), 3.54 ( s, 6H), 3.82 (s, 4H), 4.06 (t, J = 8.40Hz, 2H), 5.09-5.19 (m, 2H), 5.29-5.46 ( m, 2H), 5.88 (d, J = 12.58Hz, 2H), 7.03-7.11 (m, 2H), 7.20 (s, 1H), 7.25-7.33 ( m, 3H), 7.40 (d, J = 8.24Hz, 1H), 7.49 (d, J = 8.24Hz, 1H), 11.63-12.57 (m, 2H); MS ( ESI +) m / z1005 (M + H) ⁺ ; MS (ESI−) m / z1003 (MH) ⁻ .

実施例２．１２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（２−ナフチル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９１（ｍ、１２Ｈ）、１．２４（ｄ、Ｊ＝２．２８Ｈｚ、２Ｈ）、１．６３−２．０８（ｍ、１２Ｈ）、２．２０（ｓ、４Ｈ）、２．８６−３．１９（ｍ、５Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．２９Ｈｚ、２Ｈ）、５．１０−５．２２（ｍ、２Ｈ）、５．３２−５．４８（ｍ、２Ｈ）、５．９３（ｄ、Ｊ＝１２．９０Ｈｚ、２Ｈ）、７．０３−７．１６（ｍ、２Ｈ）、７．１９−７．３６（ｍ、４Ｈ）、７．３９−７．５５（ｍ、５Ｈ）、７．６９−７．８９（ｍ、４Ｈ）、１１．７１−１２．６３（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０７７（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０７５（Ｍ−Ｈ）⁻。

Example 2.12.
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (2-naphthyl) piperidine-1-yl]] Phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5- Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.91 (m, 12H), 1.24 (d, J = 2.28 Hz, 2H), 1.63-2.08 (m, 12H) , 2.20 (s, 4H), 2.86-3.19 (m, 5H), 3.53 (s, 6H), 3.82 (s, 4H), 4.06 (t, J =) 8.29Hz, 2H), 5.10-5.22 (m, 2H), 5.32-5.48 (m, 2H), 5.93 (d, J = 12.90Hz, 2H), 7. 03-7.16 (m, 2H), 7.19-7.36 (m, 4H), 7.39-7.55 (m, 5H), 7.69-7.89 (m, 4H), 11.71-12.63 (m, 2H); MS (ESI +) m / z 1077 (M + H) ⁺ ; MS (ESI-) m / z 1075 (MH) ⁻ .

実施例２．１３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（ピリジン−２−イル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７１−１．０２（ｍ、１２Ｈ）、１．６２−１．８３（ｍ、６Ｈ）、１．８１−２．０８（ｍ、７Ｈ）、２．１０−２．２９（ｍ、４Ｈ）、２．４７−２．６３（ｍ、２Ｈ）、２．８１−３．０７（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．８９Ｈｚ、２Ｈ）、５．１０−５．２１（ｍ、２Ｈ）、５．３１−５．４７（ｍ、２Ｈ）、５．９１（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）、７．０４−７．１３（ｍ、２Ｈ）、７．１４−７．２０（ｍ、１Ｈ）、７．２０−７．３４（ｍ、５Ｈ）、７．４１（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）、７．６２−７．７２（ｍ、１Ｈ）、８．４５（ｄ、Ｊ＝４．５５Ｈｚ、１Ｈ）、１１．７４−１２．５７（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０２８（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０２６（Ｍ−Ｈ）⁻。

Example 2.13
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (pyridin-2-yl) piperidine-1-] Il] phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole- 5-Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.71-1.02 (m, 12H), 1.62-1.83 (m, 6H), 1.81-2.08 (m, 7H), 2.10-2.29 (m, 4H), 2.47-2.63 (m, 2H), 2.81-3.07 (m, 4H), 3.53 (s, 6H), 3. 82 (s, 4H), 4.06 (t, J = 8.89Hz, 2H), 5.10-5.21 (m, 2H), 5.31-5.47 (m, 2H), 5. 91 (d, J = 12.69Hz, 2H), 7.04-7.13 (m, 2H), 7.14-7.20 (m, 1H), 7.20-7.34 (m, 5H) ), 7.41 (d, J = 8.24Hz, 1H), 7.49 (d, J = 8.35Hz, 1H), 7.62-7.72 (m, 1H), 8.45 (d) , J = 4.55Hz, 1H), 11.74-12.57 (m, 2H); MS (ESI +) m / z 1028 (M + H) ⁺ ; MS (ESI-) m / z 1026 (MH) ⁻ .

実施例２．１４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［４−（トリメチルシリル）フェニル］ピペリジン−１−イル｝フェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．２０（ｓ、９Ｈ）、０．７４−０．９４（ｍ、１２Ｈ）、１．５９−１．７５（ｍ、６Ｈ）、１．８３−２．０９（ｍ、７Ｈ）、２．１３−２．２９（ｍ、４Ｈ）、２．４４−２．５９（ｍ、２Ｈ）、２．８４−３．１５（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．４６Ｈｚ、２Ｈ）、５．１５（ｄ、Ｊ＝３．０４Ｈｚ、２Ｈ）、５．３１−５．４７（ｍ、２Ｈ）、５．９２（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）、７．０４−７．１４（ｍ、２Ｈ）、７．２１（ｄ、Ｊ＝７．９２Ｈｚ、３Ｈ）、７．２７−７．３７（ｍ、３Ｈ）、７．３７−７．４５（ｍ、３Ｈ）、７．５０（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）、１２．１０（ｄ、Ｊ＝１７．５７Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０９９（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０９７（Ｍ−Ｈ）⁻。

Example 2.14
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (3,5-difluoro-4- {4- [4- (trimethylsilyl) phenyl] piperidin-1) -Il} phenyl) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole -5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.20 (s, 9H), 0.74-0.94 (m, 12H), 1.59-1.75 (m, 6H), 1.83- 2.09 (m, 7H), 2.13-2.29 (m, 4H), 2.44-2.59 (m, 2H), 2.84-3.15 (m, 4H), 3. 53 (s, 6H), 3.82 (s, 4H), 4.06 (t, J = 8.46Hz, 2H), 5.15 (d, J = 3.04Hz, 2H), 5.31- 5.47 (m, 2H), 5.92 (d, J = 12.79Hz, 2H), 7.04-7.14 (m, 2H), 7.21 (d, J = 7.92Hz, 3H) ), 7.27-7.37 (m, 3H), 7.37-7.45 (m, 3H), 7.50 (d, J = 8.02Hz, 1H), 12.10 (d, J) = 17.57Hz, 2H); MS (ESI +) m / z 1099 (M + H) ⁺ ; MS (ESI-) m / z 1097 (MH) ⁻ .

実施例２．１５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（１−ナフチル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９４（ｍ、１２Ｈ）、１．６４−２．０５（ｍ、１２Ｈ）、２．１３−２．２９（ｍ、３Ｈ）、２．４５−２．６２（ｍ、２Ｈ）、２．９０−３．０１（ｍ、Ｊ＝１１．０６Ｈｚ、２Ｈ）、３．０８−３．２５（ｍ、２Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．２９Ｈｚ、２Ｈ）、５．０８−５．２３（ｍ、２Ｈ）、５．３２−５．５２（ｍ、２Ｈ）、５．９４（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）、７．０４−７．１７（ｍ、２Ｈ）、７．２０−７．３７（ｍ、４Ｈ）、７．３８−７．５９（ｍ、６Ｈ）、７．７５（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）、７．８６−７．９５（ｍ、１Ｈ）、８．１４（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、１１．６１−１２．６９（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０７７（Ｍ＋Ｈ）^＋；（ＥＳＩ−）ｍ／ｚ１０７５（Ｍ−Ｈ）⁻。

Example 2.15
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (1-naphthyl) piperidine-1-yl]] Phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5- Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.94 (m, 12H), 1.64-2.05 (m, 12H), 2.13-2.29 (m, 3H), 2.45-2.62 (m, 2H), 2.90-3.01 (m, J = 11.06Hz, 2H), 3.08-3.25 (m, 2H), 3.53 (s) , 6H), 3.82 (s, 4H), 4.06 (t, J = 8.29Hz, 2H), 5.08-5.23 (m, 2H), 5.32-5.52 (m) , 2H), 5.94 (d, J = 12.69Hz, 2H), 7.04-7.17 (m, 2H), 7.20-7.37 (m, 4H), 7.38-7 .59 (m, 6H), 7.75 (d, J = 8.35Hz, 1H), 7.86-7.95 (m, 1H), 8.14 (d, J = 8.24Hz, 1H) , 11.61-12.69 (m, 2H); MS (ESI +) m / z 1077 (M + H) ⁺ ; (ESI-) m / z 1075 (MH) ⁻ .

実施例２．１６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（５Ｒ）−１−［４−（３，５−ジメチルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６４−０．９４（ｍ、１８Ｈ）１．５６−１．７３（ｍ、４Ｈ）１．７５−１．９３（ｍ、６Ｈ）１．９５−２．０６（ｍ、６Ｈ）２．１２−２．２６（ｍ、４Ｈ）２．６９−２．７９（ｍ、１Ｈ）３．２０−３．２９（ｍ、１Ｈ）３．５３（ｓ、６Ｈ）３．７４−３．８９（ｍ、４Ｈ）３．９７−４．１０（ｍ、２Ｈ）５．０５−５．１９（ｍ、２Ｈ）５．４８−５．６２（ｍ、２Ｈ）５．８７（ｄｄ、Ｊ＝１１．４９、７．９２Ｈｚ、２Ｈ）７．０２（ｄｄ、Ｊ＝３．９０、１．９５Ｈｚ、１Ｈ）７．１２（ｄ、Ｊ＝６．８３Ｈｚ、１Ｈ）７．２６−７．３７（ｍ、３Ｈ）７．４０（ｄｄ、Ｊ＝１１．１１、６．０２Ｈｚ、１Ｈ）１２．０８−１２．１６（ｍ、１Ｈ）１２．２３−１２．３１（ｍ、１Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ１０１６（Ｍ＋Ｈ）^＋。

Example 2.16
Methyl {(2S) -1-[(2S) -2-{5-[(5R) -1- [4- (3,5-dimethylpiperidine-1-yl) -3,5-difluorophenyl] -5 -{6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5- Il} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.64-0.94 (m, 18H) 1.56-1.73 (m, 4H) 1.75-1.93 (m, 6H) 1.95 -2.06 (m, 6H) 2.12-2.26 (m, 4H) 2.69-2.79 (m, 1H) 3.20-3.29 (m, 1H) 3.53 (s) , 6H) 3.74-3.89 (m, 4H) 3.97-4.10 (m, 2H) 5.05-5.19 (m, 2H) 5.48-5.62 (m, 2H) ) 5.87 (dd, J = 11.49, 7.92Hz, 2H) 7.02 (dd, J = 3.90, 1.95Hz, 1H) 7.12 (d, J = 6.83Hz, 1H) ) 7.26-7.37 (m, 3H) 7.40 (dd, J = 11.11, 6.02Hz, 1H) 12.08-12.16 (m, 1H) 12.23-12.31 (M, 1H); MS (APCI +) m / z 1016 (M + H) ⁺ .

実施例２．１７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［４−（トリフルオロメチル）フェニル］ピペラジン−１−イル｝フェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６９−０．９６（ｍ、１４Ｈ）１．１０−１．２９（ｍ、２Ｈ）１．６９（ｍ、２Ｈ）１．９９（ｍ、４Ｈ）２．２０（ｍ、２Ｈ）２．９９（ｍ、６Ｈ）３．２２−３．２６（ｍ、６Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｍ、６Ｈ）５．１５（ｍ、２Ｈ）５．３９（ｍ、２Ｈ）５．９５（ｍ、２Ｈ）７．０３（ｄ、Ｊ＝８．７８Ｈｚ、２Ｈ）７．２２（ｍ、２Ｈ）７．２４−７．３６（ｍ、２Ｈ）７．４０−７．５６（ｍ、４Ｈ）１２．０６（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０９６．４、（ＥＳＩ−）ｍ／ｚ１０９４．３。

Example 2.17
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (3,5-difluoro-4- {4- [4- (trifluoromethyl) phenyl] piperazine] -1-yl} phenyl) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H- Benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.69-0.96 (m, 14H) 1.10-1.29 (m, 2H) 1.69 (m, 2H) 1.99 (m, 4H) ) 2.20 (m, 2H) 2.99 (m, 6H) 3.22-3.26 (m, 6H) 3.54 (s, 6H) 3.82 (m, 6H) 5.15 (m) , 2H) 5.39 (m, 2H) 5.95 (m, 2H) 7.03 (d, J = 8.78Hz, 2H) 7.22 (m, 2H) 7.24-7.36 (m) , 2H) 7.40-7.56 (m, 4H) 12.06 (s, 2H); MS (ESI +) m / z 1096.4, (ESI-) m / z 1094.3.

The following Example compounds 3.1 to 3.51 can be prepared from the appropriate listed intermediates according to the method of General Procedure 12 / 12A.

Intermediate amines (S) -6,6'-((2R, 5R) -1- (4- (pyridin-2-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine) -2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (2-methoxyethoxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-2-) Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-chlorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [D] Imidazole);
(S) -6,6'-((2R, 5R) -1- (biphenyl-4-yl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H -Benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl)- 1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- ((2S, 4S) -4-methoxypyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- ((2S, 4S) -4-fluoropyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 4S) -4-fluoropyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (4-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 4S) -4-methoxypyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -5,5-dimethylpyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S, S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 4S) -4-fluoro) Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5S) -1- (4-cyclopropyl-2-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-2-) Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3-fluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3-fluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-( (S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() 3S) -2-azabicyclo [2.2.1] heptane-3-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Indoline-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -4-methylenepyrrolidine-2-) Il) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis ( 2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[( 2S) -Pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12);
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis ( 5-Fluoro-2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4-fluorophenyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (3- (trimethylsilyl) phenyl) piperidine-1-yl) phenyl) pyrrolidine-2, 5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (3,4-difluorophenyl) piperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (3,5-difluorophenyl) piperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5R) -1- (2- (4-phenylpiperidine-1-yl) pyrimidin-5-yl) pyrrolidine-2,5-diyl) bis (5-fluoro) -2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5R) -1- (2- (piperidin-1-yl) pyrimidin-5-yl) pyrrolidine-2,5-diyl) bis (5-fluoro-2- ((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (2,6-difluorophenyl) piperazine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5S) -1-(4- (4- (2,6-difluorophenyl) piperazin-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole); and (S) -6,6'-((2R, 5R)- 1- (3,5-difluoro-4- (4- (4-fluorophenyl) piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S) -pyrrolidine) -2-yl) -1H-benzo [d] imidazole).

Intermediate acids (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid;
(S) -2- (Methoxycarbonylamino) -2- (Tetrahydro-2H-pyran-4-yl) acetic acid;
(S) -2-cyclohexyl-2- (methoxycarbonylamino) acetic acid;
(S) -2-Cyclopentyl-2- (methoxycarbonylamino) acetic acid;
(S) -2- (Methoxycarbonylamino) -3,3-dimethylbutane acid;
(2S, 3R) -3-methoxy-2- (methoxycarbonylamino) butanoic acid;
(2S, 3S) -3-methoxy-2- (methoxycarbonylamino) butanoic acid;
(S) -2- (Methoxycarbonylamino) -2-((R) -tetrahydrofuran-3-yl) acetic acid;
(S) -2- (Methoxycarbonylamino) -2-((S) -tetrahydrofuran-3-yl) acetic acid;
(S) -2- (2,3-dihydro-1H-indene-2-yl) -2- (methoxycarbonylamino) acetic acid;
2- (tert-butoxycarbonylamino) acetic acid;
2- (Methoxycarbonylamino) -3-methylbut-2-enoic acid;
(S) -tetra-2-carboxylic acid (S) -3-ethyl-2- (methoxycarbonylamino) pentanoic acid; and (S) -2- (ethoxycarbonylamino) -3-methylbutanoic acid.

実施例３．１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［４−（ピリジン−２−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．２８−１１．９８（ｍ、２Ｈ）、８．４２（ｄ、Ｊ＝４．４、１Ｈ）、７．７０−７．５６（ｍ、４Ｈ）、７．４６（ｄ、Ｊ＝８．２、１Ｈ）、７．３８（ｄ、Ｊ＝８．２、１Ｈ）、７．３４（ｓ、１Ｈ）、７．３０−７．２０（ｍ、３Ｈ）、７．１６−７．０２（ｍ、３Ｈ）、６．４２（ｄ、Ｊ＝８．７、２Ｈ）、５．５６−５．４２（ｍ、２Ｈ）、５．１８−５．０６（ｍ、２Ｈ）、４．０３（ｔ、Ｊ＝９．３、２Ｈ）、３．８８−３．７３（ｍ、４Ｈ）、３．５２（ｓ、６Ｈ）、２．２５−１．６２（ｍ、１４Ｈ）、０．９２−０．６７（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９０９．５（Ｍ＋Ｈ）^＋。

Example 3.1
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [4- (pyridin-2-yl) phenyl] pyrrolidine-2-yl} -1H-benzimidazole -2-yl) Pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.28-11.98 (m, 2H), 8.42 (d, J = 4.4, 1H), 7.70-7.56 (m, 4H) ), 7.46 (d, J = 8.2, 1H), 7.38 (d, J = 8.2, 1H), 7.34 (s, 1H), 7.30-7.20 (m) , 3H), 7.16-7.02 (m, 3H), 6.42 (d, J = 8.7, 2H), 5.56-5.42 (m, 2H), 5.18-5 .06 (m, 2H), 4.03 (t, J = 9.3, 2H), 3.88-3.73 (m, 4H), 3.52 (s, 6H), 2.25-1 .62 (m, 14H), 0.92-0.67 (m, 12H); MS (ESI +) m / z 909.5 (M + H) ⁺ .

実施例３．２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３−クロロ−４−（トリフルオロメトキシ）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．３１−１２．０１（ｍ、２Ｈ）、７．４８（ｄ、Ｊ＝７．９、１Ｈ）、７．４０（ｄ、Ｊ＝８．２、１Ｈ）、７．３４−７．１７（ｍ、４Ｈ）、７．１５−６．９９（ｍ、３Ｈ）、６．４４（ｓ、１Ｈ）、６．３０（ｄ、Ｊ＝８．９、１Ｈ）、５．５５−５．３７（ｍ、２Ｈ）、５．１９−５．０４（ｍ、２Ｈ）、４．０４（ｔ、Ｊ＝７．８、２Ｈ）、３．８９−３．７３（ｍ、４Ｈ）、３．５２（ｓ、６Ｈ）、２．２８−１．７９（ｍ、１２Ｈ）、１．７７−１．５９（ｍ、２Ｈ）、０．９２−０．６４（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９５０．４（Ｍ＋Ｈ）^＋。

Example 3.2
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3-chloro-4- (trifluoromethoxy) phenyl] -5-{2-[(2S) ) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H- Benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.31-12.01 (m, 2H), 7.48 (d, J = 7.9, 1H), 7.40 (d, J = 8.2) , 1H), 7.34-7.17 (m, 4H), 7.15-6.99 (m, 3H), 6.44 (s, 1H), 6.30 (d, J = 8.9) , 1H), 5.55-5.37 (m, 2H), 5.19-5.04 (m, 2H), 4.04 (t, J = 7.8, 2H), 3.89-3 .73 (m, 4H), 3.52 (s, 6H), 2.28-1.79 (m, 12H), 1.77-1.59 (m, 2H), 0.92-0.64 (M, 12H); MS (ESI +) m / z950.4 (M + H) ⁺ .

実施例３．３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［４−（２−メトキシエトキシ）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．２７−１１．９７（ｍ、２Ｈ）、７．４４（ｄ、Ｊ＝８．４、１Ｈ）、７．３６（ｄ、Ｊ＝７．７、１Ｈ）、７．３３−７．２５（ｍ、３Ｈ）、７．２０（ｓ、１Ｈ）、７．１２−７．００（ｍ、２Ｈ）、６．５８−６．４７（ｍ、２Ｈ）、６．２４（ｄ、Ｊ＝９．０、２Ｈ）、５．４０−５．２７（ｍ、２Ｈ）、５．１９−５．０８（ｍ、２Ｈ）、４．０６（ｔ、Ｊ＝８．３、２Ｈ）、３．８８−３．７６（ｍ、６Ｈ）、３．５４（ｓ、６Ｈ）、３．５１−３．４５（ｍ、２Ｈ）、３．２１（ｓ、３Ｈ）、２．２６−１．８３（ｍ、１２Ｈ）、１．７５−１．６４（ｍ、２Ｈ）、０．９３−０．７４（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９０６．４（Ｍ＋Ｈ）^＋。

Example 3.3
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [4- (2-methoxyethoxy) phenyl] pyrrolidine-2-yl} -1H-benzimidazole- 2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.27-11.97 (m, 2H), 7.44 (d, J = 8.4, 1H), 7.36 (d, J = 7.7) , 1H), 7.33-7.25 (m, 3H), 7.20 (s, 1H), 7.12-7.00 (m, 2H), 6.58-6.47 (m, 2H) ), 6.24 (d, J = 9.0, 2H), 5.40-5.27 (m, 2H), 5.19-5.08 (m, 2H), 4.06 (t, J) = 8.3, 2H), 3.88-3.76 (m, 6H), 3.54 (s, 6H), 3.51-3.45 (m, 2H), 3.21 (s, 3H) ), 2.26-1.83 (m, 12H), 1.75-1.64 (m, 2H), 0.93-0.74 (m, 12H); MS (ESI +) m / z 906.4 (M + H) ⁺ .

実施例３．４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−クロロフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．０５（ｓ、２Ｈ）、７．４４（ｄ、Ｊ＝８．２、１Ｈ）、７．３６（ｄ、Ｊ＝８．１、１Ｈ）、７．３１−７．２２（ｍ、３Ｈ）、７．１９（ｓ、１Ｈ）、７．０３（ｔ、Ｊ＝８．２、２Ｈ）、６．９４−６．８３（ｍ、２Ｈ）、６．２９（ｄ、Ｊ＝９．１、２Ｈ）、５．４２−５．３２（ｍ、２Ｈ）、５．１６−５．０４（ｍ、２Ｈ）、４．０４（ｔ、Ｊ＝８．４、２Ｈ）、３．８５−３．７５（ｍ、４Ｈ）、３．５１（ｓ、６Ｈ）、２．２５−１．５８（ｍ、１４Ｈ）、０．９０−０．７３（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８６６．４（Ｍ＋Ｈ）^＋。

Example 3.4
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-chlorophenyl) -5- {2-[(2S) -1-{(2S)-) 2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine- 1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.05 (s, 2H), 7.44 (d, J = 8.2, 1H), 7.36 (d, J = 8.1, 1H), 7.31-7.22 (m, 3H), 7.19 (s, 1H), 7.03 (t, J = 8.2, 2H), 6.94-6.83 (m, 2H), 6.29 (d, J = 9.1, 2H), 5.42-5.32 (m, 2H), 5.16-5.04 (m, 2H), 4.04 (t, J = 8) .4, 2H), 3.85-3.75 (m, 4H), 3.51 (s, 6H), 2.25-1.58 (m, 14H), 0.90-0.73 (m) , 12H); MS (ESI +) m / z 866.4 (M + H) ⁺ .

実施例３．５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（ビフェニル−４−イル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ１２．１１−１１．６６（ｍ、２Ｈ）、７．４７（ｄ、Ｊ＝８．３、１Ｈ）、７．４３−７．３３（ｍ、４Ｈ）、７．３２−７．１９（ｍ、７Ｈ）、７．１７−７．０６（ｍ、３Ｈ）、６．４３（ｄ、Ｊ＝８．８、２Ｈ）、５．５２−５．４１（ｍ、２Ｈ）、５．１８−５．０９（ｍ、２Ｈ）、４．０５（ｔ、Ｊ＝８．２、２Ｈ）、３．８７−３．７６（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、２．２５−２．１１（ｍ、４Ｈ）、２．０５−１．６２（ｍ、１０Ｈ）、０．９１−０．７４（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９０８．５（Ｍ＋Ｈ）^＋。

Example 3.5
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (biphenyl-4-yl) -5- {2-[(2S) -1-{(2S) ) -2-[(Methylcarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} Pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ12.11.1-1.66 (m, 2H), 7.47 (d, J = 8.3, 1H), 7.43-7.33 (m, 4H) ), 7.32-7.19 (m, 7H), 7.17-7.06 (m, 3H), 6.43 (d, J = 8.8, 2H), 5.52-5.41 (M, 2H), 5.18-5.09 (m, 2H), 4.05 (t, J = 8.2, 2H), 3.87-3.76 (m, 4H), 3.53 (S, 6H), 2.25-2.11 (m, 4H), 2.05-1.62 (m, 10H), 0.91-0.74 (m, 12H); MS (ESI +) m / Z908.5 (M ⁺ H) ⁺ .

実施例３．６
ジメチル（［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル］ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）dｐｐｍ１．０７（ｓ、９Ｈ）１．２２−１．３２（ｍ、２Ｈ）１．４２−１．５７（ｍ、４Ｈ）１．６４−１．７２（ｍ、２Ｈ）１．８２（ｄｄ、Ｊ＝２１．９０、１０．６３Ｈｚ、４Ｈ）１．９２−２．０２（ｍ、４Ｈ）２．１０−２．２５（ｍ、４Ｈ）２．９０−２．９９（ｍ、１Ｈ）３．０４−３．１９（ｍ、４Ｈ）３．５３（ｓ、６Ｈ）３．５６−３．６３（ｍ、１Ｈ）３．６６−３．７９（ｍ、４Ｈ）３．８３（ｄ、Ｊ＝３．０４Ｈｚ、４Ｈ）４．１４（ｑ、Ｊ＝８．１０Ｈｚ、２Ｈ）５．０７−５．１５（ｍ、２Ｈ）５．３３−５．４０（ｍ、２Ｈ）６．２４（ｄ、Ｊ＝８．８９Ｈｚ、２Ｈ）６．８５−６．９４（ｍ、２Ｈ）７．０９（ｄｄ、Ｊ＝１４．１０、８．４６Ｈｚ、２Ｈ）７．１６−７．２２（ｍ、２Ｈ）７．３０−７．４１（ｍ、３Ｈ）７．４４（ｄ、Ｊ＝９．４３Ｈｚ、１Ｈ）１１．９９−１２．１２（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９７２．５（Ｍ＋Ｈ）^＋。

Example 3.6
Dimethyl ([(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {1H-benzimidazole-5,2-diyl (2S) pyrrolidine-2,1-diyl [ (1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) dppm1.07 (s, 9H) 1.22-1.32 (m, 2H) 1.42-1.57 (m, 4H) 1.64-1.72 (M, 2H) 1.82 (dd, J = 21.90, 10.63Hz, 4H) 1.92-2.02 (m, 4H) 2.10-2.25 (m, 4H) 2.90 -2.99 (m, 1H) 3.04-3.19 (m, 4H) 3.53 (s, 6H) 3.56-3.63 (m, 1H) 3.66-3.79 (m) 4,4H) 3.83 (d, J = 3.04Hz, 4H) 4.14 (q, J = 8.10Hz, 2H) 5.07-5.15 (m, 2H) 5.33-5.40 (M, 2H) 6.24 (d, J = 8.89Hz, 2H) 6.85-6.94 (m, 2H) 7.09 (dd, J = 14.10, 8.46Hz, 2H) 7 .16-7.22 (m, 2H) 7.30-7.41 (m, 3H) 7.44 (d, J = 9.43Hz, 1H) 11.99-12.12 (m, 2H); MS (ESI +) m / z 972.5 (M + H) ⁺ .

実施例３．７
メチル｛（２Ｓ）−１−［（２Ｓ，４Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ，４Ｓ）−４−メトキシ−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−４−メトキシピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．８７（ｍ、１２Ｈ）１．３５−１．４０（ｍ、２Ｈ）１．４５（ｓ、４Ｈ）１．６６−１．７２（ｍ、２Ｈ）１．９５（ｄｄ、Ｊ＝１３．２８、７．１７Ｈｚ、２Ｈ）２．１４（ｔｄ、Ｊ＝１２．３２、５．８７Ｈｚ、２Ｈ）２．４１−２．４６（ｍ、２Ｈ）２．７６（ｓ、４Ｈ）３．０３−３．１８（ｍ、２Ｈ）３．２５（ｄ、Ｊ＝３．６６Ｈｚ、６Ｈ）３．５４（ｓ、６Ｈ）３．６４（ｔｄ、Ｊ＝１１．１４、５．６５Ｈｚ、２Ｈ）４．０５−４．１３（ｍ、４Ｈ）４．１９−４．２７（ｍ、２Ｈ）５．１０−５．１６（ｍ、２Ｈ）５．３１−５．３９（ｍ、２Ｈ）５．８８（ｄ、Ｊ＝１２．６６Ｈｚ、２Ｈ）７．０６（ｔ、Ｊ＝８．４７Ｈｚ、２Ｈ）７．２１−７．３１（ｍ、４Ｈ）７．４１（ｄ、Ｊ＝８．０９Ｈｚ、１Ｈ）７．４８（ｄｄ、Ｊ＝８．３９、１．８３Ｈｚ、１Ｈ）１１．８１−１１．９１（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０１１．６（Ｍ＋Ｈ）^＋。

Example 3.7
Methyl {(2S) -1-[(2S, 4S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {2-[(2S, 4S) -4-methoxy-1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} -4-methoxypyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δppm 0.76-0.87 (m, 12H) 1.35-1.40 (m, 2H) 1.45 (s, 4H) 1.66-1.72 (M, 2H) 1.95 (dd, J = 13.28, 7.17Hz, 2H) 2.14 (td, J = 12.32, 5.87Hz, 2H) 2.41-2.46 (m) , 2H) 2.76 (s, 4H) 3.03-3.18 (m, 2H) 3.25 (d, J = 3.66Hz, 6H) 3.54 (s, 6H) 3.64 (td) , J = 11.14, 5.65Hz, 2H) 4.05-4.13 (m, 4H) 4.19-4.27 (m, 2H) 5.10-5.16 (m, 2H) 5 .31-5.39 (m, 2H) 5.88 (d, J = 12.66Hz, 2H) 7.06 (t, J = 8.47Hz, 2H) 7.21-7.31 (m, 4H) ) 7.41 (d, J = 8.09Hz, 1H) 7.48 (dd, J = 8.39, 1.83Hz, 1H) 11.81-11.91 (m, 2H); MS (ESI +) m / z 1011.6 (M + H) ⁺ .

実施例３．８
メチル｛（２Ｓ）−１−［（２Ｓ，４Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ，４Ｓ）−４−フルオロ−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−４−フルオロピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０−０．９９（ｍ、１２Ｈ）１．３８（ｄ、Ｊ＝４．７３Ｈｚ、２Ｈ）１．４５（ｓ、４Ｈ）１．６４−１．７４（ｍ、２Ｈ）２．００−２．０８（ｍ、２Ｈ）２．３７−２．４５（ｍ、２Ｈ）２．７６（ｓ、４Ｈ）３．０８−３．１９（ｍ、２Ｈ）３．５５（ｓ、６Ｈ）３．９９−４．２６（ｍ、６Ｈ）５．３０−５．３９（ｍ、４Ｈ）５．４７（ｄ、Ｊ＝５３．４１Ｈｚ、４Ｈ）５．８９（ｄ、Ｊ＝１２．６６Ｈｚ、２Ｈ）７．０２−７．１１（ｍ、２Ｈ）７．２７（ｄ、Ｊ＝２５．０２Ｈｚ、２Ｈ）７．４１（ｄ、Ｊ＝８．０９Ｈｚ、３Ｈ）７．４７（ｄ、Ｊ＝７．９３Ｈｚ、１Ｈ）１１．８５（ｄ、Ｊ＝３１．７４Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９８７．５（Ｍ＋Ｈ）^＋。

Example 3.8
Methyl {(2S) -1-[(2S, 4S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {2-[(2S, 4S) -4-fluoro-1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} -4-fluoropyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δppm 0.80-0.99 (m, 12H) 1.38 (d, J = 4.73 Hz, 2H) 1.45 (s, 4H) 1.64-1 .74 (m, 2H) 2.00-2.08 (m, 2H) 2.37-2.45 (m, 2H) 2.76 (s, 4H) 3.08-3.19 (m, 2H) ) 3.55 (s, 6H) 3.99-4.26 (m, 6H) 5.30-5.39 (m, 4H) 5.47 (d, J = 53.41Hz, 4H) 5.89 (D, J = 12.66Hz, 2H) 7.02-7.11 (m, 2H) 7.27 (d, J = 25.02Hz, 2H) 7.41 (d, J = 8.09Hz, 3H) ) 7.47 (d, J = 7.93Hz, 1H) 11.85 (d, J = 31.74Hz, 2H); MS (ESI +) m / z987.5 (M + H) ⁺ .

実施例３．９
メチル｛（２Ｓ）−１−［（２Ｓ，４Ｓ）−４−フルオロ−２−｛５−［（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ，４Ｓ）−４−フルオロ−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−（４−フルオロフェニル）ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８２−０．９８（ｍ、１２Ｈ）１．６８−１．７７（ｍ、２Ｈ）１．９１−２．０９（ｍ、４Ｈ）２．３６−２．４４（ｍ、２Ｈ）２．５９−２．６６（ｍ、２Ｈ）３．５２−３．５７（ｍ、６Ｈ）３．７２−３．９８（ｍ、２Ｈ）４．０７−４．１８（ｍ、４Ｈ）５．１９（ｔ、Ｊ＝８．０８Ｈｚ、１Ｈ）５．３１−５．４４（ｍ、４Ｈ）５．４８−５．５７（ｍ、１Ｈ）６．２４−６．３１（ｍ、２Ｈ）６．７０−６．７８（ｍ、２Ｈ）７．０２−７．１２（ｍ、２Ｈ）７．１７（ｓ、１Ｈ）７．２４−７．３４（ｍ、２Ｈ）７．３９（ｔ、Ｊ＝７．９２Ｈｚ、２Ｈ）７．４７（ｄｄ、Ｊ＝２０．３８、８．３５Ｈｚ、１Ｈ）１１．７８−１２．０６（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８８６．４（Ｍ＋Ｈ）^＋。

Example 3.9
Methyl {(2S) -1-[(2S, 4S) -4-fluoro-2-{5-[(2R, 5R) -5-{2-[(2S, 4S) -4-fluoro-1- { (2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- (4-fluorophenyl) pyrrolidine-2-yl ] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.82-0.98 (m, 12H) 1.68-1.77 (m, 2H) 1.91-2.09 (m, 4H) 2.36 -2.44 (m, 2H) 2.59-2.66 (m, 2H) 3.52-3.57 (m, 6H) 3.72-3.98 (m, 2H) 4.07-4 .18 (m, 4H) 5.19 (t, J = 8.08Hz, 1H) 5.31-5.44 (m, 4H) 5.48-5.57 (m, 1H) 6.24-6 .31 (m, 2H) 6.70-6.78 (m, 2H) 7.02-7.12 (m, 2H) 7.17 (s, 1H) 7.24-7.34 (m, 2H) ) 7.39 (t, J = 7.92Hz, 2H) 7.47 (dd, J = 20.38, 8.35Hz, 1H) 11.78-12.06 (m, 2H); MS (ESI +) m / z 886.4 (M + H) ⁺ .

実施例３．１０
メチル｛（２Ｓ）−１−［（２Ｓ，４Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−フルオロフェニル）−５−｛２−［（２Ｓ，４Ｓ）−４−メトキシ−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−４−メトキシピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７７−０．９０（ｍ、１２Ｈ）１．６６−１．７６（ｍ、２Ｈ）１．８８−２．０１（ｍ、２Ｈ）２．０６−２．１９（ｍ、２Ｈ）２．５４−２．６２（ｍ、２Ｈ）３．２５（ｄ、Ｊ＝５．８６Ｈｚ、６Ｈ）３．５４（ｓ、６Ｈ）３．５９−３．７２（ｍ、２Ｈ）３．９７−４．１４（ｍ、６Ｈ）４．１６−４．３０（ｍ、２Ｈ）５．０５−５．１９（ｍ、２Ｈ）５．３６（ｄ、Ｊ＝３．２５Ｈｚ、２Ｈ）６．２８（ｄｄ、Ｊ＝７．２６、４．３４Ｈｚ、２Ｈ）６．６９−６．７９（ｍ、２Ｈ）７．０４（ｄ、Ｊ＝８．５７Ｈｚ、２Ｈ）７．２２−７．３３（ｍ、４Ｈ）７．３８（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）７．４５（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）１１．８１（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９１０．４（Ｍ＋Ｈ）^＋。

Example 3.10
Methyl {(2S) -1-[(2S, 4S) -2- {5-[(2R, 5R) -1- (4-fluorophenyl) -5- {2-[(2S, 4S) -4- Methoxy-1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H- Benzimidazole-2-yl} -4-methoxypyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.77-0.90 (m, 12H) 1.66-1.76 (m, 2H) 1.88-2.01 (m, 2H) 2.06 -2.19 (m, 2H) 2.54-2.62 (m, 2H) 3.25 (d, J = 5.86Hz, 6H) 3.54 (s, 6H) 3.59-3.72 (M, 2H) 3.97-4.14 (m, 6H) 4.16-4.30 (m, 2H) 5.05-5.19 (m, 2H) 5.36 (d, J = 3) .25Hz, 2H) 6.28 (dd, J = 7.26, 4.34Hz, 2H) 6.69-6.79 (m, 2H) 7.04 (d, J = 8.57Hz, 2H) 7 .22-7.33 (m, 4H) 7.38 (d, J = 8.02Hz, 1H) 7.45 (d, J = 8.24Hz, 1H) 11.81 (s, 2H); MS ( ESI +) m / z 910.4 (M + H) ⁺ .

実施例３．１１
メチル｛（２Ｓ）−１−［（５Ｓ）−５−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝−５，５−ジメチルピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−２，２−ジメチルピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８１（ｄ、Ｊ＝６．６１Ｈｚ、６Ｈ）０．８９（ｄ、Ｊ＝６．７２Ｈｚ、６Ｈ）１．０７（ｓ、９Ｈ）１．３８（ｓ、６Ｈ）１．６２（ｓ、６Ｈ）１．６８−１．７７（ｍ、４Ｈ）１．８２（ｓ、２Ｈ）１．９４（ｄｄ、Ｊ＝１３．６１、６．７８Ｈｚ、２Ｈ）２．１０−２．１８（ｍ、２Ｈ）２．２７（ｄｄ、Ｊ＝４．１２、２．６０Ｈｚ、２Ｈ）３．１５（ｄ、Ｊ＝３．３６Ｈｚ、６Ｈ）３．９６−４．０３（ｍ、２Ｈ）５．３０−５．４３（ｍ、６Ｈ）６．２４−６．３１（ｍ、２Ｈ）６．７０（ｔ、Ｊ＝６．６７Ｈｚ、２Ｈ）６．８４−６．９１（ｍ、２Ｈ）７．０５−７．１３（ｍ、２Ｈ）７．２４（ｓ、１Ｈ）７．３６（ｄ、Ｊ＝１．０８Ｈｚ、１Ｈ）７．４０（ｄ、Ｊ＝７．５９Ｈｚ、１Ｈ）７．４９（ｄ、Ｊ＝８．７８Ｈｚ、１Ｈ）１２．１６（ｄ、Ｊ＝２９．２８Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９４４．５（Ｍ＋Ｈ）^＋。

Example 3.11
Methyl {(2S) -1-[(5S) -5-{5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {2-[(2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} -5,5-dimethylpyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H- Benzimidazol-2-yl} -2,2-dimethylpyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.81 (d, J = 6.61 Hz, 6H) 0.89 (d, J = 6.72 Hz, 6H) 1.07 (s, 9H) 1.38 (S, 6H) 1.62 (s, 6H) 1.68-1.77 (m, 4H) 1.82 (s, 2H) 1.94 (dd, J = 13.61, 6.78Hz, 2H ) 2.10-2.18 (m, 2H) 2.27 (dd, J = 4.12, 2.60Hz, 2H) 3.15 (d, J = 3.36Hz, 6H) 3.96-4 .03 (m, 2H) 5.30-5.43 (m, 6H) 6.24-6.31 (m, 2H) 6.70 (t, J = 6.67Hz, 2H) 6.84-6 .91 (m, 2H) 7.05-7.13 (m, 2H) 7.24 (s, 1H) 7.36 (d, J = 1.08Hz, 1H) 7.40 (d, J = 7) .59Hz, 1H) 7.49 (d, J = 8.78Hz, 1H) 12.16 (d, J = 29.28Hz, 2H); MS (ESI +) m / z 944.5 (M + H) ⁺ .

実施例３．１２
メチル｛（２Ｓ）−１−［（２Ｓ，４Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛２−［（２Ｓ，４Ｓ）−４−フルオロ−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−４−フルオロピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７９−０．９７（ｍ、１２Ｈ）１．０７（ｓ、９Ｈ）１．６６−１．７５（ｍ、２Ｈ）１．９９−２．０８（ｍ、２Ｈ）２．４０（ｄｄ、Ｊ＝１７．０２、３．０４Ｈｚ、２Ｈ）３．０９−３．２１（ｍ、４Ｈ）３．５５（ｓ、６Ｈ）４．０５−４．１３（ｍ、４Ｈ）４．１６−４．２７（ｍ、２Ｈ）５．３５（ｄｄ、Ｊ＝８．５１、３．０９Ｈｚ、４Ｈ）５．４６（ｄ、Ｊ＝５３．２４Ｈｚ、２Ｈ）６．２３−６．２９（ｍ、２Ｈ）６．９１（ｄ、Ｊ＝８．８９Ｈｚ、２Ｈ）７．０３−７．１１（ｍ、２Ｈ）７．２３（ｄ、Ｊ＝３．４７Ｈｚ、１Ｈ）７．２８（ｓ、１Ｈ）７．３９（ｄｄ、Ｊ＝８．０８、４．７２Ｈｚ、３Ｈ）７．４４（ｄ、Ｊ＝８．５７Ｈｚ、１Ｈ）１１．８０（ｄ、Ｊ＝２０．０６Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９２４．４（Ｍ＋Ｈ）^＋。

Example 3.12
Methyl {(2S) -1-[(2S, 4S) -2-{5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {2-[(2S, 4S)- 4-Fluoro-1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl]- 1H-benzimidazol-2-yl} -4-fluoropyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.79-0.97 (m, 12H) 1.07 (s, 9H) 1.66-1.75 (m, 2H) 1.99-2.08 (M, 2H) 2.40 (dd, J = 17.02, 3.04Hz, 2H) 3.09-3.21 (m, 4H) 3.55 (s, 6H) 4.05-4.13 (M, 4H) 4.16-4.27 (m, 2H) 5.35 (dd, J = 8.51, 3.09Hz, 4H) 5.46 (d, J = 53.24Hz, 2H) 6 .23-6.29 (m, 2H) 6.91 (d, J = 8.89Hz, 2H) 7.03-7.11 (m, 2H) 7.23 (d, J = 3.47Hz, 1H) ) 7.28 (s, 1H) 7.39 (dd, J = 8.08, 4.72Hz, 3H) 7.44 (d, J = 8.57Hz, 1H) 11.80 (d, J = 20) .06Hz, 2H); MS (ESI +) m / z 924.4 (M + H) ⁺ .

実施例３．１３
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｓ）−１−（４−シクロプロピル−２−フルオロフェニル）−５−（２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．３５−０．５７（ｍ、２Ｈ）０．６６−０．８５（ｍ、２Ｈ）１．０７−１．１７（ｍ、７Ｈ）１．５９−１．６９（ｍ、１Ｈ）１．８２（ｓ、２Ｈ）１．９５−２．１２（ｍ、５Ｈ）２．１３−２．３３（ｍ、５Ｈ）３．１７−３．３５（ｍ、６Ｈ）３．４８−３．６５（ｍ、６Ｈ）３．８５−３．９５（ｍ、４Ｈ）４．２９−４．３８（ｍ、２Ｈ）５．１１−５．２５（ｍ、２Ｈ）５．５８（ｓ、２Ｈ）６．４４−６．５７（ｍ、２Ｈ）６．５９−６．７０（ｍ、１Ｈ）７．０７−７．１９（ｍ、２Ｈ）７．２５−７．３２（ｍ、２Ｈ）７．３５−７．４１（ｍ、２Ｈ）７．４５（ｄ、Ｊ＝８．２４Ｈｚ、２Ｈ）１２．０５（ｄ、Ｊ＝１６．６３Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９２２．４（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９２０．３（Ｍ−Ｈ）⁻。

Example 3.13
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2S, 5S) -1- (4-cyclopropyl-2-fluorophenyl) -5-(2-{(2S)) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazol-5-yl) pyrrolidine-2-yl] -1H-benzimidazol-2-yl } Pyrrolidine-1-yl] -3-methoxy-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δppm 0.35-0.57 (m, 2H) 0.66-0.85 (m, 2H) 1.07-1.17 (m, 7H) 1.59 -1.69 (m, 1H) 1.82 (s, 2H) 1.95-2.12 (m, 5H) 2.13-2.33 (m, 5H) 3.17-3.35 (m) , 6H) 3.48-3.65 (m, 6H) 3.85-3.95 (m, 4H) 4.29-4.38 (m, 2H) 5.11-5.25 (m, 2H) ) 5.58 (s, 2H) 6.44-6.57 (m, 2H) 6.59-6.70 (m, 1H) 7.07-7.19 (m, 2H) 7.25-7 .32 (m, 2H) 7.35-7.41 (m, 2H) 7.45 (d, J = 8.24Hz, 2H) 12.05 (d, J = 16.63Hz, 2H); MS ( ESI +) m / z 922.4 (M + H) ⁺ , (ESI-) m / z 920.3 (MH) ^- .

実施例３．１４
ｔｅｒｔ−ブチル｛２−［（２Ｓ）−２−（５−｛（２Ｓ，５Ｓ）−５−｛２−［（２Ｓ）−１−｛［（ｔｅｒｔ−ブトキシカルボニル）アミノ］アセチル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［３−フルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−２−オキソエチル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１６−１．４３（ｍ、１８Ｈ）１．４２−２．２７（ｍ、１４Ｈ）２．５８−２．７０（ｍ、５Ｈ）３．３８−４．０２（ｍ、９Ｈ）５．１４（ｓ、２Ｈ）５．３３（ｓ、３Ｈ）６．０４（ｓ、２Ｈ）６．７４（ｓ、３Ｈ）７．０４−７．６０（ｍ、７Ｈ）１１．８３−１２．４３（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９３３．４（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９３１．４（Ｍ−Ｈ）⁻。

Example 3.14
tert-Butyl {2-[(2S) -2-(5-{(2S, 5S) -5-{2-[(2S) -1-{[(tert-benzimidazole) amino] acetyl} pyrrolidine-2 -Il] -1H-benzimidazol-5-yl} -1- [3-fluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2-yl} -1H-benzimidazol-2-yl) pyrrolidine- 1-yl] -2-oxoethyl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.16-1.43 (m, 18H) 1.42-2.27 (m, 14H) 2.58-2.70 (m, 5H) 3.38 -4.02 (m, 9H) 5.14 (s, 2H) 5.33 (s, 3H) 6.04 (s, 2H) 6.74 (s, 3H) 7.04-7.60 (m) , 7H) 11.83-12.43 (m, 2H); MS (ESI +) m / z 933.4 (M + H) ⁺ , (ESI-) m / z 931.4 (MH) ⁻ .

実施例３．１５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｓ）−１−［３−フルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７３−０．９３（ｍ、１２Ｈ）１．３２−１．５７（ｍ、６Ｈ）１．５８−２．０６（ｍ、１４Ｈ）２．１８（ｓ、４Ｈ）２．６７（ｄｄ、Ｊ＝３．６９、１．９５Ｈｚ、４Ｈ）３．７５−３．８７（ｍ、６Ｈ）４．０７（ｔ、２Ｈ）５．１３（ｓ、２Ｈ）５．３７（ｄｄ、Ｊ＝６．０２、２．１１Ｈｚ、２Ｈ）６．０４（ｓ、２Ｈ）６．６５（ｓ、１Ｈ）７．０９（ｓ、２Ｈ）７．１６−７．２３（ｍ、１Ｈ）７．２３−７．４８（ｍ、５Ｈ）１２．０１（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９３３．５（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９３１．４（Ｍ−Ｈ）⁻。

Example 3.15
Methyl {(2S) -1-[(2S) -2-{5-[(2S, 5S) -1- [3-fluoro-4- (piperidin-1-yl) phenyl] -5-{2- [ (2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl]- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.73-0.93 (m, 12H) 1.32-1.57 (m, 6H) 1.58-2.06 (m, 14H) 2.18 (S, 4H) 2.67 (dd, J = 3.69, 1.95Hz, 4H) 3.75-3.87 (m, 6H) 4.07 (t, 2H) 5.13 (s, 2H) ) 5.37 (dd, J = 6.02, 2.11Hz, 2H) 6.04 (s, 2H) 6.65 (s, 1H) 7.09 (s, 2H) 7.16-7.23 (M, 1H) 7.23-7.48 (m, 5H) 12.01 (s, 2H); MS (ESI +) m / z933.5 (M + H) ⁺ , (ESI-) m / z931.4 ( MH) ^- .

実施例３．１６
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｓ）−１−［３−フルオロ−４−（ピペリジン−１−イル）フェニル］−５−（２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．００−１．１４（ｍ、６Ｈ）１．３３−１．５５（ｍ、６Ｈ）１．５９−２．２８（ｍ、１４Ｈ）２．５８−２．７１（ｍ、４Ｈ）３．１０−３．２７（ｍ、６Ｈ）３．５４（ｄ、Ｊ＝１．４１Ｈｚ、６Ｈ）３．７１−３．９０（ｍ、６Ｈ）４．２１−４．３３（ｍ、２Ｈ）５．０２−５．２２（ｍ、２Ｈ）５．３７（ｄｄ、Ｊ＝６．０２、２．０１Ｈｚ、２Ｈ）６．０４（ｓ、２Ｈ）６．５８−６．８４（ｍ、１Ｈ）７．０６（ｄ、Ｊ＝２２．８８Ｈｚ、２Ｈ）７．１６−７．３２（ｍ、２Ｈ）７．３９（ｄ、Ｊ＝８．１３Ｈｚ、２Ｈ）１１．９０−１２．３４（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９６５．５（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９６３．３（Ｍ−Ｈ）⁻。

Example 3.16
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2S, 5S) -1- [3-fluoro-4- (piperidine-1-yl) phenyl] -5- (2) -{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazol-5-yl) pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.00-1.14 (m, 6H) 1.33-1.55 (m, 6H) 1.59-2.28 (m, 14H) 2.58 -2.71 (m, 4H) 3.10-3.27 (m, 6H) 3.54 (d, J = 1.41Hz, 6H) 3.71-3.90 (m, 6H) 4.21 -4.33 (m, 2H) 5.02-5.22 (m, 2H) 5.37 (dd, J = 6.02, 2.01Hz, 2H) 6.04 (s, 2H) 6.58 -6.84 (m, 1H) 7.06 (d, J = 22.88Hz, 2H) 7.16-7.32 (m, 2H) 7.39 (d, J = 8.13Hz, 2H) 11 .90-12.34 (m, 2H); MS (ESI +) m / z965.5 (M + H) ⁺ , (ESI-) m / z963.3 (MH) ⁻ .

実施例３．１７
ジメチル｛［（２Ｓ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル］ビス［１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル（３−メチル−１−オキソブト−２−エン−１，２−ジイル）］｝ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８７−１．２０（ｍ、９Ｈ）１．６０−１．７７（ｍ、１４Ｈ）１．８０−２．３５（ｍ、１０Ｈ）３．１６−３．７９（ｍ、１０Ｈ）５．１４（ｓ、２Ｈ）５．３７（ｓ、２Ｈ）６．２４（ｄ、Ｊ＝３．０４Ｈｚ、２Ｈ）６．９２（ｄｄ、Ｊ＝８．５７、６．２９Ｈｚ、２Ｈ）７．１１（ｓ、３Ｈ）７．３１（ｓ、１Ｈ）７．３９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．５０（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）８．８９（ｄ、２Ｈ）１１．６４−１２．１４（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８８４．５（Ｍ＋Ｈ）^＋、９１８．４（Ｍ＋ＮＨ_３＋ＮＨ_４）^＋。

Example 3.17
Dimethyl {[(2S, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis [1H-benzimidazole-5,2-diyl (2S) pyrrolidine-2,1-diyl ( 3-Methyl-1-oxobut-2-ene-1,2-diyl)]} benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.87-1.20 (m, 9H) 1.60-1.77 (m, 14H) 1.80-2.35 (m, 10H) 3.16 -3.79 (m, 10H) 5.14 (s, 2H) 5.37 (s, 2H) 6.24 (d, J = 3.04Hz, 2H) 6.92 (dd, J = 8.57) , 6.29Hz, 2H) 7.11 (s, 3H) 7.31 (s, 1H) 7.39 (d, J = 8.13Hz, 1H) 7.50 (d, J = 8.24Hz, 1H) ) 8.89 (d, 2H) 11.64-12.14 (m, 2H); MS (ESI +) m / z 884.5 (M + H) ⁺ , 918.4 (M + NH ₃ + NH ₄ ) ⁺ .

実施例３．１８
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１３−１．３３（ｍ、４Ｈ）１．３６−１．５７（ｍ、１０Ｈ）１．６５−１．７１（ｍ、２Ｈ）１．７９−１．９０（ｍ、２Ｈ）１．９６−２．０３（ｍ、４Ｈ）２．１３−２．２６（ｍ、４Ｈ）２．７６（ｓ、４Ｈ）２．９３−３．１５（ｍ、４Ｈ）３．５３（ｓ、６Ｈ）３．６２（ｄｄ、Ｊ＝１０．０３、２．０１Ｈｚ、２Ｈ）３．６８−３．８０（ｍ、４Ｈ）３．８１−３．８８（ｍ、４Ｈ）４．１１−４．１８（ｍ、２Ｈ）５．１０−５．１８（ｍ、２Ｈ）５．３３−５．４０（ｍ、２Ｈ）５．８２−５．９２（ｍ、２Ｈ）７．０９（ｄｄ、Ｊ＝１２．５２、８．２９Ｈｚ、２Ｈ）７．１７−７．２４（ｍ、２Ｈ）７．３５（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）７．４１（ｄ、Ｊ＝７．９２Ｈｚ、１Ｈ）７．４７（ｄ、Ｊ＝６．９４Ｈｚ、１Ｈ）１２．０５（ｄ、Ｊ＝１．７３Ｈｚ、１Ｈ）１２．１５（ｄ、Ｊ＝２．１７Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０３５．５（Ｍ＋Ｈ）^＋。

Example 3.18
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2-diyl ( 2S) Pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm1.13-1.33 (m, 4H) 1.36-1.57 (m, 10H) 1.65-1.71 (m, 2H) 1.79 -1.90 (m, 2H) 1.96-2.03 (m, 4H) 2.13-2.26 (m, 4H) 2.76 (s, 4H) 2.93-3.15 (m) 4, 4H) 3.53 (s, 6H) 3.62 (dd, J = 10.03, 2.01Hz, 2H) 3.68-3.80 (m, 4H) 3.81-3.88 (m) , 4H) 4.11-4.18 (m, 2H) 5.10-5.18 (m, 2H) 5.33-5.40 (m, 2H) 5.82-5.92 (m, 2H) ) 7.09 (dd, J = 12.52, 8.29Hz, 2H) 7.17-7.24 (m, 2H) 7.35 (t, J = 8.35Hz, 2H) 7.41 (d) , J = 7.92Hz, 1H) 7.47 (d, J = 6.94Hz, 1H) 12.05 (d, J = 1.73Hz, 1H) 12.15 (d, J = 2.17Hz, 1H) ); MS (ESI +) m / z 1035.5 (M + H) ⁺ .

実施例３．１９
メチル｛（２Ｓ）−１−［（３Ｓ）−３−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（３Ｓ）−２−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝−２−アザビシクロ［２．２．１］ヘプト−３−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−２−アザビシクロ［２．２．１］ヘプト−２−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０−０．８７（ｍ、６Ｈ）０．９３（ｔ、Ｊ＝７．０５Ｈｚ、６Ｈ）１．３６−１．４８（ｍ、１０Ｈ）１．４９−１．５７（ｍ、２Ｈ）１．６４−１．７０（ｍ、４Ｈ）１．７２−１．７９（ｍ、４Ｈ）１．８４−１．９０（ｍ、２Ｈ）１．９２−１．９８（ｍ、２Ｈ）２．６１（ｓ、２Ｈ）２．７２−２．７８（ｍ、４Ｈ）３．５４（ｓ、６Ｈ）４．１０−４．１７（ｍ、２Ｈ）４．５０（ｓ、２Ｈ）４．５９（ｄ、Ｊ＝７．４８Ｈｚ、２Ｈ）５．３２−５．４１（ｍ、２Ｈ）５．８９（ｄ、Ｊ＝１２．５８Ｈｚ、２Ｈ）７．０７（ｄ、Ｊ＝７．７０Ｈｚ、２Ｈ）７．１８（ｄ、Ｊ＝９．６５Ｈｚ、２Ｈ）７．２１（ｓ、１Ｈ）７．３２（ｓ、１Ｈ）７．４０（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４９（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）１２．０１（ｄｄ、Ｊ＝１２．５８、１．０８Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１００３．４（Ｍ＋Ｈ）^＋。

Example 3.19
Methyl {(2S) -1-[(3S) -3-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {2 -[(3S) -2-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} -2-azabicyclo [2.2.1] hept-3-yl] -1H-benz Imidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} -2-azabicyclo [2.2.1] hept-2-yl] -3-methyl-1-oxobutane-2- Il} Carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80-0.87 (m, 6H) 0.93 (t, J = 7.05 Hz, 6H) 1.36-1.48 (m, 10H) 1 .49-1.57 (m, 2H) 1.64-1.70 (m, 4H) 1.72-1.79 (m, 4H) 1.84-1.90 (m, 2H) 1.92 -1.98 (m, 2H) 2.61 (s, 2H) 2.72-2.78 (m, 4H) 3.54 (s, 6H) 4.10-4.17 (m, 2H) 4 .50 (s, 2H) 4.59 (d, J = 7.48Hz, 2H) 5.32-5.41 (m, 2H) 5.89 (d, J = 12.58Hz, 2H) 7.07 (D, J = 7.70Hz, 2H) 7.18 (d, J = 9.65Hz, 2H) 7.21 (s, 1H) 7.32 (s, 1H) 7.40 (d, J = 8) .13Hz, 1H) 7.49 (d, J = 8.02Hz, 1H) 12.01 (dd, J = 12.58, 1.08Hz, 2H); MS (ESI +) m / z1003.4 (M + H) ⁺ .

実施例３．２０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３−フルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７７−０．９０（ｍ、１２Ｈ）１．６６−１．７５（ｍ、８Ｈ）１．８６−１．９５（ｍ、２Ｈ）１．９６−２．０５（ｍ、４Ｈ）２．１４−２．２４（ｍ、４Ｈ）３．０４−３．１４（ｍ、４Ｈ）３．５３（ｓ、６Ｈ）３．７７−３．８６（ｍ、４Ｈ）４．０６（ｔ、Ｊ＝８．４０Ｈｚ、２Ｈ）５．１１−５．１７（ｍ、２Ｈ）５．３５（ｑ、Ｊ＝６．８３Ｈｚ、２Ｈ）６．０５−６．１２（ｍ、２Ｈ）６．７１（ｄｄｄ、Ｊ＝１３．９９、９．２２、４．３４Ｈｚ、１Ｈ）７．０７（ｔ、Ｊ＝７．０５Ｈｚ、２Ｈ）７．１６（ｔ、Ｊ＝６．９４Ｈｚ、２Ｈ）７．２０−７．３２（ｍ、８Ｈ）７．３９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４７（ｄ、Ｊ＝８．４６Ｈｚ、１Ｈ）１２．０５（ｄ、Ｊ＝５．６４Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１００９．４（Ｍ＋Ｈ）^＋。

Example 3.20
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3-fluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5-{ 2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2- Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.77-0.90 (m, 12H) 1.66-1.75 (m, 8H) 1.86-1.95 (m, 2H) 1.96 -2.05 (m, 4H) 2.14-2.24 (m, 4H) 3.04-3.14 (m, 4H) 3.53 (s, 6H) 3.77-3.86 (m) , 4H) 4.06 (t, J = 8.40Hz, 2H) 5.11-5.17 (m, 2H) 5.35 (q, J = 6.83Hz, 2H) 6.05-6.12 (M, 2H) 6.71 (ddd, J = 13.99, 9.22, 4.34Hz, 1H) 7.07 (t, J = 7.05Hz, 2H) 7.16 (t, J = 6) .94Hz, 2H) 7.20-7.32 (m, 8H) 7.39 (d, J = 8.13Hz, 1H) 7.47 (d, J = 8.46Hz, 1H) 12.05 (d) , J = 5.64Hz, 2H); MS (ESI +) m / z 1009.4 (M + H) ⁺ .

実施例３．２１
メチル［（１Ｓ）−２−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３−フルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エチル］カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９２（ｍ、６Ｈ）１．４７−１．５７（ｍ、２Ｈ）１．６５−１．７６（ｍ、８Ｈ）１．８１−１．９４（ｍ、２Ｈ）１．９４−２．０４（ｍ、４Ｈ）２．１５−２．２３（ｍ、４Ｈ）３．０３−３．１５（ｍ、４Ｈ）３．５３（ｓ、６Ｈ）３．５７−３．６７（ｍ、２Ｈ）３．７０−３．７９（ｍ、２Ｈ）３．７９−３．８９（ｍ、４Ｈ）４．０７−４．２０（ｍ、２Ｈ）５．１０−５．１９（ｍ、２Ｈ）５．３２−５．４１（ｍ、２Ｈ）６．０４−６．１１（ｍ、２Ｈ）６．６６−６．７５（ｍ、１Ｈ）７．０３−７．３６（ｍ、１２Ｈ）７．３９（ｄｄ、Ｊ＝８．７８、１．６３Ｈｚ、１Ｈ）７．４６（ｔ、Ｊ＝８．７８Ｈｚ、１Ｈ）１２．０２−１２．１４（ｍ、２Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ１０５１（Ｍ＋Ｈ）^＋。

Example 3.21
Methyl [(1S) -2-[(2S) -2-{5-[(2R, 5R) -1- [3-fluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5-{ 2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2- Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethyl] carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.92 (m, 6H) 1.47-1.57 (m, 2H) 1.65-1.76 (m, 8H) 1.81 -1.94 (m, 2H) 1.94-2.04 (m, 4H) 2.15-2.23 (m, 4H) 3.03-3.15 (m, 4H) 3.53 (s) , 6H) 3.57-3.67 (m, 2H) 3.70-3.79 (m, 2H) 3.79-3.89 (m, 4H) 4.07-4.20 (m, 2H) ) 5.10-5.19 (m, 2H) 5.32-5.41 (m, 2H) 6.04-6.11 (m, 2H) 6.66-6.75 (m, 1H) 7 .03-7.36 (m, 12H) 7.39 (dd, J = 8.78, 1.63Hz, 1H) 7.46 (t, J = 8.78Hz, 1H) 12.02-12.14 (M, 2H); MS (APCI +) m / z 1051 (M + H) ⁺ .

実施例３．２２
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロヘキシル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８１−１．１４（ｍ、１１Ｈ）１．４０−１．７１（ｍ、２０Ｈ）１．９４−２．０５（ｍ、４Ｈ）２．１４−２．２６（ｍ、４Ｈ）２．８３−２．９１（ｍ、２Ｈ）２．９３−３．０２（ｍ、２Ｈ）３．５２（ｄ、Ｊ＝３．８０Ｈｚ、６Ｈ）３．７６−３．８７（ｍ、４Ｈ）４．０８（ｑ、Ｊ＝８．５３Ｈｚ、２Ｈ）５．１４（ｄ、Ｊ＝５．８６Ｈｚ、２Ｈ）５．３３−５．４５（ｍ、２Ｈ）５．８５−５．９８（ｍ、２Ｈ）７．０５−７．３１（ｍ、１１Ｈ）７．４２（ｄ、Ｊ＝９．７６Ｈｚ、１Ｈ）７．４９（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）１２．００（ｓ、１Ｈ）１２．１６（ｄ、Ｊ＝３．５８Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１０７．５（Ｍ＋Ｈ）^＋。

Example 3.22
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2 -Diyl (2S) pyrrolidine-2,1-diyl [(1S) -1-cyclohexyl-2-oxoethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.81-1.14 (m, 11H) 1.40-1.71 (m, 20H) 1.94-2.05 (m, 4H) 2.14 -2.26 (m, 4H) 2.83-2.91 (m, 2H) 2.93-3.02 (m, 2H) 3.52 (d, J = 3.80Hz, 6H) 3.76 -3.87 (m, 4H) 4.08 (q, J = 8.53Hz, 2H) 5.14 (d, J = 5.86Hz, 2H) 5.33-5.45 (m, 2H) 5 .85-5.98 (m, 2H) 7.05-7.31 (m, 11H) 7.42 (d, J = 9.76Hz, 1H) 7.49 (d, J = 8.24Hz, 1H) ) 12.00 (s, 1H) 12.16 (d, J = 3.58Hz, 1H); MS (ESI +) m / z 1107.5 (M + H) ⁺ .

実施例３．２３
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１４−１．３７（ｍ、４Ｈ）１．４３−１．５７（ｍ、４Ｈ）１．６１−１．７２（ｍ、６Ｈ）１．７７−１．９１（ｍ、２Ｈ）１．９６−２．０５（ｍ、４Ｈ）２．１４−２．２５（ｍ、４Ｈ）２．８７−３．０２（ｍ、６Ｈ）３．０６−３．２２（ｍ、２Ｈ）３．５３（ｓ、６Ｈ）３．５８−３．６７（ｍ、２Ｈ）３．６８−３．７９（ｍ、５Ｈ）３．８１−３．８９（ｍ、４Ｈ）４．１１−４．１９（ｍ、２Ｈ）５．１４（ｄｄ、Ｊ＝７．３２、２．９８Ｈｚ、２Ｈ）５．３４−５．４２（ｍ、２Ｈ）５．８５−５．９５（ｍ、２Ｈ）７．０６−７．１７（ｍ、３Ｈ）７．１９−７．２９（ｍ、６Ｈ）７．３５（ｔ、Ｊ＝９．０５Ｈｚ、２Ｈ）７．４２（ｄ、Ｊ＝８．５７Ｈｚ、１Ｈ）７．４７（ｄ、Ｊ＝８．７８Ｈｚ、１Ｈ）１２．０５（ｓ、１Ｈ）１２．１６（ｄ、Ｊ＝１．４１Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１１１．５（Ｍ＋Ｈ）^＋。

Example 3.23
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2 -Diyl (2S) pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.14-1.37 (m, 4H) 1.43-1.57 (m, 4H) 1.61-1.72 (m, 6H) 1.77 -1.91 (m, 2H) 1.96-2.05 (m, 4H) 2.14-2.25 (m, 4H) 2.87-3.02 (m, 6H) 3.06-3 .22 (m, 2H) 3.53 (s, 6H) 3.58-3.67 (m, 2H) 3.68-3.79 (m, 5H) 3.81-3.89 (m, 4H) ) 4.11-4.19 (m, 2H) 5.14 (dd, J = 7.32, 2.98Hz, 2H) 5.34-5.42 (m, 2H) 5.85-5.95 (M, 2H) 7.06-7.17 (m, 3H) 7.19-7.29 (m, 6H) 7.35 (t, J = 9.05Hz, 2H) 7.42 (d, J) = 8.57Hz, 1H) 7.47 (d, J = 8.78Hz, 1H) 12.05 (s, 1H) 12.16 (d, J = 1.41Hz, 1H); MS (ESI +) m / z1111.5 (M + H) ⁺ .

実施例３．２４
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロペンチル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１６−１．２８（ｍ、４Ｈ）１．３１−１．５４（ｍ、１０Ｈ）１．５５−１．７３（ｍ、１０Ｈ）１．９５−２．０６（ｍ、４Ｈ）２．０９−２．２４（ｍ、７Ｈ）２．８５−３．０７（ｍ、４Ｈ）３．５３（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．１５（ｔ、Ｊ＝８．５１Ｈｚ、２Ｈ）５．１１−５．１８（ｍ、２Ｈ）５．３４−５．４３（ｍ、２Ｈ）５．９２（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）７．０６−７．１８（ｍ、３Ｈ）７．１９−７．３１（ｍ、６Ｈ）７．３７−７．４５（ｍ、３Ｈ）７．５０（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）１２．０１（ｓ、１Ｈ）１２．０８（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０７９．４（Ｍ＋Ｈ）^＋。

Example 3.24
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2 -Diyl (2S) pyrrolidine-2,1-diyl [(1S) -1-cyclopentyl-2-oxoethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.16-1.28 (m, 4H) 1.31-1.54 (m, 10H) 1.55-1.73 (m, 10H) 1.95 -2.06 (m, 4H) 2.09-2.24 (m, 7H) 2.85-3.07 (m, 4H) 3.53 (s, 6H) 3.82 (s, 4H) 4 .15 (t, J = 8.51Hz, 2H) 5.11-5.18 (m, 2H) 5.34-5.43 (m, 2H) 5.92 (d, J = 12.69Hz, 2H) ) 7.06-7.18 (m, 3H) 7.19-7.31 (m, 6H) 7.37-7.45 (m, 3H) 7.50 (d, J = 8.35Hz, 1H) ) 12.01 (s, 1H) 12.08 (s, 1H); MS (ESI +) m / z 1079.4 (M + H) ⁺ .

実施例３．２５
メチル｛（２Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｒ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝−２，３−ジヒドロ−１Ｈ−インドール−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−２，３−ジヒドロ−１Ｈ−インドール−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９０（ｄｄ、Ｊ＝３１．７２、６．２３Ｈｚ、１２Ｈ）１．３１−１．５１（ｍ、７Ｈ）１．５２−１．７０（ｍ、２Ｈ）２．０６−２．２９（ｍ、４Ｈ）２．７４（ｓ、６Ｈ）３．０８（ｄ、Ｊ＝１５．４０Ｈｚ、６Ｈ）３．６９−３．８９（ｍ、２Ｈ）４．２７（ｓ、１Ｈ）５．２６−５．３９（ｍ、２Ｈ）５．７７−６．０１（ｍ、４Ｈ）７．０１−７．３３（ｍ、１２Ｈ）７．３７−７．５３（ｍ、２Ｈ）８．１２−８．２５（ｍ、２Ｈ）１２．３４（ｄ、Ｊ＝４２．０７Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０４７．４（Ｍ＋Ｈ）^＋。

Example 3.25
Methyl {(2R) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {2 -[(2S) -1-{(2R) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} -2,3-dihydro-1H-indole-2-yl] -1H-benzimidazole- 5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} -2,3-dihydro-1H-indole-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.90 (dd, J = 31.72, 6.23 Hz, 12H) 1.31-1.51 (m, 7H) 1.52-1.70 (m) , 2H) 2.06-2.29 (m, 4H) 2.74 (s, 6H) 3.08 (d, J = 15.40Hz, 6H) 3.69-3.89 (m, 2H) 4 .27 (s, 1H) 5.26-5.39 (m, 2H) 5.77-6.01 (m, 4H) 7.01-7.33 (m, 12H) 7.37-7.53 (M, 2H) 8.12-8.25 (m, 2H) 12.34 (d, J = 42.07Hz, 2H); MS (ESI +) m / z 1047.4 (M + H) ⁺ .

実施例３．２６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝−４−メチリデンピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−４−メチリデンピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９２（ｍ、１２Ｈ）１．０７（ｓ、９Ｈ）１．６８（ｓ、２Ｈ）１．９１（ｄｄｄ、Ｊ＝１４．６４、７．６４、７．４３Ｈｚ、２Ｈ）２．６１−２．７５（ｍ、２Ｈ）２．９７−３．０９（ｍ、２Ｈ）３．１３（ｓ、１Ｈ）３．５４（ｓ、６Ｈ）３．９４−４．０８（ｍ、２Ｈ）４．４６（ｄ、Ｊ＝１２．３６Ｈｚ、２Ｈ）４．６０（ｄ、Ｊ＝１４．２０Ｈｚ、２Ｈ）５．０２（ｓ、３Ｈ）５．１０（ｓ、２Ｈ）５．３１−５．４５（ｍ、４Ｈ）６．２４（ｄ、Ｊ＝８．６７Ｈｚ、２Ｈ）６．８６−６．９４（ｍ、２Ｈ）７．０７（ｔ、Ｊ＝８．５１Ｈｚ、２Ｈ）７．２０（ｓ、１Ｈ）７．２６（ｓ、１Ｈ）７．３４−７．５０（ｍ、４Ｈ）１２．０５（ｄ、Ｊ＝１５．７２Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９１２．４（Ｍ＋Ｈ）^＋。

Example 3.26
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {2-[(2S) -1-{((2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} -4-methylidenepyrrolidin-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} -4-methylidenepyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.92 (m, 12H) 1.07 (s, 9H) 1.68 (s, 2H) 1.91 (ddd, J = 14.64) , 7.64, 7.43Hz, 2H) 2.61-2.75 (m, 2H) 2.97-3.09 (m, 2H) 3.13 (s, 1H) 3.54 (s, 6H) ) 3.94-4.08 (m, 2H) 4.46 (d, J = 12.36Hz, 2H) 4.60 (d, J = 14.20Hz, 2H) 5.02 (s, 3H) 5 .10 (s, 2H) 5.31-5.45 (m, 4H) 6.24 (d, J = 8.67Hz, 2H) 6.86-6.94 (m, 2H) 7.07 (t) , J = 8.51Hz, 2H) 7.20 (s, 1H) 7.26 (s, 1H) 7.34-7.50 (m, 4H) 12.05 (d, J = 15.72Hz, 2H) ); MS (ESI +) m / z 912.4 (M + H) ⁺ .

実施例３．２７
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−（２，３−ジヒドロ−１Ｈ−インデン−２−イル）−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．５１−１．７６（ｍ、６Ｈ）１．９４−２．０６（ｍ、４Ｈ）２．１２−２．２８（ｍ、８Ｈ）２．６９−２．８９（ｍ、１２Ｈ）２．９２−３．０５（ｍ、１Ｈ）３．５５（ｓ、６Ｈ）３．７７−３．８６（ｍ、４Ｈ）４．３６−４．４３（ｍ、２Ｈ）５．１６−５．２４（ｍ、２Ｈ）５．３５−５．４８（ｍ、２Ｈ）５．９７（ｄ、Ｊ＝１２．９０Ｈｚ、２Ｈ）７．０１−７．３０（ｍ、１７Ｈ）７．３４（ｓ、１Ｈ）７．４６（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）７．５４−７．６０（ｍ、２Ｈ）１２．０７（ｓ、１Ｈ）１２．１８（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１７５．５（Ｍ＋Ｈ）^＋。

Example 3.27
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2 -Diyl (2S) pyrrolidine-2,1-diyl [(1S) -1- (2,3-dihydro-1H-inden-2-yl) -2-oxoethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.51-1.76 (m, 6H) 1.94-2.06 (m, 4H) 2.12-2.28 (m, 8H) 2.69 -2.89 (m, 12H) 2.92-3.05 (m, 1H) 3.55 (s, 6H) 3.77-3.86 (m, 4H) 4.36-4.43 (m) , 2H) 5.16-5.24 (m, 2H) 5.35-5.48 (m, 2H) 5.97 (d, J = 12.90Hz, 2H) 7.01-7.30 (m) , 17H) 7.34 (s, 1H) 7.46 (d, J = 8.35Hz, 1H) 7.54-7.60 (m, 2H) 12.07 (s, 1H) 12.18 (s) , 1H); MS (ESI +) m / z 1175.5 (M + H) ⁺ .

実施例３．２８
メチル｛（２Ｓ）−１−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ，３ａＳ，６ａＳ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝オクタヒドロシクロペンタ［ｂ］ピロール−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７２−０．９２（ｍ、１２Ｈ）１．５０−１．５９（ｍ、４Ｈ）１．６２−１．７２（ｍ、８Ｈ）１．７３−１．８１（ｍ、２Ｈ）１．８３−１．９２（ｍ、４Ｈ）１．９５−２．０３（ｍ、２Ｈ）２．０６−２．１５（ｍ、４Ｈ）２．３８−２．４６（ｍ、２Ｈ）２．７５−２．８３（ｍ、１Ｈ）２．８６−３．０１（ｍ、４Ｈ）３．５４（ｓ、６Ｈ）４．０１（ｔｄ、Ｊ＝１３．２８、６．８３Ｈｚ、４Ｈ）４．７８（ｄｄ、Ｊ＝７．７０、４．２３Ｈｚ、２Ｈ）５．１３（ｔ、Ｊ＝８．２４Ｈｚ、２Ｈ）５．３３−５．４５（ｍ、２Ｈ）５．９２（ｄｄ、Ｊ＝１２．９０、２．８２Ｈｚ、２Ｈ）７．０７（ｄ、Ｊ＝８．６７Ｈｚ、２Ｈ）７．１５（ｔ、Ｊ＝６．９４Ｈｚ、１Ｈ）７．２０−７．２９（ｍ、５Ｈ）７．３４（ｄ、Ｊ＝４．０１Ｈｚ、１Ｈ）７．３９−７．４７（ｍ、３Ｈ）７．５０（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）１１．９７（ｓ、１Ｈ）１２．０６（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１０７．４（Ｍ＋Ｈ）^＋。

Example 3.28
Methyl {(2S) -1-[(2S, 3aS, 6aS) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl)) Phenyl] -5-{2-[(2S, 3aS, 6aS) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} octahydrocyclopenta [b] pyrrole-2 -Il] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -3-methyl- 1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.72-0.92 (m, 12H) 1.50-1.59 (m, 4H) 1.62-1.72 (m, 8H) 1.73 -1.81 (m, 2H) 1.83-1.92 (m, 4H) 1.95-2.03 (m, 2H) 2.06-2.15 (m, 4H) 2.38-2 .46 (m, 2H) 2.75-2.83 (m, 1H) 2.86-3.01 (m, 4H) 3.54 (s, 6H) 4.01 (td, J = 13.28) , 6.83Hz, 4H) 4.78 (dd, J = 7.70, 4.23Hz, 2H) 5.13 (t, J = 8.24Hz, 2H) 5.33-5.45 (m, 2H) ) 5.92 (dd, J = 12.90, 2.82Hz, 2H) 7.07 (d, J = 8.67Hz, 2H) 7.15 (t, J = 6.94Hz, 1H) 7.20 -7.29 (m, 5H) 7.34 (d, J = 4.01Hz, 1H) 7.39-7.47 (m, 3H) 7.50 (d, J = 8.02Hz, 1H) 11 .97 (s, 1H) 12.06 (s, 1H); MS (ESI +) m / z 1107.4 (M + H) ⁺ .

実施例３．２９
メチル｛１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛３−エチル−２−［（メトキシカルボニル）アミノ］ペンタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−エチル−１−オキソペンタｎ−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．１６（ｔ、Ｊ＝６．０２Ｈｚ、１Ｈ）０．３４（ｔ、Ｊ＝６．８９Ｈｚ、１Ｈ）０．５６−０．９９（ｍ、１０Ｈ）１．１６−１．３６（ｍ、４Ｈ）１．５３−１．８０（ｍ、８Ｈ）１．９３−２．０９（ｍ、４Ｈ）２．１４−２．３０（ｍ、４Ｈ）２．８０−３．１３（ｍ、１１Ｈ）３．５３（ｓ、６Ｈ）３．７３−３．９５（ｍ、４Ｈ）４．２４−４．４１（ｍ、２Ｈ）５．０９−５．２０（ｍ、２Ｈ）５．３０−５．４４（ｍ、２Ｈ）５．８３−５．９６（ｍ、２Ｈ）７．０３−７．３６（ｍ、１１Ｈ）７．３９−７．６２（ｍ、２Ｈ）１２．００（ｓ、１Ｈ）１２．１３−１２．２０（ｍ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０８３．５（Ｍ＋Ｈ）^＋。

Example 3.29
Methyl {1-[(2S) -2- {5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5- {2- [(2S) -1- {3-ethyl-2-[(methoxycarbonyl) amino] pentanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazole -2-yl} pyrrolidine-1-yl] -3-ethyl-1-oxopentan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.16 (t, J = 6.02 Hz, 1H) 0.34 (t, J = 6.89 Hz, 1H) 0.56-0.99 (m, 10H) ) 1.16-1.36 (m, 4H) 1.53-1.80 (m, 8H) 1.93-2.09 (m, 4H) 2.14-2.30 (m, 4H) 2 .80-3.13 (m, 11H) 3.53 (s, 6H) 3.73-3.95 (m, 4H) 4.24-4.41 (m, 2H) 5.09-5.20 (M, 2H) 5.30-5.44 (m, 2H) 5.83-5.96 (m, 2H) 7.03-7.36 (m, 11H) 7.39-7.62 (m) , 2H) 12.000 (s, 1H) 12.13-12.20 (m, 1H); MS (ESI +) m / z 1083.5 (M + H) ⁺ .

実施例３．３０
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ，３ａＳ，６ａＳ）ヘキサヒドロシクロペンタ［ｂ］ピロール−２，１（２Ｈ）−ジイル［（１Ｓ）−１−シクロペンチル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１７−１．３２（ｍ、１０Ｈ）１．３６−１．４９（ｍ、１０Ｈ）１．５１−１．７９（ｍ、１０Ｈ）１．８７（ｄｄ、Ｊ＝１５．８３、７．２６Ｈｚ、２Ｈ）１．９８（ｄｄ、Ｊ＝１３．０７、８．４０Ｈｚ、２Ｈ）２．０５−２．１６（ｍ、６Ｈ）２．３６−２．４６（ｍ、４Ｈ）２．７２−２．８１（ｍ、６Ｈ）３．５４（ｓ、６Ｈ）４．１１（ｑ、Ｊ＝９．４０Ｈｚ、２Ｈ）４．７５−４．８５（ｍ、２Ｈ）５．０８−５．１８（ｍ、２Ｈ）５．３６（ｄｔ、Ｊ＝１３．６６、６．８３Ｈｚ、２Ｈ）５．８８（ｄｄｄ、Ｊ＝１２．６９、３．５２、３．４２Ｈｚ、２Ｈ）７．０７（ｄ、Ｊ＝８．３５Ｈｚ、２Ｈ）７．２１（ｓ、１Ｈ）７．３１（ｄ、Ｊ＝４．０１Ｈｚ、１Ｈ）７．４１（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．４６−７．５６（ｍ、３Ｈ）１１．８８（ｄ、Ｊ＝２．４９Ｈｚ、１Ｈ）１２．０１（ｄ、Ｊ＝３．３６Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０８３．５（Ｍ＋Ｈ）^＋。

Example 3.30
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2-diyl ( 2S, 3aS, 6aS) Hexahydrocyclopenta [b] pyrrole-2,1 (2H) -diyl [(1S) -1-cyclopentyl-2-oxoethane-2,1-diyl]}) Biscabamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.17-1.32 (m, 10H) 1.36-1.49 (m, 10H) 1.51-1.79 (m, 10H) 1.87 (Dd, J = 15.83, 7.26Hz, 2H) 1.98 (dd, J = 13.07, 8.40Hz, 2H) 2.05-2.16 (m, 6H) 2.36-2 .46 (m, 4H) 2.72-2.81 (m, 6H) 3.54 (s, 6H) 4.11 (q, J = 9.40Hz, 2H) 4.75-4.85 (m) , 2H) 5.08-5.18 (m, 2H) 5.36 (dt, J = 13.66, 6.83Hz, 2H) 5.88 (ddd, J = 12.69, 3.52, 3 .42Hz, 2H) 7.07 (d, J = 8.35Hz, 2H) 7.21 (s, 1H) 7.31 (d, J = 4.01Hz, 1H) 7.41 (d, J = 8) .24Hz, 1H) 7.46-7.56 (m, 3H) 11.88 (d, J = 2.49Hz, 1H) 12.01 (d, J = 3.36Hz, 1H); MS (ESI +) m / z 1083.5 (M + H) ⁺ .

実施例３．３１
（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス［１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル］）ビス［（２Ｓ）−テトラヒドロフラン−２−イルメタノン］
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．３６−１．４９（ｍ、Ｊ＝１５．８３Ｈｚ、２Ｈ）１．６０−１．７５（ｍ、８Ｈ）１．７７−１．９１（ｍ、６Ｈ）１．９４−２．１２（ｍ、８Ｈ）２．１６−２．２７（ｍ、２Ｈ）２．８６−３．０８（ｍ、５Ｈ）３．７４（ｔ、Ｊ＝６．９９Ｈｚ、６Ｈ）４．５７−４．６３（ｍ、２Ｈ）５．１３（ｄｄ、Ｊ＝９．００、１．３０Ｈｚ、２Ｈ）５．３３−５．４３（ｍ、２Ｈ）５．９３（ｄ、Ｊ＝１３．３４Ｈｚ、２Ｈ）７．０６−７．１６（ｍ、３Ｈ）７．２０−７．２９（ｍ、５Ｈ）７．３２（ｓ、１Ｈ）７．４２（ｄ、Ｊ＝８．５７Ｈｚ、１Ｈ）７．５２（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）１２．００（ｓ、１Ｈ）１２．０８（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９０９．４（Ｍ＋Ｈ）^＋。

Example 3.31
({(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis [1H-benzimidazole-5,2- Diyl (2S) pyrrolidine-2,1-diyl]) bis [(2S) -tetrahydrofuran-2-ylmethanone]
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.36-1.49 (m, J = 15.83 Hz, 2H) 1.60-1.75 (m, 8H) 1.77-1.91 (m) , 6H) 1.94-2.12 (m, 8H) 2.16-2.27 (m, 2H) 2.86-3.08 (m, 5H) 3.74 (t, J = 6.99Hz) , 6H) 4.57-4.63 (m, 2H) 5.13 (dd, J = 9.00, 1.30Hz, 2H) 5.33-5.43 (m, 2H) 5.93 (d) , J = 13.34Hz, 2H) 7.06-7.16 (m, 3H) 7.20-7.29 (m, 5H) 7.32 (s, 1H) 7.42 (d, J = 8) .57Hz, 1H) 7.52 (d, J = 8.13Hz, 1H) 12.000 (s, 1H) 12.08 (s, 1H); MS (ESI +) m / z 909.4 (M + H) ⁺ .

実施例３．３２
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ，３ａＳ，６ａＳ）ヘキサヒドロシクロペンタ［ｂ］ピロール−２，１（２Ｈ）−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１０−１．２７（ｍ、４Ｈ）１．３３−１．５１（ｍ、１２Ｈ）１．５１−１．６５（ｍ、６Ｈ）１．６７−１．８０（ｍ、４Ｈ）１．８３−２．００（ｍ、６Ｈ）２．０８−２．１７（ｍ、４Ｈ）２．３９−２．４５（ｍ、２Ｈ）２．７３−２．８５（ｍ、８Ｈ）３．０３−３．１２（ｍ、２Ｈ）３．５３（ｓ、６Ｈ）３．７０−３．８７（ｍ、２Ｈ）４．０４−４．１７（ｍ、２Ｈ）４．７４−４．８３（ｍ、２Ｈ）５．０８−５．１７（ｍ、２Ｈ）５．３１−５．４２（ｍ、２Ｈ）５．８３−５．９３（ｍ、２Ｈ）７．０４−７．１１（ｍ、２Ｈ）７．２１（ｄ、Ｊ＝１５．８３Ｈｚ、２Ｈ）７．４１（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）７．４６−７．５５（ｍ、３Ｈ）１１．９６（ｄ、Ｊ＝４．１２Ｈｚ、１Ｈ）１２．１１（ｄ、Ｊ＝４．５５Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１１５．４（Ｍ＋Ｈ）^＋。

Example 3.32
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2-diyl ( 2S, 3aS, 6aS) Hexahydrocyclopenta [b] pyrrole-2,1 (2H) -diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1 -Jeil]}) Biscarbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆₎ δppm 1.10-1.27 (m, 4H) 1.33-1.51 (m, 12H) 1.51-1.65 (m, 6H) 1.67 -1.80 (m, 4H) 1.83-2.00 (m, 6H) 2.08-2.17 (m, 4H) 2.39-2.45 (m, 2H) 2.73-2 .85 (m, 8H) 3.03-3.12 (m, 2H) 3.53 (s, 6H) 3.70-3.87 (m, 2H) 4.04-4.17 (m, 2H) ) 4.74-4.83 (m, 2H) 5.08-5.17 (m, 2H) 5.31-5.42 (m, 2H) 5.83-5.93 (m, 2H) 7 .04-7.11 (m, 2H) 7.21 (d, J = 15.83Hz, 2H) 7.41 (d, J = 8.02Hz, 1H) 7.46-7.55 (m, 3H) ) 11.96 (d, J = 4.12Hz, 1H) 12.11 (d, J = 4.55Hz, 1H); MS (ESI +) m / z 1115.4 (M + H) ⁺ .

実施例３．３３
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−（２−｛（２Ｓ，３ａＳ，６ａＳ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］オクタヒドロシクロペンタ［ｂ］ピロール−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９５（ｄ、Ｊ＝６．１８Ｈｚ、３Ｈ）１．０３（ｄ、Ｊ＝５．７５Ｈｚ、３Ｈ）１．３５−１．４９（ｍ、８Ｈ）１．５０−１．６４（ｍ、４Ｈ）１．６６−１．８１（ｍ、６Ｈ）１．８４−２．０１（ｍ、６Ｈ）２．０７−２．１６（ｍ、４Ｈ）２．７３−２．８４（ｍ、６Ｈ）３．１３（ｓ、３Ｈ）３．１７（ｓ、３Ｈ）３．５４（ｓ、６Ｈ）４．２０−４．２９（ｍ、２Ｈ）４．７６−４．８４（ｍ、２Ｈ）５．１２（ｔ、Ｊ＝８．１９Ｈｚ、２Ｈ）５．３７（ｄｄ、Ｊ＝６．５１、４．８８Ｈｚ、２Ｈ）５．８８（ｄ、Ｊ＝１３．４５Ｈｚ、２Ｈ）７．０５（ｄ、Ｊ＝８．１３Ｈｚ、２Ｈ）７．２０（ｓ、１Ｈ）７．３０（ｓ、１Ｈ）７．４０（ｄ、Ｊ＝７．８１Ｈｚ、１Ｈ）７．４７−７．５７（ｍ、３Ｈ）１１．９８−１２．１５（ｍ、２Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ１０６３．４（Ｍ＋Ｈ）^＋。

Example 3.33
Methyl {(2S, 3R) -1-[(2S, 3aS, 6aS) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl) ] -5- (2-{(2S, 3aS, 6aS) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] octahydrocyclopenta [b] pyrrole-2-yl} -1H- Benzimidazole-5-yl) pyrrolidine-2-yl] -1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -3-methoxy-1-oxobutane-2- Il} Carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.95 (d, J = 6.18 Hz, 3H) 1.03 (d, J = 5.75 Hz, 3H) 1.35-1.49 (m, 8H) ) 1.50-1.64 (m, 4H) 1.66-1.81 (m, 6H) 1.84-2.01 (m, 6H) 2.07-2.16 (m, 4H) 2 .73-2.84 (m, 6H) 3.13 (s, 3H) 3.17 (s, 3H) 3.54 (s, 6H) 4.20-4.29 (m, 2H) 4.76 -4.84 (m, 2H) 5.12 (t, J = 8.19Hz, 2H) 5.37 (dd, J = 6.51, 4.88Hz, 2H) 5.88 (d, J = 13) .45Hz, 2H) 7.05 (d, J = 8.13Hz, 2H) 7.20 (s, 1H) 7.30 (s, 1H) 7.40 (d, J = 7.81Hz, 1H) 7 .47-7.57 (m, 3H) 11.98-12.15 (m, 2H); MS (APCI +) m / z 1063.4 (M + H) ⁺ .

実施例３．３４
エチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（エトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７５−０．９１（ｍ、１２Ｈ）１．１５（ｔ、Ｊ＝７．４３Ｈｚ、６Ｈ）１．６０−１．７４（ｍ、６Ｈ）１．８５−２．０７（ｍ、８Ｈ）２．１６−２．２７（ｍ、４Ｈ）２．８６−３．０４（ｍ、４Ｈ）３．４０−３．４８（ｍ、１Ｈ）３．７６−３．８５（ｍ、４Ｈ）３．９８（ｑ、Ｊ＝７．０８Ｈｚ、４Ｈ）４．０５（ｔ、Ｊ＝８．２９Ｈｚ、２Ｈ）５．１１−５．１９（ｍ、２Ｈ）５．３４−５．４４（ｍ、２Ｈ）５．９２（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）７．０５−７．１１（ｍ、２Ｈ）７．１５（ｔ、Ｊ＝６．９４Ｈｚ、１Ｈ）７．２０−７．２７（ｍ、７Ｈ）７．３１（ｓ、１Ｈ）７．４２（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．５０（ｄ、Ｊ＝７．９２Ｈｚ、１Ｈ）１２．０７（ｓ、１Ｈ）１２．１２（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０５５．４（Ｍ＋Ｈ）^＋。

Example 3.34
Ethyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5] -5 − {2-[(2S) -1-{(2S) -2-[(ethoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.75-0.91 (m, 12H) 1.15 (t, J = 7.43 Hz, 6H) 1.60-1.74 (m, 6H) 1 .85-2.07 (m, 8H) 2.16-2.27 (m, 4H) 2.86-3.04 (m, 4H) 3.40-3.48 (m, 1H) 3.76 -3.85 (m, 4H) 3.98 (q, J = 7.08Hz, 4H) 4.05 (t, J = 8.29Hz, 2H) 5.11-5.19 (m, 2H) 5 .34-5.44 (m, 2H) 5.92 (d, J = 12.69Hz, 2H) 7.05-7.11 (m, 2H) 7.15 (t, J = 6.94Hz, 1H) ) 7.20-7.27 (m, 7H) 7.31 (s, 1H) 7.42 (d, J = 8.24Hz, 1H) 7.50 (d, J = 7.92Hz, 1H) 12 .07 (s, 1H) 12.12 (s, 1H); MS (ESI +) m / z 1055.4 (M + H) ⁺ .

実施例３．３５
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１２−１．３３（ｍ、４Ｈ）１．３８−１．５５（ｍ、１０Ｈ）１．６６−１．９０（ｍ、６Ｈ）１．９４−２．０４（ｍ、４Ｈ）２．１１−２．２４（ｍ、２Ｈ）２．７５−２．８５（ｍ、６Ｈ）３．０１−３．１９（ｍ、２Ｈ）３．５２（ｓ、６Ｈ）３．６３−３．７７（ｍ、４Ｈ）３．７８−３．８９（ｍ、６Ｈ）４．０８−４．１８（ｍ、２Ｈ）５．０７−５．１６（ｍ、２Ｈ）５．４６−５．６３（ｍ、２Ｈ）５．８１−５．９３（ｍ、２Ｈ）６．９９−７．１２（ｍ、２Ｈ）７．３１−７．４４（ｍ、４Ｈ）１２．０４−１２．１５（ｍ、１Ｈ）１２．２８−１２．３５（ｍ、１Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ１０７１．２（Ｍ＋Ｈ）^＋。

Example 3.35
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H-benzimidazole-5) , 2-Diyl) (2S) Pyrrolidine-2,1-Diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm1.12-1.33 (m, 4H) 1.38-1.55 (m, 10H) 1.66-1.90 (m, 6H) 1.94 -2.04 (m, 4H) 2.11-2.24 (m, 2H) 2.75-2.85 (m, 6H) 3.01-3.19 (m, 2H) 3.52 (s) , 6H) 3.63-3.77 (m, 4H) 3.78-3.89 (m, 6H) 4.08-4.18 (m, 2H) 5.07-5.16 (m, 2H) ) 5.46-5.63 (m, 2H) 5.81-5.93 (m, 2H) 6.99-7.12 (m, 2H) 7.31-7.44 (m, 4H) 12 .04-12.15 (m, 1H) 12.28-12.35 (m, 1H); MS (APCI +) m / z 1071.2 (M + H) ⁺ .

実施例３．３６
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−（６−フルオロ−２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８７−１．１１（ｍ、８Ｈ）１．３５−１．５２（ｍ、６Ｈ）１．７１−１．８４（ｍ、２Ｈ）１．９１−２．０７（ｍ、４Ｈ）２．１２−２．２６（ｍ、４Ｈ）２．７９（ｓ、４Ｈ）３．０８（ｄ、Ｊ＝３７．４１Ｈｚ、６Ｈ）３．４１−３．４８（ｍ、２Ｈ）３．５３（ｓ、６Ｈ）３．８２（ｄ、Ｊ＝４．８８Ｈｚ、４Ｈ）４．１８−４．３０（ｍ、２Ｈ）５．１１（ｓ、２Ｈ）５．４７−５．６３（ｍ、２Ｈ）５．８１−５．９７（ｍ、２Ｈ）６．９９−７．２８（ｍ、４Ｈ）７．３７（ｄｄ、Ｊ＝２５．５４、９．６０Ｈｚ、２Ｈ）１２．１０（ｓ、１Ｈ）１２．２２−１２．３５（ｍ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０１９．４（Ｍ＋Ｈ）^＋。

Example 3.36
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- (6-Fluor-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazol-5-yl) pyrrolidine-2- Il] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.87-1.11 (m, 8H) 1.35-1.52 (m, 6H) 1.71-1.84 (m, 2H) 1.91 -2.07 (m, 4H) 2.12-2.26 (m, 4H) 2.79 (s, 4H) 3.08 (d, J = 37.41Hz, 6H) 3.41-3.48 (M, 2H) 3.53 (s, 6H) 3.82 (d, J = 4.88Hz, 4H) 4.18-4.30 (m, 2H) 5.11 (s, 2H) 5.47 -5.63 (m, 2H) 5.81-5.97 (m, 2H) 6.99-7.28 (m, 4H) 7.37 (dd, J = 25.54, 9.60Hz, 2H ) 12.10 (s, 1H) 12.22-12.35 (m, 1H); MS (ESI +) m / z 1019.4 (M + H) ⁺ .

実施例３．３７
メチル｛（２Ｓ）−１−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛６−フルオロ−２−［（２Ｓ，３ａＳ，６ａＳ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝オクタヒドロシクロペンタ［ｂ］ピロール−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０（ｄｄ、Ｊ＝２４．１３、６．４５Ｈｚ、１２Ｈ）１．３６−１．６７（ｍ、１０Ｈ）１．６９−１．８７（ｍ、８Ｈ）１．９２−２．１７（ｍ、６Ｈ）２．３７−２．４７（ｍ、２Ｈ）２．７８（ｓ、６Ｈ）３．５３（ｓ、６Ｈ）３．９２−４．０７（ｍ、２Ｈ）４．６９−４．８４（ｍ、２Ｈ）５．０８（ｔ、Ｊ＝８．２９Ｈｚ、２Ｈ）５．３６−５．６８（ｍ、４Ｈ）５．８６（ｄｄ、Ｊ＝１１．７１、８．６７Ｈｚ、２Ｈ）７．１０（ｄｄ、Ｊ＝３１．３９、６．８９Ｈｚ、２Ｈ）７．２８−７．５１（ｍ、４Ｈ）１２．０２（ｓ、１Ｈ）１２．２１（ｄ、Ｊ＝７．２７Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６７．４（Ｍ＋Ｈ）^＋。

Example 3.37
Methyl {(2S) -1-[(2S, 3aS, 6aS) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl]- 5- {6-fluoro-2-[(2S, 3aS, 6aS) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} octahydrocyclopenta [b] pyrrole- 2-Il] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -3-Methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80 (dd, J = 24.13, 6.45 Hz, 12H) 1.36-1.67 (m, 10H) 1.69-1.87 (m) , 8H) 1.92-2.17 (m, 6H) 2.37-2.47 (m, 2H) 2.78 (s, 6H) 3.53 (s, 6H) 3.92-4.07 (M, 2H) 4.69-4.84 (m, 2H) 5.08 (t, J = 8.29Hz, 2H) 5.36-5.68 (m, 4H) 5.86 (dd, J) = 11.71, 8.67Hz, 2H) 7.10 (dd, J = 31.39, 6.89Hz, 2H) 7.28-7.51 (m, 4H) 12.02 (s, 1H) 12 .21 (d, J = 7.27Hz, 1H); MS (ESI +) m / z 1067.4 (M + H) ⁺ .

実施例３．３８
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−（６−フルオロ−２−｛（２Ｓ，３ａＳ，６ａＳ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］オクタヒドロシクロペンタ［ｂ］ピロール−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７８−１．０７（ｍ、８Ｈ）１．３６−１．５１（ｍ、８Ｈ）１．５１−１．６７（ｍ、４Ｈ）１．７５（ｄｄ、Ｊ＝１２．２０、６．５６Ｈｚ、４Ｈ）１．９０（ｄｄ、Ｊ＝２０．２２、８．９５Ｈｚ、４Ｈ）２．００−２．１４（ｍ、４Ｈ）２．３７−２．４７（ｍ、２Ｈ）２．７９（ｓ、６Ｈ）３．０４−３．２０（ｍ、６Ｈ）３．５４（ｓ、６Ｈ）４．１４−４．２９（ｍ、２Ｈ）４．７７（ｄｄ、Ｊ＝１８．００、７．４８Ｈｚ、２Ｈ）５．０７（ｔ、Ｊ＝８．２４Ｈｚ、２Ｈ）５．４７−５．６５（ｍ、２Ｈ）５．８０−５．９４（ｍ、２Ｈ）７．０８（ｄｄ、Ｊ＝２７．２７、６．７８Ｈｚ、２Ｈ）７．２８−７．５７（ｍ、４Ｈ）１２．０４（ｓ、１Ｈ）１２．２６（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０９９．４（Ｍ＋Ｈ）^＋。

Example 3.38
Methyl {(2S, 3R) -1-[(2S, 3aS, 6aS) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl) ] -5- (6-Fluor-2-{(2S, 3aS, 6aS) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] octahydrocyclopenta [b] pyrrole-2-yl } -1H-benzimidazol-5-yl) pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -3- Methoxy-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.78-1.07 (m, 8H) 1.36-1.51 (m, 8H) 1.51-1.67 (m, 4H) 1.75 (Dd, J = 12.20, 6.56Hz, 4H) 1.90 (dd, J = 20.22, 8.95Hz, 4H) 2.00-2.14 (m, 4H) 2.37-2 .47 (m, 2H) 2.79 (s, 6H) 3.04-3.20 (m, 6H) 3.54 (s, 6H) 4.14-4.29 (m, 2H) 4.77 (Dd, J = 18.00, 7.48Hz, 2H) 5.07 (t, J = 8.24Hz, 2H) 5.47-5.65 (m, 2H) 5.80-5.94 (m) , 2H) 7.08 (dd, J = 27.27, 6.78Hz, 2H) 7.28-7.57 (m, 4H) 12.04 (s, 1H) 12.26 (s, 1H); MS (ESI +) m / z 1099.4 (M + H) ⁺ .

実施例３．３９
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロペンチル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１０−１．２９（ｍ、６Ｈ）１．３４−１．６２（ｍ、１８Ｈ）１．７１−１．８６（ｍ、２Ｈ）１．９４−２．１０（ｍ、４Ｈ）２．１１−２．２４（ｍ、４Ｈ）２．７４−２．８４（ｍ、４Ｈ）２．９４−３．１２（ｍ、２Ｈ）３．５３（ｓ、６Ｈ）３．７３−３．８７（ｍ、４Ｈ）４．０６−４．１７（ｍ、２Ｈ）５．０７−５．１８（ｍ、２Ｈ）５．４７−５．６３（ｍ、２Ｈ）５．８２−５．９５（ｍ、２Ｈ）７．０３（ｄ、Ｊ＝６．４０Ｈｚ、１Ｈ）７．１３（ｄ、Ｊ＝７．３７Ｈｚ、１Ｈ）７．３０−７．４６（ｍ、４Ｈ）１２．０７（ｓ、１Ｈ）１２．２３（ｓ、１Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ１０４０．３（Ｍ＋Ｈ）^＋。

Example 3.39
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H-benzimidazole-5) , 2-Diyl) (2S) Pyrrolidine-2,1-Diyl [(1S) -1-Cyclopentyl-2-oxoethane-2,1-Diyl]}) Biscabamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.10-1.29 (m, 6H) 1.34-1.62 (m, 18H) 1.71-1.86 (m, 2H) 1.94 -2.10 (m, 4H) 2.11-2.24 (m, 4H) 2.74-2.84 (m, 4H) 2.94-3.12 (m, 2H) 3.53 (s) , 6H) 3.73-3.87 (m, 4H) 4.06-4.17 (m, 2H) 5.07-5.18 (m, 2H) 5.47-5.63 (m, 2H) ) 5.82-5.95 (m, 2H) 7.03 (d, J = 6.40Hz, 1H) 7.13 (d, J = 7.37Hz, 1H) 7.30-7.46 (m) 4, 4H) 12.07 (s, 1H) 12.23 (s, 1H); MS (APCI +) m / z 1040.3 (M + H) ⁺ .

実施例３．４０
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ，３ａＳ，６ａＳ）ヘキサヒドロシクロペンタ［ｂ］ピロール−２，１（２Ｈ）−ジイル［（１Ｓ）−１−シクロペンチル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．１２−１．２５（ｍ、８Ｈ）１．３５−１．６４（ｍ、１８Ｈ）１．７０−１．８８（ｍ、６Ｈ）１．９２−２．１５（ｍ、８Ｈ）２．３６−２．４６（ｍ、４Ｈ）２．７８（ｓ、６Ｈ）３．５３（ｓ、６Ｈ）４．０７（ｄｔ、Ｊ＝１８．３８、９．２４Ｈｚ、２Ｈ）４．７２−４．８３（ｍ、２Ｈ）５．０７（ｔ、Ｊ＝８．０８Ｈｚ、２Ｈ）５．４６−５．６５（ｍ、２Ｈ）５．８１−５．９１（ｍ、２Ｈ）７．０６（ｄ、Ｊ＝６．０７Ｈｚ、１Ｈ）７．１１−７．１９（ｍ、１Ｈ）７．３４（ｄｄ、Ｊ＝１０．６３、４．８８Ｈｚ、１Ｈ）７．４３（ｄｄ、Ｊ＝１１．２２、７．２１Ｈｚ、１Ｈ）７．５１（ｄｄ、Ｊ＝１３．９９、７．９２Ｈｚ、２Ｈ）１１．９５（ｓ、１Ｈ）１２．２０（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１１９．４（Ｍ＋Ｈ）^＋。

Example 3.40
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H-benzimidazole-5) , 2-Diyl) (2S, 3aS, 6aS) Hexahydrocyclopenta [b] pyrrole-2,1 (2H) -diyl [(1S) -1-cyclopentyl-2-oxoethane-2,1-diyl]}) Biscarbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.12-1.25 (m, 8H) 1.35-1.64 (m, 18H) 1.70-1.88 (m, 6H) 1.92 -2.15 (m, 8H) 2.36-2.46 (m, 4H) 2.78 (s, 6H) 3.53 (s, 6H) 4.07 (dt, J = 18.38, 9) .24Hz, 2H) 4.72-4.83 (m, 2H) 5.07 (t, J = 8.08Hz, 2H) 5.46-5.65 (m, 2H) 5.81-5.91 (M, 2H) 7.06 (d, J = 6.07Hz, 1H) 7.11-7.19 (m, 1H) 7.34 (dd, J = 10.63, 4.88Hz, 1H) 7 .43 (dd, J = 11.22, 7.21Hz, 1H) 7.51 (dd, J = 13.99, 7.92Hz, 2H) 11.95 (s, 1H) 12.20 (s, 1H) ); MS (ESI +) m / z 1119.4 (M + H) ⁺ .

実施例３．４１
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ，３ａＳ，６ａＳ）ヘキサヒドロシクロペンタ［ｂ］ピロール−２，１（２Ｈ）−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．３０−１．６５（ｍ、１８Ｈ）１．６９−１．９４（ｍ、１２Ｈ）２．０５−２．１５（ｍ、４Ｈ）２．３７−２．４５（ｍ、４Ｈ）２．７３−２．８７（ｍ、６Ｈ）２．９７−３．１１（ｍ、３Ｈ）３．５３（ｓ、６Ｈ）３．７７（ｄｄ、Ｊ＝２７．６５、１０．０８Ｈｚ、４Ｈ）４．０６−４．１４（ｍ、２Ｈ）４．７１−４．８１（ｍ、２Ｈ）５．０７（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）５．４３−５．６５（ｍ、２Ｈ）５．７８−５．９２（ｍ、２Ｈ）６．９９−７．０５（ｍ、１Ｈ）７．０９（ｔ、Ｊ＝６．９４Ｈｚ、１Ｈ）７．３３（ｄｄ、Ｊ＝１０．０３、６．１３Ｈｚ、１Ｈ）７．５０（ｄｄ、Ｊ＝１８．１６、７．８６Ｈｚ、２Ｈ）１１．９９（ｓ、１Ｈ）１２．２９（ｄ、Ｊ＝５．７５Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１５１．４（Ｍ＋Ｈ）^＋。

Example 3.41
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H-benzimidazole-5) , 2-Diyl) (2S, 3aS, 6aS) Hexahydrocyclopenta [b] pyrrole-2,1 (2H) -diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ) Ethane-2,1-Zyle]}) Biscarbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.30-1.65 (m, 18H) 1.69-1.94 (m, 12H) 2.05-2.15 (m, 4H) 2.37 -2.45 (m, 4H) 2.73-2.87 (m, 6H) 2.97-3.11 (m, 3H) 3.53 (s, 6H) 3.77 (dd, J = 27) .65, 10.08Hz, 4H) 4.06-4.14 (m, 2H) 4.71-4.81 (m, 2H) 5.07 (t, J = 8.35Hz, 2H) 5.43 -5.65 (m, 2H) 5.78-5.92 (m, 2H) 6.99-7.05 (m, 1H) 7.09 (t, J = 6.94Hz, 1H) 7.33 (Dd, J = 10.03, 6.13Hz, 1H) 7.50 (dd, J = 18.16, 7.86Hz, 2H) 11.99 (s, 1H) 12.29 (d, J = 5) .75Hz, 1H); MS (ESI +) m / z 1151.4 (M + H) ⁺ .

実施例３．４２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（４−フルオロフェニル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．０８（ｄ、Ｊ＝１８．９、２Ｈ）、７．５０（ｄ、Ｊ＝８．０、１Ｈ）、７．４１（ｄ、Ｊ＝８．３、１Ｈ）、７．３３−７．１８（ｍ、６Ｈ）、７．１３−７．０１（ｍ、４Ｈ）、５．９１（ｄ、Ｊ＝１３．１、２Ｈ）、５．４２−５．３３（ｍ、２Ｈ）、５．１９−５．１０（ｍ、２Ｈ）、４．０６（ｔ、Ｊ＝８．６、２Ｈ）、３．８６−３．７７（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．０３−２．８３（ｍ、５Ｈ）、２．２８−１．５４（ｍ、１８Ｈ）、０．９１−０．７３（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０４５．４（Ｍ＋Ｈ）^＋。

Example 3.42
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (4-fluorophenyl) piperidin-1-yl) ] Phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.08 (d, J = 18.9, 2H), 7.50 (d, J = 8.0, 1H), 7.41 (d, J = 8) .3, 1H), 7.33-7.18 (m, 6H), 7.13-7.01 (m, 4H), 5.91 (d, J = 13.1, 2H), 5.42 -5.33 (m, 2H), 5.19-5.10 (m, 2H), 4.06 (t, J = 8.6, 2H), 3.86-3.77 (m, 4H) , 3.53 (s, 6H), 3.03-2.83 (m, 5H), 2.28-1.54 (m, 18H), 0.91-0.73 (m, 12H); MS (ESI +) m / z 1045.4 (M + H) ⁺ .

実施例３．４３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［３−（トリメチルシリル）フェニル］ピペリジン−１−イル｝フェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．３１−１２．０４（ｍ、２Ｈ）、７．４９（ｄ、Ｊ＝８．４、１Ｈ）、７．４０（ｄ、Ｊ＝８．２、１Ｈ）、７．３４−７．１７（ｍ、８Ｈ）、７．１１−７．０４（ｍ、２Ｈ）、５．９５−５．８６（ｍ、２Ｈ）、５．４３−５．３１（ｍ、２Ｈ）、５．１８−５．０９（ｍ、２Ｈ）、４．０５（ｔ、Ｊ＝８．３、２Ｈ）、３．８６−３．７６（ｍ、４Ｈ）、３．５２（ｓ、６Ｈ）、３．１２−２．８２（ｍ、４Ｈ）、２．５８−２．５２（ｍ、２Ｈ）、２．２６−１．８３（ｍ、１１Ｈ）、１．７２−１．５８（ｍ、６Ｈ）、０．９０−０．７３（ｍ、１２Ｈ）、０．２０（ｓ、９Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０９９．４（Ｍ＋Ｈ）^＋。

Example 3.43
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (3,5-difluoro-4- {4- [3- (trimethylsilyl) phenyl] piperidin-1) -Il} phenyl) -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole -5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.31-12.04 (m, 2H), 7.49 (d, J = 8.4, 1H), 7.40 (d, J = 8.2) , 1H), 7.34-7.17 (m, 8H), 7.11-7.04 (m, 2H), 5.95-5.86 (m, 2H), 5.43-5.31 (M, 2H), 5.18-5.09 (m, 2H), 4.05 (t, J = 8.3, 2H), 3.86-3.76 (m, 4H), 3.52 (S, 6H), 3.12-2.82 (m, 4H), 2.58-2.52 (m, 2H), 2.26-1.83 (m, 11H), 1.72-1 .58 (m, 6H), 0.90-0.73 (m, 12H), 0.20 (s, 9H); MS (ESI +) m / z 1099.4 (M + H) ⁺ .

実施例３．４４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛４−［４−（３，４−ジフルオロフェニル）ピペリジン−１−イル］−３，５−ジフルオロフェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．３２−１２．０４（ｍ、２Ｈ）、７．５０（ｄ、Ｊ＝８．５、１Ｈ）、７．４１（ｄ、Ｊ＝８．３、１Ｈ）、７．３６−７．２５（ｍ、５Ｈ）、７．２１（ｓ、１Ｈ）、７．１２−７．０５（ｍ、３Ｈ）、５．９１（ｄ、Ｊ＝１２．８、２Ｈ）、５．３７（ｄｄ、Ｊ＝６．０、２．１、２Ｈ）、５．１８−５．１１（ｍ、２Ｈ）、４．０６（ｔ、Ｊ＝８．３、２Ｈ）、３．８６−３．７９（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．１２−２．８３（ｍ、４Ｈ）、２．２７−２．１０（ｍ、４Ｈ）、２．０８−１．４９（ｍ、１５Ｈ）、０．９３−０．６７（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６３．３（Ｍ＋Ｈ）^＋。

Example 3.44
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {4- [4- (3,4-difluorophenyl) pyrrolidine-1-yl] -3, 5-Difluorophenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole -5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.32-12.04 (m, 2H), 7.50 (d, J = 8.5, 1H), 7.41 (d, J = 8.3) , 1H), 7.36-7.25 (m, 5H), 7.21 (s, 1H), 7.12-7.05 (m, 3H), 5.91 (d, J = 12.8) , 2H), 5.37 (dd, J = 6.0, 2.1, 2H), 5.18-5.11 (m, 2H), 4.06 (t, J = 8.3, 2H) 3.86-3.79 (m, 4H), 3.53 (s, 6H), 3.12-2.83 (m, 4H), 2.27-2.10 (m, 4H), 2 .08-1.49 (m, 15H), 0.93-0.67 (m, 12H); MS (ESI +) m / z 1063.3 (M + H) ⁺ .

実施例３．４５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛４−［４−（３，５−ジフルオロフェニル）ピペリジン−１−イル］−３，５−ジフルオロフェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．４７−１１．９１（ｍ、２Ｈ）、７．５２−７．４０（ｍ、２Ｈ）、７．３６−７．１９（ｍ、４Ｈ）、７．１０（ｄ、Ｊ＝７．９、２Ｈ）、７．０４−６．９２（ｍ、３Ｈ）、５．９２（ｄ、Ｊ＝１２．７、２Ｈ）、５．４６−５．３２（ｍ、２Ｈ）、５．２０−５．１０（ｍ、２Ｈ）、４．０６（ｔ、Ｊ＝８．３、２Ｈ）、３．８９−３．７５（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．１３−２．８２（ｍ、４Ｈ）、２．６３−２．５４（ｍ、３Ｈ）、２．２８−２．１２（ｍ、４Ｈ）、２．０８−１．８４（ｍ、６Ｈ）、１．７７−１．５６（ｍ、６Ｈ）、０．９１−０．７１（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６３．４（Ｍ＋Ｈ）^＋。

Example 3.45
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {4- [4- (3,5-difluorophenyl) pyrrolidine-1-yl] -3, 5-Difluorophenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole -5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.47-11.91 (m, 2H), 7.52-7.40 (m, 2H), 7.36-7.19 (m, 4H), 7.10 (d, J = 7.9, 2H), 7.04-6.92 (m, 3H), 5.92 (d, J = 12.7, 2H), 5.46-5.32 (M, 2H), 5.20-5.10 (m, 2H), 4.06 (t, J = 8.3, 2H), 3.89-3.75 (m, 4H), 3.53 (S, 6H) 3.13-2.82 (m, 4H), 2.63-2.54 (m, 3H), 2.28-2.12 (m, 4H), 2.08-1 .84 (m, 6H), 1.77-1.56 (m, 6H), 0.91-0.71 (m, 12H); MS (ESI +) m / z 1063.4 (M + H) ⁺ .

実施例３．４６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（６−フルオロ−５−｛（２Ｒ，５Ｓ）−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［２−（４−フェニルピペリジン−１−イル）ピリミジン−５−イル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ＝１２．４２−１２．１６（ｍ、２Ｈ）、７．８１−７．５５（ｍ、４Ｈ）、７．４５−７．１２（ｍ、９Ｈ）、５．２３−５．０６（ｍ、２Ｈ）、５．０２−４．８６（ｍ、２Ｈ）、４．５７−４．４５（ｍ、２Ｈ）、４．１３−３．９６（ｍ、２Ｈ）、３．９２−３．７０（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、２．７５（ｔ、Ｊ＝１２．８、２Ｈ）、２．６２−２．５４（ｍ、Ｊ＝８．１、２Ｈ）、２．２８−１．５９（ｍ、１５Ｈ）、１．５３−１．３６（ｍ、２Ｈ）、０．９８−０．６６（ｍ、１２Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝１０２９．４。

Example 3.46
Methyl {(2S) -1-[(2S) -2-(6-fluoro-5-{(2R, 5S) -5- {6-fluoro-2-[(2S) -1-{(2S)-) 2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [2- (4-phenylpiperidin-1-yl) pyrimidine- 5-yl] pyrrolidine-2-yl} -1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO) δ = 12.42-12.16 (m, 2H), 7.81-7.55 (m, 4H), 7.45-7.12 (m, 9H), 5 .23-5.06 (m, 2H), 5.02-4.86 (m, 2H), 4.57-4.45 (m, 2H), 4.13-3.96 (m, 2H) 3.92-3.70 (m, 4H), 3.53 (s, 6H), 2.75 (t, J = 12.8, 2H), 2.62-2.54 (m, J = 8.1, 2H), 2.28-1.59 (m, 15H), 1.53-1.36 (m, 2H), 0.98-0.66 (m, 12H). MS (ESI; M + H) m / z = 1029.4.

実施例３．４７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（６−フルオロ−５−｛（２Ｒ，５Ｓ）−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［２−（ピペリジン−１−イル）ピリミジン−５−イル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ１２．４１−１２．１５（ｍ、２Ｈ）、７．７９−７．５４（ｍ、４Ｈ）、７．４５−７．２４（ｍ、４Ｈ）、５．２０−５．０６（ｍ、２Ｈ）、５．０１−４．８５（ｍ、２Ｈ）、４．１２−４．０１（ｍ、２Ｈ）、３．８８−３．７３（ｍ、４Ｈ）、３．５２（ｓ、６Ｈ）、３．５０−３．４２（ｍ、４Ｈ）、２．５５（ｓ、２Ｈ）、２．２７−１．７７（ｍ、１２Ｈ）、１．５１（ｓ、２Ｈ）、１．３８（ｓ、４Ｈ）、０．９３−０．７３（ｍ、１２Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝９５３．４。

Example 3.47
Methyl {(2S) -1-[(2S) -2-(6-fluoro-5-{(2R, 5S) -5- {6-fluoro-2-[(2S) -1-{(2S)-) 2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [2- (piperidine-1-yl) pyrimidine-5-yl] ] Pyrrolidine-2-yl} -1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO) δ12.41-12.15 (m, 2H), 7.79-7.54 (m, 4H), 7.45-7.24 (m, 4H), 5.20 -5.06 (m, 2H), 5.01-4.85 (m, 2H), 4.12-4.01 (m, 2H), 3.88-3.73 (m, 4H), 3 .52 (s, 6H), 3.50-3.42 (m, 4H), 2.55 (s, 2H), 2.27-1.77 (m, 12H), 1.51 (s, 2H) ), 1.38 (s, 4H), 0.93-0.73 (m, 12H). MS (ESI; M + H) m / z = 953.4.

実施例３．４８
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛４−［４−（２，６−ジフルオロフェニル）ピペラジン−１−イル］−３，５−ジフルオロフェニル｝−５−（６−フルオロ−２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ１２．３７−１２．０８（ｍ、２Ｈ）、７．４１（ｄｄ、Ｊ＝１１．２、６．３、１Ｈ）、７．３４（ｄｄ、Ｊ＝１０．４、４．７、１Ｈ）、７．２４（ｄ、Ｊ＝８．３、１Ｈ）、７．１８−６．９７（ｍ、６Ｈ）、５．９０（ｄｄ、Ｊ＝２２．３、９．７、２Ｈ）、５．５７（ｓ、２Ｈ）、５．１６−５．０６（ｍ、２Ｈ）、４．２５（ｄｄ、Ｊ＝１５．５、８．２、２Ｈ）、３．８７−３．７６（ｍ、３Ｈ）、３．５３（ｓ、６Ｈ）、３．５０−３．４０（ｍ、２Ｈ）、３．２５（ｄ、Ｊ＝３．５、１Ｈ）、３．１３（ｄ、Ｊ＝１．１、３Ｈ）、３．０９（ｓ、４Ｈ）、３．０４（ｄ、Ｊ＝２．６、３Ｈ）、２．９６（ｓ、４Ｈ）、２．５５−２．４７（ｍ、２Ｈ）、２．２６−１．７１（ｍ、１０Ｈ）、１．０８−０．８９（ｍ、６Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝１１３２．４。

Example 3.48
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- {4- [4- (2,6-difluorophenyl) piperazin-1-yl]- 3,5-Difluorophenyl} -5-(6-fluoro-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benz Imidazole-5-yl) pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO) δ12.37-12.08 (m, 2H), 7.41 (dd, J = 11.2, 6.3, 1H), 7.34 (dd, J = 10. 4, 4.7, 1H), 7.24 (d, J = 8.3, 1H), 7.18-6.97 (m, 6H), 5.90 (dd, J = 22.3, 9) .7, 2H), 5.57 (s, 2H), 5.16-5.06 (m, 2H), 4.25 (dd, J = 15.5, 8.2, 2H), 3.87 -3.76 (m, 3H), 3.53 (s, 6H), 3.50-3.40 (m, 2H), 3.25 (d, J = 3.5, 1H), 3.13 (D, J = 1.1, 3H), 3.09 (s, 4H), 3.04 (d, J = 2.6, 3H), 2.96 (s, 4H), 2.55-2 .47 (m, 2H), 2.26-1.71 (m, 10H), 1.08-0.89 (m, 6H). MS (ESI; M + H) m / z = 113.4.

実施例３．４９
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｓ）−１−｛４−［４−（２，６−ジフルオロフェニル）ピペラジン−１−イル］−３，５−ジフルオロフェニル｝−５−（６−フルオロ−２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ１２．３３−１２．０４（ｍ、２Ｈ）、７．４１（ｄｄ、Ｊ＝１１．３、４．７、１Ｈ）、７．３６（ｄｄ、Ｊ＝１０．５、３．０、１Ｈ）、７．２８（ｄ、Ｊ＝７．９、１Ｈ）、７．２１（ｄ、Ｊ＝８．１、１Ｈ）、７．１６（ｔ、Ｊ＝７．８、１Ｈ）、７．１０−６．９６（ｍ、４Ｈ）、５．９２（ｑ、Ｊ＝１０．７、２Ｈ）、５．６９−５．４９（ｍ、２Ｈ）、５．１２（ｄｄ、Ｊ＝７．６、４．１、２Ｈ）、４．２７（ｔ、Ｊ＝７．６、２Ｈ）、３．８２（ｓ、３Ｈ）、３．５３（ｄ、Ｊ＝３．１、６Ｈ）、３．４７（ｄ、Ｊ＝６．３、２Ｈ）、３．２４（ｄ、Ｊ＝２．３、１Ｈ）、３．１９（ｓ、３Ｈ）、３．１３（ｓ、３Ｈ）、３．０９（ｓ、４Ｈ）、２．９６（ｓ、４Ｈ）、２．４６（ｓ、２Ｈ）、２．２８−１．７１（ｍ、１０Ｈ）、１．０９−１．００（ｍ、６Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝１１３２．４。

Example 3.49
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2S, 5S) -1- {4- [4- (2,6-difluorophenyl) piperazin-1-yl]- 3,5-Difluorophenyl} -5-(6-fluoro-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benz Imidazole-5-yl) pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO) δ12.33-12.04 (m, 2H), 7.41 (dd, J = 11.3, 4.7, 1H), 7.36 (dd, J = 10. 5, 3.0, 1H), 7.28 (d, J = 7.9, 1H), 7.21 (d, J = 8.1, 1H), 7.16 (t, J = 7.8) , 1H), 7.10-6.96 (m, 4H), 5.92 (q, J = 10.7, 2H), 5.69-5.49 (m, 2H), 5.12 (dd) , J = 7.6, 4.1, 2H), 4.27 (t, J = 7.6, 2H), 3.82 (s, 3H), 3.53 (d, J = 3.1, 6H), 3.47 (d, J = 6.3, 2H), 3.24 (d, J = 2.3, 1H), 3.19 (s, 3H), 3.13 (s, 3H) , 3.09 (s, 4H), 2.96 (s, 4H), 2.46 (s, 2H), 2.28-1.71 (m, 10H), 1.09-1.00 (m) , 6H). MS (ESI; M + H) m / z = 113.4.

実施例３．５０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｓ）−１−｛４−［４−（２，６−ジフルオロフェニル）ピペラジン−１−イル］−３，５−ジフルオロフェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ１２．４７−１１．９７（ｍ、２Ｈ）、７．４４−７．２６（ｍ、４Ｈ）、７．１９−６．９６（ｍ、５Ｈ）、５．９３（ｑ、Ｊ＝１２．０、２Ｈ）、５．６７−５．４８（ｍ、２Ｈ）、５．１８−５．０７（ｍ、２Ｈ）、４．０５（ｄｄ、Ｊ＝１４．８、８．３、２Ｈ）、３．８７−３．７１（ｍ、４Ｈ）、３．５３（ｄ、Ｊ＝３．１、６Ｈ）、３．０９（ｓ、４Ｈ）、２．９６（ｓ、４Ｈ）、２．４６（ｓ、２Ｈ）、２．２５−１．７０（ｍ、１２Ｈ）、０．８９−０．７６（ｍ、１２Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝１１００．４。

Example 3.50
Methyl {(2S) -1-[(2S) -2-{5-[(2S, 5S) -1- {4- [4- (2,6-difluorophenyl) piperazin-1-yl] -3, 5-Difluorophenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl]- 1H-benzimidazol-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO) δ12.47-11.97 (m, 2H), 7.44-7.26 (m, 4H), 7.19-6.96 (m, 5H), 5.93 (Q, J = 12.0, 2H), 5.67-5.48 (m, 2H), 5.18-5.07 (m, 2H), 4.05 (dd, J = 14.8, 8.3, 2H), 3.87-3.71 (m, 4H), 3.53 (d, J = 3.1, 6H), 3.09 (s, 4H), 2.96 (s, 4H), 2.46 (s, 2H), 2.25-1.70 (m, 12H), 0.89-0.76 (m, 12H). MS (ESI; M + H) m / z = 1100.4.

実施例３．５１
ジメチル（［（２Ｒ，５Ｒ）−１−｛４−［４−（２，６−ジフルオロフェニル）ピペラジン−１−イル］−３，５−ジフルオロフェニル｝ピロリジン−２，５−ジイル］ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ１２．３７−１２．０８（ｍ、２Ｈ）、７．４４−７．３０（ｍ、４Ｈ）、７．１２−６．９５（ｍ、５Ｈ）、５．９０（ｑ、Ｊ＝１１．６、２Ｈ）、５．６６−５．４７（ｍ、２Ｈ）、５．１６−５．０５（ｍ、２Ｈ）、４．１７−４．０４（ｍ、２Ｈ）、３．８８−３．６１（ｍ、７Ｈ）、３．５２（ｄ、Ｊ＝３．１、６Ｈ）、３．２３−２．８０（ｍ、１３Ｈ）、２．２６−１．６７（ｍ、１２Ｈ）、１．５５−１．０５（ｍ、１０Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝１１８４．４。

Example 3.51
Dimethyl ([(2R, 5R) -1- {4- [4- (2,6-difluorophenyl) piperazin-1-yl] -3,5-difluorophenyl} pyrrolidine-2,5-diyl] bis {( 6-Fluoro-1H-benzimidazole-5,2-diyl) (2S) Pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2 , 1-Jill]}) Biscarbamate
^{1 1} H NMR (400 MHz, DMSO) δ12.37-12.08 (m, 2H), 7.44-7.30 (m, 4H), 7.12-6.95 (m, 5H), 5.90 (Q, J = 11.6, 2H) 5.66-5.47 (m, 2H) 5.16-5.05 (m, 2H) 4.17-4.04 (m, 2H) 3.88-3.61 (m, 7H), 3.52 (d, J = 3.1, 6H), 3.23-2.80 (m, 13H), 2.26-1.67 ( m, 12H), 1.55-1.05 (m, 10H). MS (ESI; M + H) m / z = 1184.4.

実施例３．５２
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（４−フルオロフェニル）ピペリジン−１−イル］フェニル｝−５−（６−フルオロ−２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ１２．３６−１２．０６（ｍ、２Ｈ）、７．４１（ｄｄ、Ｊ＝１１．２、６．３、１Ｈ）、７．３４（ｄｄ、Ｊ＝１０．４、４．８、１Ｈ）、７．３０−７．２０（ｍ、３Ｈ）、７．１７−６．９８（ｍ、５Ｈ）、５．９８−５．８２（ｍ、２Ｈ）、５．６５−５．４７（ｍ、２Ｈ）、５．１７−５．０６（ｍ、２Ｈ）、４．２５（ｄｄ、Ｊ＝１５．６、８．１、２Ｈ）、３．８８−３．７４（ｍ、３Ｈ）、３．５３（ｄ、Ｊ＝１．３、６Ｈ）、３．４９−３．３８（ｍ、２Ｈ）、３．３１（ｄ、１Ｈ）、３．２５（ｄ、Ｊ＝３．７、１Ｈ）、３．１３（ｄ、Ｊ＝１．３、３Ｈ）、３．０３（ｄ、Ｊ＝２．３、３Ｈ）、３．００−２．８４（ｍ、３Ｈ）、２．６０−２．５３（ｍ、Ｊ＝２．５、２Ｈ）、２．２６−１．５５（ｍ、１４Ｈ）、１．２８−１．１３（ｍ、１Ｈ）、１．１０−０．８８（ｍ、６Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝１１１３．４。

Example 3.52
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (4-fluorophenyl) pyrrolidine-1) -Il] Phenyl} -5-(6-fluoro-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazole- 5-yl) Pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO) δ12.36-12.06 (m, 2H), 7.41 (dd, J = 11.2, 6.3, 1H), 7.34 (dd, J = 10. 4,4.8, 1H), 7.30-7.20 (m, 3H), 7.17-6.98 (m, 5H), 5.98-5.82 (m, 2H), 5. 65-5.47 (m, 2H), 5.17-5.06 (m, 2H), 4.25 (dd, J = 15.6, 8.1, 2H), 3.88-3.74 (M, 3H), 3.53 (d, J = 1.3, 6H), 3.49-3.38 (m, 2H), 3.31 (d, 1H), 3.25 (d, J) = 3.7, 1H), 3.13 (d, J = 1.3, 3H), 3.03 (d, J = 2.3, 3H), 3.00-2.84 (m, 3H) 2.60-2.53 (m, J = 2.5, 2H), 2.26-1.55 (m, 14H), 1.28-1.13 (m, 1H), 1.10- 0.88 (m, 6H). MS (ESI; M + H) m / z = 1113.4.

実施例３．５３
ジメチル（［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（４−フルオロフェニル）ピペリジン−１−イル］フェニル｝ピロリジン−２，５−ジイル］ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ１２．３６−１２．０７（ｍ、２Ｈ）、７．４４−７．２２（ｍ、６Ｈ）、７．１２−６．９９（ｍ、４Ｈ）、５．８８（ｄｄ、Ｊ＝２３．６、１１．２、２Ｈ）、５．６４−５．４７（ｍ、２Ｈ）、５．１５−５．０６（ｍ、２Ｈ）、４．１７−４．０６（ｍ、２Ｈ）、３．８９−３．６１（ｍ、７Ｈ）、３．５２（ｄ、Ｊ＝３．３、６Ｈ）、３．２５−２．８２（ｍ、９Ｈ）、２．２６−２．０８（ｍ、４Ｈ）、２．０５−１．９２（ｍ、４Ｈ）、１．９１−１．５７（ｍ、９Ｈ）、１．５４−１．３８（ｍ、４Ｈ）、１．３８−１．０２（ｍ、６Ｈ）。ＭＳ（ＥＳＩ；Ｍ＋Ｈ）ｍ／ｚ＝１１６５．５。

Example 3.53
Dimethyl ([(2R, 5R) -1- {3,5-difluoro-4- [4- (4-fluorophenyl) piperidine-1-yl] phenyl} pyrrolidine-2,5-diyl] bis {(6-- Fluoro-1H-benzimidazol-5,2-diyl) (2S) pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1 -Jeil]}) Biscarbamate
^{1 1} H NMR (400 MHz, DMSO) δ12.36-12.07 (m, 2H), 7.44-7.22 (m, 6H), 7.12-6.99 (m, 4H), 5.88 (Dd, J = 23.6, 11.2, 2H) 5.64-5.47 (m, 2H), 5.15-5.06 (m, 2H), 4.17-4.06 ( m, 2H), 3.89-3.61 (m, 7H), 3.52 (d, J = 3.3, 6H), 3.25-2.82 (m, 9H), 2.26- 2.08 (m, 4H), 2.05-1.92 (m, 4H), 1.91-1.57 (m, 9H), 1.54-1.38 (m, 4H), 1. 38-1.02 (m, 6H). MS (ESI; M + H) m / z = 1165.5.

The following Example compounds 4.1 to 4.62 can be prepared from the appropriate listed intermediates according to the method of General Procedure 12 / 12B.

Intermediate amines (S) -6,6'-((2R, 5R) -1-(4- (cyclopentyloxy) -3-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) ) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3-methyl-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4-((3aR, 7aS) -1H-isoindole-2 (3H, 3aH, 4H, 5H, 6H) , 7H, 7aH) -yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-dichloro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (2,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((() S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4-((2R, 6S) -2,6-dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2 , 5-Diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (2,3,5-trifluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-cyclohexyl-3-fluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) ) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,4-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl)- 1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-ethoxyphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H- Benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (2,2-difluoroethoxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (3,5-dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
6,6'-{(2R, 5R) -1- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] pyrrolidine-2,5-diyl} bis {2-[(2S) -pyrrolidin-2-yl) ] -1H-benzimidazole} (ACD Name v12);
(S) -6,6'-((2S, 5S) -1- (4-cyclopropylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H -Benzo [d] imidazole);
(S) -6,6'-((2S, 5S) -1- (4-cyclopropyl-3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-) 2-Il) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl)- 1H-benzo [d] imidazole);
1-(1-(4-((2R, 5R) -2,5-bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazol-6-yl) pyrrolidine-1) -Il) -2,6-difluorophenyl) -4-phenylpiperidine-4-yl) etanone;
(S, S, S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis ( 2-((2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
(S, S, S) -6,6'-((2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 3aS, 6aS)) -Octahydrocyclopenta [b] pyrrole-2-yl) -1H-benzo [d] imidazole);
2- (4-((2R, 5R) -2,5-bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazol-6-yl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-azabicyclo [2.2.2] octane;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-isopropylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4,4-dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (3,3-dimethylazetidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) Bis (2-((S) -pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)-)- Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (3-phenylpropyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (5-Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (naphthalen-2-yl) piperidine-1-yl) phenyl) pyrrolidine-2,5 -Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (2,3-dihydrospiro [indene-1,4'-piperidine] -1'-yl) -3,5-difluoro) Phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (3-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (3-phenylpyrrolidin-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4-methoxyphenyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-fluoro-4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-fluoro-4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-( (S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (fluorodiphenylmethyl) piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) ) Bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5) -Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (benzyloxy) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) phenyl) pyrrolidine- 2,5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
6-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) -5-(2-((S) -pyrrolidin-2-yl) -1H-benzo [D] Imidazole-6-yl) pyrrolidine-2-yl) -5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole;
(S) -6,6'-((2R, 5R) -1- (4- (4-benzylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (5) -Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-benzylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2S, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
4- (4-((2R, 5R) -2,5-bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazol-6-yl) pyrrolidine-1-yl) -2,6-difluorophenyl) -2-phenylmorpholine;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (2-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(2S, 6R) -4- (4-((2R, 5R) -2,5-bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole- 6-yl) Pyrrolidine-1-yl) -2,6-difluorophenyl) -2,6-dimethylmorpholine;
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (3-azaspiro [5.5] undecane-3-yl) phenyl) pyrrolidine-2,5- Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (4- (4-cyclohexylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (5) -Fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -4- (4-((2R, 5R) -2,5-bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole-6- Il) Pyrrolidine-1-yl) -2,6-difluorophenyl) -2-phenylmorpholine;
(S) -6,6'-((2S, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-) 2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperazine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S, R) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- ((2S, 4R) -4-fluoropyrrolidine-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (pyrimidine-2-yl) piperazin-1-yl) phenyl) pyrrolidine-2,5 -Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1-(4- (4- (2,4-difluorophenyl) piperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2, 5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4-fluorophenyl) piperidine-1-yl) phenyl) pyrrolidine-2,5- Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole);
(S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (5-methylthiophen-2-yl) piperidine-1-yl) phenyl) pyrrolidine- 2,5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole); and (S) -6,6'-((2R, 5R) ) -1- (3,5-difluoro-4- (4-fluoro-4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S)-)- Pyrrolidine-2-yl) -1H-benzo [d] imidazole).

Intermediate acids (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid;
(S) -2- (Methoxycarbonylamino) -2- (Tetrahydro-2H-pyran-4-yl) acetic acid;
(2S, 3R) -3-methoxy-2- (methoxycarbonylamino) butanoic acid;
(S) -2-Cyclopropyl-2- (methoxycarbonylamino) acetic acid;
(2S, 3R) -3-tert-butoxy-2- (methoxycarbonylamino) butanoic acid;
(S) -2- (Methoxycarbonylamino) -2- (Tetrahydro-2H-pyran-4-yl) acetic acid;
(S) -2-cyclopentyl-2- (methoxycarbonylamino) acetic acid; and (2S, 3R) -3-methoxy-2- (methoxycarbonylamino) butanoic acid.

実施例４．１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（シクロペンチルオキシ）−３−フルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．８９（ｍ、１２Ｈ）、１．３７−１．７７（ｍ、１２Ｈ）、１．８１−２．０６（ｍ、６Ｈ）、２．１１−２．２９（ｍ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．７２−３．９２（ｍ、４Ｈ）、３．９５−４．１６（ｍ、２Ｈ）、４．４０−４．５２（ｍ、１Ｈ）、５．０７−５．２３（ｍ、２Ｈ）、５．２６−５．４４（ｍ、２Ｈ）、５．９６−６．１７（ｍ、２Ｈ）、６．６３−６．９８（ｍ、２Ｈ）、７．００−７．１６（ｍ、２Ｈ）、７．１６−７．３５（ｍ、４Ｈ）、７．３５−７．５４（ｍ、Ｊ＝３１．２３Ｈｚ、２Ｈ）、１１．９３−１２．３２（ｍ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ＝９３４．５（Ｍ＋Ｈ）^＋。

Example 4.1
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [4- (cyclopentyloxy) -3-fluorophenyl] -5- {2-[(2S)) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.89 (m, 12H), 1.37-1.77 (m, 12H), 1.81-2.06 (m, 6H), 2.11-2.29 (m, 4H), 3.54 (s, 6H), 3.72-3.92 (m, 4H), 3.95-4.16 (m, 2H), 4. 40-4.52 (m, 1H), 5.07-5.23 (m, 2H), 5.26-5.44 (m, 2H), 5.96-6.17 (m, 2H), 6.63-6.98 (m, 2H), 7.00-7.16 (m, 2H), 7.16-7.35 (m, 4H), 7.35-7.54 (m, J) = 31.23Hz, 2H), 11.93-12.32 (m, 2H); MS (ESI) m / z = 934.5 (M + H) ⁺ .

実施例４．２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［３−メチル−４−（ピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．８９（ｍ、１２Ｈ）１．３５−１．４１（ｍ、２Ｈ）１．４４−１．５２（ｍ、４Ｈ）１．６２−１．６７（ｍ、２Ｈ）１．８６−１．９３（ｍ、５Ｈ）１．９４−２．０３（ｍ、４Ｈ）２．１５−２．２４（ｍ、４Ｈ）２．４８−２．５４（ｍ、６Ｈ）３．５２（ｓ、６Ｈ）３．７４−３．８４（ｍ、４Ｈ）４．００−４．０９（ｍ、２Ｈ）５．０６−５．１８（ｍ、２Ｈ）５．２８−５．３７（ｍ、２Ｈ）６．０７−６．１２（ｍ、１Ｈ）６．１７−６．２１（ｍ、１Ｈ）６．５６−６．６２（ｍ、１Ｈ）６．９９−７．３０（ｍ、６Ｈ）７．３５（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．４４（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）１１．９４−１２．０４（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９２９．５（Ｍ＋Ｈ）^＋。

Example 4.2
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [3-methyl-4- (piperidine-1-yl) phenyl] pyrrolidine-2-yl}- 1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.89 (m, 12H) 1.35-1.41 (m, 2H) 1.44-1.52 (m, 4H) 1.62 -1.67 (m, 2H) 1.86-1.93 (m, 5H) 1.94-2.03 (m, 4H) 2.15-2.24 (m, 4H) 2.48-2 .54 (m, 6H) 3.52 (s, 6H) 3.74-3.84 (m, 4H) 4.00-4.09 (m, 2H) 5.06-5.18 (m, 2H) ) 5.28-5.37 (m, 2H) 6.07-6.12 (m, 1H) 6.17-6.21 (m, 1H) 6.56-6.62 (m, 1H) 6 .99-7.30 (m, 6H) 7.35 (d, J = 8.24Hz, 1H) 7.44 (d, J = 8.24Hz, 1H) 11.94-12.04 (m, 2H) ); MS (ESI +) m / z 929.5 (M + H) ⁺ .

実施例４．３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［（３ａＲ，７ａＳ）−オクタヒドロ−２Ｈ−イソインドール−２−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７１−０．９４（ｍ、１２Ｈ）１．２２−１．３１（ｍ、２Ｈ）１．３５−１．５３（ｍ、６Ｈ）１．６６−１．７４（ｍ、２Ｈ）１．８６−２．２４（ｍ、１２Ｈ）２．９０−２．９７（ｍ、２Ｈ）３．０５−３．１５（ｍ、２Ｈ）３．３６−３．４２（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．７７−３．８６（ｍ、４Ｈ）４．０６（ｔ、Ｊ＝８．２９Ｈｚ、２Ｈ）５．０９−５．２０（ｍ、２Ｈ）５．２９−５．４０（ｍ、２Ｈ）５．８９（ｄ、Ｊ＝１２．２５Ｈｚ、２Ｈ）７．０３−７．１３（ｍ、２Ｈ）７．１８−７．３３（ｍ、４Ｈ）７．４０（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４８（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）１１．９５−１２．２５（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９９１．５（Ｍ＋Ｈ）^＋。

Example 4.3
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4-[(3aR, 7aS) -octahydro-2H-isoindole- 2-Il] phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benz Imidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.71-0.94 (m, 12H) 1.22-1.31 (m, 2H) 1.35-1.53 (m, 6H) 1.66 -1.74 (m, 2H) 1.86-2.24 (m, 12H) 2.90-2.97 (m, 2H) 3.05-3.15 (m, 2H) 3.36-3 .42 (m, 2H) 3.54 (s, 6H) 3.77-3.86 (m, 4H) 4.06 (t, J = 8.29Hz, 2H) 5.09-5.20 (m) , 2H) 5.29-5.40 (m, 2H) 5.89 (d, J = 12.25Hz, 2H) 7.03-7.13 (m, 2H) 7.18-7.33 (m) 4, 4H) 7.40 (d, J = 8.13Hz, 1H) 7.48 (d, J = 8.24Hz, 1H) 11.95-12.25 (m, 2H); MS (ESI +) m / z991.5 (M + H) ⁺ .

実施例４．４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジクロロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６８−０．９４（ｍ、１２Ｈ）１．３６−２．２８（ｍ、２０Ｈ）２．８４（ｓ、４Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０４−４．０９（ｍ、２Ｈ）５．０９−５．１９（ｍ、２Ｈ）５．３３−５．５０（ｍ、２Ｈ）６．３０（ｔ、Ｊ＝２．４９Ｈｚ、２Ｈ）６．９９−７．５７（ｍ、８Ｈ）１２．０４（ｓ、１Ｈ）１２．０９（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９８３（Ｍ＋Ｈ）^＋。

Example 4.4
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-dichloro-4- (piperidin-1-yl) phenyl] -5- {2 -[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl ] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.68-0.94 (m, 12H) 1.36-2.28 (m, 20H) 2.84 (s, 4H) 3.54 (s, 6H) ) 3.82 (s, 4H) 4.04-4.09 (m, 2H) 5.09-5.19 (m, 2H) 5.33-5.50 (m, 2H) 6.30 (t) , J = 2.49Hz, 2H) 6.99-7.57 (m, 8H) 12.04 (s, 1H) 12.09 (s, 1H); MS (ESI +) m / z983 (M + H) ⁺ .

実施例４．５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［２，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０（ｓ、１２Ｈ）１．０８−２．７１（ｍ、２４Ｈ）３．５３（ｓ、６Ｈ）３．８１（ｓ、４Ｈ）３．９７−４．１１（ｍ、２Ｈ）５．１３（ｓ、２Ｈ）５．５１（ｓ、２Ｈ）６．３４−６．７０（ｍ、２Ｈ）７．００−７．６０（ｍ、８Ｈ）１１．８７−１２．３０（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９５２（Ｍ＋Ｈ）^＋。

Example 4.5
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [2,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {2 -[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl ] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80 (s, 12H) 1.08-2.71 (m, 24H) 3.53 (s, 6H) 3.81 (s, 4H) 3.97 -4.11 (m, 2H) 5.13 (s, 2H) 5.51 (s, 2H) 6.34-6.70 (m, 2H) 7.00-7.60 (m, 8H) 11 .87-12.30 (m, 2H); MS (ESI +) m / z 952 (M + H) ⁺ .

実施例４．６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛４−［（２Ｒ，６Ｓ）−２，６−ジメチルピペリジン−１−イル］−３，５−ジフルオロフェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．５８（ｓ、６Ｈ）０．７３−０．９２（ｍ、１２Ｈ）１．０８−２．３７（ｍ、２０Ｈ）３．５３（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０６（ｑ、Ｊ＝７．９２Ｈｚ、２Ｈ）５．１５（ｓ、２Ｈ）５．３９（ｓ、２Ｈ）５．８８（ｄ、Ｊ＝１３．０１Ｈｚ、２Ｈ）７．０２−７．５８（ｍ、１０Ｈ）１２．０１（ｓ、１Ｈ）１２．１８（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９７９（Ｍ＋Ｈ）^＋。

Example 4.6
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {4-[(2R, 6S) -2,6-dimethylpiperidine-1-yl] -3 , 5-Difluorophenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benz Imidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.58 (s, 6H) 0.73-0.92 (m, 12H) 1.08-2.37 (m, 20H) 3.53 (s, 6H) ) 3.82 (s, 4H) 4.06 (q, J = 7.92Hz, 2H) 5.15 (s, 2H) 5.39 (s, 2H) 5.88 (d, J = 13.01Hz) , 2H) 7.02-7.58 (m, 10H) 12.01 (s, 1H) 12.18 (s, 1H); MS (ESI +) m / z 979 (M + H) ⁺ .

実施例４．７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［２，３，５−トリフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７２−０．９３（ｍ、１２Ｈ）１．３４−２．３８（ｍ、２０Ｈ）２．７７（ｓ、４Ｈ）３．５３（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．００−４．１３（ｍ、２Ｈ）５．１４（ｓ、２Ｈ）５．５６（ｓ、２Ｈ）６．２７−６．４７（ｍ、１Ｈ）６．９７−７．４９（ｍ、８Ｈ）１２．０１（ｓ、１Ｈ）１２．０８（ｄ、Ｊ＝１．８４Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９７０（Ｍ＋Ｈ）^＋。

Example 4.7
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [2,3,5-trifluoro-4- (piperidine-1-yl) phenyl] pyrrolidine- 2-Il} -1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.72-0.93 (m, 12H) 1.34-2.38 (m, 20H) 2.77 (s, 4H) 3.53 (s, 6H) ) 3.82 (s, 4H) 4.00-4.13 (m, 2H) 5.14 (s, 2H) 5.56 (s, 2H) 6.27-6.47 (m, 1H) 6 .97-7.49 (m, 8H) 12.01 (s, 1H) 12.08 (d, J = 1.84Hz, 1H); MS (ESI +) m / z 970 (M + H) ⁺ .

実施例４．８
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−シクロヘキシル−３−フルオロフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．４８（ｍ、１Ｈ）、１０．３２（ｓ、１Ｈ）、７．７０（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．５３（ｓ、１Ｈ）、７．３４（ｄ、Ｊ＝８．１Ｈｚ、１Ｈ）、７．１３（ｄ、Ｊ＝５．５Ｈｚ、３Ｈ）、６．７２（ｓ、１Ｈ）、６．０３（ｍ、２Ｈ）、５．４０（ｍ、５Ｈ）、５．２６（ｄ、Ｊ＝１．７Ｈｚ、３Ｈ）、４．３４（ｄｄ、Ｊ＝８．７、７．０Ｈｚ、２Ｈ）、３．８４（ｄ、Ｊ＝７．６Ｈｚ、２Ｈ）、３．７０（ｓ、６Ｈ）、３．６２（ｍ、３Ｈ）、３．０９（ｍ、２Ｈ）、２．５７（ｍ、４Ｈ）、２．３３（ｍ、２Ｈ）、２．１７（ｍ、５Ｈ）、１．９７（ｍ、３Ｈ）、１．７３（ｍ、８Ｈ）、１．１７（ｍ、８Ｈ）、０．８９（ｔ、Ｊ＝６．４、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対的存在比）９３３（１００、Ｍ＋Ｈ）、９３４（５３）。

Example 4.8
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-cyclohexyl-3-fluorophenyl) -5- {2-[(2S) -1-] {(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -1H-benzimidazole-2 -Il} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.48 (m, 1H), 10.32 (s, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.53 (s, 1H) , 7.34 (d, J = 8.1Hz, 1H), 7.13 (d, J = 5.5Hz, 3H), 6.72 (s, 1H), 6.03 (m, 2H), 5 .40 (m, 5H), 5.26 (d, J = 1.7Hz, 3H), 4.34 (dd, J = 8.7, 7.0Hz, 2H), 3.84 (d, J = 7.6Hz, 2H), 3.70 (s, 6H), 3.62 (m, 3H), 3.09 (m, 2H), 2.57 (m, 4H), 2.33 (m, 2H) ), 2.17 (m, 5H), 1.97 (m, 3H), 1.73 (m, 8H), 1.17 (m, 8H), 0.89 (t, J = 6.4, 12H); MS (ESI +) m / z (relative presence ratio) 933 (100, M + H), 934 (53).

実施例４．９
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（３，４−ジフルオロフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．４９（ｄ、Ｊ＝９．０Ｈｚ、１Ｈ）、１０．３８（ｓ、１Ｈ）、７．７０（ｄ、Ｊ＝８．１Ｈｚ、１Ｈ）、７．５１（ｓ、１Ｈ）、７．３５（ｄ、Ｊ＝８．３Ｈｚ、１Ｈ）、７．１２（ｄｄ、Ｊ＝１０．９、６．３Ｈｚ、３Ｈ）、６．６９（ｄｄ、Ｊ＝９．４、５．７Ｈｚ、１Ｈ）、６．１３（ｄ、Ｊ＝７．２Ｈｚ、１Ｈ）、６．００（ｓ、１Ｈ）、５．４１（ｍ、４Ｈ）、５．２７（ｍ、２Ｈ）、４．３４（ｍ、２Ｈ）、４．０６（ｄ、Ｊ＝６．６Ｈｚ、１Ｈ）、３．８５（ｍ、２Ｈ）、３．７３（ｓ、６Ｈ）、３．６４（ｍ、２Ｈ）、３．０８（ｍ、２Ｈ）、２．６１（ｍ、２Ｈ）、２．３４（ｍ、２Ｈ）、２．１９（ｍ、４Ｈ）、１．９６（ｍ、２Ｈ）、１．７９（ｍ、２Ｈ）、１．６４（ｍ、４Ｈ）、０．９２（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対的存在比）８６８（１００、Ｍ＋Ｈ）、８６９（４３）。

Example 4.9
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (3,4-difluorophenyl) -5- {2-[(2S) -1-{((2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-6-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl } Pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.49 (d, J = 9.0 Hz, 1H), 10.38 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7. 51 (s, 1H), 7.35 (d, J = 8.3Hz, 1H), 7.12 (dd, J = 10.9, 6.3Hz, 3H), 6.69 (dd, J = 9) .4, 5.7Hz, 1H), 6.13 (d, J = 7.2Hz, 1H), 6.00 (s, 1H), 5.41 (m, 4H), 5.27 (m, 2H) ), 4.34 (m, 2H), 4.06 (d, J = 6.6Hz, 1H), 3.85 (m, 2H), 3.73 (s, 6H), 3.64 (m, 2H), 3.08 (m, 2H), 2.61 (m, 2H), 2.34 (m, 2H), 2.19 (m, 4H), 1.96 (m, 2H), 1. 79 (m, 2H), 1.64 (m, 4H), 0.92 (m, 12H); MS (ESI +) m / z (relative abundance ratio) 868 (100, M + H), 869 (43).

実施例４．１０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１− （４−エトキシフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９２−０．７５（ｍ、１２Ｈ）、１．２１−１．１０（ｍ、３Ｈ）、１．３３−１．２１（ｍ、１Ｈ）、１．７６−１．６４（ｍ、２Ｈ）、２．０６−１．８５（ｍ、７Ｈ）、２．２８−２．０８（ｍ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．７３（ｑ、Ｊ＝７．０、２Ｈ）、３．８１（ｓ、４Ｈ）、４．１１−３．９９（ｍ、２Ｈ）、５．１８−５．０６（ｍ、２Ｈ）、５．３３（ｓ、２Ｈ）、６．２４（ｄ、Ｊ＝８．９、２Ｈ）、６．５１（ｄｔ、Ｊ＝４．９、９．４、２Ｈ）、７．０４（ｔ、Ｊ＝７．７、２Ｈ）、７．３４−７．１８（ｍ、４Ｈ）、７．３６（ｄ、Ｊ＝８．２、１Ｈ）、７．４４（ｄ、Ｊ＝８．２、１Ｈ）、１２．０２（ｓ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ８７６（Ｍ＋Ｈ）^＋、８７４（Ｍ−Ｈ）⁻。

Example 4.10
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- (4-ethoxyphenyl) -5- {2-[(2S) -1-{(2S)) -2-[(Methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-6-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine -1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.92 to 0.75 (m, 12H), 1.21-1.10 (m, 3H), 1.33-1.21 (m, 1H), 1.76-1.64 (m, 2H), 2.06-1.85 (m, 7H), 2.28-2.08 (m, 4H), 3.54 (s, 6H), 3. 73 (q, J = 7.0, 2H), 3.81 (s, 4H), 4.11-3.99 (m, 2H), 5.18-5.06 (m, 2H), 5. 33 (s, 2H), 6.24 (d, J = 8.9, 2H), 6.51 (dt, J = 4.9, 9.4, 2H), 7.04 (t, J = 7) .7, 2H), 7.34-7.18 (m, 4H), 7.36 (d, J = 8.2, 1H), 7.44 (d, J = 8.2, 1H), 12 .02 (s, 2H); MS (ESI) m / z 876 (M + H) ⁺ , 874 (MH) ^- .

実施例４．１１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（２，２−ジフルオロエトキシ）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、メタノール−ｄ_４）δｐｐｍ０．８５（ｄｄ、Ｊ＝６．７、２０．０、１２Ｈ）、１．８８−１．７５（ｍ、２Ｈ）、２．０６−１．９５（ｍ、３Ｈ）、２．２２−２．０６（ｍ、３Ｈ）、２．３４−２．２３（ｍ、２Ｈ）、２．４９−２．３４（ｍ、２Ｈ）、２．７１−２．５６（ｍ、２Ｈ）、３．６４（ｓ、６Ｈ）、４．１３−３．７６（ｍ、６Ｈ）、４．２２（ｄｄ、Ｊ＝５．４、１０．３、１Ｈ）、５．２８−５．１７（ｍ、２Ｈ）、５．３７（ｔ、Ｊ＝６．４、２Ｈ）、５．９６（ｔｔ、Ｊ＝３．９、５５．２、１Ｈ）、６．３１（ｔ、Ｊ＝９．７、２Ｈ）、６．６０−６．５１（ｍ、２Ｈ）、６．９８（ｄ、Ｊ＝８．４、１Ｈ）、７．２３（ｄ、Ｊ＝８．３、２Ｈ）、７．３５（ｄ、Ｊ＝１７．８、２Ｈ）、７．５０（ｄ、Ｊ＝８．３、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９１２（Ｍ＋Ｈ）^＋、９１０（Ｍ−Ｈ）⁻。

Example 4.11
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [4- (2,2-difluoroethoxy) phenyl] -5- {2-[(2S)) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, methanol-d ₄ ) δppm 0.85 (dd, J = 6.7, 20.0, 12H), 1.88-1.75 (m, 2H), 2.06-1.95 (M, 3H), 2.22-2.06 (m, 3H), 2.34-2.23 (m, 2H), 2.49-2.34 (m, 2H), 2.71-2 .56 (m, 2H), 3.64 (s, 6H), 4.13-3.76 (m, 6H), 4.22 (dd, J = 5.4, 10.3, 1H), 5 .28-5.17 (m, 2H), 5.37 (t, J = 6.4, 2H), 5.96 (tt, J = 3.9, 55.2, 1H), 6.31 ( t, J = 9.7, 2H), 6.60-6.51 (m, 2H), 6.98 (d, J = 8.4, 1H), 7.23 (d, J = 8.3) , 2H), 7.35 (d, J = 17.8, 2H), 7.50 (d, J = 8.3, 2H); MS (ESI) m / z 912 (M + H) ⁺ , 910 (M-) H) ^- .

実施例４．１２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（３，５−ジメチルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．５０（ｑ、Ｊ＝１１．９、１Ｈ）、０．９７−０．６４（ｍ、１８Ｈ）、１．３２−１．２０（ｍ、２Ｈ）、１．８１−１．４６（ｍ、５Ｈ）、２．０９−１．８０（ｍ、６Ｈ）、２．３２−２．１３（ｍ、５Ｈ）、２．７５（ｄｄ、Ｊ＝１０．０、４０．２、２Ｈ）、３．１８−３．０５（ｍ、１Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．１４−３．９５（ｍ、２Ｈ）、５．１４（ｓ、２Ｈ）、５．３６（ｄ、Ｊ＝７．２、２Ｈ）、５．８８（ｄ、Ｊ＝１２．８、２Ｈ）、７．１４−７．０２（ｍ、２Ｈ）、７．１９（ｓ、１Ｈ）、７．３３−７．２３（ｍ、３Ｈ）、７．４１（ｄ、Ｊ＝８．２、１Ｈ）、７．４９（ｄ、Ｊ＝８．２、１Ｈ）、１２．３７−１１．９８（ｍ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９７９（Ｍ＋Ｈ）^＋。

Example 4.12
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [4- (3,5-dimethylpiperidine-1-yl) -3,5-difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.50 (q, J = 11.9, 1H), 0.97-0.64 (m, 18H), 1.32-1.20 (m, 2H) ), 1.81-1.46 (m, 5H), 2.09-1.80 (m, 6H), 2.32-2.13 (m, 5H), 2.75 (dd, J = 10) .0, 40.2, 2H), 3.18-3.05 (m, 1H), 3.54 (s, 6H), 3.82 (s, 4H), 4.14-3.95 (m) , 2H), 5.14 (s, 2H), 5.36 (d, J = 7.2, 2H), 5.88 (d, J = 12.8, 2H), 7.14-7.02 (M, 2H), 7.19 (s, 1H), 7.33-7.23 (m, 3H), 7.41 (d, J = 8.2, 1H), 7.49 (d, J) = 8.2, 1H), 12.37-11.98 (m, 2H); MS (ESI) m / z 979 (M + H) ⁺ .

実施例４．１３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（６−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝−１−［４−（ペンタフルオロ−λ〜６〜−スルファニル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９２−０．６９（ｍ、１２Ｈ）、２．０８−１．６１（ｍ、８Ｈ）、２．２０（ｓ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０５（ｔ、Ｊ＝８．０、２Ｈ）、５．１３（ｄｔ、Ｊ＝４．９、９．８、２Ｈ）、５．４９（ｄｄ、Ｊ＝１０．８、１５．８、２Ｈ）、６．３７（ｄ、Ｊ＝８．６、２Ｈ）、７．１３−６．８１（ｍ、３Ｈ）、７．２０（ｄ、Ｊ＝８．８、１Ｈ）、７．２８（ｄｄ、Ｊ＝４．６、９．９、３Ｈ）、７．４５−７．３４（ｍ、４Ｈ）、７．４８（ｄ、Ｊ＝８．２、１Ｈ）、１２．１６（ｄｄ、Ｊ＝２２．６、６８．２、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９５８（Ｍ＋Ｈ）^＋、９５６（Ｍ−Ｈ）⁻。

Example 4.13
Methyl {(2S) -1-[(2S) -2-(6-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} -1- [4- (pentafluoro-λ ~ 6-sulfanyl) phenyl] pyrrolidine-2-yl}- 1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.92-0.69 (m, 12H), 2.08-1.61 (m, 8H), 2.20 (s, 4H), 3.53 ( s, 6H), 3.82 (s, 4H), 4.05 (t, J = 8.0, 2H), 5.13 (dt, J = 4.9, 9.8, 2H), 5. 49 (dd, J = 10.8, 15.8, 2H), 6.37 (d, J = 8.6, 2H), 7.13-6.81 (m, 3H), 7.20 (d) , J = 8.8, 1H), 7.28 (dd, J = 4.6, 9.9, 3H), 7.45-7.34 (m, 4H), 7.48 (d, J = 8.2, 1H), 12.16 (dd, J = 22.6, 68.2, 2H); MS (ESI) m / z 958 (M + H) ⁺ , 956 (MH) ⁻ .

実施例４．１４
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｓ）−１−（４−シクロプロピルフェニル）−５−（２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．３７（ｍ、２Ｈ）０．６８、（ｓ、２Ｈ）１．０８（ｄ、６Ｈ）１．５４−１．６４（ｍ、２Ｈ）１．６９（ｓ、２Ｈ）１．９９（ｓ、４Ｈ）２．１７（ｓ、７Ｈ）３．１８（ｓ、６Ｈ）３．４２−３．５３（ｍ、２Ｈ）３．５４（ｓ、Ｊ＝１．４１Ｈｚ、６Ｈ）３．８４（ｓ、３Ｈ）４．２８（ｓ、２Ｈ）５．１２（ｓ、２Ｈ）５．３４（ｓ、２Ｈ）６．２２（ｓ、２Ｈ）６．６１（ｓ、２Ｈ）７．０５（ｓ、２Ｈ）７．１６（ｓ、２Ｈ）７．３６（ｓ、２Ｈ）１１．９７（ｓ、１Ｈ），１２．０８（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９０４．５（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９０２．３（Ｍ−Ｈ）⁻。

Example 4.14
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2S, 5S) -1- (4-cyclopropylphenyl) -5-(2-{(2S) -1-[ N- (Methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazol-5-yl) pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1 -Il] -3-methoxy-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.37 (m, 2H) 0.68, (s, 2H) 1.08 (d, 6H) 1.54-1.64 (m, 2H) 1. 69 (s, 2H) 1.99 (s, 4H) 2.17 (s, 7H) 3.18 (s, 6H) 3.42-3.53 (m, 2H) 3.54 (s, J = 1.41Hz, 6H) 3.84 (s, 3H) 4.28 (s, 2H) 5.12 (s, 2H) 5.34 (s, 2H) 6.22 (s, 2H) 6.61 ( s, 2H) 7.05 (s, 2H) 7.16 (s, 2H) 7.36 (s, 2H) 11.97 (s, 1H), 12.08 (s, 1H); MS (ESI +) m / z 904.5 (M + H) ⁺ , (ESI-) m / z 902.3 (MH) ⁻ .

実施例４．１５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−（４−シクロプロピル−３，５−ジフルオロフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．４７（ｂｒｓ、１Ｈ）１０．３０−１０．４１（ｂｒｓ、１Ｈ）７．６９（ｂｒｓ、１Ｈ）７．４９（ｓ、１Ｈ）７．３０−７．４３（ｂｒｓ、１Ｈ）７．０４−７．２０（ｍ、３Ｈ）５．７５−５．８９（ｍ、２Ｈ）５．３７（ｍ、４Ｈ）５．２３（ｓ、２Ｈ）４．３４（ｔ、２Ｈ）３．８３（ｍ、２Ｈ）３．７１（ｓ、６Ｈ）３．５６−３．６７（ｍ、２Ｈ）３．１１（ｍ、２Ｈ）２．５８（ｂｒｓ、２Ｈ）２．３３（ｍ、２Ｈ）２．０８−２．２７（ｍ、４Ｈ）２．０１（ｍ、２Ｈ）１．７８（ｂｒｓ、２Ｈ）０．８２−０．９６（ｍ、１２Ｈ）０．７１（ｍ、４Ｈ）。

Example 4.15
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- (4-cyclopropyl-3,5-difluorophenyl) -5-{2-[(2S)) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -1H-benz Imidazole-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.47 (brs, 1H) 10.30-10.41 (brs, 1H) 7.69 (brs, 1H) 7.49 (s, 1H) 7.30-7 .43 (brs, 1H) 7.04-7.20 (m, 3H) 5.75-5.89 (m, 2H) 5.37 (m, 4H) 5.23 (s, 2H) 4.34 (T, 2H) 3.83 (m, 2H) 3.71 (s, 6H) 3.56-3.67 (m, 2H) 3.11 (m, 2H) 2.58 (brs, 2H) 2 .33 (m, 2H) 2.08-2.27 (m, 4H) 2.01 (m, 2H) 1.78 (brs, 2H) 0.82-0.96 (m, 12H) 0.71 (M, 4H).

実施例４．１６
ジメチル（［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル］ビス｛１Ｈ−ベンズイミダゾール−６，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロプロピル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．４８−０．２４（ｍ、７Ｈ）、０．８９−０．８１（ｍ、１Ｈ）、１．０１（ｓ、３Ｈ）、１．０７（ｓ、６Ｈ）、１．１４（ｄｄ、Ｊ＝８．７、１６．６、１Ｈ）、１．３２−１．１７（ｍ、４Ｈ）、１．７５−１．６４（ｍ、１Ｈ）、２．０５−１．７８（ｍ、４Ｈ）、２．２４−２．０９（ｍ、３Ｈ）、２．４５−２．３９（ｍ、２Ｈ）、３．２１−３．１２（ｍ、１Ｈ）、３．５３（ｓ、６Ｈ）、３．７２−３．６３（ｍ、２Ｈ）、３．７６（ｓ、２Ｈ）、４．０３−３．８５（ｍ、２Ｈ）、５．１７−５．０４（ｍ、１Ｈ）、５．４４−５．２６（ｍ、２Ｈ）、６．２６（ｄ、Ｊ＝８．８、１Ｈ）、６．９５−６．８１（ｍ、２Ｈ）、７．０６−６．９５（ｍ、１Ｈ）、７．０９（ｔ、Ｊ＝８．３、１Ｈ）、７．２０（ｄ、Ｊ＝４．３、１Ｈ）、７．３５−７．２５（ｍ、１Ｈ）、７．５５−７．３６（ｍ、４Ｈ）、１２．２８−１１．８４（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８８４（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ８８２（Ｍ−Ｈ）⁻。

Example 4.16
Dimethyl ([(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {1H-benzimidazole-6,2-diyl (2S) pyrrolidine-2,1-diyl [ (1S) -1-cyclopropyl-2-oxoethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δppm 0.48-0.24 (m, 7H), 0.89-0.81 (m, 1H), 1.01 (s, 3H), 1.07 ( s, 6H), 1.14 (dd, J = 8.7, 16.6, 1H), 1.32-1.17 (m, 4H), 1.75-1.64 (m, 1H), 2.05-1.78 (m, 4H), 2.24-2.09 (m, 3H), 2.45-2.39 (m, 2H), 3.21-3.12 (m, 1H) ), 3.53 (s, 6H), 3.72-3.63 (m, 2H), 3.76 (s, 2H), 4.03-3.85 (m, 2H), 5.17- 5.04 (m, 1H), 5.44-5.26 (m, 2H), 6.26 (d, J = 8.8, 1H), 6.95-6.81 (m, 2H), 7.06-6.95 (m, 1H), 7.09 (t, J = 8.3, 1H), 7.20 (d, J = 4.3, 1H), 7.35-7.25 (M, 1H), 7.55-7.36 (m, 4H), 12.28-11.84 (m, 2H); MS (ESI +) m / z884 (M + H) ⁺ , (ESI-) m / z882 (MH) ^- .

実施例４．１７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４−アセチル−４−フェニルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７５−０．９１（ｍ、１２Ｈ）１．６８（ｄ、Ｊ＝４．６６Ｈｚ、２Ｈ）１．８３（ｓ、３Ｈ）１．８７−２．３８（ｍ、１６Ｈ）２．７８−２．９０（ｍ、４Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０６（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）５．０９−５．１８（ｍ、２Ｈ）５．２７−５．４１（ｍ、２Ｈ）５．８８（ｄ、Ｊ＝１２．９０Ｈｚ、２Ｈ）７．０２−７．５１（ｍ、１３Ｈ）１２．０７（ｄ、Ｊ＝１６．９１Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０７０（Ｍ＋Ｈ）^＋。

Example 4.17
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4-acetyl-4-phenylpiperidine-1-yl) -3,5-difluoro Phenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5- Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.75-0.91 (m, 12H) 1.68 (d, J = 4.66 Hz, 2H) 1.83 (s, 3H) 1.87-2 .38 (m, 16H) 2.78-2.90 (m, 4H) 3.54 (s, 6H) 3.82 (s, 4H) 4.06 (t, J = 8.35Hz, 2H) 5 .09-5.18 (m, 2H) 5.27-5.41 (m, 2H) 5.88 (d, J = 12.90Hz, 2H) 7.02-7.51 (m, 13H) 12 .07 (d, J = 16.91Hz, 2H); MS (ESI +) m / z 1070 (M + H) ⁺ .

実施例４．１８
メチル｛（２Ｓ）−１−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（３ａＳ，６ａＳ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝オクタヒドロシクロペンタ［ｂ］ピロール−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６４−０．９６（ｍ、１３Ｈ）１．３１−２．１８（ｍ、２１Ｈ）３．５０−３．５７（ｍ、６Ｈ）３．９３−４．０７（ｍ、２Ｈ）４．７２−４．８５（ｍ、１Ｈ）５．１３（ｔ、１Ｈ）５．３７（ｓ、２Ｈ）５．９０（ｄｄ、２Ｈ）７．０６（ｄ、２Ｈ）７．２１（ｓ、１Ｈ）７．３３（ｄ、１Ｈ）７．３６−７．５６（ｍ、Ｊ＝８．１３Ｈｚ、４Ｈ）１１．９６（ｓ、１Ｈ）１２．０３−１２．０８（ｍ、１Ｈ）１２．２４（なし、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０３１．５（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ１０２９．４（Ｍ−Ｈ）⁻。

Example 4.18
Methyl {(2S) -1-[(2S, 3aS, 6aS) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl]- 5- {2-[(3aS, 6aS) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} octahydrocyclopenta [b] pyrrole-2-yl] -1H -Benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -3-methyl-1-oxobutane-2 -Il} benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.64-0.96 (m, 13H) 1.31-2.18 (m, 21H) 3.50-3.57 (m, 6H) 3.93 -4.07 (m, 2H) 4.72-4.85 (m, 1H) 5.13 (t, 1H) 5.37 (s, 2H) 5.90 (dd, 2H) 7.06 (d) , 2H) 7.21 (s, 1H) 7.33 (d, 1H) 7.36-7.56 (m, J = 8.13Hz, 4H) 11.96 (s, 1H) 12.03-12 .08 (m, 1H) 12.24 (none, 1H); MS (ESI +) m / z 1031.5 (M + H) ⁺ , (ESI-) m / z 1029.4 (MH) ⁻ .

実施例４．１９
メチル｛（２Ｓ）−１−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛２−［（３ａＳ，６ａＳ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝オクタヒドロシクロペンタ［ｂ］ピロール−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６２−０．９３（ｍ、１３Ｈ）１．４２−２．１６（ｍ、２５Ｈ）２．７８（ｓ、１Ｈ）３．５４（ｓ、６Ｈ）４．０１（ｓ、２Ｈ）４．７７（ｓ、１Ｈ）５．１１（ｔ、Ｊ＝８．０８Ｈｚ、２Ｈ）５．３５（ｓ、２Ｈ）６．２６（ｄ、Ｊ＝８．６７Ｈｚ、２Ｈ）６．８３−６．９７（ｍ、２Ｈ）７．０５（ｓ、２Ｈ）７．２１（ｓ、１Ｈ）７．２７−７．３２（ｍ、１Ｈ）７．３４−７．５５（ｍ、４Ｈ）１１．９２（ｓ、１Ｈ）１２．０１（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９６８．５（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９６６．４（Ｍ−Ｈ）⁻、１０１１．７（Ｍ＋ＣＯＯＨ−Ｈ）⁻。

Example 4.19
Methyl {(2S) -1-[(2S, 3aS, 6aS) -2- {5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {2-[(3aS, 6aS) ) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} octahydrocyclopenta [b] pyrrole-2-yl] -1H-benzimidazole-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.62-0.93 (m, 13H) 1.42-2.16 (m, 25H) 2.78 (s, 1H) 3.54 (s, 6H) ) 4.01 (s, 2H) 4.77 (s, 1H) 5.11 (t, J = 8.08Hz, 2H) 5.35 (s, 2H) 6.26 (d, J = 8.67Hz) , 2H) 6.83-6.97 (m, 2H) 7.05 (s, 2H) 7.21 (s, 1H) 7.27-7.32 (m, 1H) 7.34-7.55 (M, 4H) 11.92 (s, 1H) 12.01 (s, 1H); MS (ESI +) m / z968.5 (M + H) ⁺ , (ESI-) m / z966.4 (MH) ^- , 1011.7 (M + COOH-H) ^- .

実施例４．２０
メチル［（２Ｓ）−１−（２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル）−３−メチル−１−オキソブタン−２−イル］カーバメート
アミンを、酸２当量ではなく１当量と反応させることで、標題化合物を製造することができる。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６７−０．９０（ｍ、６Ｈ）０．９７−１．１７（ｍ、９Ｈ）１．５３−２．４６（ｍ、１３Ｈ）３．２６−３．４２（ｍ、Ｊ＝１１．３９Ｈｚ、２Ｈ）３．５４（ｓ、３Ｈ）３．８５（ｄ、Ｊ＝４．３４Ｈｚ、２Ｈ）４．０７−４．１３（ｍ、１Ｈ）４．８８−４．９８（ｍ、１Ｈ）５．１５−５．２３（ｍ、１Ｈ）５．４５（ｄ、Ｊ＝７．１６Ｈｚ、１Ｈ）５．５０（ｄ、Ｊ＝６．９４Ｈｚ、１Ｈ）６．２６（ｄ、Ｊ＝８．７８Ｈｚ、２Ｈ）６．９２（ｄ、Ｊ＝８．７８Ｈｚ、２Ｈ）７．１９−７．７７（ｍ、７Ｈ）９．１５（ｓ、１Ｈ）９．６６（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ７３１（Ｍ＋Ｈ）^＋。

Example 4.20
Methyl [(2S) -1-(2- {5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {2-[(2S) -pyrrolidin-2-yl] -1H -Benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl) -3-methyl-1-oxobutan-2-yl] carbamateamine in 2 equivalents of acid The title compound can be produced by reacting with 1 equivalent instead of. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.67-0.90 (m, 6H) 0.97-1.17 (m, 9H) 1.53-2.46 (m, 13H) 3.26 -3.42 (m, J = 11.39Hz, 2H) 3.54 (s, 3H) 3.85 (d, J = 4.34Hz, 2H) 4.07-4.13 (m, 1H) 4 .88-4.98 (m, 1H) 5.15-5.23 (m, 1H) 5.45 (d, J = 7.16Hz, 1H) 5.50 (d, J = 6.94Hz, 1H) ) 6.26 (d, J = 8.78Hz, 2H) 6.92 (d, J = 8.78Hz, 2H) 7.19-7.77 (m, 7H) 9.15 (s, 1H) 9 .66 (s, 1H); MS (ESI +) m / z 731 (M + H) ⁺ .

実施例４．２１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（２−アザビシクロ［２．２．２］オクト−２−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−１．０２（ｍ、１２Ｈ）、１．４１−２．２７（ｍ、２６Ｈ）、２．６５（ｓ、１Ｈ）、３．０５−３．２６（ｍ、３Ｈ）、３．５４（ｓ、６Ｈ）、４．０６（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）、５．０７−５．２０（ｍ、２Ｈ）、５．２６−５．４５（ｍ、２Ｈ）、５．８９（ｄ、Ｊ＝１２．３６Ｈｚ、２Ｈ）、７．００−７．１４（ｍ、２Ｈ）、７．１６−７．３３（ｍ、４Ｈ）、７．４４（ｄｄ、Ｊ＝３２．４２、８．２４Ｈｚ、２Ｈ）、１２．０６（２個のｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９７７（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９７５（Ｍ−Ｈ）⁻。

Example 4.21
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (2-azabicyclo [2.2.2] oct-2-yl) -3, 5-Difluorophenyl] -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole -5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-1.02 (m, 12H), 1.41-2.27 (m, 26H), 2.65 (s, 1H), 3.05- 3.26 (m, 3H), 3.54 (s, 6H), 4.06 (t, J = 8.35Hz, 2H), 5.07-5.20 (m, 2H), 5.26- 5.45 (m, 2H), 5.89 (d, J = 12.36Hz, 2H), 7.00-7.14 (m, 2H), 7.16-7.33 (m, 4H), 7.44 (dd, J = 32.42, 8.24Hz, 2H), 12.06 (2 s, 2H); MS (ESI +) m / z 977 (M + H) ⁺ , (ESI-) m / z 975 (MH) ^- .

実施例４．２２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（プロパン−２−イル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９１（ｍ、１８Ｈ）、０．９１−１．０５（ｍ、１Ｈ）、１．０７−１．２１（ｍ、３Ｈ）、１．３１−１．４３（ｍ、１Ｈ）、１．５１（ｄ、Ｊ＝１１．１７Ｈｚ、２Ｈ）、１．６３−１．７７（ｍ、２Ｈ）、１．８４−２．２６（ｍ、１１Ｈ）、２．７２−２．８８（ｍ、４Ｈ）、３．５４（ｓ、６Ｈ）３．８２（ｂｒｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）、５．０７−５．２３（ｍ、２Ｈ）、５．２９−５．４５（ｍ、２Ｈ）、５．８８（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）、７．０２−７．１２（ｍ、２Ｈ）、７．１６−７．３２（ｍ、４Ｈ）、７．４１（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、１２．０７（２個のｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９９４（Ｍ＋Ｈ）^＋。

Example 4.22
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (propane-2-yl) piperidine-1-] Il] phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole- 5-Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.91 (m, 18H), 0.91-1.05 (m, 1H), 1.07-1.21 (m, 3H), 1.31-1.43 (m, 1H), 1.51 (d, J = 11.17Hz, 2H), 1.63-1.77 (m, 2H), 1.84-2.26 (m) , 11H), 2.72-2.88 (m, 4H), 3.54 (s, 6H) 3.82 (brs, 4H), 4.06 (t, J = 8.35Hz, 2H), 5 .07-5.23 (m, 2H), 5.29-5.45 (m, 2H), 5.88 (d, J = 12.79Hz, 2H), 7.02-7.12 (m, 2H), 7.16-7.32 (m, 4H), 7.41 (d, J = 8.13Hz, 1H), 7.49 (d, J = 8.13Hz, 1H), 12.07 ( 2 s, 2H); MS (ESI +) m / z 994 (M + H) ⁺ .

実施例４．２３
ジメチル（｛（２Ｒ，５Ｒ）−１−［４−（４，４−ジメチルピペリジン−１−イル）−３，５−ジフルオロフェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８７（ｓ、６Ｈ）、１．１８−１．３４（ｍ、９Ｈ）、１．３４−１．５９（ｍ、４Ｈ）、１．６１−１．９３（ｍ、５Ｈ）、１．９３−２．０６（ｍ、４Ｈ）、２．０９−２．２７（ｍ、４Ｈ）、２．７７（ｓ、４Ｈ）、２．９０−３．２７（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．６２（ｄ、Ｊ＝１１．７１Ｈｚ、１Ｈ）、３．６７−３．８９（ｍ、７Ｈ）、４．１４（ｑ、Ｊ＝８．１０Ｈｚ、２Ｈ）、５．０８−５．２０（ｍ、２Ｈ）、５．３０−５．４３（ｍ、２Ｈ）、５．８１−５．９４（ｍ、２Ｈ）、７．０３−７．５２（ｍ、８Ｈ）、１２．１０（２個のｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６３（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ１０６１（Ｍ−Ｈ）⁻。

Example 4.23
Dimethyl ({(2R, 5R) -1- [4- (4,4-dimethylpiperidine-1-yl) -3,5-difluorophenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5 , 2-Diyl (2S) pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1-diyl]}) benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.87 (s, 6H), 1.18-1.34 (m, 9H), 1.34-1.59 (m, 4H), 1.61- 1.93 (m, 5H), 1.93-2.06 (m, 4H), 2.09-2.27 (m, 4H), 2.77 (s, 4H), 2.90-3. 27 (m, 4H), 3.53 (s, 6H), 3.62 (d, J = 11.71Hz, 1H), 3.67-3.89 (m, 7H), 4.14 (q, J = 8.10Hz, 2H), 5.08-5.20 (m, 2H), 5.30-5.43 (m, 2H), 5.81-5.94 (m, 2H), 7. 03-7.52 (m, 8H), 12.10 (2 s, 2H); MS (ESI +) m / z 1063 (M + H) ⁺ , (ESI-) m / z 1061 (MH) ⁻ .

実施例４．２４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（３，３−ジメチルアゼチジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９４（ｍ、１２Ｈ）、１．１３（ｓ、６Ｈ）、１．６１−１．７４（ｍ、２Ｈ）、１．８１−２．２８（ｍ、９Ｈ）、３．０７−３．１８（ｍ、１Ｈ）、３．４９（ｓ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｂｒｓ、４Ｈ）、４．０７（ｔ、Ｊ＝８．２４Ｈｚ、２Ｈ）、５．１４（ｔ、Ｊ＝７．５４Ｈｚ、２Ｈ）、５．２５−５．４０（ｍ、２Ｈ）、５．７９−５．９４（ｍ、２Ｈ）、７．０１−７．０７（ｍ、２Ｈ）、７．０８−７．３４（ｍ、４Ｈ）、７．３９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、７．４７（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、１２．０５（２個のｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９５１（Ｍ＋Ｈ）^＋。

Example 4.24
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (3,3-dimethylazetidine-1-yl) -3,5-difluorophenyl) ] -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl } Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.94 (m, 12H), 1.13 (s, 6H), 1.61-1.74 (m, 2H), 1.81- 2.28 (m, 9H), 3.07-3.18 (m, 1H), 3.49 (s, 4H), 3.54 (s, 6H), 3.82 (brs, 4H), 4 .07 (t, J = 8.24Hz, 2H), 5.14 (t, J = 7.54Hz, 2H), 5.25-5.40 (m, 2H), 5.79-5.94 ( m, 2H), 7.01-7.07 (m, 2H), 7.08-7.34 (m, 4H), 7.39 (d, J = 8.13Hz, 1H), 7.47 ( d, J = 8.24Hz, 1H) 12.05 (2 s, 2H); MS (ESI +) m / z951 (M + H) ⁺ .

実施例４．２５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９３（ｍ、１２Ｈ）、１．６１−１．７９（ｍ、６Ｈ）、１．８４−２．０９（ｍ、６Ｈ）、２．１１−２．２７（ｍ、４Ｈ）、２．４０−２．６０（ｍ、４Ｈ）、３．３５（ｓ、３Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．２９Ｈｚ、２Ｈ）、５．０８−５．１９（ｍ、２Ｈ）、５．２８−５．４６（ｍ、２Ｈ）、６．２６（ｄ、Ｊ＝８．６７Ｈｚ、２Ｈ）、６．５５−６．６７（ｍ、２Ｈ）、７．０６（ｔ、Ｊ＝７．３２Ｈｚ、２Ｈ）、７．１３−７．３２（ｍ、９Ｈ）、７．３７（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４５（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、１２．０２（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９９１（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９８９（Ｍ−Ｈ）⁻。

Example 4.25
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [4- (4-phenylpiperidin-1-yl) phenyl] pyrrolidine-2-yl} -1H -Benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.93 (m, 12H), 1.61-1.79 (m, 6H), 1.84-2.09 (m, 6H), 2.11-2.27 (m, 4H), 2.40-2.60 (m, 4H), 3.35 (s, 3H), 3.53 (s, 6H), 3.82 (s, 4H), 4.06 (t, J = 8.29Hz, 2H), 5.08-5.19 (m, 2H), 5.28-5.46 (m, 2H), 6.26 (d, J = 8.67Hz, 2H), 6.55-6.67 (m, 2H), 7.06 (t, J = 7.32Hz, 2H), 7.13-7.32 (m, 9H), 7.37 (d, J = 8.24Hz, 1H), 7.45 (d, J = 8.24Hz, 1H), 12.02 (s, 2H); MS (ESI +) m / z 991 (M + H) ⁺ , (ESI-) m / z 989 (MH) ^- .

実施例４．２６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（３−フェニルプロピル）ピペリジン−１−イル］フェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６８−０．８４（ｍ、１２Ｈ）、０．９８−１．３０（ｍ、８Ｈ）、１．４７−１．６０（ｍ、５Ｈ）、１．６３−２．０７（ｍ、９Ｈ）、２．０９−２．２４（ｍ、３Ｈ）、２．７８（ｓ、４Ｈ）、３．５１（ｓ、６Ｈ）、３．７１−３．８７（ｍ、４Ｈ）、３．９７−４．１２（ｍ、２Ｈ）、５．０３−５．１７（ｍ、２Ｈ）、５．４３−５．６３（ｍ、２Ｈ）、５．７８−５．９６（ｍ、２Ｈ）、７．０２（ｄｄ、Ｊ＝６．７８、２．３３Ｈｚ、１Ｈ）、７．０８−７．１９（ｍ、４Ｈ）、７．１９−７．３５（ｍ、５Ｈ）、７．３９（ｄｄ、Ｊ＝１１．２８、６．２９Ｈｚ、１Ｈ）、１１．５０−１２．７３（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１０５（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１１０３（Ｍ−Ｈ）⁻。

Example 4.26
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (3-phenylpropyl) piperidine-1-yl) ] Phenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H- Benzimidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.68-0.84 (m, 12H), 0.98-1.30 (m, 8H), 1.47-1.60 (m, 5H), 1.63-2.07 (m, 9H), 2.09-2.24 (m, 3H), 2.78 (s, 4H), 3.51 (s, 6H), 3.71-3. 87 (m, 4H), 3.97-4.12 (m, 2H), 5.03-5.17 (m, 2H), 5.43-5.63 (m, 2H), 5.78- 5.96 (m, 2H), 7.02 (dd, J = 6.78, 2.33Hz, 1H), 7.08-7.19 (m, 4H), 7.19-7.35 (m) , 5H), 7.39 (dd, J = 11.28, 6.29Hz, 1H) 11.50-12.73 (m, 2H); MS (ESI +) m / z1105 (M + H) ⁺ ; MS ( ESI-) m / z 1103 (MH) ^- .

実施例４．２７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６９−０．７６（ｍ、４Ｈ）、０．７６−０．９１（ｍ、１７Ｈ）、１．１３−１．２７（ｍ、３Ｈ）、１．５５（ｄ、Ｊ＝１１．３９Ｈｚ、２Ｈ）、１．６７−２．０９（ｍ、９Ｈ）、２．１１−２．２６（ｍ、４Ｈ）、２．７２−２．９４（ｍ、４Ｈ）、３．５０−３．５７（ｍ、６Ｈ）、３．６２−３．８６（ｍ、５Ｈ）、３．９９−４．１１（ｍ、２Ｈ）、５．０３−５．１７（ｍ、２Ｈ）、５．４６−５．６３（ｍ、２Ｈ）、５．８７（ｄｄ、Ｊ＝１２．５２、７．２１Ｈｚ、２Ｈ）、７．０３（ｄ、Ｊ＝６．４０Ｈｚ、１Ｈ）、７．１３（ｄ、Ｊ＝６．９４Ｈｚ、１Ｈ）、７．２５−７．３７（ｍ、３Ｈ）、７．４０（ｄｄ、Ｊ＝１１．１７、６．２９Ｈｚ、１Ｈ）、１１．６７−１２．６３（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０４３（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０４１（Ｍ−Ｈ）⁻。

Example 4.27
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl] -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole- 5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.69-0.76 (m, 4H), 0.76-0.91 (m, 17H), 1.13-1.27 (m, 3H), 1.55 (d, J = 11.39Hz, 2H), 1.67-2.09 (m, 9H), 2.11-2.26 (m, 4H), 2.72-2.94 (m) 4, 4H), 3.50-3.57 (m, 6H), 3.62-3.86 (m, 5H), 3.99-4.11 (m, 2H), 5.03-5.17 (M, 2H), 5.46-5.63 (m, 2H), 5.87 (dd, J = 12.52, 7.21Hz, 2H), 7.03 (d, J = 6.40Hz, 1H), 7.13 (d, J = 6.94Hz, 1H), 7.25-7.37 (m, 3H), 7.40 (dd, J = 11.17, 6.29Hz, 1H), 11.67-12.63 (m, 2H); MS (ESI +) m / z 1043 (M + H) ⁺ ; MS (ESI-) m / z 1041 (MH) ⁻ .

実施例４．２８
ジメチル（｛（２Ｒ，５Ｒ）−１−［４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロペンチル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０（ｓ、９Ｈ）、１．０８−１．６３（ｍ、２４Ｈ）、１．６５−１．８７（ｍ、３Ｈ）、１．９２−２．２５（ｍ、１０Ｈ）、２．３７−２．４５（ｍ、１Ｈ）、２．７３−２．９３（ｍ、４Ｈ）、３．６０−３．９１（ｍ、４Ｈ）、４．１３（ｔ、Ｊ＝８．２４Ｈｚ、２Ｈ）、５．１１（ｄ、Ｊ＝６．８３Ｈｚ、２Ｈ）、５．４５−５．６３（ｍ、２Ｈ）、５．８０−５．９７（ｍ、２Ｈ）、６．９５−７．０８（ｍ、１Ｈ）、７．１３（ｄ、Ｊ＝６．６１Ｈｚ、１Ｈ）、７．３４（ｄｄ、Ｊ＝１０．２５、３．７４Ｈｚ、１Ｈ）、７．３７−７．４６（ｍ、３Ｈ）、１１．７３−１２．５０（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０９５（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０９３（Ｍ−Ｈ）⁻。

Example 4.28
Dimethyl ({(2R, 5R) -1- [4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H) -Benzimidazole-5,2-diyl) (2S) pyrrolidine-2,1-diyl [(1S) -1-cyclopentyl-2-oxoethane-2,1-diyl]}) Biscabamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80 (s, 9H), 1.08-1.63 (m, 24H), 1.65-1.87 (m, 3H), 1.92- 2.25 (m, 10H), 2.37-2.45 (m, 1H), 2.73-2.93 (m, 4H), 3.60-3.91 (m, 4H), 4. 13 (t, J = 8.24Hz, 2H), 5.11 (d, J = 6.83Hz, 2H), 5.45-5.63 (m, 2H), 5.80-5.97 (m) , 2H), 6.95-7.08 (m, 1H), 7.13 (d, J = 6.61Hz, 1H), 7.34 (dd, J = 10.25, 3.74Hz, 1H) , 7.37-7.46 (m, 3H), 11.73-12.50 (m, 2H); MS (ESI +) m / z 1095 (M + H) ⁺ ; MS (ESI-) m / z 1093 (M-) H) ^- .

実施例４．２９
メチル｛（２Ｓ，３Ｒ）−３−ｔｅｒｔ−ブトキシ−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−｛２−［（２Ｓ）−１−｛（２Ｓ，３Ｒ）−３−ｔｅｒｔ−ブトキシ−２−［（メトキシカルボニル）アミノ］ブタノイル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−５−イル｝−１−［４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル］ピロリジン−２−イル｝−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８２（ｄ、Ｊ＝１４．６４Ｈｚ、１３Ｈ）、０．８８−０．９６（ｍ、４Ｈ）、１．０２（ｓ、７Ｈ）、１．１２（ｄ、Ｊ＝３３．８３Ｈｚ、１１Ｈ）、１．４９−２．３１（ｍ、９Ｈ）、２．６９−２．９３（ｍ、４Ｈ）、３．２７（ｓ、１Ｈ）、３．５０−３．５７（ｍ、６Ｈ）、３．６４−３．９４（ｍ、９Ｈ）、４．０３−４．３１（ｍ、３Ｈ）、５．０６−５．２３（ｍ、１Ｈ）、５．３８−５．６９（ｍ、２Ｈ）、５．７８−５．９５（ｍ、２Ｈ）、６．４６−６．６３（ｍ、１Ｈ）、６．７０−６．８７（ｍ、１Ｈ）、６．９２−７．０４（ｍ、１Ｈ）、７．０８−７．２９（ｍ、１Ｈ）、７．３４（ｄｄ、Ｊ＝１０．６３、１．８４Ｈｚ、１Ｈ）、７．３８−７．５５（ｍ、１Ｈ）、１１．４０−１２．８８（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１５９（Ｍ＋Ｈ）^＋。

Example 4.29
Methyl {(2S, 3R) -3-tert-butoxy-1-[(2S) -2-(5-{(2R, 5R) -5-{2-[(2S) -1-{(2S, 3R) ) -3-tert-Butoxy-2-[(methoxycarbonyl) amino] butanoyl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-5-yl} -1- [4- (4-tert-) Butylpiperidin-1-yl) -3,5-difluorophenyl] pyrrolidine-2-yl} -6-fluoro-1H-benzimidazol-2-yl) pyrrolidine-1-yl] -1-oxobutan-2-yl} Carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.82 (d, J = 14.64 Hz, 13H), 0.88-0.96 (m, 4H), 1.02 (s, 7H), 1. 12 (d, J = 33.83Hz, 11H), 1.49-2.31 (m, 9H), 2.69-2.93 (m, 4H), 3.27 (s, 1H), 3. 50-3.57 (m, 6H), 3.64-3.94 (m, 9H), 4.03-4.31 (m, 3H), 5.06-5.23 (m, 1H), 5.38-5.69 (m, 2H), 5.78-5.95 (m, 2H), 6.46-6.63 (m, 1H), 6.70-6.87 (m, 1H) ), 6.92-7.04 (m, 1H), 7.08-7.29 (m, 1H), 7.34 (dd, J = 10.63, 1.84Hz, 1H), 7.38 -7.55 (m, 1H), 11.40-12.88 (m, 2H); MS (ESI +) m / z 1159 (M + H) ⁺ .

実施例４．３０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（２−ナフチル）ピペリジン−１−イル］フェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７３（ｄ、Ｊ＝６．５１Ｈｚ、４Ｈ）、０．７６−０．８５（ｍ、８Ｈ）、１．１９−１．３２（ｍ、２Ｈ）、１．６９−２．０８（ｍ、１２Ｈ）、２．１１−２．２５（ｍ、３Ｈ）、２．６７−２．７８（ｍ、１Ｈ）、２．９２−３．１８（ｍ、５Ｈ）、３．５２（ｄ、Ｊ＝１．１９Ｈｚ、６Ｈ）、３．７２−３．８７（ｍ、４Ｈ）、３．９９−４．１１（ｍ、２Ｈ）、５．０６−５．１９（ｍ、２Ｈ）、５．４９−５．６７（ｍ、２Ｈ）、５．８３−６．００（ｍ、２Ｈ）、７．０１−７．０９（ｍ、１Ｈ）、７．１６（ｄ、Ｊ＝７．０５Ｈｚ、１Ｈ）、７．２５−７．３７（ｍ、３Ｈ）、７．３８−７．５３（ｍ、４Ｈ）、７．６８−７．９３（ｍ、４Ｈ）、１１．８８−１２．６５（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１１３（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１１１１（Ｍ−Ｈ）⁻。

Example 4.30
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (2-naphthyl) piperidine-1-yl]] Phenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benz Imidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.73 (d, J = 6.51 Hz, 4H), 0.76-0.85 (m, 8H), 1.19-1.32 (m, 2H) ), 1.69-2.08 (m, 12H), 2.11-2.25 (m, 3H), 2.67-2.78 (m, 1H), 2.92-3.18 (m) , 5H), 3.52 (d, J = 1.19Hz, 6H), 3.72-3.87 (m, 4H), 3.99-4.11 (m, 2H), 5.06-5 .19 (m, 2H), 5.49-5.67 (m, 2H), 5.83-6.00 (m, 2H), 7.01-7.09 (m, 1H), 7.16 (D, J = 7.05Hz, 1H), 7.25-7.37 (m, 3H), 7.38-7.53 (m, 4H), 7.68-7.93 (m, 4H) , 11.88-12.65 (m, 2H); MS (ESI +) m / z 1113 (M + H) ⁺ ; MS (ESI-) m / z 1111 (MH) ⁻ .

実施例４．３１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（２，３−ジヒドロ−１′Ｈ−スピロ［インデン−１，４′−ピペリジン］−１′−イル）−３，５−ジフルオロフェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．５３−１０．６３（ｍ、１Ｈ）１０．３１−１０．４１（ｍ、１Ｈ）７．４３−７．５２（ｍ、１Ｈ）７．３０−７．４０（ｍ、１Ｈ）７．１０−７．２５（ｍ、５Ｈ）６．９２−７．００（ｍ、１Ｈ）５．８６（ｄ、２Ｈ）５．２３−５．５１（ｍ、６Ｈ）４．２６−４．４０（ｍ、２Ｈ）３．７７−３．９１（ｍ、２Ｈ）３．６８−３．７２（ｍ、６Ｈ）３．５６−３．６６（ｍ、２Ｈ）２．８３−３．２６（ｍ、８Ｈ）１．８１−２．６１（ｍ、１６Ｈ）０．７１−１．１０（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０８９（Ｍ＋Ｈ）^＋。

Example 4.31
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (2,3-dihydro-1'H-spiro] [inden-1,4'- Piperidine] -1'-yl) -3,5-difluorophenyl] -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3- Methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl -1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.53-10.63 (m, 1H) 10.31-10.41 (m, 1H) 7.43-7.52 (m, 1H) 7.30-7 .40 (m, 1H) 7.10-7.25 (m, 5H) 6.92-7.00 (m, 1H) 5.86 (d, 2H) 5.23-5.51 (m, 6H) ) 4.26-4.40 (m, 2H) 3.77-3.91 (m, 2H) 3.68-3.72 (m, 6H) 3.56-3.66 (m, 2H) 2 .83-3.26 (m, 8H) 1.81-2.61 (m, 16H) 0.71-1.10 (m, 12H); MS (ESI) m / z 1089 (M + H) ⁺ .

実施例４．３２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（３−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．０７（ｓ、１Ｈ）、１２．０１（ｓ、１Ｈ）、７．４８（ｄ、Ｊ＝８．３Ｈｚ、１Ｈ）、７．３８（ｍ、２Ｈ）、７．２０（ｓ、８Ｈ）、７．０９（ｍ、２Ｈ）、５．９０（ｄ、Ｊ＝１２．９Ｈｚ、２Ｈ）、５．３６（ｄ、Ｊ＝７．５Ｈｚ、２Ｈ）、５．１４（ｓ、２Ｈ）、４．０５（ｔ、Ｊ＝８．１Ｈｚ、２Ｈ）、３．８１（ｓ、４Ｈ）、３．５４（ｓ、６Ｈ）、２．８５（ｓ、４Ｈ）、２．１８（ｓ、５Ｈ）、１．９４（ｍ、７Ｈ）、１．６１（ｍ、５Ｈ）、０．７７（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対的存在比）１０２７（１００、Ｍ＋Ｈ）^＋。

Example 4.32
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (3-phenylpiperidine-1-yl) phenyl] -5] -5 -{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.07 (s, 1H), 12.01 (s, 1H), 7.48 (d, J = 8.3Hz, 1H), 7.38 (m, 2H), 7.20 (s, 8H), 7.09 (m, 2H), 5.90 (d, J = 12.9Hz, 2H), 5.36 (d, J = 7.5Hz, 2H) 5.14 (s, 2H), 4.05 (t, J = 8.1Hz, 2H), 3.81 (s, 4H), 3.54 (s, 6H), 2.85 (s, 4H) ), 2.18 (s, 5H), 1.94 (m, 7H), 1.61 (m, 5H), 0.77 (m, 12H); MS (ESI +) m / z (relative abundance ratio) ) 1027 (100, M + H) ⁺ .

実施例４．３３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（３−フェニルピロリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）dｐｐｍ１２．０９（ｄ、Ｊ＝１４．８Ｈｚ、２Ｈ）、７．４７（ｍ、２Ｈ）、７．４５（ｍ、２Ｈ）、７．２４（ｍ、８Ｈ）、７．０８（ｓ、２Ｈ）、５．９３（ｄ、Ｊ＝１２．１Ｈｚ、２Ｈ）、５．３８（ｓ、２Ｈ）、５．１５（ｓ、２Ｈ）、４．０６（ｔ、Ｊ＝８．４Ｈｚ、２Ｈ）、３．８２（ｓ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．１３（ｍ、４Ｈ）、２．１９（ｓ、４Ｈ）、１．９０（ｍ、６Ｈ）、１．７０（ｓ、２Ｈ）、０．８０（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対的存在比）１０１３（１００、Ｍ＋Ｈ）^＋、１０１４（５８）。

Example 4.33
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (3-phenylpyrrolidine-1-yl) phenyl] -5] -5 − {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) dppm12.09 (d, J = 14.8 Hz, 2H), 7.47 (m, 2H), 7.45 (m, 2H), 7.24 (m, 8H), 7.08 (s, 2H), 5.93 (d, J = 12.1Hz, 2H), 5.38 (s, 2H), 5.15 (s, 2H), 4.06 (t) , J = 8.4Hz, 2H), 3.82 (s, 4H), 3.53 (s, 6H), 3.13 (m, 4H), 2.19 (s, 4H), 1.90 ( m, 6H), 1.70 (s, 2H), 0.80 (m, 12H); MS (ESI +) m / z (relative abundance ratio) 1013 (100, M + H) ⁺ 1014 (58).

実施例４．３４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（４−メトキシフェニル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９７−０．６９（ｍ、１２Ｈ）、１．２４（ｓ、１Ｈ）、１．７８−１．５０（ｍ、６Ｈ）、２．１０−１．８５（ｍ、７Ｈ）、２．１９（ｓ、４Ｈ）、２．４７−２．３８（ｍ、１Ｈ）、３．０３−２．８０（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．６９（ｓ、３Ｈ）、３．８２（ｓ、４Ｈ）、４．１７−３．９３（ｍ、２Ｈ）、５．２２−５．０８（ｍ、２Ｈ）、５．４５−５．２９（ｍ、２Ｈ）、５．９１（ｄ、Ｊ＝１２．８、２Ｈ）、６．８１（ｄ、Ｊ＝８．７、２Ｈ）、７．１７−７．０２（ｍ、４Ｈ）、７．２１（ｓ、１Ｈ）、７．３４−７．２６（ｍ、３Ｈ）、７．４１（ｄ、Ｊ＝８．２、１Ｈ）、７．５０（ｄ、Ｊ＝８．２、１Ｈ）、１２．１７（ｄｄ、Ｊ＝１９．９、７４．７、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０５７（Ｍ＋Ｈ）^＋、１０５５（Ｍ−Ｈ）^＋。

Example 4.34
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- {3,5-difluoro-4- [4- (4-methoxyphenyl) piperidin-1-yl) ] Phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.97-0.69 (m, 12H), 1.24 (s, 1H), 1.78-1.50 (m, 6H), 2.10- 1.85 (m, 7H), 2.19 (s, 4H), 2.47-2.38 (m, 1H), 3.03-2.80 (m, 4H), 3.53 (s, 6H), 3.69 (s, 3H), 3.82 (s, 4H), 4.17-3.93 (m, 2H), 5.22-5.08 (m, 2H), 5.45 -5.29 (m, 2H), 5.91 (d, J = 12.8, 2H), 6.81 (d, J = 8.7, 2H), 7.17-7.02 (m, 4H), 7.21 (s, 1H), 7.34-7.26 (m, 3H), 7.41 (d, J = 8.2, 1H), 7.50 (d, J = 8. 2, 1H), 12.17 (dd, J = 19.9, 74.7, 2H); MS (ESI) m / z 1057 (M + H) ^{+ +} 1055 (MH) ⁺ .

実施例４．３５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フルオロ−４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９１−０．７５（ｍ、１２Ｈ）、２．１１−１．６０（ｍ、１２Ｈ）、２．２８−２．１２（ｍ、４Ｈ）、２．５５（ｄ、Ｊ＝５．５、２Ｈ）、２．８４−２．７１（ｍ、２Ｈ）、３．２８−３．０６（ｍ、２Ｈ）、３．５３（ｓ、６Ｈ）、３．８３（ｓ、４Ｈ）、４．１１−３．９９（ｍ、２Ｈ）、５．１９−５．０９（ｍ、２Ｈ）、５．４５−５．３０（ｍ、２Ｈ）、５．９４（ｄ、Ｊ＝１２．８、２Ｈ）、７．１３−７．０５（ｍ、２Ｈ）、７．４５−７．１８（ｍ、１０Ｈ）、７．５０（ｄ、Ｊ＝８．３、１Ｈ）、１２．１１（ｄ、Ｊ＝１５．２、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０４５（Ｍ＋Ｈ）^＋、１０４３（Ｍ−Ｈ）^＋。

Example 4.35
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [3,5-difluoro-4- (4-fluoro-4-phenylpiperidine-1-yl)) Phenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6- Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.91 to 0.75 (m, 12H), 2.11-1.60 (m, 12H), 2.28-2.12 (m, 4H), 2.55 (d, J = 5.5, 2H), 2.84-2.71 (m, 2H), 3.28-3.06 (m, 2H), 3.53 (s, 6H), 3.83 (s, 4H), 4.11-3.99 (m, 2H), 5.19-5.09 (m, 2H), 5.45-5.30 (m, 2H), 5. 94 (d, J = 12.8, 2H), 7.13-7.05 (m, 2H), 7.45-7.18 (m, 10H), 7.50 (d, J = 8.3) , 1H), 12.11 (d, J = 15.2, 2H); MS (ESI) m / z 1045 (M + H) ⁺ , 1043 (MH) ⁺ .

実施例４．３６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（４−フルオロ−４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９２−０．７４（ｍ、１２Ｈ）、１．２３（ｄ、Ｊ＝３．９、１Ｈ）、１．６９（ｄ、Ｊ＝３．６、２Ｈ）、２．０９−１．８０（ｍ、９Ｈ）、２．２６−２．０９（ｍ、５Ｈ）、２．８１−２．６９（ｍ、２Ｈ）、３．２６−３．１０（ｍ、３Ｈ）、３．５３（ｓ、６Ｈ）、３．８９−３．７４（ｍ、４Ｈ）、４．０５（ｔ、Ｊ＝８．４、２Ｈ）、５．１８−５．０６（ｍ、２Ｈ）、５．３４（ｄ、Ｊ＝４．５、２Ｈ）、６．２７（ｄ、Ｊ＝８．７、２Ｈ）、６．６５（ｄｔ、Ｊ＝４．２、８．６、２Ｈ）、７．０６（ｔ、Ｊ＝７．８、２Ｈ）、７．２１（ｓ、１Ｈ）、７．４３−７．２６（ｍ、９Ｈ）、７．４５（ｄ、Ｊ＝８．２、１Ｈ）、１２．０４（ｓ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１００９（Ｍ＋Ｈ）^＋、１００７（Ｍ−Ｈ）^＋。

Example 4.36
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [4- (4-fluoro-4-phenylpiperidine-1-yl) phenyl] -5-{ 2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-6-yl} pyrrolidine-2- Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.92-0.74 (m, 12H), 1.23 (d, J = 3.9, 1H), 1.69 (d, J = 3.6) , 2H), 2.09-1.80 (m, 9H), 2.26-2.09 (m, 5H), 2.81-2.69 (m, 2H), 3.26-3.10 (M, 3H), 3.53 (s, 6H), 3.89-3.74 (m, 4H), 4.05 (t, J = 8.4, 2H), 5.18-5.06 (M, 2H), 5.34 (d, J = 4.5, 2H), 6.27 (d, J = 8.7, 2H), 6.65 (dt, J = 4.2, 8. 6, 2H), 7.06 (t, J = 7.8, 2H), 7.21 (s, 1H), 7.43-7.26 (m, 9H), 7.45 (d, J = 8.2, 1H), 12.04 (s, 2H); MS (ESI) m / z 1009 (M + H) ⁺ , 1007 (MH) ⁺ .

実施例４．３７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［フルオロ（ジフェニル）メチル］ピペリジン−１−イル｝フェニル）−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、メタノール−ｄ_４）δｐｐｍ０．９９−０．６９（ｍ、１２Ｈ）、１．４２−１．２６（ｍ、３Ｈ）、１．５５（ｄｄ、Ｊ＝１２．０、２４．４、２Ｈ）、２．４２−１．８５（ｍ、１２Ｈ）、２．６２−２．４３（ｍ、３Ｈ）、３．０１−２．７４（ｍ、４Ｈ）、３．６３（ｓ、６Ｈ）、３．９０−３．７７（ｍ、２Ｈ）、４．０５−３．９０（ｍ、２Ｈ）、４．２０（ｄ、Ｊ＝７．４、１Ｈ）、５．２４−５．０８（ｍ、２Ｈ）、５．５２（ｔ、Ｊ＝５．８、２Ｈ）、５．９２−５．７２（ｍ、２Ｈ）、７．０７（ｓ、１Ｈ）、７．１８（ｔ、Ｊ＝７．３、２Ｈ）、７．２９（ｔ、Ｊ＝７．５、６Ｈ）、７．３３（ｓ、１Ｈ）、７．４３（ｄ、Ｊ＝７．３、４Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１１７１（Ｍ＋Ｈ）^＋。

Example 4.37
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (3,5-difluoro-4- {4- [fluoro (diphenyl) methyl] pyrrolidine-1-] Il} phenyl) -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H -Benzimidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, methanol-d ₄ ) δppm 0.99-0.69 (m, 12H), 1.42-1.26 (m, 3H), 1.55 (dd, J = 12.0, 24) .4, 2H), 2.42-1.85 (m, 12H), 2.62-2.43 (m, 3H), 3.01-2.74 (m, 4H), 3.63 (s) , 6H), 3.90-3.77 (m, 2H), 4.05-3.90 (m, 2H), 4.20 (d, J = 7.4, 1H), 5.24-5 .08 (m, 2H), 5.52 (t, J = 5.8, 2H), 5.92-5.72 (m, 2H), 7.07 (s, 1H), 7.18 (t) , J = 7.3, 2H), 7.29 (t, J = 7.5, 6H), 7.33 (s, 1H), 7.43 (d, J = 7.3, 4H); MS (ESI) m / z 1171 (M + H) ⁺ .

実施例４．３８
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−（６−フルオロ−２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．９２（ｄ、Ｊ＝５．５、２Ｈ）、１．０４（ｄｄ、Ｊ＝５．８、１２．０、４Ｈ）、１．６８（ｓ、４Ｈ）、１．８０（ｓ、２Ｈ）、２．０９−１．９１（ｍ、４Ｈ）、２．２７−２．１０（ｍ、４Ｈ）、３．０１−２．８２（ｍ、３Ｈ）、３．０３（ｓ、４Ｈ）、３．１３（ｓ、４Ｈ）、３．２５（ｓ、２Ｈ）、３．４４（ｄｄ、Ｊ＝６．５、１２．８、３Ｈ）、３．５３（ｓ、６Ｈ）、３．８１（ｓ、３Ｈ）、４．３１−４．１４（ｍ、２Ｈ）、５．１７−５．０２（ｍ、２Ｈ）、５．６６−５．４１（ｍ、２Ｈ）、５．９７−５．８０（ｍ、２Ｈ）、７．１３−６．９９（ｍ、２Ｈ）、７．１９−７．１３（ｍ、２Ｈ）、７．３１−７．１９（ｍ、５Ｈ）、７．３８（ｄｄ、Ｊ＝９．８、２６．３、２Ｈ）、１２．３９−１２．０１（ｍ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０９５（Ｍ＋Ｈ）^＋、１０９３（Ｍ−Ｈ）^＋。

Example 4.38
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] -5- (6-fluoro-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazole-5-yl) pyrrolidine -2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.92 (d, J = 5.5, 2H), 1.04 (dd, J = 5.8, 12.0, 4H), 1.68 (s) 4,80 (s, 2H), 2.09-1.91 (m, 4H), 2.27-2.10 (m, 4H), 3.01-2.82 (m, 3H) ), 3.03 (s, 4H), 3.13 (s, 4H), 3.25 (s, 2H), 3.44 (dd, J = 6.5, 12.8, 3H), 3. 53 (s, 6H), 3.81 (s, 3H), 4.31-4.14 (m, 2H), 5.17-5.02 (m, 2H), 5.66-5.41 ( m, 2H), 5.97-5.80 (m, 2H), 7.13-6.99 (m, 2H), 7.19-7.13 (m, 2H), 7.31-7. 19 (m, 5H), 7.38 (dd, J = 9.8, 26.3, 2H), 12.39-12.01 (m, 2H); MS (ESI) m / z 1095 (M + H) ⁺ , 1093 (MH) ⁺ .

実施例４．３９
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．３７−１．０７（ｍ、６Ｈ）、１．５６−１．３６（ｍ、４Ｈ）、１．７３−１．６０（ｍ、４Ｈ）、１．７８（ｓ、４Ｈ）、２．０６−１．９３（ｍ、４Ｈ）、２．２６−２．０６（ｍ、４Ｈ）、３．２６−２．８１（ｍ、８Ｈ）、３．５２（ｓ、６Ｈ）、３．９１−３．６０（ｍ、８Ｈ）、４．１２（ｄｄ、Ｊ＝６．９、１５．８、２Ｈ）、５．１１（ｓ、２Ｈ）、５．５４（ｄ、Ｊ＝１０．０、２Ｈ）、５．９９−５．８１（ｍ、２Ｈ）、７．０５（ｄｄ、Ｊ＝６．３、２３．５、２Ｈ）、７．１６（ｔ、Ｊ＝６．９、１Ｈ）、７．３１−７．２０（ｍ、５Ｈ）、７．４５−７．３０（ｍ、４Ｈ）、１２．２３（ｄ、Ｊ＝８３．３、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１１４７（Ｍ＋Ｈ）^＋。

Example 4.39
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H-benz) Imidazole-5,2-diyl) (2S) pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1-diyl]}) Biscarbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.37-1.07 (m, 6H), 1.56-1.36 (m, 4H), 1.73-1.60 (m, 4H), 1.78 (s, 4H), 2.06-1.93 (m, 4H), 2.26-2.06 (m, 4H), 3.26-2.81 (m, 8H), 3. 52 (s, 6H), 3.91-3.60 (m, 8H), 4.12 (dd, J = 6.9, 15.8, 2H), 5.11 (s, 2H), 5. 54 (d, J = 10.0, 2H), 5.99-5.81 (m, 2H), 7.05 (dd, J = 6.3, 23.5, 2H), 7.16 (t) , J = 6.9, 1H), 7.31-7.20 (m, 5H), 7.45-7.30 (m, 4H), 12.23 (d, J = 83.3, 2H) MS (ESI) m / z 1147 (M + H) ⁺ .

実施例４．４０
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロペンチル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．６１−１．１０（ｍ、１８Ｈ）、１．６７（ｓ、４Ｈ）、１．９０−１．７２（ｍ、２Ｈ）、２．１３−１．９３（ｍ、６Ｈ）、２．１８（ｓ、４Ｈ）、３．０８−２．８６（ｍ、４Ｈ）、３．１７（ｄ、Ｊ＝５．１、１Ｈ）、３．５２（ｓ、６Ｈ）、３．８９−３．７０（ｍ、４Ｈ）、４．２０−４．０１（ｍ、２Ｈ）、５．１１（ｓ、２Ｈ）、５．５６（ｄ、Ｊ＝２１．５、２Ｈ）、５．９６−５．８３（ｍ、２Ｈ）、７．０４（ｄ、Ｊ＝６．７、１Ｈ）、７．１６（ｔ、Ｊ＝７．０、２Ｈ）、７．３１−７．２０（ｍ、４Ｈ）、７．３９（ｄｔ、Ｊ＝８．１、２５．５、４Ｈ）、１２．１６（ｄ、Ｊ＝６１．１、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１１１５（Ｍ＋Ｈ）^＋、１１１３（Ｍ−Ｈ）^＋。

Example 4.40
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H-benz) Imidazole-5,2-diyl) (2S) Pyrrolidine-2,1-diyl [(1S) -1-cyclopentyl-2-oxoethane-2,1-diyl]}) Biscabamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.61-1.10 (m, 18H), 1.67 (s, 4H), 1.90-1.72 (m, 2H), 2.13- 1.93 (m, 6H), 2.18 (s, 4H), 3.08-2.86 (m, 4H), 3.17 (d, J = 5.1, 1H), 3.52 ( s, 6H), 3.89-3.70 (m, 4H), 4.20-4.01 (m, 2H), 5.11 (s, 2H), 5.56 (d, J = 21. 5, 2H), 5.96-5.83 (m, 2H), 7.04 (d, J = 6.7, 1H), 7.16 (t, J = 7.0, 2H), 7. 31-7.20 (m, 4H), 7.39 (dt, J = 8.1, 25.5, 4H), 12.16 (d, J = 61, 2H); MS (ESI) m / Z1115 (M + H) ⁺ , 1113 (MH) ⁺ .

実施例４．４１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（ベンジルオキシ）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．０２（ｓ、２Ｈ）、７．２８（ｍ、１３Ｈ）、６．６０（ｍ、２Ｈ）、６．２３（ｍ、２Ｈ）、５．３３（ｍ、２Ｈ）、５．１４（ｍ、２Ｈ）、４．９０（ｍ、２Ｈ）、３．８１（ｍ、４Ｈ）、３．５６（ｓ、６Ｈ）、２．２０（ｍ、６Ｈ）、１．９８（ｍ、６Ｈ）、１．７０（ｍ、２Ｈ）、０．８６（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９３８（Ｍ＋Ｈ）^＋。

Example 4.41
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (benzyloxy) phenyl] -5- {2-[(2S) -1- { (2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2- Il} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.02 (s, 2H), 7.28 (m, 13H), 6.60 (m, 2H), 6.23 (m, 2H), 5.33 (M, 2H), 5.14 (m, 2H), 4.90 (m, 2H), 3.81 (m, 4H), 3.56 (s, 6H), 2.20 (m, 6H) 1.98 (m, 6H), 1.70 (m, 2H), 0.86 (m, 12H); MS (ESI) m / z 938 (M + H) ⁺ .

実施例４．４２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［４−（トリフルオロメチル）フェニル］ピペラジン−１−イル｝フェニル）−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ７．５５（ｍ、２Ｈ）、７．４８（ｄ、Ｊ＝８．８Ｈｚ、２Ｈ）、７．３４（ｍ、２Ｈ）、７．１８（ｍ、２Ｈ）、７．０４（ｄ、Ｊ＝７．８Ｈｚ、２Ｈ）、５．９９（ｍ、２Ｈ）、５．６３（ｍ、２Ｈ）、５．１３（ｍ、２Ｈ）、４．０６（ｍ、２Ｈ）、３．８０（ｍ、２Ｈ）、３．５３（ｓ、６Ｈ）、３．２５（ｍ、８Ｈ）、２．９９（ｍ、４Ｈ）、２．０５（ｍ、１２Ｈ）、０．８１（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１１３２（Ｍ＋Ｈ）^＋。

Example 4.42
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (3,5-difluoro-4- {4- [4- (trifluoromethyl) phenyl] piperazine] -1-yl} phenyl) -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl ] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} Carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm7.55 (m, 2H), 7.48 (d, J = 8.8Hz, 2H), 7.34 (m, 2H), 7.18 (m, 2H), 7.04 (d, J = 7.8Hz, 2H), 5.99 (m, 2H), 5.63 (m, 2H), 5.13 (m, 2H), 4.06 (m) , 2H), 3.80 (m, 2H), 3.53 (s, 6H), 3.25 (m, 8H), 2.99 (m, 4H), 2.05 (m, 12H), 0 .81 (m, 12H); MS (ESI) m / z 1132 (M + H) ⁺ .

実施例４．４３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛５−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６８−０．８９（ｍ、１２Ｈ）１．３４−１．５０（ｍ、６Ｈ）１．６５−２．０６（ｍ、９Ｈ）２．１２−２．２４（ｍ、４Ｈ）２．７０−２．８２（ｍ、４Ｈ）３．５２（ｄ、Ｊ＝２．４９Ｈｚ、６Ｈ）３．７３−３．８６（ｍ、４Ｈ）３．９９−４．０８（ｍ、２Ｈ）５．０６−５．１９（ｍ、２Ｈ）５．２６−５．４３（ｍ、１Ｈ）５．４６−５．５６（ｍ、１Ｈ）５．８６（ｄ、Ｊ＝１２．０４Ｈｚ、２Ｈ）６．９８（ｄ、Ｊ＝６．５１Ｈｚ、１Ｈ）７．０２−７．１１（ｍ、１Ｈ）７．２１（ｄ、Ｊ＝６．９４Ｈｚ、１Ｈ）７．２６−７．３５（ｍ、２Ｈ）７．３９（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）７．４５−７．５１（ｍ、１Ｈ）１２．０１−１２．２６（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９６９（Ｍ＋Ｈ）^＋。

Example 4.43
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {5 -Fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine -2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.68-0.89 (m, 12H) 1.34-1.50 (m, 6H) 1.65-2.06 (m, 9H) 2.12 -2.24 (m, 4H) 2.70-2.82 (m, 4H) 3.52 (d, J = 2.49Hz, 6H) 3.73-3.86 (m, 4H) 3.99 -4.08 (m, 2H) 5.06-5.19 (m, 2H) 5.26-5.43 (m, 1H) 5.46-5.56 (m, 1H) 5.86 (d) , J = 12.04Hz, 2H) 6.98 (d, J = 6.51Hz, 1H) 7.02-7.11 (m, 1H) 7.21 (d, J = 6.94Hz, 1H) 7 .26-7.35 (m, 2H) 7.39 (d, J = 8.35Hz, 1H) 7.45-7.51 (m, 1H) 12.01-12.26 (m, 2H); MS (ESI +) m / z 969 (M + H) ⁺ .

実施例４．４４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（４−ベンジルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛５−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−５−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６７−０．８８（ｍ、１２Ｈ）１．２２（ｓ、１２Ｈ）１．４２−１．５１（ｍ、５Ｈ）１．７３−２．０４（ｍ、１２Ｈ）２．１２−２．２１（ｍ、４Ｈ）２．７２−２．８１（ｍ、５Ｈ）３．４８−３．５４（ｍ、６Ｈ）３．７２−３．８３（ｍ、３Ｈ）３．９７−４．０６（ｍ、２Ｈ）５．０５−５．１３（ｍ、２Ｈ）５．４６−５．５８（ｍ、２Ｈ）５．７９−５．８９（ｍ、２Ｈ）６．９９−７．０４（ｍ、１Ｈ）７．０９−７．１６（ｍ、５Ｈ）７．２０−７．３４（ｍ、６Ｈ）７．３５−７．４２（ｍ、１Ｈ）７．５１−７．６４（ｍ、３Ｈ）１２．１０（ｓ、１Ｈ）１２．２３（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０７７（Ｍ＋Ｈ）^＋。

Example 4.44
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [4- (4-benzylpiperidin-1-yl) -3,5-difluorophenyl] -5 -{5-Fluor-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6- Il} pyrrolidine-2-yl] -5-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.67-0.88 (m, 12H) 1.22 (s, 12H) 1.42-1.51 (m, 5H) 1.73-2.04 (M, 12H) 2.12-2.21 (m, 4H) 2.72-2.81 (m, 5H) 3.48-3.54 (m, 6H) 3.72-3.83 (m) , 3H) 3.97-4.06 (m, 2H) 5.05-5.13 (m, 2H) 5.46-5.58 (m, 2H) 5.79-5.89 (m, 2H) ) 6.99-7.04 (m, 1H) 7.09-7.16 (m, 5H) 7.20-7.34 (m, 6H) 7.35-7.42 (m, 1H) 7 .51-7.64 (m, 3H) 12.10 (s, 1H) 12.23 (s, 1H); MS (ESI +) m / z 1077 (M + H) ⁺ .

実施例４．４５
ジメチル（［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［４−（トリフルオロメチル）フェニル］ピペラジン−１−イル｝フェニル）ピロリジン−２，５−ジイル］ビス｛（５−フルオロ−１Ｈ−ベンズイミダゾール−６，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロペンチル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．０９−１．６４（ｍ、１８Ｈ）１．７１−１．８６（ｍ、２Ｈ）１．９２−２．２３（ｍ、１０Ｈ）２．９１−３．０３（ｍ、５Ｈ）３．２２−３．３０（ｍ、４Ｈ）３．５２（ｓ、６Ｈ）３．７１−３．８７（ｍ、４Ｈ）４．１２（ｔ、Ｊ＝８．４０Ｈｚ、２Ｈ）５．０５−５．１６（ｍ、２Ｈ）５．４８−５．６５（ｍ、２Ｈ）５．８５−５．９９（ｍ、２Ｈ）７．０３（ｄ、Ｊ＝８．８９Ｈｚ、３Ｈ）７．１４（ｄ、Ｊ＝６．２９Ｈｚ、１Ｈ）７．３０−７．３８（ｍ、１Ｈ）７．４０（ｄ、Ｊ＝９．５４Ｈｚ、２Ｈ）７．４６（ｄ、Ｊ＝８．６７Ｈｚ、２Ｈ）１２．０８（ｓ、１Ｈ）１２．２０（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１８４（Ｍ＋Ｈ）^＋。

Example 4.45
Dimethyl ([(2R, 5R) -1- (3,5-difluoro-4- {4- [4- (trifluoromethyl) phenyl] piperazin-1-yl} phenyl) pyrrolidine-2,5-diyl] bis {(5-Fluoro-1H-benzimidazole-6,2-diyl) (2S) pyrrolidine-2,1-diyl [(1S) -1-cyclopentyl-2-oxoethane-2,1-diyl]}) Biscabamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.09-1.64 (m, 18H) 1.71-1.86 (m, 2H) 1.92-2.23 (m, 10H) 2.91 -3.03 (m, 5H) 3.22-3.30 (m, 4H) 3.52 (s, 6H) 3.71-3.87 (m, 4H) 4.12 (t, J = 8) .40Hz, 2H) 5.05-5.16 (m, 2H) 5.48-5.65 (m, 2H) 5.85-5.99 (m, 2H) 7.03 (d, J = 8) .89Hz, 3H) 7.14 (d, J = 6.29Hz, 1H) 7.30-7.38 (m, 1H) 7.40 (d, J = 9.54Hz, 2H) 7.46 (d) , J = 8.67Hz, 2H) 12.08 (s, 1H) 12.20 (s, 1H); MS (ESI +) m / z 1184 (M + H) ⁺ .

実施例４．４６
ジメチル（［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［４−（トリフルオロメチル）フェニル］ピペラジン−１−イル｝フェニル）ピロリジン−２，５−ジイル］ビス｛（５−フルオロ−１Ｈ−ベンズイミダゾール−６，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．０９−１．３３（ｍ、４Ｈ）１．３８−１．５４（ｍ、４Ｈ）１．７０−１．８８（ｍ、４Ｈ）１．９２−２．０５（ｍ、４Ｈ）２．１０−２．２５（ｍ、３Ｈ）２．９５−３．０３（ｍ、４Ｈ）３．０３−３．２０（ｍ、３Ｈ）３．２１−３．２９（ｍ、４Ｈ）３．５１（ｓ、６Ｈ）３．６２−３．８９（ｍ、６Ｈ）４．０５−４．１７（ｍ、２Ｈ）５．０６−５．１５（ｍ、２Ｈ）５．４８−５．６４（ｍ、２Ｈ）５．８３−５．９８（ｍ、２Ｈ）７．０３（ｄ、Ｊ＝８．６７Ｈｚ、３Ｈ）７．０７（ｄ、Ｊ＝６．２９Ｈｚ、１Ｈ）７．２９−７．４２（ｍ、３Ｈ）７．４６（ｄ、Ｊ＝８．７８Ｈｚ、２Ｈ）１２．１１（ｓ、１Ｈ）１２．３２（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１２１６（Ｍ＋Ｈ）^＋。

Example 4.46
Dimethyl ([(2R, 5R) -1- (3,5-difluoro-4- {4- [4- (trifluoromethyl) phenyl] piperazin-1-yl} phenyl) pyrrolidine-2,5-diyl] bis {(5-Fluoro-1H-benzimidazole-6,2-diyl) (2S) pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane -2,1-Jill]}) Biscabamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.09-1.33 (m, 4H) 1.38-1.54 (m, 4H) 1.70-1.88 (m, 4H) 1.92 -2.05 (m, 4H) 2.10-2.25 (m, 3H) 2.95-3.03 (m, 4H) 3.03-3.20 (m, 3H) 3.21-3 .29 (m, 4H) 3.51 (s, 6H) 3.62-3.89 (m, 6H) 4.05-4.17 (m, 2H) 5.06-5.15 (m, 2H) ) 5.48-5.64 (m, 2H) 5.83-5.98 (m, 2H) 7.03 (d, J = 8.67Hz, 3H) 7.07 (d, J = 6.29Hz) , 1H) 7.29-7.42 (m, 3H) 7.46 (d, J = 8.78Hz, 2H) 12.11 (s, 1H) 12.32 (s, 1H); MS (ESI +) m / z 1216 (M + H) ⁺ .

実施例４．４７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（４−ベンジルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１２．０７（ｄ、Ｊ＝１９．１、２Ｈ）、７．４８（ｄ、Ｊ＝８．３、２Ｈ）、７．４０（ｄ、Ｊ＝８．１、２Ｈ）、７．３４−７．１０（ｍ、８Ｈ）、７．０７（ｓ、２Ｈ）、５．８７（ｄ、Ｊ＝１２．３、２Ｈ）、５．３５（ｓ、２Ｈ）、５．１４（ｓ、１Ｈ）、３．７８（ｄ、Ｊ＝２８．９、２Ｈ）、３．５４（ｓ、６Ｈ）、２．７６（ｓ、３Ｈ）、２．１９（ｓ、４Ｈ）、２．０７−１．８０（ｍ、６Ｈ）、１．６８（ｓ、２Ｈ）、１．４６（ｄ、Ｊ＝１０．４、３Ｈ）、１．２５−１．０８（ｍ、２Ｈ）、０．９２−０．７１（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０４１．４（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ１０３９．３（Ｍ−Ｈ）⁻。

Example 4.47
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [4- (4-benzylpiperidin-1-yl) -3,5-difluorophenyl] -5 -{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-6-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 12.07 (d, J = 19.1, 2H), 7.48 (d, J = 8.3, 2H), 7.40 (d, J = 8) .1, 2H), 7.34-7.10 (m, 8H), 7.07 (s, 2H), 5.87 (d, J = 12.3, 2H), 5.35 (s, 2H) , 5.14 (s, 1H), 3.78 (d, J = 28.9, 2H), 3.54 (s, 6H), 2.76 (s, 3H), 2.19 (s, 4H), 2.07-1.80 (m, 6H), 1.68 (s, 2H), 1.46 (d, J = 10.4, 3H), 1.25 to 1.08 (m, 2H), 0.92-0.71 (m, 12H); MS (ESI +) m / z 1041.4 (M + H) ⁺ , (ESI-) m / z 1039.3 (MH) ⁻ .

実施例４．４８
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９４（ｍ、１２Ｈ）、１．６０−２．３０（ｍ、１４Ｈ）、２．８８−３．０９（ｍ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．８４（ｓ、３Ｈ）、４．０２−４．１５（ｍ、Ｊ＝８．１、８．１Ｈｚ、２Ｈ）、４．７７−４．９７（ｍ、２Ｈ）、５．１７（ｄ、Ｊ＝２．９Ｈｚ、２Ｈ）、５．９５−６．１０（ｍ、２Ｈ）、７．０８−７．７０（ｍ、１３Ｈ）、１２．０９−１２．２３（ｍ、２Ｈ）。

Example 4.48
Methyl {(2S) -1-[(2S) -2-{5-[(2S, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5] -5 -{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.94 (m, 12H), 1.60-2.30 (m, 14H), 2.88-3.09 (m, 4H), 3.54 (s, 6H), 3.84 (s, 3H), 4.02-4.15 (m, J = 8.1, 8.1Hz, 2H), 4.77-4.97 (m) , 2H), 5.17 (d, J = 2.9Hz, 2H), 5.95-6.10 (m, 2H), 7.08-7.70 (m, 13H), 12.09-12 .23 (m, 2H).

実施例４．４９
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（２−フェニルモルホリン−４−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６９−０．９２（ｍ、１２Ｈ）、１．６９（ｄ、Ｊ＝５．１Ｈｚ、２Ｈ）、１．８２−２．３０（ｍ、１２Ｈ）、２．７０−３．１６（ｍ、Ｊ＝６３．６Ｈｚ、６Ｈ）、３．５４（ｓ、６Ｈ）、３．８１（ｓ、３Ｈ）、３．９９−４．１２（ｍ、２Ｈ）、４．４７（ｄｄ、Ｊ＝９．１、３．７Ｈｚ、１Ｈ）、５．０８−５．１９（ｍ、２Ｈ）、５．２９−５．４８（ｍ、２Ｈ）、５．９２（ｄ、Ｊ＝１３．４Ｈｚ、２Ｈ）、７．０７（ｔ、Ｊ＝７．９Ｈｚ、２Ｈ）、７．１６−７．３５（ｍ、Ｊ＝０．８Ｈｚ、１０Ｈ）、７．４０（ｄ、Ｊ＝８．１Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．３Ｈｚ、１Ｈ）、１２．０６（ｓ、１Ｈ）、１２．１１（ｓ、１Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ１０３０．１（Ｍ＋Ｈ）。

Example 4.49
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (2-phenylmorpholin-4-yl) phenyl] -5] -5 − {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.69-0.92 (m, 12H), 1.69 (d, J = 5.1 Hz, 2H) 1.82-2.30 (m, 12H) ), 2.70-3.16 (m, J = 63.6Hz, 6H), 3.54 (s, 6H), 3.81 (s, 3H), 3.99-4.12 (m, 2H) ), 4.47 (dd, J = 9.1, 3.7Hz, 1H), 5.08-5.19 (m, 2H), 5.29-5.48 (m, 2H), 5.92 (D, J = 13.4Hz, 2H), 7.07 (t, J = 7.9Hz, 2H), 7.16-7.35 (m, J = 0.8Hz, 10H), 7.40 ( d, J = 8.1Hz, 1H), 7.49 (d, J = 8.3Hz, 1H), 12.06 (s, 1H), 12.11 (s, 1H); MS (APCI +) m / z1030.1 (M + H).

実施例４．５０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（２−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８１−１．０１（ｍ、１２Ｈ）、１．２４−２．３５（ｍ、２２Ｈ）、３．６０（ｓ、６Ｈ）、３．８９（ｓ、４Ｈ）、３．９４−４．２０（ｍ、３Ｈ）、５．２２（ｓ、２Ｈ）、５．３０（ｄ、Ｊ＝４．３Ｈｚ、２Ｈ）、５．７３（ｄｄ、Ｊ＝１３．１、３．６Ｈｚ、２Ｈ）、６．９２−７．４４（ｍ、１３Ｈ）、７．４８（ｄ、Ｊ＝８．１Ｈｚ、１Ｈ）、１２．０８（ｓ、１Ｈ）、１２．１７（ｓ、１Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ１０２８．２（Ｍ＋Ｈ）^＋。

Example 4.50
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (2-phenylpiperidin-1-yl) phenyl] -5] -5 -{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.81-1.01 (m, 12H), 1.24-2.35 (m, 22H), 3.60 (s, 6H), 3.89 ( s, 4H), 3.94-4.20 (m, 3H), 5.22 (s, 2H), 5.30 (d, J = 4.3Hz, 2H), 5.73 (dd, J = 13.1, 3.6Hz, 2H), 6.92-7.44 (m, 13H), 7.48 (d, J = 8.1Hz, 1H), 12.08 (s, 1H), 12. 17 (s, 1H); MS (APCI +) m / z 1028.2 (M + H) ⁺ .

実施例４．５１
メチル［（２Ｓ）−１−｛（２Ｓ）−２−［５−（１−｛４−［（２Ｒ，６Ｓ）−２，６−ジメチルモルホリン−４−イル］−３，５−ジフルオロフェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル）−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル］ピロリジン−１−イル｝−３−メチル−１−オキソブタン−２−イル］カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６７−０．９０（ｍ、１２Ｈ）、０．９６（ｓ、６Ｈ）、１．０１−１．３１（ｍ、２Ｈ）、１．６８−２．２５（ｍ、１２Ｈ）、３．５１（ｓ、６Ｈ）、３．７８（ｓ、３Ｈ）、４．０１（ｑ、Ｊ＝７．２Ｈｚ、２Ｈ）、５．１０（ｄ、Ｊ＝４．８Ｈｚ、２Ｈ）、５．４３−５．６５（ｍ、２Ｈ）、５．７９−５．９７（ｍ、２Ｈ）、７．０２（ｄ、Ｊ＝５．３Ｈｚ、１Ｈ）、７．１１（ｄ、Ｊ＝６．８Ｈｚ、１Ｈ）、７．２１−７．４６（ｍ、４Ｈ）、１２．１１（ｓ、１Ｈ）、１２．２４（ｓ、１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０１７．４（Ｍ＋Ｈ）^＋。

Example 4.51
Methyl [(2S) -1-{(2S) -2- [5- (1- {4-[(2R, 6S) -2,6-dimethylmorpholin-4-yl] -3,5-difluorophenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole- 5-yl} pyrrolidine-2-yl) -6-fluoro-1H-benzimidazol-2-yl] pyrrolidine-1-yl} -3-methyl-1-oxobutan-2-yl] carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.67-0.90 (m, 12H), 0.96 (s, 6H), 1.01-1.31 (m, 2H), 1.68- 2.25 (m, 12H), 3.51 (s, 6H), 3.78 (s, 3H), 4.01 (q, J = 7.2Hz, 2H), 5.10 (d, J = 4.8Hz, 2H), 5.43-5.65 (m, 2H), 5.79-5.97 (m, 2H), 7.02 (d, J = 5.3Hz, 1H), 7. 11 (d, J = 6.8Hz, 1H), 7.21-7.46 (m, 4H), 12.11 (s, 1H), 12.24 (s, 1H); MS (ESI) m / z1017.4 (M + H) ⁺ .

実施例４．５２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｓ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７２−０．９４（ｍ、Ｊ＝１０．５、１０．５Ｈｚ、１２Ｈ）、１．３６−１．５８（ｍ、６Ｈ）、１．７７−２．２８（ｍ、１４Ｈ）、２．８３（ｓ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、３．９７−４．１４（ｍ、２Ｈ）、４．９２−５．０７（ｍ、２Ｈ）、５．０９−５．２０（ｍ、２Ｈ）、５．８３−６．０２（ｍ、２Ｈ）、７．２１−７．７９（ｍ、６Ｈ）、１２．１４−１２．４４（ｍ、２Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ９８７．８（Ｍ＋Ｈ）^＋。

Example 4.52
Methyl {(2S) -1-[(2S) -2-{5-[(2S, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5-{6 -Fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine -2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.72-0.94 (m, J = 10.5, 10.5 Hz, 12H), 1.36-1.58 (m, 6H), 1.77 -2.28 (m, 14H), 2.83 (s, 4H), 3.53 (s, 6H), 3.82 (s, 4H), 3.97-4.14 (m, 2H), 4.92-5.07 (m, 2H), 5.09-5.20 (m, 2H), 5.83-6.02 (m, 2H), 7.21-7.79 (m, 6H) ), 12.14-12.44 (m, 2H); MS (APCI +) m / z 987.8 (M + H) ⁺ .

実施例４．５３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（３−アザスピロ［５．５］ウンデク−３−イル）−３，５−ジフルオロフェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６４−０．９４（ｍ、１２Ｈ）、１．２１−１．４４（ｍ、１６Ｈ）、１．６８−２．２５（ｍ、Ｊ＝７８．０Ｈｚ、１２Ｈ）、２．７８（ｓ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．８０（ｓ、４Ｈ）、４．０４（ｔ、Ｊ＝７．１Ｈｚ、２Ｈ）、５．１１（ｓ、２Ｈ）、５．５５（ｄｄ、Ｊ＝１９．８、４．２Ｈｚ、２Ｈ）、５．７９−５．９９（ｍ、２Ｈ）、７．０３（ｄ、Ｊ＝６．０Ｈｚ、１Ｈ）、７．１３（ｄ、Ｊ＝６．５Ｈｚ、１Ｈ）、７．２４−７．４８（ｍ、４Ｈ）、１２．１２（ｓ、１Ｈ）、１２．２４（ｓ、１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０５５．４（Ｍ＋Ｈ）^＋。

Example 4.53
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (3-azaspiro [5.5] undex-3-yl) -3,5- Difluorophenyl] -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H- Benzimidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.64-0.94 (m, 12H), 1.21-1.44 (m, 16H), 1.68-2.25 (m, J = 78) .0Hz, 12H), 2.78 (s, 4H), 3.53 (s, 6H), 3.80 (s, 4H), 4.04 (t, J = 7.1Hz, 2H), 5. 11 (s, 2H), 5.55 (dd, J = 19.8, 4.2Hz, 2H), 5.79-5.99 (m, 2H), 7.03 (d, J = 6.0Hz) , 1H), 7.13 (d, J = 6.5Hz, 1H), 7.24-7.48 (m, 4H), 12.12 (s, 1H), 12.24 (s, 1H); MS (ESI) m / z 1055.4 (M + H) ⁺ .

実施例４．５４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４−シクロヘキシルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６５−０．９７（ｍ、１２Ｈ）、０．９８−１．３３（ｍ、１０Ｈ）、１．５０−２．２５（ｍ、２０Ｈ）、２．７２−２．９１（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．７９（ｓ、４Ｈ）、４．０４（ｔ、Ｊ＝８．１Ｈｚ、２Ｈ）、５．１１（ｓ、２Ｈ）、５．５４（ｄｄ、Ｊ＝１４．７、６．７Ｈｚ、２Ｈ）、５．７９−５．９７（ｍ、２Ｈ）、７．０３（ｄ、Ｊ＝６．７Ｈｚ、１Ｈ）、７．１３（ｄ、Ｊ＝６．９Ｈｚ、１Ｈ）、７．２４−７．４６（ｍ、４Ｈ）、１２．１１（ｓ、１Ｈ）、１２．２３（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６９．５（Ｍ＋Ｈ）^＋。

Example 4.54
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4-cyclohexylpiperidine-1-yl) -3,5-difluorophenyl] -5 -{6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5- Il} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.65-0.97 (m, 12H), 0.98-1.33 (m, 10H), 1.50-2.25 (m, 20H), 2.72-2.91 (m, 4H), 3.53 (s, 6H), 3.79 (s, 4H), 4.04 (t, J = 8.1Hz, 2H), 5.11 ( s, 2H), 5.54 (dd, J = 14.7, 6.7Hz, 2H), 5.79-5.97 (m, 2H), 7.03 (d, J = 6.7Hz, 1H) ), 7.13 (d, J = 6.9Hz, 1H), 7.24-7.46 (m, 4H), 12.11 (s, 1H), 12.23 (s, 1H); MS ( ESI +) m / z 1069.5 (M + H) ⁺ .

実施例４．５５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［（２Ｓ）−２−フェニルモルホリン−４−イル］フェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６０−０．９５（ｍ、１２Ｈ）、１．６４−２．０８（ｍ、１０Ｈ）、２．０９−２．２５（ｍ、４Ｈ）、２．７０−３．１８（ｍ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．６４−３．８６（ｍ、４Ｈ）、３．９１（ｄ、Ｊ＝１１．４Ｈｚ、１Ｈ）、４．０３（ｔ、Ｊ＝８．２Ｈｚ、２Ｈ）、４．４８（ｄ、Ｊ＝７．５Ｈｚ、１Ｈ）、５．１０（ｓ、２Ｈ）、５．４３−５．６９（ｍ、２Ｈ）、５．８０−６．０３（ｍ、２Ｈ）、７．０３（ｄ、Ｊ＝６．８Ｈｚ、１Ｈ）、７．１４（ｄ、Ｊ＝６．７Ｈｚ、１Ｈ）、７．２０−７．４５（ｍ、１０Ｈ）、１２．１０（ｓ、１Ｈ）、１２．２４（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６５．４（Ｍ＋Ｈ）^＋。

Example 4.55
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4-[(2S) -2-phenylmorpholin-4-yl]] Phenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benz Imidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.60-0.95 (m, 12H), 1.64-2.08 (m, 10H), 2.09-2.25 (m, 4H), 2.70-3.18 (m, 4H), 3.53 (s, 6H), 3.64-3.86 (m, 4H), 3.91 (d, J = 11.4Hz, 1H), 4.03 (t, J = 8.2Hz, 2H), 4.48 (d, J = 7.5Hz, 1H), 5.10 (s, 2H), 5.43-5.69 (m, 2H) ), 5.80-6.03 (m, 2H), 7.03 (d, J = 6.8Hz, 1H), 7.14 (d, J = 6.7Hz, 1H), 7.20-7 .45 (m, 10H), 12.10 (s, 1H), 12.24 (s, 1H); MS (ESI +) m / z 1065.4 (M + H) ⁺ .

実施例４．５６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛４−［４−（２，４−ジフルオロフェニル）ピペリジン−１−イル］−３，５−ジフルオロフェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６８−０．９２（ｍ、１４Ｈ）、１．５８−２．０８（ｍ、１１Ｈ）、２．０９−２．２７（ｍ、４Ｈ）、２．７１−３．１４（ｍ、６Ｈ）、３．５２（ｓ、６Ｈ）、３．６８−３．８９（ｍ、４Ｈ）、３．９８−４．１０（ｍ、２Ｈ）、５．０５−５．１７（ｍ、２Ｈ）、５．４８−５．６８（ｍ、２Ｈ）、５．８３−５．９９（ｍ、２Ｈ）、６．９５−７．０８（ｍ、２Ｈ）、７．０９−７．２１（ｍ、２Ｈ）、７．２５−７．４６（ｍ、５Ｈ）、１２．０６−１２．３９（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０９９．３（Ｍ＋Ｈ）^＋。

Example 4.56
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {4- [4- (2,4-difluorophenyl) pyrrolidine-1-yl] -3, 5-Difluorophenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl]- 1H-benzimidazol-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.68-0.92 (m, 14H), 1.58-2.08 (m, 11H), 2.09-2.27 (m, 4H), 2.71-3.14 (m, 6H), 3.52 (s, 6H), 3.68-3.89 (m, 4H), 3.98-4.10 (m, 2H), 5. 05-5.17 (m, 2H), 5.48-5.68 (m, 2H), 5.83-5.99 (m, 2H), 6.95-7.08 (m, 2H), 7.09-7.21 (m, 2H), 7.25-7.46 (m, 5H), 12.06-12.39 (m, 2H); MS (ESI +) m / z 1099.3 (M + H) ) ⁺ .

実施例４．５７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（４−フルオロフェニル）ピペリジン−１−イル］フェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６７−０．９３（ｍ、１４Ｈ）、１．５３−２．０９（ｍ、１１Ｈ）、２．１０−２．２５（ｍ、４Ｈ）、２．８３−３．１５（ｍ、６Ｈ）、３．５３（ｓ、６Ｈ）、３．６９−３．８８（ｍ、４Ｈ）、３．９８−４．１０（ｍ、２Ｈ）、５．０５−５．１７（ｍ、２Ｈ）、５．４８−５．６７（ｍ、２Ｈ）、５．８３−５．９９（ｍ、２Ｈ）、６．９９−７．２０（ｍ、４Ｈ）、７．２２−７．４７（ｍ、６Ｈ）、１２．０２−１２．４７（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０８１．４（Ｍ＋Ｈ）^＋。

Example 4.57
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (4-fluorophenyl) piperidin-1-yl) ] Phenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H- Benzimidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.67-0.93 (m, 14H), 1.53-2.09 (m, 11H), 2.10-2.25 (m, 4H), 2.83-3.15 (m, 6H), 3.53 (s, 6H), 3.69-3.88 (m, 4H), 3.98-4.10 (m, 2H), 5. 05-5.17 (m, 2H), 5.48-5.67 (m, 2H), 5.83-5.99 (m, 2H), 6.99-7.20 (m, 4H), 7.22-7.47 (m, 6H) 12.02-12.47 (m, 2H); MS (ESI +) m / z 1081.4 (M + H) ⁺ .

実施例４．５８
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペラジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７２−０．９５（ｍ、１２Ｈ）１．６９（ｓ、１Ｈ）１．８４−２．１１（ｍ、２Ｈ）２．２０（ｓ、４Ｈ）２．９７（ｓ、４Ｈ）３．０９（ｓ、４Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０３（ｑ、Ｊ＝７．０５Ｈｚ、６Ｈ）５．１５（ｓ、２Ｈ）５．３９（ｓ、２Ｈ）５．９５（ｓ、２Ｈ）６．７５（ｓ、２Ｈ）６．９０（ｄ、Ｊ＝８．２４Ｈｚ、２Ｈ）７．０８（ｔ、２Ｈ）７．１７（ｔ、Ｊ＝７．９２Ｈｚ、２Ｈ）７．３０（ｓ、２Ｈ）７．４８（ｓ、２Ｈ）７．６６（ｓ、２Ｈ）７．９２（ｓ、２Ｈ）１２．０９（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０２８．４、（ＥＳＩ−）ｍ／ｚ１０２６．４（Ｍ−Ｈ）⁻。

Example 4.58
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperazin-1-yl) phenyl] -5] -5 -{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.72-0.95 (m, 12H) 1.69 (s, 1H) 1.84-2.11 (m, 2H) 2.20 (s, 4H) ) 2.97 (s, 4H) 3.09 (s, 4H) 3.54 (s, 6H) 3.82 (s, 4H) 4.03 (q, J = 7.05Hz, 6H) 5.15 (S, 2H) 5.39 (s, 2H) 5.95 (s, 2H) 6.75 (s, 2H) 6.90 (d, J = 8.24Hz, 2H) 7.08 (t, 2H) ) 7.17 (t, J = 7.92Hz, 2H) 7.30 (s, 2H) 7.48 (s, 2H) 7.66 (s, 2H) 7.92 (s, 2H) 12.09 (S, 2H); MS (ESI +) m / z 1028.4, (ESI-) m / z 1026.4 (MH) ⁻ .

実施例４．５９
メチル｛（２Ｓ）−１−［（２Ｓ，４Ｒ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ，４Ｒ）−４−フルオロ−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−４−フルオロピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６（ｍ、１６Ｈ）０．８９（ｍ、３Ｈ）１．４５（ｍ、５Ｈ）１．７０（ｍ、２Ｈ）１．８５（ｍ、１Ｈ）２．７６（ｄ、２Ｈ）３．１７（ｄ、Ｊ＝５．１０Ｈｚ、２Ｈ）３．５３（ｓ、６Ｈ）３．８７−４．１３（ｍ、４Ｈ）４．３１（ｍ、１Ｈ）５．１７（ｄ、２Ｈ）５．３６（ｍ、３Ｈ）５．５７（ｓ、１Ｈ）５．８９（ｄ、２Ｈ）７．０９（ｍ、２Ｈ）７．１８−７．２５（ｍ、１Ｈ）７．２９（ｍ、３Ｈ）７．４８（ｍ、３Ｈ）１２．２２（ｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９８７．４、（ＥＳＩ−）ｍ／ｚ９８５．２（Ｍ−Ｈ）⁻。

Example 4.59
Methyl {(2S) -1-[(2S, 4R) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {2-[(2S, 4R) -4-fluoro-1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} -4-fluoropyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76 (m, 16H) 0.89 (m, 3H) 1.45 (m, 5H) 1.70 (m, 2H) 1.85 (m, 1H) ) 2.76 (d, 2H) 3.17 (d, J = 5.10Hz, 2H) 3.53 (s, 6H) 3.87-4.13 (m, 4H) 4.31 (m, 1H) ) 5.17 (d, 2H) 5.36 (m, 3H) 5.57 (s, 1H) 5.89 (d, 2H) 7.09 (m, 2H) 7.18-7.25 (m) , 1H) 7.29 (m, 3H) 7.48 (m, 3H) 12.22 (s, 2H); MS (ESI +) m / z987.4, (ESI-) m / z985.2 (M-) H) ^- .

実施例４．６０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（ピリミジン−２−イル）ピペラジン−１−イル］フェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６７−０．９３（ｍ、１２Ｈ）１．９９（ｍ、１６Ｈ）２．１８（ｍ、４Ｈ）２．８７（ｍ、４Ｈ）３．５３（ｓ、６Ｈ）３．５６（ｍ、２Ｈ）３．７４（ｍ、１０Ｈ）５．１１（ｍ、２Ｈ）５．５３（ｍ、２Ｈ）５．９０（ｍ、２Ｈ）６．６０（ｔ、Ｊ＝４．７２Ｈｚ、１Ｈ）７．０４（ｍ、２Ｈ）７．３２（ｍ、４Ｈ）８．３３（ｄ、Ｊ＝４．７７Ｈｚ、２Ｈ）１２．１４（ｓ、１Ｈ）１２．２２（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６６．４、（ＥＳＩ−）ｍ／ｚ１０６４．１（Ｍ−Ｈ）⁻。

Example 4.60
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (pyrimidine-2-yl) piperazine-1- Il] phenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H -Benzimidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.67-0.93 (m, 12H) 1.99 (m, 16H) 2.18 (m, 4H) 2.87 (m, 4H) 3.53 (S, 6H) 3.56 (m, 2H) 3.74 (m, 10H) 5.11 (m, 2H) 5.53 (m, 2H) 5.90 (m, 2H) 6.60 (t) , J = 4.72Hz, 1H) 7.04 (m, 2H) 7.32 (m, 4H) 8.33 (d, J = 4.77Hz, 2H) 12.14 (s, 1H) 12.22 (S, 1H); MS (ESI +) m / z 1066.4, (ESI-) m / z 1064.1 (MH) ⁻ .

実施例４．６１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（５−メチル−２−チエニル）ピペリジン−１−イル］フェニル｝−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−Ｄ_６）δｐｐｍ０．７１−０．９８（ｍ、１２Ｈ）、１．４９−２．３１（ｍ、１８Ｈ）、２．４２（ｓ、３Ｈ）、２．８７−３．１１（ｍ、Ｊ＝１４．１Ｈｚ、５Ｈ）、３．５９（ｓ、６Ｈ）、３．７７−３．９４（ｍ、Ｊ＝９．１Ｈｚ、４Ｈ）、４．０５−４．１７（ｍ、２Ｈ）、５．０８−５．２６（ｍ、２Ｈ）、５．５３−５．７４（ｍ、２Ｈ）、５．８９−６．０５（ｍ、２Ｈ）、６．６４（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、６．６８（ｄ、Ｊ＝３．５Ｈｚ、１Ｈ）、７．０４−７．１４（ｍ、１Ｈ）、７．１６−７．２５（ｍ、１Ｈ）、７．３１−７．５３（ｍ、４Ｈ）、１２．０９−１２．２３（ｍ、１Ｈ）、１２．２６−１２．４１（ｍ、１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０８３．３（Ｍ＋Ｈ）。

Example 4.61
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (5-methyl-2-thienyl) piperidine- 1-yl] phenyl} -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-D ₆ ) δppm 0.71-0.98 (m, 12H), 1.49-2.31 (m, 18H), 2.42 (s, 3H), 2.87- 3.11 (m, J = 14.1Hz, 5H), 3.59 (s, 6H), 3.77-3.94 (m, J = 9.1Hz, 4H), 4.05-4.17 (M, 2H), 5.08-5.26 (m, 2H), 5.53-5.74 (m, 2H), 5.89-6.05 (m, 2H), 6.64 (d) , J = 2.4Hz, 1H), 6.68 (d, J = 3.5Hz, 1H), 7.04-7.14 (m, 1H), 7.16-7.25 (m, 1H) , 7.31-7.53 (m, 4H), 12.09-12.23 (m, 1H), 12.26-12.41 (m, 1H); MS (ESI) m / z 1083.3 ( M + H).

実施例４．６２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フルオロ−４−フェニルピペリジン−１−イル）フェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ）δ０．８４−０．６９（ｍ、１２Ｈ）、０．９０−０．８４（ｍ、２Ｈ）、１．９３−１．７６（ｍ、７Ｈ）、２．００（ｄｄ、Ｊ＝６．８、１４．５、８Ｈ）、２．２３−２．１２（ｍ、５Ｈ）、３．５２（ｓ、６Ｈ）、３．８７−３．７３（ｍ、４Ｈ）、４．０８−３．９７（ｍ、２Ｈ）、５．１６−５．０６（ｍ、２Ｈ）、５．６５−５．４８（ｍ、２Ｈ）、５．９９−５．８６（ｍ、２Ｈ）、７．０６（ｄ、Ｊ＝６．７、１Ｈ）、７．１５（ｄ、Ｊ＝６．９、１Ｈ）、７．３１（ｄ、Ｊ＝７．０、３Ｈ）、７．３６（ｄ、Ｊ＝７．７、２Ｈ）、７．４１（ｔ、Ｊ＝７．６、４Ｈ）、１２．１９（ｄ、Ｊ＝４４．３、２Ｈ）。ＭＳ（ＥＳＩ）ｍ／ｚ１０８１（Ｍ＋Ｈ）^＋。

Example 4.62
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-fluoro-4-phenylpiperidine-1-yl)) Phenyl] -5-{6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benz Imidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO) δ0.84-0.69 (m, 12H), 0.90-0.84 (m, 2H), 1.93-1.76 (m, 7H), 2.00 (Dd, J = 6.8, 14.5, 8H) 2.23-2.12 (m, 5H), 3.52 (s, 6H), 3.87-3.73 (m, 4H) 4.08-3.97 (m, 2H), 5.16-5.06 (m, 2H), 5.65-5.48 (m, 2H), 5.99-5.86 (m, 2H), 7.06 (d, J = 6.7, 1H), 7.15 (d, J = 6.9, 1H), 7.31 (d, J = 7.0, 3H), 7. 36 (d, J = 7.7, 2H), 7.41 (t, J = 7.6, 4H), 12.19 (d, J = 44.3, 2H). MS (ESI) m / z 1081 (M + H) ⁺ .

実施例５．１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
氷浴で冷却した２５０ｍリットル丸底フラスコにおいて、ＤＭＦ（２５ｍＬ）中で（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（２．５７ｍｍｏｌ）、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（０．９４５ｇ、５．４０ｍｍｏｌ）および１Ｈ−ベンゾ［ｄ］［１，２，３］トリアゾール−１−オール水和物（０．９８４ｇ、６．４３ｍｍｏｌ）を加えて、橙赤色溶液を得た。４−メチルモルホリン（２．８３ｍＬ、２５．７ｍｍｏｌ）およびＮ^１−（（エチルイミノ）メチレン）−Ｎ^３，Ｎ^３−ジメチルプロパン−１，３−ジアミン塩酸塩（１．２３２ｇ、６．４３ｍｍｏｌ）を加え、混合物を環境温度で２時間撹拌し、ＥｔＯＡｃで希釈した。ＥｔＯＡｃ層を飽和ＮａＨＣＯ_３水溶液、Ｈ_２Ｏおよび飽和ＮａＣｌで洗浄した。有機層を３−メルカプトプロピルシリカで１時間処理し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮して黄色泡状物（２．７４ｇ）を得た。２％から５％メタノール／ジクロロメタンで溶離を行う１２０ｇシリカカートリッジでのフラッシュクロマトグラフィーによる精製によって、標題化合物１．７ｇ（６１％）を黄色粉末として得た。標題化合物をさらに、アセトニトリルからの再結晶によって精製することができる。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７３−０．９１（ｍ、１２Ｈ）１．６０−１．７４（ｍ、６Ｈ）１．８６−２．０４（ｍ、６Ｈ）２．１７−２．３０（ｍ、４Ｈ）２．５２−２．５３（ｍ、４Ｈ）２．８４−３．０２（ｍ、４Ｈ）３．５２−３．５６（ｍ、６Ｈ）３．７８−３．８７（ｍ、３Ｈ）４．００−４．１２（ｍ、２Ｈ）５．１０−５．１８（ｍ、２Ｈ）５．３２−５．４２（ｍ、２Ｈ）５．８８−５．９５（ｍ、２Ｈ）７．０５−７．３３（ｍ、１１Ｈ）７．４１（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．５０（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）１１．９７−１２．３０（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０２７（Ｍ＋Ｈ）^＋。

Example 5.1
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpyrrolidine-1-yl) phenyl] -5] -5 − {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} Carbamate In a 250 ml round bottom flask cooled in an ice bath, DMF (25 mL) Among them, (S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole) (2.57 mmol), (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (0.945 g, 5.40 mmol) and 1H-benzo [d] [1,2,3] triazole-1-ol hydrate (0.984 g, 6.43 mmol) were added to obtain an orange-red solution. 4-Methylmorpholine (2.83 mL, 25.7 mmol) and N ¹ -((ethylimino) methylene) -N ³ , N ³ -dimethylpropan-1,3-diamine hydrochloride (1.232 g, 6.43 mmol) In addition, the mixture was stirred at ambient temperature for 2 hours and diluted with EtOAc. The EtOAc layer was washed with saturated aqueous NaHCO _3, washed with _{H 2} O and saturated NaCl. The organic layer was treated with 3-mercaptopropyl silica for 1 hour, dehydrated (Na ₂ SO ₄ ), filtered and concentrated to give a yellow foam (2.74 g). Purification by flash chromatography on a 120 g silica cartridge eluting with 2% to 5% methanol / dichloromethane gave 1.7 g (61%) of the title compound as a yellow powder. The title compound can be further purified by recrystallization from acetonitrile. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.73-0.91 (m, 12H) 1.60-1.74 (m, 6H) 1.86-2.04 (m, 6H) 2.17 -2.30 (m, 4H) 2.52-2.53 (m, 4H) 2.84-3.02 (m, 4H) 3.52-3.56 (m, 6H) 3.78-3 .87 (m, 3H) 4.00-4.12 (m, 2H) 5.10-5.18 (m, 2H) 5.32-5.42 (m, 2H) 5.88-5.95 (M, 2H) 7.05-7.33 (m, 11H) 7.41 (d, J = 8.24Hz, 1H) 7.50 (d, J = 8.35Hz, 1H) 11.97-12 .30 (m, 2H); MS (ESI +) m / z 1027 (M + H) ⁺ .

実施例５．２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４，４−ジフェニルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
１００ｍＬ丸底容器において、ＤＭＦ（２５ｍＬ）中で（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（４−（４，４−ジフェニルピペリジン−１−イル）−３，５−ジフルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（０．３８５ｇ、０．４８８ｍｍｏｌ）、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（０．１８０ｇ、１．０２５ｍｍｏｌ）および１Ｈ−ベンゾ［ｄ］［１，２，３］トリアゾール−１−オール水和物（０．１８７ｇ、１．２２０ｍｍｏｌ）を加えて橙赤色溶液を得た。４−メチルモルホリン（０．５３７ｍＬ、４．８８ｍｍｏｌ）およびＮ^１−（（エチルイミノ）メチレン）−Ｎ^３，Ｎ^３−ジメチルプロパン−１，３−ジアミン塩酸塩（０．２３４ｇ、１．２２０ｍｍｏｌ）を加え、混合物を環境温度で２時間撹拌し、ＥｔＯＡｃで希釈した。有機溶液を飽和ＮａＨＣＯ_３、Ｈ_２Ｏおよび飽和ＮａＣｌの順で洗浄した。有機層を３−メルカプトプロピルシリカで１時間処理し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮して黄色泡状物を得た。２％から７％メタノール／ＣＨ_２Ｃｌ_２で溶離を行う２４ｇシリカカートリッジでのフラッシュクロマトグラフィーによる精製によって、ＨＰＬＣによる純度９０％の取得物を得た。選択された分画について２％から５％メタノール／ＣＨ_２Ｃｌ_２で溶離を行う１２ｇシリカカートリッジでの２回目のクロマトグラフィーを行って、標題化合物をクリーム色固体として得た（１００ｍｇ、１７％）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９１（ｍ、１２Ｈ）１．６８（ｄ、Ｊ＝４．０１Ｈｚ、２Ｈ）１．８５−２．０７（ｍ、６Ｈ）２．１９（ｓ、４Ｈ）２．３８（ｓ、４Ｈ）２．８６（ｓ、４Ｈ）３．５４（ｓ、６Ｈ）３．８２（ｓ、４Ｈ）４．０６（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）５．１０−５．１７（ｍ、２Ｈ）５．３４（ｄ、Ｊ＝７．１６Ｈｚ、２Ｈ）５．８５（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）６．８４−７．５４（ｍ、２０Ｈ）１２．０６（ｄ、Ｊ＝１８．９８Ｈｚ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１０３（Ｍ＋Ｈ）^＋。

Example 5.2
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4,4-diphenylpiperidin-1-yl) -3,5-difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate 100 mL in a round bottom container in DMF (25 mL) (S) ) -6,6'-((2R, 5R) -1- (4- (4,4-diphenylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2) -((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole) (0.385 g, 0.488 mmol), (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (0. 180 g, 1.025 mmol) and 1H-benzbenz [d] [1,2,3] triazole-1-ol hydrate (0.187 g, 1.220 mmol) were added to obtain an orange-red solution. 4-Methylmorpholine (0.537 mL, 4.88 mmol) and N ¹ -((ethylimino) methylene) -N ³ , N ³ -dimethylpropane-1,3-diamine hydrochloride (0.234 g, 1.220 mmol) In addition, the mixture was stirred at ambient temperature for 2 hours and diluted with EtOAc. The organic solution was washed sequentially with saturated NaHCO _{3, H 2} O and saturated NaCl. The organic layer was treated with 3-mercaptopropyl silica for 1 hour, dehydrated (Na ₂ SO ₄ ), filtered and concentrated to give a yellow foam. Purification by flash chromatography on a 24 g silica cartridge eluting with 2% to 7% methanol / CH ₂ Cl ₂ gave a 90% pure product by HPLC. The selected fractions were subjected to a second chromatography on a 12 g silica cartridge eluting with 2% to 5% methanol / CH ₂ Cl ₂ to give the title compound as a cream solid (100 mg, 17%). .. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.91 (m, 12H) 1.68 (d, J = 4.01 Hz, 2H) 1.85-2.07 (m, 6H) 2 .19 (s, 4H) 2.38 (s, 4H) 2.86 (s, 4H) 3.54 (s, 6H) 3.82 (s, 4H) 4.06 (t, J = 8.35Hz , 2H) 5.10-5.17 (m, 2H) 5.34 (d, J = 7.16Hz, 2H) 5.85 (d, J = 12.79Hz, 2H) 6.84-7.54 (M, 20H) 12.06 (d, J = 18.98Hz, 2H); MS (ESI +) m / z 1103 (M + H) ⁺ .

実施例５．３
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−（２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）塩酸塩（０．１２ｇ）をジメチルスルホキシド（２ｍＬ）に溶かし、環境温度でジイソプロピルエチルアミン（０．１９５ｍＬ、１．１２ｍｍｏｌ）と次に（２Ｓ，３Ｒ）−３−メトキシ−２−（メトキシカルボニルアミノ）ブタン酸（０．０５９ｇ、０．３０７ｍｍｏｌ）およびＨＡＴＵ（０．１１２ｇ、０．２９３ｍｍｏｌ）で処理した。１時間後、溶液を水で希釈し、ジクロロメタンで抽出し、濃縮し、０％から８％メタノール／ジクロロメタンで溶離を行うクロマトグラフィーによって精製して、黄色固体０．０７１ｇ（４８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ１．０３（ｄｄ、Ｊ＝１８．２２、６．１８Ｈｚ、６Ｈ）１．６３−１．７２（ｍ、６Ｈ）１．９９−２．０８（ｍ、６Ｈ）２．１５−２．２６（ｍ、６Ｈ）２．８７−３．００（ｍ、２Ｈ）３．１０（ｓ、３Ｈ）３．１５（ｓ、３Ｈ）３．１７−３．２０（ｍ、１Ｈ）３．４３−３．５２（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．７９−３．８９（ｍ、４Ｈ）４．２５−４．３０（ｍ、２Ｈ）５．１１−５．１８（ｍ、２Ｈ）５．３５−５．４２（ｍ、２Ｈ）５．８７−５．９５（ｍ、２Ｈ）７．０９（ｔ、Ｊ＝８．１９Ｈｚ、２Ｈ）７．１２−７．３２（ｍ、９Ｈ）７．４１（ｄ、Ｊ＝８．３５Ｈｚ、１Ｈ）７．４９（ｄ、Ｊ＝８．７８Ｈｚ、１Ｈ）１２．０３（ｓ、１Ｈ）１２．１０（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０５９．４（Ｍ＋Ｈ）^＋。

Example 5.3
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpyrrolidine-1-yl) phenyl]] -5-(2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazol-5-yl) pyrrolidine-2-yl ] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate (S) -6,6'-((2R, 5R) -1-( 3,5-Difluoro-4- (4-phenylpiperidin-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] Imidazole) hydrochloride (0.12 g) is dissolved in dimethyl sulfoxide (2 mL), diisopropylethylamine (0.195 mL, 1.12 mmol) at ambient temperature and then (2S, 3R) -3-methoxy-2- (methoxycarbonyl). It was treated with amino) butanoic acid (0.059 g, 0.307 mmol) and HATU (0.112 g, 0.293 mmol). After 1 hour, the solution was diluted with water, extracted with dichloromethane, concentrated and purified by chromatography eluting with 0% to 8% methanol / dichloromethane to give 0.071 g (48%) of a yellow solid. .. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 1.03 (dd, J = 18.22, 6.18 Hz, 6H) 1.63-1.72 (m, 6H) 1.99-2.08 (m) , 6H) 2.15-2.26 (m, 6H) 2.87-3.00 (m, 2H) 3.10 (s, 3H) 3.15 (s, 3H) 3.17-3.20 (M, 1H) 3.43-3.52 (m, 2H) 3.54 (s, 6H) 3.79-3.89 (m, 4H) 4.25-4.30 (m, 2H) 5 .11-5.18 (m, 2H) 5.35-5.42 (m, 2H) 5.87-5.95 (m, 2H) 7.09 (t, J = 8.19Hz, 2H) 7 .12-7.32 (m, 9H) 7.41 (d, J = 8.35Hz, 1H) 7.49 (d, J = 8.78Hz, 1H) 12.03 (s, 1H) 12.10 (S, 1H); MS (ESI +) m / z 1059.4 (M + H) ⁺ .

実施例５．４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３，３−ジメチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３，３−ジメチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）塩酸塩（０．１２ｇ）をジメチルスルホキシド（２ｍＬ）に溶かし、環境温度でジイソプロピルエチルアミン（０．１９５ｍＬ、１．１２ｍｍｏｌ）と次に（Ｓ）−２−（メトキシカルボニルアミノ）−３，３−ジメチルブタン酸（０．０５８ｇ、０．３０７ｍｍｏｌ）およびＨＡＴＵ（０．１１２ｇ、０．２９３ｍｍｏｌ）で処理した。１時間後、溶液を水で希釈し、ジクロロメタンで抽出した。有機相を濃縮し、０％から６％メタノール／ジクロロメタンで溶離を行うクロマトグラフィーによって精製して、標題化合物（０．０６５ｇ、４４％）を黄色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８９（ｄ、Ｊ＝１３．８８Ｈｚ、１８Ｈ）１．６１−１．７３（ｍ、８Ｈ）１．９５−２．０８（ｍ、４Ｈ）２．１５−２．２４（ｍ、６Ｈ）２．８６−３．０２（ｍ、４Ｈ）３．５５（ｓ、６Ｈ）３．７８−３．８５（ｍ、４Ｈ）４．２３（ｄｄ、Ｊ＝８．８９、４．６６Ｈｚ、２Ｈ）５．１３−５．２２（ｍ、２Ｈ）５．３３−５．４３（ｍ、２Ｈ）５．９２（ｄｄ、Ｊ＝１２．８５、２．９８Ｈｚ、２Ｈ）７．０５−７．１８（ｍ、４Ｈ）７．２０−７．２９（ｍ、５Ｈ）７．３３（ｓ、１Ｈ）７．４２（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）７．４９（ｄ、Ｊ＝８．４６Ｈｚ、１Ｈ）１２．０５（ｄ、Ｊ＝１．６３Ｈｚ、１Ｈ）１２．０９（ｄ、Ｊ＝１．３０Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０５５．４（Ｍ＋Ｈ）^＋。

Example 5.4
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5] -5 -{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3,3-dimethylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3,3-dimethyl-1-oxobutan-2-yl} carbamate (S) -6,6'-((2R) , 5R) -1- (3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-Benzimeter [d] imidazole) hydrochloride (0.12 g) was dissolved in dimethylsulfoxide (2 mL), diisopropylethylamine (0.195 mL, 1.12 mmol) and then (S) -2- (methoxy) at ambient temperature. It was treated with carbonylamino) -3,3-dimethylbutanoic acid (0.058 g, 0.307 mmol) and HATU (0.112 g, 0.293 mmol). After 1 hour, the solution was diluted with water and extracted with dichloromethane. The organic phase was concentrated and purified by chromatography eluting with 0% to 6% methanol / dichloromethane to give the title compound (0.065 g, 44%) as a yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.89 (d, J = 13.88 Hz, 18H) 1.61-1.73 (m, 8H) 1.95-2.08 (m, 4H) 2 .15-2.24 (m, 6H) 2.86-3.02 (m, 4H) 3.55 (s, 6H) 3.78-3.85 (m, 4H) 4.23 (dd, J) = 8.89, 4.66Hz, 2H) 5.13-5.22 (m, 2H) 5.33-5.43 (m, 2H) 5.92 (dd, J = 12.85, 2.98Hz , 2H) 7.05-7.18 (m, 4H) 7.20-7.29 (m, 5H) 7.33 (s, 1H) 7.42 (d, J = 8.13Hz, 1H) 7 .49 (d, J = 8.46Hz, 1H) 12.05 (d, J = 1.63Hz, 1H) 12.09 (d, J = 1.30Hz, 1H); MS (ESI +) m / z 1055. 4 (M + H) ⁺ .

実施例５．５
メチル｛（２Ｓ）−１−［（２Ｓ，４Ｒ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ，４Ｒ）−４−メトキシ−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝−４−メトキシピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ，Ｒ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（２Ｓ，４Ｒ）−４−メトキシピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（０．２０ｇ、０．２８７ｍｍｏｌ）をジメチルスルホキシド（３ｍＬ）に溶かし、環境温度でジイソプロピルエチルアミン（０．４００ｍＬ、２．２９ｍｍｏｌ）と次に（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（０．１１１ｇ、０．６３１ｍｍｏｌ）およびＨＡＴＵ（０．２２９ｇ、０．６０３ｍｍｏｌ）で処理した。２時間後、溶液を水で希釈し、ジクロロメタンで抽出した。有機層を濃縮し、０％から６％メタノール／ジクロロメタンで溶離を行うクロマトグラフィーによって精製して、標題化合物（０．１６３ｇ、５６％）を黄色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７１−０．８４（ｍ、１２Ｈ）１．３５−１．４９（ｍ、８Ｈ）１．６９（ｄ、Ｊ＝５．４２Ｈｚ、２Ｈ）１．８３−１．９４（ｍ、２Ｈ）２．２２−２．３２（ｍ、４Ｈ）２．７６（ｓ、４Ｈ）３．２９（ｓ、６Ｈ）３．５４（ｓ、６Ｈ）３．８７（ｄｄ、Ｊ＝１１．１１、３．８５Ｈｚ、２Ｈ）４．０３（ｑ、Ｊ＝７．０５Ｈｚ、４Ｈ）４．２１（ｓ、２Ｈ）５．０２−５．１５（ｍ、２Ｈ）５．３６（ｄ、Ｊ＝３．２５Ｈｚ、２Ｈ）５．８４−５．９４（ｍ、２Ｈ）７．０４−７．１１（ｍ、２Ｈ）７．１９（ｓ、１Ｈ）７．２７−７．３４（ｍ、３Ｈ）７．４１（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）７．４８（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）１２．１３（ｓ、１Ｈ）１２．１９（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０１１．６（Ｍ＋Ｈ）^＋。

Example 5.5
Methyl {(2S) -1-[(2S, 4R) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] -5- {2-[(2S, 4R) -4-methoxy-1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} piperidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} -4-methoxypyrrolidin-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate (S, R) -6 , 6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((2S, 4R)-) 4-Methoxypyrrolidin-2-yl) -1H-benzo [d] imidazole) (0.20 g, 0.287 mmol) is dissolved in dimethylsulfoxide (3 mL) and diisopropylethylamine (0.400 mL, 2.29 mmol) at ambient temperature. And then treated with (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (0.111 g, 0.631 mmol) and HATU (0.229 g, 0.603 mmol). After 2 hours, the solution was diluted with water and extracted with dichloromethane. The organic layer was concentrated and purified by chromatography eluting with 0% to 6% methanol / dichloromethane to give the title compound (0.163 g, 56%) as a yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.71-0.84 (m, 12H) 1.35-1.49 (m, 8H) 1.69 (d, J = 5.42 Hz, 2H) 1 .83-1.94 (m, 2H) 2.22-2.32 (m, 4H) 2.76 (s, 4H) 3.29 (s, 6H) 3.54 (s, 6H) 3.87 (Dd, J = 11.11, 3.85Hz, 2H) 4.03 (q, J = 7.05Hz, 4H) 4.21 (s, 2H) 5.02-5.15 (m, 2H) 5 .36 (d, J = 3.25Hz, 2H) 5.84-5.94 (m, 2H) 7.04-7.11 (m, 2H) 7.19 (s, 1H) 7.27-7 .34 (m, 3H) 7.41 (d, J = 8.24Hz, 1H) 7.48 (d, J = 8.24Hz, 1H) 12.13 (s, 1H) 12.19 (s, 1H) ); MS (ESI +) m / z 1011.6 (M + H) ⁺ .

実施例５．６
ジメチル（｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛１Ｈ−ベンズイミダゾール−５，２−ジイル（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−１−シクロヘキシル−２−オキソエタン−２，１−ジイル］｝）ビスカーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（０．１９２ｇ、０．３０２ｍｍｏｌ）をジメチルスルホキシド（４ｍＬ）に溶かし、環境温度でジイソプロピルエチルアミン（０．４２１ｍＬ、２．４１ｍｍｏｌ）と次に（Ｓ）−２−シクロヘキシル−２−（メトキシカルボニルアミノ）酢酸（０．１４３ｇ、０．６６３ｍｍｏｌ）およびＨＡＴＵ（０．２４１ｇ、０．６３３ｍｍｏｌ）で処理した。１時間後、溶液を水で希釈し、ジクロロメタンで抽出した。有機相を濃縮し、残留物を０％から８％メタノール／ジクロロメタンで溶離を行うクロマトグラフィーによって精製して、標題化合物（０．１６６ｇ、５３％）を黄色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０−１．１２（ｍ、８Ｈ）１．３６−１．７０（ｍ、２４Ｈ）１．９８（ｄ、Ｊ＝４．４５Ｈｚ、４Ｈ）２．１５−２．２５（ｍ、４Ｈ）２．７５（ｓ、４Ｈ）３．５２（ｓ、６Ｈ）３．８１（ｄ、Ｊ＝２．３９Ｈｚ、４Ｈ）４．０８（ｑ、Ｊ＝８．５７Ｈｚ、２Ｈ）５．１４（ｄ、Ｊ＝４．２３Ｈｚ、２Ｈ）５．３６（ｄ、Ｊ＝３．５８Ｈｚ、２Ｈ）５．８２−５．９３（ｍ、２Ｈ）７．１０（ｄｄ、Ｊ＝１３．９３、８．３０Ｈｚ、２Ｈ）７．１５−７．２８（ｍ、４Ｈ）７．４２（ｄ、Ｊ＝７．３７Ｈｚ、１Ｈ）７．４８（ｄｄ、Ｊ＝８．３５、１．８４Ｈｚ、１Ｈ）１２．００（ｓ、１Ｈ）１２．１６（ｓ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０３１．４（Ｍ＋Ｈ）^＋。

Example 5.6
Dimethyl ({(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {1H-benzimidazole-5,2-diyl ( 2S) Pyrrolidine-2,1-diyl [(1S) -1-cyclohexyl-2-oxoethane-2,1-diyl]}) benzimidazole (S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (piperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) (0.192 g, 0.302 mmol) was dissolved in dimethylsulfoxide (4 mL), diisopropylethylamine (0.421 mL, 2.41 mmol) and then (S) -2-cyclohexyl-2- (methoxycarbonylamino) at ambient temperature. It was treated with acetic acid (0.143 g, 0.663 mmol) and HATU (0.241 g, 0.633 mmol). After 1 hour, the solution was diluted with water and extracted with dichloromethane. The organic phase was concentrated and the residue was purified by chromatography eluting with 0% to 8% methanol / dichloromethane to give the title compound (0.166 g, 53%) as a yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80-1.12 (m, 8H) 1.36-1.70 (m, 24H) 1.98 (d, J = 4.45 Hz, 4H) 2 .15-2.25 (m, 4H) 2.75 (s, 4H) 3.52 (s, 6H) 3.81 (d, J = 2.39Hz, 4H) 4.08 (q, J = 8) .57Hz, 2H) 5.14 (d, J = 4.23Hz, 2H) 5.36 (d, J = 3.58Hz, 2H) 5.82-5.93 (m, 2H) 7.10 (dd) , J = 13.93, 8.30Hz, 2H) 7.15-7.28 (m, 4H) 7.42 (d, J = 7.37Hz, 1H) 7.48 (dd, J = 8.35) 1.84Hz, 1H) 12.00 (s, 1H) 12.16 (s, 1H); MS (ESI +) m / z 1031.4 (M + H) ⁺ .

実施例５．７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−［４−（３，５−ジメチルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
ジイソプロピルエチルアミン（３ｍＬ、１７．１８ｍｍｏｌ）を、（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（４−（３，５−ジメチルピペリジン−１−イル）−３，５−ジフルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）（１．０４５ｇ、１．５７２ｍｍｏｌ）、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（０．６８５２ｇ、３．９１ｍｍｏｌ）およびＨＡＴＵ（１．４９９５ｇ、３．９４ｍｍｏｌ）のジクロロメタン（２０ｍＬ）中懸濁液に加えた。反応混合物を環境温度で３０分間撹拌した。反応液をジクロロメタンで希釈し、水（２回）、ブライン（１回）で洗浄し、濃縮した。残留物をフラッシュクロマトグラフィー（２％から５％メタノール／ジクロロメタン）によって精製して標題化合物を得た（０．７１０７ｇ、４６％）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．５０（ｑ、Ｊ＝１１．９、１Ｈ）、０．９７−０．６４（ｍ、１８Ｈ）、１．３２−１．２０（ｍ、２Ｈ）、１．８１−１．４６（ｍ、５Ｈ）、２．０９−１．８０（ｍ、６Ｈ）、２．３２−２．１３（ｍ、５Ｈ）、２．７５（ｄｄ、Ｊ＝１０．０、４０．２、２Ｈ）、３．１８−３．０５（ｍ、１Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．１４−３．９５（ｍ、２Ｈ）、５．１４（ｓ、２Ｈ）、５．３６（ｄ、Ｊ＝７．２、２Ｈ）、５．８８（ｄ、Ｊ＝１２．８、２Ｈ）、７．１４−７．０２（ｍ、２Ｈ）、７．１９（ｓ、１Ｈ）、７．３３−７．２３（ｍ、３Ｈ）、７．４１（ｄ、Ｊ＝８．２、１Ｈ）、７．４９（ｄ、Ｊ＝８．２、１Ｈ）、１２．３７−１１．９８（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９７９（Ｍ＋Ｈ）^＋。

Example 5.7
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- [4- (3,5-dimethylpiperidine-1-yl) -3,5-difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate diisopropylethylamine (3 mL, 17.18 mmol), (S) -6,6'-((2R, 5R) -1- (4- (3,5-dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2- ((S) -Pyrrolidine-2-yl) -1H-benzo [d] imidazole) (1.045 g, 1.572 mmol), (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (0.6852 g) 3.91 mmol) and HATU (1.4995 g, 3.94 mmol) were added to a suspension in dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was diluted with dichloromethane, washed with water (twice) and brine (once), and concentrated. The residue was purified by flash chromatography (2% to 5% methanol / dichloromethane) to give the title compound (0.7107g, 46%). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.50 (q, J = 11.9, 1H), 0.97-0.64 (m, 18H), 1.32-1.20 (m, 2H) ), 1.81-1.46 (m, 5H), 2.09-1.80 (m, 6H), 2.32-2.13 (m, 5H), 2.75 (dd, J = 10) .0, 40.2, 2H), 3.18-3.05 (m, 1H), 3.54 (s, 6H), 3.82 (s, 4H), 4.14-3.95 (m) , 2H), 5.14 (s, 2H), 5.36 (d, J = 7.2, 2H), 5.88 (d, J = 12.8, 2H), 7.14-7.02 (M, 2H), 7.19 (s, 1H), 7.33-7.23 (m, 3H), 7.41 (d, J = 8.2, 1H), 7.49 (d, J) = 8.2, 1H), 12.37-11.98 (m, 2H); MS (ESI +) m / z 979 (M + H) ⁺ .

実施例５．８
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−｛３，５−ジフルオロ−４−［４−（トリフルオロメチル）ピペリジン−１−イル］フェニル｝−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−（トリフルオロメチル）ピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）テトラヒドロクロライド（２５０ｍｇ、０．２９４ｍｍｏｌ）および（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１１３ｍｇ、０．６４７ｍｍｏｌ）を、窒素下に脱水ＤＭＦ（３ｍＬ）中で合わせた。ＨＯＢＴ水和物（１１３ｍｇ、０．７３５ｍｍｏｌ）およびＥＤＡＣ（１４４ｍｇ、０．７３５ｍｍｏｌ）を加えた。琥珀色溶液を冷却して０℃とした。４−メチルモルホリン（０．３２３ｍＬ、２．９４ｍｍｏｌ）を加え、冷却浴を外し、反応混合物を２０℃で撹拌した。２時間後、反応液をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２５ｍＬで３回）およびブライン（２５ｍＬ）で洗浄した。有機相を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して黄褐色固体（３００ｍｇ）を得た。粗取得物の少量サンプル（５０ｍｇ）をアセトニトリル２ｍＬおよび０．１％ＴＦＡ／Ｈ_２Ｏ ２ｍＬに溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分間の勾配と、次に１０分間で１００％アセトニトリルとする（１０ｍＬずつの分画）溶離を行うＲＰ−Ｃ１８ＨＰＬＣ（Ｎｏｖａ−Ｐａｋ ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋカートリッジを搭載したＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液（２ｍＬ／管）で処理し、各管を渦撹拌して、ＴＦＡを十分に中和し、中和した溶液を２５０ｍリットル丸底フラスコ中で合わせた。アセトニトリルをロータリーエバポレータによって除去し、残った水相をＥｔＯＡｃで抽出した（５０ｍＬで２回）。合わせた有機抽出液を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、標題化合物を白色固体として得た（１８ｍｇ）。５０ｍｇずつの注入量を２回で、分取ＨＰＬＣによって追加の１００ｍｇの精製を繰り返した。上記のような後処理を行って、追加の標題化合物を白色固体として得た（３４ｍｇ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７３−０．９０（ｍ、１２Ｈ）、１．２３（ｓ、１Ｈ）、１．３４−１．４９（ｍ、２Ｈ）、１．６３−１．７６（ｍ、４Ｈ）、１．８３−２．０４（ｍ、６Ｈ）、２．１１−２．２５（ｍ、４Ｈ）、２．８４（ｍ、４Ｈ）、３．５２（ｓ、６Ｈ）、３．８１（ｂｒｓ、４Ｈ）、４．００−４．０９（ｍ、２Ｈ）、５．０８−５．１８（ｍ、２Ｈ）、５．２８−５．４２（ｍ、２Ｈ）、５．８９（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）、７．０６（ｔ、Ｊ＝７．２６Ｈｚ、２Ｈ）、７．１６−７．３２（ｍ、４Ｈ）、７．３９（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４７（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、１２．０６（２個のｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０１９（Ｍ＋Ｈ）^＋。

Example 5.8
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (trifluoromethyl) pyrrolidine-1-yl]] Phenyl} -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5- Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate (S) -6,6'-((2R) , 5R) -1- (3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidine-) 2-Il) -1H-benz [d] imidazole) tetrahydrochloride (250 mg, 0.294 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (113 mg, 0.647 mmol) under nitrogen. Was combined in dehydrated DMF (3 mL). HOBT hydrate (113 mg, 0.735 mmol) and EDAC (144 mg, 0.735 mmol) were added. The amber solution was cooled to 0 ° C. 4-Methylmorpholine (0.323 mL, 2.94 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 ° C. After 2 hours, the reaction was diluted with EtOAc (50 mL) and washed with water (25 mL 3 times) and brine (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated by a rotary evaporator to give a tan solid (300 mg). A small sample (50 mg) of the crude product was dissolved in ₂ mL of acetonitrile and 2 mL of 0.1% TFA / H ₂ O and at 20 mL / min 95: 5 from H ₂ O / acetonitrile containing 0.1% TFA 25:75 0. RP-C18HPLC (Nova-Pak HR C18 6 μm 40 × 100 mm Prep) elution with 1% TFA-containing H ₂ O / acetonitrile for 30 minutes and then 100% acetonitrile in 10 minutes (fractions of 10 mL each) Purified by Waters Prep LC (40 mm module) equipped with a Pak cartridge. The pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to fully neutralize the TFA, and the neutralized solutions were combined in a 250 ml round bottom flask. Acetonitrile was removed by rotary evaporator and the remaining aqueous phase was extracted with EtOAc (twice at 50 mL). The combined organic extracts were dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give the title compound as a white solid (18 mg). Purification of an additional 100 mg was repeated by preparative HPLC with two injections of 50 mg each. Post-treatment as described above gave an additional title compound as a white solid (34 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.73-0.90 (m, 12H), 1.23 (s, 1H), 1.34-1.49 (m, 2H), 1.63- 1.76 (m, 4H), 1.83-2.04 (m, 6H), 2.11-2.25 (m, 4H), 2.84 (m, 4H), 3.52 (s, 6H), 3.81 (brs, 4H), 4.00-4.09 (m, 2H), 5.08-5.18 (m, 2H), 5.28-5.42 (m, 2H) 5.89 (d, J = 12.79Hz, 2H), 7.06 (t, J = 7.26Hz, 2H), 7.16-7.32 (m, 4H), 7.39 (d, J = 8.24Hz, 1H), 7.47 (d, J = 8.13Hz, 1H), 12.06 (2 s, 2H); MS (ESI +) m / z 1019 (M + H) ⁺ .

実施例５．９
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）テトラヒドロクロライド（２５０ｍｇ、０．２９８ｍｍｏｌ）および（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１１５ｍｇ、０．６５６ｍｍｏｌ）を、窒素下に脱水ＤＭＦ（３ｍＬ）中で合わせた。ＨＯＢＴ水和物（１１４ｍｇ、０．７４５ｍｍｏｌ）およびＥＤＡＣ（１４６ｍｇ、０．７４５ｍｍｏｌ）を加え、琥珀色溶液を冷却して０℃とした。４−メチルモルホリン（０．３２８ｍＬ、２．９８ｍｍｏｌ）を加え、冷却浴を外し、反応混合物を２０℃で撹拌した。１８時間後、反応混合物をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２５ｍＬで３回）およびブライン（２５ｍＬ）で洗浄した。有機相を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して黄色固体を得た。３％ＣＨ_３ＯＨ／ＣＨ_２Ｃｌ_２で溶離を行うＳｉＯ_２フラッシュクロマトグラフィー（Ａｌｌｔｅｃｈ Ｅｘｔｒａｃｔ−Ｃｌｅａｎ（商標名）カラム、１０ｇ床）によって予備精製して黄色固体を得た（１１９ｍｇ）。残留物の少量サンプル（５０ｍｇ）をアセトニトリル２ｍＬおよび０．１％ＴＦＡ／Ｈ_２Ｏ２ｍＬに溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分間勾配、次に１０分間で１００％アセトニトリルとする（１０ｍＬずつの分画）溶離を行うＲＰ−Ｃ１８ ＨＰＬＣ（Ｎｏｖａ−Ｐａｋ ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋ カートリッジを搭載したＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液（２ｍＬ／管）で処理し、各管を渦撹拌してＴＦＡを十分に中和し、溶液を２５０ｍリットル丸底フラスコ中で合わせた。残った取得物６９ｍｇを、上記で記載の分取ＨＰＬＣによって精製した。純粋な生成物を含む分画を上記のように飽和ＮａＨＣＯ_３水溶液で処理し、同じ２５０ｍＬ丸底フラスコ中で合わせた。アセトニトリルをロータリーエバポレータによって除去し、残った水相をＥｔＯＡｃで抽出した（５０ｍＬで２回）。合わせた有機抽出液を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して標題化合物を白色固体として得た（５６ｍｇ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．６８−０．９３（ｍ、２２Ｈ）、１．０９−１．２５（ｍ、２Ｈ）、１．５３（ｄ、Ｊ＝１１．９３Ｈｚ、２Ｈ）、１．６３−１．７５（ｍ、２Ｈ）、１．８０−２．０８（ｍ、７Ｈ）、２．１２−２．２７（ｍ、４Ｈ）、２．７１−２．９１（ｍ、５Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｂｒｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．３５Ｈｚ、２Ｈ）、５．０９−５．１９（ｍ、２Ｈ）、５．３０−５．４４（ｍ、２Ｈ）、５．８９（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）、７．０２−７．１１（ｍ、２Ｈ）、７．１７−７．３２（ｍ、４Ｈ）、７．４０（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、１２．０７（２個のｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１００７（Ｍ＋Ｈ）^＋。

Example 5.9
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate (S) -6,6'-((2R, 5R) ) -1- (4- (4-tert-Butylpiperidin-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) tetrahydrochloride (250 mg, 0.298 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (115 mg, 0.656 mmol) dehydrated under nitrogen (DMF) 3 mL) was combined. HOBT hydrate (114 mg, 0.745 mmol) and EDAC (146 mg, 0.745 mmol) were added and the amber solution was cooled to 0 ° C. 4-Methylmorpholine (0.328 mL, 2.98 mmol) was added, the cooling bath was removed and the reaction mixture was stirred at 20 ° C. After 18 hours, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL 3 times) and brine (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated by a rotary evaporator to give a yellow solid. Pre-purification was performed by SiO ₂ flash chromatography (Alltech Extract-Clean (trade name) column, 10 g bed) eluting with 3% CH ₃ OH / CH ₂ Cl ₂ to obtain a yellow solid (119 mg). A small sample (50 mg) of residue was dissolved in ₂ mL of acetonitrile and 2 mL of 0.1% TFA / H ₂ O and 25:75 0.1% from H ₂ O / acetonitrile containing 95: 5 0.1% TFA at 20 mL / min. 30 min gradient of TFA in _H 2 O / acetonitrile, then 100% acetonitrile for 10 minutes (fractions by 10mL) RP-C18 HPLC eluting (Nova-Pak HR C18 6μm 40 × 100mm Prep Pak cartridge Purified by on-board Waters Prep LC, 40 mm module). Pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize TFA, and the solutions were combined in a 250 ml round bottom flask. The remaining 69 mg of the obtained product was purified by the preparative HPLC described above. Fractions containing the pure product were treated with saturated aqueous NaHCO ₃ solution as described above and combined in the same 250 mL round bottom flask. Acetonitrile was removed by rotary evaporator and the remaining aqueous phase was extracted with EtOAc (twice at 50 mL). The combined organic extracts were dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give the title compound as a white solid (56 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.68-0.93 (m, 22H), 1.09-1.25 (m, 2H), 1.53 (d, J = 11.93Hz, 2H) ), 1.63-1.75 (m, 2H), 1.80-2.08 (m, 7H), 2.12-2.27 (m, 4H), 2.71-2.91 (m) , 5H), 3.54 (s, 6H), 3.82 (brs, 4H), 4.06 (t, J = 8.35Hz, 2H), 5.09-5.19 (m, 2H), 5.30-5.44 (m, 2H), 5.89 (d, J = 12.69Hz, 2H), 7.02-7.11 (m, 2H), 7.17-7.32 (m) , 4H), 7.40 (d, J = 8.24Hz, 1H), 7.49 (d, J = 8.13Hz, 1H), 12.07 (2 s, 2H); MS (ESI +) m / z 1007 (M + H) ⁺ .

実施例５．１０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４，４−ジメチルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（４−（４，４−ジメチルピペリジン−１−イル）−３，５−ジフルオロフェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）ペンタ塩酸塩（２５０ｍｇ、０．２９５ｍｍｏｌ）および（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１０９ｍｇ、０．６２０ｍｍｏｌ）を、窒素下に脱水ＤＭＦ（３ｍＬ）中で合わせた。ＨＯＢＴ水和物（１０４ｍｇ、０．６７９ｍｍｏｌ）およびＥＤＡＣ（１３３ｍｇ、０．６７９ｍｍｏｌ）を加え、琥珀色溶液を冷却して０℃とした。４−メチルモルホリン（０．３２５ｍＬ、２．９５ｍｍｏｌ）を加え、冷却浴を外し、反応混合物を２０℃で撹拌した。２時間後、反応混合物をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２５ｍＬで３回）およびブライン（２５ｍＬ）で洗浄した。有機相を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して黄褐色固体を得た。３％から４％ＣＨ_３ＯＨ／ＣＨ_２Ｃｌ_２の段階的勾配で溶離を行うＳｉＯ_２フラッシュクロマトグラフィー（３．８ｃｍ×１５ｃｍ）による精製によって、標題化合物を固体として得た（１１５ｍｇ）。少量サンプル（５０ｍｇ）をアセトニトリル１．５ｍＬおよび０．１％ＴＦＡ／Ｈ_２Ｏ １．５ｍＬに溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分間勾配、次に１０分間で１００％アセトニトリルまとする（１０ｍＬずつの分画）溶離を行うＲＰ−Ｃ１８ ＨＰＬＣ（Ｎｏｖａ−Ｐａｋ ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋ カートリッジを搭載したＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液（２ｍＬ／管）で処理し、各管を渦撹拌してＴＦＡを十分に中和し、溶液を２５０ｍリットル丸底フラスコ中で合わせた。アセトニトリルを減圧下での濃縮によって除去した。残った水相をＥｔＯＡｃで抽出した（５０ｍＬで２回）。合わせた有機抽出液を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、標題化合物を白色固体として得た（３３ｍｇ）。残った低純度生成物６５ｍｇ（シリカゲルカラムから）を、上記で記載のＲＰ−Ｃ１８分取ＨＰＬＣによって精製して、追加の標題化合物を白色固体として得た（３３ｍｇ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７５−０．９１（ｍ、１２Ｈ）、０．８７（ｓ、６Ｈ）、１．２１−１．３５（ｍ、４Ｈ）、１．６３−１．７７（ｍ、２Ｈ）、１．８１−２．０９（ｍ、６Ｈ）、２．１１−２．２９（ｍ、４Ｈ）、２．４９−２．５９（ｍ、２Ｈ）、２．７６（ｓ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｂｒｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．４６Ｈｚ、２Ｈ）、５．０９−５．２２（ｍ、２Ｈ）、５．３０−５．４４（ｍ、２Ｈ）、５．８９（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）、７．０３−７．１１（ｍ、２Ｈ）、７．１７−７．３２（ｍ、４Ｈ）、７．４１（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）、１２．０７（２個のｓ、２Ｈ）；（ＥＳＩ＋）ｍ／ｚ９７９（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ９７７（Ｍ−Ｈ）⁻。

Example 5.10
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4,4-dimethylpiperridine-1-yl) -3,5-difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} Pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate (S) -6,6'-((2R, 5R) ) -1- (4- (4,4-Dimethylpiperidine-1-yl) -3,5-difluorophenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) pentahydrochloride (250 mg, 0.295 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (109 mg, 0.620 mmol) dehydrated under nitrogen DMF Combined in (3 mL). HOBT hydrate (104 mg, 0.679 mmol) and EDAC (133 mg, 0.679 mmol) were added and the amber solution was cooled to 0 ° C. 4-Methylmorpholine (0.325 mL, 2.95 mmol) was added, the cooling bath was removed and the reaction mixture was stirred at 20 ° C. After 2 hours, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL 3 times) and brine (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated by a rotary evaporator to give a tan solid. Purification by SiO ₂ flash chromatography (3.8 cm × 15 cm) eluting with a stepwise gradient of 3% to 4% CH ₃ OH / CH ₂ Cl ₂ gave the title compound as a solid (115 mg). A small sample (50 mg) was dissolved in 1.5 mL of acetonitrile and 1.5 mL of 0.1% TFA / H ₂ O and 95: 5 0.1% TFA-containing H ₂ O / acetonitrile at 20 mL / min 25:75 0. A 30-minute gradient of H ₂ O / acetonitrile containing 1% TFA, followed by elution with 100% acetonitrile in 10 minutes (fractions of 10 mL each) RP-C18 HPLC (Nova-Pak HR C18 6 μm 40 × 100 mm Prep Purified by Waters Prep LC (40 mm module) equipped with a Pak cartridge. Pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize TFA, and the solutions were combined in a 250 ml round bottom flask. Acetonitrile was removed by concentration under reduced pressure. The remaining aqueous phase was extracted with EtOAc (twice at 50 mL). The combined organic extracts were dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give the title compound as a white solid (33 mg). The remaining 65 mg of low-purity product (from the silica gel column) was purified by the RP-C18 preparative HPLC described above to give the additional title compound as a white solid (33 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.75-0.91 (m, 12H), 0.87 (s, 6H), 1.21-1.35 (m, 4H), 1.63- 1.77 (m, 2H), 1.81-2.09 (m, 6H), 2.11-2.29 (m, 4H), 2.49-2.59 (m, 2H), 2. 76 (s, 4H), 3.54 (s, 6H), 3.82 (brs, 4H), 4.06 (t, J = 8.46Hz, 2H), 5.09-5.22 (m, 2H), 5.30-5.44 (m, 2H), 5.89 (d, J = 12.79Hz, 2H), 7.03-7.11 (m, 2H), 7.17-7. 32 (m, 4H), 7.41 (d, J = 8.13Hz, 1H), 7.49 (d, J = 8.02Hz, 1H), 12.07 (2 s, 2H); ESI +) m / z 979 (M + H) ⁺ ; MS (ESI-) m / z 977 (MH) ^- .

実施例５．１１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（６−アザスピロ［２．５］オクト−６−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（６−アザスピロ［２．５］オクタン−６−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）テトラヒドロクロライド（２５０ｍｇ、０．３０９ｍｍｏｌ）および（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１１９ｍｇ、０．６８０ｍｍｏｌ）を、窒素下に脱水ＤＭＦ（３ｍＬ）中で合わせた。ＨＯＢＴ水和物（１１８ｍｇ、０．７７３ｍｍｏｌ）およびＥＤＡＣ（１５１ｍｇ、０．７７３ｍｍｏｌ）を加え、琥珀色溶液を冷却して０℃とした。４−メチルモルホリン（０．３４０ｍＬ、３．０９ｍｍｏｌ）を加え、冷却浴を外し、反応混合物を２０℃で撹拌した。１６．５時間後、反応混合物をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２５ｍＬで３回）およびブライン（２５ｍＬ）で洗浄した。有機相を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して黄色固体を得た。３％ＣＨ_３ＯＨ／ＣＨ_２Ｃｌ_２で溶離を行うＳｉＯ_２フラッシュクロマトグラフィー（Ａｌｌｔｅｃｈ Ｅｘｔｒａｃｔ−Ｃｌｅａｎ（商標名）カラム、１０ｇ床）による予備精製によって、ベージュ固体（１７２ｍｇ）を得た。少量サンプル（５０ｍｇ）をアセトニトリル１．５ｍＬおよび０．１％ＴＦＡ含有Ｈ_２Ｏ １．５ｍＬに溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分間勾配、次に１０分間で１００％アセトニトリルとする（１０ｍＬずつの分画）溶離を行うＲＰ−Ｃ１８ ＨＰＬＣ（Ｎｏｖａ−Ｐａｋ ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋ カートリッジ搭載のＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液（２ｍＬ／管）で処理し、各管を渦撹拌してＴＦＡを十分に中和し、溶液を２５０ｍリットル丸底フラスコ中で合わせた。二つの追加の５０ｍｇロットを、上記で記載の分取ＨＰＬＣによって精製し、純粋な生成物を含む分画を上記のように飽和ＮａＨＣＯ_３水溶液で処理し、同じ２５０ｍリットル丸底フラスコ中で合わせた。アセトニトリルを減圧下での濃縮によって除去し、残った水相をＥｔＯＡｃで抽出した（５０ｍＬで２回）。合わせた有機相を無水ＭｇＳＯ_４で脱水し、濾過し、濃縮しロータリーエバポレータによって標題化合物を白色固体として得た（４２ｍｇ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．２２（ｓ、４Ｈ）、０．７２−０．９３（ｍ、１２Ｈ）、１．２１−１．３６（ｍ、５Ｈ）、１．６１−１．７８（ｍ、２Ｈ）、１．８３−２．０８（ｍ、７Ｈ）、２．１３−２．２７（ｍ、４Ｈ）、２．８１（ｂｒｓ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．８２（ｂｒｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．４０Ｈｚ、２Ｈ）、５．１０−５．１９（ｍ、２Ｈ）、５．２９−５．４５（ｍ、２Ｈ）、５．９０（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）、７．０２−７．３２（ｍ、６Ｈ）、７．４１（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、１２．０７（２個のｓ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９７７（Ｍ＋Ｈ）^＋。

Example 5.11
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (6-azaspiro [2.5] octo-6-yl) -3,5- Difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate (S) -6,6'-((( 2R, 5R) -1- (3,5-difluoro-4- (6-azaspiro [2.5] octane-6-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)-)- Pyrrolidine-2-yl) -1H-benzo [d] imidazole) tetrahydrochloride (250 mg, 0.309 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (119 mg, 0.680 mmol), Combined in dehydrated DMF (3 mL) under nitrogen. HOBT hydrate (118 mg, 0.773 mmol) and EDAC (151 mg, 0.773 mmol) were added and the amber solution was cooled to 0 ° C. 4-Methylmorpholine (0.340 mL, 3.09 mmol) was added, the cooling bath was removed and the reaction mixture was stirred at 20 ° C. After 16.5 hours, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL 3 times) and brine (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated by a rotary evaporator to give a yellow solid. A beige solid (172 mg) was obtained by pre-purification by SiO ₂ flash chromatography (Alltech Extract-Clean (trade name) column, 10 g bed) eluting with 3% CH ₃ OH / CH ₂ Cl ₂ . A small sample (50 mg) was dissolved in 1.5 mL of acetonitrile and 1.5 mL of H ₂ O containing 0.1% TFA and 95: 5 from H ₂ O / acetonitrile containing 0.1% TFA at 20 mL / min 25:75 0. A 30-minute gradient of H ₂ O / acetonitrile containing 1% TFA, followed by elution to 100% acetonitrile in 10 minutes (fractions of 10 mL each) RP-C18 HPLC (Nova-Pak HR C18 6 μm 40 × 100 mm Prep Pak Purified by a cartridge-mounted Waters Prep LC (40 mm module). Pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize TFA, and the solutions were combined in a 250 ml round bottom flask. Two additional 50 mg lots were purified by preparative HPLC as described above and fractions containing the pure product were treated with saturated aqueous NaHCO ₃ solution as described above and combined in the same 250 ml round bottom flask. .. Acetonitrile was removed by concentration under reduced pressure and the remaining aqueous phase was extracted with EtOAc (twice at 50 mL). The combined organic phases were dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated to give the title compound as a white solid by rotary evaporator (42 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.22 (s, 4H), 0.72-0.93 (m, 12H), 1.21-1.36 (m, 5H), 1.61- 1.78 (m, 2H), 1.83-2.08 (m, 7H), 2.13-2.27 (m, 4H), 2.81 (brs, 4H), 3.53 (s, 6H), 3.82 (brs, 4H), 4.06 (t, J = 8.40Hz, 2H), 5.10-5.19 (m, 2H), 5.29-5.45 (m, 2H), 5.90 (d, J = 12.79Hz, 2H), 7.02-7.32 (m, 6H), 7.41 (d, J = 8.24Hz, 1H), 7.49 ( d, J = 8.24Hz, 1H), 12.07 (2 s, 2H); MS (ESI +) m / z977 (M + H) ⁺ .

実施例５．１２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（３−アザスピロ［５．５］ウンデク−３−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（３−アザスピロ［５．５］ウンデカン−３−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）テトラヒドロクロライド（２５０ｍｇ、０．２９４ｍｍｏｌ）および（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１１３ｍｇ、０．６４６ｍｍｏｌ）を、窒素下に脱水ＤＭＦ（３ｍＬ）中で合わせた。ＨＯＢＴ水和物（１１３ｍｇ、０．７３５ｍｍｏｌ）およびＥＤＡＣ（１４４ｍｇ、０．７３５ｍｍｏｌ）を加え、混合物を冷却して０℃とした。４−メチルモルホリン（０．３２３ｍＬ、２．９４ｍｍｏｌ）を加え、冷却浴を外し、反応混合物を２０℃で１８時間撹拌した。反応混合物をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２５ｍＬで３回）およびブライン（２５ｍＬ）で洗浄した。有機相を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮してベージュ泡状物を得た。粗取得物を、４％ＣＨ_３ＯＨ／ＣＨ_２Ｃｌ_２で溶離を行うＳｉＯ_２フラッシュクロマトグラフィー（３．８ｃｍ×１５ｃｍ）によって精製して、標題化合物を白色固体として得た（８２ｍｇ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７２−０．９３（ｍ、１２Ｈ）、１．２２−１．４１（ｍ、１５Ｈ）、１．６３−１．７４（ｍ、２Ｈ）、１．８０−２．０７（ｍ、７Ｈ）、２．１２−２．２７（ｍ、４Ｈ）、２．７５（ｓ、４Ｈ）、３．５４（ｓ、６Ｈ）、３．８２（ｓ、４Ｈ）、４．０６（ｔ、Ｊ＝８．４０Ｈｚ、２Ｈ）、５．１４（ｄ、Ｊ＝１．１９Ｈｚ、２Ｈ）、５．２７−５．４２（ｍ、２Ｈ）、５．８８（ｄ、Ｊ＝１２．６９Ｈｚ、２Ｈ）、７．０３−７．１１（ｍ、２Ｈ）、７．２０（ｓ、１Ｈ）、７．２９（ｄ、Ｊ＝５．９６Ｈｚ、３Ｈ）、７．４０（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．４９（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、１２．０７（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０１９（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ１０１７（Ｍ−Ｈ）⁻。

Example 5.12
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (3-azaspiro [5.5] undec-3-yl) -3,5- Difluorophenyl] -5-{2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5 -Il} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate (S) -6,6'-((( 2R, 5R) -1- (3,5-difluoro-4- (3-azaspiro [5.5] undecane-3-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S)-)- Pyrrolidine-2-yl) -1H-benzo [d] imidazole) tetrahydrochloride (250 mg, 0.294 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (113 mg, 0.646 mmol), Combined in dehydrated DMF (3 mL) under nitrogen. HOBT hydrate (113 mg, 0.735 mmol) and EDAC (144 mg, 0.735 mmol) were added and the mixture was cooled to 0 ° C. 4-Methylmorpholine (0.323 mL, 2.94 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 ° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL 3 times) and brine (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated by a rotary evaporator to give a beige foam. The crude product was purified by SiO ₂ flash chromatography (3.8 cm × 15 cm) eluting with 4% CH ₃ OH / CH ₂ Cl ₂ to give the title compound as a white solid (82 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.72-0.93 (m, 12H), 1.22-1.41 (m, 15H), 1.63-1.74 (m, 2H), 1.80-2.07 (m, 7H), 2.12-2.27 (m, 4H), 2.75 (s, 4H), 3.54 (s, 6H), 3.82 (s, 4H), 4.06 (t, J = 8.40Hz, 2H), 5.14 (d, J = 1.19Hz, 2H), 5.27-5.42 (m, 2H), 5.88 ( d, J = 12.69Hz, 2H), 7.03-7.11 (m, 2H), 7.20 (s, 1H), 7.29 (d, J = 5.96Hz, 3H), 7. 40 (d, J = 8.24Hz, 1H), 7.49 (d, J = 8.24Hz, 1H), 12.07 (m, 2H); MS (ESI +) m / z 1019 (M + H) ⁺ , ( ESI-) m / z 1017 (MH) ^- .

実施例５．１３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（１，３−ジヒドロ−２Ｈ−イソインドール−２−イル）−３，５−ジフルオロフェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（イソインドリン−２−イル）フェニル）ピロリジン−２，５−ジイル）ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）テトラヒドロクロライド（２５０ｍｇ、０．３０６ｍｍｏｌ）および（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１１８ｍｇ、０．６７３ｍｍｏｌ）を、窒素下に脱水ＤＭＦ（３ｍＬ）中で合わせた。ＨＯＢＴ水和物（１１７ｍｇ、０．７６５ｍｍｏｌ）およびＥＤＡＣ（１５０ｍｇ、０．７６５ｍｍｏｌ）を加え、琥珀色溶液を冷却して０℃とした。４−メチルモルホリン（０．３３７ｍＬ、３．０６ｍｍｏｌ）を加え、冷却浴を外し、反応混合物を２０℃で１６時間撹拌した。反応混合物をＥｔＯＡｃ（５０ｍＬ）で希釈し、この混合物を水（２５ｍＬで３回）およびブライン（２５ｍＬ）で洗浄した。有機相を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、緑色様黄色固体を得た。その固体を４％ＣＨ_３ＯＨ／ＣＨ_２Ｃｌ_２で溶離を行うＳｉＯ_２フラッシュクロマトグラフィー（３．８ｃｍ×１５ｃｍ）によって精製して、オフホワイト固体を得た（１０４ｍｇ）。少量サンプル（５２ｍｇ）をアセトニトリル（２ｍＬ）および０．１％ＴＦＡ／Ｈ_２Ｏ（２ｍＬ）に溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分間勾配、次に１０分間で１００％アセトニトリルとする（１０ｍＬずつの分画）溶離を行うＲＰ−Ｃ１８ＨＰＬＣ（Ｎｏｖａ−Ｐａｋ ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋ カートリッジ搭載のＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液（２ｍＬ／管）で処理し、各管を渦撹拌してＴＦＡを十分に中和し、溶液を５００ｍリットル丸底フラスコ中で合わせた。残った取得物５２ｍｇを、上記で記載の分取ＨＰＬＣによって精製し、純粋な生成物を含む分画を上記で記載のように飽和ＮａＨＣＯ_３水溶液で処理した。生成物含有分画を、同じ５００ｍリットル丸底フラスコ中で合わせた。アセトニトリルをロータリーエバポレータによって除去した。残った水相をＥｔＯＡｃで抽出した（５０ｍＬで２回）。合わせた有機相を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、標題化合物を白色固体として得た（８８ｍｇ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７５−０．９２（ｍ、１２Ｈ）、１．６１−２．０８（ｍ、８Ｈ）、２．１１−２．２６（ｍ、３Ｈ）、２．５７（ｓ、２Ｈ）、３．５４（ｓ、６Ｈ）、３．８３（ｓ、４Ｈ）、４．０７（ｔ、Ｊ＝８．２９Ｈｚ、２Ｈ）、４．２６−４．４３（ｍ、４Ｈ）、５．１０−５．２３（ｍ、２Ｈ）、５．３３−５．５０（ｍ、２Ｈ）、５．９９（ｄ、Ｊ＝１２．７９Ｈｚ、２Ｈ）、７．０９（ｔ、Ｊ＝６．８３Ｈｚ、２Ｈ）、７．２０（ｓ、４Ｈ）、７．２２−７．３７（ｍ、４Ｈ）、７．４２（ｄ、Ｊ＝８．２４Ｈｚ、１Ｈ）、７．５０（ｄ、Ｊ＝８．１３Ｈｚ、１Ｈ）、１２．０９（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ９８５（Ｍ＋Ｈ）^＋、（ＥＳＩ−）ｍ／ｚ９８３（Ｍ−Ｈ）⁻。

Example 5.13
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (1,3-dihydro-2H-isoindole-2-yl) -3,5 -Difluorophenyl] -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole- 5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate (S) -6,6'-( (2R, 5R) -1- (3,5-difluoro-4- (isoindole-2-yl) phenyl) pyrrolidine-2,5-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) tetrahydrochloride (250 mg, 0.306 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (118 mg, 0.673 mmol) dehydrated under nitrogen (DMF) 3 mL) was combined. HOBT hydrate (117 mg, 0.765 mmol) and EDAC (150 mg, 0.765 mmol) were added and the amber solution was cooled to 0 ° C. 4-Methylmorpholine (0.337 mL, 3.06 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 ° C. for 16 hours. The reaction mixture was diluted with EtOAc (50 mL) and the mixture was washed with water (25 mL 3 times) and brine (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give a greenish yellow solid. The solid was purified by SiO ₂ flash chromatography (3.8 cm × 15 cm) eluting with 4% CH ₃ OH / CH ₂ Cl ₂ to give an off-white solid (104 mg). A small sample (52 mg) was dissolved in acetonitrile (2 mL) and 0.1% TFA / H ₂ O (2 mL) and at 20 mL / min 95: 5 from H ₂ O / acetonitrile containing 0.1% TFA 25:75 0. 30 min gradient of containing 1% TFA _H 2 O / acetonitrile, then 100% acetonitrile at 10 min (fractions by 10 mL) RP-C18 HPLC eluting (Nova-Pak HR C18 6μm 40 × 100mm Prep Pak cartridge Purified by on-board Waters Prep LC, 40 mm module). The pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize the TFA, and the solutions were combined in a 500 ml round bottom flask. The remaining 52 mg of the obtained product was purified by the preparative HPLC described above, and the fraction containing the pure product was treated with saturated aqueous NaHCO ₃ solution as described above. Product-containing fractions were combined in the same 500 ml round bottom flask. Acetonitrile was removed by rotary evaporator. The remaining aqueous phase was extracted with EtOAc (twice at 50 mL). The combined organic phases were dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give the title compound as a white solid (88 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.75-0.92 (m, 12H), 1.61-2.08 (m, 8H), 2.11-2.26 (m, 3H), 2.57 (s, 2H), 3.54 (s, 6H), 3.83 (s, 4H), 4.07 (t, J = 8.29Hz, 2H), 4.26-4.43 ( m, 4H), 5.10-5.23 (m, 2H), 5.33-5.50 (m, 2H), 5.99 (d, J = 12.79Hz, 2H), 7.09 ( t, J = 6.83Hz, 2H), 7.20 (s, 4H), 7.22-7.37 (m, 4H), 7.42 (d, J = 8.24Hz, 1H), 7. 50 (d, J = 8.13Hz, 1H) 12.09 (m, 2H); MS (ESI +) m / z985 (M + H) ⁺ , (ESI-) m / z983 (MH) ⁻ .

Example 5.14
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (1,4-dioxa-8-azaspiro [4.5] dex-8-yl) ) -3,5-Difluorophenyl] -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl]- 1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate

Part A
Compound 8-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -1,4-dioxa-8 -Azaspiro [4.5] decan is converted according to the method of general procedure 8.1 and general procedure 9D (PtO ₂ ) to dimethyl (2S, 2'S) -1,1'-((2S, 2'). S) -2,2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (1,4-dioxa-8-azaspiro [4.5] decan-8) -Il) Phenyl) Pyrrolidine-2,5-diyl) Bis (2-amino-4,1-phenylene)) Bis (Azanesil) Bis (oxomethylene) Bis (Pyrrolidine-2,1-Diyl)) Bis (3-yl) Methyl-1-oxobutane-2,1-diyl) dicarbamate can be obtained.

Part B
Dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R)) in a 10 ml round-bottom flask dried in a dryer. , 5R) -1- (3,5-difluoro-4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) pyrrolidine-2,5-diyl) bis (2- Amino-4,1-phenylene)) Bis (azaneyl) Bis (oxomethylene) Bis (pyrrolidine-2,1-diyl)) Bis (3-methyl-1-oxobutane-2,1-diyl) Dicarbamate (200 mg, 0.191 mmol) was dissolved in dehydrated toluene (2 mL) under nitrogen. Glacial acetic acid (0.110 mL, 1.914 mmol) was added and the solution was stirred in an oil bath at 60 ° C. After 1.5 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO ₃ solution (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give the crude title compound as a tan solid (185 mg). A small sample (93 mg) of the low-purity obtained was dissolved in acetonitrile (2 mL) and 0.1% TFA / H ₂ O (2 mL) from H ₂ O / acetonitrile containing 95: 5 0.1% TFA at 20 mL / min. 30 min gradient of 25:75 0.1% TFA-containing _H 2 O / acetonitrile, equipped with RP-C18HPLC (Nova Pak HR C18 6μm 40 × 100mm Prep Pak cartridge eluting to 100% acetonitrile and then at 10 minutes Purified by Waters Prep LC, 40 mm module). The pure fraction was immediately treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize the TFA, and the solutions were combined in a 500 ml round bottom flask. The remaining 92 mg was purified by preparative-HPLC described above and the fraction containing the pure product was treated with saturated aqueous NaHCO ₃ solution as described above. Additional fractions were combined in the same 500 ml round bottom flask. Acetonitrile was removed by rotary evaporator and the remaining aqueous phase was extracted with EtOAc (twice at 50 mL). The combined organic extracts were dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give the title compound as a white solid (103 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.73-0.94 (m, 12H), 1.51-1.61 (m, 4H), 1.63-1.75 (m, 2H), 1.83-2.10 (m, 8H), 2.13-2.29 (m, 4H), 2.86 (s, 4H), 3.54 (s, 6H), 3.83 (s, 8H), 4.06 (t, J = 8.51Hz, 2H), 5.09-5.21 (m, 2H), 5.30-5.42 (m, 2H), 5.90 (d, J = 12.69Hz, 2H), 7.01-7.12 (m, 2H), 7.17-7.32 (m, 4H), 7.40 (s, 1H), 7.49 (d, J = 8.24Hz, 1H), 11.71-12.53 (m, 2H); MS (ESI +) m / z1009 (M + H) ⁺ , (ESI-) m / z1007 (MH) ⁻ .

Example 5.15
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenyl-3,6-dihydropyridine-1) (2H) ) -Il) Phenyl] -5- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benz Imidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate

Part A
Compound 1-(4-((2R, 5R) -2,5-bis (4-chloro-3-nitrophenyl) pyrrolidine-1-yl) -2, according to the methods of general procedure 8.1 and general procedure 9E), 6-Difluorophenyl) -4-phenyl-1,2,3,6-tetrahydropyridine is converted to dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2, 2'-(4,4'-((2R, 5R) -1- (3,5-difluoro-4- (4-phenyl-5,6-dihydropyridin-1 (2H) -yl) phenyl) pyrrolidine-2) , 5-Diyl) bis (2-amino-4,1-phenylene)) bis (azaneyl) bis (oxomethylene) bis (pyrrolidin-2,1-diyl)) bis (3-methyl-1-oxobutane-2, 1-Zyle) Dicarbamate can be obtained.

Part B
In a 5 mL round bottom flask dried in a dryer, dimethyl (2S, 2'S) -1,1'-((2S, 2'S) -2,2'-(4,4'-((2R, 2R,) 5R) -1- (3,5-difluoro-4- (4-phenyl-5,6-dihydropyridine-1 (2H) -yl) phenyl) pyrrolidine-2,5-diyl) bis (2-amino-4, 1-Phenylene)) Bis (azaneyl) Bis (oxomethylene) Bis (pyrrolidine-2,1-diyl)) Bis (3-methyl-1-oxobutane-2,1-diyl) Dicarbamate (75 mg, 0.071 mmol) Was dissolved in dehydrated toluene (1 mL) under nitrogen. Glacial acetic acid (0.041 mL, 0.707 mmol) was added and the solution was stirred in an oil bath at 60 ° C. After 1.5 hours, the yellow reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO ₃ solution (25 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give a yellow solid (about 80 mg). Dissolve the residue in 2 mL of acetonitrile and 2 mL of 0.1% TFA / H ₂ O, from 95: 5 0.1% TFA-containing H ₂ O / acetonitrile at 20 mL / min to 25:75 0.1% TFA-containing H ₂ O. / A 30-minute gradient of acetonitrile, then elution to 100% acetonitrile in 10 minutes (fractions of 10 mL each) RP-C18 HPLC (Nova-Pak HR C18 6 μm 40 × 100 mm Waters Prep LC with Prep Pak cartridge) , 40 mm module). Pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize TFA, and the solutions were combined in a 250 ml round bottom flask. Acetonitrile was removed by rotary evaporator and the remaining aqueous phase was extracted with EtOAc (twice at 50 mL). The organic phase was dehydrated with anhydrous sulfonyl ₄ , filtered and concentrated on a rotary evaporator to give the product as an off-white solid (34 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.94 (m, 12H) 1.70 (d, J = 4.55 Hz, 2H) 1.83-2.10 (m, 6H) ), 2.11-2.26 (m, 3H), 2.44 (s, 1H), 2.56 (s, 4H), 3.09 (s, 2H), 3.48 (s, 2H) , 3.54 (s, 6H), 3.82 (s, 4H), 4.07 (t, J = 8.35Hz, 2H), 5.09-5.22 (m, 2H), 5.30 -5.46 (m, 2H), 5.95 (d, J = 12.90Hz, 2H), 6.09 (s, 1H), 7.04-7.17 (m, 2H), 7.19 -7.25 (m, 2H), 7.26-7.34 (m, 5H), 7.36-7.45 (m, 3H), 7.50 (d, J = 8.35Hz, 1H) , 11.71-12.63 (m, 2H); MS (ESI +) m / z 1025 (M + H) ⁺ , (ESI-) m / z 1023 (MH) ⁻ .

実施例６．１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛５−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
６，６′−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）ピロリジン−２，５−ジイル］ビス｛５−フルオロ−２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール｝に、ＤＭＦ（１．０ｍＬ）と次にＮ−メチルモルホリン（０．０４５ｍＬ、０．４１ｍｍｏｌ）、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（１５ｍｇ、０．０９ｍｍｏｌ）、ＥＤＣ（２０ｍｇ、０．１ｍｍｏｌ）およびＨＯＢＴ（１６ｍｇ、０．１ｍｍｏｌ）を加えた。溶液を室温で１８時間撹拌した。反応混合物をＥｔＯＡｃで希釈し、Ｈ_２Ｏおよびブラインで洗浄し、脱水し（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。生成物を、逆相ＨＰＬＣクロマトグラフィー（５％から１００％ＣＨ_３ＣＮ／０．１％ＴＦＡ−Ｈ_２Ｏ）によって精製し、所望の分画をＮａＨＣＯ_３水溶液で中和し、ＥｔＯＡｃで抽出し、脱水し、濾過し、溶媒溶媒留去して、標題化合物を得た（６．７ｍｇ、７．２μｍｏｌ、１８％）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．４８（ｍ、１Ｈ）１０．２５（ｍ、１Ｈ）７．３９（ｍ、１Ｈ）７．１４（ｍ、１Ｈ）６．９８（ｍ、３Ｈ）６．２９（ｍ、１Ｈ）５．５４（ｂｒｓ、１Ｈ）５．３４（ｂｒｓ、４Ｈ）４．３１（ｍ、１Ｈ）３．８２（ｍ、２Ｈ）３．７０（ｓ、６Ｈ）３．５１−３．６５（ｍ、２Ｈ）３．０３（ｂｒｓ、２Ｈ）２．５１（ｂｒｓ、２Ｈ）２．２３−２．４０（ｍ、２Ｈ）２．１４（ｍ、４Ｈ）１．９５（ｍ、４Ｈ）１．２７（ｍ、２Ｈ）１．０９−１．２３（ｍ、９Ｈ）１．０７（ｍ、３Ｈ）０．８７（ｍ、９Ｈ）０．６７−０．７９（ｍ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９２４（Ｍ＋Ｈ）^＋。

Example 6.1
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {5-fluoro-2-[(2S)-) 1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -6-fluoro- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate 6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) ) Pyrrolidine-2,5-diyl] bis {5-fluoro-2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazole}, DMF (1.0 mL) and then N-methylmorpholin ( 0.045 mL, 0.41 mmol), (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (15 mg, 0.09 mmol), EDC (20 mg, 0.1 mmol) and HOBT (16 mg, 0.1 mmol) Was added. The solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with _{H 2} O and brine, dried _(Na 2 _SO 4), filtered, and concentrated. The product was purified by reverse phase HPLC chromatography (5% to 100% CH ₃ CN / 0.1% TFA-H ₂ O), the desired fraction was neutralized with aqueous NaHCO ₃ and extracted with EtOAc. , Dehydrated, filtered and the solvent was evaporated to give the title compound (6.7 mg, 7.2 μmol, 18%). ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.48 (m, 1H) 10.25 (m, 1H) 7.39 (m, 1H) 7.14 (m, 1H) 6.98 (m, 3H) 6 .29 (m, 1H) 5.54 (brs, 1H) 5.34 (brs, 4H) 4.31 (m, 1H) 3.82 (m, 2H) 3.70 (s, 6H) 3.51 -3.65 (m, 2H) 3.03 (brs, 2H) 2.51 (brs, 2H) 2.23-2.40 (m, 2H) 2.14 (m, 4H) 1.95 (m) 4, 4H) 1.27 (m, 2H) 1.09-1.23 (m, 9H) 1.07 (m, 3H) 0.87 (m, 9H) 0.67-0.79 (m, 2H) ); MS (ESI) m / z 924 (M + H) ⁺ .

実施例６．２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛５−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
実施例６．１のＨＰＬＣ精製から、シス異性体（６．４ｍｇ、６．９μｍｏｌ、１７％）も得られた。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１１．６２（ｓ、１Ｈ）１１．３７（ｓ、１Ｈ）７．４５−７．５５（ｍ、３Ｈ）７．３６（ｄ、１Ｈ）７．０４（ｄ、２Ｈ）６．９２（ｄ、１Ｈ）６．７７（ｄ、１Ｈ）６．４１（ｄ、２Ｈ）５．３６−５．４０（ｍ、２Ｈ）５．３３（ｍ、１Ｈ）５．０７（ｔ、１Ｈ）３．９８−４．０７（ｍ、１Ｈ）３．９３（ｍ、１Ｈ）３．７４−３．８６（ｍ、２Ｈ）３．７２（ｍ、１Ｈ）３．５９（ｍ、２Ｈ）２．８０（ｍ、１Ｈ）２．５０（ｓ、６Ｈ）２．３２（ｓ、４Ｈ）１．８６−２．２７（ｍ、７Ｈ）１．７８（ｍ、１Ｈ）１．１７（ｓ、９Ｈ）０．８６−１．０１（ｍ、９Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９２４（Ｍ＋Ｈ）^＋。

Example 6.2
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5S) -1- (4-tert-butylphenyl) -5- {5-fluoro-2-[(2S)-) 1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -6-fluoro- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate From the HPLC purification of Example 6.1, the cis isomer (6.4 mg, 6.9 μmol) , 17%) was also obtained. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 11.62 (s, 1H) 11.37 (s, 1H) 7.45-7.55 (m, 3H) 7.36 (d, 1H) 7.04 (d) , 2H) 6.92 (d, 1H) 6.77 (d, 1H) 6.41 (d, 2H) 5.36-5.40 (m, 2H) 5.33 (m, 1H) 5.07 (T, 1H) 3.98-4.07 (m, 1H) 3.93 (m, 1H) 3.74-3.86 (m, 2H) 3.72 (m, 1H) 3.59 (m) , 2H) 2.80 (m, 1H) 2.50 (s, 6H) 2.32 (s, 4H) 1.86-2.27 (m, 7H) 1.78 (m, 1H) 1.17 (S, 9H) 0.86-1.01 (m, 9H); MS (ESI) m / z 924 (M + H) ⁺ .

The following Example compounds 6.3 to 6.11 can be prepared from the intermediate amines listed appropriately, much according to the method of Example 6.1.

Intermediate amines 6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-fluoro-2-[(2S) -pyrrolidine-2 -Il] -1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-fluoro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-chloro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-chloro-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5R) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-methyl-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-[(2R, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2,5-diyl] bis {7-methyl-2-[(2S) -pyrrolidine-2-yl]- 1H-benzimidazole} (ACD Name v12);
6,6'-{(2R, 5R) -1- [3-fluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[(2S)) -Pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12);
6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[( 2S) -pyrrolidine-2-yl] -1H-benzimidazole} (ACD Name v12); and 6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine) -1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazole} (ACD Name v12).

実施例６．３
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛７−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−４−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．４１−１０．６４（ｍ、２Ｈ）６．８４−７．０６（ｍ、６Ｈ）６．２５−６．３６（ｍ、２Ｈ）５．５５−５．６８（ｍ、１Ｈ）５．２５−５．４６（ｍ、４Ｈ）４．２７−４．４０（ｍ、１Ｈ）３．７９−３．９２（ｍ、２Ｈ）３．７１（ｓ、６Ｈ）３．５６−３．６７（ｍ、２Ｈ）３．０３−３．２７（ｍ、２Ｈ）１．８３−２．６６（ｍ、１０Ｈ）１．１４（ｓ、９Ｈ）０．７７−１．３１（ｍ、１４Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９２４（Ｍ＋Ｈ）^＋。

Example 6.3
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {7-fluoro-2-[(2S)-) 1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -4-fluoro- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.41-10.64 (m, 2H) 6.84-7.06 (m, 6H) 6.25-6.36 (m, 2H) 5.55-5 .68 (m, 1H) 5.25-5.46 (m, 4H) 4.27-4.40 (m, 1H) 3.79-3.92 (m, 2H) 3.71 (s, 6H) ) 3.56-3.67 (m, 2H) 3.03-3.27 (m, 2H) 1.83-2.66 (m, 10H) 1.14 (s, 9H) 0.77-1 .31 (m, 14H); MS (ESI) m / z 924 (M + H) ⁺ .

実施例６．４
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛７−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−４−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．５４−１０．７１（ｍ、２Ｈ）７．５４−７．６８（ｍ、２Ｈ）７．００−７．２１（ｍ、４Ｈ）６．４３−６．５４（ｍ、２Ｈ）５．２７−５．５０（ｍ、４Ｈ）５．２０（ｂｒｓ、２Ｈ）４．２９−４．４２（ｍ、１Ｈ）３．８０−３．９４（ｍ、２Ｈ）３．７１（ｓ、６Ｈ）３．５９−３．６９（ｍ、２Ｈ）３．０４−３．２９（ｍ、２Ｈ）１．８６−２．６６（ｍ、１０Ｈ）１．１８（ｓ、９Ｈ）０．７９−１．３３（ｍ、１４Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９２４（Ｍ＋Ｈ）^＋。

Example 6.4
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5S) -1- (4-tert-butylphenyl) -5- {7-fluoro-2-[(2S)-) 1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-6-yl} pyrrolidine-2-yl] -4-fluoro- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.54-10.71 (m, 2H) 7.54-7.68 (m, 2H) 7.00-7.21 (m, 4H) 6.43-6 .54 (m, 2H) 5.27-5.50 (m, 4H) 5.20 (brs, 2H) 4.29-4.42 (m, 1H) 3.80-3.94 (m, 2H) ) 3.71 (s, 6H) 3.59-3.69 (m, 2H) 3.04-3.29 (m, 2H) 1.86-2.66 (m, 10H) 1.18 (s) , 9H) 0.79-1.33 (m, 14H); MS (ESI) m / z 924 (M + H) ⁺ .

実施例６．５
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛４−クロロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−４−クロロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ１２．７０（ｓ、０Ｈ）、１２．３９（ｓ、１Ｈ）、８．０７（ｓ、１Ｈ）、７．３２（ｄｄ、Ｊ＝２６．１、８．１、３Ｈ）、６．９１（ｄ、Ｊ＝３７．０、４Ｈ）、６．０８（ｄ、Ｊ＝７．９、１Ｈ）、５．６４（ｓ、１Ｈ）、５．１７（ｓ、１Ｈ）、４．６６（ｓ、１Ｈ）、４．１０（ｄ、Ｊ＝５．２、１Ｈ）、３．８６（ｓ、３Ｈ）、３．５２（ｄ、Ｊ＝１４．１、６Ｈ）、３．１７（ｄ、Ｊ＝５．２、１Ｈ）、２．３０−２．１０（ｍ、２Ｈ）、２．００（ｓ、４Ｈ）、１．７７（ｓ、１Ｈ）、１．２３（ｓ、１Ｈ）、１．１８−１．０１（ｍ、９Ｈ）、１．０１−０．７２（ｍ、１１Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ９５８．７６（Ｍ＋Ｈ）^＋。

Example 6.5
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {4-chloro-2-[(2S)- 1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -4-chloro- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ12.70 (s, 0H), 12.39 (s, 1H), 8.07 (s, 1H), 7.32 (dd, J = 26.1, 8.1, 3H), 6.91 (d, J = 37.0, 4H), 6.08 (d, J = 7.9, 1H), 5.64 (s, 1H), 5.17 ( s, 1H), 4.66 (s, 1H), 4.10 (d, J = 5.2, 1H), 3.86 (s, 3H), 3.52 (d, J = 14.1), 6H), 3.17 (d, J = 5.2, 1H), 2.30-2.10 (m, 2H), 2.00 (s, 4H), 1.77 (s, 1H), 1 .23 (s, 1H), 1.18-1.01 (m, 9H), 1.01-0.72 (m, 11H); MS (APCI +) m / z958.76 (M + H) ⁺ .

実施例６．６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛４−クロロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−４−クロロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ１２．４５（ｓ、１Ｈ）、８．０６（ｄ、Ｊ＝３．３、１Ｈ）、７．６８（ｄ、Ｊ＝８．６、２Ｈ）、７．４８（ｔ、Ｊ＝１２．５、２Ｈ）、７．３１（ｄ、Ｊ＝８．２、２Ｈ）、７．００（ｄ、Ｊ＝８．１、２Ｈ）、６．２０（ｄ、Ｊ＝８．７、２Ｈ）、５．１６（ｄ、Ｊ＝３２．０、４Ｈ）、４．６６（ｓ、１Ｈ）、４．１１（ｓ、１Ｈ）、３．８８（ｓ、３Ｈ）、３．５６（ｄ、Ｊ＝８．１、６Ｈ）、２．３０−２．０９（ｍ、５Ｈ）、２．０２（ｓ、７Ｈ）、１．８０（ｓ、２Ｈ）、１．２３（ｓ、２Ｈ）、１．０９（ｓ、９Ｈ）、１．００−０．７８（ｍ、１２Ｈ）；ＭＳ（ＡＰＣＩ＋）ｍ／ｚ９５８．６４（Ｍ＋Ｈ）^＋。

Example 6.6
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5S) -1- (4-tert-butylphenyl) -5- {4-chloro-2-[(2S)- 1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -4-chloro- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ12.45 (s, 1H), 8.06 (d, J = 3.3, 1H), 7.68 (d, J = 8.6, 2H), 7.48 (t, J = 12.5, 2H), 7.31 (d, J = 8.2, 2H), 7.00 (d, J = 8.1, 2H), 6.20 (d) , J = 8.7, 2H), 5.16 (d, J = 32.0, 4H), 4.66 (s, 1H), 4.11 (s, 1H), 3.88 (s, 3H) ), 3.56 (d, J = 8.1, 6H), 2.30-2.09 (m, 5H), 2.02 (s, 7H), 1.80 (s, 2H), 1. 23 (s, 2H), 1.09 (s, 9H), 1.00-0.78 (m, 12H); MS (APCI +) m / z958.64 (M + H) ⁺ .

実施例６．７
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−４−メチル−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−４−メチル−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）dｐｐｍ０．７８−１．０５（ｍ、１４Ｈ）、１．０６（ｓ、９Ｈ）、１．８６−２．０６（ｍ、８Ｈ）、２．０９−２．３１（ｍ、４Ｈ）、２．５８−２．７２（ｍ、６Ｈ）、３．５４（ｓ、６Ｈ）、３．７９−３．９３（ｍ、４Ｈ）、４．０２−４．１７（ｍ、２Ｈ）、５．１１−５．２３（ｍ、２Ｈ）、５．４２−５．５１（ｍ、２Ｈ）、６．０２−６．１２（ｍ、２Ｈ）、６．７１−６．８３（ｍ、２Ｈ）、６．８３−６．９６（ｍ、２Ｈ）、７．０４−７．１９（ｍ、２Ｈ）、７．２４−７．３５（ｍ、２Ｈ）、１１．８４−１２．２６（ｍ、２Ｈ）。

Example 6.7
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- (4-tert-butylphenyl) -5- {2-[(2S) -1-{((2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -4-methyl-1H-benzimidazol-5-yl} pyrrolidine-2-yl] -4-methyl- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) dppm 0.78-1.05 (m, 14H), 1.06 (s, 9H), 1.86-2.06 (m, 8H), 2.09- 2.31 (m, 4H), 2.58-2.72 (m, 6H), 3.54 (s, 6H), 3.79-3.93 (m, 4H), 4.02-4. 17 (m, 2H), 5.11-5.23 (m, 2H), 5.42-5.51 (m, 2H), 6.02-6.12 (m, 2H), 6.71- 6.83 (m, 2H), 6.83-6.96 (m, 2H), 7.04-7.19 (m, 2H), 7.24-7.35 (m, 2H), 11. 84-12.26 (m, 2H).

実施例６．８
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｓ）−１−（４−ｔｅｒｔ−ブチルフェニル）−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−４−メチル−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−４−メチル−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）dｐｐｍ０．７９−１．０６（ｍ、１２Ｈ）、１．２３（ｓ、９Ｈ）、１．８７−２．３１（ｍ、Ｊ＝３０．６９Ｈｚ、１２Ｈ）、２．５８−２．６５（ｍ、Ｊ＝３．２５Ｈｚ、６Ｈ）、３．５５（ｓ、６Ｈ）、３．８１−３．９６（ｍ、４Ｈ）、４．０１−４．１９（ｍ、２Ｈ）、４．９２（ｓ、２Ｈ）、５．１２−５．２６（ｍ、２Ｈ）、６．１４−６．２６（ｍ、２Ｈ）、６．８６−７．０２（ｍ、２Ｈ）、７．２２−７．３９（ｍ、４Ｈ）、７．５７−７．７９（ｍ、２Ｈ）、１１．９０−１２．３２（ｍ、２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ＝９１６．４（Ｍ＋Ｈ）^＋。

Example 6.8
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5S) -1- (4-tert-butylphenyl) -5- {2-[(2S) -1-{((2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -4-methyl-1H-benzimidazol-5-yl} pyrrolidine-2-yl] -4-methyl- 1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) dppm 0.79-1.06 (m, 12H), 1.23 (s, 9H), 1.87-2.31 (m, J = 30.69Hz, 12H) ), 2.58-2.65 (m, J = 3.25Hz, 6H), 3.55 (s, 6H), 3.81-3.96 (m, 4H), 4.01-4.19 (M, 2H), 4.92 (s, 2H), 5.12-5.26 (m, 2H), 6.14-6.26 (m, 2H), 6.86-7.02 (m) , 2H), 7.22-7.39 (m, 4H), 7.57-7.79 (m, 2H), 11.90-12.32 (m, 2H); MS (ESI) m / z = 916.4 (M + H) ⁺ .

実施例６．９
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（６−フルオロ−５−｛（２Ｒ，５Ｒ）−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝−１−［３−フルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．２１−１０．６７（ｍ、２Ｈ）６．５５−７．９９（ｍ、６Ｈ）５．９５−６．１４（ｍ、１Ｈ）５．１９−５．５６（ｍ、６Ｈ）４．２５−４．３９（ｍ、１Ｈ）３．７７−３．９２（ｍ、２Ｈ）３．７０（ｓ、６Ｈ）３．４２−３．７６（ｍ、３Ｈ）２．９５−３．１７（ｍ、２Ｈ）２．６４−２．９５（ｍ、２Ｈ）２．４３−２．６４（ｍ、１Ｈ）１．７８−２．４２（ｍ、１１Ｈ）０．６２−１．７８（ｍ、１８Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９６９（Ｍ＋Ｈ）^＋。

Example 6.9
Methyl {(2S) -1-[(2S) -2-(6-fluoro-5-{(2R, 5R) -5- {6-fluoro-2-[(2S) -1-{(2S)-) 2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} -1- [3-fluoro-4- (piperidine-1-yl) phenyl ] Pyrrolidine-2-yl} -1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.21-10.67 (m, 2H) 6.55-7.99 (m, 6H) 5.95-6.14 (m, 1H) 5.19-5 .56 (m, 6H) 4.25-4.39 (m, 1H) 3.77-3.92 (m, 2H) 3.70 (s, 6H) 3.42-3.76 (m, 3H) ) 2.95-3.17 (m, 2H) 2.64-2.95 (m, 2H) 2.43-2.64 (m, 1H) 1.78-2.42 (m, 11H) 0 .62-1.78 (m, 18H); MS (ESI) m / z969 (M + H) ⁺ .

実施例６．１０
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
６，６′−｛（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］ピロリジン−２，５−ジイル｝ビス｛５−フルオロ−２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール｝（６４ｍｇ、０．０９５ｍｍｏｌ）のＤＭＦ（２３７８μＬ）中溶液に、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（３５．０ｍｇ、０．２００ｍｍｏｌ）、ＥＤＣ（４５．６ｍｇ、０．２３８ｍｍｏｌ）、ＨＯＢＴ（３６．４ｍｇ、０．２３８ｍｍｏｌ）およびＮ−メチルモルホリン（１０５μＬ、０．９５１ｍｍｏｌ）を加え、得られた溶液を環境温度で終夜撹拌した。反応溶液をＥｔＯＡｃで希釈し、Ｈ_２Ｏおよびブラインで洗浄し、脱水し（ＭｇＳＯ_４）、濾過し、濃縮した。粗取得物を１：１ＣＨ_３ＣＮ：０．１％ＴＦＡ／Ｈ_２Ｏに溶かし、ＨＰＬＣ（Ｃ１８、０％から１００％ＣＨ_３ＣＮ／０．１％ＴＦＡ／Ｈ_２Ｏ）によって精製した。生成物を含有する分画を合わせ、飽和重炭酸ナトリウム溶液で塩基性とし、ＥｔＯＡｃで抽出した。有機層を脱水し（ＭｇＳＯ_４）、濾過し、濃縮して、標題化合物を得た（４３．３ｍｇ、０．０４４ｍｍｏｌ、収率４６．１％）。標題化合物は、上記の一般手順１２Ｃに従っても製造することができる。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．２５−１０．７０（ｍ、２Ｈ）６．８３−７．５３（ｍ、４Ｈ）５．７０−５．９１（ｍ、２Ｈ）５．２０−５．５２（ｍ、４Ｈ）４．２１−４．４２（ｍ、２Ｈ）３．７０（ｓ、６Ｈ）３．５３−３．９４（ｍ、６Ｈ）１．７５−３．１７（ｍ、１６Ｈ）０．６３−１．７４（ｍ、１８Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ９８７（Ｍ＋Ｈ）^＋。

Example 6.10
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperridine-1-yl) phenyl] -5- {6 −Fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazol-5-yl} pyrrolidine -2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate 6,6'-{(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {5-fluoro-2-[(2S) -pyrrolidin-2-yl] -1H In a solution of −benzimidazole} (64 mg, 0.095 mmol) in DMF (2378 μL), (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (35.0 mg, 0.200 mmol), EDC (45. 6 mg (0.238 mmol), HOBT (36.4 mg, 0.238 mmol) and N-methylmorpholine (105 μL, 0.951 mmol) were added and the resulting solution was stirred at ambient temperature overnight. The reaction solution was diluted with EtOAc, washed with _{H 2} O and brine, dried (MgSO _4), filtered, and concentrated. The crude obtained was dissolved in 1: 1 CH ₃ CN: 0.1% TFA / H ₂ O and purified by HPLC (C18, 0% to 100% CH ₃ CN / 0.1% TFA / H ₂ O). Fractions containing the products were combined, basicized with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was dehydrated (sulfonyl ₄ ), filtered and concentrated to give the title compound (43.3 mg, 0.044 mmol, 46.1% yield). The title compound can also be prepared according to the above general procedure 12C. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm10.25-10.70 (m, 2H) 6.83-7.53 (m, 4H) 5.70-5.91 (m, 2H) 5.20-5 .52 (m, 4H) 4.21-4.42 (m, 2H) 3.70 (s, 6H) 3.53-3.94 (m, 6H) 1.75-3.17 (m, 16H) ) 0.63-1.74 (m, 18H); MS (ESI) m / z987 (M + H) ⁺ .

実施例６．１１
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ１０．５４（ｂｒｓ、２Ｈ）７．０９−７．３３（ｍ、９Ｈ）５．７７−５．９２（ｍ、２Ｈ）５．２３−５．５２（ｍ、４Ｈ）４．２４−４．３９（ｍ、２Ｈ）３．７９−３．９１（ｍ、２Ｈ）３．７０（ｓ、６Ｈ）３．５５−３．６７（ｍ、２Ｈ）２．９２−３．２１（ｍ、５Ｈ）１．７３−２．６５（ｍ、１０Ｈ）０．９７−１．７４（ｍ、８Ｈ）０．７６−０．９６（ｍ、１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１０６３（Ｍ＋Ｈ）^＋。

Example 6.11
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5] -5 -{6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5- Il} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate
^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 10.54 (brs, 2H) 7.09-7.33 (m, 9H) 5.77-5.92 (m, 2H) 5.23-5.52 (m) , 4H) 4.24-4.39 (m, 2H) 3.79-3.91 (m, 2H) 3.70 (s, 6H) 3.55-3.67 (m, 2H) 2.92 -3.21 (m, 5H) 1.73-2.65 (m, 10H) 0.97-1.74 (m, 8H) 0.76-0.96 (m, 12H); MS (ESI) m / z 1063 (M + H) ⁺ .

実施例６．１２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（６−アザスピロ［２．５］オクト−６−イル）−３，５−ジフルオロフェニル］−５−｛６−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
乾燥機で乾燥させた５ｍＬナシ型フラスコ中、窒素下に（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（５６．６ｍｇ、０．３２３ｍｍｏｌ）を脱水ＣＨ_２Ｃｌ_２（１ｍＬ）に溶かし、ＥＤＡＣ（６３．２ｍｇ、０．３２３ｍｍｏｌ）を加え、２０℃で２０分間撹拌した。得られた溶液を気密注射器によって窒素下に（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（６−アザスピロ［２．５］オクタン−６−イル）フェニル）ピロリジン−２，５−ジイル）ビス（５−フルオロ−２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）塩酸塩（９１ｍｇ）およびジイソプロピルエチルアミン（０．１８８ｍＬ、１．０７７ｍｍｏｌ）の脱水ＣＨ_２Ｃｌ_２（２ｍＬ）中溶液に加え、ＨＯＢｔ水和物（４９．５ｍｇ、０．３２３ｍｍｏｌ）を加え、２０℃で１時間撹拌した。反応液をＣＨ_２Ｃｌ_２（５０ｍＬ）で希釈し、水（２５ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、暗黄色泡状物（約１４０ｍｇ）を得た。低純度取得物７０ｍｇをアセトニトリル２ｍＬおよび０．１％ＴＦＡ／Ｈ_２Ｏ ２ｍＬに溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分勾配、次に１０分で１００％アセトニトリルとする溶離を行うＲＰ−Ｃ_１８ＨＰＬＣ（Ｎｏｖａ Ｐａｋ ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋ カートリッジを搭載したＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液で処理し（２ｍＬ／管）、各管を渦撹拌してＴＦＡを十分に中和し、溶液を５００ｍリットル丸底フラスコ中で合わせた。残った７０ｍｇを上記の分取ＨＰＬＣによって精製し、純粋な生成物を含む分画を上記のように飽和ＮａＨＣＯ_３水溶液で処理し、同じ５００ｍリットル丸底フラスコ中で合わせた。アセトニトリルをロータリーエバポレータによって除去し、残った水相をＥｔＯＡｃで抽出し（５０ｍＬで２回）、合わせた有機抽出液を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、生成物を白色固体として得た（４９ｍｇ、０．０４８ｍｍｏｌ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．２４（ｓ、４Ｈ）、０．６８−０．９１（ｍ、１２Ｈ）、１．２１−１．３５（ｍ、５Ｈ）、１．６７−２．０７（ｍ、９Ｈ）、２．１３−２．２４（ｍ、４Ｈ）、２．８４（ｓ、４Ｈ）、３．５３（ｓ、６Ｈ）、３．７３−３．８７（ｍ、４Ｈ）、３．９９−４．１１（ｍ、２Ｈ）、５．０２−５．２３（ｍ、２Ｈ）、５．４５−５．６５（ｍ、２Ｈ）、５．８１−５．９９（ｍ、２Ｈ）、７．０４（ｄ、Ｊ＝６．０７Ｈｚ、１Ｈ）、７．１４（ｄ、Ｊ＝６．９４Ｈｚ、１Ｈ）、７．２６−７．３６（ｍ、３Ｈ）、７．４１（ｄｄ、Ｊ＝１１．０６、６．１８Ｈｚ、１Ｈ）、１１．７３−１２．６３（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０１３（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０１１（Ｍ−Ｈ）⁻。

Example 6.12
Methyl {(2S) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (6-azaspiro [2.5] octo-6-yl) -3,5- Difluorophenyl] -5- {6-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H- Benzimidazole-5-yl} pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} in a carbamate dryer In a dried 5 mL pear-shaped flask, (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (56.6 mg, 0.323 mmol) was dissolved in dehydrated CH ₂ Cl ₂ (1 mL) under nitrogen, and EDAC. (63.2 mg, 0.323 mmol) was added, and the mixture was stirred at 20 ° C. for 20 minutes. The resulting solution was placed under nitrogen by an airtight syringe (S) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (6-azaspiro [2.5] octane-6). -Il) phenyl) pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) hydrochloride (91 mg) and diisopropylethylamine ( To a solution in dehydrated CH ₂ Cl ₂ (2 mL) of 0.188 mL, 1.077 mmol) was added HOBt hydrate (49.5 mg, 0.323 mmol), and the mixture was stirred at 20 ° C. for 1 hour. The reaction mixture is diluted with CH ₂ Cl ₂ (50 mL), washed with water (25 mL), dehydrated with anhydrous Na ₂ SO ₄ , filtered, concentrated by a rotary evaporator, and dark yellow foam (about 140 mg). Got 70 mg of low-purity obtained product is dissolved in ₂ mL of acetonitrile and 2 mL of 0.1% TFA / H ₂ O, and contains 95: 5 0.1% TFA at 20 mL / min. Contains 25:75 0.1% TFA from H ₂ O / acetonitrile. H ₂ O / 30 min gradient of acetonitrile, then eluted to 100% acetonitrile in 10 min _{RP-C 18 HPLC (Nova Pak} HR C18 6μm 40 × 100mm Prep Pak cartridge equipped with Waters Prep LC, 40 mm module) Purified by. The pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize the TFA, and the solutions were combined in a 500 ml round bottom flask. The remaining 70 mg was purified by preparative HPLC above and fractions containing the pure product were treated with saturated aqueous NaHCO ₃ solution as described above and combined in the same 500 ml round bottom flask. Acetonitrile was removed by rotary evaporation, the remaining aqueous phase was extracted with EtOAc (2 x 50 mL), the combined organic extracts were dried over anhydrous MgSO _4, filtered, and concentrated by rotary evaporation, the product Obtained as a white solid (49 mg, 0.048 mmol). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.24 (s, 4H), 0.68-0.91 (m, 12H), 1.21-1.35 (m, 5H), 1.67- 2.07 (m, 9H), 2.13-2.24 (m, 4H), 2.84 (s, 4H), 3.53 (s, 6H), 3.73-3.87 (m, 4H), 3.99-4.11 (m, 2H), 5.02-5.23 (m, 2H), 5.45-5.65 (m, 2H), 5.81-5.99 ( m, 2H), 7.04 (d, J = 6.07Hz, 1H), 7.14 (d, J = 6.94Hz, 1H), 7.26-7.36 (m, 3H), 7. 41 (dd, J = 11.06, 6.18Hz, 1H), 11.73-12.63 (m, 2H); MS (ESI +) m / z 1013 (M + H) ⁺ ; MS (ESI-) m / z 1011 (MH) ^- .

実施例６．１３
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル］−５−（６−フルオロ−２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
（２Ｓ，３Ｒ）−３−メトキシ−２−（メトキシカルボニルアミノ）ブタン酸（６５．６ｍｇ、０．３４３ｍｍｏｌ）を窒素下に脱水ＣＨ_２Ｃｌ_２（１ｍＬ）に溶かした。ＥＤＡＣ（６７．１ｍｇ、０．３４３ｍｍｏｌ）を加え、混合物を２０℃で２０分間撹拌した。得られた溶液を、窒素下に（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル）ピロリジン−２，５−ジイル）ビス（５−フルオロ−２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）塩酸塩（１００ｍｇ）およびジイソプロピルアミン（０．２００ｍＬ、１．１４３ｍｍｏｌ）の脱水ＣＨ_２Ｃｌ_２（２ｍＬ）中溶液に加えた。ＨＯＢｔ水和物（５２．５ｍｇ、０．３４３ｍｍｏｌ）を加え、混合物を２０℃で１時間撹拌した。反応液をＣＨ_２Ｃｌ_２（５０ｍＬ）で希釈し、水（２５ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮し暗黄色泡状物（１４０ｍｇ）を得た。粗取得物（７０ｍｇ）をアセトニトリル（２ｍＬ）および０．１％ＴＦＡ／Ｈ_２Ｏ（２ｍＬ）に溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分間勾配、次に１０分間で１００％アセトニトリルとする溶離を行うＲＰ−Ｃ_１８ＨＰＬＣ（Ｎｏｖａ−Ｐａｋ（登録商標）ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋ カートリッジを搭載したＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液で処理し（２ｍＬ／管）、各管を渦撹拌してＴＦＡを十分に中和し、分画を５００ｍリットル丸底フラスコ中で合わせた。残った取得物７０ｍｇを上記で記載の分取ＨＰＬＣによって精製し、純粋な生成物を含む分画を上記のように飽和ＮａＨＣＯ_３水溶液で処理し、同じ５００ｍリットル丸底フラスコ中で合わせた。アセトニトリルをロータリーエバポレータによって除去し、残った水相をＥｔＯＡｃで抽出し（５０ｍＬで２回）、合わせた有機抽出液を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、生成物を白色固体として得た（６２ｍｇ、０．０５７ｍｍｏｌ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０（ｓ、９Ｈ）、０．９２（ｄ、Ｊ＝６．０７Ｈｚ、２Ｈ）、０．９８−１．０９（ｍ、４Ｈ）、１．１２−１．２２（ｍ、２Ｈ）、１．４４−１．６３（ｍ、３Ｈ）、１．６５−１．８９（ｍ、３Ｈ）、１．９１−２．１０（ｍ、４Ｈ）、２．１１−２．２８（ｍ、４Ｈ）、２．７３−２．９２（ｍ、４Ｈ）、３．０４（ｄ、Ｊ＝１．７３Ｈｚ、２Ｈ）、３．１３（ｓ、３Ｈ）、３．２５（ｄ、Ｊ＝３．４７Ｈｚ、１Ｈ）、３．４１−３．５０（ｍ、３Ｈ）、３．５３（ｓ、６Ｈ）、３．７２−３．９２（ｍ、４Ｈ）、４．２５（ｑ、Ｊ＝７．９９Ｈｚ、２Ｈ）、５．０２−５．１７（ｍ、２Ｈ）、５．４６−５．６３（ｍ、２Ｈ）、５．７９−６．００（ｍ、２Ｈ）、７．０２（ｄ、Ｊ＝６．７２Ｈｚ、１Ｈ）、７．０８−７．１８（ｍ、２Ｈ）、７．２４（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）、７．３３（ｄｄ、Ｊ＝１０．３６、４．５０Ｈｚ、１Ｈ）、７．４０（ｄｄ、Ｊ＝１１．２２、６．２３Ｈｚ、１Ｈ）、１１．８４−１２．６３（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０７５（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１０７３（Ｍ−Ｈ）⁻。

Example 6.13
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- [4- (4-tert-butylpiperidin-1-yl) -3,5-difluoro Phenyl] -5-(6-fluoro-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazole-5-yl ) Pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate (2S, 3R) -3-methoxy -2- (Methoxycarbonylamino) butanoic acid (65.6 mg, 0.343 mmol) was dissolved in dehydrated CH ₂ Cl ₂ (1 mL) under nitrogen. EDAC (67.1 mg, 0.343 mmol) was added and the mixture was stirred at 20 ° C. for 20 minutes. The obtained solution was subjected to (S) -6,6'-((2R, 5R) -1- (4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl) under nitrogen). Pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) hydrochloride (100 mg) and diisopropylamine (0.200 mL, 1) .143 mmol) was added to the solution in dehydrated CH ₂ Cl ₂ (2 mL). HOBt hydrate (52.5 mg, 0.343 mmol) was added and the mixture was stirred at 20 ° C. for 1 hour. The reaction was diluted with CH ₂ Cl ₂ (50 mL), washed with water (25 mL), dehydrated with anhydrous Na ₂ SO ₄ , filtered and concentrated by a rotary evaporator to give a dark yellow foam (140 mg). .. The crude acquisition (70 mg) was dissolved in acetonitrile (2 mL) and 0.1% TFA / H ₂ O (2 mL) and 95: 5 0.1% TFA-containing H ₂ O / acetonitrile at 20 mL / min 25: 750. .1% TFA-containing H ₂ O / acetonitrile 30-minute gradient followed by elution to 100% acetonitrile in 10 minutes RP-C ₁₈ HPLC (Nova-Pak® HR C18 6 μm 40 × 100 mm Prep Pak cartridge Purified by Waters Prep LC (40 mm module) equipped with. The pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to adequately neutralize the TFA, and the fractions were combined in a 500 ml round bottom flask. The remaining 70 mg of the obtained product was purified by the preparative HPLC described above, and the fraction containing the pure product was treated with saturated aqueous NaHCO ₃ solution as described above and combined in the same 500 ml round bottom flask. Acetonitrile was removed by rotary evaporation, the remaining aqueous phase was extracted with EtOAc (2 x 50 mL), the combined organic extracts were dried over anhydrous MgSO _4, filtered, and concentrated by rotary evaporation, the product Obtained as a white solid (62 mg, 0.057 mmol). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80 (s, 9H), 0.92 (d, J = 6.07 Hz, 2H), 0.98-1.09 (m, 4H), 1. 12-1.22 (m, 2H), 1.44-1.63 (m, 3H), 1.65-1.89 (m, 3H), 1.91-2.10 (m, 4H), 2.11-2.28 (m, 4H), 2.73-2.92 (m, 4H), 3.04 (d, J = 1.73Hz, 2H), 3.13 (s, 3H), 3.25 (d, J = 3.47Hz, 1H), 3.41-3.50 (m, 3H), 3.53 (s, 6H), 3.72-3.92 (m, 4H), 4.25 (q, J = 7.99Hz, 2H), 5.02-5.17 (m, 2H), 5.46-5.63 (m, 2H), 5.79-6.00 (m) , 2H), 7.02 (d, J = 6.72Hz, 1H), 7.08-7.18 (m, 2H), 7.24 (d, J = 8.02Hz, 1H), 7.33 (Dd, J = 10.36, 4.50 Hz, 1H), 7.40 (dd, J = 11.22, 6.23 Hz, 1H), 11.84-12.63 (m, 2H); MS ( ESI +) m / z 1075 (M + H) ⁺ ; MS (ESI-) m / z 1073 (MH) ⁻ .

実施例６．１４
ジメチル（｛（２Ｒ，５Ｒ）−１−［４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル］ピロリジン−２，５−ジイル｝ビス｛（６−フルオロ−１Ｈ−ベンズイミダゾール−５，２−ジイル）（２Ｓ）ピロリジン−２，１−ジイル［（１Ｓ）−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エタン−２，１−ジイル］｝）ビスカーバメート
（Ｓ）−２−（メトキシカルボニルアミノ）−２−（テトラヒドロ−２Ｈ−ピラン−４−イル）酢酸（７４．５ｍｇ、０．３４３ｍｍｏｌ）を、窒素下に脱水ＣＨ_２Ｃｌ_２（１ｍＬ）に溶かした。ＥＤＡＣ（６７．１ｍｇ、０．３４３ｍｍｏｌ）を加え、混合物を２０℃で２０分間撹拌した。得られた溶液を、窒素下に（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（４−（４−ｔｅｒｔ−ブチルピペリジン−１−イル）−３，５−ジフルオロフェニル）ピロリジン−２，５−ジイル）ビス（５−フルオロ−２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）塩酸塩（１００ｍｇ）およびジイソプロピルエチルアミン（０．２００ｍＬ、１．１４３ｍｍｏｌ）の脱水ＣＨ_２Ｃｌ_２（２ｍＬ）中溶液に加えた。ＨＯＢｔ水和物（５２．５ｍｇ、０．３４３ｍｍｏｌ）を加え、混合物を２０℃で１時間撹拌した。反応液をＣＨ_２Ｃｌ_２（５０ｍＬ）で希釈し、水（２５ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して暗黄色固体を得た（２１０ｍｇ）。純度の低い取得物（７０ｍｇ）をアセトニトリル２ｍＬおよび０．１％ＴＦＡ／Ｈ_２Ｏ ２ｍＬに溶かし、２０ｍＬ／分で９５：５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルから２５：７５ ０．１％ＴＦＡ含有Ｈ_２Ｏ／アセトニトリルの３０分間勾配、次に１０分間で１００％アセトニトリルとする溶離を行うＲＰ−Ｃ_１８ＨＰＬＣ（Ｎｏｖａ−Ｐａｋ（登録商標）ＨＲ Ｃ１８ ６μｍ ４０×１００ｍｍ Ｐｒｅｐ Ｐａｋ カートリッジを搭載したＷａｔｅｒｓ Ｐｒｅｐ ＬＣ、４０ｍｍモジュール）によって精製した。純粋な分画を飽和ＮａＨＣＯ_３水溶液（２ｍＬ／管）で処理し、各管を渦撹拌してＴＦＡを十分に中和し、分画を５００ｍリットル丸底フラスコ中で合わせた。残った取得物を上記で記載の分取ＨＰＬＣによって２回の７０ｍｇ注入で精製し、純粋な生成物を含む分画を上記のように飽和ＮａＨＣＯ_３水溶液で処理し、同じ５００ｍリットル丸底フラスコ中で合わせた。アセトニトリルをロータリーエバポレータによって除去し、残った水相をＥｔＯＡｃで抽出し（５０ｍＬで２回）、合わせた有機抽出液を無水ＭｇＳＯ_４で脱水し、濾過し、ロータリーエバポレータによって濃縮して、生成物を白色固体として得た（６９ｍｇ、０．０６０ｍｍｏｌ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８０（ｓ、９Ｈ）、０．８９−１．０１（ｍ、１Ｈ）、１．０７−１．３８（ｍ、７Ｈ）、１．３９−１．６３（ｍ、６Ｈ）、１．６７−１．９１（ｍ、５Ｈ）、１．９２−２．０５（ｍ、４Ｈ）、２．１０−２．２６（ｍ、４Ｈ）、２．７１−２．９５（ｍ、５Ｈ）、２．９６−３．２５（ｍ、３Ｈ）、３．５２（ｓ、６Ｈ）、３．６２−３．９２（ｍ、８Ｈ）、４．０６−４．２３（ｍ、２Ｈ）、５．１０（ｔ、Ｊ＝６．２３Ｈｚ、２Ｈ）、５．３９−５．６５（ｍ、２Ｈ）、５．７７−５．９９（ｍ、２Ｈ）、７．０１（ｄ、Ｊ＝６．７２Ｈｚ、１Ｈ）、７．０７（ｄ、Ｊ＝７．０５Ｈｚ、１Ｈ）、７．２８−７．４９（ｍ、４Ｈ）、１１．７８−１２．４２（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１２７（Ｍ＋Ｈ）^＋；ＭＳ（ＥＳＩ−）ｍ／ｚ１１２５（Ｍ−Ｈ）⁻。

Example 6.14
Dimethyl ({(2R, 5R) -1- [4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl] pyrrolidine-2,5-diyl} bis {(6-fluoro-1H) -Benzimidazole-5,2-diyl) (2S) pyrrolidine-2,1-diyl [(1S) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethane-2,1-diyl] }) Biscarbamate (S) -2- (methoxycarbonylamino) -2- (tetrahydro-2H-pyran-4-yl) acetic acid (74.5 mg, 0.343 mmol) was dehydrated under nitrogen CH ₂ Cl ₂ (}) It was dissolved in 1 mL). EDAC (67.1 mg, 0.343 mmol) was added and the mixture was stirred at 20 ° C. for 20 minutes. The obtained solution was subjected to (S) -6,6'-((2R, 5R) -1- (4- (4-tert-butylpiperidin-1-yl) -3,5-difluorophenyl) under nitrogen). Pyrrolidine-2,5-diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) hydrochloride (100 mg) and diisopropylethylamine (0.200 mL, 1) .143 mmol) was added to the solution in dehydrated CH ₂ Cl ₂ (2 mL). HOBt hydrate (52.5 mg, 0.343 mmol) was added and the mixture was stirred at 20 ° C. for 1 hour. The reaction was diluted with CH ₂ Cl ₂ (50 mL), washed with water (25 mL), dehydrated with anhydrous Na ₂ SO ₄ , filtered and concentrated by rotary evaporator to give a dark yellow solid (210 mg). The low purity acquisition (70 mg) was dissolved in ₂ mL of acetonitrile and 2 mL of 0.1% TFA / H ₂ O and 25:75 0.1 from 95: 5 0.1% TFA-containing H ₂ O / acetonitrile at 20 mL / min. RP-C ₁₈ HPLC (Nova-Pak® HR C18 6 μm 40 × 100 mm Prep Pak cartridge with a 30-minute gradient of H ₂ O / acetonitrile containing% TFA followed by elution to 100% acetonitrile in 10 minutes Purified by Waters Prep LC (40 mm module). The pure fractions were treated with saturated aqueous NaHCO ₃ solution (2 mL / tube), each tube was swirled to sufficiently neutralize the TFA, and the fractions were combined in a 500 ml round bottom flask. The remaining obtained product was purified by the preparative HPLC described above in two 70 mg injections, and the fraction containing the pure product was treated with saturated NaHCO ₃ aqueous solution as described above in the same 500 ml round bottom flask. I matched it with. Acetonitrile was removed by rotary evaporation, the remaining aqueous phase was extracted with EtOAc (2 x 50 mL), the combined organic extracts were dried over anhydrous MgSO _4, filtered, and concentrated by rotary evaporation, the product Obtained as a white solid (69 mg, 0.060 mmol). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.80 (s, 9H), 0.89-1.01 (m, 1H), 1.07-1.38 (m, 7H), 1.39- 1.63 (m, 6H), 1.67-1.91 (m, 5H), 1.92-2.05 (m, 4H), 2.10-2.26 (m, 4H), 2. 71-2.95 (m, 5H), 2.96-3.25 (m, 3H), 3.52 (s, 6H), 3.62-3.92 (m, 8H), 4.06- 4.23 (m, 2H), 5.10 (t, J = 6.23Hz, 2H), 5.39-5.65 (m, 2H), 5.77-5.99 (m, 2H), 7.01 (d, J = 6.72Hz, 1H), 7.07 (d, J = 7.05Hz, 1H), 7.28-7.49 (m, 4H), 11.78-12.42 (M, 2H); MS (ESI +) m / z 1127 (M + H) ⁺ ; MS (ESI-) m / z 1125 (MH) ⁻ .

実施例６．１５
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−｛４−［４−（トリフルオロメチル）フェニル］ピペラジン−１−イル｝フェニル）−５−（６−フルオロ−２−｛（２Ｓ）−１−［Ｎ−（メトキシカルボニル）−Ｏ−メチル−Ｌ−トレオニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−５−イル）ピロリジン−２−イル］−６−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−（４−（トリフルオロメチル）フェニル）ピペラジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（５−フルオロ−２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）塩酸塩（８８ｍｇ）、（２Ｓ，３Ｒ）−３−メトキシ−２−（メトキシカルボニルアミノ）ブタン酸（４１ｍｇ、０．２１６ｍｍｏｌ）、Ｎ−（３−ジメチルアミノプロピル）−Ｎ′−エチルカルボジイミド塩酸塩（４６ｍｇ、０．２３８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール水和物（３６ｍｇ、０．２３８ｍｍｏｌ）および４−メチルモルホリン（０．０９５ｍＬ、０．８６４ｍｍｏｌ）をＤＭＦ（３．０ｍＬ）に溶かし、混合物を室温で３時間撹拌した。その後、イソプロピルアルコールおよびクロロホルム混合物を加え、１Ｎ塩酸水溶液で抽出した。有機抽出液を脱水し、濾過し、濃縮し、残留物をクロマトグラフィー（シリカゲル、メタノール／ジクロロメタン）によって精製して、標題化合物７１ｍｇを得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ７．５６（ｍ、２Ｈ）、７．４８（ｄ、Ｊ＝８．８Ｈｚ、２Ｈ）、７．３４（ｍ、２Ｈ）、７．１８（ｍ、２Ｈ）、７．０４（ｄ、Ｊ＝８．６Ｈｚ、２Ｈ）、５．９７（ｍ、２Ｈ）、５．６２（ｍ、２Ｈ）、５．１７（ｍ、２Ｈ）、４．２８（ｍ、２Ｈ）、３．８２（ｍ、２Ｈ）、３．６０（ｍ、２Ｈ）、３．５４（ｓ、６Ｈ）、３．２５（ｍ、８Ｈ）、３．１７（ｓ、６Ｈ）、２．９９（ｍ、４Ｈ）、２．０５（ｍ、１２Ｈ）、１．２５（ｍ、６Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ１１６４（Ｍ＋Ｈ）^＋。

Example 6.15
Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- (3,5-difluoro-4- {4- [4- (trifluoromethyl) phenyl) ] Piperazin-1-yl} phenyl) -5- (6-fluoro-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H -Benzimidazole-5-yl) pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate (S) ) -6,6'-((2R, 5R) -1- (3,5-difluoro-4- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) phenyl) pyrrolidine-2, 5-Diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) hydrochloride (88 mg), (2S, 3R) -3-methoxy-2- (Methoxycarbonylamino) butanoic acid (41 mg, 0.216 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (46 mg, 0.238 mmol), 1-hydroxybenzotriazole hydrate (36 mg) , 0.238 mmol) and 4-methylmorpholine (0.095 mL, 0.864 mmol) were dissolved in DMF (3.0 mL) and the mixture was stirred at room temperature for 3 hours. Then, a mixture of isopropyl alcohol and chloroform was added, and the mixture was extracted with a 1N aqueous hydrochloric acid solution. The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, methanol / dichloromethane) to give 71 mg of the title compound. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 7.56 (m, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.34 (m, 2H), 7.18 (m, 2H), 7.04 (d, J = 8.6Hz, 2H), 5.97 (m, 2H), 5.62 (m, 2H), 5.17 (m, 2H), 4.28 (m) , 2H), 3.82 (m, 2H), 3.60 (m, 2H), 3.54 (s, 6H), 3.25 (m, 8H), 3.17 (s, 6H), 2 .99 (m, 4H), 2.05 (m, 12H), 1.25 (m, 6H); MS (ESI) m / z1164 (M + H) ⁺ .

実施例６．１６
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［（２Ｒ，５Ｒ）−１−｛４−［４−（２，６−ジフルオロフェニル）ピペラジン−１−イル］−３，５−ジフルオロフェニル｝−５−｛５−フルオロ−２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−６−イル｝ピロリジン−２−イル］−５−フルオロ−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（０．０７２ｇ、０．４１０ｍｍｏｌ）およびＨＯＢｔ（０．０６３ｇ、０．４１０ｍｍｏｌ）をＤＭＦ（２ｍＬ）中で合わせた。得られた透明溶液に、ＥＤＡＣ（０．０７９ｇ、０．４１０ｍｍｏｌ）を加え、ＤＭＦ ０．２ｍＬで洗い、得られた透明溶液を室温で２０分間撹拌した。（Ｓ）−６，６′−（（２Ｒ，５Ｒ）−１−（４−（４−（２，６−ジフルオロフェニル）ピペラジン−１−イル）−３，５−ジフルオロフェニル）ピロリジン−２，５−ジイル）ビス（５−フルオロ−２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール）塩酸塩（０．１６０ｇ）をＤＭＦ ２ｍＬに溶かし、Ｎ−メチルモルホリン（１．８６３ｍｍｏｌ、０．２０５ｍＬ）で処理し、次に活性化アミノ酸溶液で処理し、得られた透明褐色溶液を室温で１時間撹拌した。溶液のｐＨをｐＨ試験紙によって測定したところ８であった。１時間目に反応進行をＬＣ−ＭＳによって確認し、分析したところ反応が完結していると主合われた。反応混合物を減圧下に濃縮して、褐色流動性油状物を得た。その油状物をＥｔＯＡｃ ５０ｍＬで希釈し、１０％ＮａＨＣＯ_３ ３０ｍＬで洗浄した。層を分離し、水層を追加のＥｔＯＡｃ ５０ｍＬで抽出した。合わせた有機抽出液を１０％ＮａＣｌで洗浄し、無水Ｎａ_２ＳＯ_４（固体）で脱水し、濾過し、溶媒を減圧下に除去したところ、褐色油状残留物が残った。残留物を、ＣＨ_２Ｃｌ_２／ＣＨ_３ＯＨの１３分間かけての９９／１から９５／５、次に８分間かけての９５／５から９０／１０の勾配で溶離を行う１２ｇシリカゲルカラムで精製した。生成物を含む分画を合わせ、１５分かけてのＣＨ_２Ｃｌ_２／ＣＨ_３ＯＨ、９８／２から９０／１０の勾配で溶離する１２ｇ ｇｏｌｄカラムで再精製した。分画を減圧下に濃縮したところ、標題化合物としての明褐色固体が残った（５０．３ｍｇ）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．８２（ｍ、１２Ｈ）１．９９（ｍ、９Ｈ）２．１８（ｍ、２Ｈ）２．９５（ｍ、４Ｈ）３．０５−３．１７（ｍ、５Ｈ）３．５３（ｓ、６Ｈ）３．７９（ｍ、４Ｈ）３．９５−４．１１（ｍ、４Ｈ）５．１１（ｍ、２Ｈ）５．５５（ｍ、２Ｈ）５．９１（ｍ、２Ｈ）７．０１（ｍ、５Ｈ）７．２９（ｍ、４Ｈ）１２．１４（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１１００．３、（ＥＳＩ−）ｍ／ｚ１０９８．３（Ｍ−Ｈ）⁻。

Example 6.16
Methyl {(2S) -1-[(2S) -2-{6-[(2R, 5R) -1- {4- [4- (2,6-difluorophenyl) piperazin-1-yl] -3, 5-Difluorophenyl} -5- {5-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl]- 1H-benzimidazole-6-yl} pyrrolidine-2-yl] -5-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate ( S) -2- (Methoxycarbonylamino) -3-methylbutanoic acid (0.072 g, 0.410 mmol) and HOBt (0.063 g, 0.410 mmol) were combined in DMF (2 mL). EDAC (0.079 g, 0.410 mmol) was added to the obtained transparent solution, washed with 0.2 mL of DMF, and the obtained transparent solution was stirred at room temperature for 20 minutes. (S) -6,6'-((2R, 5R) -1-(4- (4- (2,6-difluorophenyl) piperazin-1-yl) -3,5-difluorophenyl) pyrrolidine-2, N-Methylmorpholine (5-diyl) bis (5-fluoro-2-((S) -pyrrolidin-2-yl) -1H-benzo [d] imidazole) hydrochloride (0.160 g) was dissolved in 2 mL of DMF. It was treated with 1.863 mmol, 0.205 mL), then treated with an activated amino acid solution, and the resulting clear brown solution was stirred at room temperature for 1 hour. The pH of the solution was measured with pH test paper and found to be 8. The reaction progress was confirmed by LC-MS at the 1st hour, and it was analyzed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a brown fluid oil. The oil was diluted with 50 mL of EtOAc and washed with 30 mL of 10% NaHCO ₃ . The layers were separated and the aqueous layer was extracted with an additional 50 mL of EtOAc. The combined organic extracts were washed with 10% NaCl, dehydrated with anhydrous Na ₂ SO ₄ (solid), filtered and the solvent removed under reduced pressure, leaving a brown oily residue. The residue is eluted on a 12 g silica gel column with a gradient of 99/1 to 95/5 over 13 minutes of CH ₂ Cl ₂ / CH ₃ OH and then 95/5 to 90/10 over 8 minutes. Purified. Fractions containing the products were combined and repurified on a 12 g gold column eluting with a gradient of CH ₂ Cl ₂ / CH ₃ OH over 15 minutes, 98/2 to 90/10. When the fraction was concentrated under reduced pressure, a light brown solid as the title compound remained (50.3 mg). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.82 (m, 12H) 1.99 (m, 9H) 2.18 (m, 2H) 2.95 (m, 4H) 3.05-3.17 (M, 5H) 3.53 (s, 6H) 3.79 (m, 4H) 3.95-4.11 (m, 4H) 5.11 (m, 2H) 5.55 (m, 2H) 5 .91 (m, 2H) 7.01 (m, 5H) 7.29 (m, 4H) 12.14 (m, 2H); MS (ESI +) m / z 1100.3, (ESI-) m / z 1098. 3 (MH) ^- .

Example 7.1
Methyl {(2S) -1-[(2S) -2-(4- {4- [2- (4-tert-butylphenyl) -1- (4- {2-[(2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-imidazol-4-yl} phenyl) -1H-pyrrole-3-yl] phenyl} -1H- Imidazole-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate

実施例７．１Ａ
２−（４−ブロモフェニルアミノ）−２−（４−ｔｅｒｔ−ブチルフェニル）アセトニトリル
４−ブロモアニリン（１０．０ｇ、５８．１ｍｍｏｌ）のＴＨＦ（１００ｍＬ）中溶液に４−ｔｅｒｔ−ブチルベンズアルデヒド（９．７２ｍＬ、５８．１ｍｍｏｌ）、酢酸（１３．３ｍＬ、２３３ｍｍｏｌ）、シアン化カリウム（３．７９ｇ、５８．１ｍｍｏｌ）および水（５０ｍＬ）を加えた。得られた混合物を室温で１６時間撹拌した。得られた生成固体を減圧濾過によって回収し、ヘキサンで洗浄し、乾燥させて、標題化合物１５．３ｇ（７７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ７．４９（ｍ、４Ｈ）、７．３７（ｄ、Ｊ＝８．７Ｈｚ、２Ｈ）、６．６６（ｄ、Ｊ＝８．８Ｈｚ、２Ｈ）、５．３４（ｄ、Ｊ＝８．１Ｈｚ、１Ｈ）、４．０２（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、１．３４（ｓ、９Ｈ）。

Example 7.1A
4-tert- Butylbenzaldehyde (9) in a solution of 2- (4-bromophenylamino) -2- (4-tert-butylphenyl) acetonitrile 4-bromoaniline (10.0 g, 58.1 mmol) in THF (100 mL). .72 mL, 58.1 mmol), acetic acid (13.3 mL, 233 mmol), potassium cyanide (3.79 g, 58.1 mmol) and water (50 mL) were added. The resulting mixture was stirred at room temperature for 16 hours. The resulting solid was recovered by vacuum filtration, washed with hexane and dried to give 15.3 g (77%) of the title compound. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 7.49 (m, 4H), 7.37 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 5. 34 (d, J = 8.1Hz, 1H), 4.02 (d, J = 8.0Hz, 1H), 1.34 (s, 9H).

実施例７．１Ｂ
（Ｅ）−３−（４−ブロモフェニル）プロプ−２−エン−１−オール
冷却して−７８℃とした（Ｅ）−３−（４−ブロモフェニル）アクリル酸エチル（１０．０ｇ、３９．２ｍｍｏｌ）のジクロロメタン（１５１ｍＬ）中溶液に、水素化アルミニウムジイソブチル溶液（１．０Ｍジクロロメタン中溶液、８２ｍＬ、８２ｍｍｏｌ）を１５分の時間をかけて滴下した。溶液をさらに２時間撹拌し、次に１０％水酸化ナトリウム水溶液（２５０ｍＬ）を加えた。混合物を昇温させて室温とし、混合物をジクロロメタンで抽出した。有機層を脱水し、濃縮して、標題化合物８．３５ｇ（１００％）を得て、次の反応に直接用いた。

Example 7.1B
Ethyl (E) -3- (4-bromophenyl) prop-2-ene-1-ol cooled to −78 ° C. (E) -3- (4-bromophenyl) ethyl acrylate (10.0 g, 39) A solution in diisobutyl hydride (1.0 M solution in dichloromethane, 82 mL, 82 mmol) was added dropwise to a solution in dichloromethane (151 mL) of .2 mmol) over a time of 15 minutes. The solution was stirred for an additional 2 hours, then 10% aqueous sodium hydroxide solution (250 mL) was added. The temperature of the mixture was raised to room temperature, and the mixture was extracted with dichloromethane. The organic layer was dehydrated and concentrated to give 8.35 g (100%) of the title compound, which was used directly in the next reaction.

実施例７．１Ｃ
（Ｅ）−３−（４−ブロモフェニル）アクリルアルデヒド
ジクロロメタン（１５１ｍＬ）に溶かした実施例７．１Ｂの生成物（８．３５ｇ、３９．２ｍｍｏｌ）に、ジクロム酸ピリジニウム（２２．１１ｇ、５８．８ｍｍｏｌ）を加え、得られた混合物を室温で１６時間撹拌した。ヘキサンの溶液を加え、得られた混合物を珪藻土で濾過し、濃縮した。水を残留物に加え、混合物を酢酸エチルで抽出した。有機層を合わせ、脱水し、濃縮した。残留物をクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）によって精製して、標題化合物５．５ｇ（６７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ９．６２（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、７．５７（ｄ、Ｊ＝８．５Ｈｚ、２Ｈ）、７．４２（ｍ、３Ｈ）、６．７０（ｄｄ、Ｊ＝１５．９、７．６Ｈｚ、１Ｈ）。

Example 7.1C
(E) -3- (4-Bromophenyl) acrolein aldehyde Pyridinium dichromate (22.11 g, 58.) in the product (8.35 g, 39.2 mmol) of Example 7.1B dissolved in dichloromethane (151 mL). 8 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. A solution of hexane was added and the resulting mixture was filtered through diatomaceous earth and concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layers were combined, dehydrated and concentrated. The residue was purified by chromatography (silica gel, hexane / ethyl acetate) to give 5.5 g (67%) of the title compound. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm9.62 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.42 (m, 3H), 6. 70 (dd, J = 15.9, 7.6 Hz, 1H).

実施例７．１Ｄ
１，３−ビス（４−ブロモフェニル）−２−（４−ｔｅｒｔ−ブチルフェニル）−１Ｈ−ピロール
実施例７．１Ｃの生成物（０．６７６ｇ、３．２ｍｍｏｌ）および実施例７．１Ａからの生成物（１．０ｇ、２．９１ｍｍｏｌ）に、エタノール（３０ｍＬ）を加え、次に水酸化カリウム（０．１６３ｇ、２．９１ｍｍｏｌ）を加え、混合物を室温で１６時間撹拌した。その後、混合物を濃縮した。残留物を水と酢酸エチルとの間で分配した。有機層を合わせ、脱水し、濃縮した。残留物をクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）によって精製して、標題化合物１５０ｍｇ（１０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δｐｐｍ７．３７（ｍ、３Ｈ）、７．３２（ｄ、Ｊ＝８．５、２Ｈ）、７．２１（ｄ、Ｊ＝８．４Ｈｚ、２Ｈ）、７．０６（ｄ、Ｊ＝８．３Ｈｚ、２Ｈ）、６．９３（ｍ、４Ｈ）、６．５１（ｄｄ、Ｊ＝２．９Ｈｚ、１Ｈ）、１．２９（ｓ、９Ｈ）。

Example 7.1D
From 1,3-bis (4-bromophenyl) -2- (4-tert-butylphenyl) -1H-pyrrole Example 7.1C product (0.676 g, 3.2 mmol) and Example 7.1A Ethanol (30 mL) was added to the product (1.0 g, 2.91 mmol), then potassium hydroxide (0.163 g, 2.91 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was then concentrated. The residue was partitioned between water and ethyl acetate. The organic layers were combined, dehydrated and concentrated. The residue was purified by chromatography (silica gel, hexane / ethyl acetate) to give the title compound 150 mg (10%). ^{1 1} H NMR (400 MHz, CDCl ₃ ) δppm 7.37 (m, 3H), 7.32 (d, J = 8.5, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7. 06 (d, J = 8.3Hz, 2H), 6.93 (m, 4H), 6.51 (dd, J = 2.9Hz, 1H), 1.29 (s, 9H).

実施例７．１Ｅ
２−（４−ｔｅｒｔ−ブチルフェニル）−１，３−ビス（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）−１Ｈ−ピロール
実施例７．１Ｄからの生成物（１５０ｍｇ、０．２９５ｍｍｏｌ）、４，４，４′，４′，５，５，５′，５′−オクタメチル−２，２′−ビ（１，３，２−ジオキサボロラン）（１６５ｍｇ、０．６４８ｍｍｏｌ）、酢酸カリウム（８７ｍｇ、８．８４ｍｍｏｌ）および［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）のジクロロメタンとの錯体（２１．６ｍｇ、０．０２９ｍｍｏｌ）のジオキサン（５．５ｍＬ）中溶液を１００℃で１８時間加熱した。混合物を珪藻土で濾過し、濃縮して油状物を得て、それをＥｔＯＡｃに溶かし、ブラインで抽出した。有機抽出液を濃縮して標題化合物を２３０ｍｇ得て、それを次の段階で直接用いた。

Example 7.1E
2- (4-tert-Butylphenyl) -1,3-bis (4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -1H-pyrrole Product from Example 7.1D (150 mg, 0.295 mmol), 4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2) -Dioxaborolane) (165 mg, 0.648 mmol), potassium acetate (87 mg, 8.84 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (21.6 mg, 21.6 mg, A solution of 0.029 mmol) in dichloromethane (5.5 mL) was heated at 100 ° C. for 18 hours. The mixture was filtered through diatomaceous earth and concentrated to give an oil, which was dissolved in EtOAc and extracted with brine. The organic extract was concentrated to give 230 mg of the title compound, which was used directly in the next step.

実施例７．１Ｆ
（２Ｓ，２′Ｓ）−２，２′−｛［２−（４−ｔｅｒｔ−ブチルフェニル）−１Ｈ−ピロール−１，３−ジイル］ビス（ベンゼン−４，１−ジイル−１Ｈ−イミダゾール−４，２−ジイル）｝ジピロリジン−１−カルボン酸ジ−ｔｅｒｔ−ブチル（ＡＣＤ Ｎａｍｅ ｖ１２）
実施例７．１Ｅからの生成物（２２７ｍｇ、０．３７６ｍｍｏｌ）、（Ｓ）−２−（５−ブロモ−１Ｈ−イミダゾール−２−イル）ピロリジン−１−カルボン酸ｔｅｒｔ−ブチルまたは（Ｓ）−２−（４−ブロモ−１Ｈ−イミダゾール−２−イル）ピロリジン−１−カルボン酸ｔｅｒｔ−ブチル（３５７ｍｇ、１．１３ｍｍｏｌ）、［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）のジクロロメタンとの錯体（２７．５ｍｇ、０．０３８ｍｍｏｌ）および炭酸ナトリウム溶液（１．０Ｍ水溶液、１．１３ｍＬ、１．１３ｍｍｏｌ）をエタノール（３ｍＬ）およびトルエン（３ｍＬ）の溶液中にて８５℃で１８時間加熱した。混合物に水（１０ｍＬ）を加え、次にＥｔＯＡｃによって抽出した（１０ｍＬで２回）。有機抽出液を脱水し、濾過し、濃縮し、残留物をクロマトグラフィー（シリカゲル、メタノール／ジクロロメタン）によって精製して、標題化合物２９ｍｇ（９％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ８２３（Ｍ＋Ｈ）^＋。

Example 7.1F
(2S, 2'S) -2,2'-{[2- (4-tert-butylphenyl) -1H-pyrrole-1,3-diyl] bis (benzene-4,1-diyl-1H-imidazole- 4,2-Diyl)} di-tert-butyl dipyrrolidine-1-carboxylate (ACD Name v12)
Product from Example 7.1E (227 mg, 0.376 mmol), (S) -2- (5-bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl or (S)- 2- (4-Bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl (357 mg, 1.13 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) With dichloromethane (27.5 mg, 0.038 mmol) and sodium carbonate solution (1.0 M aqueous solution, 1.13 mL, 1.13 mmol) in a solution of ethanol (3 mL) and toluene (3 mL) at 85 ° C. Was heated for 18 hours. Water (10 mL) was added to the mixture and then extracted with EtOAc (twice at 10 mL). The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, methanol / dichloromethane) to give the title compound 29 mg (9%). MS (ESI) m / z 823 (M + H) ⁺ .

実施例７．１Ｇ
４，４′−｛［２−（４−ｔｅｒｔ−ブチルフェニル）−１Ｈ−ピロール−１，３−ジイル］ジベンゼン−４，１−ジイル｝ビス｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−イミダゾール｝（ＡＣＤ Ｎａｍｅ ｖ１２）
実施例７．１Ｆの生成物（２９ｍｇ、０．０３５ｍｍｏｌ）をジオキサン（０．５ｍＬ）に溶かし、塩酸／ジオキサン（４．０Ｎ、０．１４ｍＬ、０．５４ｍｍｏｌ）を加えた。混合物を室温で４時間撹拌した。その後、混合物を濃縮して、標題化合物を塩酸塩として得た。ＭＳ（ＥＳＩ）ｍ／ｚ６２２（Ｍ＋Ｈ）^＋。

Example 7.1G
4,4'-{[2- (4-tert-butylphenyl) -1H-pyrrole-1,3-diyl] dibenzene-4,1-diyl} bis {2-[(2S) -pyrrolidine-2-yl] ] -1H-imidazole} (ACD Name v12)
The product of Example 7.1F (29 mg, 0.035 mmol) was dissolved in dioxane (0.5 mL) and hydrochloric acid / dioxane (4.0 N, 0.14 mL, 0.54 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was then concentrated to give the title compound as hydrochloride. MS (ESI) m / z 622 (M + H) ⁺ .

Example 7.1H
Methyl {(2S) -1-[(2S) -2-(4- {4- [2- (4-tert-butylphenyl) -1- (4- {2-[(2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-imidazol-4-yl} phenyl) -1H-pyrrole-3-yl] phenyl} -1H- Imidazole-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate Product from Example 7.1G (22 mg, 0.036 mmol), (S) -2- ( Methoxycarbonylamino) -3-methylbutanoic acid (12.7 mg, 0.072 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (15.2 mg, 0.079 mmol), 1-hydroxybenzo Triazole hydrate (12.2 mg, 0.079 mmol) and 4-methylmorpholin (0.021 mL, 0.29 mmol) were dissolved in DMF (0.7 mL) and the mixture was stirred at room temperature for 3 hours. Then, 1N aqueous hydrochloric acid solution (5 mL) was added, and then the mixture was extracted with dichloromethane (5 mL twice). The organic extract was dehydrated, filtered and concentrated. The residue was then purified by chromatography (silica gel, methanol / dichloromethane) to give the title compound 3.3 mg (10%). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 10.57 (s, 1H) 10.26 (s, 1H), 7.62 (m, 4H), 7.20 (m, 8H), 6.99 (M, 4H), 5.37 (m, 2H), 5.24 (m, 2H), 4.30 (m, 2H), 3.80 (m, 2H), 3.08 (m, 1H) 2.96 (s, 3H), 2.88 (s, 3H), 2.30 (m, 2H), 2.19 (m, 2H), 2.08 (m, 2H), 1.92 ( m, 2H), 1.23 (m, 9H), 0.85 (m, 12H); MS (ESI) m / z 936 (M + H) ⁺ .

Example 8
Dimethyl ({(2S) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {4,1-phenylenecarbamoyl (2S) pyrrolidine -2,1-diyl [(2S) -3-methyl-1-oxobutane-1,2-diyl]}) Biscabamate

実施例８Ａ
１−（４−（（２Ｓ，５Ｓ）−２，５−ビス（４−ニトロフェニル）ピロリジン−１−イル）−２，６−ジフルオロフェニル）−４−フェニルピペリジン
中間体６（２．６８ｇ、５．４９ｍｍｏｌ）、３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）アニリン（１．９０ｇ、６．５８ｍｍｏｌ）およびジイソプロピルエチルアミン（９．５８ｍＬ、５４．９ｍｍｏｌ）のＤＭＦ（１８．３ｍＬ）中混合物を６０℃で１８時間加熱した。その後、酢酸エチルを溶液に加え、次に水によって抽出した。有機抽出液を脱水し、濾過し、濃縮し、残留物をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、標題化合物１９７ｍｇ（６％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ５８５（Ｍ＋Ｈ）^＋。

Example 8A
1-(4-((2S, 5S) -2,5-bis (4-nitrophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidine intermediate 6 (2.68 g, DMF (18.49 mmol), 3,5-difluoro-4- (4-phenylpiperidine-1-yl) aniline (1.90 g, 6.58 mmol) and diisopropylethylamine (9.58 mL, 54.9 mmol). The mixture in 3 mL) was heated at 60 ° C. for 18 hours. Ethyl acetate was then added to the solution and then extracted with water. The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give 197 mg (6%) of the title compound. MS (ESI) m / z 585 (M + H) ⁺ .

実施例８Ｂ
４，４′−（（２Ｓ，５Ｓ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ジアニリン
実施例８Ａの生成物（１９７ｍｇ、０．３３７ｍｍｏｌ）をＴＨＦ（３ｍＬ）、エタノール（３ｍＬ）および水（０．５ｍＬ）の混合物に溶かし、鉄（９５ｍｇ、１．６９ｍｍｏｌ）および塩化アンモニウム（２７ｍｇ、０．５０６ｍｍｏｌ）を加え、混合物を８０℃で３時間加熱した。その後、酢酸エチルを溶液に加え、次に重炭酸ナトリウムによって抽出した。有機抽出液を脱水し、濾過し、濃縮して、標題化合物１７７ｍｇ（１００％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ５２５（Ｍ＋Ｈ）^＋。

Example 8B
4,4'-((2S, 5S) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine-2,5-diyl) dianiline Product of Example 8A (197 mg, 0.337 mmol) is dissolved in a mixture of THF (3 mL), ethanol (3 mL) and water (0.5 mL), iron (95 mg, 1.69 mmol) and ammonium chloride (27 mg, 0.506 mmol) are added. The mixture was heated at 80 ° C. for 3 hours. Ethyl acetate was then added to the solution and then extracted with sodium bicarbonate. The organic extract was dehydrated, filtered and concentrated to give 177 mg (100%) of the title compound. MS (ESI) m / z 525 (M + H) ⁺ .

実施例８Ｃ
（２Ｓ，２′Ｓ）−２，２′−（４，４′−（（２Ｓ，５Ｓ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ビス（アザネジル）ビス（オキソメチレン）ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
実施例８Ｂからの生成物（１７７ｍｇ、０．３３７ｍｍｏｌ）、（Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピロリジン−２−カルボン酸（１６０ｍｇ、０．７４２ｍｍｏｌ）、Ｎ−（３−ジメチルアミノプロピル）−Ｎ′−エチルカルボジイミド塩酸塩（１６２ｍｇ、０．８４３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール水和物（１２９ｍｇ、０．８４３ｍｍｏｌ）および４−メチルモルホリン（０．３７０ｍＬ、３．３７ｍｍｏｌ）をジクロロメタン（３．５ｍＬ）に溶かし、混合物を室温で１９時間撹拌した。その後、重炭酸ナトリウム水溶液を加え、次にジクロロメタンによって抽出した。有機抽出液を脱水し、濾過し、濃縮し、残留物をクロマトグラフィー（シリカゲル、メタノール／ジクロロメタン）によって精製して、標題化合物１３０ｍｇ（４２％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ９２０（Ｍ＋Ｈ）^＋。

Example 8C
(2S, 2'S) -2,2'-(4,4'-((2S, 5S) -1- (3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl) pyrrolidine) -2,5-diyl) bis (4,1-phenylene)) bis (azaneyl) bis (oxomethylene) dipyrrolidine-1-carboxylate tert-butyl Product from Example 8B (177 mg, 0.337 mmol), S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (160 mg, 0.742 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (162 mg, 0.843 mmol), 1-Hydroxybenzotriazole hydrate (129 mg, 0.843 mmol) and 4-methylmorpholine (0.370 mL, 3.37 mmol) were dissolved in dichloromethane (3.5 mL) and the mixture was stirred at room temperature for 19 hours. Then, aqueous sodium bicarbonate solution was added, and then the mixture was extracted with dichloromethane. The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, methanol / dichloromethane) to give 130 mg (42%) of the title compound. MS (ESI) m / z 920 (M + H) ⁺ .

実施例８Ｄ
（２Ｓ，２′Ｓ）−Ｎ，Ｎ′−（４，４′−（（２Ｓ，５Ｓ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ジピロリジン−２−カルボキサミド
実施例８Ｃの生成物（１３０ｍｇ、０．１４１ｍｍｏｌ）をジクロロメタン（２．７ｍＬ）およびトリフルオロ酢酸（０．２７ｍＬ、３．５ｍｍｏｌ）に溶かし、混合物を室温で１時間撹拌した。その後、混合物を濃縮し、残留物をイソプロピルアルコールおよびクロロホルム混合物に溶かし、重炭酸ナトリウム水溶液で抽出した。有機相を脱水し、濃縮して、標題化合物１００ｍｇ（９９％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ７１９（Ｍ＋Ｈ）^＋。

Example 8D
(2S, 2'S) -N, N'-(4,4'-((2S, 5S) -1- (3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) pyrrolidine) -2,5-diyl) bis (4,5-phenylene)) dipyrrolidine-2-carboxamide Example 8C product (130 mg, 0.141 mmol) with dichloromethane (2.7 mL) and trifluoroacetic acid (0.27 mL, It was dissolved in 3.5 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated and the residue was dissolved in a mixture of isopropyl alcohol and chloroform and extracted with aqueous sodium bicarbonate solution. The organic phase was dehydrated and concentrated to give the title compound 100 mg (99%). MS (ESI) m / z 719 (M + H) ⁺ .

Example 8E
Dimethyl ({(2S) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl] pyrrolidine-2,5-diyl} bis {4,1-phenylenecarbamoyl (2S) pyrrolidine -2,1-diyl [(2S) -3-methyl-1-oxobutane-1,2-diyl]}) Biscabamate Product from Example 8D (100 mg, 0.142 mmol), (S) -2- (Methoxycarbonylamino) -3-methylbutanoic acid (60 mg, 0.341 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (68 mg, 0.355 mmol), 1-hydroxybenzotriazole hydration The product (54 mg, 0.355 mmol) and 4-methylmorpholine (0.156 mL, 1.42 mmol) were dissolved in DMF (1.5 mL) and the mixture was stirred at room temperature for 19 hours. Then, a mixture of isopropyl alcohol and chloroform was added, and the mixture was extracted with an aqueous sodium bicarbonate solution. The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, methanol / dichloromethane) to give the title compound 20 mg (14%). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 10.03 (s, 2H), 7.53 (d, J = 8.5 Hz, 4H), 7.30 (m, 9H), 5.83 (d, J = 12.6Hz, 2H), 5.18 (m, 2H), 5.08 (m, 2H), 4.43 (m, 2H), 4.02 (m, 4H), 3.61 (m) , 2H), 3.54 (s, 6H), 2.98 (m, 4H), 2.18 (m, 2H), 1.93 (m, 6H), 1.70 (m, 6H), 0 .81 (m, 12H); MS (ESI) m / z 1033 (M + H) ⁺ .

Example 9
Methyl {(2S) -1-[(2S) -2-(4- {4-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidine-1-yl) phenyl) ] -5- (4- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-imidazole-4 -Il} phenyl) pyrrolidine-2-yl] phenyl} -1H-imidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate

実施例９Ａ
１−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−ブロモフェニル）ピロリジン−１−イル）−２，６−ジフルオロフェニル）−４−フェニルピペリジン
中間体７（２．３５ｇ、４．２２ｍｍｏｌ）、３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）アニリン（２．４４ｇ、８．４５ｍｍｏｌ）およびジイソプロピルエチルアミン（２．２１ｍＬ、１２．６７ｍｍｏｌ）のアセトニトリル（２５ｍＬ）中混合物を８０℃で９時間加熱した。その後、得られた固体を濾過によって除去し、クロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル、次にジクロロメタン／ヘキサン）によって精製して、標題化合物１３０ｍｇ（４．７％）を得た。ＭＳ（ＥＳＩ＋）ｍ／ｚ６５３（Ｍ＋Ｈ）^＋。

Example 9A
1-(4-((2R, 5R) -2,5-bis (4-bromophenyl) pyrrolidine-1-yl) -2,6-difluorophenyl) -4-phenylpiperidine intermediate 7 (2.35 g, 4.22 mmol), 3,5-difluoro-4- (4-phenylpiperidine-1-yl) aniline (2.44 g, 8.45 mmol) and diisopropylethylamine (2.21 mL, 12.67 mmol) in acetonitrile (25 mL) The medium mixture was heated at 80 ° C. for 9 hours. The resulting solid was then removed by filtration and purified by chromatography (silica gel, hexane / ethyl acetate, then dichloromethane / hexane) to give 130 mg (4.7%) of the title compound. MS (ESI +) m / z 653 (M + H) ⁺ .

実施例９Ｂ
１−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）ピロリジン−１−イル）−２，６−ジフルオロフェニル）−４−フェニルピペリジン
実施例９Ａからの生成物（１３０ｍｇ、０．１９９ｍｍｏｌ）、４，４，４′，４′，５，５，５′，５′−オクタメチル−２，２′−ビ（１，３，２−ジオキサボロラン）（１２１ｍｇ、０．４７８ｍｍｏｌ）、酢酸カリウム（５９ｍｇ、０．５９８ｍｍｏｌ）および［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）（２９ｍｇ、０．０４ｍｍｏｌ）のジオキサン（４．５ｍＬ）中溶液を１００℃で３時間加熱した。混合物を珪藻土で濾過し、濃縮して油状物を得て、それをＥｔＯＡｃに溶かし、１Ｎ塩酸水溶液で抽出した。有機抽出液を脱水し、濾過し、濃縮し、残留物をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、標題化合物５０ｍｇ（３４％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ７４７（Ｍ＋Ｈ）^＋。

Example 9B
1-(4-((2R, 5R) -2,5-bis (4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) pyrrolidine-1- Il) -2,6-difluorophenyl) -4-phenylpiperidine Product from Example 9A (130 mg, 0.199 mmol), 4,4,4', 4', 5,5,5', 5'- Octamethyl-2,2'-bi (1,3,2-dioxaborolane) (121 mg, 0.478 mmol), potassium acetate (59 mg, 0.598 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloro A solution of palladium (II) (29 mg, 0.04 mmol) in dioxane (4.5 mL) was heated at 100 ° C. for 3 hours. The mixture was filtered through diatomaceous earth and concentrated to give an oil, which was dissolved in EtOAc and extracted with 1N aqueous hydrochloric acid solution. The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give the title compound 50 mg (34%). MS (ESI) m / z 747 (M + H) ⁺ .

実施例９Ｃ
（２Ｓ，２′Ｓ）−２，２′−（４，４′−（４，４′−（（２Ｒ，５Ｒ）−１−（３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル）ピロリジン−２，５−ジイル）ビス（４，１−フェニレン））ビス（１Ｈ−イミダゾール−４，２−ジイル））ジピロリジン−１−カルボン酸ｔｅｒｔ−ブチル
実施例９Ｂからの生成物（５０ｍｇ、０．０６７ｍｍｏｌ）、中間体１（６４ｍｇ、０．２０１ｍｍｏｌ）、［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）（６．１ｍｇ、０．００８４ｍｍｏｌ）および炭酸ナトリウム（１．０Ｍ水溶液、０．２７ｍＬ、０．２７ｍｍｏｌ）をエタノール（１．５ｍＬ）およびトルエン（１．５ｍＬ）中にて８５℃で１７時間加熱した。水（１０ｍＬ）を混合物に加え、次にジクロロメタンによって抽出した。有機抽出液を脱水し、濾過し、濃縮し、残留物をクロマトグラフィー（シリカゲル、メタノール／ジクロロメタン）によって精製して、標題化合物５１ｍｇ（７９％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ９６６（Ｍ＋Ｈ）^＋。

Example 9C
(2S, 2'S) -2,2'-(4,4'-(4,4'-((2R, 5R))-1- (3,5-difluoro-4- (4-phenylpiperidine-1) -Il) Phenyl) Pyrrolidine-2,5-diyl) Bis (4,1-phenylene)) Bis (1H-imidazole-4,2-diyl)) Dipyrrolidine-1-carboxylate tert-butyl Production from Example 9B (50 mg, 0.067 mmol), intermediate 1 (64 mg, 0.201 mmol), [1,1'-bis (diphenylphosphino) phenylene] dichloropalladium (II) (6.1 mg, 0.0084 mmol) and carbonate. Sodium (1.0 M aqueous solution, 0.27 mL, 0.27 mmol) was heated in ethanol (1.5 mL) and toluene (1.5 mL) at 85 ° C. for 17 hours. Water (10 mL) was added to the mixture and then extracted with dichloromethane. The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, methanol / dichloromethane) to give 51 mg (79%) of the title compound. MS (ESI) m / z 966 (M + H) ⁺ .

実施例９Ｄ
１−（４−（（２Ｒ，５Ｒ）−２，５−ビス（４−（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−イミダゾール−４−イル）フェニル）ピロリジン−１−イル）−２，６−ジフルオロフェニル）−４−フェニルピペリジン
実施例９Ｃの生成物（５０ｍｇ、０．０５２ｍｍｏｌ）をジオキサン（１．５ｍＬ）および塩酸／ジオキサン（４．０Ｎ、０．６５ｍＬ、２．６ｍｍｏｌ）に溶かし、混合物を室温で４時間撹拌した。その後、混合物を濃縮して標題化合物を塩酸塩として得た。ＭＳ（ＥＳＩ）ｍ／ｚ７６５（Ｍ＋Ｈ）^＋。

Example 9D
1-(4-((2R, 5R) -2,5-bis (4-(2-((S) -pyrrolidine-2-yl) -1H-imidazol-4-yl) phenyl) pyrrolidine-1-yl) ) -2,6-Difluorophenyl) -4-phenylpiperidine The product of Example 9C (50 mg, 0.052 mmol) was mixed with dioxane (1.5 mL) and hydrochloric acid / dioxane (4.0 N, 0.65 mL, 2.6 mmol). ), And the mixture was stirred at room temperature for 4 hours. The mixture was then concentrated to give the title compound as hydrochloride. MS (ESI) m / z765 (M + H) ⁺ .

Example 9E
Methyl {(2S) -1-[(2S) -2-(4- {4-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl) ] -5- (4- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-imidazole-4 -Il} phenyl) pyrrolidine-2-yl] phenyl} -1H-imidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate Product from Example 9D ( 40 mg, 0.052 mmol), (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (18.3 mg, 0.105 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (22.1 mg, 0.115 mmol), 1-hydroxybenzotriazole hydrate (17.6 mg, 0.115 mmol) and 4-methylmorpholin (0.046 mL, 0.418 mmol) were dissolved in DMF (1.5 mL). , The mixture was stirred at room temperature for 19 hours. Then, 1N aqueous hydrochloric acid solution was added, and then the mixture was extracted with dichloromethane. The organic extract was dehydrated, filtered, concentrated and the residue was purified by chromatography (silica gel, methanol / dichloromethane) to give the title compound 25 mg (44%). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 7.64 (m, 5H), 7.23 (m, 11H), 5.89 (d, J = 12.8Hz, 2H), 5.23 (m, 2H), 5.08 (m, 2H), 4.06 (m, 2H), 3.80 (m, 4H), 3.53 (s, 6H), 2.96 (m, 4H), 2. 18 (m, 2H), 1.99 (m, 6H), 1.70 (m, 6H), 0.83 (m, 12H); MS (ESI) m / z 1080 (M + H) ⁺ .

From the product of General Procedure 11C, (1) the step of coupling with (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid; (2) the step of elimination of one Boc protecting group; and (3) The compounds of Examples 10.1 and 10.2 can be obtained by the step of coupling with the second selected carbamate protected amino acid.

実施例１０．１
メチル［（１Ｓ）−２−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ，３ａＳ，６ａＳ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝オクタヒドロシクロペンタ［ｂ］ピロール−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エチル］カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７０−０．９１（ｍ、６Ｈ）１．１０−１．２７（ｍ、２Ｈ）１．３４−１．４９（ｍ、８Ｈ）１．５０−１．６４（ｍ、４Ｈ）１．６５−１．８１（ｍ、４Ｈ）１．８４−２．０３（ｍ、６Ｈ）２．０５−２．１８（ｍ、４Ｈ）２．３６−２．４６（ｍ、４Ｈ）２．７２−２．８６（ｍ、６Ｈ）３．０２−３．２１（ｍ、２Ｈ）３．５４（ｓ、６Ｈ）３．７０−３．８９（ｍ、２Ｈ）３．９７−４．１７（ｍ、２Ｈ）４．７２−４．８６（ｍ、２Ｈ）５．０７−５．２０（ｍ、２Ｈ）５．３２−５．４３（ｍ、２Ｈ）５．８４−５．９４（ｍ、２Ｈ）７．０７（ｔ、Ｊ＝１０．０８Ｈｚ、２Ｈ）７．１７−７．２７（ｍ、２Ｈ）７．３０−７．５６（ｍ、４Ｈ）１１．９２−１１．９９（ｍ、１Ｈ）１２．０３−１２．１３（ｍ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０７３．４（Ｍ＋Ｈ）^＋。

Example 10.1
Methyl [(1S) -2-[(2S, 3aS, 6aS) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl]- 5- {2-[(2S, 3aS, 6aS) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} octahydrocyclopenta [b] pyrrole-2-yl] -1H-benzimidazole-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -2-oxo-1-( Tetrahydro-2H-pyran-4-yl) ethyl] benzimidazole
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.70-0.91 (m, 6H) 1.10-1.27 (m, 2H) 1.34-1.49 (m, 8H) 1.50 -1.64 (m, 4H) 1.65-1.81 (m, 4H) 1.84-2.03 (m, 6H) 2.05-2.18 (m, 4H) 2.36-2 .46 (m, 4H) 2.72-2.86 (m, 6H) 3.02-3.21 (m, 2H) 3.54 (s, 6H) 3.70-3.89 (m, 2H) ) 3.97-4.17 (m, 2H) 4.72-4.86 (m, 2H) 5.07-5.20 (m, 2H) 5.32-5.43 (m, 2H) 5 .84-5.94 (m, 2H) 7.07 (t, J = 10.08Hz, 2H) 7.17-7.27 (m, 2H) 7.30-7.56 (m, 4H) 11 .92-11.99 (m, 1H) 12.03-12.13 (m, 1H); MS (ESI +) m / z1073.4 (M + H) ⁺ .

実施例１０．２
メチル｛（２Ｓ，３Ｒ）−１−［（２Ｓ，３ａＳ，６ａＳ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（ピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ，３ａＳ，６ａＳ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝オクタヒドロシクロペンタ［ｂ］ピロール−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ヘキサヒドロシクロペンタ［ｂ］ピロール−１（２Ｈ）−イル］−３−メトキシ−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７０−０．８９（ｍ、６Ｈ）０．９９（ｄｄｄ、Ｊ＝３４．４３、６．２９、３．３１Ｈｚ、３Ｈ）１．３５−１．４８（ｍ、６Ｈ）１．５０−１．６３（ｍ、４Ｈ）１．６６−１．８０（ｍ、６Ｈ）１．８３−２．００（ｍ、６Ｈ）２．０５−２．１６（ｍ、４Ｈ）２．７２−２．８３（ｍ、４Ｈ）３．１７（ｓ、３Ｈ）３．２１−３．２８（ｍ、４Ｈ）３．５４（ｓ、６Ｈ）４．０２（ｔ、Ｊ＝７．４８Ｈｚ、１Ｈ）４．２０−４．３０（ｍ、１Ｈ）４．８０（ｔ、Ｊ＝７．９７Ｈｚ、２Ｈ）５．０８−５．１７（ｍ、２Ｈ）５．３２−５．４３（ｍ、２Ｈ）５．８３−５．９４（ｍ、２Ｈ）７．０５（ｄｄ、Ｊ＝８．２４、１．３０Ｈｚ、２Ｈ）７．２１（ｓ、１Ｈ）７．３０（ｄ、Ｊ＝３．１４Ｈｚ、１Ｈ）７．４０（ｄ、Ｊ＝７．９２Ｈｚ、１Ｈ）７．４５−７．５６（ｍ、３Ｈ）１１．９９（ｄｄ、Ｊ＝９．８７、１．６３Ｈｚ、１Ｈ）１２．０４−１２．１３（ｍ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０４７．５（Ｍ＋Ｈ）^＋。

Example 10.2
Methyl {(2S, 3R) -1-[(2S, 3aS, 6aS) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (piperidine-1-yl) phenyl) ] -5- {2-[(2S, 3aS, 6aS) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} octahydrocyclopenta [b] pyrrole-2- Il] -1H-benzimidazol-5-yl} pyrrolidine-2-yl] -1H-benzimidazol-2-yl} hexahydrocyclopenta [b] pyrrole-1 (2H) -yl] -3-methoxy-1 -Oxobutane-2-yl} carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.70-0.89 (m, 6H) 0.99 (ddd, J = 34.43, 6.29, 3.31 Hz, 3H) 1.35-1 .48 (m, 6H) 1.50-1.63 (m, 4H) 1.66-1.80 (m, 6H) 1.83-2.00 (m, 6H) 2.05-2.16 (M, 4H) 2.72-2.83 (m, 4H) 3.17 (s, 3H) 3.21-3.28 (m, 4H) 3.54 (s, 6H) 4.02 (t) , J = 7.48Hz, 1H) 4.20-4.30 (m, 1H) 4.80 (t, J = 7.97Hz, 2H) 5.08-5.17 (m, 2H) 5.32 -5.43 (m, 2H) 5.83-5.94 (m, 2H) 7.05 (dd, J = 8.24, 1.30Hz, 2H) 7.21 (s, 1H) 7.30 (D, J = 3.14Hz, 1H) 7.40 (d, J = 7.92Hz, 1H) 7.45-7.56 (m, 3H) 11.99 (dd, J = 9.87, 1) .63Hz, 1H) 12.04-12.13 (m, 1H); MS (ESI +) m / z 1047.5 (M + H) ⁺ .

General Procedure 8B From the product of Example 1B (mono-substitution) to (1) the step of Buchwald reaction with a suitable second amide (see General Procedure 8); (2) Nitro reduction (see General Procedure 9). Steps; and (3) Cyclization (see General Procedure 10) can give compounds of Examples 11.1 and 11.2.

実施例１１．１
メチル［（１Ｓ）−２−［（２Ｓ）−２−｛５−［（２Ｒ，５Ｒ）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］−５−｛２−［（２Ｓ）−１−｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３−メチルブタノイル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−５−イル｝ピロリジン−２−イル］−１Ｈ−ベンズイミダゾール−２−イル｝ピロリジン−１−イル］−２−オキソ−１−（テトラヒドロ−２Ｈ−ピラン−４−イル）エチル］カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７４−０．９１（ｍ、６Ｈ）１．４４−１．５６（ｍ、２Ｈ）１．６２−１．７５（ｍ、６Ｈ）１．８２−１．９５（ｍ、２Ｈ）１．９７−２．０７（ｍ、４Ｈ）２．１６−２．２６（ｍ、４Ｈ）２．８７−３．１６（ｍ、７Ｈ）３．４３−３．５０（ｍ、２Ｈ）３．５３（ｓ、６Ｈ）３．５８−３．６６（ｍ、２Ｈ）３．７０−３．７８（ｍ、２Ｈ）３．８０−３．８９（ｍ、４Ｈ）４．０６（ｔ、Ｊ＝８．５１Ｈｚ、２Ｈ）５．１１−５．１９（ｍ、２Ｈ）５．３３−５．４３（ｍ、２Ｈ）５．８６−５．９５（ｍ、２Ｈ）７．０６−７．１１（ｍ、２Ｈ）７．１２−７．３７（ｍ、９Ｈ）７．４２（ｄｄ、Ｊ＝７．９２、１．７３Ｈｚ、１Ｈ）７．４６−７．５３（ｍ、１Ｈ）１２．０４−１２．２０（ｍ、２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ１０６９．４（Ｍ＋Ｈ）^＋。

Example 11.1
Methyl [(1S) -2-[(2S) -2-{5-[(2R, 5R) -1- [3,5-difluoro-4- (4-phenylpiperidin-1-yl) phenyl] -5] − {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-benzimidazole-5-yl} pyrrolidine- 2-Il] -1H-benzimidazol-2-yl} pyrrolidine-1-yl] -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethyl] carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.74-0.91 (m, 6H) 1.44-1.56 (m, 2H) 1.62-1.75 (m, 6H) 1.82 -1.95 (m, 2H) 1.97-2.07 (m, 4H) 2.16-2.26 (m, 4H) 2.87-3.16 (m, 7H) 3.43-3 .50 (m, 2H) 3.53 (s, 6H) 3.58-3.66 (m, 2H) 3.70-3.78 (m, 2H) 3.80-3.89 (m, 4H) ) 4.06 (t, J = 8.51Hz, 2H) 5.11-5.19 (m, 2H) 5.33-5.43 (m, 2H) 5.86-5.95 (m, 2H) ) 7.06-7.11 (m, 2H) 7.12-7.37 (m, 9H) 7.42 (dd, J = 7.92, 1.73Hz, 1H) 7.46-7.53 (M, 1H) 12.04-12.20 (m, 2H); MS (ESI +) m / z 1069.4 (M + H) ⁺ .

実施例１１．２
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛（２Ｒ，５Ｒ）−５−（２−シクロペンチル−１Ｈ−ベンズイミダゾール−５−イル）−１−［３，５−ジフルオロ−４−（４−フェニルピペリジン−１−イル）フェニル］ピロリジン−２−イル｝−１Ｈ−ベンズイミダゾール−２−イル）ピロリジン−１−イル］−３−メチル−１−オキソブタン−２−イル｝カーバメート
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）δｐｐｍ０．７６−０．９１（ｍ、６Ｈ）１．５９−１．７３（ｍ、１０Ｈ）１．７３−１．８０（ｍ、２Ｈ）１．８３−１．９４（ｍ、４Ｈ）１．９７−２．０８（ｍ、４Ｈ）２．１６−２．２４（ｍ、１Ｈ）２．８６−３．０４（ｍ、６Ｈ）３．１９−３．２９（ｍ、１Ｈ）３．５３（ｓ、３Ｈ）３．７９−３．８７（ｍ、２Ｈ）５．１１−５．１９（ｍ、１Ｈ）５．３４−５．４２（ｍ、２Ｈ）５．８８−５．９５（ｍ、２Ｈ）７．０３−７．１１（ｍ、２Ｈ）７．１３−７．１９（ｍ、２Ｈ）７．２０−７．２７（ｍ、４Ｈ）７．２８−７．３４（ｍ、２Ｈ）７．４０（ｄｄ、Ｊ＝１３．８８、８．２４Ｈｚ、１Ｈ）７．５０（ｄ、Ｊ＝８．０２Ｈｚ、１Ｈ）１２．０５（ｄ、Ｊ＝１０．６３Ｈｚ、１Ｈ）１２．１２（ｄ、Ｊ＝３．９０Ｈｚ、１Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ８６９．４（Ｍ＋Ｈ）^＋。

Example 11.2
Methyl {(2S) -1-[(2S) -2-(5-{(2R, 5R) -5- (2-cyclopentyl-1H-benzimidazol-5-yl) -1- [3,5-difluoro) -4- (4-Phenylpiperidine-1-yl) phenyl] pyrrolidine-2-yl} -1H-benzimidazol-2-yl) pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} Carbamate
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δppm 0.76-0.91 (m, 6H) 1.59-1.73 (m, 10H) 1.73-1.80 (m, 2H) 1.83 -1.94 (m, 4H) 1.97-2.08 (m, 4H) 2.16-2.24 (m, 1H) 2.86-3.04 (m, 6H) 3.19-3 .29 (m, 1H) 3.53 (s, 3H) 3.79-3.87 (m, 2H) 5.11-5.19 (m, 1H) 5.34-5.42 (m, 2H) ) 5.88-5.95 (m, 2H) 7.03-7.11 (m, 2H) 7.13-7.19 (m, 2H) 7.20-7.27 (m, 4H) 7 .28-7.34 (m, 2H) 7.40 (dd, J = 13.88, 8.24Hz, 1H) 7.50 (d, J = 8.02Hz, 1H) 12.05 (d, J) = 10.63Hz, 1H) 12.12 (d, J = 3.90Hz, 1H); MS (ESI +) m / z 869.4 (M + H) ⁺ .

Example 12.1
Methyl {(2S) -1-[(2S) -2-(5-{3- [1- (4-tert-butylphenyl) -3- (3- {2-[(2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-imidazole-5-yl} phenyl) azetidine-3-yl] phenyl} -1H-imidazole-2 -Il) pyrrolidine-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate

Example 12.1A
N-BuLi (26.5 mL, 42.4 mmol, 1.6 M hexane) in a solution of bis (3-bromophenyl) methanol 1,3-dibromobenzene (10 g, 42.4 mmol) in THF (50 mL) at −78 ° C. Medium solution) was added. After stirring at −78 ° C. for 2 hours, 3-bromobenzaldehyde (7.84 g, 42.4 mmol) was added to the reaction mixture. The temperature of the reaction mixture was raised to room temperature, and the mixture was stirred at 30 ° C. for 12 hours. It was quenched with aqueous NH ₄ Cl (100 mL). The mixture was extracted with dichloromethane (80 mL 5 times). The combined organic layers were dehydrated and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether to petroleum ether: EtOAc = 20: 1 elution) to give 8.4 g of the title compound (24.5 mmol, 58%). LC / MS: [M-18 + 1] = 325. ^{1 1} H NMR (DMSO-d ₆ ), 400 MHz: δ5.74 (d, 1H, J = 4.0 Hz), 6.19 (d, 1H, J = 4.4 Hz), 7.26-7.31 ( m, 2H), 7.37-7.43 (m, 4H), 7.59 (s, 2H).

Example 12.1B
Bis (3-bromophenyl) metanon MnO ₂ (21.61 g, 249 mmol) was added to a solution of bis (3-bromophenyl) methanol (8.4 g, 24.5 mmol) in dichloromethane (80 mL). The mixture was stirred at 25 ° C. for 12 hours and filtered. The filter cake was washed with dichloromethane (60 mL 5 times). The filtrate was concentrated to give 7.6 g of the title compound (22.3 mmol, 90%). LC / MS: [M + 1] = 341. ^{1 1} H NMR (DMSO-d ₆ ), 400 MHz: δ7.52-7.56 (m, 2H), 7.71 (d, 2H, J = 7.2 Hz), 7.88-7.92 (m, 4H).

実施例１２．１Ｃ
２，２−ビス（３−ブロモフェニル）オキシラン
ビス（３−ブロモフェニル）メタノン（７．５ｇ、２２．０６ｍｍｏｌ）およびヨウ化トリメチルスルホニウム（４．５０ｇ、２２．０６ｍｍｏｌ）のＤＭＳＯ（２０ｍＬ）中懸濁液を撹拌しながら、それにＫＯｔ−Ｂｕ（２．７２ｇ、２４．２６ｍｍｏｌ）を加え、得られた混合物を３０℃で８時間撹拌した。混合物を酢酸エチル（５００ｍＬ）で希釈し、水（５００ｍＬで３回）およびブライン（５００ｍＬ）で洗浄した。有機層を分離し、減圧下に溶媒留去して標題化合物を得て、それをそれ以上精製せずに直接用いた。

Example 12.1C
Suspension of 2,2-bis (3-bromophenyl) oxylambis (3-bromophenyl) metanone (7.5 g, 22.06 mmol) and trimethylsulfonium iodide (4.50 g, 22.06 mmol) in DMSO (20 mL) While stirring the turbid liquid, KOt-Bu (2.72 g, 24.26 mmol) was added thereto, and the obtained mixture was stirred at 30 ° C. for 8 hours. The mixture was diluted with ethyl acetate (500 mL) and washed with water (500 mL 3 times) and brine (500 mL). The organic layer was separated and the solvent was evaporated under reduced pressure to give the title compound, which was used directly without further purification.

実施例１２．１Ｄ
２，２−ビス（３−ブロモフェニル）プロパン−１，３−ジオール
粗２，２−ビス（３−ブロモフェニル）オキシラン（７．４ｇ、２０．９０ｍｍｏｌ）およびｐ−トルエンスルホン酸・１水和物（３６０ｍｇ、２．１ｍｍｏｌ）のトルエン（２５ｍＬ）中混合物を９５℃で１時間撹拌した。溶液をＮａＨＣＯ_３水溶液（１０ｍＬ）および水（２０ｍＬ）で洗浄した。有機層を脱水し、濃縮した。残留物をＥｔＯＨ（２０ｍＬ）に溶かした。その溶液に、ホルムアルデヒド（１５．５６ｍＬ、２０９ｍｍｏｌ、３７％水溶液）およびＫ_２ＣＯ_３（１．４４ｇ、１０．４５ｍｍｏｌ）を加えた。混合物を８５℃で１２時間撹拌した。冷却して室温とした後、反応混合物を水（５０ｍＬ）で希釈し、ジクロロメタンで抽出した（６０ｍＬで４回）。合わせた有機層を脱水し、濃縮した。残留物をカラムクロマトグラフィー（シリカゲル、石油エーテル約石油エーテル：ＥｔＯＡｃ＝２：１で溶離）によって精製して、２，２−ビス（３−ブロモフェニル）プロパン−１，３−ジオール４．６ｇを得た（１１．９ｍｍｏｌ、２段階後に５７％）。ＬＣ／ＭＳ：［Ｍ−１８＋１］＝３６８。^１Ｈ ＮＭＲ（ＣＤＣｌ_３）、４００ＭＨｚ：δ２．５３（ｂｒｓ、２Ｈ）、２．４１（ｓ、４Ｈ）、７．０９−７．２０（ｍ、４Ｈ）、７．３６−７．４０（ｍ、４Ｈ）。

Example 12.1D
2,2-bis (3-bromophenyl) propane-1,3-diol crude 2,2-bis (3-bromophenyl) oxylane (7.4 g, 20.90 mmol) and p-toluenesulfonic acid monohydrate A mixture of the product (360 mg, 2.1 mmol) in toluene (25 mL) was stirred at 95 ° C. for 1 hour. The solution was washed with ₃ aqueous NaHCO solution (10 mL) and water (20 mL). The organic layer was dehydrated and concentrated. The residue was dissolved in EtOH (20 mL). To the solution, formaldehyde (15.56mL, 209mmol, 37% aqueous solution) and _{K 2 CO 3 (1.44g, 10.45mmol} ) was added. The mixture was stirred at 85 ° C. for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mL 4 times). The combined organic layers were dehydrated and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether, about petroleum ether: EtOAc = 2: 1 elution) to give 4.6 g of 2,2-bis (3-bromophenyl) propane-1,3-diol. Obtained (11.9 mmol, 57% after 2 steps). LC / MS: [M-18 + 1] = 368. ^{1 1} H NMR (CDCl ₃ ), 400 MHz: δ2.53 (brs, 2H), 2.41 (s, 4H), 7.09-7.20 (m, 4H), 7.36-7.40 (m) 4H).

実施例１２．１Ｅ
ジメタンスルホン酸２，２−ビス（３−ブロモフェニル）プロパン−１，３−ジイル
２，２−ビス（３−ブロモフェニル）プロパン−１，３−ジオール（６．０ｇ、１５．５４ｍｍｏｌ）のジクロロメタン（５０ｍＬ）中溶液を０℃で撹拌しながら、それにメタンスルホニルクロライド（２７．１ｇ、１５５ｍｍｏｌ）およびＥｔ_３Ｎ（１７．３ｍＬ、１２４ｍｍｏｌ）を加えて、橙赤色溶液を得た。反応混合物を０℃で１時間撹拌し、次に４０℃で８時間撹拌した。反応液をＮＨ_４Ｃｌ水溶液（８０ｍＬ）で洗浄した。水層をジクロロメタンで抽出した（５０ｍＬで３回）。合わせた有機層を脱水し、濃縮した。残留物をクロマトグラフィー（シリカゲルカラム、石油エーテル：ＥｔＯＡｃ＝２：１）によって精製して、標題化合物３．２ｇを得た（５．９ｍｍｏｌ、３８％）。ＬＣ／ＭＳ：［Ｍ＋１８］＝５６０。^１Ｈ ＮＭＲ（ＣＤＣｌ_３）、４００ＭＨｚ：δ２．９３（ｓ、６Ｈ）、４．４９（ｓ、４Ｈ）、７．１５−７．４８（ｍ、８Ｈ）。

Example 12.1E
Dimethanesulfonic acid 2,2-bis (3-bromophenyl) propane-1,3-diyl 2,2-bis (3-bromophenyl) propane-1,3-diol (6.0 g, 15.54 mmol) while stirring dichloromethane (50 mL) was treated at 0 ° C., it methanesulfonyl chloride (27.1 g, 155 mmol) and _Et 3 N _{(17.3mL, 124mmol)} was added to give a orange solution. The reaction mixture was stirred at 0 ° C. for 1 hour and then at 40 ° C. for 8 hours. The reaction mixture was washed with aqueous _NH 4 Cl (80 mL) and. The aqueous layer was extracted with dichloromethane (3 times at 50 mL). The combined organic layers were dehydrated and concentrated. The residue was purified by chromatography (silica gel column, petroleum ether: EtOAc = 2: 1) to give 3.2 g of the title compound (5.9 mmol, 38%). LC / MS: [M + 18] = 560. ^{1 1} H NMR (CDCl ₃ ), 400 MHz: δ2.93 (s, 6H), 4.49 (s, 4H), 7.15-7.48 (m, 8H).

実施例１２．１Ｆ
メタンスルホン酸３−アジド−２，２−ビス（３−ブロモフェニル）プロピル
Ｎ_２下に、ジメタンスルホン酸２，２−ビス（３−ブロモフェニル）プロパン−１，３−ジイル（３．６ｇ、６．６４ｍｍｏｌ）のＤＭＰＵ（２５ｍＬ、２０７ｍｍｏｌ）中溶液にＮａＮ_３（０．５２ｇ、７．９７ｍｍｏｌ）を撹拌しながら加えた。混合物を加熱して１１０℃として５時間経過させた。冷却して室温とした後、反応混合物をＥｔＯＡｃ（１００ｍＬ）で希釈し、水（３０ｍＬで２回）およびブライン（２５ｍＬ）で洗浄し、脱水し、濃縮した。残留物をカラムクロマトグラフィー（シリカゲル、石油エーテル：ＥｔＯＡｃ＝３：１で溶離）によって精製して、標題化合物１．３ｇ（２．６６ｍｍｏｌ、４０％）を得た。ＬＣ／ＭＳ：［Ｍ＋１８］＝５０７．^１Ｈ ＮＭＲ（ＣＤＣｌ_３）、４００ＭＨｚ：δ２．８３（ｓ、３Ｈ）、４．０７（ｓ、２Ｈ）、４．７７（ｓ、２Ｈ）、７．０７−７．０９（ｍ、２Ｈ）、７．２１−７．３１（ｍ、４Ｈ）、７．４４−７．４６（ｍ、２Ｈ）。

Example 12.1F
Methanesulfonic acid 3-azido-2,2-bis (3-bromophenyl) propyl N ₂ under, di- methanesulfonic acid 2,2-bis (3-bromophenyl) propane-1,3-diyl (3.6 g , 6.64 mmol) of NaN ₃ (0.52 g, 7.97 mmol) in a solution in DMPU (25 mL, 207 mmol) with stirring. The mixture was heated to 110 ° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), washed with water (twice at 30 mL) and brine (25 mL), dehydrated and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether: eluted with EtOAc = 3: 1) to give 1.3 g (2.66 mmol, 40%) of the title compound. LC / MS: [M + 18] = 507. ^{1 1} H NMR (CDCl ₃ ), 400 MHz: δ2.83 (s, 3H), 4.07 (s, 2H), 4.77 (s, 2H), 7.07-7.09 (m, 2H), 7.21-7.31 (m, 4H), 7.44-7.46 (m, 2H).

実施例１２．１Ｇ
ホスホン酸ジエチル３，３−ビス（３−ブロモフェニル）アゼチジン−１−イル
Ｎ_２下に、メタンスルホン酸３−アジド−２，２−ビス（３−ブロモフェニル）プロピル（１．３ｇ、２．６６ｍｍｏｌ）の脱水トルエン（１０ｍＬ）および脱水ＴＨＦ（５ｍＬ）中溶液に、２５℃でトリエチルホスファイト（０．４９ｍＬ、２．７９ｍｍｏｌ）を加えた。混合物を１８時間撹拌した。乾燥容器中、反応液をロータリーエバポレータによって濃縮した。残留物を真空乾燥し、それ以上精製せずに次の段階で用いた。Ｎ_２下に、粗トリエチルホスホルイミデートを脱水ｍ−キシレン（５ｍＬ）に溶かし、１５０℃の油浴で１２時間加熱した。冷却して室温とした後、溶媒をロータリーエバポレータによって除去して（真空ポンプで支援）、粘稠明橙赤色油状物を得て、それを分取ＴＬＣ（ＥｔＯＡｃ：ジクロロメタン＝１：５で溶離）によって精製して、ホスホン酸ジエチル３，３−ビス（３−ブロモフェニル）アゼチジン−１−イル９６０ｍｇを得た（１．９ｍｍｏｌ、２段階後に７１％）。ＬＣ／ＭＳ：［Ｍ＋１］＝５０４．^１Ｈ ＮＭＲ（ＣＤＣｌ_３）、４００ＭＨｚ：δ１．２５−１．３６（ｍ、６Ｈ）、４．０５−４．３９（ｍ、４Ｈ）、４．４０（ｄ、２Ｈ、Ｊ＝５．２Ｈｚ）、７．０９−７．１１（ｍ、２Ｈ）、７．２０−７．２７（ｍ、２Ｈ）、７．４０−７．４２（ｍ、４Ｈ）。

Example 12.1G
Phosphonic acid diethyl 3,3-bis (3-bromophenyl) azetidin-1-yl under N _2, methanesulfonic acid 3-azido-2,2-bis (3-bromophenyl) propyl (1.3 g, 2. To a solution of 66 mmol) in dehydrated toluene (10 mL) and dehydrated THF (5 mL) was added triethylphosphite (0.49 mL, 2.79 mmol) at 25 ° C. The mixture was stirred for 18 hours. The reaction solution was concentrated by a rotary evaporator in a drying vessel. The residue was vacuum dried and used in the next step without further purification. Under N _2, the crude triethyl phosphoramidate imidate was dissolved in anhydrous m- xylene (5 mL), and heated in an oil bath at 0.99 ° C. 12 hours. After cooling to room temperature, the solvent is removed with a rotary evaporator (assisted by a vacuum pump) to give a viscous orange-red oil, which is fractionated TLC (Eluted at EtOAc: dichloromethane = 1: 5). To obtain 960 mg of diethyl 3,3-bis (3-bromophenyl) azetidine-1-yl phosphonate (1.9 mmol, 71% after 2 steps). LC / MS: [M + 1] = 504. ^{1 1} H NMR (CDCl ₃ ), 400 MHz: δ1.25-1.36 (m, 6H), 4.05-4.39 (m, 4H), 4.40 (d, 2H, J = 5.2 Hz) , 7.09-7.11 (m, 2H), 7.20-7.27 (m, 2H), 7.40-7.42 (m, 4H).

実施例１２．１Ｈ
３，３−ビス（３−ブロモフェニル）アゼチジン
Ｎ_２下に、ホスホン酸ジエチル３，３−ビス（３−ブロモフェニル）アゼチジン−１−イル（９６０ｍｇ、１．９ｍｍｏｌ）の脱水ジクロロメタン（５ｍＬ）中溶液に、ＴＦＡ（５ｍＬ）を加えた。混合物を２０℃で３時間撹拌し、ロータリーエバポレータによって濃縮した。残留物をジクロロメタン（２０ｍＬ）に溶かし、ＮａＨＣＯ_３水溶液（３０ｍＬ）で洗浄した。有機層を脱水し、濃縮し、標題化合物５９５ｍｇ（１．６ｍｍｏｌ、８５％）を黄色油状物として得て、それを精製せずに次の段階に直接用いた。ＬＣ／ＭＳ：［Ｍ＋１］＝３６８。

Example 12.1H
In dehydrated dichloromethane (5 mL) of diethyl phosphonate 3,3-bis (3-bromophenyl) azetidine-1-yl (960 mg, 1.9 mmol) under 3,3-bis (3-bromophenyl) azetidine N _2. TFA (5 mL) was added to the solution. The mixture was stirred at 20 ° C. for 3 hours and concentrated by rotary evaporator. The residue was dissolved in dichloromethane (20 mL) and washed with aqueous NaHCO ₃ solution (30 mL). The organic layer was dehydrated and concentrated to give 595 mg (1.6 mmol, 85%) of the title compound as a yellow oil, which was used directly in the next step without purification. LC / MS: [M + 1] = 368.

実施例１２．１Ｉ
３，３−ビス（３−ブロモフェニル）−１−（４−ｔｅｒｔ−ブチルフェニル）アゼチジン
３，３−ビス（３−ブロモフェニル）アゼチジン（６０ｍｇ、０．１６３ｍｍｏｌ）、１−ｔｅｒｔ−ブチル−４−ヨードベンゼン（８５ｍｇ、０．３２７ｍｍｏｌ）、ｘａｎｔｐｈｏｓ（９．４６ｍｇ、０．０１６ｍｍｏｌ）、Ｐｄ_２（ｄｂａ）_３（３．７４ｍｇ、４．０９μｍｏｌ）およびｔｅｒｔ−ブトキシド（１８．８５ｍｇ、０．１９６ｍｍｏｌ）のジオキサン（５ｍＬ）中混合物を１１０℃で１２時間撹拌した。反応液を冷却して室温とした後、水（１５ｍＬ）およびジクロロメタン（１５ｍＬ）を加えた。水相をジクロロメタンで抽出した（１５ｍＬで３回）。合わせた有機層を脱水し、濃縮した。残留物を分取ＨＰＬＣ（装置：ｗａｔｅｒｓ ２７６７ ＰＨＷ００４、カラム：ＹＭＣ−Ｔｒｉａｒｔ Ｃ１８ １５０×２０ｍｍ Ｓ−５μｍ。１２ｎｍ、移動相Ａ：水（０．０５％ＮＨ_４ＨＣＯ_３）Ｂ：ＡＣＮ勾配９５−９５％Ｂで８分、１４分で停止、流量（ｍＬ／分）：２０．００、検出波長（ｎｍ）：２１４／２５４、保持時間（分）：７．４）によって精製して、標題化合物２６ｍｇを得た（０．０５２ｍｍｏｌ、収率３１．８％）。ＬＣ／ＭＳ：［Ｍ＋１］＝５００。

Example 12.1I
3,3-bis (3-Bromophenyl) -1- (4-tert-butylphenyl) azetidine 3,3-bis (3-bromophenyl) azetidine (60 mg, 0.163 mmol), 1-tert-butyl-4 -Iodobenzene (85 mg, 0.327 mmol), xanthphos (9.46 mg, 0.016 mmol), Pd ₂ (dba) ₃ (3.74 mg, 4.09 μmol) and tert-butoxide (18.85 mg, 0.196 mmol). The mixture in dioxane (5 mL) was stirred at 110 ° C. for 12 hours. After cooling the reaction to room temperature, water (15 mL) and dichloromethane (15 mL) were added. The aqueous phase was extracted with dichloromethane (15 mL 3 times). The combined organic layers were dehydrated and concentrated. Preparative HPLC of residue (equipment: waters 2767 PHW004, column: YMC-Triart C18 150 × 20 mm S-5 μm. 12 nm, mobile phase A: water (0.05% NH ₄ HCO ₃ ) B: ACN gradient 95-95 Stop at% B for 8 minutes and 14 minutes, purify by flow rate (mL / min): 20.00, detection wavelength (nm): 214/254, retention time (minutes): 7.4), and title compound 26 mg. Was obtained (0.052 mmol, yield 31.8%). LC / MS: [M + 1] = 500.

実施例１２．１Ｊ
１−（４−ｔｅｒｔ−ブチルフェニル）−３，３−ビス（３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）アゼチジン
Ｎ_２下に、３，３−ビス（３−ブロモフェニル）−１−（４−ｔｅｒｔ−ブチルフェニル）アゼチジン（５０ｍｇ、０．１００ｍｍｏｌ）、ビス（ピナコラト）ジボロン（６５．９ｍｇ、０．２６０ｍｍｏｌ）、ＫＯＡｃ（５８．８ｍｇ、０．５９９ｍｍｏｌ）およびＰｄＣｌ_２（ｄｐｐｆ）−ＣＨ_２Ｃｌ_２付加物（２０．３９ｍｇ、０．０２５ｍｍｏｌ）の混合物を１００℃で２時間撹拌した。冷却して室温とした後、水（１５ｍＬ）およびジクロロメタン（１５ｍＬ）を加えた。水層をジクロロメタンで抽出した（１５ｍＬで３回）。合わせた有機層を脱水し、濃縮した。残留物をによって精製し分取ＴＬＣ（ジクロロメタン：ヘキサン＝１：１で溶離）によって、標題化合物５０ｍｇを得た（０．０７８ｍｍｏｌ、収率７８％）。ＬＣ／ＭＳ：［Ｍ−Ｃ_１２Ｈ_２０＋１］＝４３０；［Ｍ−Ｃ_６Ｈ_１０＋１］＝５１２。

Example 12.1J
1-(4-tert-butylphenyl) -3,3-bis (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidin under N ₂ , 3,3-bis (3-bromophenyl) -1- (4-tert-butylphenyl) azetidine (50 mg, 0.100 mmol), bis (pinacolato) diboron (65.9 mg, 0.260 mmol), KOAc (58) A mixture of .8 mg, 0.599 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (20.39 mg, 0.025 mmol) was stirred at 100 ° C. for 2 hours. After cooling to room temperature, water (15 mL) and dichloromethane (15 mL) were added. The aqueous layer was extracted with dichloromethane (15 mL 3 times). The combined organic layers were dehydrated and concentrated. The residue was purified by preparative TLC (dichloromethane: hexane = 1: 1 elution) to give 50 mg of the title compound (0.078 mmol, 78% yield). LC / MS: [MC ₁₂ H ₂₀ +1] = 430; [MC ₆ H ₁₀ +1] = 512.

Example 12.1K
Methyl {(2S) -1-[(2S) -2-(5-{3- [1- (4-tert-butylphenyl) -3- (3- {2-[(2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine-2-yl] -1H-imidazole-5-yl} phenyl) azetidine-3-yl] phenyl} -1H-imidazole-2 -Il ) pyrrolidine-1-yl] -3-methyl-1-oxobutane-2-yl} carbamate 1- (4-tert-butylphenyl) -3,3-bis (3- (4,4,5,5) -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidine (50 mg, 0.084 mmol), intermediate 4 (66.0 mg, 0.177 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (13.76mg, 0.017mmol) and was _{K 2 CO 3 (69.9mg, 0.506mmol} ) in dioxane (5 mL) in a mixture of was stirred for 2 hours at 100 ° C.. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (20 mL), washed with aqueous _NH 4 Cl (15 mL). The aqueous layer was extracted with dichloromethane (15 mL 3 times) and the combined organic layers were washed with brine (25 mL), dehydrated and concentrated. Preparative HPLC (Equipment: Waters2767 PHW003, Column: Boston C18 10 μm 21 × 250 mm, Mobile Phase A: Water (0.05% NH ₄ HCO ₃ ); B: ACN Gradient 60-82% B for 8 minutes , Stopped at 14 minutes, flow rate (mL / min): 30.00, detection wavelength (nm): 214/254, retention time (minutes): 8.32). After the first purification by preparative HPLC, the purity was 83%. The compound was further purified by preparative TLC (MeOH: dichloromethane = 1:15 elution) to give 22 mg of the title compound (0.024 mmol, yield 28.2%). LC / MS: [M + 1] = 926. ^{1 1} H NMR (MeOD-d ₄ ), 400 MHz: δ0.77-0.85 (m, 12H), 1.18 (s, 9H), 1.88-2.23 (m, 10H), 3.07 (D, 2H, J = 6.4Hz), 3.56 (s, 6H), 3.75-3.89 (m, 4H), 4.12-4.14 (m, 2H), 4.36 -4.42 (m, 4H), 5.03-5.07 (m, 2H), 6.46-6.48 (m, 2H), 6.73-6.77 (m, 1H), 7 .10-7.23 (m, 9H), 7.39-7.41 (m, 2H), 7.68-7.72 (m, 2H).

Example 12.2
Methyl {(2S) -1-[(2S) -2-(5-{3- [3- (3- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-imidazol-5-yl} phenyl) -1-phenylazetidine-3-yl] phenyl} -1H-imidazol-2-yl) pyrrolidine-1 -Il] -3-methyl-1-oxobutane-2-yl} carbamate

実施例１２．２Ａ
３，３−ビス（３−ブロモフェニル）−１−フェニルアゼチジン
３，３−ビス（３−ブロモフェニル）アゼチジン（２００ｍｇ、０．５４５ｍｍｏｌ）、ヨードベンゼン（２２２ｍｇ、１．０９０ｍｍｏｌ）、ｘａｎｔｐｈｏｓ（３１．５ｍｇ、０．０５４ｍｍｏｌ）、Ｐｄ_２（ｄｂａ）_３（１２．４７ｍｇ、０．０１４ｍｍｏｌ）およびナトリウムｔｅｒｔ−ブトキシド（６２．８ｍｇ、０．６５４ｍｍｏｌ）のジオキサン（３ｍＬ）中混合物を１００℃で１２時間撹拌した。冷却して室温とした後、水（１５ｍＬ）およびジクロロメタン（１５ｍＬ）を加えた。水層をジクロロメタンで抽出した（１５ｍＬで３回）。合わせた有機層を脱水し、濃縮した。残留物を分取ＴＬＣ（ジクロロメタン：ＥｔＯＡｃ＝５：１で溶離）によって精製して、標題化合物１４０ｍｇを得た（０．３１ｍｍｏｌ、５８％）。ＬＣ／ＭＳ：［Ｍ＋１］＝４４４、保持時間：２．６９分。^１Ｈ ＮＭＲ（ＣＤＣｌ_３）、４００ＭＨｚ：４．４２（ｓ、４Ｈ）、６．５４（ｄ、２Ｈ、Ｊ＝７．６Ｈｚ）、７．０９−７．１１（ｍ、２Ｈ）、６．７９（ｔ、１Ｈ、Ｊ＝７．２Ｈｚ）、７．１７−７．２６（ｍ、６Ｈ）、７．３７−７．４５（ｍ、４Ｈ）。

Example 12.2A
3,3-Bis (3-Bromophenyl) -1 -phenyl Azetidine 3,3-Bis (3-Bromophenyl) Azetidine (200 mg, 0.545 mmol), iodobenzene (222 mg, 1.090 mmol), xantphos (31) A mixture of .5 mg, 0.054 mmol), Pd ₂ (dba) ₃ (12.47 mg, 0.014 mmol) and sodium tert-butoxide (62.8 mg, 0.654 mmol) in dioxane (3 mL) at 100 ° C. for 12 hours. Stirred. After cooling to room temperature, water (15 mL) and dichloromethane (15 mL) were added. The aqueous layer was extracted with dichloromethane (15 mL 3 times). The combined organic layers were dehydrated and concentrated. The residue was purified by preparative TLC (dichloromethane: EtOAc = 5: 1 elution) to give 140 mg of the title compound (0.31 mmol, 58%). LC / MS: [M + 1] = 444, holding time: 2.69 minutes. ^{1 1} H NMR (CDCl ₃ ), 400 MHz: 4.42 (s, 4H), 6.54 (d, 2H, J = 7.6 Hz), 7.09-7.11 (m, 2H), 6.79 (T, 1H, J = 7.2Hz), 7.17-7.26 (m, 6H), 7.37-7.45 (m, 4H).

実施例１２．２Ｂ
１−フェニル−３，３−ビス（３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）アゼチジン
３，３−ビス（３−ブロモフェニル）−１−フェニルアゼチジン（１４０ｍｇ、０．２８４ｍｍｏｌ）、ＫＯＡｃ（１６７ｍｇ、１．７０５ｍｍｏｌ）、ＰｄＣｌ_２（ｄｐｐｆ）−ＣＨ_２Ｃｌ_２付加物（５８．０ｍｇ、０．０７１ｍｍｏｌ）およびビス（ピナコラト）ジボロン（１８８ｍｇ、０．７３９ｍｍｏｌ）のジオキサン（３ｍＬ）中混合物を１１０℃で２時間撹拌した。冷却して室温とした後、反応混合物をジクロロメタン（２０ｍＬ）で希釈し、ＮＨ_４Ｃｌ水溶液（１５ｍＬ）で洗浄した。水層をジクロロメタンで抽出した（１５ｍＬで３回）。合わせた有機層をブライン（２５ｍＬ）で洗浄した。有機層を脱水し、濃縮した。粗生成物を分取ＴＬＣ（ジクロロメタン：ヘキサン＝１：２で溶離）によって精製して、標題化合物１４２ｍｇを得た（０．２０９ｍｍｏｌ、収率７３．６％）。ＬＣ／ＭＳ：［Ｍ＋１］＝５３８。

Example 12.2B
1-Phenyl-3,3-bis (3- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) Azetidine 3,3-bis (3-bromophenyl) -1-Phenylazetidine (140 mg, 0.284 mmol), KOAc (167 mg, 1.705 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (58.0 mg, 0.071 mmol) and bis (pinacolato) diboron The mixture in (188 mg, 0.739 mmol) dioxane (3 mL) was stirred at 110 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (20 mL), washed with aqueous _NH 4 Cl (15 mL). The aqueous layer was extracted with dichloromethane (15 mL 3 times). The combined organic layers were washed with brine (25 mL). The organic layer was dehydrated and concentrated. The crude product was purified by preparative TLC (dichloromethane: hexane = 1: 2 elution) to give 142 mg of the title compound (0.209 mmol, yield 73.6%). LC / MS: [M + 1] = 538.

Example 12.2C
Methyl {(2S) -1-[(2S) -2-(5-{3- [3- (3- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino) ] -3-Methylbutanoyl} pyrrolidine-2-yl] -1H-imidazol-5-yl} phenyl) -1-phenylazetidine-3-yl] phenyl} -1H-imidazol-2-yl) pyrrolidine-1 -Il] -3-Methyl-1-oxobutane-2-yl} carbamate N ₂ under 1-phenyl-3,3-bis (3- (4,4,5,5-tetramethyl-1,3,3) 2-dioxaborolan-2-yl) phenyl) azetidine (60 mg, 0.112 mmol), intermediate _{4 (88mg, 0.235mmol), PdCl} 2 (dppf) -CH 2 Cl 2 adduct (18.24mg, 0.022mmol ) And K ₂ CO ₃ (93 mg, 0.670 mmol) in dioxane (5 mL) and water (1 mL) were stirred at 100 ° C. for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL), washed with aqueous _NH 4 Cl (15 mL). The aqueous phase was extracted with dichloromethane (15 mL 3 times). The combined organic layers were washed with brine (25 mL). The organic layer was dehydrated and concentrated. Preparative HPLC of crude product (equipment: Waters2767 PHW003, column: BoostonC18 10 μm 21 × 250 mm, mobile phase A: water (0.05% NH ₄ HCO ₃ ); B: ACN gradient 45-70% B for 8 minutes, Stopped at 14 minutes, purified by flow rate (mL / min): 30.00 detection wavelength (nm): 214/254, retention time (minutes) 8.47). The compound was then further purified by preparative TLC (MeOH: dichloromethane = 1:15 elution) to give the title compound 20 mg (0.022 mmol, yield 19.53%). LC / MS: [M + 1] = 870. ^{1 1} H NMR (MeOD-d ₄ ), 400 MHz: δ0.86-0.97 (m, 12H), 1.97-2.33 (m, 10H), 3.07 (d, 2H, J = 6. 4Hz), 3.66 (s, 6H), 3.83-3.99 (m, 5H), 4.21-4.23 (m, 2H), 4.49-4.55 (m, 5H) 5,13-5.16 (m, 2H), 6.61-6.63 (m, 2H), 6.73-6.77 (m, 1H), 7.19-7.58 (m, 12H), 7.78-7.80 (m, 2H).

The present invention also conceives pharmaceutically acceptable salts of the title compounds described in the above Examples. All examples disclosed in US Patent Application Publication No. 2010/0317568 and US Patent Application Nos. 12 / 903,822 and 12 / 964,027 are also incorporated herein by reference.

When examined using the HCV1b-Con1 replicon assay in the presence of 5% FBS, 1.1, 1.3, 1.5, 1.6, 1.7, 1.8, 2.1, 2.2, 2.4, 2.5, 2.6, 2.9, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 3. 1, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.11, 3.12, 3.13, 3.15, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3. 31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.40, 3.41, 3,42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 4.1, 4.2, 4. 3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.26, 4.27, 4.28, 4. 29, 4.30, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.40, 4.41 4.42, 4.43, 4.44, 4.45, 4.46, 4.47, 4.49, 4.50, 4.51, 4.52, 4.53, 4.54, 4. 55, 4.56, 4.57, 4.58, 4.59, 4.60, 4.61, 4.62, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 6.1, 6.2, 6. 3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.10, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16,7.1,8,9,10.1,10.2,11.1 and the title compound in 11.2, exhibited _{EC 50} values of less than about 0.1 nM. When examined using the HCV1b-Con1 Replicon Assay in the presence of 5% FBS, each in Examples 1.4, 2.8, 3.3, 3.9, 3.10, 3.16 and 4.25. the title compounds exhibited _{EC 50} values of from about 0.1 to about 1 nM. If under the 5% FBS presence was investigated using HCV-infected-Con1 replicon assay, each title compound in Example 2.3,2.7,12.1 and 12.2, _{EC 50} of about 1 to about 10nM The value is shown. If under the 5% FBS presence was investigated using HCV-infected-Con1 replicon assay, title compounds of Examples 1.2 and 3.14 showed an _{EC 50} value of greater than 10 [mu] M.

HCV2a in the absence of human plasma (HP), 2b, when examined using 3a and 4a replicon assay, is _{The EC 50} values of Examples 5.1 for Example 4.25 (500 pM to about 200) at least about 1/50; _{EC 50} values of examples 3.20 was at least about 1/15 for example 4.25. The AUC value of Example 5.1 (defined above) was about 30 times that of Example 2.9. When examined using HCV1a replicon assay in the presence of 40% HP, L31M, _{EC 50} values of Examples 6.1 for Y93H or Y93N mutant U.S. Patent Application Publication No. 2010/0317568 (U.S. Patent Application No. At least one-fifth of Example 109 (approximately 10 to 100 nM) of 12 / 833,301 (hereinafter referred to as the '301 application); the AUC value of Example 6.1 is the Example of the '301 application. 109 9 times a which was HCV2a in the absence of .HP the case, 2b, 3a and 4a replicon when examined using a Con assay, example 4.15 and '301 _{EC 50} value of example 302, filed Was about 1/2 to 1/4 of the case of Example 163 (about 10 to 50 pM) of the '301 application. When examined using the HCV2b and 4a replicon assays in the absence of HP, '301 HCV2a in the absence of .HP was about half of that of example 163 _{the EC 50} values are '301 filed embodiment 251, 2b, when examined using 3a and 4a replicon assay, '301 _{EC 50} value of example 120 of application' 301 is at least about half of that of the application example 164 (1200pM about 300), '301 EC of examples 245,256 and 271 of the application _{The 50} value was at least about 1/10 of that of Example 164 of the '301 application, and the AUC values of Examples 245, 256 and 271 were at least about 10 times that of Example 164.

The anti-HCV activity of each compound can be determined by measuring the activity of the luciferase reporter gene in the replicon in the presence of 5% FBS. The luciferase reporter gene is under translational control of the poliovirus IRES in place of the HCV IRES and uses HuH-7 cells to support replicon replication.

The inhibitory activity of the compounds of the present invention can be evaluated using various assays known in the art. For example, two stable subgenome replicon cell lines can be used to characterize compounds in cell culture, one from genotype 1a-H77 and the other from genotype 1b-Con1 respectively. University of Texas Medical Branch, Galveston, TX or Apath, LLC, St. Obtained from Louis, MO. The replicon construct can be a bicistronic subgenome replicon. The genotype Ia replicon construct comprises the NS3-NS5B coding region (1a-H77) from the HCV H77 strain. The replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. These two coding regions separated by the FMDV2a protease contain the first cistron of the bicistronic replicon construct, the second cistron containing the NS3-NS5B coding region with adaptive mutations E1202G, K1691R, K2040R and S2204I. The 1b-Con1 replicon construct is identical to the 1a-H77 replicon except that the HCV5'UTR, 3'UTR and NS3-NS5B coding regions are from the 1b-Conc1 strain and the adaptive mutations are K1609E, K1846T and Y3005C. In addition, the 1b-Con1 replicon construct comprises a poliovirus IRES between the HCVIRES and the luciferase gene. Replicon cell lineage is maintained in Dalveco's Modified Eagle's Medium (DMEM) containing 10% (volume ratio) fetal bovine serum (FBS), 100 IU / mL penicillin, 100 mg / mL streptomycin (Invitrogen) and 200 mg / mL G418 (Invitrogen). be able to.

The inhibitory effect of the compound of the present invention on HCV replication can be determined by measuring the activity of the luciferase reporter gene. For example, Replicon-containing cells can be inoculated into a 96-well plate at a density of 5000 cells / well in DMEM 100 μL containing 5% FBS. The next day, the compound can be diluted with dimethyl sulfoxide (DMSO) to give a 200-fold stock solution with a series of 8 half logarithmic dilutions. The dilution series can then be further diluted 100-fold with medium containing 5% FBS. Add medium containing the inhibitor to the overnight cell culture plate already containing 100 μL of DMEM containing 5% FBS. In assays that measure inhibitory activity in the presence of human plasma, medium from overnight cell culture plates can be replaced with DMEM containing 40% human plasma and 5% FBS. The cells can be incubated in a tissue culture incubator for 3 days, after which 30 μL of Passive Lysis buffer (Promega) can be added to each well and then incubated for 15 minutes while shaking the plate to lyse the cells. .. A luciferin solution (100 μL, Promega) can be added to each well and the luciferase activity can be measured using a Victor II illuminometer (Perkin-Elmer). The percent inhibition of HCV RNA replication, can be calculated for each compound concentration, can be calculated and _{EC 50} value using non-linear regression curve and GraphPad Prism 4 software adapted to a four parameter logistic equation. Using the above assay or a similar cell-based replicon assay, the representative compounds of the invention showed significantly higher inhibitory activity against HCV replication.

The present invention is also characterized by a pharmaceutical composition containing the compound of the present invention. The pharmaceutical compositions of the present invention, one or more may contain a compound of the present invention, each of which formula I (or _{I A, I B, I C} , I D, I E, I F or _{I G)} of Have.

Furthermore, the present invention is characterized by a pharmaceutical composition containing a pharmaceutically acceptable salt, solvate or prodrug of the compound of the present invention. The pharmaceutically acceptable salt can be, but is not limited to, a zwitterion or a pharmaceutically acceptable inorganic or organic acid or base derived. Preferably, the pharmaceutically acceptable salt retains the biological effect of the free acid or base of the compound without causing excessive toxicity, irritation and allergic response and has a reasonable benefit / risk ratio. However, it is effective in the intended use and is not biologically or otherwise undesirable.

The present invention is further characterized by a pharmaceutical composition comprising a compound of the present invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. These other therapeutic agents include, but are not limited to, antiviral agents (eg, anti-HIV agents, anti-HBV agents or HCV protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, IRES. Inhibitors or other anti-HCV agents such as NS5A inhibitors), antibacterial agents, antifungal agents, immunomodulators, anticancer agents or chemotherapeutic agents, antiinflammatory agents, antisense RNA, siRNA, antibodies or liver cirrhosis or liver inflammation You can choose from drugs to treat. Specific examples of these other therapeutic agents include ribavirin, α-interferon, β-interferon, pegated interferon-α, pegated interferon-λ, ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Devio-. 025, NIM-811, R7128, R1626, R4048, T-1106, PSI-7977 (Pharmasset) (Nucleoside polymerase inhibitor), PSI-7851 (Pharmasset) (Nucleoside polymerase inhibitor), PSI-938 (Pharmasset) (Nucleoside) Polymerase inhibitor), PF-000868554, ANA-598, IDX184 (nucleoside polymerase inhibitor), IDX102, IDX375 (non-nucleoside polymerase inhibitor), GS-9190 (non-nucleoside polymerase inhibitor), VCH-759, VCH-916 , MK-3281, BCX-4678, MK-3281, VBY708, ANA598, GL59728, GL60667, BMS-790052 (NS5A inhibitor), BMS-791325 (protease inhibitor), BMS-650032, BMS-824393, GS-9132 , ACH-1095 (Protease Inhibitor), AP-H005, A-831 (Arrow Therapeutics) (NS5A Inhibitor), A-689 (Arrow Therapeutics) (NS5A Inhibitor), INX08189 (Inhibitex) (Polymer Inhibitor), AZD2836, Terraprevir (protease inhibitor), boceprevir (protease inhibitor), ITMN-191 (Intermune / Roche), BI-13335 (protease inhibitor), VBY-376, VX-500 (Vertex) (protease inhibitor) Drugs), PHX-B, ACH-1625, IDX136, IDX316, VX-813 (Vertex) (protease inhibitor), SCH900518 (Schering-Ploug), TMC-435 (Tibotec) (protease inhibitor), ITMN-191 (protease inhibitor) Intermune, Roche (protease inhibitor), MK-709 (Merck) (protease inhibitor), IDX-PI (Novartis), BI-13335 (Boehringer) Ingelheim), R7128 (Roche) (Nucleoside polymerase inhibitor), MK-3281 (Merck), MK-0608 (Merck) (Nucleoside polymerase inhibitor), PF-868554 (Pfizer) (non-nucleoside polymerase inhibitor), PF- 4878691 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset), PPI-461 (Presido) (NS5A inhibitor), BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), B BMS), Albuferon (Novartis), ABT-333 (Abbott) (non-nucleoside polymerase inhibitor), ABT-072 (Abbott) (non-nucleoside polymerase inhibitor), ritonavir, another cytochrome P450 monooxygenase inhibitor Alternatively, there are combinations of any of these, but the present invention is not limited to these.

In one embodiment, the pharmaceutical composition of the invention comprises one or more compounds of the invention (or salts, solvates or prodrugs thereof) and one or more other antiviral agents.

In another embodiment, the pharmaceutical composition of the invention comprises one or more compounds of the invention (or salts, solvates or prodrugs thereof) and one or more other anti-HCV agents. For example, a pharmaceutical composition of the invention is a compound of Formula _{I, I A, I B,} I C, I D, I E, compounds of the present invention having _{I F} or _{I G} (or a salt, solvate or prodrug thereof ) And HCV polymerase inhibitors (such as nucleoside or non-nucleoside type polymerase inhibitors), HCV protease inhibitors, HCV helicase inhibitors, CD81 inhibitors, cyclophilin inhibitors, IRES inhibitors or NS5A inhibitors. Can be included.

In yet another embodiment, the pharmaceutical composition of the invention comprises one or more compounds of the invention (or salts, solvates or prodrugs thereof) and anti-HBV agents, anti-HIV agents or anti-hepatitis A agents, anti. Includes one or more other antiviral agents such as hepatitis D agents, anti-hepatitis E agents or anti-G hepatitis agents. Examples of anti-HBV drugs include, but are not limited to, adefovir, lamivudine and tenofovir. Examples of antiviral drugs include ritonavir, ropinavir, indinavir, nerphinavir, sakuinavir, amprenavir, atazanavir, tiprinavir, TMC-114, hosamprenavir, zidobudin, ramibdin, didanosine, stubdine, tenofovir, zalcitabine, abacavir. , Efavirenz, Nevirapine, Delavirdine, TMC-125, L-870812, S-1360, Enfvirtide, T-1249 or other HIV proteases, reverse transcription enzymes, integrases or fusion inhibitors, but are limited thereto. It's not a thing. As will be apparent to those skilled in the art, any other desirable antiviral agent can also be included in the pharmaceutical compositions of the present invention.

In a preferred embodiment, the pharmaceutical compositions of the present invention, the compounds of the present invention (e.g., Formula _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G} or preferably above Contains the compounds described or salts thereof, solvates or prodrugs) and HCV protease inhibitors. In another preferred embodiment, the pharmaceutical compositions of the present invention, the compounds of the present invention (e.g., Formula _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G} or preferably Includes the compounds described above or salts thereof, solvates or prodrugs) and HCV polymerase inhibitors (eg, non-nucleoside polymerase inhibitors or preferably nucleoside polymerase inhibitors). In yet another preferred embodiment, the pharmaceutical compositions of the present invention, (1) a compound of the invention (e.g., Formula _{I, I A, I B,} I C, I D, I E, the _{I F} or _{I G} Compounds or preferably compounds or salts thereof, solvates or prodrugs thereof), (2) HCV protease inhibitors and (3) HCV polymerase inhibitors (eg, non-nucleoside polymerase inhibitors or preferably nucleoside polymerase inhibitors). Includes medicine). Non-limiting examples of proteases and polymerase inhibitors are described above.

In yet another embodiment, the pharmaceutical compositions of the present invention, (1) _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G,} or preferably the above-described embodiment, Alternatively, the title compounds in Table 5 or salts thereof, compounds selected from solvents or prodrugs and (2) ABT-072 (Abbott), ABT-333 (Abbott), ACH-1095 (Achillion), ACH-1625. (Achillion), ACH-2864 (Achillion), ACH-2928 (Achillion), Aliceporovir, ANA-598 (Anadys), ANA-773 (Anadys), VAL-181 (Avila), AVL-192 (Achillion) Avila), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BCX-4678 (BioCryst), BI-13335 (Boehringer Ingelheim), BI-207127 (BoehringerIngel) 650032 (BMS), BMS-7900052 (BMS), BMS-791325 (BMS), BMS-824393 (BMS), Boseprevir, CTS-1027 (Conatus), Danoprevir, EDP-239 (Enanta), Philibvil, GL59728 (Glaxo), GL60667 (Glaxo), GS-5858 (Gilead), GS-6620 (Gilead), GS-9132 (Gilead), GS-9256 (Gilead), GS-9451 (Gilead), GS-9620 (Gilad) , GS-9669 (Giled), GSK625433 (GlaxoSmithKline), IDX-102 (Idenix), IDX-136 (Idenix), IDX-184 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix), IDX 375 (Idenix), INX-189 (Inhibitex), ITX-4520 (iTherx), ITX-5061 (iTherx), MK-0608 (Merck), MK-3281 (Merck), MK-5172 (Merck), Narra Preville, NM -811 (Nov artis), PF-4886891 (Pfizer), PHX-1766 (Phenomix), PPI-1301 (Presido), PPI-461 (Presidio), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (R) RO5302353 (Roche), SCY-635 (Synexis), Tegobville, Telaprevir, TMC-435 (Tibotec), TMC-647055 (Tibotec), TMC64912 (Medivir), Baniprevir, VBY708 (Virobay) Vry7Ver , VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-500 (Vertex), VX-759 (Vertex), VX-813 (Vertex), VX-985 (Vertex) or Includes one or more HCV inhibitors / regulators selected from these combinations.

In another embodiment, the pharmaceutical compositions of the present invention, (1) _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G,} or preferably the above-described embodiment or Compounds selected from the title compounds in Table 5 or salts thereof, solvates or proteases and (2) ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2864 (Achillion), AVL-181 (Avila). ), AVL-192 (Avila), BI-1335 (Boehringer Ingelheim), BMS-650032 (BMS), Boceprevir, Danoprevir, GS-9132 (Gilead), GS-9256 (Gilead), GS-9451 (Gilead), IDX -136 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), Narra Previr, PHX-1766 (Phenomix), Telaprevir, TMC-435 (Tibotec), Baniprevir, VBY708 (Viro) ), VX-500 (Vertex), VX-813 (Vertex), VX-985 (Vertex) or one or more HCV protease inhibitors selected from these combinations.

In yet another preferred embodiment, the pharmaceutical compositions of the present invention, (1) _{I, I A, I B,} I C, a compound of _{I D,} I _E, I _F, or _{I G,} or preferably the above-described Examples or compounds selected from the title compounds in Table 5 or salts thereof, solvates or prodrugs and (2) ABT-072 (Abbott), ABT-333 (Abbott), ANA-598 (Anadys), BI- 207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), Philibville, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), GS-9669 (Gilead) (Merck), Tegobville, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (VX-759) GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst) or one or more HCV polymerase inhibitors selected from these combinations. The polymerase inhibitors include (i) GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset). , PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir) or one or more nucleotide polymerase inhibitors selected from these; or (ii) ABT-072 (Abbott), ABT-333 (Abbott). , ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), Philibville, GL59728 (Glaxo), GL69667 (Glaxo), GL60967 (Glaxo) IDX-375 (Idenix), MK-3281 (Merck), Tegobville, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & There can be one or more non-nucleoside polymerase inhibitors selected from ViraChem), VX-759 (Vertex) or a combination thereof; or both (iii) nucleotide polymerase inhibitors and non-nucleoside polymerase inhibitors.

In yet another embodiment, the pharmaceutical compositions of the present invention, (1) _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G} or preferably the above-described embodiment, Alternatively, a compound selected from the title compounds in Table 5 or salts thereof, solvates or prodrugs (2) ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2864 (Achillion), AVL-181 (2) Avila), AVL-192 (Avila), BI-13335 (Boehringer Ingelheim), BMS-650032 (BMS), Boseprevir, Danoprevir, GS-9132 (Gilead), GS-9256 (Gilead), GS-9451 (Gilead) IDX-136 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), Narra Preville, PHX-1766 (Phenomix), Terra Preville, TMC-435 (Tibotec), Vanipreville, VBY708 ( Virobay), VX-500 (Vertex), VX-813 (Vertex), VX-985 (Vertex) or one or more HCV protease inhibitors selected from these combinations and (3) ABT-072 (Abbott), ABT -333 (Abbott), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), Philibville, GL57928 (Gla), GL59728 (Gla) 9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), Tegobville, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH- 222) (Vertex & ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Ph) Armasset), RG7128 (Roche), TMC64912 (Mediavir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst) or one or more HCV polymerase inhibitors selected from these combinations. The polymerase inhibitors include (i) GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK- selected from one or more nucleotide polymerase inhibitors. 0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir) or a combination thereof; or (ii) ABT-072 (Abbott), ABT-333 (Ab) , ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), Philibville, GL59728 (Glaxo), GL69667 (Glaxo), GL60967 (Glaxo) IDX-375 (Idenix), MK-3281 (Merck), Tegobville, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & There can be one or more non-nucleoside polymerase inhibitors selected from ViraChem), VX-759 (Vertex) or a combination thereof; or both (iii) nucleotide polymerase inhibitors and non-nucleoside polymerase inhibitors.

In yet another embodiment, the pharmaceutical compositions of the present invention, (1) _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G} or preferably the above-described embodiment, Alternatively, compounds selected from the title compounds in Table 5 or salts thereof, solvates or proteases and (2) cyclophilin inhibitors (eg, Alice Polovir, NM-811 (Novartis), SCY-635 (Synexis)). ), Invasion inhibitor (eg, ITX-4520 (iTherx) or ITX-5061 (iTherx)), another NS5A inhibitor (eg) or TLR-7 agonist (eg, GS-9620 (Giled) or PF- 4878691 (Psizer)) and (3) optionally include one or more of the above HCV proteases or polymerase inhibitors.

The pharmaceutical composition containing a plurality of active ingredients can be a co-formulation product, a co-packaging product, or a combination thereof.

The pharmaceutical compositions of the present invention typically include pharmaceutically acceptable carriers or excipients. Examples of suitable pharmaceutically acceptable carriers / excipients are sugars (eg lactose, glucose or sucrose), starches (eg cornstarch or potato starch), cellulose or derivatives thereof (eg sodium carboxymethyl cellulose). , Ethyl cellulose or cellulose acetate), oils (eg peanut oil, cottonseed oil, red flower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (eg propylene glycol), buffers (eg magnesium hydroxide or water) (Aluminum oxide), agar, excipients, powdered tragacanth, malt, gelatin, talc, cocoa butter, thermos-free water, isotonic physiological saline, Ringer's solution, ethanol or phosphate buffer, etc., but limited to these It is not something that is done. Lubricants, colorants, mold release agents, coating agents, sweeteners, flavors or fragrances, preservatives or antioxidants can also be included in the pharmaceutical compositions of the present invention.

The pharmaceutical composition of the present invention can be formulated based on the route of administration thereof by using a method known in the art. For example, sterile injectable formulations can be prepared as sterile injectable aqueous or oil-based suspensions with suitable dispersants or wettable powders and suspensions. Suppositories for rectal administration are solid at room temperature but liquid at rectal temperature, so suitable non-irritating excipients and drugs such as cocoa butter or polyethylene glycol that melt and release the drug in the rectum. Can be prepared by mixing with. Solid preparations for oral administration can be capsules, tablets, pills, powders or granules. In such solid formulations, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. The solid formulation may also contain other substances, such as lubricants, in addition to the Inactive Diluent. For capsules, tablets and pills, the formulation can also include buffering agents. Tablets and pills can also be prepared with an enteric coating. Liquid formulations for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, including diluents commonly used in the art. Liquid formulations can also include wettable powders, emulsifiers, suspensions, sweeteners, flavors or fragrances. The pharmaceutical composition of the present invention can also be administered in the form of liposomes according to the method described in US Pat. No. 6,703,403. For the formulation of drugs applicable to the present invention, for example, Hoover's work (Hover, John E., REMINGTON'S PHARMACEUTICAL SCIENCES (Mac Publishing Co., Easton, PA: 1975) and Lachman, L. et al. There is a general remark in eds., PHARMACEUTICAL DOSAGEFORMS (Marcel Decker, New York, NY, 1980).

The pharmaceutical composition of the present invention can be produced by using the compound described in the present specification or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compounds of the present invention (e.g., Formula _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G,} or preferably the compound or salt thereof described above , Solvates or prodrugs) are formulated with solid dispersants, where the compounds of the invention are dispersed at the molecular level in an amorphous base containing a pharmaceutically acceptable hydrophilic polymer. Can be done. The base may also include a pharmaceutically acceptable surfactant. Suitable solid dispersion techniques for formulating the compounds of the present invention include, but are not limited to, melt extrusion, spray drying, coprecipitation, lyophilization or other solvent distillation techniques. Extrusion and spray drying are preferred. In one example, the compounds of the invention are formulated with a solid dispersant containing copovidone and vitamin E TPGS. In another example, the compounds of the invention are formulated with a solid dispersant containing copovidone and Span20.

The solid dispersants described herein can include at least 30% by weight pharmaceutically acceptable hydrophilic polymers or combinations of such hydrophilic polymers. Preferably, the solid dispersant comprises at least 40% by weight pharmaceutically acceptable hydrophilic polymer or a combination of such hydrophilic polymers. More preferably, the solid dispersant comprises at least 50% by weight (eg, at least 60%, 70%, 80% or 90%, etc.) of pharmaceutically acceptable hydrophilic polymers or combinations of such polymers. The solid dispersants described herein can also include at least 1% by weight pharmaceutically acceptable surfactants or combinations of such surfactants. Preferably, the solid dispersant comprises at least 2% by weight pharmaceutically acceptable surfactant or a combination of such surfactants. More preferably, the solid dispersant comprises 4% to 20% by weight of surfactant, for example 5% to 10% by weight of surfactant. In addition, the solid dispersants described herein can contain at least 1% by weight, preferably at least 5% (eg, at least 10%) of the compounds of the invention. In one example, the solid dispersant, a compound of 5% of the present invention which are molecularly dispersed in amorphous Shitsumoto agent containing 7% Vitamin E-TPGS and 88% copovidone (e.g., Formula I, I _{A, I B, I C, I D} , I E, compounds of _{I F} or _{I G,} or preferably comprise the aforementioned compound or a salt, solvate or prodrug thereof); solid dispersion, mannitol / Aerosil (99 It can also be mixed with other excipients such as 1), and the weight ratio of the solid dispersant to other excipients can range from 5: 1 to 1: 5, preferably 1: 1. .. In another example, solid dispersion, 5% Span 20 and compound 5% of the present invention which are molecularly dispersed in amorphous Shitsumoto agent containing 90% copovidone (e.g., Formula _I, I A, _{I B , I C, I D, I} E, compounds of _{I F} or _{I G,} or preferably comprise the aforementioned compound or a salt, solvate or prodrug thereof), the solid dispersant is mannitol / Aerosil (99: It can also be mixed with other excipients such as 1), the solid dispersant can also be mixed with other excipients such as mannitol / aerosil (99: 1), and other solid dispersants. The weight ratio to the excipient can be in the range of 5: 1 to 1: 5, preferably 1: 1.

Various additives can be included in the solid dispersant or mixed with the solid dispersant. For example, at least one additive selected from flow regulators, binders, lubricants, fillers, disintegrants, plasticizers, colorants or stabilizers can be used in tablet production by compression of solid dispersants. it can. These additives can be miscible with solid dispersants that have been ground or milled prior to compression molding. The disintegrant promotes the rapid disintegration of the compressant in the stomach and is released to keep the granules separated from each other. Examples of suitable disintegrants include, but are not limited to, cross-linked polymers such as cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or sodium croscarmellose. Examples of suitable fillers (also referred to as bulking agents) include lactose / monohydrate, calcium hydrogen phosphate, microcrystalline cellulose (eg, Avicell), silicates, especially silicon dioxide, magnesium oxide, talc, etc. Examples include, but are not limited to, potato or corn starch, isomalt or polyvinyl alcohol. Examples of suitable flow regulators include, but are not limited to, highly dispersed silica (eg, colloidal silica such as Aerosil) and animal or vegetable fats or waxes. Examples of suitable lubricants include, but are not limited to, polyethylene glycol (eg, those having a molecular weight of 1000 to 6000), magnesium and calcium stearate, sodium stearyl fumarate, and the like. Examples of stabilizers include, but are not limited to, antioxidants, light stabilizers, radical scavengers or stabilizers against microbial attack.

The present invention further features a method of using the compound of the present invention (or a salt, solvate or prodrug thereof) in inhibiting HCV replication. The method comprises contacting HCV virus-infected cells with an effective amount of a compound of the invention (or a salt, solvate or prodrug thereof) to inhibit HCV virus replication in the cells. As used herein, "inhibition" means a significant reduction or elimination of the activity being inhibited (eg, viral replication). In many cases, the representative compounds of the invention will replicate at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80 of HCV virus replication (eg, in the HCV replicon assay described above). It can be reduced by%, 90%, 95% or more.

The compounds of the present invention can inhibit one or more HCV subtypes. Examples of HCV subtypes susceptible to the present invention include HCV genotypes 1, 2, 3, 4, 5 and 6, such as HCV genotypes 1a, 1b, 2a, 2b, 2c, 3a or 4a. However, it is not limited to these. In one embodiment, the compounds of the invention or compounds (or salts, solvates or prodrugs thereof) are used to inhibit the replication of the HCV1a genotype. In another embodiment, the compounds of the invention or compounds (or salts, solvates or prodrugs thereof) are used to inhibit the replication of the HCV1b genotype. In yet another embodiment, the compounds of the invention or compounds (or salts, solvates or prodrugs thereof) are used to inhibit the replication of both genotypes of HCV 1a and 1b.

The present invention is also characterized by a method of using the compound of the present invention (or a salt, solvate or prodrug thereof) in treating HCV infection. The method is typically by administering to the HCV patient a therapeutically effective amount of the compound of the invention (or a salt, solvate or prodrug thereof) or a pharmaceutical composition comprising it, in the patient's blood or It has a step of lowering HCV virus levels in the liver. As used herein, the term "treat" improves, ameliorates, suppresses or prevents progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition. Point to that. The term "treatment" refers to a therapeutic activity. In one embodiment, the method comprises administering to an HCV patient a therapeutically effective amount of two or more compounds of the invention (or salts, solvates or prodrugs thereof) or pharmaceutical compositions comprising them. Has a step of lowering HCV virus levels in the blood or liver of.

The compounds of the invention (or salts, solvents or prodrugs thereof) can be used as a single active pharmaceutical agent or other anti-HCV, anti-HIV, anti-HBV, anti-hepatitis A, anti-D types. It can be administered in combination with other desired agents such as hepatitis agents, anti-hepatitis E agents, anti-hepatitis G agents or other antiviral agents. The compounds described herein or pharmaceutically acceptable salts thereof can be used in the methods of the invention. In one embodiment, the compounds of the present invention, the present invention (e.g., Formula _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G,} or preferably compounds described above Alternatively, a method of treating HCV infection, comprising administering to an HCV patient a salt thereof, a solvate or a prodrug), interferon and ribavirin. The interferon is preferably α-interferon, more preferably pegylated interferon-α such as PEGASYS (peginterferon α-2a).

In another embodiment, the present invention provides a compound of the invention (e.g., Formula _{I, I A, I B,} I C, I D, I E, compounds of _{I F} or _{I G,} or preferably the above-described embodiment or HCV infection comprising administering the title compound of Table 5 or a compound thereof selected from a solvate or a prodrug) and one or more of the above HCV inhibitors / modifiers with or without interferon. It features a treatment method for.

The compound of the present invention (or a salt, solvent or prodrug thereof) can be administered to a patient in a single dose or in divided doses. Typical daily doses can range from 0.1 to 200 mg / kg, such as 0.25 to 100 mg / kg, but are not limited thereto. The single dose composition can include an amount or a partial amount thereof constituting a daily dose. Preferably, each formulation comprises a sufficient amount of a compound of the invention effective in reducing the HCV virus load in the patient's blood or liver. The amount of active ingredient or multiple active ingredients combined in producing a single formulation may vary depending on the host being treated and the particular dosage form. Specific dose levels used in specific patients Activity of specific compounds used, age, weight, general health, gender, diet, time of administration, route of administration, rate of excretion, concomitant medications and specific diseases to be treated It will be clear that it depends on various factors such as the severity of.

The present invention further features a method of using the pharmaceutical composition of the present invention in treating HCV infection. The method typically comprises the step of reducing HCV virus levels in the patient's blood or liver by administering the pharmaceutical composition of the invention to an HCV patient. The pharmaceutical compositions described herein can be used in the methods of the invention.

Furthermore, the present invention is characterized by the use of the compounds or salts of the present invention in the manufacture of pharmaceuticals for the treatment of HCV infection. The compounds described herein or pharmaceutically acceptable salts thereof can be used to produce the medicament of the present invention.

The compounds of the present invention can also be replaced with isotopes. Preferred isotope substitutions include substitutions with stable or non-radioactive isotopes such as deuterium, ¹³ C, ¹⁵ N or ¹⁸ O. Incorporation of heavy atoms, such as the substitution of hydrogen with deuterium, can produce isotope effects that can alter the pharmacokinetics of the drug. In one example, at least 5 of the compounds of the invention also replace l% (eg, at least 10 mol%) of hydrogen with deuterium. In another example, at least 25 mol% of hydrogen in the compounds of the invention is replaced with deuterium. In another example, at least 50, 60, 70, 80 or 90 mol% of hydrogen in the compounds of the invention is replaced with deuterium. The natural abundance of deuterium is about 0.015%. Substitution with deuterium or its concentration can be performed by either exchanging protons with deuterium or synthesizing molecules using concentrated or substituted raw materials, but is not limited thereto. Other methods known in the art can also be used for isotope substitution.

The above description of the present invention provides examples and explanations, and is not intended to be complete or to limit the present invention to the details of the disclosure. Modifications and modifications are possible in view of the above, or they can be obtained from the practice of the present invention. Therefore, it should be noted that the scope of the present invention is defined by the scope of claims and their equivalents.

Claims (2)

Methyl {(2S, 3R) -1-[(2S) -2-{5-[(2R, 5R) -1- {3,5-difluoro-4- [4- (4-fluorophenyl) pyrrolidine-1) -Il] Phenyl} -5-(6-fluoro-2-{(2S) -1- [N- (methoxycarbonyl) -O-methyl-L-threonyl] pyrrolidine-2-yl} -1H-benzimidazole- 5-yl) Pyrrolidine-2-yl] -6-fluoro-1H-benzimidazol-2-yl} pyrrolidine-1-yl] -3-methoxy-1-oxobutan-2-yl} carbamate or as a pharmaceutical for the compound A pharmaceutical composition for treating HCV-infected patients, comprising an acceptable salt. The pharmaceutical composition according to claim 1, further comprising an HCV protease inhibitor.