JP5906253B2 - Antiviral compounds - Google Patents

Description

  This application includes US Patent Application Publication Nos. 2010/0317568, 2011/0092415, 2011/0107699, US Patent Application Nos. 13 / 100,827 and 20112 filed on May 4, 2011. The entire contents of US Provisional Application No. 61 / 446,800, filed on May 25, are incorporated by reference.

  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 comprising these compounds and methods of using these compounds to treat HCV infection.

  HCV is an RNA virus belonging to the genus Hepacivirus genus of the Flaviviridae family. The coat HCV virion contains a positive-strand RNA genome that all encodes a known virus-specific protein in a single uninterrupted open reading frame. The open reading frame contains approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. Polyproteins include core proteins, envelope proteins E1 and E2, membrane-bound protein p7, and nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

  HCV infection is associated with progressive liver lesions including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C can be treated with pegylated interferon-α in combination with ribavirin. Because many users suffer from side effects and the elimination of viruses from the body is often inadequate, substantial limitations remain in effectiveness and tolerability. Thus, there is a need for new drugs to treat HCV infection.

(Summary)
The present invention provides a compound of formula _{I, I A, I B,} I C, I D, I E, features a salt thereof the compounds and pharmaceutically acceptable _{I F} or _{I G.} These compounds and salts can inhibit HCV replication and are therefore useful in the treatment of HCV infection.

  The invention also features a composition comprising a compound or salt of the invention. The composition also includes additional 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. be able to.

  The invention further features a method of using a compound or salt of the invention to inhibit HCV replication. This method comprises contacting a cell infected with an HCV virus with a compound or salt of the invention, thereby inhibiting replication of the HCV virus in the cell.

  Furthermore, the invention features a method of using a compound or salt of the invention or a composition comprising the same to treat HCV infection. This method comprises the step of administering a compound or salt of the present invention or a pharmaceutical composition comprising the same to a patient in need thereof, thereby reducing the blood or tissue concentration of HCV virus in the patient.

  The invention also features the use of a compound or salt of the invention for the manufacture of a medicament for the treatment of HCV infection.

  Furthermore, the present invention features a process for producing a compound or salt of the present invention.

  Other features, objects, and advantages of the present invention are apparent in the detailed description that follows. However, while preferred embodiments of the invention are shown, it is to be understood that the detailed description is only illustrative and not restrictive. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description.

(Detailed explanation)

  The invention features a compound having Formula I and pharmaceutically acceptable salts thereof.

（式中：
ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されており；
Ｌ_１およびＬ_２はそれぞれ独立に結合；または、それぞれが出現ごとに独立に１つもしくは複数のＲ_Ｌで場合によって置換されている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_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員から１２員の複素環であり、それぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されており；
ＤはＣ_３−Ｃ_１２炭素環または３員から１２員の複素環であり、１つもしくは複数のＲ_Ａで場合によって置換されているか；またはＤはＣ_３−Ｃ_１２炭素環または３員から１２員の複素環であり、Ｊで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_１２炭素環または３員から１２員の複素環であり、１つもしくは複数のＲ_Ａで場合によって置換されているか；またはＪは−ＳＦ_５であるか；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であるか；またはＲ_１はＲ_Ｃであり、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている３員から１２員の複素環を形成しており；
Ｒ_３、Ｒ_４、Ｒ_６およびＲ_７はそれぞれ独立にＲ_Ｃであるか；または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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている３員から１２員の炭素環もしくは複素環を形成しており；
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であるか；またはＲ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている３員から１２員の複素環を形成しており；
Ｒ_１０、Ｒ_１１、Ｒ_１３およびＲ_１４はそれぞれ独立にＲ_Ｃであるか；または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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている３員から１２員の炭素環もしくは複素環を形成しており；
ＴおよびＴ’はそれぞれ出現ごとに独立に、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’はそれぞれ出現ごとに独立に、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員から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員から１２員の複素環はそれぞれ出現ごとに独立に、１つもしくは複数のＲ_Ａで場合によって置換されており；
Ｌ_Ｋは、出現ごとに独立に結合、−Ｌ_Ｓ−Ｎ（Ｒ_Ｂ）Ｃ（Ｏ）−Ｌ_Ｓ’−もしくは−Ｌ_Ｓ−Ｃ（Ｏ）Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ’−；または、それぞれが出現ごとに独立に１つもしくは複数のＲ_Ｌで場合によって置換されているＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレンもしくはＣ_２−Ｃ_６アルキニレン；または、それぞれが出現ごとに独立に１つもしくは複数のＲ_Ａで場合によって置換されているＣ_３−Ｃ_１２炭素環または３員から１２員の複素環から選択され；
Ｅは出現ごとに独立にＣ_３−Ｃ_１２炭素環または３員から１２員の複素環から選択され、出現ごとに独立に１つもしくは複数のＲ_Ａで場合によって置換されており；
Ｒ_Ｄはそれぞれ出現ごとに独立に、水素またはＲ_Ａから選択され；
Ｒ_Ａは出現ごとに独立にハロゲン、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つの隣接するＲ_Ａは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の間の任意の原子と一緒になって炭素環もしくは複素環を場合によって形成していてよく；
Ｒ_ＢおよびＲ_Ｂ’はそれぞれ出現ごとに独立に、水素；または、それぞれが出現ごとに独立にハロゲン、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、シアノまたは３員から６員の炭素環もしくは複素環から選択される１つもしくは複数の置換基で場合によって置換されている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員から６員の炭素環もしくは複素環から選択され；Ｒ_ＢまたはＲ_Ｂ’の中の各３員から６員の炭素環もしくは複素環は、出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されており；
Ｒ_Ｃは、出現ごとに独立に水素、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、それぞれが出現ごとに独立にハロゲン、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、シアノまたは３員から６員の炭素環もしくは複素環から選択される１つもしくは複数の置換基で場合によって置換されている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員から６員の炭素環もしくは複素環から選択され；Ｒ_Ｃ中の各３員から６員の炭素環もしくは複素環は、出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されており；
Ｒ_Ｅは、出現ごとに独立に−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、−Ｃ（Ｏ）Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）−Ｒ_Ｓ’；または、それぞれが出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されている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、それぞれが出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環から選択され；
Ｒ_Ｆは出現ごとに独立に、それぞれが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、１つもしくは複数のＲ_Ｌで場合によって置換されている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’）（Ｑは０、１、２、３または４であり、各Ｒｘは独立にＯ、ＳまたはＮ（Ｒ_Ｂ）であり、各Ｒ_Ｙは独立に、それぞれがハロゲン、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つもしくは複数の置換基で独立に場合によって置換されている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、各Ｒ_Ｙ’は独立に、それぞれがハロゲン、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つもしくは複数の置換基で独立に場合によって置換されているＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニルまたはＣ_２−Ｃ_６アルキニルである）から選択され；
Ｒ_Ｌは、出現ごとに独立にハロゲン、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’）もしくは−Ｎ（Ｒ_Ｓ）Ｃ（Ｏ）Ｒ_Ｓ’；または、それぞれが出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環 ３員から６員の複素環から選択され；２つの隣接するＲ_Ｌは、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の間の任意の原子と一緒になって炭素環もしくは複素環を場合によって形成することができ；
Ｌ_Ｓ、Ｌ_Ｓ’およびＬ_Ｓ''はそれぞれ出現ごとに独立に、結合；またはそれぞれが出現ごとに１つもしくは複数のＲ_Ｌで独立に場合によって置換されているＣ_１−Ｃ_６アルキレン、Ｃ_２−Ｃ_６アルケニレン、Ｃ_２−Ｃ_６アルキニレンから選択され；
Ｒ_Ｓ、Ｒ_Ｓ’およびＲ_Ｓ''はそれぞれ出現ごとに独立に、水素；または、それぞれが出現ごとに独立にハロゲン、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、−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、３員から６員の炭素環もしくは複素環から選択される１つもしくは複数の置換基で場合によって置換されている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員から６員の炭素環もしくは複素環から選択され；Ｒ_Ｓ、Ｒ_Ｓ’またはＲ_Ｓ''の中の各３員から６員の炭素環もしくは複素環は、出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されている。）

(Where:
X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl, optionally substituted with one or more R _A or R _F ;
L ₁ and L ₂ are each independently a bond; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ each optionally substituted independently with one or more R _L for each occurrence It is selected from -C ₆ alkynylene;
L ₃ is a bond or —L _S —K—L _S ′ —, and K is a 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 carbocycle or a 3 to 12 membered heterocycle, each independently substituted optionally with one or more _RA ;
D is a C ₃ -C ₁₂ carbocycle or a 3 to 12 membered heterocycle and is optionally substituted with one or more R _A ; or D is from a C ₃ -C ₁₂ carbocycle or 3 member a 12 membered heterocyclic ring is substituted with J, is optionally substituted with one or more R _a, J is an 12-membered heterocycle C ₃ -C ₁₂ carbocyclic or 3-membered or it is optionally substituted with one or more _{R a;} or J or is -SF _5; or D is hydrogen or _{R a;}
Y is _{-T'-C (R 1 R 2} ) N (R 5) -T-R D, -T'-C (R 3 R 4) C (R 6 R 7) -T-R D, -L It is selected from the _{K -T-R D} or _-L K -E;
R ₁ and R ₂ are each independently R _C and R ₅ is R _B ; or R ₁ is R _C and R ₂ and R ₅ together with the atoms to which they are attached Forming a 3- to 12-membered heterocycle optionally substituted with one or more _RA ;
R ₃ , R ₄ , R ₆ and R ₇ are each independently R _C ; or R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ are the atoms to which they are attached. Taken together form a 3 to 12 membered carbocyclic or heterocyclic ring optionally substituted with one or more _RA ;
Z is _{-T'-C (R 8 R 9} ) N (R 12) -T-R D, -T'-C (R 10 R 11) C (R 13 R 14) -T-R D, -L It is selected from the _{K -T-R D} or _-L K -E;
R ₈ and R ₉ are each independently R _C and R ₁₂ is R _B ; or R ₈ is R _C and R ₉ and R ₁₂ are taken together with the atoms to which they are attached. Forming a 3- to 12-membered heterocycle optionally substituted with one or more _RA ;
R ₁₀ , R ₁₁ , R ₁₃ and R ₁₄ are each independently R _C ; or R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ are the atoms to which they are attached. Taken together form a 3 to 12 membered carbocyclic or heterocyclic ring optionally substituted with one or more _RA ;
T and T 'are independently at each occurrence, respectively, _{binding, -L S -, - L S} -M-L S' - or _{-L S -M-L S '-M'} -L S''- selected from M and M ′ are each independently a 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 ( _{B) SO 2 N (R B} ') -, - N (R B) S (O) N (R B') -, is selected from heterocycles 12 membered C 3 _{-C 12} carbocyclic or 3-membered, independently at each occurrence a C ₃ -C ₁₂ respectively from 12-membered heterocyclic carbon ring and three-membered, is optionally substituted with one or more R _a;
L _K is a bond independently at each _{occurrence, -L S -N (R B)} C (O) -L S '- or _{-L S -C (O) N (} R B) -L S'-; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, each optionally substituted with one or more R _L independently for each occurrence; or Independently selected from a C ₃ -C ₁₂ carbocycle or a 3 to 12 membered heterocycle optionally substituted with one or more R _A ;
E is independently selected at each occurrence from C ₃ -C ₁₂ carbocyclic or 3 membered heterocycle 12 members, being optionally substituted by independently at each occurrence with one or more R _A;
R _D is independently selected for each occurrence from hydrogen or R _A ;
R _A is independently halogen at each occurrence, nitro, oxo, selected phosphonoxy, phosphono, thioxo, cyano or -L _S -R _E, 2 two adjacent R _A is bonded atoms and their they are attached Optionally combined with any atom between the atoms in question to form a carbocyclic or heterocyclic ring;
R _B and R _B ′ are each independently for each occurrence, hydrogen; or each is independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3 C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from membered to 6-membered carbocyclic or heterocyclic rings; or Selected from 3- to 6-membered carbocycles or heterocycles; each 3- to 6-membered carbocycle or heterocycle in R _B or R _B ′ is independently halogen, hydroxy, mercapto, amino , carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl, _{C 2} Optionally substituted with one or more substituents selected from —C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl. And;
R _C is independently hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano for each occurrence; or each independently halogen, hydroxy, mercapto, C _1- optionally substituted with one or more substituents selected from amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-membered carbocyclic or heterocyclic ring C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; or selected from 3 to 6 membered carbocycle or heterocycle; each 3 to 6 membered carbocycle or heterocycle in R _C Is independently halogen, hydroxy, mercapto, amino, carboxy, ni B, 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 Optionally substituted with one or more substituents selected from C ₂ -C ₆ haloalkynyl;
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 ) for each occurrence. R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N (R _S R _S '), -N (R _S ) 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 (R _S ) 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 _{O) N (R S) C} (O) -R S '; or, each selected independently at each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents as defined above; or halogen, hydroxy, each independently at each occurrence 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 ( Selected from C ₃ -C ₆ carbocycles or 3- to 6-membered heterocycles optionally substituted with one or more substituents selected from R _S R _S ′);
R _F independently at each occurrence contains 0, 1, 2, 3, 4 or 5 heteroatoms, each selected from O, S or N, optionally substituted with one or more R _L C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl; or-(R _X -R _Y ) _Q- (R _X -R _Y ') (Q is 0, 1, 2 Each Rx is independently O, S or N (R _B ), and each R _Y is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkyl optionally independently substituted with one or more substituents selected from thioxo, formyl or cyano Nylene, each R _Y 'is independently independent with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Selected from optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl);
R _L is independently halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R _S , —S—R _S , —C (O) R _S , —OC (O) R _S for each occurrence. , -C (O) OR _S , -N (R _S R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N (R _S R _S ') or -N ( R _S ) C (O) R _S ′; or each independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl With one or more substituents selected from 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 haloalkynyl Replaced by Is selected from C ₃ -C ₆ carbocycle 3-membered are from 6 membered heterocyclic ring; two adjacent R _L can consist of any atoms between the atoms to which atoms they are attached and they are attached Together they can optionally form a carbocyclic or heterocyclic ring;
L _S , L _S ′ and L _S ″ are each independently, each occurrence of a bond; or C ₁ -C ₆ alkylene, each optionally substituted independently with one or more R _L for each occurrence, C ₂ -C _{6 alkenylene,} is selected from C 2 -C ₆ alkynylene;
R _S , R _S ′ and R _S ″ are each independently for each occurrence hydrogen; or each is independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, One selected from formyl, cyano, —O—C ₁ -C ₆ alkyl, —O—C ₁ -C ₆ alkylene-O—C ₁ -C ₆ alkyl, 3 to 6 membered carbocyclic or heterocyclic ring Or C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with multiple substituents; or selected from 3 to 6 membered carbocyclic or heterocyclic rings; _S, carbocyclic or heterocyclic ring 6 membered from each 3-membered in the R S _'or R _S' 'is independently halogen at each occurrence, 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 optionally substituted with one or more substituents selected from C ₂ -C ₆ haloalkynyl. )

A and B are preferably C ₅ -C ₆ carbocycles (eg phenyl), 5 to 6 membered heterocycles (eg pyridinyl or thiazolyl) or 8 to 12 membered bicycles, eg

または

Or

であり、Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から独立に選択され、Ｚ_２は出現ごとにＮまたはＣＨから選択され、Ｚ_３は出現ごとに独立にＮまたはＣＨから独立に選択され、Ｚ_４は出現ごとに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はそれぞれ出現ごとに独立に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つもしくは複数のＲ_Ａで場合によって置換されている。

Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence, Z ₂ is selected from N or CH at each occurrence, and Z ₃ is independently from N or CH at each occurrence. Independently selected, Z ₄ is selected from O, S, NH or CH ₂ for each occurrence, and W ₁ , W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are each independently CH or N for each occurrence Selected from. A and B are each optionally substituted with one or more _RA .

More preferably, A is a C ₅ -C ₆ carbocycle, a 5 to 6 membered heterocycle,

または

Or

から選択され、１つまたは複数のＲ_Ａで場合によって置換されており；ＢはＣ_５−Ｃ_６炭素環、５員から６員の複素環、

Is selected from one or more of which is optionally substituted with R _A; B is C ₅ -C ₆ carbocyclic ring, 6-membered heterocyclic ring from a 5-membered,

または

Or

から選択され、１つまたは複数のＲ_Ａで場合によって置換されており；Ｚ_１、Ｚ_２、Ｚ_３、Ｚ_４、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５、Ｗ_６は上記定義通りである。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、

And optionally substituted with one or more _RA ; Z ₁ , Z ₂ , Z ₃ , Z ₄ , W ₁ , W ₂ , W ₃ , W ₄ , W ₅ , W ₆ are as defined above As defined. Preferably Z ₃ is N and Z ₄ is NH. For example, A is
Phenyl (eg,

）、ピリジニル（例えば、

), Pyridinyl (e.g.,

）、チアゾリル（例えば、

), Thiazolyl (e.g.,

）、

),

（例えば、

(For example,

）または

Or

（例えば、

(For example,

または

Or

）から選択することができ、１つまたは複数のＲ_Ａで場合によって置換されており；Ｂはフェニル（例えば、

And optionally substituted with one or more _RA ; B is phenyl (eg,

）、ピリジニル（例えば、

), Pyridinyl (e.g.,

）、チアゾリル（例えば、

), Thiazolyl (e.g.,

）、

),

（例えば、

(For example,

）または

Or

（例えば、

(For example,

または

Or

）から選択することができ、１つまたは複数のＲ_Ａで場合によって置換されている。非常に好ましくは、ＡとＢはどちらもフェニルである（例えば、ＡとＢはどちらも

), Optionally substituted with one or more _RA . Most preferably, A and B are both phenyl (eg, A and B are both

である。）。やはり非常に好ましくは、Ａは

It is. ). Still very preferably, A is

であり、Ｂは

And B is

であるか、またはＡは

Or A is

であり、Ｂは

And B is

であるか、またはＡは

Or A is

であり、Ｂは

And B is

であるか、またはＡは

Or A is

であり、Ｂは

And B is

であるか、またはＡは

Or A is

であり、Ｂは

And B is

であり；各ＡおよびＢは１つまたは複数のＲ_Ａで独立に場合によって置換されている。

Each A and B is optionally substituted independently with one or more R _A.

D is preferably selected from C ₅ -C ₆ carbocycles, 5 to 6 membered heterocycles or 6 to 12 membered bicyclic rings, optionally substituted with one or more _RA . D may also preferably be selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, optionally substituted with one or more substituents selected from R _L Has been. More preferably, D _is, C 5 -C ₆ carbocyclic (e.g., phenyl), 6-membered heterocyclic ring from 5- (e.g., pyridinyl, pyrimidinyl, thiazolyl), or from 6-membered to 12-membered bicyclic (e.g., indanyl 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, benzo [d] [1,3] dioxol-5-yl), one or more R _M are substituted, the _{R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Again preferably, D is phenyl, optionally substituted with one or more _RA . More preferably, D is phenyl, substituted with one or more R _M , where R _M is as defined above. Very preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F.

D is also preferably pyridinyl, pyrimidinyl or thiazolyl optionally substituted with one or more _RA . More preferably, D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted by one or more R _M. Most preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。Ｄはやはり好ましくは、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つまたは複数のＲ_Ａで場合によって置換されている。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つまたは複数のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl or indazolyl, optionally substituted with one or more _RA . More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, One or substituted with a plurality of R _M. Most preferably, D is

または

Or

であり、１つまたは複数のＲ_Ｍで場合によって置換されている。

, 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 each occurrence of halogen, hydroxy, mercapto, amino, carboxy, nitro, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or each halogen is independently at each occurrence, 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} - _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 one selected from haloalkynyl or a plurality of _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent 6-membered Heterocycle. More preferably, R _M is optionally halogen, hydroxy, mercapto, amino, carboxy; or optionally one or more substituents each independently selected from halogen, hydroxy, mercapto, amino or carboxy for each occurrence. Substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. Most preferably, R _M is C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, or a 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 ′), —O—R _S , —C (O) R—, —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 R _S and R _S ′ are, for example, independently for each occurrence (1) hydrogen or (2) each occurrence one or more independently halogen, hydroxy, _-O-C 1 -C ₆ alkyl or a 3- Membered C ₁ -C ₆ or may be selected from alkyl optionally substituted with heterocycle; or, R _M are each independently halogen at each occurrence, hydroxy, mercapto, amino, carboxy, nitro, oxo, Is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphonoxy, phosphono, thioxo, formyl or cyano Or R _M is independently for each occurrence 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 Haroa _Kenyir, C 2 -C ₆ haloalkynyl, -C (O) OR _S, or -N _{(R S} R S ') is optionally substituted with one or more substituents selected from _C 3 -C ₆ A carbocyclic ring or a 3- to 6-membered heterocyclic ring. More preferably, R _M is selected from halogen (eg, fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or each independently from each occurrence halogen, hydroxy, mercapto, amino, cyano or carboxy C ₁ -C ₆ alkyl (eg, methyl, isopropyl, tert-butyl), C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents as defined. For example, _RM represents 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 . Also 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 ′, —SO ₂ R _S or —SR _S. For example, when L _S is a bond, R _E is —N (C ₁ -C ₆ alkyl) ₂ (eg, —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-O—C ₁ -C ₆ alkyl) (eg, —N ( _{CH 3) (CH 2 CH 2} OMe)); - O-C 1 -C 6 alkyl (e.g., -O-Me, -O-Et , -O- isopropyl, -O-tert-butyl, -O-n - _{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 _{(e.g., -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 (e.g. , —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 —S—C ₁ -C ₆ haloalkyl (eg, SCF ₃ ). Also 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 _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 represents —C ₁ -C ₆ alkylene-O—R _S (eg, —C (CH ₃ ) ₂ —CH ₂ —OMe); —C ₁ -C ₆ alkylene-C (O) OR _S (eg, _{, -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 (eg, —CH ₂ —P (O) (OEt) ₂ ). Again more preferably, _{R M} are each independently halogen at each occurrence, 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 ' A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle optionally substituted with one or more substituents selected from: For example, _RM can be cycloalkyl (eg, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (eg, morpholin-4-yl, 1,1-di). Oxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 3, 5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6- (dimethylamino) pyridin-3-yl). Most preferably, R _M is C ₁ -C optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (eg tert-butyl, CF ₃ ). ₆ alkyl.

More preferably, D is a C ₅ -C ₆ carbocyclic ring, a 5 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, substituted with J, and one or more R _A Optionally substituted, J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A Yes. Preferably, J is substituted with 6-membered heterocyclic ring from the _C 3 -C ₆ carbocycle or 3-membered, heterocyclic ring 6 membered from the _C 3 -C ₆ carbocycle or 3 members of 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} Optionally independently substituted with one or more substituents selected from —C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) , J may be optionally substituted with one or more _RA . Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more R _A , preferably J is 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 ₃ optionally substituted independently with one or more substituents selected from C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle. Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A 6 to 12 membered bicycle (eg, a 7 to 12 membered fused, bridged or spiro bicyclic ring containing a nitrogen ring atom through which J is covalently bonded to D), and one or more Optionally substituted with _RA . More preferably, D is phenyl, substituted with J, optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered heterocycle Or a 6 to 12 membered bicycle, optionally substituted with one or more _RA , preferably J is 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 ')} C 3 -C 6 the carbocycle is optionally substituted independently with one or more substituents selected from It is at least substituted with 6-membered heterocyclic ring from 3 members. Very preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されており、好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。やはり好ましくは、Ｄは

, And the respective R _N is independently selected from R _D, preferably hydrogen or halogen, J is C ₃ -C ₆ carbocycle, bicyclic 12-membered to 6-membered heterocyclic ring or 3 to 6-membered Optionally substituted with one or more R _A , preferably J is 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 If (R _S R _S ') less in one or more of which is optionally substituted independently with substituents C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring selected from It has been replaced. Still preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環であり、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。やはり好ましくは、Ｄは、

And in each R _N is independently selected from R _D, preferably hydrogen or halogen, J is a 6-membered heterocycle C ₃ -C ₆ carbocycle or a 3-, 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle, and J may be optionally substituted with one or more _RA . Again preferably, D is

であり、ＪはＣ_３−Ｃ_６炭素環または３員から６員の複素環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。

Wherein J is a C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more _RA ; preferably, J is 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle.

X is preferably _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} X may be C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl optionally substituted with one or more R _A ; R _A on two adjacent X are Together with the ring atoms to which are attached, optionally form a 5- to 6-membered carbocyclic or heterocyclic ring. More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F , and two R _A on adjacent X are attached to them. Together with the ring atoms, optionally forms a 5- to 6-membered carbocyclic or heterocyclic ring.

Preferred non-limiting examples of X include the following cyclopropyl rings, each of which is optionally substituted with one or more R _A or R _F ;

。
示されているように、上記シクロプロピル環の位置のいずれかでの相対的立体構造はｃｉｓ型であってもｔｒａｎｓ型であってもよい。シクロプロピルの位置のいずれかでの場合による置換基Ｒ_ＡまたはＲ_Ｆの立体構造は、シクロプロピル環上の他の任意の位置での任意の置換基に対して変化することができる。シクロプロピルと結合している具体的な置換基に応じて、任意の炭素での立体構造は（Ｒ）であっても（Ｓ）であってもよい。

.
As shown, the relative steric structure at any of the above cyclopropyl ring positions may be cis or trans. The conformation of the optional substituent R _A or R _F at any of the cyclopropyl positions can vary with respect to any substituent at any other position on the cyclopropyl ring. Depending on the specific substituent attached to the cyclopropyl, the steric structure at any carbon may be (R) or (S).

Preferred non-limiting examples of X include the following cyclopentyl or cyclopentenyl rings, each of which is optionally substituted with one or more R _A or R _F :

。
示されているように、上記シクロペンチル環の位置のいずれかでの相対立体構造はｃｉｓ型であってもｔｒａｎｓ型であってもよい。シクロペンチルまたはシクロペンテニルの位置のいずれかでのＲ_ＡまたはＲ_Ｆの場合による置換基の立体構造は、シクロプロピル環上の他の任意の位置での任意の置換基に対して変化することができる。シクロペンチルまたはシクロペンテニルと結合している具体的な置換基に応じて、任意の炭素での立体構造は（Ｒ）であっても（Ｓ）であってもよい。

.
As shown, the relative steric structure at any of the positions of the cyclopentyl ring may be cis or trans. The optional substituent conformation of R _A or R _F at either the cyclopentyl or cyclopentenyl position can vary with respect to any substituent at any other position on the cyclopropyl ring. . Depending on the specific substituents attached to cyclopentyl or cyclopentenyl, the steric structure at any carbon may be (R) or (S).

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 0, 1, 2, 3, 4 Or optionally substituted with one or more substituents containing 5 heteroatoms and selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. ing. Also preferably, R _F is C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl, each of which contains 0, 1, 2, 3, 4 or 5 O; Optionally substituted independently with one or more R _L. Again preferably, R _F is — (R _X —R _Y ) _Q — (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 one or more selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano Each independently substituted or substituted C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene; each R _Y 'is independently halogen, hydroxy, mercapto Independently with one or more substituents selected from amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl substituted by Preferably each R _X is O. More preferably, X is optionally substituted with one or more R _A or R _F , wherein each R _F is independent of C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl. Each of which contains 0, 1, 2 or 3 O, one or more selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano Optionally substituted with multiple substituents independently. Again preferably, X is optionally substituted with one or more R _A or R _F , wherein each R _F is — (O—C ₁ -C ₆ alkylene) _Q — (O—C ₁ -C ₆ alkyl). Q) is preferably 0, 1, 2 or 3.

L ₁ and L ₂ are independently a bond or C ₁ -C ₆ alkylene, and L ₃ is preferably selected from a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L Each ₃ is independently substituted with one or more R _L. More preferably, L ₁ , L ₂ and L ₃ are each independently a bond or C ₁ -C ₆ alkylene (eg, —CH ₂ — or —CH ₂ CH ₂ —), and one or more R _L Independently substituted in some cases. Most preferably, L ₁ , L ₂ and L ₃ are each a bond.

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, -N (R B) C (O) -L S -E or _{-C (O) N (R B} ) is selected from _-L S -E. G is _C 5 -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring, for example,

または

Or

であり、１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のクロロまたはブロモ）で場合によって置換されている。Ｅは好ましくは７員から１２員の二環（例えば

Optionally substituted with one or more R _A (eg, one or more chloro or bromo). E is preferably a 7 to 12 membered bicycle (eg,

であり、Ｕは出現ごとに独立に−（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、その中で少なくとも１個の炭素原子はＯ、ＳまたはＮで独立に場合によって置き換えられていてよい。）であり、１つもしくは複数のＲ_Ａで場合によって置換されている。より好ましくは、Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａ（これらに限定されないが、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）で場合によって置換された５員から６員の複素環または６員から１２員の二環（例えば、

And U is independently selected from — (CH ₂ ) — or — (NH) — for each occurrence; V and Z ₂₀ are each independently C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene or C _2. Selected from —C ₄ alkynylene, in which at least one carbon atom may optionally be independently replaced by O, S or N. And optionally substituted with one or more _RA . More preferably, R ₁ is R _C and R ₂ and R ₅ together with the atoms to which they are attached are one or more R _A (including but not limited to hydroxy, halo (eg , Fluoro), C ₁ -C ₆ alkyl (eg methyl) or C ₂ -C ₆ alkenyl (eg allyl)), optionally substituted 5 to 6 membered heterocycle or 6 to 12 membered Bicyclic (for example,

もしくは

Or

、または

Or

、または

Or

もしくは

Or

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａ（これらに限定されないが、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））で場合によって置換された５員から６員の炭素環／複素環または６員から１２員の二環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are combined with one or more R _A ( 5- to 6-membered carbon optionally substituted with, but not limited to, hydroxy, halo (eg, fluoro), C ₁ -C ₆ alkyl (eg, methyl) or C ₂ -C ₆ alkenyl (eg, allyl)) A ring / heterocycle or a 6 to 12 membered bicycle (eg,

または

Or

）を形成している。

) Is formed.

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 '-M'-R} D or _{-L S -C (R 3 R 4} ) C (R 6 R 7) -L Y' can also be selected from _{-M'-R D,} M is Preferably, it is a bond, —C (O) N (R _B ) — or —N (R _B ) C (O) —, and 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 —, wherein L _Y ′ is preferably a C ₁ -C ₆ alkylene optionally substituted with one or more R _L It is. L _Y 'is L _S '. L _Y ′ is, for example, C ₁ -C ₆ alkylene, such as, but not limited to,

または

Or

であり；場合によるＲ_Ｌは、これらに限定されないが、フェニル、−ＳＭｅまたはメトキシなどの置換基である。基Ｌ_Ｙ’内の炭素での任意の立体構造は（Ｒ）であっても（Ｓ）であってもよい。より好ましくは、Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のヒドロキシ）で場合によって置換された５員から６員の複素環または６員から１２員の二環（例えば、

Optional R _L is a substituent such as, but not limited to, phenyl, —SMe, or methoxy. Any steric structure at the carbon in the group L _Y ′ may be (R) or (S). More preferably, R ₁ is R _C and R ₂ and R ₅ together with the atoms to which they are attached are one or more R _A (eg one or more hydroxy). 5- to 6-membered heterocycle or 6- to 12-membered bicycle substituted by

または

Or

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された５員から６員の炭素環／複素環または６員から１２員の二環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocycle / heterocycle or 6- to 12-membered bicycle (eg,

または

Or

）を形成している。

) Is formed.

Again 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} ), CR 6 R 7) - L _Y ′ selected from R _D is preferably C ₁ -C ₆ alkylene optionally substituted with one or more R _L. R ₁ may be R _C and R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocycles optionally substituted with one or more R _A A ring or a 6 to 12 membered bicyclic ring (eg,

または

Or

）を形成していてよく；Ｒ_３およびＲ_６はそれぞれ独立にＲ_Ｃであってよく、Ｒ_４およびＲ_７はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環／複素環または６員から１２員の二環（例えば

R ₃ and R ₆ may each independently be R _C , and R ₄ and R ₇ together with the atoms to which they are attached are one or more R _A Optionally substituted 5- to 6-membered carbocycle / heterocycle or 6- to 12-membered bicycle (eg

または

Or

）を形成していてよい。

) May be formed.

Most 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— 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 —GC (R ₁ R ₂ ) N (R ₅ ) —C (O) —L _Y —N (R _B ″) C (O) —L _S —R _E , and L _Y is one or C ₁ -C ₆ alkylene optionally substituted with a plurality of R _L , and R _B ″ is independently R _B. R _B ″ and R ₁ are each preferably hydrogen or C ₁ -C ₆ alkyl. There, R ₂ and R ₅ together with the atoms to which they are attached, preferably, one or more of R _{a (but} not limited to, hydroxide , Halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl) or _C 2 -C ₆ alkenyl (e.g., allyl), etc.) heterocycle 6 from 5 members which is optionally substituted with or 6 2 to 12 members (for example,

または

Or

）を形成している。Ｌ_Ｙはそれぞれ独立にＬ_Ｓである。好ましくは、Ｌ_Ｙは１つもしくは複数のＲ_Ｌ、例えば、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環３員から６員の複素環で置換されたＣ_１−Ｃ_６アルキレンである。非常に好ましくは、Ｌ_ＹはＣ_１−Ｃ_６アルキレン、例えば、これらに限定されないが、

) Is formed. L _Y is independently L _S. Preferably, L _Y is one or more R _L , such as halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, C _2- Optionally substituted with one or more substituents selected from C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl. C ₃ -C ₆ carbocycle is a C ₁ -C ₆ alkylene substituted with a 3 to 6 membered heterocycle. Most preferably, L _Y is C ₁ -C ₆ alkylene, such as, but not limited to,

または

Or

（基Ｌ_Ｙ内の炭素での立体構造は（Ｒ）であっても（Ｓ）であってもよい。）であり、Ｌ_Ｙは１つもしくは複数のＲ_Ｌ（例えば、１つもしくは複数のフェニルまたはメトキシ）で場合によって置換されており、Ｇは好ましくは

(The steric structure at the carbon in the group L _Y may be (R) or (S)), and L _Y may be one or more R _L (eg, one or more Optionally substituted with phenyl or methoxy) and G is preferably

であり、Ｒ_Ｂ”は水素であり；
−Ｃ（Ｒ_１Ｒ_２）Ｎ（Ｒ_５）−は

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。

L _S is a bond; R _E is methoxy.

  Preferred non-limiting examples of Y include:

または

Or

が含まれ、ＴおよびＲ_Ｄは本明細書で定義する通りである。Ｔは例えば−Ｌ_Ｓ−Ｍ−Ｌ_Ｓ’−Ｍ’−Ｌ_Ｓ”−であってよく、Ｌ_Ｓは結合であり；ＭはＣ（Ｏ）であり；Ｌ_Ｓ’はＣ_１−Ｃ_６アルキレン、例えば、これらに限定されないが：

And T and _RD are as defined herein. T is for example _{-L S -M-L S '-M'} -L S "- a may be, _{L S} is a bond; M is C (O); _{L S'} is _C 1 -C ₆ Alkylene, such as, but not limited to:

または

Or

であり、Ｌ_Ｓ’は１つもしくは複数のＲ_Ｌで場合によって置換されており；Ｒ_Ｌは、これらに限定されないが、フェニルまたはメトキシなどの置換基であり；Ｍ’は−ＮＨＣ（Ｏ）−または−ＮＭｅＣ（Ｏ）−であり；Ｌ_Ｓ”は結合である。基Ｌ_Ｓ’内の炭素での任意の立体構造は（Ｒ）であっても（Ｓ）であってもよい。Ｒ_Ｄは例えばメトキシである。Ｔ−Ｒ_Ｄには、これらに限定されないが：

L _S ′ is optionally substituted with one or more R _L ; R _L is a substituent such as, but not limited to, phenyl or methoxy; M ′ is —NHC (O) -Or -NMeC (O)-; L _S ″ is a bond. Any steric structure at the carbon in the group L _S ′ may be (R) or (S). _D is, for example, methoxy, T-R _D includes, but is not limited to:

または

Or

が含まれる。Ｔ−Ｒ_Ｄは特定の立体化学的配置を含むこともでき；したがって、Ｔ−Ｒ_Ｄは、これらに限定されないが：

Is included. T- _RD may also include a specific stereochemical configuration; therefore, T- _RD is not limited to:

および

and

を含む。

including.

  Preferred non-limiting examples of Y include:

または

Or

または

Or

も含まれる。

Is also included.

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, -N (R B) C (O) -L S -E or _{-C (O) N (R B} ) is selected from _-L S -E. G is _C 5 -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring, for example,

または

Or

であり、１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のクロロまたはブロモ）で場合によって置換されている。Ｅは好ましくは８員から１２員の二環（例えば

Optionally substituted with one or more R _A (eg, one or more chloro or bromo). E is preferably an 8- to 12-membered bicycle (eg,

、ここでＵは出現ごとに独立に−（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、その中で少なくとも１個の炭素原子はＯ、ＳまたはＮで独立に場合によって置き換えられている。）であり、１つもしくは複数のＲ_Ａで場合によって置換されている。より好ましくは、Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａ（例えば、これらに限定されないが、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）で場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

Where U is independently selected from — (CH ₂ ) — or — (NH) — for each occurrence; V and Z ₂₀ are each independently C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene or C _2. is selected from -C ₄ alkynylene, at least one carbon atom therein is O, it is replaced independently with S or N. And optionally substituted with one or more _RA . More preferably, R ₈ is R _C and R ₉ and R ₁₂ together with the atom to which they are attached are one or more R _A (eg, but not limited to, hydroxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl) or _C 2 -C ₆ alkenyl (e.g., allyl), etc.) from a heterocyclic or 6 membered 6 from 5 members which is substituted by at 12-membered bicyclic ring (eg,

または

Or

；または

Or

；または

Or

もしくは

Or

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａ（これらに限定されないが、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）で場合によって置換されている５員から６員の炭素環／複素環または６員から１２員の二環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are combined with one or more R _A ( 5-6 membered optionally substituted with, but not limited to, hydroxy, halo (eg fluoro), C ₁ -C ₆ alkyl (eg methyl) or C ₂ -C ₆ alkenyl (eg allyl)) Carbocycles / heterocycles or 6 to 12 membered bicycles (eg,

または

Or

）を形成している。

) Is formed.

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' can also be selected from _{-M'-R D,} M It is preferably a _{bond, -C (O) N (R} B) - or _{-N (R B) C (O} ) - There, 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 L _Y ′ is preferably one or more C ₁ -C ₆ alkylene optionally substituted with _RL . L _Y ′ is independently L _S. L _Y ′ is, for example, C ₁ -C ₆ alkylene, such as, but not limited to,

または

Or

であり；場合によるＲ_Ｌは、これらに限定されないが、フェニル、−ＳＭｅまたはメトキシなどの置換基である。基Ｌ_Ｙ’内の炭素での任意の立体構造は（Ｒ）であっても（Ｓ）であってもよい。より好ましくは、Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のヒドロキシ）で場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

Optional R _L is a substituent such as, but not limited to, phenyl, —SMe, or methoxy. Any steric structure at the carbon in the group L _Y ′ may be (R) or (S). More preferably, R ₈ is R _C and R ₉ and R ₁₂ together with the atoms to which they are attached are one or more R _A (eg one or more hydroxy). A 5- to 6-membered heterocycle or a 6- to 12-membered bicycle substituted by

または

Or

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環／複素環または６員から１２員の二環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocycle / heterocycle or 6- to 12-membered bicycle (eg,

または

Or

）を形成している。

) Is formed.

Still 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 _{2) -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 _{3 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} 8') -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 (R 13} R 14) -C (O) -L Y '-R D or _{-L S -C (R 10 R 11} ,) C (R 13 R 14) is selected from -R _D, L _Y ′ is preferably C ₁ -C ₆ alkylene optionally substituted with one or more R _L. R ₈ can be R _C and R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocycles optionally substituted with one or more R _A. A ring or a 6 to 12 membered bicyclic ring (eg,

または

Or

）を形成していてよく；Ｒ_１０およびＲ_１３はそれぞれ独立にＲ_Ｃであってよく、Ｒ_１１およびＲ_１４はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環／複素環または６員から１２員の二環（例えば、

R ₁₀ and R ₁₃ may each independently be R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are one or more R _A Optionally substituted 5- to 6-membered carbocycle / heterocycle or 6- to 12-membered bicycle (eg,

または

Or

）を形成していてよい。

) May be formed.

Most 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} , or Z _{-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 C ₁ -C ₆ alkylene optionally substituted with R _L and each R _B ″ is independently R _B. R _B ″ and R ₈ are each preferably hydrogen or C ₁ -C ₆ alkyl. , R ₉ and R ₁₂ together with the atoms to which they are attached, preferably, one or more of R _{a (but} not limited to, hydrin Alkoxy, halo (e.g., _fluoro), C 1 -C ₆ alkyl (e.g., methyl) or _C 2 -C ₆ alkenyl (e.g., allyl) and the like) 6-membered heterocyclic ring or a 5-membered optionally substituted with 6 to 12 membered bicyclic rings (eg,

または

Or

）を形成している。Ｌ_Ｙはそれぞれ独立にＬ_Ｓである。好ましくは、Ｌ_Ｙは、１つもしくは複数のＲ_Ｌ、例えばハロゲン、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環３員から６員の複素環で置換されたＣ_１−Ｃ_６アルキレンである。非常に好ましくは、Ｌ_ＹはＣ_１−Ｃ_６アルキレン、例えば、これらに限定されないが、

) Is formed. L _Y is independently L _S. Preferably, L _Y is one or more R _L , such as halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, C _2- Optionally substituted with one or more substituents selected from C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl. C ₃ -C ₆ carbon ring is a C ₁ -C ₆ alkylene substituted with a 3 to 6 membered heterocyclic ring. Most preferably, L _Y is C ₁ -C ₆ alkylene, such as, but not limited to,

または

Or

（基Ｌ_Ｙ内の炭素での立体構造は（Ｒ）であっても（Ｓ）であってもよい。）であり；Ｌ_Ｙは１つもしくは複数のＲ_Ｌ（例えば、１つもしくは複数のフェニルまたはメトキシ）で場合によって置換されており；Ｇは好ましくは

(The steric structure at the carbon in the group L _Y may be (R) or (S)); L _Y may be one or more R _L (eg, one or more Optionally substituted with phenyl or methoxy; G is preferably

であり；Ｒ_Ｂ”は水素であり；−Ｃ（Ｒ_８Ｒ_９）Ｎ（Ｒ_１２）−は

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。

L _S is a bond; R _E is methoxy.

  Preferred non-limiting examples of Z include:

または

Or

が含まれ、ＴおよびＲ_Ｄは本明細書で定義する通りである。Ｔは、例えば−Ｌ_Ｓ−Ｍ−Ｌ_Ｓ’−Ｍ’−Ｌ_Ｓ”−であってよく、Ｌ_Ｓは結合であり；ＭはＣ（Ｏ）であり；Ｌ_Ｓ’はＣ_１−Ｃ_６アルキレン、例えばこれらに限定されないが、

And T and _RD are as defined herein. T, for example _{-L S -M-L S '-M'} -L S "- a may be, _{L S} is a bond; M is C (O); _{L S'} is _C 1 -C ₆ alkylene, such as, but not limited to,

または

Or

であり、Ｌ_Ｓ’は１つもしくは複数のＲ_Ｌで場合によって置換されており；場合によるＲ_Ｌは、これらに限定されないが、フェニルまたはメトキシなどの置換基であり；Ｍ’は−ＮＨＣ（Ｏ）−または−ＮＭｅＣ（Ｏ）−であり；Ｌ_Ｓ”は結合である。基Ｌ_Ｓ’内の炭素での任意の立体構造は（Ｒ）であっても（Ｓ）であってもよい。Ｒ_Ｄは例えばメトキシである。Ｔ−Ｒ_Ｄには、これらに限定されないが：

L _S ′ is optionally substituted with one or more R _L ; optional R _L is a substituent such as, but not limited to, phenyl or methoxy; M ′ is —NHC ( O) — or —NMeC (O) —; L _S ″ is a bond. Any steric structure at the carbon in the group L _S ′ may be (R) or (S). _RD is, for example, methoxy, T- _RD includes, but is not limited to:

または

Or

が含まれる。Ｔ−Ｒ_Ｄは特定の立体化学的配置を含むこともでき、したがってＴ−Ｒ_Ｄには、これらに限定されないが

Is included. T- _RD may also include a specific stereochemical configuration, and thus T- _RD includes, but is not limited to,

および

and

が含まれる。

Is included.

  Preferred non-limiting examples of Z include:

または

Or

も含まれる。

Is also included.

T is not limited to, -C in each occurrence _{(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 ″ — may be independently selected. Preferably, T is independently —C (O) —L _S ′ — for each occurrence. _{M'-L S} "- or _{-N (R B) C (O} ) -L S '-M'-L S" -. more preferably chosen from, T is -C independently at each occurrence (O _{) -L S '-N (R B} ) C (O) -L S "- or _{-C (O) -L S' -N} (R B) C (O) O-L _S ″ — is selected.

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

）であり、Ｌ_Ｓ’はＲ_Ｔで場合によって置換されており；場合による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員から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カルボシクリル（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, _{L S} 'is optionally substituted with _{R T;} is _{R T} by case, _-C 1 -C ₆ alkyl, _-C 2 -C ₆ alkenyl, _-C 1 -C ₆ alkyl -OH, Substitution selected from —C ₁ -C ₆ alkyl-O—C ₁ -C ₆ alkyl, 3 to 6 membered heterocycle (eg, tetrahydrofuranyl) or C ₃ -C ₆ carbocyclyl (eg, phenyl, cyclohexyl) M ′ is —NHC (O) —, —N (Et) C (O) — or —N (Me) C (O) —; L _S ″ is a bond. R _D is preferably Is hydrogen, —C ₁ -C ₆ alkyl (eg, methyl), —O—C ₁ -C ₆ alkyl (eg, methoxy, tert-butoxy), methoxymethyl or —N (C ₁ -C ₆ alkyl) ₂ ( For example, a -NMe _2).

T- _RD is not limited to these,

または

Or

であってよく、基Ｔ−Ｒ_Ｄ内の炭素での立体構造は（Ｒ）であっても（Ｓ）であってもよい。

The steric structure at the carbon in the group T- _RD may be (R) or (S).

T also include, but are not limited _{to, -L S -M-L S '} - a may 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Ｒ_Ｔで場合によって置換されており；場合による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カルボシクリル（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つもしくは複数のハロゲン、オキソで場合によって置換された３員から１０員のヘテロシクリル（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で場合によって置換されたＣ_３−Ｃ_１０炭素環（例えば、シクロペンチル）；−ＯＨで場合によって置換された−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員から６員のヘテロシクリル（例えば、チアゾリル、ピリミジニル）である。Ｔ−Ｒ_Ｄには、これらに限定されないが：

), And, _{L S} 'is optionally substituted with _{R T;} is _{R T} by case, _-C 1 -C ₆ alkyl, _-C 1 -C ₆ alkyl -OH, _-C 1 _{-C 6} alkyl - A substituent selected from O—C ₁ -C ₆ alkyl or C ₃ -C ₆ carbocyclyl (eg, phenyl, cyclohexyl). R _D is, for example, —OH; —OC (O) Me; —NH (C ₁ -C ₆ alkyl) (eg, —NHMe, —NHEt); —N (C ₁ -C ₆ alkyl) ₂ (eg, — NMe _2, -NEt _2); 1 one or more halogen, heterocyclyl 10-membered 3- to optionally substituted with oxo (e.g., pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, morpholinyl, piperidinyl); - optionally with OH A substituted C ₃ -C ₁₀ carbocycle (eg, cyclopentyl); —C ₁ -C ₆ alkyl optionally substituted with —OH (eg, isopropyl, 3-pentyl); or NHR _T , wherein R _T is 3 to 6 membered heterocyclyl (eg thiazolyl, pyrimidinyl). The _{T-R D,} but are not limited to:

または

Or

が含まれ、基Ｔ−Ｒ_Ｄ内の炭素での立体構造は（Ｒ）であっても（Ｓ）であってもよい。

And the steric structure at the carbon in the group T- _RD may be (R) or (S).

For each compound of Formula I, _{L K} is coupled independently each _{occurrence; -L S '-N (R B} ) C (O) -L S -; - L S' -C (O) N (R B) -L _S- ; or each independently for each occurrence, halogen, R _T , -O-R _S , -S-R _S , -N ( _RS R _S '), -OC (O) R _S ,- C ₁ -C ₆ alkylene, C ₂ -C ₆ optionally substituted with one or more substituents selected from C (O) OR _S , nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Alkenylene, C ₂ -C ₆ alkynylene, C ₃ -C ₁₀ carbocycle or a 3 to 10 membered heterocycle may be selected, and L _S and L _S ′ are as defined above.

Formula I and Formula _I A described _below, I _C, I _D, I E, the _{I F} or _{I G,} where including any embodiment described, the _{R A} is preferably halogen, hydroxy, mercapto, amino , Carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano for each occurrence C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents; or each independently occurrence of halogen, hydroxy, mercapto , Amino, carboxy, nitro, oxo, phosphonox , 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 A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle optionally substituted with one or more substituents selected from alkynyl, C (O) OR _S or R _F ; 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 - _{(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 a _{-C (O) N (R S} ) C (O) -R S ', the _{L a bond,} C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene.

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence is independently halogen, hydroxy, mercapto, amino, carboxy, nitro C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano ; or, each independently halogen at each occurrence, 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 3 -C which are optionally substituted with one or more substituents selected from C (O) OR _S or _{R F A 6-} carbon ring or a 3- to 6-membered heterocyclic ring.

Most preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each is independently halogen, hydroxy, mercapto, amino, carboxy, nitro C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano It is.

L _S , L _S ′ and L _S ″ are preferably each independently linked for each occurrence; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene.

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

  In one embodiment, A and B are each independently a 5 or 6 membered carbocyclic or heterocyclic ring (eg,

などのフェニル）であり、１つもしくは複数のＲ_Ａでそれぞれ独立に場合によって置換されている。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄは、Ｃ_５−Ｃ_６炭素環または５員から６員の複素環（例えば、フェニル）であり、１つもしくは複数のＲ_Ａで場合によって置換されているか；またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Phenyl), each optionally substituted independently with one or more _RA . X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), optionally substituted with one or more _RA ; or substituted with J; Optionally substituted with one or more R _A , J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, wherein one or more Optionally substituted with _RA . Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. 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 ) -T- _RD and 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 R _C and R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

) Is formed. R ₈ is R _C and R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｔは好ましくは、出現ごとに独立に−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−）であり、Ｒ_Ｌから選択される１つもしくは複数の置換基で場合によって置換されている。Ｔは、これらに限定されないが、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｌ_Ｓ''−、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｏ−ＬＳ''−、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ''−または−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ''−から選択されてもよい。いくつかの場合、ＹおよびＺの少なくとも１つ、またはＹとＺの両方は独立に、

) Is formed. T is preferably -C (O) -L _Y '-N (R _B ) C (O) -L _S ''-or -C (O) -L _Y ' -N (R _B independently for each occurrence. ) C (O) O-L S '' - it is selected from. L _Y 'is independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), and with one or more substituents selected from R _L Has been replaced by T is not limited _{to, -C (O) -L Y '} -L S''-, - C (O) -L Y' -O-LS '' -, - C (O) -L Y '-N (R _B ) -L _S ″-or -C (O) -L _Y ' -N (R _B ) S (O) ₂ -L _S ″-may be selected. In some cases, at least one of Y and Z, or both Y and Z are independently

であり、Ｒ_Ｄの非限定的な例には、（１）それぞれが出現ごとに独立にハロゲン、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_３−Ｃ_６炭素環または３員から６員の複素環から選択される１つもしくは複数の置換基で場合によって置換されている−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）それぞれが出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環が含まれ；Ｌ_Ｙ’の非限定的な例には、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員から６員の炭素環もしくは複素環で場合によって置換されたＣ_１−Ｃ_６アルキレンが含まれ、前記３員から６員の炭素環もしく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つもしくは複数の置換基で場合によって置換されている。

Non-limiting examples of _RD include: (1) each independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or one or more _-O-C 1 -C ₆ alkyl which is optionally substituted with substituents from 3 members from 6 membered heterocyclic ring, _-O-C 2 -C ₆ Alkenyl, —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 at each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, C C ₃ -C optionally 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. ₆ contains a heterocyclic 6-membered carbocyclic or 3 members; non-limiting examples of _{L Y} ', 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 C ₁ -C ₆ alkylene optionally substituted with a 3 to 6 membered carbocyclic or heterocyclic ring, including said 3 member To 6-membered carbocyclic or heterocyclic rings are 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,} one or more selected from C 2 -C ₆ haloalkenyl or _C 2 -C ₆ haloalkynyl Optionally substituted with a substituent of

  In other embodiments, A is

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは

Optionally substituted with one or more _RA ; B is

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は出現ごとに独立にＮまたはＣＨから選択される。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄは、Ｃ_５−Ｃ_６炭素環または５員から６員の複素環（例えば、フェニル）であり、１つもしくは複数のＲ_Ａで場合によって置換されているか；またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Optionally substituted with one or more _RA . Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence; Z ₂ is independently selected from N or CH at each occurrence. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), optionally substituted with one or more _RA ; or substituted with J; Optionally substituted with one or more R _A , J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, wherein one or more Optionally substituted with _RA . Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. 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 R _C and R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

) Is formed. R ₈ is R _C and R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｔは好ましくは、出現ごとに−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''−から独立に選択される。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つもしくは複数の置換基で場合によって置換されている。Ｔは、これらに限定されないが、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｌ_Ｓ''−、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｏ−ＬＳ''−、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ''−または−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ''−から選択されてもよい。いくつかの場合、ＹおよびＺの少なくとも１つ、またはＹとＺの両方は独立に、

) Is formed. T is preferably -C (O) -L _Y '-N (R _B ) C (O) -L _S ''-or -C (O) -L _Y ' -N (R _B ) C for each occurrence. (O) independently selected from O-L _S ″-. L _Y ′ is independently L _S ′, preferably independently C ₁ -C ₆ alkylene (eg, —CH ₂ —), optionally with one or more substituents selected from R _L Has been replaced. T is not limited _{to, -C (O) -L Y '} -L S''-, - C (O) -L Y' -O-LS '' -, - C (O) -L Y '-N (R _B ) -L _S ″-or -C (O) -L _Y ' -N (R _B ) S (O) ₂ -L _S ″-may be selected. In some cases, at least one of Y and Z, or both Y and Z are independently

であり、Ｒ_Ｄの非限定的な例には、（１）それぞれが出現ごとに独立にハロゲン、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_３−Ｃ_６炭素環または３員から６員の複素環から選択される１つもしくは複数の置換基で場合によって置換されている−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）それぞれが出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環が含まれ；Ｌ_Ｙ’の非限定的な例には、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員から６員の炭素環もしくは複素環で場合によって置換されたＣ_１−Ｃ_６アルキレンが含まれ、前記３員から６員の炭素環もしく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つもしくは複数の置換基で場合によって置換されている。

Non-limiting examples of _RD include: (1) each independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or one or more _-O-C 1 -C ₆ alkyl which is optionally substituted with substituents from 3 members from 6 membered heterocyclic ring, _-O-C 2 -C ₆ Alkenyl, —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 at each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, C C ₃ -C optionally 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. ₆ contains a heterocyclic 6-membered carbocyclic or 3 members; non-limiting examples of _{L Y} ', 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 C ₁ -C ₆ alkylene optionally substituted with a 3 to 6 membered carbocyclic or heterocyclic ring, including said 3 member To 6-membered carbocyclic or heterocyclic rings are 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,} one or more selected from C 2 -C ₆ haloalkenyl or _C 2 -C ₆ haloalkynyl Optionally substituted with a substituent of

  In still other embodiments, A and B are each independently a 5- or 6-membered carbocyclic or heterocyclic ring (eg, A and B are each independently phenyl, such as

である。）であり、それぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されている。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄは、例えばＣ_５−Ｃ_６炭素環または５員から６員の複素環（例えば、フェニル）であってよく、１つもしくは複数のＲ_Ａで場合によって置換されているか；またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

It is. Each optionally independently substituted with one or more _RA . X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D may be, for example, a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), optionally substituted with one or more _RA ; or substituted with J Optionally substituted with one or more R _A , J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring; or it is optionally substituted with a plurality of R _a. Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。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であり、Ｇは独立にＣ_５−Ｃ_６炭素環または５員から６員の複素環、例えば

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. 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, Z is -G-C (R < ₈ > R < ₉ >) N (R < ₁₂ >)-T- _RD or -GC (R < ₁₀ > R < ₁₁ >) C (R < ₁₃ > R < ₁₄ >)-T- _RD and G is independently C ₅ -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring, for example,

または

Or

であり、１つもしくは複数のＲ_Ａで独立に場合によって置換されている。Ｒ_１はＲ_Ｃであり、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された５員から６員の複素環式環（例えば、

Optionally independently substituted with one or more _RA . R ₁ is R _C and R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocyclic rings optionally substituted with one or more R _A (For example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

) Is formed. R ₈ is R _C and R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｔは好ましくは、出現ごとに独立に−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−）であり、Ｒ_Ｌから選択される１つもしくは複数の置換基で場合によって置換されている。Ｔは、これらに限定されないが、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｌ_Ｓ”−、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｏ−ＬＳ”−、−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｎ（Ｒ_Ｂ）−Ｌ_Ｓ”−または−Ｃ（Ｏ）−Ｌ_Ｙ’−Ｎ（Ｒ_Ｂ）Ｓ（Ｏ）_２−Ｌ_Ｓ”−から選択されてもよい。いくつかの場合、ＹおよびＺの少なくとも１つ、またはＹとＺの両方は独立に、

) Is formed. T is preferably -C (O) -L _Y '-N (R _B ) C (O) -L _S "-or -C (O) -L _Y ' -N (R _B ) independently for each occurrence. _{C (O) O-L S} "- is selected from. L _Y 'is independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), and with one or more substituents selected from R _L Has been replaced by Although T is not limited to these, -C (O) -L _Y '-L _S "-, -C (O) -L _Y '-O-LS"-, -C (O) -L _Y '- _{N (R B) -L S "} - or _{-C (O) -L Y '-N} (R B) S (O) 2 -L S" - may be selected from. In some cases, at least one of Y and Z, or both Y and Z are independently

または

Or

であり、Ｒ_Ｄの非限定的な例には、（１）それぞれが出現ごとに独立にハロゲン、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_３−Ｃ_６炭素環または３員から６員の複素環から選択される１つもしくは複数の置換基で場合によって置換されている−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）それぞれが出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環が含まれ；Ｌ_Ｙ’の非限定的な例には、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員から６員の炭素環もしくは複素環で場合によって置換されたＣ_１−Ｃ_６アルキレンが含まれ、前記３員から６員の炭素環もしく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つもしくは複数の置換基で場合によって置換されている。

Non-limiting examples of _RD include: (1) each independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or one or more _-O-C 1 -C ₆ alkyl which is optionally substituted with substituents from 3 members from 6 membered heterocyclic ring, _-O-C 2 -C ₆ Alkenyl, —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 at each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, C C ₃ -C optionally 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. ₆ contains a heterocyclic 6-membered carbocyclic or 3 members; non-limiting examples of _{L Y} ', 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 C ₁ -C ₆ alkylene optionally substituted with a 3 to 6 membered carbocyclic or heterocyclic ring, including said 3 member To 6-membered carbocyclic or heterocyclic rings are 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,} one or more selected from C 2 -C ₆ haloalkenyl or _C 2 -C ₆ haloalkynyl Optionally substituted with a substituent of

  In still other embodiments, A and B are each independently a 5- or 6-membered carbocyclic or heterocyclic ring (eg, A and B are each independently phenyl, such as

である。）であり、それぞれ１つもしくは複数のＲ_Ａで独立に場合によって置換されている。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄは、例えばＣ_５−Ｃ_６炭素環または５員から６員の複素環（例えば、フェニル）であってよく、１つもしくは複数のＲ_Ａで場合によって置換されているか；またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

It is. Each independently substituted with one or more _RA independently. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D may be, for example, a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), optionally substituted with one or more _RA ; or substituted with J Optionally substituted with one or more R _A , J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring; or it is optionally substituted with a plurality of R _a. Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。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であるか；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. 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 >)-T- _RD and Z is -GC (R < ₈ > R < ₉ >) N (R < ₁₂ >)-T- _RD or -GC (R < ₁₀ > R < ₁₁ >) C (R <_13>. R < ₁₄ >)-T- _RD ; or Y is -GC (R < ₁ > R < ₂ >) N (R < ₅ >)-T- _RD or -GC (R < ₃ > R < ₄ >) C (R < ₆ >. R < ₇ >)-T- _RD and 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)} is _{C (R 13 R 14) -T} -R D. R ₁ is R _C and R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally substituted with one or more R _A 5- to 6-membered carbocyclic or heterocyclic rings (e.g.

）を形成している。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

) Is formed. R ₈ is R _C and R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｇは独立にＣ_５−Ｃ_６炭素環または５員から６員の複素環、例えば

) Is formed. G is independently _C 5 -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring, for example,

または

Or

であり、１つもしくは複数のＲ_Ａで独立に場合によって置換されている。Ｔは好ましくは、出現ごとに−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”−から独立に選択される。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−）であり、Ｒ_Ｌから選択される１つもしくは複数の置換基で場合によって置換されている。Ｔは、これらに限定されないが、−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”−から選択されてもよい。いくつかの場合、Ｙは
上述したような

Optionally independently substituted with one or more _RA . T is preferably -C (O) -L _Y '-N (R _B ) C (O) -L _S "-or -C (O) -L _Y ' -N (R _B ) C ( O) independently selected from _OLs "-. L _Y 'is independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), and with one or more substituents selected from R _L Has been replaced by Although T is not limited to these, -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" - may be selected from. In some cases Y is as described above

であり、Ｚは上述したような

And Z is as described above.

または

Or

である。他のいくつかの場合、Ｙは上述したような

It is. In some other cases, Y is as described above.

または

Or

であり、Ｚは上述したような

And Z is as described above.

である。

It is.

  In still other embodiments, A is a 5- or 6-membered carbocyclic or heterocyclic ring (eg, phenyl, such as

）であり、Ｂは

) And B is

または

Or

（例えば、

(For example,

または

Or

）であるか；またはＡは

Or A is

または

Or

（例えば、

(For example,

または

Or

）であり、Ｂは５員もしくは６員の炭素環もしくは複素環（例えば、フェニル、例えば

And B is a 5- or 6-membered carbocyclic or heterocyclic ring (eg phenyl, eg

）である。ＡおよびＢはそれぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されている。Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は出現ごとに独立にＮまたはＣＨから選択される。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄは、Ｃ_５−Ｃ_６炭素環または５員から６員の複素環（例えば、フェニル）であり、１つもしくは複数のＲ_Ａで場合によって置換されているか；またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

). A and B are each optionally substituted with one or more _RA . Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence; Z ₂ is independently selected from N or CH at each occurrence. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), optionally substituted with one or more _RA ; or substituted with J; Optionally substituted with one or more R _A , J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, wherein one or more Optionally substituted with _RA . Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。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員の炭素環もしくは複素環（例えば、フェニル、例えば

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. A is a 5- or 6-membered carbocyclic or heterocyclic ring (eg phenyl, eg

）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員の炭素環もしくは複素環（例えば、フェニル、例えば

), 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 carbocyclic or heterocyclic ring (eg phenyl, eg

）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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された５員から６員の複素環式環（例えば、

If) is, 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) -T- is 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 R _C and R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocyclic rings optionally substituted with one or more R _A (For example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｒ_８はＲ_Ｃであり、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

) Is formed. R ₈ is R _C and R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）を形成している。Ｇは独立にＣ_５−Ｃ_６炭素環または５員から６員の複素環、例えば

) Is formed. G is independently _C 5 -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring, for example,

または

Or

であり、１つもしくは複数のＲ_Ａで独立に場合によって置換されている。Ｔは好ましくは、出現ごとに−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”−から独立に選択される。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−）であり、Ｒ_Ｌから選択される１つもしくは複数の置換基で場合によって置換されている。Ｔは、これらに限定されないが、−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”−から選択されてもよい。いくつかの場合、Ａが５員もしくは６員の炭素環もしくは複素環（例えば、フェニル、例えば

Optionally independently substituted with one or more _RA . T is preferably -C (O) -L _Y '-N (R _B ) C (O) -L _S "-or -C (O) -L _Y ' -N (R _B ) C ( O) independently selected from _OLs "-. L _Y 'is independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), and with one or more substituents selected from R _L Has been replaced by Although T is not limited to these, -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" - may be selected from. In some cases, A is a 5- or 6-membered carbocyclic or heterocyclic ring (eg, phenyl, such as

）である場合、Ｙは上述したような

), Y is as described above.

または

Or

であり、Ｚは上述したような

And Z is as described above.

である。他のいくつかの場合、Ｂが５員もしくは６員の炭素環もしくは複素環（例えば、フェニル、例えば

It is. In some other cases, B is a 5- or 6-membered carbocyclic or heterocyclic ring (eg, phenyl, such as

）である場合、Ｙは上述したような

), Y is as described above.

であり、Ｚは上述したような

And Z is as described above.

または

Or

である。

It is.

The invention also features compounds of Formulas I, I _A , I _B , Ic and _ID , as described herein (including the embodiments described below), and pharmaceutically acceptable salts thereof. To: where
D is a C ₃ -C ₁₂ carbocycle or a 3 to 12 membered heterocycle and is optionally substituted with one or more R _A ; or D is substituted with J and a _C 3 _{-C 12} carbocyclic or 3 12-membered membered heterocyclic ring is optionally substituted with a plurality of _{R a,} J is _C 3 _{-C 15} carbocyclic or 3 15-membered membered heterocyclic ring (e.g. 3 to 6 membered monocycle, 6 to 12 membered fused, bridged or spiro bicyclic, 10 to 15 membered tricyclic or 13 to 15 membered carbocyclic ring, including fused, bridged or spiro ring heterocycle), either being optionally substituted with one or more R _a; or J or is -SF _5; or D is hydrogen or R _a;
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) for each occurrence. _{S '), - S (O} ) R S, -SO 2 R S, -C (O) N (R S R S'), - N (R S) 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 (R _S ) 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, = _{(R S R} S ') or _{-C (O) N (R S} ) C (O) -R S'; or, each independently halogen at each occurrence, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, _C 1 -C ₆ alkyl optionally substituted with one or more substituents selected from formyl or _cyano, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or appearance halogen independently in each, 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 Haroaru _{Alkenyl, -O-R S, -S-} R S, -C (O) R S, 1 one or more substituents selected from -C (O) OR _S, or -N _{(R S} R S ') And optionally substituted C ₃ -C ₁₂ carbocycles or 3 to 12 membered heterocycles (eg, 7 to 12 membered carbocycles or heterocycles).

  In one embodiment, A and B are each independently a 5- or 6-membered carbocyclic or heterocyclic ring (preferably A and B are each independently phenyl, such as

である。）であり、それぞれ、１つもしくは複数のＲ_Ａで独立に場合によって置換されている（好ましくは、ＡおよびＢはそれぞれ独立に、Ｆなどの少なくとも１個のハロで置換されている。）。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述されている。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。ＤはＣ_５−Ｃ_６炭素環または５員から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つもしくは複数のＲ_Ａで場合によって置換されている。ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環、１０員から１５員の三環または１３員から１５員の炭素環／複素環であり、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊは、（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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環または７員から１２員の炭素環／複素環で置換されており；Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

It is. Each independently substituted with one or more R _A (preferably A and B are each independently substituted with at least one halo such as F). X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), substituted with J and optionally substituted with one or more _RA . J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring, a 6 to 12 membered bicyclic ring, a 10 to 15 membered tricyclic ring, or a 13 to 15 membered carbocyclic / heterocyclic ring , J is optionally substituted with one or more _RA . Preferably, J is (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 S, -S-R} S, -C (O) C is optionally substituted independently with one or more substituents selected from _{R S} 3 -C ₆ carbocycle, from 3-membered Substituted with 6-membered heterocycle, 6-membered 12-membered bicycle or 7-membered 12-membered carbocycle / heterocycle; J may be optionally substituted with one or more R _A . Preferably, D is

または

Or

であり、Ｊは上記定義通りであり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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つもしくは複数のＲ_Ｌで場合によって置換されている。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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

Where J is as defined above and each _RN is independently selected from _RD and is preferably hydrogen or halo such as F. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. 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 it 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 it is a -R _D. R ₁ is R _C ; R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）または６員から１２員の二環を形成している。Ｒ_８はＲ_Ｃであり；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

) Or a 6 to 12 membered bicycle. R ₈ is R _C ; R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）または６員から１２員の二環を形成している。Ｇは独立に、Ｃ_５−Ｃ_６炭素環または５員から６員の複素環、例えば

) Or a 6 to 12 membered bicycle. G is _{independently,} C 5 -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring, for example,

または

Or

であり、１つもしくは複数のＲ_Ａで独立に場合によって置換されている。Ｔは好ましくは、出現ごとに独立に−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−）であり、Ｒ_Ｌから選択される１つもしくは複数の置換基で場合によって置換されている。Ｔは、これらに限定されないが、−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”−から選択されてもよい。いくつかの場合、Ｙは上述したような

Optionally independently substituted with one or more _RA . T is preferably -C (O) -L _Y '-N (R _B ) C (O) -L _S "-or -C (O) -L _Y ' -N (R _B ) independently for each occurrence. _{C (O) O-L S} "- is selected from. L _Y 'is independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), and with one or more substituents selected from R _L Has been replaced by Although T is not limited to these, -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" - may be selected from. In some cases Y is as described above

または

Or

であり、Ｚは上述したような

And Z is as described above.

または

Or

である。

It is.

  In other embodiments, A is

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは

Optionally substituted with one or more _RA ; B is

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は出現ごとに独立に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、Ｆなどの少なくとも１個のハロで置換されている。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述されている。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。ＤはＣ_５−Ｃ_６炭素環または５員から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つもしくは複数のＲ_Ａで場合によって置換されている。ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環、１０員から１５員の三環または１３員から１５員の炭素環／複素環であり、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊは、（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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環または７員から１２員の炭素環／複素環で置換されており；Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Optionally substituted with one or more _RA . Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence; Z ₂ is independently selected from N or CH at each occurrence. Preferably, A and B are each independently substituted with at least one halo such as F. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), substituted with J and optionally substituted with one or more _RA . J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring, a 6 to 12 membered bicyclic ring, a 10 to 15 membered tricyclic ring, or a 13 to 15 membered carbocyclic / heterocyclic ring , J is optionally substituted with one or more _RA . Preferably, J is (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 S, -S-R} S, -C (O) C is optionally substituted independently with one or more substituents selected from _{R S} 3 -C ₆ carbocycle, from 3-membered Substituted with 6-membered heterocycle, 6-membered 12-membered bicycle or 7-membered 12-membered carbocycle / heterocycle; J may be optionally substituted with one or more R _A . Preferably, D is

または

Or

であり、Ｊは上記定義通りであり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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つもしくは複数のＲ_Ｌで場合によって置換されている。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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

Where J is as defined above and each _RN is independently selected from _RD and is preferably hydrogen or halo such as F. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. 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 R _C ; R ₂ and R ₅ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₃ and R ₆ are each independently R _C , and R ₄ and R ₇ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）または６員から１２員の二環を形成している。Ｒ_８はＲ_Ｃであり；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

) Or a 6 to 12 membered bicycle. R ₈ is R _C ; R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic optionally substituted with one or more R _A A ring (for example,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成しており；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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の炭素環式もしくは複素環式環（例えば、

R ₁₀ and R ₁₃ are each independently R _C , and R ₁₁ and R ₁₄ together with the atoms to which they are attached are optionally one or more R _A Substituted 5- to 6-membered carbocyclic or heterocyclic rings (eg,

）または６員から１２員の二環を形成している。Ｔは好ましくは、出現ごとに独立に−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−）であり、Ｒ_Ｌから選択される１つもしくは複数の置換基で場合によって置換されている。Ｔは、これらに限定されないが、−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''−から選択されてもよい。いくつかの場合、ＹおよびＺは独立に、

) Or a 6 to 12 membered bicycle. T is preferably -C (O) -L _Y '-N (R _B ) C (O) -L _S ''-or -C (O) -L _Y ' -N (R _B independently for each occurrence. ) C (O) O-L S '' - it is selected from. L _Y 'is independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), and with one or more substituents selected from R _L Has been replaced by Although T is not limited to these, -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 ″ — may be selected. In some cases, Y and Z are independently

または

Or

であり、Ｒ_Ｄの非限定的な例には、（１）それぞれが出現ごとに独立にハロゲン、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_３−Ｃ_６炭素環または３員から６員の複素環から選択される１つもしくは複数の置換基で場合によって置換されている−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）それぞれが出現ごとに独立にハロゲン、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つもしくは複数の置換基で場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環が含まれ；Ｌ_Ｙ’の非限定的な例には、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員から６員の炭素環もしくは複素環で場合によって置換されたＣ_１−Ｃ_６アルキレンが含まれ、前記３員から６員の炭素環もしく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つもしくは複数の置換基で場合によって置換されている。

Non-limiting examples of _RD include: (1) each independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or one or more _-O-C 1 -C ₆ alkyl which is optionally substituted with substituents from 3 members from 6 membered heterocyclic ring, _-O-C 2 -C ₆ Alkenyl, —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 at each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, C C ₃ -C optionally 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. ₆ contains a heterocyclic 6-membered carbocyclic or 3 members; non-limiting examples of _{L Y} ', 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 C ₁ -C ₆ alkylene optionally substituted with a 3 to 6 membered carbocyclic or heterocyclic ring, including said 3 member To 6-membered carbocyclic or heterocyclic rings are 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,} one or more selected from C 2 -C ₆ haloalkenyl or _C 2 -C ₆ haloalkynyl Optionally substituted with a substituent of

In another aspect, the invention features compounds and pharmaceutically acceptable salts thereof 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は、それらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された３員から１２員の複素環を形成しており；Ｒ_９およびＲ_１２は、それらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された３員から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、ＲｃおよびＲ_Ｄは式Ｉで上記に定義した通りである。

In the formula:
Each R _NB is independently selected from R _B ;
Each R _C 'is independently selected from R _C ;
Each R _D 'is independently selected from R _D ;
R ₂ and R ₅ together with the atoms to which they are attached form a 3- to 12-membered heterocycle optionally substituted with one or more R _A ; and R ₉ and R ₁₂ together with the atoms to which they are attached form a 3 to 12 membered heterocycle optionally substituted with one or more R _A ;
A, B, D, X, L ₁ , L ₂ , L ₃ , T, R _A , R _B , Rc and R _D are as defined above in Formula I.

In this embodiment, A and B are preferably independently selected from C ₅ -C ₆ carbocycles or 5- to 6-membered heterocycles, each independently substituted with one or more _RA . . More preferably, at least one of A and B is phenyl (eg,

）であり、１つもしくは複数のＲ_Ａで場合によって置換されている。非常に好ましくは、ＡとＢはどちらもそれぞれ独立にフェニル（例えば、

And optionally substituted with one or more _RA . Most preferably, both A and B are each independently phenyl (eg,

）であり、それぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されている。

Each optionally independently substituted with one or more _RA .

D is preferably C ₅ -C ₆ carbocyclic ring, selected from the bicyclic 12-membered to 6-membered heterocyclic ring or 8-membered 5-membered, optionally substituted with one or more R _A. D may also preferably be selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, optionally substituted with one or more _RL . More preferably, D _is, C 5 -C ₆ carbocyclic ring, a bicyclic 12-membered to 6-membered heterocyclic ring or a 6-membered to 5-membered, is substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Again preferably, D is phenyl, optionally substituted with one or more _RA . More preferably, D is phenyl, substituted with one or more R _M , where R _M is as defined above. Very preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F.

D is also preferably pyridinyl, pyrimidinyl or thiazolyl optionally substituted with one or more _RA . More preferably, D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted by one or more R _M. Most preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。Ｄはやはり好ましくは、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つまたは複数のＲ_Ａで場合によって置換されている。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つまたは複数のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl or indazolyl, optionally substituted with one or more _RA . More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, One or substituted with a plurality of R _M. Most preferably, D is

または

Or

であり、１つまたは複数のＲ_Ｍで場合によって置換されている。

, 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 each occurrence of halogen, hydroxy, mercapto, amino, carboxy, nitro, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or each halogen is independently at each occurrence, 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} - _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 one selected from haloalkynyl or a plurality of _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent 6-membered Heterocycle. More preferably, R _M is optionally halogen, hydroxy, mercapto, amino, carboxy; or optionally one or more substituents each independently selected from halogen, hydroxy, mercapto, amino or carboxy for each occurrence. Substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. Highly preferably, R _M is C ₁ -C ₆ alkyl optionally independently substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, or a thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond Or C ₁ -C ₆ alkylene, and R _E is —N (R _S R _S ′), —O—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 ', -SO ₂ R _S, it is -SR _S, or _{-P (O) (oR S)} 2, R S and _{R S} 'are, for example, each independently at each occurrence (1) hydrogen or (2) each occurrence Independently one or more of halogen, hydroxy, —O—C ₁ -C ₆ alkyl or 3 membered Or may be selected from C ₁ -C ₆ alkyl optionally substituted with a 6-membered heterocycle; or R _M is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, each occurrence With C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano there are a; or _{R M} each halogen is independently at each occurrence, 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 c _Alkenyl, C 2 -C ₆ haloalkynyl, -C (O) OR _S, or -N _{(R S} R S ') is optionally substituted with one or more substituents selected from _C 3 -C ₆ A carbocyclic ring or a 3- to 6-membered heterocyclic ring. More preferably, R _M is selected from halogen (eg, fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or each independently from each occurrence halogen, hydroxy, mercapto, amino, cyano or carboxy C ₁ -C ₆ alkyl (eg, methyl, isopropyl, tert-butyl), C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents as defined. For example, _RM represents 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 . Also 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 ′, —SO ₂ R _S or —SR _S. For example, when L _S is a bond, R _E is —N (C ₁ -C ₆ alkyl) ₂ (eg, —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-O—C ₁ -C ₆ alkyl) (eg, —N ( _{CH 3) (CH 2 CH 2} OMe)); - O-C 1 -C 6 alkyl (e.g., -O-Me, -O-Et , -O- isopropyl, -O-tert-butyl, -O-n - _{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 _{(e.g., -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 (e.g. , —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 —S—C ₁ -C ₆ haloalkyl (eg, SCF ₃ ). Also 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 _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 represents —C ₁ -C ₆ alkylene-O—R _S (eg, —C (CH ₃ ) ₂ —CH ₂ —OMe); —C ₁ -C ₆ alkylene-C (O) OR _S (eg, _{, -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 (eg, —CH ₂ —P (O) (OEt) ₂ ). Again more preferably, _{R M} are each independently halogen at each occurrence, 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 ' A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle optionally substituted with one or more substituents selected from: For example, _RM can be cycloalkyl (eg, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (eg, morpholin-4-yl, 1,1-di). Oxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 3, 5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6- (dimethylamino) pyridin-3-yl). Most preferably, R 1 _M is independently optionally substituted C _{1 with} one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (eg tert-butyl, CF ₃ ). -C is ₆ alkyl.

More preferably, D is a C ₅ -C ₆ carbocyclic ring, a 5 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, substituted with J, and one or more R _A Optionally substituted, J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A Yes. Preferably, J is substituted with 6-membered heterocyclic ring from the _C 3 -C ₆ carbocycle or 3-membered, heterocyclic ring 6 membered from the _C 3 -C ₆ carbocycle or 3 members of 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} Optionally independently substituted with one or more substituents selected from —C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) , J may be optionally substituted with one or more _RA . Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more R _A ; preferably J is 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 ₃ optionally substituted independently with one or more substituents selected from C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle. Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A 6 to 12 membered bicycle (eg, a 7 to 12 membered fused, bridged or spiro bicyclic ring containing a nitrogen ring atom through which J is covalently bonded to D), and one or more Optionally substituted with _RA . More preferably, D is phenyl, substituted with J, optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered heterocycle Or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A ; preferably J is 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 ')} C 3 -C 6 the carbocycle is optionally substituted independently with one or more substituents selected from It is at least substituted with 6-membered heterocyclic ring from 3 members. Very preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。やはり好ましくは、Ｄは

, And the respective R _N is independently selected from R _D, preferably hydrogen or halogen, J is C ₃ -C ₆ carbocycle, bicyclic 12-membered to 6-membered heterocyclic ring or 3 to 6-membered And optionally substituted with one or more R _A ; preferably J is 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 If (R _S R _S ') less in one or more of which is optionally substituted independently with substituents C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring selected from It has been replaced. Still preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環であり、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。やはり好ましくは、Ｄは、

And in each R _N is independently selected from R _D, preferably hydrogen or halogen, J is a 6-membered heterocycle C ₃ -C ₆ carbocycle or a 3-, 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle, and J may be optionally substituted with one or more _RA . Again preferably, D is

であり、ＪはＣ_３−Ｃ_６炭素環または３員から６員の複素環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。

Wherein J is a C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more _RA ; preferably, J is 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle.

X is preferably _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. Non-limiting examples of X are as described above.

L ₁ and L ₂ are preferably independently a bond or C ₁ -C ₆ alkylene, and L ₃ is preferably selected from a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ And L ₃ are each optionally substituted independently with one or more R _L. More preferably, L ₁ , L ₂ and L ₃ are each independently a bond or C ₁ -C ₆ alkylene (eg, —CH ₂ — or —CH ₂ CH ₂ —), each having one or more R _L Is optionally substituted independently. Most preferably, L ₁ , L ₂ and L ₃ are each a bond.

R ₂ and R ₅ together with the atoms to which they are attached are preferably 5 to 6 membered heterocycles or 6 to 12 members optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。

) Is formed.

R ₉ and R ₁₂ together with the atoms to which they are attached are preferably 5- to 6-membered heterocycles or 6 to 12-membered rings optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。

) Is formed.

_{-T-R D} 'is not limited to, -C independently at each occurrence _{(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" -R D' L _Y ′ each independently is L _S ′, preferably each independently C ₁ -C ₆ alkylene (eg, —CH ₂ —), one selected from R _L or is optionally substituted with plural substituents. preferably, -T-R '-C independently each occurrence is _{(O) -L Y'-M'-} L S "-R D ' or _{-N (R B) C (O} ) -L Y'-M'-LS" - 'more preferably. selected from, _{-T-R D' R D} is -C independently at each occurrence _{(O) -L Y '-N (} R B) C (O) -L S "-R D 'Or -C (O) -L _Y ' -N (R _B ) C (O) O L _S '-R _D '. Very preferably, -T-R _D 'is Independently -C (O) -L _Y '-N (R _B ) C (O) -R _D ' or -C (O) -L _Y '-N (R _B ) C (O) O-R _D ' L _Y ′ is preferably each independently C ₁ -C ₆ alkylene (eg, —CH ₂ —), optionally substituted with one or more substituents selected from R _L Yes.

R _NB and R _C ′ are preferably hydrogen and R _D ′ is preferably independently selected from R _E for each occurrence. More preferably, R _D ′ is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or 3-membered, each occurrence C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from 1 to 6 membered heterocycles; or each occurrence halogen independently in each, 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 Haroarukini Are independently selected from heterocycle 6-membered C ₃ -C ₆ carbocycle or 3-membered optionally substituted with one or more substituents selected from.

R _A is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence independently of halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphonoxy, phosphono, thioxo, formyl or cyano; or , each halogen is independently at each occurrence, 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 C ₃ -C ₆ carbocycle optionally substituted with one or more substituents selected from haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl or 3 to 6 membered heterocycle ring; 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'), - L A -C (O) N (R S) C ( O) a -R _S 'or _{-L a -P (O) (oR} S) 2, the _{L a binding,} is C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene .

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence is independently halogen, hydroxy, mercapto, amino, carboxy, nitro C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano ; or, each independently halogen at each occurrence, 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 haloalkynyl one selected from or a plurality of 6-membered _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent Is a heterocyclic ring.

Most preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence of halogen, hydroxy, mercapto, amino, carboxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ optionally substituted with one or more substituents selected from nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano Alkynyl.

L _S , L _S ′ and L _S ″ are preferably each independently selected at each occurrence from a bond; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene.

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

In one embodiment of this aspect, A and B are each independently phenyl, each independently is optionally substituted with one or more R _A ; D is phenyl, and one or more R Optionally substituted with _A ; or substituted with J and optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered heterocycle A ring or a 6 to 12 membered bicyclic ring, optionally substituted with one or more _RA . Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。好ましくは、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 be selected from. preferably, _{R 2} and _{R 5} are they are attached Together with the atom, one thing It is optionally substituted with a plurality of R _A

を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

R ₉ and R ₁₂ are optionally substituted with one or more R _A together with the atoms to which they are attached.

を形成している。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。

Is forming. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F.

  In other embodiments of this aspect, A and B are each independently phenyl (eg,

）であり、それぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されている（好ましくは、ＡおよびＢはそれぞれ独立に、Ｆなどの少なくとも１個のハロで置換されている。）。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄはフェニルであり、Ｊで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されている。ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環、１０員から１５員の三環または１３員から１５員の炭素環／複素環であり、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊは、（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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環または７員から１２員の炭素環／複素環で置換されており；Ｊは、１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Each independently substituted with one or more R _A (preferably A and B are each independently substituted with at least one halo such as F). X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is phenyl, substituted with J, and optionally substituted with one or more _RA . J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring, a 6 to 12 membered bicyclic ring, a 10 to 15 membered tricyclic ring, or a 13 to 15 membered carbocyclic / heterocyclic ring , J is optionally substituted with one or more _RA . Preferably, J is (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 C ₃ -C ₆ carbocyclic ring, optionally substituted independently with one or more substituents selected from: —O—R _S , —S—R _S or —C (O) R _S To 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle / heterocycle; J is optionally substituted with one or more R _A Moyo . Preferably, D is

または

Or

であり、Ｊは上記定義通りであり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

Where J is as defined above and each _RN is independently selected from _RD and is preferably hydrogen or halo such as F. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 together with _{-C (O) -L Y '-N} (R B) S (O) 2 -L S "-R D' may be selected from .R ₂ and _{R 5} atom to which they are attached turned, one or more R _a If 6-membered heterocyclic ring from a 5-membered substituted by (e.g.,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic rings optionally substituted with one or more R _A (For example,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成している。

) Is formed.

In yet another aspect, the invention features compounds and pharmaceutically acceptable salts thereof of 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は、それらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された３員から１２員の複素環を形成しており；
Ｒ_９およびＲ_１２は、それらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された３員から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、ＲｃおよびＲ_Ｄは式Ｉで上記に定義した通りである。

In the formula:
Each R _C 'is independently selected from R _C ;
Each R _D 'is independently selected from R _D ;
R ₂ and R ₅ together with the atoms to which they are attached form a 3 to 12 membered heterocycle optionally substituted with one or more R _A ;
R ₉ and R ₁₂ together with the atoms to which they are attached form a 3 to 12 membered heterocycle optionally substituted with one or more R _A ;
A, B, D, X, L ₁ , L ₂ , L ₃ , T, R _A , Rc and R _D are as defined above for Formula I.

  In this embodiment, A and B are preferably 8- to 12-membered bicycles, such as

または

Or

から独立に選択され、Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｚ_２は出現ごとに独立にＮまたはＣＨから選択され、Ｚ_３は出現ごとに独立にＮまたはＣＨから選択され、Ｚ_４は出現ごとに独立に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はそれぞれ出現ごとに独立に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つもしくは複数のＲ_Ａで場合によって置換されている。

Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence, Z ₂ is independently selected from N or CH at each occurrence, and Z ₃ is independently N at each occurrence. Or selected from CH, Z ₄ is independently selected from O, S, NH or CH _{2 at} each occurrence, and W ₁ , W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are each independently at each occurrence Selected from CH or N. A and B are each optionally substituted with one or more _RA .

  More preferably, A is

または

Or

から選択され、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは

Selected from and optionally substituted with one or more R _A ;

または

Or

から選択され、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｚ_１、Ｚ_２、Ｚ_３、Ｚ_４、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５、Ｗ_６は上記定義通りである。好ましくは、Ｚ_３はＮであり、Ｚ_４はＮＨである。例えば、Ａは

And optionally substituted with one or more _RA ; Z ₁ , Z ₂ , Z ₃ , Z ₄ , W ₁ , W ₂ , W ₃ , W ₄ , W ₅ , W ₆ are as defined above As defined. Preferably Z ₃ is N and Z ₄ is NH. For example, A is

（例えば、

(For example,

）または

Or

（例えば、

(For example,

または

Or

）から選択することができ、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは、

), Optionally substituted with one or more R _A ;

（例えば、

(For example,

）または

Or

（例えば、

(For example,

または

Or

）から選択することができ、１つもしくは複数のＲ_Ａで場合によって置換されている。

) And optionally substituted with one or more _RA .

  Again 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、Ｃ_５−Ｃ_６炭素環または５員から６員の複素環から独立に選択され、ＡおよびＢは、１つもしくは複数のＲ_Ａで独立に場合によって置換されている。

And A ′ and B ′ are independently selected from C ₅ -C ₆ carbocycles or 5- to 6-membered heterocycles, and A and B are optionally independently at one or more R _A Has been replaced.

D is preferably selected from C ₅ -C ₆ carbocycles, 5 to 6 membered heterocycles or 6 to 12 membered bicyclic rings, optionally substituted with one or more _RA . D may also preferably be selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, optionally substituted with one or more substituents selected from R _L Has been. More preferably, D _is, C 5 -C ₆ carbocyclic ring, a bicyclic 12-membered to 6-membered heterocyclic ring or a 6-membered to 5-membered, is substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Again preferably, D is phenyl, optionally substituted with one or more _RA . More preferably, D is phenyl, substituted with one or more R _M , where R _M is as defined above. Very preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F.

D is also preferably pyridinyl, pyrimidinyl or thiazolyl optionally substituted with one or more _RA . More preferably, D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted by one or more R _M. Most preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。Ｄはやはり好ましくは、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つまたは複数のＲ_Ａで場合によって置換されている。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つまたは複数のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl or indazolyl, optionally substituted with one or more _RA . More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, One or substituted with a plurality of R _M. Most preferably, D is

または

Or

であり、１つまたは複数のＲ_Ｍで場合によって置換されている。

, 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 each occurrence of halogen, hydroxy, mercapto, amino, carboxy, nitro, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or each halogen is independently at each occurrence, 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} - _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 one selected from haloalkynyl or a plurality of _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent 6-membered Heterocycle. More preferably, R _M is optionally halogen, hydroxy, mercapto, amino, carboxy; or optionally one or more substituents each independently selected from halogen, hydroxy, mercapto, amino or carboxy for each occurrence. Substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. Most preferably, R _M is C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, or a thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond Or C ₁ -C ₆ alkylene, and R _E is —N (R _S R _S ′), —O—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 ',- SO ₂ R _S , —SR _S or —P (O) (OR _S ) ₂ , where R _S and R _S ′ are, for example, independently for each occurrence (1) hydrogen or (2) each occurrence One or more halogen, hydroxy, —O—C ₁ -C ₆ alkyl or 3 to 6 membered May be selected from C ₁ -C ₆ alkyl optionally substituted with a heterocycle; or R _M is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, each occurrence of Is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphono, thioxo, formyl or cyano; or R _M 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 for each occurrence. -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C ₆ Haroaruke _Le, C 2 -C ₆ haloalkynyl, -C (O) OR _S, or _{-N (R S R S ')} C 3 are substituted with one or more substituents selected from -C ₆ A carbocyclic ring or a 3- to 6-membered heterocyclic ring. More preferably, R _M is selected from halogen (eg, fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or each independently from each occurrence halogen, hydroxy, mercapto, amino, cyano or carboxy C ₁ -C ₆ alkyl (eg, methyl, isopropyl, tert-butyl), C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents as defined. For example, _RM represents 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 . Also 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 ′, —SO ₂ R _S or —SR _S. For example, when L _S is a bond, R _E is —N (C ₁ -C ₆ alkyl) ₂ (eg, —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-O—C ₁ -C ₆ alkyl) (eg, —N ( _{CH 3) (CH 2 CH 2} OMe)); - O-C 1 -C 6 alkyl (e.g., -O-Me, -O-Et , -O- isopropyl, -O-tert-butyl, -O-n - _{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 _{(e.g., -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 (e.g. , —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 —S—C ₁ -C ₆ haloalkyl (eg, SCF ₃ ). Also 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 _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 represents —C ₁ -C ₆ alkylene-O—R _S (eg, —C (CH ₃ ) ₂ —CH ₂ —OMe); —C ₁ -C ₆ alkylene-C (O) OR _S (eg, _{, -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 (eg, —CH ₂ —P (O) (OEt) ₂ ). Again more preferably, _{R M} are each independently halogen at each occurrence, 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 ' A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle optionally substituted with one or more substituents selected from: For example, _RM can be cycloalkyl (eg, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (eg, morpholin-4-yl, 1,1-di). Oxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 3, 5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6- (dimethylamino) pyridin-3-yl). Most preferably, R _M is C ₁ -C optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (eg tert-butyl, CF ₃ ). ₆ alkyl.

More preferably, D is a C ₅ -C ₆ carbocyclic ring, a 5 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, substituted with J, and one or more R _A Optionally substituted, J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A Yes. Preferably, J is substituted with 6-membered heterocyclic ring from the _C 3 -C ₆ carbocycle or 3-membered, heterocyclic ring 6 membered from the _C 3 -C ₆ carbocycle or 3 members of 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} Optionally independently substituted with one or more substituents selected from —C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) , J may be optionally substituted with one or more _RA . Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more R _A ; preferably J is 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 ₃ optionally substituted independently with one or more substituents selected from C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle. Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A 6 to 12 membered bicycle (eg, a 7 to 12 membered fused, bridged or spiro bicyclic ring containing a nitrogen ring atom through which J is covalently bonded to D), and one or more Optionally substituted with _RA . More preferably, D is phenyl, substituted with J, optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered heterocycle Or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A ; preferably J is 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 ')} C 3 -C 6 the carbocycle is optionally substituted independently with one or more substituents selected from It is at least substituted with 6-membered heterocyclic ring from 3 members. Very preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。やはり好ましくは、Ｄは

, And the respective R _N is independently selected from R _D, preferably hydrogen or halogen, J is C ₃ -C ₆ carbocycle, bicyclic 12-membered to 6-membered heterocyclic ring or 3 to 6-membered And optionally substituted with one or more R _A ; preferably J is 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 If (R _S R _S ') less in one or more of which is optionally substituted independently with substituents C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring selected from It has been replaced. Still preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環であり、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。やはり好ましくは、Ｄは、

And in each R _N is independently selected from R _D, preferably hydrogen or halogen, J is a 6-membered heterocycle C ₃ -C ₆ carbocycle or a 3-, 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle, and J may be optionally substituted with one or more _RA . Again preferably, D is

であり、ＪはＣ_３−Ｃ_６炭素環または３員から６員の複素環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。

Wherein J is a C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more _RA ; preferably, J is 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle.

X is preferably _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. Preferred non-limiting examples of X are as defined above.

L ₁ and L ₂ are preferably independently a bond or C ₁ -C ₆ alkylene, and L ₃ is preferably selected from a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ And L ₃ are each independently substituted with one or more R _L. More preferably, L ₁ , L ₂ and L ₃ are each independently a bond or C ₁ -C ₆ alkylene (eg, —CH ₂ — or —CH ₂ CH ₂ —), and one or more R _L Each is independently replaced by the case. Most preferably, L ₁ , L ₂ and L ₃ are each a bond.

R ₂ and R ₅ together with the atoms to which they are attached are preferably 5 to 6 membered heterocycles or 6 to 12 members optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、好ましくは、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

) Is formed. R ₉ and R ₁₂ together with the atoms to which they are attached are preferably 5- to 6-membered heterocycles or 6 to 12-membered rings optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。

) Is formed.

_{-T-R D} 'is not limited to, -C independently at each occurrence _{(O) -L Y' -R D} ', -C (O) O-L Y' -R D ', -C _{(O) -L Y '-N (} R B) C (O) -L S''-RD', -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 ', wherein L _Y 's are each independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), selected from R _L Optionally substituted with one or more substituents. Preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y'-M'-} L S '' -R D ' or _{-N (R B) C (O} ) -L Y It is selected from '-M'-L _S ''-R _D '. More preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S '' -R D ' or -C (O) -L _Y '-N (R _B ) C (O) O--L _S ″ -R _D ′ Very preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -R D ' or -C (O) -L _Y' 'is selected _{from, L Y' -N (R B} ) C (O) O-R D are preferably each independently _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, selected from _{R L} Optionally substituted with one or more substituents.

R _C 'is preferably hydrogen and R _D ' is preferably independently selected from R _E for each occurrence. More preferably, R _D ′ is independently for each occurrence, each independently for each occurrence, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C _6. C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from carbocycles or 3- to 6-membered heterocycles; or each halogen is independently at each occurrence, 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} - ₆ is selected from heterocycle 6-membered C ₃ -C ₆ carbocycle or 3-membered optionally substituted with one or more substituents selected from haloalkynyl.

R _A is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence independently of halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphonoxy, phosphono, thioxo, formyl or cyano; or , each halogen is independently at each occurrence, 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 C ₃ -C ₆ carbocycle optionally substituted with one or more substituents selected from haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl or 3 to 6 membered heterocycle ring; 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 _{'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'), - L A -C (O) N (R S) C ( O) a -R _S 'or _{-L a -P (O) (oR} S) 2, the _{L a binding,} is C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene .

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence is independently halogen, hydroxy, mercapto, amino, carboxy, nitro C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano ; or, each independently halogen at each occurrence, 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 haloalkynyl one selected from or a plurality of 6-membered _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent Is a heterocyclic ring.

Most preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence of halogen, hydroxy, mercapto, amino, carboxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ optionally substituted with one or more substituents selected from nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano Alkynyl.

L _S , L _S ′ and L _S ″ are preferably each independently selected at each occurrence from a bond; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene.

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

  In one embodiment of this aspect, A is

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは

Optionally substituted with one or more _RA ; B is

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されており；ＤはＣ_５−Ｃ_６炭素環または５員から６員の複素環（例えば、フェニル）であり、１つもしくは複数のＲ_Ａで場合によって置換されている、またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは、

, And the being optionally substituted with one or more R _A; is D is C ₅ -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring (e.g., phenyl), one or more of R Optionally substituted with _A or substituted with J and optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered heterocycle Or a 6- to 12-membered bicycle, optionally substituted with one or more _RA . Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは、

And R _M and R _N are as defined above. Again preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から選択され；Ｚ_２は出現ごとに独立にＮまたはＣＨから選択される。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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。

And J and _RN are as defined above. Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence; Z ₂ is independently selected from N or CH at each occurrence. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 be selected from .X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ Cycloalkenyl, one if Specific examples of .X which is optionally substituted with a plurality of R _A are as described above. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, one or more of R _A or R Optionally substituted with _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F.

  In other embodiments of this aspect, A is

であり、１つもしくは複数のＲ_Ａ（例えば、ハロゲン）で場合によって置換されており；Ｂは

Optionally substituted with one or more R _A (eg, halogen);

であり、１つもしくは複数のＲ_Ａ（例えば、ハロゲン）で場合によって置換されており；ＤはＣ_５−Ｃ_６炭素環または５員から６員の複素環（例えば、フェニル）であり、１つもしくは複数のＲ_Ａで場合によって置換されている、またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Optionally substituted with one or more R _A (eg, halogen); D is a C ₅ -C ₆ carbocycle or a 5- to 6-membered heterocycle (eg, phenyl); Optionally substituted with one or more R _A or substituted with J and optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, A 6-membered heterocyclic ring or a 6- to 12-membered bicyclic ring, optionally substituted with one or more _RA . Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、好ましくは、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 together with _{-C (O) -L Y '-N} (R B) S (O) 2 -L S "-R D' may be selected from .R ₂ and _{R 5} atom to which they are attached And preferably one Bicyclic 12-membered heterocyclic or a 6 membered 6 from 5 members which is optionally substituted with a plurality of R _A (e.g.,

または

Or

）を形成している。Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、好ましくは、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

) Is formed. R ₉ and R ₁₂ together with the atoms to which they are attached are preferably 5- to 6-membered heterocycles or 6 to 12-membered rings optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。より好ましくは、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

) Is formed. More preferably, R ₂ and R ₅ are optionally substituted with one or more R _A together with the atom to which they are attached.

を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

R ₉ and R ₁₂ are optionally substituted with one or more R _A together with the atoms to which they are attached.

を形成している。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。

Is forming. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F.

  In yet another embodiment of this aspect, A is

であり、１つもしくは複数のＲ_Ａで場合によって置換されており（好ましくは、ＡはＦなどの少なくとも１つのハロゲンで置換されている。）；Ｂは

Optionally substituted with one or more R _A (preferably A is substituted with at least one halogen such as F);

であり、１つもしくは複数のＲ_Ａで場合によって置換されている（好ましくは、ＢはＦなどの少なくとも１つのハロゲンで置換されている。）。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄはフェニルであり、Ｊで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されている。ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環、１０員から１５員の三環または１３員から１５員の炭素環／複素環であり、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊは、（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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環または７員から１２員の炭素環／複素環で置換されており；Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Optionally substituted with one or more _RA (preferably B is substituted with at least one halogen such as F). X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is phenyl, substituted with J, and optionally substituted with one or more _RA . J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring, a 6 to 12 membered bicyclic ring, a 10 to 15 membered tricyclic ring, or a 13 to 15 membered carbocyclic / heterocyclic ring , J is optionally substituted with one or more _RA . Preferably, J is (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 C ₃ -C ₆ carbocyclic ring, optionally substituted independently with one or more substituents selected from: —O—R _S , —S—R _S or —C (O) R _S To 6-membered heterocycle, 6- to 12-membered bicyclic or 7- to 12-membered carbocycle / heterocycle; and J may be optionally substituted with one or more R _A Good Preferably, D is

または

Or

であり、Ｊは上記定義通りであり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、好ましくは、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

Where J is as defined above and each _RN is independently selected from _RD and is preferably hydrogen or halo such as F. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 together with _{-C (O) -L Y '-N} (R B) S (O) 2 -L S "-R D' may be selected from .R ₂ and _{R 5} atom to which they are attached And preferably one Bicyclic 12-membered heterocyclic or a 6 membered 6 from 5 members which is optionally substituted with a plurality of R _A (e.g.,

または

Or

）を形成している。Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、好ましくは、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

) Is formed. R ₉ and R ₁₂ together with the atoms to which they are attached are preferably 5- to 6-membered heterocycles or 6 to 12-membered rings optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。より好ましくは、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

) Is formed. More preferably, R ₂ and R ₅ are optionally substituted with one or more R _A together with the atom to which they are attached.

を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

R ₉ and R ₁₂ are optionally substituted with one or more R _A together with the atoms to which they are attached.

を形成している。

Is forming.

In yet another aspect, the invention features a salt thereof the compounds of formula I _C and pharmaceutically acceptable.

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は、それらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された３員から１２員の複素環を形成しており；
Ｒ_９およびＲ_１２は、それらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換された３員から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、ＲｃおよびＲ_Ｄは式Ｉで上記に定義した通りである。

In the formula:
R _NB is an _{R B;}
Each R _C 'is independently selected from R _C ;
Each R _D 'is independently selected from R _D ;
R ₂ and R ₅ together with the atoms to which they are attached form a 3 to 12 membered heterocycle optionally substituted with one or more R _A ;
R ₉ and R ₁₂ together with the atoms to which they are attached form a 3 to 12 membered heterocycle optionally substituted with one or more R _A ;
A, B, D, X, L ₁ , L ₂ , L ₃ , T, R _A , R _B , Rc and R _D are as defined above in Formula I.

In this embodiment, A is preferably a 6-membered heterocycle C ₅ -C ₆ carbocyclic ring or 5-membered, is optionally substituted with one or more R _A; B is preferably 8-membered To 12-membered bicyclic rings (for example,

または

Or

）であり、１つもしくは複数のＲ_Ａで場合によって置換されている。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。

And optionally substituted with one or more _RA . 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 each independently selected from CH or N.

  More preferably, A is phenyl (eg,

）であり、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは

Optionally substituted with one or more _RA ; B is

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されており；Ｚ_１、Ｚ_２、Ｚ_３、Ｚ_４、Ｗ_１、Ｗ_２、Ｗ_３、Ｗ_４、Ｗ_５、Ｗ_６は上記定義通りである。好ましくは、Ｚ_３はＮであり、Ｚ_４はＮＨである。例えば、Ｂは、

Optionally substituted with one or more _RA ; Z ₁ , Z ₂ , Z ₃ , Z ₄ , W ₁ , W ₂ , W ₃ , W ₄ , W ₅ , W ₆ are as defined above Street. Preferably Z ₃ is N and Z ₄ is NH. For example, B is

（例えば、

(For example,

）または

Or

（例えば、

(For example,

または

Or

）であってよく、１つもしくは複数のＲ_Ａで場合によって置換されている。

Optionally substituted with one or more _RA .

Again preferably, A is a C ₅ -C ₆ carbocycle (eg phenyl, eg

）または５員から６員の複素環であり；Ｂは

Or a 5- to 6-membered heterocycle;

（例えば、

(For example,

）であり、Ｂ’はＣ_５−Ｃ_６炭素環または５員から６員の複素環から選択される。ＡおよびＢは独立に、１つもしくは複数のＲ_Ａで場合によって置換されている。

And B ′ is selected from a C ₅ -C ₆ carbocyclic ring or a 5- to 6-membered heterocyclic ring. A and B are independently optionally substituted with one or more _RA .

D is preferably selected from C ₅ -C ₆ carbocycles, 5 to 6 membered heterocycles or 6 to 12 membered bicyclic rings, optionally substituted with one or more _RA . D may also preferably be selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, optionally substituted with one or more substituents selected from R _L Has been. More preferably, D _is, C 5 -C ₆ carbocyclic ring, a bicyclic 12-membered to 6-membered heterocyclic ring or a 6-membered to 5-membered, is substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Again preferably, D is phenyl, optionally substituted with one or more _RA . More preferably, D is phenyl, substituted with one or more R _M , where R _M is as defined above. Very preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F.

D is also preferably pyridinyl, pyrimidinyl or thiazolyl optionally substituted with one or more _RA . More preferably, D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted by one or more R _M. Most preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。Ｄはやはり好ましくは、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つまたは複数のＲ_Ａで場合によって置換されている。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つまたは複数のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl or indazolyl, optionally substituted with one or more _RA . More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, One or substituted with a plurality of R _M. Most preferably, D is

または

Or

であり、１つまたは複数のＲ_Ｍで場合によって置換されている。

, 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 each occurrence of halogen, hydroxy, mercapto, amino, carboxy, nitro, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or each halogen is independently at each occurrence, 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} - _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 one selected from haloalkynyl or a plurality of _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent 6-membered Heterocycle. More preferably, R _M is optionally halogen, hydroxy, mercapto, amino, carboxy; or optionally one or more substituents each independently selected from halogen, hydroxy, mercapto, amino or carboxy for each occurrence. Substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. Most preferably, R _M is C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, or a thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond Or C ₁ -C ₆ alkylene, and R _E is —N (R _S R _S ′), —O—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 ', -SO ₂ R _S, it is -SR _S, or _{-P (O) (oR S)} 2, R S and _{R S} 'are, for example, each independently at each occurrence (1) hydrogen or (2) each occurrence One or more halogens, hydroxy, —O—C ₁ -C ₆ alkyl or 3 to 6 members May be selected from C ₁ -C ₆ alkyl optionally substituted with a heterocycle; or R _M is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy for each occurrence Is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphono, thioxo, formyl or cyano; or _{R M} independently halogen at each occurrence each is 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 Haroaru _{Cycloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) OR _S, or _{-N (R S R S ')} C 3 are substituted with one or more substituents selected from -C ₆ A carbocyclic ring or a 3- to 6-membered heterocyclic ring. More preferably, R _M is selected from halogen (eg, fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or each independently from each occurrence halogen, hydroxy, mercapto, amino, cyano or carboxy C ₁ -C ₆ alkyl (eg, methyl, isopropyl, tert-butyl), C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents as defined. For example, _RM represents 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 . Also 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 ′, —SO ₂ R _S or —SR _S. For example, when L _S is a bond, R _E is —N (C ₁ -C ₆ alkyl) ₂ (eg, —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-O—C ₁ -C ₆ alkyl) (eg, —N ( _{CH 3) (CH 2 CH 2} OMe)); - O-C 1 -C 6 alkyl (e.g., -O-Me, -O-Et , -O- isopropyl, -O-tert-butyl, -O-n - _{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 _{(e.g., -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 (e.g. , —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 —S—C ₁ -C ₆ haloalkyl (eg, SCF ₃ ). Also 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 _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 represents —C ₁ -C ₆ alkylene-O—R _S (eg, —C (CH ₃ ) ₂ —CH ₂ —OMe); —C ₁ -C ₆ alkylene-C (O) OR _S (eg, _{, -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 (eg, —CH ₂ —P (O) (OEt) ₂ ). Again more preferably, _{R M} are each independently halogen at each occurrence, 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 ' A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle optionally substituted with one or more substituents selected from: For example, _RM can be cycloalkyl (eg, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (eg, morpholin-4-yl, 1,1-di). Oxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 3, 5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6- (dimethylamino) pyridin-3-yl). Most preferably, R _M is C ₁ -C optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (eg tert-butyl, CF ₃ ). ₆ alkyl.

More preferably, D is a C ₅ -C ₆ carbocyclic ring, a 5 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, substituted with J, and one or more R _A Optionally substituted, J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A Yes. Preferably, J is substituted with 6-membered heterocyclic ring from the _C 3 -C ₆ carbocycle or 3-membered, heterocyclic ring 6 membered from the _C 3 -C ₆ carbocycle or 3 members of 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} Optionally independently substituted with one or more substituents selected from —C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) , J may be optionally substituted with one or more _RA . Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more R _A ; preferably J is 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 ₃ optionally substituted independently with one or more substituents selected from C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle. Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A 6 to 12 membered bicycle (eg, a 7 to 12 membered fused, bridged or spiro bicyclic ring containing a nitrogen ring atom through which J is covalently bonded to D), and one or more Optionally substituted with _RA . More preferably, D is phenyl, substituted with J, optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered heterocycle Or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A ; preferably J is 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 ')} C 3 -C 6 the carbocycle is optionally substituted independently with one or more substituents selected from It is at least substituted with 6-membered heterocyclic ring from 3 members. Very preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。やはり好ましくは、Ｄは

, And the respective R _N is independently selected from R _D, preferably hydrogen or halogen, J is C ₃ -C ₆ carbocycle, bicyclic 12-membered to 6-membered heterocyclic ring or 3 to 6-membered And optionally substituted with one or more R _A ; preferably J is 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 If (R _S R _S ') less in one or more of which is optionally substituted independently with substituents C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring selected from It has been replaced. Still preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環であり、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。やはり好ましくは、Ｄは、

And in each R _N is independently selected from R _D, preferably hydrogen or halogen, J is a 6-membered heterocycle C ₃ -C ₆ carbocycle or a 3-, 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle, and J may be optionally substituted with one or more _RA . Again preferably, D is

であり、ＪはＣ_３−Ｃ_６炭素環または３員から６員の複素環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。

Wherein J is a C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more _RA ; preferably, J is 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle.

X is preferably _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. Non-limiting examples of X are as defined above.

L ₁ and L ₂ are preferably independently a bond or C ₁ -C ₆ alkylene, and L ₃ is preferably selected from a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ And L ₃ are each independently substituted with one or more R _L. More preferably, L ₁ , L ₂ and L ₃ are each independently a bond or C ₁ -C ₆ alkylene (eg, —CH ₂ — or —CH ₂ CH ₂ —), and one or more R _L Independently substituted in some cases. Most preferably, L ₁ , L ₂ and L ₃ are each a bond. L ₁ and L ₂ may be the same or different.

R ₂ and R ₅ together with the atoms to which they are attached are preferably 5 to 6 membered heterocycles or 6 to 12 members optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、好ましくは、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環または６員から１２員の二環（例えば、

) Is formed. R ₉ and R ₁₂ together with the atoms to which they are attached are preferably 5- to 6-membered heterocycles or 6 to 12-membered rings optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。

) Is formed.

_{-T-R D} 'is not limited to, -C independently at each occurrence _{(O) -L Y' -R D} ', -C (O) O-L Y' -R D ', -C _{(O) -L Y '-N (} R B) C (O) -L S''-RD', -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 ', wherein L _Y 's are each independently L _S ', preferably each independently C ₁ -C ₆ alkylene (eg, -CH _2- ), selected from R _L Optionally substituted with one or more substituents. Preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y'-M'-} L S '' -R D ' or _{-N (R B) C (O} ) -L Y It is selected from '-M'-L _S ''-R _D '. More preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S '' -R D ' or -C (O) -L _Y '-N (R _B ) C (O) O-L _S ″ -R _D ′ Very preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -R D ' or -C (O) -L _Y' 'is selected _{from, L Y' -N (R B} ) C (O) O-R D are preferably each independently _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, selected from _{R L} Optionally substituted with one or more substituents.

R _NB and R _C ′ are preferably hydrogen and R _D ′ is preferably independently selected from R _E for each occurrence. More preferably, R _D ′ is independently for each occurrence, each independently for each occurrence, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C _6. C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from carbocycles or 3- to 6-membered heterocycles; or each halogen is independently at each occurrence, 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} - ₆ is selected from heterocycle 6-membered C ₃ -C ₆ carbocycle or 3-membered optionally substituted with one or more substituents selected from haloalkynyl.

R _A is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence of halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, optionally substituted independently with one or more substituents selected from phosphono, thioxo, formyl or cyano; or , each halogen is independently at each occurrence, 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 C ₃ -C ₆ carbocycle optionally substituted with one or more substituents selected from haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl or 3 to 6 membered heterocycle ring; 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 _{'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'), - L A -C (O) N (R S) C ( O) a -R _S 'or _{-L a -P (O) (oR} S) 2, the _{L a binding,} is C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene .

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence is independently halogen, hydroxy, mercapto, amino, carboxy, nitro C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano ; or, each independently halogen at each occurrence, 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 haloalkynyl one selected from or a plurality of 6-membered _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent Is a heterocyclic ring.

Most preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence of halogen, hydroxy, mercapto, amino, carboxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ optionally substituted with one or more substituents selected from nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano Alkynyl.

L _S , L _S ′ and L _S ″ are preferably each independently selected at each occurrence from a bond; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene.

In one embodiment of this aspect, A is phenyl and is optionally substituted with one or more R _A ;

または

Or

であり、１つもしくは複数のＲ_Ａで場合によって置換されており、Ｚ_１はＯ、Ｓ、ＮＨまたは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員から６員の複素環（例えば、フェニル）であり、１つもしくは複数のＲ_Ａで場合によって置換されている、またはＪで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されており、ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

And optionally substituted with one or more R _A , Z ₁ is O, S, NH or CH ₂ ; Z ₂ is N or CH. D is a C ₅ -C ₆ carbocycle or a 5 to 6 membered heterocycle (eg, phenyl), optionally substituted with one or more _RA , or substituted with J; Optionally substituted with one or more R _A , J is a C ₃ -C ₆ carbocycle, a 3 to 6 membered heterocycle or a 6 to 12 membered bicyclic ring, wherein one or more R Optionally substituted with _A. Preferably, J is 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 One or more substitutions selected from: 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 ′) is substituted with C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring optionally substituted independently with groups, J may be substituted with one or more R _a . Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。好ましくは、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 be selected from. preferably, _{R 2} and _{R 5} are they are attached Together with the atom, one thing It is optionally substituted with a plurality of R _A

を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

R ₉ and R ₁₂ are optionally substituted with one or more R _A together with the atoms to which they are attached.

を形成している。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。

Is forming. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F.

  In other embodiments of this aspect, A is phenyl (eg,

）であり、１つもしくは複数のＲ_Ａで場合によって置換されており（好ましくは、ＡはＦなどの少なくとも１つのハロゲンで置換されている。）；Ｂは

And optionally substituted with one or more R _A (preferably A is substituted with at least one halogen such as F);

であり、１つもしくは複数のＲ_Ａで場合によって置換されている（好ましくは、ＢはＦなどの少なくとも１つのハロゲンで置換されている。）。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄはフェニルであり、Ｊで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されている。ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環、１０員から１５員の三環または１３員から１５員の炭素環／複素環であり、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊは、（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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環または７員から１２員の炭素環／複素環で置換されており；Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Optionally substituted with one or more _RA (preferably B is substituted with at least one halogen such as F). X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is phenyl, substituted with J, and optionally substituted with one or more _RA . J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring, a 6 to 12 membered bicyclic ring, a 10 to 15 membered tricyclic ring, or a 13 to 15 membered carbocyclic / heterocyclic ring , J is optionally substituted with one or more _RA . Preferably, J is (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 C ₃ -C ₆ carbocyclic ring, optionally substituted independently with one or more substituents selected from: —O—R _S , —S—R _S or —C (O) R _S To 6-membered heterocycle, 6- to 12-membered bicyclic or 7- to 12-membered carbocycle / heterocycle; and J may be optionally substituted with one or more R _A Good Preferably, D is

または

Or

であり、Ｊは上記定義通りであり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。好ましくは、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

Where J is as defined above and each _RN is independently selected from _RD and is preferably hydrogen or halo such as F. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 be selected from. preferably, _{R 2} and _{R 5} are they are attached Together with the atom, one thing A plurality of 6-membered heterocyclic ring from the 5-membered is optionally substituted with R _A (e.g.,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic rings optionally substituted with one or more R _A (For example,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成している。

) Is formed.

In yet another aspect, the invention features a compound of Formula _ID and pharmaceutically acceptable salts 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員から６員の複素環から選択され、それぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されており；
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はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている３員から１２員の複素環を形成しており；
Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている３員から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で上記に定義した通りである。

In the formula:
G ₁ and G ₂ are each independently selected from C ₅ -C ₆ carbocycles or 5- to 6-membered heterocycles, each independently substituted with one or more R _A ;
Each R _C 'is independently selected from R _C ;
Each R _D 'is independently selected from R _D ;
R ₂ and R ₅ together with the atoms to which they are attached form a 3- to 12-membered heterocycle optionally substituted with one or more R _A ;
R ₉ and R ₁₂ together with the atoms to which they are attached form a 3- to 12-membered heterocycle optionally substituted with one or more R _A ;
A, B, D, X, L ₁ , L ₂ , L ₃ , T, R _A , R _c and R _D are as defined above for Formula I.

In this embodiment, A and B are preferably independently selected from C ₅ -C ₆ carbocycles or 5- to 6-membered heterocycles, each independently substituted with one or more _RA . . More preferably, at least one of A and B is phenyl (eg,

）であり、１つもしくは複数のＲ_Ａで場合によって置換されている。

And optionally substituted with one or more _RA .

  Most preferably, both A and B are independently phenyl (eg

）であり、それぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されている。

Each optionally independently substituted with one or more _RA .

D is preferably C ₅ -C ₆ carbocyclic ring, selected from the bicyclic 12-membered to 6-membered heterocyclic ring or 8-membered 5-membered, optionally substituted with one or more R _A. D may also preferably be selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, optionally substituted with one or more _RL . More preferably, D _is, C 5 -C ₆ carbocyclic ring, a bicyclic 12-membered to 6-membered heterocyclic ring or a 6-membered to 5-membered, is substituted with one or more _{R M, R M} is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano or _-L S -R _E. Again preferably, D is phenyl, optionally substituted with one or more _RA . More preferably, D is phenyl, substituted with one or more R _M , where R _M is as defined above. Very preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F.

D is also preferably pyridinyl, pyrimidinyl or thiazolyl optionally substituted with one or more _RA . More preferably, D is pyridinyl, pyrimidinyl or thiazolyl, which is substituted by one or more R _M. Most preferably, D is

または

Or

であり、Ｒ_Ｍは上記定義通りであり、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つまたは複数のＲ_Ｎは、やはり好ましくはＦなどのハロであってもよい。Ｄはやはり好ましくは、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つまたは複数のＲ_Ａで場合によって置換されている。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つまたは複数のＲ_Ｍで置換されている。非常に好ましくは、Ｄは

And R _M is as defined above, and each R _N is independently selected from R _D and is preferably hydrogen. One or more R _N is again preferably may be halo, such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl or indazolyl, optionally substituted with one or more _RA . More preferably, D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl or benzo [d] [1,3] dioxol-5-yl, One or substituted with a plurality of R _M. Most preferably, D is

または

Or

であり、１つまたは複数のＲ_Ｍで場合によって置換されている。

, 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 each occurrence of halogen, hydroxy, mercapto, amino, carboxy, nitro, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or each halogen is independently at each occurrence, 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} - _{6 haloalkyl,} C 2 -C ₆ haloalkenyl or _C 2 -C ₆ 1 one selected from haloalkynyl or a plurality of _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent 6-membered Heterocycle. More preferably, R _M is optionally halogen, hydroxy, mercapto, amino, carboxy; or optionally one or more substituents each independently selected from halogen, hydroxy, mercapto, amino or carboxy for each occurrence. Substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. Most preferably, R _M is C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, _{R M} is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, or a thioxo or cyano; or _{R M} is _{-L S} -R _{E, L} S is a bond Or C ₁ -C ₆ alkylene, and R _E is —N (R _S R _S ′), —O—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 ', -SO ₂ R _S, it is -SR _S, or _{-P (O) (oR S)} 2, R S and _{R S} 'are, for example, each independently at each occurrence (1) hydrogen or (2) each occurrence One or more halogens, hydroxy, —O—C ₁ -C ₆ alkyl or 3 to 6 members May be selected from C ₁ -C ₆ alkyl optionally substituted with a heterocycle; or R _M is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy for each occurrence Is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphono, thioxo, formyl or cyano; or _{R M} independently halogen at each occurrence each is 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 Haroaru _{Cycloalkenyl,} C 2 -C ₆ haloalkynyl, -C (O) OR _S, or _{-N (R S R S ')} C 3 are substituted with one or more substituents selected from -C ₆ A carbocyclic ring or a 3- to 6-membered heterocyclic ring. More preferably, R _M is selected from halogen (eg, fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy or each independently from each occurrence halogen, hydroxy, mercapto, amino, cyano or carboxy C ₁ -C ₆ alkyl (eg, methyl, isopropyl, tert-butyl), C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents as defined. For example, _RM represents 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 . Also 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 ′, —SO ₂ R _S or —SR _S. For example, when L _S is a bond, R _E is —N (C ₁ -C ₆ alkyl) ₂ (eg, —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-O—C ₁ -C ₆ alkyl) (eg, —N ( _{CH 3) (CH 2 CH 2} OMe)); - O-C 1 -C 6 alkyl (e.g., -O-Me, -O-Et , -O- isopropyl, -O-tert-butyl, -O-n - _{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 _{(e.g., -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 (e.g. , —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 —S—C ₁ -C ₆ haloalkyl (eg, SCF ₃ ). Also 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 _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 represents —C ₁ -C ₆ alkylene-O—R _S (eg, —C (CH ₃ ) ₂ —CH ₂ —OMe); —C ₁ -C ₆ alkylene-C (O) OR _S (eg, _{, -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 (eg, —CH ₂ —P (O) (OEt) ₂ ). Again more preferably, _{R M} are each independently halogen at each occurrence, 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 ' A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle optionally substituted with one or more substituents selected from: For example, _RM can be cycloalkyl (eg, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (eg, morpholin-4-yl, 1,1-di). Oxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 3, 5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6- (dimethylamino) pyridin-3-yl). Most preferably, R _M is C ₁ -C optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (eg tert-butyl, CF ₃ ). ₆ alkyl.

More preferably, D is a C ₅ -C ₆ carbocyclic ring, a 5 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, substituted with J, and one or more R _A Optionally substituted, J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A Yes. Preferably, J is substituted with 6-membered heterocyclic ring from the _C 3 -C ₆ carbocycle or 3-membered, heterocyclic ring 6 membered from the _C 3 -C ₆ carbocycle or 3 members of 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} Optionally independently substituted with one or more substituents selected from —C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) , J may be optionally substituted with one or more _RA . Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more R _A ; preferably J is 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 ₃ optionally substituted independently with one or more substituents selected from C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle. Also preferably, D is a C ₅ -C ₆ carbocyclic ring or a 5 6 membered heterocycle members, is substituted with J, is optionally substituted with one or more R _A, J is A 6 to 12 membered bicycle (eg, a 7 to 12 membered fused, bridged or spiro bicyclic ring containing a nitrogen ring atom through which J is covalently bonded to D), and one or more Optionally substituted with _RA . More preferably, D is phenyl, substituted with J, optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered heterocycle Or a 6 to 12 membered bicyclic ring, optionally substituted with one or more R _A ; preferably J is 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 ')} C 3 -C 6 the carbocycle is optionally substituted independently with one or more substituents selected from It is at least substituted with 6-membered heterocyclic ring from 3 members. Very preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環または６員から１２員の二環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。やはり好ましくは、Ｄは

, And the respective R _N is independently selected from R _D, preferably hydrogen or halogen, J is C ₃ -C ₆ carbocycle, bicyclic 12-membered to 6-membered heterocyclic ring or 3 to 6-membered And optionally substituted with one or more R _A ; preferably J is 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 If (R _S R _S ') less in one or more of which is optionally substituted independently with substituents C ₃ -C ₆ carbocycle or 3 6-membered membered heterocyclic ring selected from It has been replaced. Still preferably, D is

であり、各Ｒ_ＮはＲ_Ｄから独立に選択され、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員から６員の複素環であり、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で置換されており、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。やはり好ましくは、Ｄは、

And in each R _N is independently selected from R _D, preferably hydrogen or halogen, J is a 6-membered heterocycle C ₃ -C ₆ carbocycle or a 3-, 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle, and J may be optionally substituted with one or more _RA . Again preferably, D is

であり、ＪはＣ_３−Ｃ_６炭素環または３員から６員の複素環であり、１つもしくは複数のＲ_Ａで場合によって置換されており；好ましくは、Ｊ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、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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環または３員から６員の複素環で少なくとも置換されている。

Wherein J is a C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle, optionally substituted with one or more _RA ; preferably, J is 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 C ₃ optionally independently substituted with one or more substituents selected from ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C (O) OR _S or —N (R _S R _S ′) It is at least substituted with a -C ₆ carbocycle or a 3 to 6 membered heterocycle.

X is preferably _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. Non-limiting examples of X are as defined above.

L ₁ and L ₂ are preferably independently a bond or C ₁ -C ₆ alkylene, and L ₃ is preferably selected from a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ And L ₃ are each independently substituted with one or more R _L. More preferably, L ₁ , L ₂ and L ₃ are each independently a bond or C ₁ -C ₆ alkylene (eg, —CH ₂ — or —CH ₂ CH ₂ —), and one or more R _L Each is independently replaced by the case. Most preferably, L ₁ , L ₂ and L ₃ are each a bond.

R ₂ and R ₅ together with the atoms to which they are attached are preferably 5 to 6 membered heterocycles or 6 to 12 members optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。

) Is formed.

R ₉ and R ₁₂ together with the atoms to which they are attached are preferably 5- to 6-membered heterocycles or 6 to 12-membered rings optionally substituted with one or more R _A Bicycle (e.g.,

または

Or

）を形成している。

) Is formed.

G ₁ and G ₂ are preferably each independently

または

Or

から選択され、それぞれ独立に、１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のクロロまたはブロモ）で場合によって置換されている。より好ましくは、Ｇ_１は

Each independently is optionally substituted with one or more R _A (eg, one or more chloro or bromo). More preferably, G ₁ is

（その任意の互変異性体を含む）であり、Ｇ_２は

(Including any tautomer thereof) and G ₂ is

（その任意の互変異性体を含む。）であり、各Ｇ_１およびＧ_２は１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のクロロまたはブロモ）で独立に場合によって置換されている。

(Including any tautomers thereof), wherein each G ₁ and G ₂ is independently optionally substituted with one or more R _A (eg, one or more chloro or bromo) .

_{-T-R D} 'is not limited to, -C independently at each occurrence _{(O) -L Y' -,} - C (O) O-L Y '-R D', -C (O) _{-L Y '-N (R B)} C (O) -L S''-RD', -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''-RD' or _{-N (R B) C (O} ) -L Y '-N (R B) -L S''-R _D ′ may be selected from L ′ ′, each L _Y ′ is independently L _S ′, preferably each independently C ₁ -C ₆ alkylene (eg, —CH ₂ —), and 1 selected from R _L Optionally substituted with one or more substituents. Preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y'-M'-} L S '' -R D ' or _{-N (R B) C (O} ) -L Y It is selected from '-M'-L _S ''-R _D '. More preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) O-L S '' -R D ' or -C (O ) -L _Y '-N (R _B ) C (O) O-L _S ″ -R _D ′. Very preferably, _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -R D ' or -C (O) -L _Y' 'is selected _{from, L Y' -N (R B} ) C (O) O-R D are preferably each independently _C 1 -C ₆ alkylene (e.g., -CH ₂ -) a, selected from _{R L} Optionally substituted with one or more substituents.

R _C 'is preferably hydrogen and R _D ' is preferably independently selected from R _E for each occurrence. More preferably, R _D ′ is independently for each occurrence, each independently for each occurrence, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C _6. C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from carbocycles or 3- to 6-membered heterocycles; or each halogen is independently at each occurrence, 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} - ₆ is selected from heterocycle 6-membered C ₃ -C ₆ carbocycle or 3-membered optionally substituted with one or more substituents selected from haloalkynyl.

R _A is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence independently of halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphonoxy, phosphono, thioxo, formyl or cyano; or , each halogen is independently at each occurrence, 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 C ₃ -C ₆ carbocycle optionally substituted with one or more substituents selected from haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl or 3 to 6 membered heterocycle ring; 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 _{'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'), - L A -C (O) N (R S) C ( O) a -R _S 'or _{-L a -P (O) (oR} S) 2, the _{L a binding,} is C 1 -C _{6 alkylene,} C 2 -C ₆ alkenylene or _C 2 -C ₆ alkynylene .

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence is independently halogen, hydroxy, mercapto, amino, carboxy, nitro C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from oxo, phosphonoxy, phosphono, thioxo, formyl or cyano ; or, each independently halogen at each occurrence, 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 haloalkynyl one selected from or a plurality of 6-membered _C 3 -C ₆ carbocycle or 3-membered optionally substituted with a substituent Is a heterocyclic ring.

Most preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or each occurrence of halogen, hydroxy, mercapto, amino, carboxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ optionally substituted with one or more substituents selected from nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano Alkynyl.

L _S , L _S ′ and L _S ″ are preferably each independently selected at each occurrence from a bond; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene.

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

In one embodiment of this aspect, A and B are each independently phenyl, each independently is optionally substituted with one or more R _A ; D is phenyl, and one or more R Optionally independently substituted with _A or substituted with J and optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocycle, 3 to 6 membered Heterocycle or 6- to 12-membered bicycle, optionally substituted with one or more _RA . Preferably, J is 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 One or more substitutions selected from: 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 ′) Optionally substituted with a C ₃ -C ₆ carbocycle independently substituted with a group or a 3- to 6-membered heterocycle, and J may be optionally substituted with one or more R _A ; _{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１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のクロロまたはブロモ）で独立に場合によって置換されている。
好ましくは、Ｄは

Wherein each G ₁ and G ₂ is independently optionally substituted with one or more R _A (eg, one or more chloro or bromo).
Preferably, D is

または

Or

であり、Ｒ_ＭおよびＲ_Ｎは上記定義通りである。やはり好ましくは、Ｄは

And R _M and R _N are as defined above. Still preferably, D is

または

Or

であり、ＪおよびＲ_Ｎは上記定義通りである。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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。好ましくは、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

And J and _RN are as defined above. L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 be selected from. preferably, _{R 2} and _{R 5} are they are attached Together with the atom, one thing It is optionally substituted with a plurality of R _A

を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている

R ₉ and R ₁₂ are optionally substituted with one or more R _A together with the atoms to which they are attached.

を形成している。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。

Is forming. X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F.

  In other embodiments of this aspect, A and B are each independently phenyl (eg,

）であり、それぞれ独立に１つもしくは複数のＲ_Ａで場合によって置換されている（好ましくは、ＡおよびＢはそれぞれ独立にＦなどの少なくとも１つのハロゲンで置換されている。）。ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されている。Ｘの具体的な例は上述の通りである。好ましくは、Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。より好ましくは、Ｘはシクロプロピルであり、１つもしくは複数のＲ_ＡまたはＲ_Ｆで場合によって置換されている。Ｄはフェニルであり、Ｊで置換されており、１つもしくは複数のＲ_Ａで場合によって置換されている。ＪはＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環、１０員から１５員の三環または１３員から１５員の炭素環／複素環であり、Ｊは１つもしくは複数のＲ_Ａで場合によって置換されている。好ましくは、Ｊは、（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つもしくは複数の置換基で独立に場合によって置換されているＣ_３−Ｃ_６炭素環、３員から６員の複素環、６員から１２員の二環または７員から１２員の炭素環／複素環で置換されており；Ｊは１つもしくは複数のＲ_Ａで場合によって置換されていてもよい。好ましくは、Ｄは

Each independently substituted with one or more R _A (preferably A and B are each independently substituted with at least one halogen such as F). X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, optionally substituted with one or more _{R A.} Specific examples of X are as described above. Preferably X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more R _A or R _F. More preferably, X is cyclopropyl and is optionally substituted with one or more R _A or R _F. D is phenyl, substituted with J, and optionally substituted with one or more _RA . J is a C ₃ -C ₆ carbocyclic ring, a 3 to 6 membered heterocyclic ring, a 6 to 12 membered bicyclic ring, a 10 to 15 membered tricyclic ring, or a 13 to 15 membered carbocyclic / heterocyclic ring , J is optionally substituted with one or more _RA . Preferably, J is (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 C ₃ -C ₆ carbocyclic ring, optionally substituted independently with one or more substituents selected from: —O—R _S , —S—R _S or —C (O) R _S To 6-membered heterocycle, 6- to 12-membered bicyclic or 7- to 12-membered carbocycle / heterocycle; and J may be optionally substituted with one or more R _A Good Preferably, D is

または

Or

であり、Ｊは上記定義通りであり、各Ｒ_ＮはＲ_Ｄから独立に選択され、好ましくは水素またはＦなどのハロである。Ｇ_１は

Where J is as defined above and each _RN is independently selected from _RD and is preferably hydrogen or halo such as 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１つもしくは複数のＲ_Ａ（例えば、１つもしくは複数のクロロまたはブロモ）で独立に場合によって置換されている。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つもしくは複数のＲ_Ｌで場合によって置換されている。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。−Ｔ−Ｒ_Ｄ’は出現ごとに独立に−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つもしくは複数の置換基で場合によって置換されており、Ｌ_Ｓ”は好ましくは結合である。−Ｔ−Ｒ_Ｄ’は、これらに限定されないが、−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’から選択されてもよい。好ましくは、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

Wherein each G ₁ and G ₂ is independently optionally substituted with one or more R _A (eg, one or more chloro or bromo). L ₁ and L ₂ are each independently a bond or C ₁ -C ₆ alkylene, L ₃ is a bond, C ₁ -C ₆ alkylene or —C (O) —, and L ₁ , L ₂ and L ₃ are Each independently is optionally substituted with one or more R _L. Preferably L ₁ , L ₂ and L ₃ are a bond. _{-T-R D} 'is -C independently at each occurrence _{(O) -L Y' -N (} R B) C (O) -L S "-R D ' or -C (O) -L _Y' - N (R _B ) C (O) OL— _S ″ —R _D ′, L _Y ′ is C ₁ -C ₆ alkylene (eg, —CH ₂ —), 1 selected from R _L Optionally substituted with one or more substituents, L _S ″ is preferably a bond. —T—R _D ′ is not limited to, but 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 be selected from. preferably, _{R 2} and _{R 5} are they are attached Together with the atom, one thing A plurality of 6-membered heterocyclic ring from the 5-membered is optionally substituted with R _A (e.g.,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成しており；Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、１つもしくは複数のＲ_Ａで場合によって置換されている５員から６員の複素環式環（例えば、

R ₉ and R ₁₂ together with the atoms to which they are attached are 5- to 6-membered heterocyclic rings optionally substituted with one or more R _A (For example,

）または６員から１２員の二環（例えば、

) Or 6 to 12 membered bicyclic rings (eg,

）を形成している。

) Is formed.

In another aspect, the invention features a compound having Formula _IE and pharmaceutically acceptable salts thereof.

式中、
ＸはＣ_３−Ｃ_８シクロアルキルまたはＣ_５−Ｃ_８シクロアルケニルであり、１つもしくは複数のＲ_Ａで場合によって置換されており；
Ｌ_１およびＬ_２はそれぞれ独立に結合または出現ごとに独立に１つもしくは複数のハロ、ヒドロキシ、−Ｏ−Ｃ_１−Ｃ_６アルキルまたは−Ｏ−Ｃ_１−Ｃ_６ハロアルキルで場合によって置換されているＣ_１−Ｃ_６アルキレンから選択され；
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

Where
X is _C 3 -C ₈ cycloalkyl or _C 5 -C ₈ cycloalkenyl, which is optionally substituted with one or more _{R A;}
L ₁ and L ₂ are each independently bonded or optionally substituted with one or more halo, hydroxy, —O—C ₁ -C ₆ alkyl or —O—C ₁ -C ₆ haloalkyl, independently for each occurrence Selected from C ₁ -C ₆ alkylene;
L ₃ is a bond or C ₁ -C ₆ alkylene;
A and B are each independently phenyl, pyridinyl, thiazolyl or

であり、Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｚ_３は出現ごとに独立にＮまたはＣＨから選択され、Ｗ_１、Ｗ_２およびＷ_３はそれぞれ出現ごとに独立に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つもしくは複数のＲ_Ａで場合によって置換されている。

Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence, Z ₃ is independently selected from N or CH at each occurrence, and W ₁ , W ₂ and W ₃ are each at each occurrence Independently selected from CH or N; A and B are each independently substituted with one or more _RA .

D are each one or more C ₆ -C ₁₀ carbocyclic or 5 12-membered membered heterocyclic ring is optionally substituted with R _M;
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-R D;
R ₁ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or a 3 to 6 membered carbocyclic or heterocyclic ring, each said 3 to 6 membered carbocyclic or heterocyclic ring appearing One or more substituents each independently 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 Optionally substituted with;
R ₂ and R ₅ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or a 3- to 6-membered carbocyclic or heterocyclic ring, each of the 3- to 6-membered carbocycle Alternatively, the heterocycle is _one independently 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 for each occurrence. Or optionally substituted with a plurality of substituents; or R ₂ and R ₅ together with the atoms to which they are attached, one or more R _A (eg, 1, 2, 3 or 4 R _A ) form an optionally substituted 3- to 12-membered heterocycle;
R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or a 3 to 6 membered carbocyclic or heterocyclic ring, each said 3 to 6 membered carbocyclic or heterocyclic ring being With one or more substituents independently 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 Optionally substituted;
R ₉ and R ₁₂ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or a 3- to 6-membered carbocyclic or heterocyclic ring, each of the 3- to 6-membered carbocyclic ring Alternatively, the heterocycle is independently selected at each occurrence 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. Optionally substituted with one or more substituents; or R ₉ and R ₁₂ together with the atoms to which they are attached are one or more R _A (eg, 1, 2, 3 or 4 R _A ) form an optionally substituted 3 to 12 membered heterocycle;
T is at each occurrence independently bond or -C (O) -L _S '- is selected from;
T ′ is independently a bond for each occurrence, selected from —C (O) N (R _B ) —, —N (R _B ) C (O) —, or a 3- to 12-membered heterocyclic ring, The 12-membered heterocycle is optionally substituted with one or more R _A independently for each occurrence;
R _D is independently selected for each occurrence from hydrogen or R _A ;
R _A is independently halogen at each occurrence, nitro, oxo, phosphonoxy, phosphono, thioxo, is selected from cyano or _-L S -R _E;
R _B and R _B ′ are each optionally substituted independently with each occurrence, hydrogen; or independently with each occurrence, one or more substituents selected from halogen or a 3- to 6-membered carbocyclic or heterocyclic ring C ₁ -C ₆ alkyl; or selected from 3 to 6 membered carbocycle or heterocycle; each 3 to 6 membered carbocycle or heterocycle in R _B or R _B ′ is One or more each independently selected from 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 Optionally substituted with a substituent;
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 ) for each occurrence. R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N (R _S R _S '), -N (R _S ) 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 (R _S ) 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'), - C (O) N (R S) C (O -R _S 'or _{= C (R S R S'} ); or are selected each independently at each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents; or each independently occurrence of 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- One selected from C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl Or a C ₃ -C ₁₂ carbocycle optionally substituted with multiple substituents or a 3 to 12 membered heterocycle;
R _L is independently halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R _S , —S—R _S , —C (O) R _S , —OC (O) R _S for each occurrence. , -C (O) OR _S , -N (R _S R _S '), -S (O) R _S , -SO ₂ R _S , -C (O) N (R _S R _S ') or N (R _S ) C (O) R _S ′; or each occurrence independently of halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, Optionally with one or more substituents selected from 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 haloalkynyl. Has been replaced From C ₃ -C ₁₂ carbocyclic or 3-membered are chosen from 12-membered heterocyclic ring;
L _S is independently linked at each occurrence; or is selected from C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, each optionally substituted independently with halogen;
L _S ′ is independently bonded for each occurrence; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ , each optionally substituted with one or more R _L independently for each occurrence. It is selected from -C ₆ alkynylene;
R _S , R _S ′ and R _S ″ are each independently for each occurrence, hydrogen; each independently for each occurrence, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano Optionally substituted with one or more substituents selected from: -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl or a 3 to 12 membered carbocyclic or heterocyclic ring. Selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; or a 3 to 12 membered carbocyclic or heterocyclic ring; within R _S , R _S ′ or R _S ″ Each 3- to 12-membered carbocyclic or heterocyclic ring is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, Suhonokishi, 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 Optionally substituted with one or more substituents selected from _6- haloalkynyl;
_RM is independent for each occurrence:
Halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, SF ₅ , —N (R _S R _S ′), —O—R _S , —OC (O) R _S , — _{OC (O) OR S, -OC} (O) N (R S 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 (R _S R _S ′), —SR _S , —Si (R _S ) ₃ or —P (O) (OR _S ) ₂ ;
Each occurrence is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, —N (R _S R _S ′), —O—R _S , —OC ( _{O) R S, -OC (O} ) OR S, -OC (O) N (R S 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 (R S R S '), - SR S or -P (O) (1 one or more substituents selected from _{oR S) 2} in _C 1 -C ₆ alkyl which is optionally _substituted, C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or G ₂ ( ₂ are each a _C 3 _{-C 12} carbocyclic or 3- to 12-membered heterocycle optionally substituted with is one or more independently at each occurrence _{R G2,} each _{R G2} 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, -O-R S, -C (} O) oR S, -C (O) R S, -N (R S R S ') or -L ₄ It is selected from -G ₃ independently.)
Selected from;
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 ')-;
G ₃ is a C ₃ -C ₁₂ carbocycle or a 3 to 12 membered heterocycle, optionally substituted with one or more R _G3 ;
R _G3 is independently for each occurrence, 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 carbocycle or a 3 to 6 membered heterocycle.

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

であり、Ｚ_１は出現ごとに独立にＯ、Ｓ、ＮＨまたはＣＨ_２から選択され、Ｚ_３は出現ごとに独立にＮまたはＣＨから選択され、Ｗ_１、Ｗ_２およびＷ_３はそれぞれ出現ごとに独立に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つもしくは複数のＲ_Ａで場合によって置換されている。

Z ₁ is independently selected from O, S, NH or CH _{2 at} each occurrence, Z ₃ is independently selected from N or CH at each occurrence, and W ₁ , W ₂ and W ₃ are each at each occurrence Independently selected from CH or N; A and B are each independently substituted with one or more _RA .

  Preferably A is phenyl (eg,

）、ピリジニル（例えば、

), Pyridinyl (e.g.,

）、
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つもしくは複数のＲ_Ａで場合によって置換されている。

And optionally substituted with one or more _RA .

  Preferably B is phenyl (eg,

）、ピリジニル（例えば、

), Pyridinyl (e.g.,

）、チアゾリル（例えば、

), Thiazolyl (e.g.,

）または

Or

（例えば、

(For example,

）から選択され、１つもしくは複数のＲ_Ａで場合によって置換されている。

And optionally substituted with one or more _RA .

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

である。）であるか；またはＡは

It is. Or A is

であり、Ｂは

And B is

であるか；またはＡは

Or A is

であり、Ｂは

And B is

であるか；またはＡは

Or A is

であり、Ｂは

And B is

であるか；またはＡは

Or A is

であり、Ｂは

And B is

であるか；またはＡは

Or A is

であり、Ｂは

And B is

であり；各ＡおよびＢは１つもしくは複数のＲ_Ａで独立に場合によって置換されている。

Each A and B is optionally substituted independently with one or more R _A.

In certain embodiments of this aspect of the invention, A and B are substituted with one or more R _A , and each R _A is halogen (eg, fluoro, chloro), L _S -R _E (L _S is a bond and R _E is —C ₁ -C ₆ alkyl (eg, methyl), —O—R _S (eg, —O—C ₁ -C ₆ alkyl, —OCH ₃ ) or one or more -C ₁ -C ₆ alkyl optionally substituted with halogen (eg, -CF ₃ ), or L _S -R _E (L _S is C ₁ -C ₆ alkylene, R _E is -O Independently selected from —R _S (eg, —C ₁ -C ₆ alkyl-O—C ₁ -C ₆ alkyl, —CH ₂ OCH ₃ ). For example, in certain embodiments, A is

または

Or

であり、Ｂは上記定義通りである。特定の他の実施形態では、Ｂは

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

または

Or

であり、Ａは上記定義通りである。さらに他の実施形態では、Ａは

And A is as defined above. In still other embodiments, A is

または

Or

であり、Ｂは

And B is

または

Or

である。

It is.

As described above for compounds of formula I _E, D is one or more C ₆ -C ₁₀ carbocyclic or 3 12-membered membered heterocyclic ring optionally substituted with R _M. Preferably, D is C ₆ -C ₁₀ aryl (eg, phenyl, naphthyl, indanyl) or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, a benzo [d] [1,3] dioxol-5-yl), D is substituted with one or more _{R M.} For example, in certain embodiments, D is preferably phenyl substituted with one or more R _M , each R _M independently being a halogen (eg, fluoro, chloro, bromo); C ₁ -C ₆ alkyl (eg tert-butyl); C ₁ -C ₆ alkyl substituted with one or more halogens (eg CF ₃ ); —O—R _S , eg —O—C ₁ -C ₆ alkyl ( For example, —O—CH ₂ CH ₃ ); or —O—C ₁ -C ₆ alkyl (eg, —O—CF ₃ , —O—CH ₂ CHF) substituted with one or more halogens at each occurrence. ₂ ) or —O—C ₁ -C ₆ alkyl (eg, —O—CH ₂ CH ₂ OCH ₃ ); a 3- to 12-membered heterocycle (eg, 3-ethyloxetane-3-yl, 1,3- Dioxolane-4- -O—R _S (eg, —O—C ₁ -C ₆ alkyl, eg, —O—CH ₂ ) substituted with yl); a 3- to 12-membered carbocycle or heterocycle wherein R _S is optionally substituted —O—R _S which is a ring (eg, cyclopentyl, cyclohexyl, phenyl, 1,3-dioxane-5-yl); —N (R wherein R _S and R _S ′ are each independently C ₁ -C ₆ alkyl. _{S) C (O) R S} '( e.g., -N (t-Bu) C (O) Me); SF 5; -SO 2 R S is _C 1 -C ₆ alkyl _{R S} (e.g., -SO ₂ Me); or a C ₃ -C ₁₂ carbocycle (eg, cyclopropyl, cyclohexyl, phenyl).

In a particular embodiment of this aspect of the present invention, D is preferably phenyl or pyridyl, one of R _M is substituted with one or more R _M is a G _2. In certain embodiments D is phenyl or pyridyl, D is substituted with G _2, a G ₂ is 12-membered heterocyclic ring from 3- (eg, 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 (eg, CF ₃ ), C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, —O—C ₁ -C ₆ alkyl (eg, —O—CH ₃ ), —C (O) OR Optionally substituted with _S (eg, —C (O) OCH ₃ ), —C (O) R _S (eg, —C (O) CH ₃ ) or —N (R _S R _S ′). D is optionally further substituted with one or more R _M , where R _M is halogen (eg, fluoro, chloro), C ₁ -C ₆ alkyl (eg, methyl), C ₁ -C ₆ Haloalkyl (eg, CF ₃ ) or —O—C ₁ -C ₆ alkyl (eg, —O—CH ₃ ). In certain other embodiments, D is phenyl or pyridyl and G ₂ is, for example, substituted with L ₄ -G ₃ and monocyclic 3 optionally substituted with one or more R _G2 A membered to 8-membered carbocyclic ring or a monocyclic 4- to 8-membered heterocyclic ring, 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 —. It is. G ₃ is, for example, a C ₃ -C ₁₂ carbocycle optionally substituted with one or more R _G3 . R _G2 and R _G3 each independently represent halogen, —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. In certain embodiments, G ₂ is

であり、

And

は、窒素原子を介して親分子部分と結合しており、１つまたは２つのＬ_４−Ｇ_３で置換されており、１つまたは複数のＲ_Ｇ２で場合によって置換されている単環式４員から８員の窒素含有複素環（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）である。したがって、特定の実施形態では、Ｌ_４は結合であり、Ｇ_２は

Is attached to the parent molecular moiety through a nitrogen atom, is substituted with one or two L ₄ -G ₃ , and is optionally substituted with one or more R _G2 monocyclic 4 A membered to 8-membered nitrogen-containing heterocycle (eg azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl). Thus, in certain embodiments, L ₄ is a bond and G ₂ is

であり、

And

はＲ_Ｇ２で場合によって置換されており、Ｇ_３はＲ_Ｇ３で場合によって置換されている。したがって、

Is optionally substituted with R _G2 and G ₃ is optionally substituted with 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−イルであってよく、Ｄは、さらに１つもしくは複数のＲ_Ｍ（例えば、フルオロ、クロロ、メチル、メトキシ）で場合によって置換されていてよい。

For example, 3-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperazin-1-yl, 4-phenylpiperidin-1-yl, 4-phenyl-3,6-dihydropyridine- 1 (2H) -yl, 4,4-diphenylpiperidin-1-yl, 4-acetyl-4-phenylpiperidin-1-yl, 4- (4-methoxyphenyl) piperidin-1-yl, 4- (4- Fluorophenyl) piperidin-1-yl or 3-phenylpiperidin-1-yl, wherein D is further optionally substituted with one or more R _M (eg, fluoro, chloro, methyl, methoxy). It's okay.

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

は上記定義通りであり、Ｒ_Ｇ２で場合によって置換されており、Ｇ_３は上記定義通りであり、Ｒ_Ｇ３で場合によって置換されている。したがって、

Is as defined above and optionally substituted with R _G2 and G ₃ is as defined above and optionally 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−イルであってよい。

For example 4-tosylpiperazin-1-yl, 4-phenoxypiperidin-1-yl, 3-phenoxypyrrolidin-1-yl, 4-benzylpiperidin-1-yl, 4-phenethylpiperidin-1-yl or 3- Phenylpropyl) piperidin-1-yl.

In certain other embodiments of this aspect of the invention, D is phenyl or pyridyl, D is substituted with G ₂ , and G ₂ is L ₄ -G ₃ and one or more R _G2 A spiro, bridged or fused bicyclic carbocycle or heterocycle substituted by, D is optionally substituted with one or more R _M , and L ₄ , G ₃ and R _G2 are as defined herein As defined. In certain embodiments, G ₂ is

であり、

And

は、窒素原子を介して親分子部分と結合しており、Ｇ_３および１つもしくは複数のＲ_Ｇ２で場合によって置換されているスピロ、架橋または縮合二環式窒素含有複素環（例えば、３−アザビシクロ［３．２．０］ヘプタ−３−イル、２−アザビシクロ［２．２．２］オクタ−２−イル、６−アザスピロ［２．５］オクタ−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］ウンデカ−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］デカ−８−イル）である。したがって、Ｇ_２は、３−アザビシクロ［３．２．０］ヘプタ−３−イル、２−アザビシクロ［２．２．２］オクタ−２−イル、６−アザスピロ［２．５］オクタ−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］ウンデカ−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］デカ−８イルであり；Ｌ_４は結合であり、Ｄは１つもしくは複数のＲ_Ｍ（例えば、フルオロ、クロロ、メチル、メトキシ）で場合によって置換されている。

Is attached to the parent molecular moiety through a nitrogen atom and is a spiro, bridged or fused bicyclic nitrogen containing heterocycle optionally substituted with G ₃ and one or more R _G2 (eg, 3- Azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [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] deca- 8-yl). Thus, G ₂ is 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] oct-2-yl, 6-azaspiro [2.5] oct-6- Yl, octahydro-2H-isoindol-2-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl or 1,4-dioxa-8- Azaspiro [4.5] dec-8yl; L ₄ is a bond and D is optionally substituted with one or more R _M (eg, fluoro, chloro, methyl, methoxy).

  In certain embodiments of this aspect of the invention, D is

であり、Ｒ_Ｍは式Ｉ_Ｅの関連で上記に定義した通りであり、Ｄは１つもしくは複数の追加のＲ_Ｍで場合によって置換されている。例えば、Ｄが

In and, R _M is as defined above in connection with formula I _E, D is optionally substituted with one or more additional R _M. For example, D is

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であってよく、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つもしくは複数の追加のＲ_Ｍで場合によって置換されていてよい。

, R _M 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- _{ethyloxetan-3-yl), - O-CH 2 -} (1,3- dioxolan-4-yl), - O-cyclopentyl, -O- cyclohexyl, -O- phenyl, -O - (1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, _phenyl, SF 5, _-SO 2 Me, or -N (t-Bu) may be a C (O) Me, D is halogen ( For example, it may be optionally substituted with one or more additional R _M selected from the group consisting of fluoro, chloro) and C ₁ -C ₆ alkyl (eg, 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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。

In and, _{R M} 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, - SO ₂ Me or —N (t-Bu) C (O) Me, wherein D is selected from the group consisting of halogen (eg, fluoro, chloro) and C ₁ -C ₆ alkyl (eg, methyl). One or is optionally substituted with a plurality of additional R _M.

  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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。

R _M is cyclopropyl, cyclohexyl or phenyl, D is one or more selected from the group consisting of halogen (eg, fluoro, chloro) and C ₁ -C ₆ alkyl (eg, methyl) Optionally substituted with additional R _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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。

And a, _{R M} is _-O-CH 2 - (3- _{ethyloxetan-3-yl), - O-CH 2 -} (1,3- dioxolan-4-yl), - O-cyclopentyl, -O- cyclohexyl , —O-phenyl or —O- (1,3-dioxane-5-yl), D is selected from the group consisting of halogen (eg, fluoro, chloro) and C ₁ -C ₆ alkyl (eg, methyl). Optionally substituted with one or more additional R _Ms selected.

  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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。

And G ₂ is pyridinyl (eg, pyridin-2-yl), piperidin-1-yl, 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 2,6- Dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidine -1-yl, 4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, 3,3-dimethylazetidin-1-yl or oxazolyl (eg, 1,3-oxazol-2-yl) and D consists of halogen (eg, fluoro, chloro) and C ₁ -C ₆ alkyl (eg, methyl). It is optionally substituted with one or more additional R _M is selected from that group.

  In other embodiments of this aspect of the invention, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

G ₁ is N, 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と結合しており、Ｌ_４−Ｇ_３で置換され１つもしくは複数のＲ_Ｇ２で場合によって置換されている単環式４員から８員の窒素含有複素環（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つもしくは複数のＲ_Ｇ３で場合によって置換されており；Ｒ_Ｇ２およびＲ_Ｇ３は出現ごとに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の関連で上記に定義した通りである。この実施形態による化合物の１つ群において、Ｄは

Is attached to the parent molecular moiety through a nitrogen atom and is a monocyclic 4- to 8-membered nitrogen-containing complex substituted with L ₄ -G ₃ and optionally substituted with one or more R _G2. A ring (eg, azetidinyl, pyrrolidinyl, piperidinyl); L ₄ is a bond, C ₁ -C ₆ alkylene, —O— or —S (O) ₂ —; G ₃ is aryl (eg, phenyl), cyclo Alkyl (eg, cyclohexyl) or heterocycle (eg, thienyl), wherein each G ₃ is optionally substituted with one or more R _G3 ; each occurrence of R _G2 and R _G3 is independently halogen, -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 Haroaruki In it; g is 0, 1, 2 or 3; _{R M} is as defined above in connection with formula _{I E.} In one group of compounds according to this embodiment, D is

であり、Ｇ_３は１つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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；

G ₃ is phenyl optionally substituted with one or two R _G3 ; g is 0, 1 or 2; each R _M is independently fluoro, chloro, methyl, methoxy, trifluoro Methyl or trifluoromethoxy;

およびＲ_Ｇ３は上記定義通りである。この実施形態の化合物の他の下位群において、Ｄは

And R _G3 is as defined above. In another subgroup of compounds of this embodiment, D is

であり、Ｇ_３は１つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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は本明細書で説明されるような、場合による置換基である。この実施形態による化合物の他の群において、Ｄは

G ₃ is phenyl optionally substituted with one or two R _G3 ; R _M1 is each independently hydrogen, fluoro, chloro or methyl; R _G2 is as described herein An optional substituent. In another group of compounds according to this embodiment, D is

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つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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 phenyl optionally substituted with one or two R _G3 ; g is 0 1 or 2; each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

およびＲ_Ｇ３は上記定義通りである。

And R _G3 is as defined above.

  In still other embodiments of this aspect of the invention, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

G ₁ is N, 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と結合しており、Ｌ_４−Ｇ_３および１つもしくは複数のＲ_Ｇ２で場合によって置換されているスピロ、架橋または縮合二環式窒素含有複素環（例えば、３−アザビシクロ［３．２．０］ヘプタ−３−イル、２−アザビシクロ［２．２．２］オクタ−２−イル、６−アザスピロ［２．５］オクタ−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］ウンデカ−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］デカ−８−イル）であり；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つもしくは複数のＲ_Ｇ３で場合によって置換されており；Ｒ_Ｇ２およびＲ_Ｇ３はそれぞれ出現ごとに独立にハロゲン、−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の関連で上記に定義した通りである。この実施形態による化合物の１つ群において、Ｄは

Is attached to the parent molecular moiety through a nitrogen atom and is a spiro, bridged or fused bicyclic nitrogen-containing heterocycle optionally substituted with L ₄ -G ₃ and one or more R _G2 (eg, 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] oct-2-yl, 6-azaspiro [2.5] oct-6-yl, octahydro-2H -Isoindol-2-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl, 1,4-dioxa-8-azaspiro [4.5 L ₄ is a bond, C ₁ -C ₆ alkylene, —O— or —S (O) ₂ —; G ₃ is aryl (eg, phenyl), cycloalkyl (eg, Cyclohexyl) also Heterocyclic (e.g., thienyl), and each _{G 3} are to have substituted with one or more _{R G3;} halogen independently each occurrence each _{R G2} and _{R G3} is, -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; R _M is as defined above in connection with Formula _IE . In one group of compounds according to this embodiment, D is

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; each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

は上記定義通りである。化合物の他の下位群では、Ｄは

Is as defined above. In other subgroups 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、

Each R _M1 is independently hydrogen, fluoro, chloro or methyl;

は上記定義通りである（例えば、３−アザビシクロ［３．２．０］ヘプタ−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］オクタ−２−イル、６−アザスピロ［２．５］オクタ−６−イル、３−アザスピロ［５．５］ウンデカ−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］デカ−８−イル）。

Are as defined above (e.g. 3-azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindol-2yl, 2-azabicyclo [2.2.2] oct-2-yl 6-azaspiro [2.5] oct-6-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).

  In still other embodiments of this aspect of the invention, D is

であり、

And

は、１つもしくは複数のＲ_Ｇ２で置換された単環式４員から８員の窒素含有複素環（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は出現ごとに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つ群において、

Is a monocyclic 4- to 8-membered nitrogen-containing heterocycle (eg, azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R _G2 , and each R _G2 is independently halogen, 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 Each _M is 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つまたは２つのＲ_Ｇ２で置換されたアゼチジニル、ピロリジニルまたはピペリジニルであり、Ｒ_Ｇ２は出現ごとに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, pyrrolidinyl or piperidinyl substituted with 1 or 2 R _G2 , and R _G2 is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro or trifluoromethyl for each occurrence; R Each _M is 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。

Are 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4 -Fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidin-1-yl, 4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1- Yl, 2-oxopiperidin-1-yl or 3,3-dimethylazetidin-1-yl.

In certain preferred embodiments of this aspect of the invention, X is cyclopropyl, cyclopentyl, or cyclopentenyl, optionally substituted with one or more _RA ; each of L ₁ , L _2, and L ₃ is It is a bond. In other embodiments, X is cyclopropyl, cyclopentyl or cyclopentenyl, L ₁ and L ₂ are each methylene (ie, —CH ₂ —), 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 ) be the _{-T-R D; 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 each independently hydrogen; C ₁ -C ₆ alkyl; or a 3 to 6 membered carbocyclic or heterocyclic ring, each 3 A 6 to 6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from halogen or C ₁ -C ₆ alkyl; R ₂ and R ₅ are Together with the atoms to which are attached form a 3- to 12-membered heterocycle optionally substituted with 0, 1, 2, 3 or 4 R _A , R ₉ and R ₁₂ together with the atoms to which they are attached form a 3- to 12-membered heterocycle optionally substituted with 0, 1, 2, 3 or 4 R _A ; _A is as defined herein.

In certain embodiments of this aspect of the invention, R ₁ is hydrogen and R ₂ and R ₅ together with the atoms to which they are attached are 0, 1, 2, 3 or 4 R _A 3- to 12-membered heterocyclic ring substituted with _A (eg,

または

Or

）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、

R _A is halogen (eg, fluoro, chloro); cyano; L _S is a single bond, R _E is C ₁ -C ₆ alkyl (eg, methyl, ethyl), —O—C L _S —R _E that is _1- C ₆ alkyl (eg, methoxy) or —O—C ₁ -C ₆ haloalkyl (eg, trifluoromethoxy); or L _S is a double bond, and R _E is ═C (R _S R _S ') (for example,

）であるＬ_Ｓ−Ｒ_Ｅである。好ましい実施形態では、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、０または１個のＲ_Ａで置換されたピロリジン環（すなわち、

) Is an _L S -R _E is. In a preferred embodiment, R ₂ and R ₅ together with the atoms to which they are attached are pyrrolidine rings substituted with 0 or 1 R _A (ie,

）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。好ましい他の実施形態では、Ｒ_２およびＲ_５はそれらが結合している原子と一緒になって、ピロリジン環（すなわち、

R _A is fluoro, methoxy, methyl, ethyl or cyano. In other preferred embodiments, R ₂ and R ₅ together with the atoms to which they are attached, combine to form a pyrrolidine ring (ie,

）を形成している。

) Is formed.

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

、

,

、

,

、

,

または

Or

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、

R _A is halogen (eg, fluoro, chloro); cyano; L _S is a single bond, R _E is C ₁ -C ₆ alkyl (eg, methyl, ethyl), —O—C L _S —R _E that is _1- C ₆ alkyl (eg, methoxy) or —O—C ₁ -C ₆ haloalkyl (eg, trifluoromethoxy); or L _S is a double bond, and R _E is ═C (R _S R _S ') (for example,

）であるＬ_Ｓ−Ｒ_Ｅである。好ましい実施形態では、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、０または１個のＲ_Ａで置換されたピロリジン環（すなわち、

) Is an _L S -R _E is. In a preferred embodiment, R ₉ and R ₁₂ together with the atoms to which they are attached are pyrrolidine rings substituted with 0 or 1 R _A (ie,

）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。好ましい他の実施形態では、Ｒ_９およびＲ_１２はそれらが結合している原子と一緒になって、ピロリジン環（すなわち、

R _A is fluoro, methoxy, methyl, ethyl or cyano. In other preferred embodiments, R ₉ and R ₁₂ together with the atoms to which they are attached, joins the pyrrolidine ring (ie,

）を形成している。

) Is formed.

As used herein, a chiral carbon in any ring formed by combining R ₂ and R ₅ or R ₉ and R ₁₂ has an (R) -type configuration, but also an (S) -type configuration. It may have a structure. A pyrrolidine ring formed from R ₂ and R ₅ or R ₉ and R ₁₂ (ie,

）は好ましくは（Ｓ）型立体構造（すなわち、

) Is preferably of the (S) type (ie

）を有する。

).

In this aspect of the invention, T ′ is independently at each occurrence a bond, —C (O) N (R _B ) —, —N (R _B ) C (O) —, or independently from a 3 to 12 membered heterocycle. And wherein each of the 3- to 12-membered heterocycle is optionally substituted with one or more R _A independently for each occurrence, R _A and R _B are as defined herein. . In particular, when T ′ is —C (O) N (R _B ) —, R _B may be hydrogen (ie, T ′ is —C (O) N (H) —). In certain embodiments, T ′ is imidazolyl optionally substituted with one or more R _A for each occurrence (ie,

）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。特定の実施形態では、Ｔ’はイミダゾリル（すなわち、

R _A is 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,

）である。

).

This aspect of the invention contemplates specific combinations of A and Y and B and Z. Preferred Y when A is a C ₅ -C ₆ carbocycle (eg, phenyl) or a 5 to 6 membered heterocycle (eg, pyridinyl or thiazolyl), and B is a C ₅ -C ₆ carbocycle (eg, Preferred non-limiting examples of Z when it is phenyl) or a 5 to 6 membered heterocycle (eg, pyridinyl or thiazolyl) include:

または

Or

が含まれ、ＴおよびＲ_Ｄは本明細書で定義する通りである。

And T and _RD are as defined herein.

In certain embodiments of this aspect of the invention, A is optionally substituted with one or more R _A as described herein.

であるか、またはＹ−Ａは

Or Y-A is

であり、Ｔ’が結合である好ましいＹの非限定的な例には：

Preferred non-limiting examples of Y where T ′ is a bond include:

が含まれ、ＴおよびＲ_Ｄは本明細書で定義する通りである。

And T and _RD are as defined herein.

In certain embodiments of this aspect of the invention, B is optionally substituted with one or more R _A as described herein.

であるか、またはＢ−Ｚは

Or B-Z is

であり、Ｔ’が結合である好ましいＺの非限定的な例には：ＴおよびＲ_Ｄが本明細書で定義する通りである

Non-limiting examples of preferred Z where T ′ is a bond are: T and R _D are as defined herein

が含まれる。

Is included.

T is independently a bond or —C (O) —L _S ′ — at each occurrence, and L _S ′ is as defined herein. L _S 'is not limited to these,

または

Or

が含まれ、Ｌ_Ｓ’は１つもしくは複数のＲ_Ｌで場合によって置換されており；Ｒ_Ｌは、これらに限定されないが、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）などの置換基である。

L _S 'is optionally substituted with one or more R _L ; R _L is, but is not limited to, a carbocycle (eg, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl), Substituents such as methoxy or heterocycle (eg tetrahydrofuranyl, tetrahydropyranyl).

R _D is hydrogen or _{R A} is an _{R A} is as defined herein. The thus _{R D,} but are not limited to, _{R A} is _{L S} -R _{E, L} S and _{R E} are included _{R A} is as defined herein. Therefore, _RD is not limited to these, but L _S -R _E (L _S is a bond, R _E is -N (R _S R _S '), -N (R _S ) C (O) R _S ', -N (R _S ) C (O) N (R _S ' RS "), -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 'or -N (R _S ) S (O) -R _S '; Or one or more of each independently selected from halogen, hydroxy, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ haloalkyl for each occurrence A C ₃ -C ₁₂ carbocyclic ring or a 3 to 12 membered heterocyclic ring optionally substituted with a substituent of

In one embodiment of this aspect of the invention, R _D is L _S is a bond, R _E is —N (R _S ) C, where R _S and R _S ′ are as defined herein. (O) OR _S ′ or L _S —R _E which is a 3 to 12 membered heterocyclic ring (eg, pyrrolidine, piperidine, azepanyl). For example, R _D is preferably L _S —R _E where L _S is a bond and R _E is —N (H) C (O) OMe.

Thus, according to the above description, T- _RD is not limited to:

および

and

が含まれる。Ｔ−Ｒ_Ｄは特定の立体化学的配置を含むこともでき；したがって、Ｔ−Ｒ_Ｄには、これらに限定されないが：

Is included. T- _RD may also include a specific stereochemical configuration; therefore, T- _RD includes, but is not limited to:

等が含まれる。

Etc. are included.

According to this aspect of the invention, preferred Y where A is a C ₅ -C ₆ carbocycle (eg phenyl) or a 5 to 6 membered heterocycle (eg pyridinyl or thiazolyl), and B is C _5- Non-limiting examples of preferred Z that are C ₆ carbocycles (eg, phenyl) or 5- to 6-membered heterocycles (eg, pyridinyl or thiazolyl) include:

および

and

が含まれる。

Is included.

A is optionally substituted with one or more R _A as described herein.

であり、Ｙ−Ａが

And YA is

である好ましいＹの非限定的な例には；

Non-limiting examples of preferred Y that are:

および

and

が含まれる。

Is included.

B is optionally substituted with one or more R _A as described herein.

であり、Ｂ−Ｚが

And B-Z is

である好ましいＺの非限定的な例には；

Non-limiting examples of preferred Z that are:

、

,

および

and

が含まれる。

Is included.

In yet another aspect, the invention features a salt thereof the compounds and pharmaceutically acceptable of the formula I _F:

式中：
Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_Ａで場合によって置換されており；
Ａは

In the formula:
X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more _RA ;
A is

であり、Ａは１つもしくは複数のＲ_Ａで場合によって置換されており；
Ｂは

And A is optionally substituted with one or more R _A ;
B is

または

Or

であり、Ｂは１つもしくは複数のＲ_Ａで場合によって置換されており；
Ｙ、Ｚ、Ｒ_ＡおよびＤは上記に定義した通りである（例えば、式Ｉ、Ｉ_Ａ、Ｉ_Ｂ、Ｉｃ、Ｉ_ＤまたはＩ_Ｅについて説明したような、好ましくは式Ｉ_Ｅについて説明したようなＹ、Ｚ、Ｒ_ＡおよびＤ）。

And B is optionally substituted with one or more _RA ;
Y, Z, R _A and D are as defined above (eg as described for formula I, I _A , I _B , Ic, _ID or _IE , preferably as described for formula _IE Y, Z, _RA and D).

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

であり、Ａは１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは

And A is optionally substituted with one or more _RA ; B is

であり、Ｂは１つもしくは複数のＲ_Ａで場合によって置換されており；Ｙは

And B is optionally substituted with one or more _RA ; Y is

または

Or

であり、Ｚは

And Z is

または

Or

であり；Ｄ、Ｒ_Ａ、ＴおよびＲ_Ｄは上記に定義した通りである（例えば、式Ｉ、Ｉ_Ａ、Ｉ_Ｂ、Ｉｃ、Ｉ_ＤまたはＩ_Ｅについて説明したような、好ましくは式Ｉ_Ｅについて説明したような）。

D, R _A , T, and R _D are as defined above (preferably as described for formula I, I _A , I _B , Ic, _ID, or _IE , preferably formula I _E Like explained).

In other embodiments according to this aspect of the invention, A or B are: R _A (R _A is each independently halogen (eg, fluoro, chloro)); L _S -R _E (L _S is a single bond) And R _E is —C ₁ -C ₆ alkyl (eg, methyl), —O—R _S (eg, —O—C ₁ -C ₆ alkyl, —OCH ₃ ) or one or more halogens —C ₁ -C ₆ alkyl substituted by (eg, —CF ₃ ); or L _S —R _E (L _S is C ₁ -C ₆ alkylene and R _E is —O—R _S ( For example, —C ₁ -C ₆ alkyl-O—C ₁ -C ₆ alkyl, —CH ₂ OCH ₃ ).) Optionally substituted with one or more substituents selected from form, location a and B are both 1 R _a Compounds are: compounds both A and B is substituted with zero or of R _A; A is substituted with one R _A, compound B is substituted with zero or of R _A; And A is substituted with zero R _A and B is substituted with 1 R _A. Preferably, A is

であり、Ｂは

And B is

であるか、またはＡは

Or A is

であり、Ｂは

And B is

であるか、またはＡは

Or A is

であり、Ｂは

And B is

であるか、またはＡは

Or A is

であり、Ｂは

And B is

である。

It is.

In other embodiments of this aspect of the invention, T- _RD is independently at each occurrence,

および

and

からなる群から選択され；（Ｓ）型立体構造（例えば、

Selected from the group consisting of: (S) type conformations (eg,

）を有する化合物が好ましく、ここでＤは上記定義通りである。

), Wherein D is as defined above.

In other embodiments, this aspect of the invention features a salt thereof the compounds of formula I _F and pharmaceutically acceptable:
Where
A is

であり、Ａは１つもしくは複数のＲ_Ａで場合によって置換されており；Ｂは

And A is optionally substituted with one or more _RA ; B is

であり、Ｂは１つもしくは複数のＲ_Ａで場合によって置換されており；Ｙは

And B is optionally substituted with one or more _RA ; Y is

であり；Ｚは

Z is

または

Or

であり；Ｄ、Ｒ_Ａ、ＴおよびＲ_Ｄは上記定義通りである。この実施形態による特定の下位群には、Ａが

D, R _A , T and R _D are as defined above. Specific subgroups according to this embodiment include A

または

Or

であり；Ｂが

And B is

であり；Ｙが

Y is

であり；Ｚが

And Z is

または

Or

であり；Ｔ−Ｒ_Ｄがそれぞれ独立に

T- _RDs are independent of each other

または

Or

であり；Ｄが上記定義通りである化合物が含まれる。

And compounds in which D is as defined above are included.

In yet another embodiment, this aspect of the invention features a salt thereof the compounds and pharmaceutically acceptable of the formula I _F:
Where
A and B are each

であり；ＹおよびＺはそれぞれ独立に

Y and Z are each independently

または

Or

であり；Ｄ、ＴおよびＲ_Ｄは上記定義通りである。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

D, T and R _D are as defined above. In certain subgroups according to this embodiment, each T- _RD is independently

または

Or

から選択され；Ｄが上記定義通りである化合物が含まれる。

A compound wherein D is as defined above is included.

Due to the each of the above embodiments and description of this aspect of the invention of formula I _F are the groups and subgroups of compounds having a specific value for D. Included in each of the above embodiments is a group and subgroup of compounds having the following specific values for D:
In the above embodiment and description of this aspect of the particular group, as well as the invention of the compounds 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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。

R _M 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-ethyloxetan-3-yl), - O-CH 2 -} (1,3- dioxolan-4-yl), - O-cyclopentyl, -O- cyclohexyl, -O- phenyl, -O- ( 1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, _phenyl, SF 5, _-SO 2 Me, or -N (t-Bu) C ( O) Me, D is a halogen (e.g., fluoro, Optionally substituted with one or more additional R _M selected from the group consisting of (chloro) or C ₁ -C ₆ alkyl (eg, methyl).

In another group, as well as the above embodiments and the description of the compounds according to formula I _F of this aspect of the present invention, 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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。特にこれらの群によるものは、Ｄが

And G ₂ is pyridinyl (eg, pyridin-2-yl), piperidin-1-yl, 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 2,6- Dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidine -1-yl, 4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, 3,3-dimethylazetidin-1-yl or oxazolyl (eg, 1,3-oxazol-2-yl) and D consists of halogen (eg, fluoro, chloro) or C ₁ -C ₆ alkyl (eg, methyl). It is optionally substituted with one or more additional R _M is selected from that group. Especially those by these groups, D is

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。

In 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-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidin-1-yl, 4-methylpiperidin-1 -Yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl or 3,3-dimethylazetidin-1-yl; each R _M1 is independently hydrogen, fluoro, chloro or methyl It is a compound which is.

In another group, as well as the above embodiments and the description of the compounds according to formula I _F of this aspect of the present invention, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

G ₁ is N, C—H or C—R _M ; G ₂ is

であり、

And

、Ｒ_Ｍおよびｇは上記定義通りである。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. In particular according to these groups, each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2;

は上記定義通りである。他の下位群では、Ｌ_４は結合であり；Ｇ_２は

Is as defined above. In other subgroups, 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、

Each R _M 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。他の下位群では、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-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperazin-1-yl, 4-phenylpiperidin-1-yl, 4-phenyl-3,6-dihydropyridine-1 (2H) -yl, 4,4-diphenylpiperidin-1-yl, 4-acetyl-4-phenylpiperidin-1-yl, 4- (4-methoxyphenyl) piperidin-1-yl, 4- (4-fluoro Phenyl) piperidin-1-yl or 3-phenylpiperidin-1-yl; R _M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2 It is. In 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。特定の下位群では、

Each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2; In certain subgroups,

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。化合物の他の下位群では、Ｄは

4-tosylpiperazin-1yl, 4-phenoxypiperidin-1yl, 3-phenoxypyrrolidin-1yl, 4-benzylpiperidin-1-yl, 4-phenethylpiperidin-1-yl or 3-phenylpropyl) piperidine -1-yl; each _RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In other subgroups of compounds, D is

であり、Ｇ_３は１つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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；

G ₃ is phenyl optionally substituted with one or two R _G3 ; g is 0, 1 or 2; R _M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl Or trifluoromethoxy;

およびＲ_Ｇ３は上記定義通りである。化合物の他の群では、
Ｄは

And R _G3 is as defined above. In other groups of compounds,
D is

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つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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 phenyl optionally substituted with one or two R _G3 ; g is 0 1 or 2; each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

およびＲ_Ｇ３は上記定義通りである。化合物の他の下位群では、Ｄは

And R _G3 is as defined above. In other subgroups of compounds, D is

であり、Ｇ_３は、上記で定義したような１つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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述のような、場合による置換基である。

And G ₃ is phenyl optionally substituted with one or two R _G3 as defined above; R _M1 is each independently hydrogen, fluoro, chloro or methyl; R _G2 is The group consisting of —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. Optional substituents as described above selected from

In another group, as well as the above embodiments and the description of the compounds according to formula I _F of this aspect of the present invention, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

G ₁ is N, C—H or C—R _M ; G ₂ is

であり、

And

、Ｒ_Ｍおよびｇは上記定義通りである。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. In particular, according to these subgroups, R _M is 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］ヘプタ−３−イル、２−アザビシクロ［２．２．２］オクタ−２−イル、６−アザスピロ［２．５］オクタ−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］ウンデカ−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］デカ−８−イルである。化合物の他の下位群では、Ｄは

Are 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] oct-2-yl, 6-azaspiro [2.5] oct-6-yl, octahydro- 2H-isoindol-2-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl or 1,4-dioxa-8-azaspiro [4. 5] Dec-8-yl. In other subgroups of compounds, D is

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；

G is 0, 1 or 2; each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

は上記定義通りである。化合物の他の下位群では、Ｄは

Is as defined above. In other subgroups of compounds, D is

であり；Ｒ_Ｍ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、

Each R _M is independently hydrogen, fluoro, chloro or methyl;

は上記定義通りである（例えば、３−アザビシクロ［３．２．０］ヘプタ−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］オクタ−２−イル、６−アザスピロ［２．５］オクタ−６−イル、３−アザスピロ［５．５］ウンデカ−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］デカ−８−イル）。

Are as defined above (eg 3-azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindol-2-yl, 2-azabicyclo [2.2.2] oct-2- Yl, 6-azaspiro [2.5] oct-6-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).

In another group, as well as the above embodiments and the description of the compounds according to formula I _F of this aspect of the present invention, D is

であり、

And

は１つもしくは複数のＲ_Ｇ２で置換されている単環式４員から８員の窒素含有複素環（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は出現ごとに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。上記実施形態による化合物の各群では、

Is a monocyclic 4- to 8-membered nitrogen-containing heterocycle (eg, azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R _G2 , and each R _G2 is independently halogen, 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 Each _M is 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 above embodiment,

は、１つもしくは２つの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は出現ごとにそれぞれメチル、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, pyrrolidinyl or piperidinyl substituted with 1 or 2 R _G2 , R _G2 is each occurrence of methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro or trifluoromethyl; R Each _M is 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。

Are 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4 -Fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidin-1-yl, 4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1- Yl, 2-oxopiperidin-1-yl or 3,3-dimethylazetidin-1-yl.

In yet another aspect, the invention features a salt thereof the compounds of formula I _G and pharmaceutically acceptable;

式中：
Ｘはシクロプロピル、シクロペンチルまたはシクロペンテニルであり、１つもしくは複数のＲ_Ａで場合によって置換されており；
Ａは

In the formula:
X is cyclopropyl, cyclopentyl or cyclopentenyl, optionally substituted with one or more _RA ;
A is

または

Or

であり、Ａは１つもしくは複数のＲ_Ａで場合によって置換されており；
Ｂは

And A is optionally substituted with one or more R _A ;
B is

または

Or

であり、Ｂは１つもしくは複数のＲ_Ａで場合によって置換されており；
Ｙ、Ｚ、Ｒ_ＡおよびＤは上記に定義した通りである（例えば、式Ｉ、Ｉ_Ａ、Ｉ_Ｂ、Ｉｃ、Ｉ_Ｄ、Ｉ_ＥまたはＩ_Ｆについて説明したような、好ましくは式Ｉ_Ｅについて説明したような）。

And B is optionally substituted with one or more _RA ;
Y, Z, R _A and D are as defined above (eg preferably for formula I _E as described for formula I, I _A , I _B , Ic, I _D , I _E or I _F). As explained).

In one embodiment, this aspect of the invention features a salt thereof the compounds of formula I _G and pharmaceutically acceptable: wherein: A-

または

Or

であり、Ａは１つのＲ_Ａで場合によって置換されており；Ｂは

And A is optionally substituted with one R _A ; B is

または

Or

であり、Ｂは１つのＲ_Ａで場合によって置換されており；Ｒ_Ａは、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１つもしくは複数のハロゲン（例えば、−ＣＦ_３）で場合によって置換されている−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−Ｃ_１−Ｃ_６アルキルである。）；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はそれぞれ独立に

B is optionally substituted with one R _A ; R _A is halogen (eg, fluoro, chloro); L _S -R _E (L _S is a single bond and R _E is one or —C ₁ -C ₆ alkyl (eg, methyl) optionally substituted with multiple halogens (eg, —CF ₃ ), —O—R _S (eg, —O—C ₁ -C ₆ alkyl, —OCH ₃ ) or —C ₁ -C ₆ alkyl); or L _S —R _E (L _S is C ₁ -C ₆ alkylene and R _E is —O—R _S (eg, —C ₁ -C ₆ alkyl-O—C ₁ -C ₆ alkyl, —CH ₂ OCH ₃ )); and Y and Z are each independently

または

Or

であり；Ｔ−Ｒ_Ｄはそれぞれ独立に

Each T- _RD is independently

または

Or

であり、Ｄは上記定義通りである。

And D is as defined above.

In other embodiments, this aspect of the invention features a salt thereof the compounds of formula I _G and pharmaceutically acceptable:
Where A is

であり、Ａは１つのＲ_Ａで場合によって置換されており；Ｂは

And A is optionally substituted with one R _A ; B is

であり、Ｂは１つのＲ_Ａで場合によって置換されており；Ｒ_Ａは、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１つもしくは複数のハロゲン（例えば、−ＣＦ_３）で場合によって置換されている−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−Ｃ_１−Ｃ_６アルキルである。）；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はそれぞれ独立に

B is optionally substituted with one R _A ; R _A is halogen (eg, fluoro, chloro); L _S -R _E (L _S is a single bond and R _E is one or —C ₁ -C ₆ alkyl (eg, methyl) optionally substituted with multiple halogens (eg, —CF ₃ ), —O—R _S (eg, —O—C ₁ -C ₆ alkyl, —OCH ₃ ) or —C ₁ -C ₆ alkyl); or L _S —R _E (L _S is C ₁ -C ₆ alkylene and R _E is —O—R _S (eg, —C ₁ -C ₆ alkyl-O—C ₁ -C ₆ alkyl, —CH ₂ OCH ₃ )); and Y and Z are each independently

または

Or

であり、Ｔ−Ｒ_Ｄはそれぞれ独立に

And T- _RD is independently

または

Or

であり、（Ｓ）型立体構造を有する化合物（例えば、

And a compound having an (S) type steric structure (for example,

）
が特に考慮され；Ｄは上記定義通りである。この下位群には、ＡとＢがどちらも１個のＲ_Ａで置換されている化合物；ＡとＢがどちらもゼロ個のＲ_Ａで置換されている化合物；Ａが１個のＲ_Ａで置換されており、Ｂがゼロ個のＲ_Ａで置換されている化合物；およびＡがゼロ個のＲ_Ａで置換されており、Ｂが１個のＲ_Ａで置換されている化合物が含まれる。特に、この下位群によるものには、Ａが

)
Are specifically considered; D is as defined above. This subgroup, A and B compounds are substituted both with one R _A; compound is substituted with A and B either zero or R _A; A is with one R _A is substituted, the compound B is substituted with zero or of R _a; and a is substituted by zero of R _a, B, include compounds which are substituted with 1 R _a. In particular, for this subgroup, A is

であり、Ｂが

And B is

であるか、またはＡが

Or A is

であり、Ｂが

And B is

であるか、またはＡが

Or A is

であり、Ｂが

And B is

であるか、またはＡが

Or A is

であり、Ｂが

And B is

である化合物が含まれる。

Is included.

Due to the each of the above embodiments and description of this aspect of the invention of formula I _G is the group and subgroup of compounds having a specific value for D. Included in each of the above embodiments is a group and subgroup of compounds having the following specific values for D:
Groups of compounds according to this aspect of the invention include D is C ₆ -C ₁₀ aryl (eg, phenyl, naphthyl, indanyl) or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7 - tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, a benzo [d] [1,3] dioxol-5-yl), compound D is substituted with one or more _{R M} is included. In certain subgroups according to this aspect and these embodiments, R _M is halogen (eg, fluoro, chloro, bromo); C ₁ -C ₆ alkyl (eg, tert-butyl); one or more halogen ( For example, C ₁ -C ₆ alkyl substituted with CF ₃ ); —O—C ₁ -C ₆ alkyl (eg, —O—CH ₂ CH ₃ ); each occurrence substituted with one or more halogens _-O-C 1 -C ₆ alkyl _{(e.g., -O-CF 3, -O-} CH 2 CHF 2) or _-O-C 1 -C ₆ alkyl _{(-O-CH 2 CH 2 OCH} 3); optionally —O—C ₁ -C ₆ alkyl substituted with a substituted 3 to 12 membered heterocyclic ring (eg, 3-ethyloxetane-3-yl, 1,3-dioxolan-4-yl) (eg, — O-CH ₂ ; _{R S} is optionally in the 12-membered 3- to substituted carbocyclic or heterocyclic ring (e.g., cyclopentyl, cyclohexyl, phenyl, 1,3-dioxan-5-yl) a _{-O-R S;} R S and -N (R _S ) C (O) R _S '; SF ₅ ; R _S where R _S ' is independently C ₁ -C ₆ alkyl (eg, -N (t-Bu) C (O) Me) There _-SO 2 _{R S} is _C 1 -C ₆ alkyl (e.g., _-SO 2 Me); or _C 3 _{-C 12} carbocycle (e.g., cyclopropyl, cyclohexyl, phenyl) include compounds it is. Other subgroup of this embodiment, D is phenyl optionally substituted with one or more R _M is substituted with G _2, 12 membered heterocycle G ₂ is 3- (eg , 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, —O—C 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 (R _S R _S ′) or L _4. from -G ₃ It is optionally substituted with one or more substituents-option; _{R M} is halogen (e.g., fluoro, chloro), alkyl (e.g., methyl), haloalkyl (e.g., CF _3), or _{-O-C 1} -C ₆ alkyl (e.g., -O-CH _{3) be; L 4, G 3, R} S and _{R S} 'are includes compounds defined as above.

In a particular group, as well as the above embodiments and the description of the compounds according to formula I _G of this aspect of the present invention, 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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。

R _M 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-ethyloxetan-3-yl), - O-CH 2 -} (1,3- dioxolan-4-yl), - O-cyclopentyl, -O- cyclohexyl, -O- phenyl, -O- ( 1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, _phenyl, SF 5, _-SO 2 Me, or -N (t-Bu) C ( O) Me, D is a halogen (e.g., fluoro, Optionally substituted with one or more additional R _M selected from the group consisting of (chloro) or C ₁ -C ₆ alkyl (eg, methyl).

In another group, as well as the above embodiments and the description of the compounds according to formula I _G of this aspect of the present invention, 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つもしくは複数の追加のＲ_Ｍで場合によって置換されている。特にこれらの群によるものは、Ｄが

And G ₂ is pyridinyl (eg, pyridin-2-yl), piperidin-1-yl, 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 2,6- Dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidine -1-yl, 4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, 3,3-dimethylazetidin-1-yl or oxazolyl (eg, 1,3-oxazol-2-yl) and D consists of halogen (eg, fluoro, chloro) or C ₁ -C ₆ alkyl (eg, methyl). It is optionally substituted with one or more additional R _M is selected from that group. Especially those by these groups, D is

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-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidin-1-yl, 4-methylpiperidin-1- Yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl or 3,3-dimethylazetidin-1-yl; each R _M1 is independently hydrogen, fluoro, chloro or methyl It is a certain compound.

In another group, as well as the above embodiments and the description of the compounds according to formula I _G of this aspect of the present invention, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

G ₁ is N, C—H or C—R _M ; G ₂ is

であり、

And

、Ｒ_Ｍおよびｇは上記定義通りである。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. In particular according to these groups, each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2;

は上記定義通りである。他の下位群では、Ｌ_４は結合であり；Ｇ_２は

Is as defined above. In other subgroups, 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、

Each R _M 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。他の下位群では、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-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperazin-1-yl, 4-phenylpiperidin-1-yl, 4-phenyl-3,6-dihydropyridine-1 (2H) -yl, 4,4-diphenylpiperidin-1-yl, 4-acetyl-4-phenylpiperidin-1-yl, 4- (4-methoxyphenyl) piperidin-1-yl, 4- (4-fluoro Phenyl) piperidin-1-yl or 3-phenylpiperidin-1-yl; R _M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2 is there. In 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。特定の下位群では、

Each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2; In certain subgroups,

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。化合物の他の下位群では、Ｄは

4-tosylpiperazin-1yl, 4-phenoxypiperidin-1yl, 3-phenoxypyrrolidin-1yl, 4-benzylpiperidin-1-yl, 4-phenethylpiperidin-1-yl or 3-phenylpropyl) piperidine -1-yl; each _RM is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy; g is 0, 1 or 2. In other subgroups of compounds, D is

であり、Ｇ_３は１つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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；

G ₃ is phenyl optionally substituted with one or two R _G3 ; g is 0, 1 or 2; R _M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl Or trifluoromethoxy;

およびＲ_Ｇ３は上記定義通りである。化合物の他の群では、Ｄは

And R _G3 is as defined above. In other groups of compounds, D is

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つまたは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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 phenyl optionally substituted with one or two R _G3 ; g is 0 1 or 2; each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

およびＲ_Ｇ３は上記定義通りである。化合物の他の下位群では、Ｄは

And R _G3 is as defined above. In other subgroups of compounds, D is

であり、Ｇ_３は上記で定義されるような１つもしくは２つのＲ_Ｇ３で場合によって置換されたフェニルであり；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に定義したような、場合による置換基である。

And G ₃ is phenyl optionally substituted with one or two R _G3 as defined above; R _M1 is each independently hydrogen, fluoro, chloro or methyl; R _G2 is The group consisting of —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. Optional substituents as defined above selected from

In another group, as well as the above embodiments and the description of the compounds according to formula I _G of this aspect of the present invention, D is

であり、Ｇ_１はＮ、Ｃ−ＨまたはＣ−Ｒ_Ｍであり；Ｇ_２は

G ₁ is N, C—H or C—R _M ; G ₂ is

であり、

And

、Ｒ_Ｍおよびｇは上記定義通りである。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. In particular, according to these subgroups, R _M is 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］ヘプタ−３−イル、２−アザビシクロ［２．２．２］オクタ−２−イル、６−アザスピロ［２．５］オクタ−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］ウンデカ−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］デカ−８−イルである。化合物の他の下位群では、Ｄは

Are 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] oct-2-yl, 6-azaspiro [2.5] oct-6-yl, octahydro- 2H-isoindol-2-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl or 1,4-dioxa-8-azaspiro [4. 5] Dec-8-yl. In other subgroups of compounds, D is

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；

G is 0, 1 or 2; each R _M is independently fluoro, chloro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;

は上記定義通りである。化合物の他の下位群では、Ｄは

Is as defined above. In other subgroups 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、

Each R _M1 is independently hydrogen, fluoro, chloro or methyl;

は上記定義通りである（例えば、３−アザビシクロ［３．２．０］ヘプタ−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］オクタ−２−イル、６−アザスピロ［２．５］オクタ−６−イル、３−アザスピロ［５．５］ウンデカ−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］デカ−８−イル）。

Are as defined above (eg 3-azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindol-2-yl, 2-azabicyclo [2.2.2] oct-2- Yl, 6-azaspiro [2.5] oct-6-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).

In another group, as well as the above embodiments and the description of the compounds according to formula I _G of this aspect of the present invention, D is

であり、

And

は、１つもしくは複数のＲ_Ｇ２で置換された単環式４員から８員の窒素含有複素環（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、出現ごとにそれぞれ独立に、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。上記実施形態による化合物の各群において、

Is a monocyclic 4- to 8-membered nitrogen-containing heterocycle (eg, azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R _G2 , and each R _G2 is independently halogenated 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 Each R _M is 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 above embodiment,

は１つまたは２つのＲ_Ｇ２で置換されたアゼチジニル、ピロリジニルまたはピペリジニルであり、Ｒ_Ｇ２は出現ごとにそれぞれメチル、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, pyrrolidinyl or piperidinyl substituted with 1 or 2 R _G2 , R _G2 is methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro or trifluoromethyl, respectively, on each occurrence; R _M is 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。

Are 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piperidin-1-yl, 4-methylpiperidin-1-yl, 4-tert-butylpiperidin-1 -Yl, 2-oxopiperidin-1-yl or 3,3-dimethylazetidin-1-yl.

The present invention provides a compound of formula I _E as described _herein, also salts thereof (including. For the embodiments to be described below) and a pharmaceutically acceptable compound of I _F and I _G featuring. here:
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) for each occurrence. _{S '), - S (O} ) R S, -SO 2 R S, -C (O) N (R S R S'), - N (R S) 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 (R _S ) 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, = _{(R S R} S ') or _{-C (O) N (R S} ) C (O) -R S'; or, each independently halogen at each occurrence, hydroxy, mercapto, amino, carboxy, nitro, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from phosphonoxy, phosphono, thioxo, formyl or cyano; or each independently halogen at each occurrence, 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 One or more selected from _6- haloalkynyl, —O—R _S , —S—R _S , —C (O) R _S , —C (O) OR _S or —N (R _S R _S ′) Selected from C ₃ -C ₁₂ carbocycles optionally substituted with substituents or from 3 to 12 membered heterocycles.

  The compounds of the present invention can be used in the form of salts. Depending on the specific compound, the salt of the compound is beneficial due to one or more of its physical properties, such as high drug stability under certain conditions or the desired solubility in water or oil. There is a possibility. In some cases, a salt of a compound may be useful for isolation or purification of the compound.

  Where a salt is to be administered 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 prepared 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, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic acid and sulfonic acid classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, Aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenyl acetate, mandelate, ebonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethane Sulfonate, sulfanilate, cyclohexylaminosulfonate, alginic acid, b-hydroxybutyric acid Galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, hemisulphate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, Oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, thiocyanates, tosylate and undecanoates are included.

  Pharmaceutically acceptable base addition salts include, but are not limited to, metal salts and organic salts. Non-limiting examples of suitable metal salts include alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other pharmaceutically acceptable metal salts. Such salts can be made from, but not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc. Non-limiting examples of suitable organic salts include tertiary amines such as tromethamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine and It can be made from a quaternary amine. Basic nitrogen-containing groups are alkyl halides (eg methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl and stearyl chloride / bromide / iodide), dialkyl sulfates (eg dimethyl, diethyl, dibutyl and diamyl sulfate) Can be quaternized with agents such as aralkyl halides (eg, benzyl and phenethyl bromide) and others.

  The compounds or salts of the invention are for example in the form of solvates with water (ie hydrates) or organic solvents (eg methanolate, ethanolate or acetonitrate formed with methanol, ethanol or acetonitrile, respectively). Can exist.

  The compounds or salts of the invention can also be used in the form of a prodrug. Some prodrugs are aliphatic or aromatic esters derived from acid groups on the compounds of the present invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of the present invention. Hydroxyl phosphate prodrugs are preferred prodrugs.

  The compounds of the present invention can contain asymmetrically substituted carbon atoms known as chiral centers. These compounds include, but are not limited to, a single stereoisomer (eg, single enantiomer or single diastereomer), a mixture of stereoisomers (eg, enantiomer or diastereomer). Or a racemic mixture. A compound identified herein as a single stereoisomer is substantially free of other stereoisomers (eg, substantially free of other enantiomers or diastereomers). It is meant to describe the compound that is present. “Substantially free” means that at least 80% of the compounds in the composition are the described stereoisomer; preferably, at least 90% of the compounds in the composition are described More preferably, it means that at least 95%, 96%, 97%, 98% or 99% of the compounds in the composition are the described stereoisomers. If a chiral carbon stereostructure is not specified in the chemical structure of the compound, the chemical structure is intended to encompass compounds containing any stereoisomer of the chiral center.

  Individual stereoisomers of the compounds of the present invention can be prepared using various methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in a mixture of enantiomers to diastereomers, Subsequent chromatographic separation of the diastereomers and regeneration of the individual enantiomers and enzymatic resolution are included.

  Stereospecific synthesis is generally used for suitable optically pure (enantiomerically pure) or substantially optically pure materials and for synthesis reactions that do not cause racemization or conformational changes at chiral centers. With use. For example, a mixture of stereoisomers of a compound, including a racemic mixture, obtained by a synthesis reaction can be separated by chromatographic techniques as understood by those skilled in the art. Chromatographic resolution of enantiomers can be carried out using chiral chromatography resins, many of which are commercially available. In a non-limiting example, the racemate is placed in solution and loaded onto a column equipped with a chiral stationary phase. The enantiomers can then be separated by HPLC.

  Resolution of enantiomers can also be carried out by reacting with a chiral auxiliary to convert the enantiomers in the mixture to diastereomers. 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 will form a salt or covalent bond with the chiral auxiliary. Non-limiting examples of suitable chiral auxiliaries include chirally pure amino acids, organic carboxylic acids or organic sulfonic acids. Once the diastereomers are separated by chromatography, the individual enantiomers can be regenerated. Often, the chiral auxiliary can be recovered and reused.

  Enzymes such as esterases, phosphatases or lipases can be useful for resolution of enantiomeric derivatives in enantiomeric mixtures. For example, an ester derivative of a carboxyl group in a 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, the enantiomeric salts in the mixture can be treated with a carboxylic acid with an appropriate optically pure base such as an alkaloid or phenethylamine, followed by precipitation or crystallization / recrystallization of the enantiomerically pure salt. Can be prepared using any suitable method known in the art, including Suitable methods for resolution / separation of stereoisomeric mixtures, including racemic mixtures, can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et al., 1981, John Wiley and Sons, New York, NY).

  The compounds of the present invention can contain one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as cis (Z) isomers and trans (E) isomers and mixtures thereof, are intended to be included within the scope of the referenced compound, unless otherwise specified. . Further, when a compound exists in various tautomeric forms, the referenced compound is not limited to any one particular tautomer, but is intended to encompass all tautomeric forms.

  Certain compounds of the present invention can exist in different stable conformational forms that can be separated. For example, torsional asymmetry due to constrained rotation around an asymmetric single bond due to steric hindrance or ring strain can make different conformers separable. The present invention includes each conformational isomer of these compounds and mixtures thereof.

  Certain compounds of the present invention may exist in zwitterionic form and the present invention includes each zwitterionic form of these compounds and mixtures thereof.

The compounds of the invention are generally described herein using standard nomenclature. It should be understood that for reference compounds having asymmetric centers, unless otherwise specified, all stereoisomers of the compounds and mixtures thereof are encompassed by the present invention. Non-limiting examples of stereoisomers include enantiomers, diastereomers and cis-trans type isomers. Where the referenced compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms. Specific compounds are used herein with general formulas that include variables (eg, A, B, D, X, L ₁ , L ₂ , L ₃ , Y, Z, T, R _A or R _B ). Described. Unless otherwise specified, each variable in such an expression is defined independently of any other variable, and any variable that occurs more than once in the expression is defined independently for each occurrence. Where parts are described as being “independently” selected from a group, each part is selected independently of each other. Accordingly, each portion may be the same as or different from one or more other portions.

The number of carbon atoms in the hydrocarbyl moiety can be represented by the prefix “C _x -C _y ”. Here, x is the minimum number of carbon atoms in the portion, and y is the maximum number of carbon atoms. Thus, for example, “C ₁ -C ₆ alkyl” refers to an alkyl substituent containing from _{1 to 6} carbon atoms. Further To illustrate, C ₃ -C ₆ cycloalkyl means a saturated hydrocarbyl ring containing 3-6 carbon ring atoms. A prefix attached to a substituent of more than one component applies only to the first component that immediately follows that prefix. Illustratively, the term “carbocyclylalkyl” includes two components: carbocyclyl and alkyl. Thus, for example, _C 3 -C ₆ carbocyclyl _C 1 -C ₆ alkyl _refers to a _C 3 -C ₆ carbocyclyl appended to the parent molecular moiety through a C 1 -C ₆ alkyl group.

Unless otherwise specified, when a linking element is linked to two other elements in the indicated chemical structure, the leftmost component of that linking element is the left side of the indicated structure. The rightmost component of the connecting element is connected to the right element in the structure shown. 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 '-.

When the connecting element in the structure shown is a bond, the element to the left of the connecting element is directly connected to the element to the right of the connecting element via a covalent bond. For example, the chemical structure is _{-L S -M-L} S '- denoted as, if M is selected as the binding, its chemical structure is _{-L S -L} S' - a. When two or more adjacent connecting elements in the structure shown are bonds, the elements to the left of these connecting elements are directly connected to the elements to the right of these connecting elements via a covalent bond . For example, the chemical structure is _{-L S -M-L S '-M'} -L S "- is expressed as, M and _{L S'} If is selected as the binding, its chemical structure is _-L S -M'- L _S ″ −. Similarly, the chemical structure is _{-L S -M-L S '-M'} -L S "- is expressed as, M, _{L S'} and when M 'is a bond, its chemical structure is _-L S -L _S "-.

  When a chemical formula is used to describe a part, a dash represents a portion of the moiety having a free valence.

  Where a moiety is described as “optionally substituted”, the moiety may be substituted or unsubstituted. If a moiety is described as being optionally substituted with up to a certain number of non-hydrogen groups, the moiety may be unsubstituted or up to that particular number of non-hydrogen groups or moieties May be replaced up to the maximum number of replaceable positions, whichever is smaller. Thus, for example, if a moiety is described as a heterocycle optionally substituted with up to three non-hydrogen groups, any heterocycle having no more than two substitutable positions is substituted by that heterocycle It will be optionally substituted with as many non-hydrogen groups as there are possible positions. To illustrate, tetrazolyl (which has only one substitutable position) will be optionally substituted with up to one non-hydrogen group. To further illustrate, when an amino nitrogen is described as optionally substituted with up to two non-hydrogen groups, the primary amino nitrogen is optionally substituted with up to two non-hydrogen groups. On the other hand, the secondary amino nitrogen will be optionally substituted with at most one non-hydrogen group.

  The term “alkenyl” refers to a straight or branched hydrocarbyl chain containing one or more double bonds. Each carbon-carbon double bond may have a cis configuration or a trans configuration in the alkenyl moiety relative to the group substituted on the double bond carbon. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl. .

The term “alkenylene” refers to a diunsaturated hydrocarbyl chain that may be linear or branched and that contains at least one carbon-carbon double bond. Non-limiting examples of alkenylene groups, -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 ) — is included.

  The term “alkyl” means a linear or branched saturated hydrocarbyl chain. Non-limiting examples of alkyl groups include 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 may be linear or branched. Representative examples of alkylene include, but are not limited _{to, -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 — is included.

  The term “alkynyl” refers to a straight or branched hydrocarbyl chain containing one or more triple bonds. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl and 3-butynyl.

The term “alkynylene” refers to a diunsaturated hydrocarbon group that may be linear or branched and has at least one carbon-carbon triple bond. Representative examples of alkynylene groups include, for example _{-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 ) — are included.

  The term “carbocycle”, “carbocycle” or “carbocyclyl” includes saturated (eg, “cycloalkyl”), partially saturated (eg, “cycloalkyl”) containing zero heteroatom ring atoms. “Cycloalkenyl” or “cycloalkynyl”) or a fully unsaturated (eg, “aryl”) ring system. “Ring atoms” or “ring members” are atoms that are joined together to form one or more rings. A carbocyclyl may be, but is not limited to, a single ring, two fused rings, or a bridged or spiro ring. The substituted carbocyclyl may have a cis configuration or a trans configuration. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro -Indenyl, cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl and norpinanyl. A carbocyclic group may be attached to the parent molecular moiety through any substitutable carbon ring atom. When a carbocyclic group is a divalent moiety that connects to the other two elements in the indicated chemical structure (eg, A in Formula I), the carbocyclic group has two optional substitutable ring atoms. It may be combined with the other two elements via Similarly, when a carbocyclic group is a trivalent moiety (eg, X in Formula I) that connects to the other three elements in the indicated chemical structure, each carbocyclic group can be replaced with any three optional substituents. It may be linked to the other three elements through a ring atom.

The term “carbocyclylalkyl” refers to a carbocyclyl group appended to the parent molecular moiety through an alkylene group. For _example, C 3 -C ₆ carbocyclyl _C 1 -C ₆ alkyl _refers to a _C 3 -C ₆ carbocyclyl group appended to the parent molecular moiety through a C 1 -C ₆ alkylene.

  The term “cycloalkenyl” refers to a non-aromatic, partially unsaturated carbocyclyl 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 carbocyclyl group containing zero heteroatom ring members. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.

The prefix “halo” indicates that the substituent to which the prefix is attached 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 with independently selected halogen groups. Non-limiting examples of C ₁ -C ₆ haloalkyl include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl. It should be understood that when a substituent is substituted with more than one halogen group, the halogen groups may be the same or different (unless otherwise stated).

  The term “heterocycle”, “heterocyclo” or “heterocyclyl” means that at least one of the ring atoms is a heteroatom (ie, nitrogen, oxygen or sulfur) and the remaining ring atoms are from carbon, nitrogen, oxygen and sulfur. A saturated (eg, “heterocycloalkyl”), partially unsaturated (eg, “heterocycloalkenyl” or “heterocycloalkynyl”) or fully unsaturated (eg, “heteroaryl”) ring independently selected from the group Refers to the system. Heterocycles may be, but are not limited to, a single ring, two fused rings, or a bridged or spiro ring. The heterocyclic group may be linked to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. When a heterocyclic group is a divalent moiety (eg, A in Formula I) that connects to the other two elements in the indicated chemical structure, the heterocyclic group contains two optional substitutable ring atoms. It may be combined with the other two elements via Similarly, when a heterocyclic group is a trivalent moiety (eg, X in Formula I) that connects to the other three elements in the indicated chemical structure, each of the heterocyclic groups can be optionally substituted in any of three It may be linked to the other three elements through a ring atom.

  A heterocyclyl may be a monocycle including but not limited to a monocycle. Non-limiting examples of monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl , Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (1,2,4-oxadiazolyl, 1,2,4-oxadiazolyl (also known as “azoxymil”) ), 1,2,5-oxadiazolyl (also known as “furazanyl”) and 1,3,4-oxadiazolyl. ), Oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl and 1,3,4-dioxazolyl.), Oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyrani , Pyridinyl, piperidinyl, diazinyl (also known as pyridazinyl (also known as “1,2-diazinyl”), pyrimidinyl (also known as “1,3-diazinyl”) and pyrazinyl (“1,4-diazinyl”). ), Piperazinyl, triazinyl ((s-triazinyl ("1,3,5-triazinyl" and Oxazinyl, including as-triazinyl (also known as 1,2,4-triazinyl) and v-triazinyl (also known as “1,2,3-triazinyl”). (1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as “pentoxazolyl”), 1,2,6-oxazinyl and 1,4 -Oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl ), Oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl). ), Morpholinyl, azepinyl, oxepinyl, thiepinyl, thiomorpholinyl and diazepinyl.

  Heterocyclyl also includes, but is not limited to, two rings containing two fused rings, such as naphthyridinyl (including [1,8] naphthyridinyl and [1,6] naphthyridinyl), thiazolepyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl , Pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyridinyl, pyranopyrrolyl, 4H-quinolidinyl, purinyl, pyridopyridinyl (pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl and pyrido [4,3 -B] -pyridinyl), pyridopyrimidine and pteridinyl. Other non-limiting examples of fused-ring heterocycles include benzo-fused heterocyclyl, such as indolyl, isoindolyl, indolenyl (also known as “pseudoindolyl”), isoindazolyl (“benzpyrazolyl” or indazolyl). Benzazinyl (also known as “1-benzazinyl”) and isoquinolinyl (also known as “2-benzazinyl”)), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl. (Including cinnolinyl (also known as “1,2-benzodiazinyl”) and quinazolinyl (also known as “1,3-benzodiazinyl”)), benzopyranyl (including “chromenyl” and “isochromenyl”). ), Benzo Opyranyl (also known as “thiochromenyl”), benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxanyl, Benzooxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothienyl (also known as “benzothiophenyl”, “thionaphthenyl” and “benzothiofuranyl”), Isobenzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl” and “isobenzothiofuranyl”), benzothiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo Thiadiazolyl, benzimidazolyl, benzotriazolyl Benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl and 3,1,4-benzoxazinyl ), Benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl) and tetrahydroisoquinolinyl.

  Heterocyclyl may be, but is not limited to, a spiro ring system such as 1,4-dioxa-8-azaspiro [4.5] decanyl.

A heterocyclyl can contain one or more sulfur atoms as ring members; in some cases, the sulfur atom is oxidized to SO or SO ₂ . The nitrogen heteroatom in the heterocyclyl may or may not be quaternized and may or may not be oxidized to N oxide. Furthermore, the nitrogen heteroatom may or may not be N-protected.

  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 as an adjective, meaning that the modified noun is suitable for use as a medicament or as part of a medicament.

  The term “therapeutically effective amount” refers to the total amount of each active agent that is sufficient to show a meaningful patient benefit, eg, a reduction in viral load.

  The term “prodrug” has a group that is chemically or metabolically cleavable and becomes a compound of the invention that is pharmaceutically active in vivo under solvolytic or physiological conditions. A derivative of Prodrugs of a compound can be formed in a conventional manner by reaction of the functional group of the compound (such as an amino, hydroxy or carboxy group). Prodrugs often provide the advantage of solubility, histocompatibility or delayed release in mammals (see Bungard, H., DESIGN OF PRODRUGS, 7-9, pp. 21-24, Elsevier, Amsterdam 1985). .) Prodrugs include, for example, acid derivatives well known to those skilled in the art, such as esters prepared by reaction of an acidic compound with an appropriate alcohol, or amides prepared by reaction of an acidic compound with an appropriate amine. Is included. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amine functional groups in the compounds of the present invention.

  The term “solvate” refers to a physical association of a compound of the invention with one or more solvent molecules that are organic or inorganic. This physical bond often includes hydrogen bonds. In certain cases, for example, if one or more solvent molecules are incorporated into the crystalline lattice of a crystalline solid, the solvate can be isolated. “Solvate” encompasses both solution-phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates and methanolates.

  The term “N-protecting group” or “N-protected” refers to a group capable of protecting an amino group against undesired reactions. Commonly used N-protecting groups are described in Greene and Wuts, PROTECTIVE GROUPS in ORGANIC SYNTHESIS (3rd ed., John Wiley & Sons, NY (1999). Non-limiting examples of N-protecting groups include: An acyl group such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl or 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or Liphenylmethylsulfenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S (O)-) or t-butylsulfinyl (t-Bu-S (O)-); Carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethyl Toxibenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, Ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl; alkyl Groups such as benzyl, p-methoxybenzyl, triphenylmethyl or benzyloxymethyl; Alkenyl; and silyl groups such trimethylsilyl. Preferred N protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

Abbreviations used in the following scheme, intermediate and example descriptions are: Ac is acetyl; aq or aq. Boc is t-butoxycarbonyl; Bu is butyl; n-Bu or n-butyl; t-Bu or tert-butyl or tert-butyl; Cbz is benzyloxycarbonyl; DCI is elimination chemical ionization; DEPBT is 3 -(Diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) -one; DME is 1,2-dimethoxyethane; DMF is N, N-dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1 , 1'-bis (diphenylphosphino) ferrocene; EDC, EDAC or EDCI is N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; ESI is electrospray ionization; Et is ethyl; EtOAc is ethyl acetate EtOH is ethanol; Et ₂ O is diethyl Eq or equiv is equivalent; Fmoc is 9-fluorenylmethoxycarbonyl; HATU is O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluoro HMDS is hexamethyldisilazane; HOBt is 1-hydroxybenzotriazole; HPLC is high performance liquid chromatography; LCMS is liquid chromatography / mass spectrometry; Me is methyl; MeOH is methanol; NBS is N-bromosuccinimide; OAc is OTf is triflate or trifluoromethanesulfonate; PA-Ph is 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane; Ph is phenyl; psi or psig Is pound Square inch (gas); PyBOP® is (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; SEM is 2- (trimethylsilyl) ethoxymethyl; T3P is propanephosphonic anhydride; Tf is trifluoro TFA is trifluoroacetic acid; THF is tetrahydrofuran; Troc is 2,2,2-trichloroethoxycarbonyl; v / v is volume / volume; wt% is weight percent; and w / v is weight / volume.

As another non-limiting example, the compounds of the invention can be prepared as shown in Scheme I. Add a diamine (I-1) to an amine base such as Hunig's base, pyridine, 2,6-lutidine, 4-methylmorpholine or triethylamine in a solvent such as tetrahydrofuran, N, N-dimethylformamide, dichloromethane or dimethyl sulfoxide. However, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole [EDAC / HOBT], (benzotriazol-1-yl-oxy) tripyrrolidinophosphonium hexafluorophosphate [PyBOP®], O- (7-azazenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate [HATU] or 3- (diethoxyphosphoryl) Oxy) -1, , 3-benzotriazin-4 (3H) -one [DEPBT], in the presence of a peptide coupling reagent, shows a suitably protected prophosphoric acid [t-butoxycarbonyl (Boc), but benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc) or 9-fluorenylmethoxycarbonyl (Fmoc) may be substituted] to produce (I-2). . Reaction of an aldehyde of formula (I-3) with a trialkyltin anion such as tri-n-butyltin in an organic solvent such as tetrahydrofuran, dioxane or dichloromethane followed by reaction with a chloroformate such as methyl chloroformate (wherein, R _P is alkyl (methyl, ethyl, etc.), benzyl (e.g., benzyl, 4-methoxy-ben hexyl, etc.), trialkylsilyl (e.g., a non-electron withdrawing substituent such as triisopropylsilyl) R ′ is an alkyl group; R _A is alkyl, alkoxy, halo, haloalkyl or haloalkoxy and n is 0, 1, 2, 3 or 4.) represents a compound of formula (I-4) Can bring. Alkene (I-2) is prepared in the presence of a suitable acid such as toluenesulfonic acid or other reagents such as boron trifluoride etherate in an organic solvent such as dichloromethane or toluene. Reaction with a compound of (I-4) can produce a cyclopropane compound of formula (I-5) [Sugawara, M .; Et al. Am. Chem. Soc. 1997, 119, 11986]. Removal of the t-butoxycarbonyl (Boc) protecting group to give (I-6) can be carried out by treatment with an acid such as trifluoroacetic acid, HCl or formic acid. Compound (I-7) of the present invention, where T and _RD are as described above, can be coupled to (I-6) with an optimal acid using standard peptide coupling reagents and conditions described above. Can be prepared.

The present invention optionally substituted with 1, 2, 3 or 4 groups R _A , where R _A and R _P are as defined in Scheme I and R _D and T are as described above Certain compounds (II-7) can be prepared according to the general method illustrated in Scheme II.

Dibromostilbene (II-1) is reacted with bis (pinacolato) diboron with potassium acetate in a solvent such as but not limited to toluene at a temperature of about 80 ° C. to about 120 ° C. to give an alkene (II-2). ) Can be obtained. The alkene (II-2) is converted to 1 to 5 equivalents or more in an organic solvent such as dichloromethane or toluene in the presence of a suitable acid such as toluenesulfonic acid or other reagents such as boron trifluoride etherate. By reacting with the compound of (1-4), the cyclopropane compound of the formula (II-3) can be obtained. The cyclopropane compound (II-3) can be reacted with bromoimidazole (II-4) in which P ₁ is a nitrogen protecting group using Suzuki reaction conditions to give phenylimidazole (II-5). Various reaction conditions that are effective in mediating the Suzuki reaction are well known to those skilled in the art. In particular, the reaction of (II-3) and (II-4) to produce (II-5) is carried out in a mixture of toluene and water with [1,1′-bis (diphenylphosphino) ferrocene. ] Using dichloropalladium (II) [Pd (dppf) Cl ₂ ] catalyst and potassium carbonate, heating to about 100 ° C can be performed. Removal of the protecting group to obtain (II-6) is known to those skilled in the art and can be accomplished using methods that depend on the particular protecting group used. Compound (II-7) of the present invention, wherein T and _RD are as described above, is prepared from (II-6) and an appropriately functionalized amino acid derivative using standard peptide coupling reagents and conditions described above. Can be prepared by coupling.

Intermediates of general formula (II-4) where P ₁ is a nitrogen protecting group as described above can be prepared using the general method in Scheme III.

For example, using a well-known method such as reacting alcohol (III-1) with Dess-Martin periodinane in a solvent such as but not limited to dichloromethane in the presence of sodium bicarbonate, alcohol (III -1) can be oxidized to aldehyde (III-2). Compound (III-2) can be reacted with glyoxal and ammonium hydroxide in methanol / water to give (III-3). Next, compound (III-3) is brominated with N-bromosuccinimide in a solvent such as but not limited to dichloromethane at a temperature of 0 ° C. to room temperature to obtain (III-4). Can do. Compound (III-4) is monodebrominated by reacting with sodium sulfite (Na ₂ SO ₃ ) in a mixture of dioxane and water with heating under reflux to obtain intermediate (II-4) Can do. Although no specific stereochemistry is specified for intermediate (II-4), (II-4) is prepared as a racemate or a single enantiomer (R or S stereochemistry) using the chemical methods described above. it can. Selecting the (R) or (S) stereochemistry of the starting alcohol (III-1) leads to compounds of the invention having a single absolute stereochemistry at the corresponding carbon of the final compound.

  Benzimidazole derivatives of general structural formula (VI-2) can be prepared by the synthetic sequence summarized in Schemes IV-VI. As shown in Scheme IV, the required stilbene derivative (IV-6) can be prepared by converting bromide (IV-1) to di-tert-dicarbonate in the presence of a suitable base such as but not limited to aqueous sodium bicarbonate. Can be prepared starting from treatment with butyldi to obtain bis-t-butoxycarbonyl protection (IV-2). Bromide (IV-2) with a suitable copper catalyst such as bis (triphenylphosphine) palladium (II) chloride under Sonogashira conditions, a copper salt such as but not limited to copper (I) iodide and Reacting with an acetylene derivative such as trimethylsilylacetylene in the presence of a suitable amine base such as triethylamine or diisopropylamine. The acetylene (IV-3) thus obtained is then treated with a base in a suitable alcohol such as potassium carbonate or potassium hydroxide or with fluoride ions in the form of tetrabutylammonium fluoride. To obtain the acetylene derivative (IV-4). Hydroboration of (IV-4) with diisopinocinfeylborane followed by reaction of the resulting trialkylborane with an aldehyde such as acetaldehyde and hydrolysis of the dialkylborate in water yields the boronate (IV -5) is prepared to give the boronic acid (IV-5). The stilbene (IV-6) is then preferably combined with a phosphine ligand in the presence of an aqueous base such as tripotassium phosphate, potassium carbonate, in a suitable solvent such as tetrahydrofuran, dimethoxyethane, and preferably Cytec® phenylphospha With adamantyl ligand (PA-Ph) (Adjabeng, J. et al., Org. Lett. 2003, 5, 953; Adjabeng, J. et al., J. Org. Chem. 2004, 69, 5082), Suzuki of boronic acid (IV-5) and bromide (IV-2) catalyzed by either a palladium (II) salt or a palladium (0) source such as tris (dibenzylideneacetone) dipalladium (0) It can be obtained from the Miyaura coupling.

  As shown in Scheme V, stilbene (IV-6) is then converted to stannane (I-4) in a solvent such as toluene or dichloromethane (or mixtures thereof) in the presence of a Lewis acid such as boron trifluoride etherate. ) To obtain cyclopropane (V-1). The cyclopropane derivative (V-1) can be converted to the benzimidazole ring system according to the order of conversion summarized in Schemes V and VI. Tetraamine (V-2) is obtained by treating (V-1) under some acidic conditions known to those skilled in the art. Tetraamine (V-2) is preferably O- (7-azabenzotriazol-1-yl) -N, N, N which is a coupling agent in the presence of an amine base such as diisopropylethylamine or N-methylmorpholine. Two equivalents of appropriately protected prophosphoric acid (t-butoxy) using ', N'-tetramethyluronium hexafluorophosphate (HATU) or using other coupling agents known to those skilled in the art. Carbonyl (Boc) is shown, and other protecting groups such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl are also useful) to couple the two regioisomeric anilides (V- 3) and (V-4) can be obtained. The regioisomeric anilide is not separated, but directly to (V-6) by treatment with 5-10 equivalents of glacial acetic acid in toluene or tetrahydrofuran (or mixtures thereof) at temperatures in the range of 50-85 ° C. Cyclize.

Benzimidazole (V-6) can be converted to a representative compound of the invention by the order of conversion shown in Scheme VI. As shown, the two t-butoxycarbonyl (Boc) protecting groups are removed by treating (V-6) with a suitable acid to give the diamine (VI-1). The diamine (VI-1) is then coupled with 2 equivalents of an appropriately functionalized amino acid derivative by using amino acid coupling methods known to those skilled in the art to obtain R _A and R _P as a scheme. The final benzimidazole derivative (VI-2) can be obtained, as defined in I, where n, _RD and T are as defined above.

Additional compounds of the invention can be prepared according to the methods outlined in Scheme VII. Compound (VII-1), in which R is a group such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, methyl, triisopropylsilyl, etc., is a known standard condition for removing these groups from phenolic oxygen. Can be converted to compound (VII-2). For example, when R is benzyl or methyl, (VII-1) can be converted by treatment with BBr ₃ in (VII) -2. When R is triisopropylsilyl, (VII-1) can be converted to (VII-2) by reacting with a fluoride source. Compound (VII-2) can be converted to Compound (VII-3) by reacting with a triflate source such as trifluoromethanesulfonic anhydride. Compound (VII-3) can be converted to further compounds of the invention using well-known organic transformations of aromatic triflate such as Suzuki, Sonogashira or Buchwald reaction. Using Suzuki reaction, (VII-3), 1- cyclohexen - yl - but boronic acid pinacol ester or other boronic acid / ester, and the like, but not limited to, an appropriate boronic acid or ester R ₁₀₀ B (OR ′) ₂ (wherein R ′ is hydrogen, alkyl, or together with the oxygen atom and the adjacent boron atom to which they are attached, forms dioxaborolane or dioxaborinane). , Palladium sources and phosphine ligands (eg PdCl ₂ [dppf] ₂ ) and bases (eg triethylamine, sodium carbonate, potassium carbonate, potassium phosphate, sodium bicarbonate) in the presence of DME and water, etc. Reacting at a temperature of about 80 ° C. to about 100 ° C. in a non-limiting solvent; Can convert the compound into a compound (VII-4) in which R ₁₀₀ is a group such as alkenyl, aryl, heteroaryl or cycloalkenyl. Compounds derived from the Suzuki reaction using alkeneboronic acid / ester or cycloalkenylboronic acid / ester and having an alkene in the R ₁₀₀ group (VII-4) can be obtained by reacting an alkene present in R ₁₀₀ (eg, catalytic Reduction by mechanical hydrogenation), the compounds of the invention can be further prepared. Various reaction conditions that are effective in mediating the Suzuki reaction are well known to those skilled in the art. Obtaining compound (VII-4) having heteroaryl, heterocyclic or aryl group at R ₁₀₀ from other substrates utilized for Suzuki reaction such as aromatic, heteroaromatic or heterocyclic boronate or boronic acid Can do. An appropriately substituted amine is coupled with triflate (VII-3) in a Buchwald-type reaction to give compound (VII-5), wherein R ₁₀₁ and R ₁₀₂ are each alkyl or they are bonded. Together with the nitrogen atom being formed to form a heterocycloalkyl). Appropriate conditions effective for this transformation can be found in the following references: Wolfe and Buchwald, J. et al. Org. Chem. 1997, 1264-1267; Louie et al., J. Biol. Org. Chem. 1997, 1268-1273; Peng, T .; Yang, D .; , Organic Lett. 2010, 12, 496-499; Hartwig, J. et al. F. Handbook of Organopalladium Chemistry for Organic Synthesis; Ed., Wiley-Interscience: New York, 2002, 1051-1096; Muci, A. et al. R. Buchwald, S .; L. , Top. Curr. Chem. 2002, 219, 131-209; Jiang, L .; Buchwald, S .; L. , Metal-Catalyzed Cross-Coupling Reactions; De Meijere, A .; Diederich, F .; Ed., Wiley-VCH: New York, 2004; 699-760 and references cited therein. Further, the substituted alkyne can be coupled with (VII-3) by Sonogashira reaction to give compound (VII-6) wherein R ₁₀₃ is aryl or heteroaryl.

Additional compounds of the invention can be prepared according to the methods outlined in Scheme VIII. J. et al. Org. Chem. Compound (VIII-1) can be converted to compound (VIII-2) as described in 2002, pages 5993-6000. Compound (VIII-2) is described in J. Org. Org. Chem. Suzuki reaction with an appropriate boronic acid or ester using conditions such as those described in 2002, pages 5993-6000 or conditions generally known in the art, give compound (VIII-3). Can be converted. Either aryl or heteroaryl boronic acids or esters can be used (the product of reaction with phenylboronic acid is shown in Scheme VIII). J. et al. Org. Chem. 2002, as further described on pages 5993-6000, compound (VIII-3) can be converted to the compound (VIII-4) by reaction with PBr _3. Compound (VIII-4) is obtained using Suzuki reaction conditions (see, for example, J. Chem. Soc. Chem. Commun. (1994) 2305-2306; Org. Lett. (1999) 1839-1842). By reacting with 4- (tert-butoxycarbonylamino) phenylboronic acid or tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbamate Can be converted to compound (VIII-5). Compound (VIII-5) was prepared according to Aust. J. et al. Chem. (1997) 149-152; Med. Chem. (1976) 414-419 (see bottom of Table III on page 417); and Org. Lett. (2009) pages 5450-5453 and supplemental information can be converted to compound (VIII-6) by catalytic hydrogenation using PtO ₂ or Pd / C as described for enone reduction. Compound (VIII-6) can be obtained from the following reference: Ang. Chem. Int. Ed. Eng. (2005) pages 403-406 and supplemental information; Med. Chem. (2008) pages 8077-8087 (see Scheme 2 step iv) and supplemental information, treatment with base (eg NaH, LiHMDS, KHMDS) followed by reaction with (Tf) ₂ NPh. Thus, the compound can be converted to compound (VIII-7). Instead, compound (VIII-5) was prepared according to the following reference: Org. Chem. (2007) page 4616 and supplemental information, see page S33; see also WO20070444174, page 25; http: // en. wikipedia. org / wiki / L-selectide, as described in, reduced using L-selectride or sodium selectride, followed by enolate formed in situ using (Tf) ₂ NPh or Comins reagent Can be directly converted to compound (VIII-7). Compound (VIII-7) can be converted to compound (VIII-8) by Suzuki reaction using the appropriate boronic acid or ester as described above or as generally known in the art. Compound (VIII-8) can be converted to compound (VIII-9) by Boc removal using standard conditions such as TFA / CH ₂ Cl ₂ or HCl in dioxane. Compound (VIII-9) is a peptide in a solvent such as THF, DMF, dichloromethane or DMSO, with or without the addition of an amine base such as N-methylmorpholine, Hunig base, pyridine, 2,6-lutidine or triethylamine. Using standard amine bond formation techniques such as using coupling reagents (eg, EDAC / HOBT, PyBOP®, HATU, T3P or DEPBT), (S) -1- (tert-butoxycarbonyl) pyrrolidine By reacting with -2-carboxylic acid, it can be converted to compound (VIII-10). Compound (VIII-10) can be converted to compound (VIII-11) using the Boc removal conditions mentioned above. Compound (VIII-11) is prepared from 2- (methoxycarbonylamino) -3-methylbutanoic acid, 2- (methoxycarbonylamino) -3,3-dimethylbutanoic acid using the standard amine bond formation conditions referred to above. Reaction with a suitable carboxylic acid such as, but not limited to, 2-cyclohexyl-2- (methoxycarbonylamino) acetic acid, 2- (methoxycarbonylamino) -2- (tetrahydro-2H-pyran-4-yl) acetic acid Can be converted to compound (VIII-12). Compound (VIII-12) is obtained by catalytic hydrogenation using a catalyst such as PtO ₂ or Pd / C in a typical organic solvent (eg, ethyl acetate, methanol, etc.) under 1-4 atmospheres of hydrogen. It can be converted to (VIII-13).

  By analogy with the method outlined in Scheme VIII, further compounds of the invention can be prepared according to the method outlined in Scheme IX. Compound (IX-2) can be obtained by reacting compound (VIII-4) with compound (IX-1) under standard Suzuki conditions. Compound (IX-2) is converted to Compound (IX-3) using conditions and steps similar to those in Scheme VIII used for the conversion of (VIII-5) to (VIII-8). it can. Alternatively, (IX-1) and (IX-2) benzimidazoles can be protected as SEM derivatives. Compound (IX-3) can be converted to compound (IX-4) by deprotection and reaction with an appropriate acid in the same manner as in Scheme VIII, which converts (VIII-10) to (VIII-12). The compound can be obtained by conversion. Compound (IX-4) can be converted to (IX-5) by catalytic hydrogenation, similar to the conversion of (VIII-12) to (VIII-13).

  By analogy with the methods outlined in Schemes VIII and IX, further compounds of the invention can be prepared according to the methods outlined in Scheme X. Compound (VIII-4) can be reacted with compound (X-1) under standard Suzuki conditions to give compound (X-2). Compound (X-2) is converted to Compound (X-3) using conditions and steps similar to those in Scheme VIII used for the conversion of (VIII-5) to (VIII-8). it can. Compound (X-3) can be converted to compound (X-4) having either a cyclopentene or cyclopentane core, similar to the methods of Schemes VIII and IX.

  The foregoing schemes VIII, IX and X show, by way of example, the synthesis of compounds of the invention having a 5-membered carbocyclic core. As will be readily apparent to those skilled in the art, these methods are modified to include 2-bromo-3-ethoxycyclohex-2-enone (see J. Org. Chem. 1990, pages 4025-33) or 3- By selecting appropriate starting materials such as but not limited to ethoxycyclohept-2-enone (see Helv. Chim. Acta, 2010, pages 17-24, Synthesis, 1995, pages 1432-4) Compounds with 6 or 7 membered carbocyclic cores can also be prepared. Scheme VIII-X above can be modified to produce compounds of the invention in which different groups are adjacent to the central core by appropriate selection of distinguishable boronic acids or esters for each Suzuki reaction. . For example, compounds can be prepared having a benzimidazole moiety on one side and phenylimidazole on the other side, benzimidazole on the other side, phenylamide on the other side, phenylamide on the other side and phenylimidazole on the other side.

Compound (XI-1), wherein X ₁₃ is alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, etc. is converted to an acid (eg, (S) -1- (tert-butoxycarbonyl) using the peptide coupling procedure described above. Pyrrolidine-2-carboxylic acid) to give the amide, which can be heated to about 100 ° C. in acetic acid to give (XI-2). Compound (XI-2) can be reacted with SEM-Cl and diisopropylethylamine in dichloromethane to give (XI-3). For convenience, the SEM protecting group on benzimidazole is shown to be attached to a specific nitrogen of benzimidazole. The actual substitution position of the SEM group may be on any nitrogen (ie (XI-3) may be a mixture of regioisomers). In subsequent compounds, the positional isomerism of the SEM group results in a mixture of SEM positional isomers that can or cannot be separated. Indeed, SEM regioisomers can be a mixture to the end. Compound (XI-2) and each of (XI-3), a base such as potassium _acetate, PdCl 2 (dppf) the presence of a catalyst such as _-CH 2 Cl _2, DMSO, in a solvent such as dimethoxyethane or dioxane, It can be converted into the corresponding pinacol boronate by reacting with bis (pinacolato) diboron while heating between 60-100 ° C.

Compound (VIII-2) can react with various boronic acids or esters as described above. Certain boronic acids suitable for reaction with (VIII-2), wherein q is 0, 1 or 2, and R _A is halo, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, and the like; n is 0, 1, 2, 3 or 4.) can be prepared as outlined in Scheme XII. Bromoaniline is generally reacted with a dihaloalkane (eg, 1,5-dibromopentane) while heating to about 50-100 ° C. in a solvent such as benzene, toluene, DMF, etc. to give azetidine, pyrrolidine, piperidine, etc. (See J. Org. Chem. 1984, 269-276; J. Org. Chem. 1983, 4649-4658). Next, these products are reacted with a base such as KOAc, a palladium catalyst such as bis (pinacolato) diboron, PdCl ₂ (dppf) while heating to about 50-100 ° C. in a solvent such as DMSO. Can be converted to the corresponding pinacol boronate.

An alternative to the procedure in Scheme VIII for converting a compound of formula (VIII-5) to a compound of formula (VIII-12) is described in Scheme XIII. A compound of formula (VIII-5) can be hydrogenated in methanol in the presence of a palladium catalyst on activated carbon to give a compound of formula (XIII-1). The cyclopentanol moiety can then be oxidized using a suitable oxidizing agent such as, but not limited to, Dess-Martin periodinane. Subsequently, the tert-butoxycarbonyl group can be removed under acidic conditions to give the compound of formula (XIII-2). The compound of formula (XIII-2) can then be reacted with hexane-2,5-dione in the presence of heat and acid to give a pyrrole protecting group. Subsequent treatment with a base (eg, NaH, LiHMDS, KHMDS) followed by reaction with (Tf) ₂ NPh provides the compound of formula (XIII-3). Under the reaction conditions of Suzuki described for converting the compound of formula (XIII-7) to the compound of formula (XIII-8) in Scheme VIII, the compound of formula (XIII-3) is converted to the compound of formula (XIII-4). Can be converted. The protecting group of the compound of formula (XIII-4) can be removed in a two-step procedure. In the first step, the compound of formula (XIII-4) is treated with hydroxylamine hydrochloride in a mixture of heated ethanol and water in the presence of potassium hydroxide to remove 2,4-dimethylpyrrole. can do. It is then treated with acid under conditions known to those skilled in the art to remove the tert-butoxycarbonyl protecting group to give compounds of formula (VIII-9). A compound of formula (VIII-9) can be coupled with a compound of formula (XIII-5) under standard amide bond coupling procedures to give a compound of formula (VIII-12). Compounds of formula (VIII-12) can be further converted as described in Scheme VIII.

  In the above scheme, compounds are shown in which an aromatic ring (eg, phenyl) is substituted with a group at a specific regiochemistry (eg, para). Starting materials or intermediates with para substitution give the final product with para substitution in the above scheme. It will be apparent to those skilled in the art that substitution of starting materials or intermediates with different regiochemistry (eg, meta) in the above scheme would give the final product with different regiochemistry. For example, replacing a para-substituted starting material or intermediate in the above scheme with a meta-substituted starting material or intermediate would lead to a meta-substituted product.

If a moiety 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 the method. be able to. The protecting group can be removed at an appropriate point in the reaction procedure to provide the desired intermediate or target compound. Suitable protecting groups and methods for protecting or deprotecting moieties are well known to those skilled in the art, examples of which can be found in Greene and Wuts, supra. The optimum reaction conditions and reaction times for each individual step can vary depending on the particular reactants used and the substituents present in the reactants 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 present invention can be similarly prepared according to the procedures described in the above schemes as well as in the following examples. It should be understood that the above embodiments and schemes and the following examples are provided by way of illustration and not limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the present description.

  The following example compounds were named using either ChemDraw version 9.0 or ACD / Name release 12.00 12 (ACD v12). The final compounds in Examples 1-8 were named using ChemDraw unless otherwise stated that they were named using ACD v12. Intermediates were named using ChemDraw unless otherwise stated to be named using ACD v12.

  The following example compounds were named using ACD Name version 12 (ACD Name v12). Other compounds were named using ChemDraw version 9.0 (v9) unless otherwise stated to be named using ACD Name v12. Both naming programs can provide chemical names that depend on the tautomeric structure selected for naming. The structure may be shown or named as any chemically distinguishable tautomer.

  For example, tautomeric structures:

（Ｓ）−５，５’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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）には以下の名が与えられる：
（Ｓ）−５，５’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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−（２−［４−（ベンジルオキシ）フェニル］−３−｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンゾイミダゾール−６−イル｝シクロプロピル）−２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンゾイミダゾール（ＡＣＤ Ｎａｍｅ ｖ１２）。

(S) -5,5 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [ d] imidazole) is given the following name:
(S) -5,5 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [ d] imidazole) (Chemdraw v9);
5- (2- [4- (Benzyloxy) phenyl] -3- {2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopropyl) -2-[(2S ) -Pyrrolidin-2-yl] -1H-benzimidazole (ACD Name v12).

  Tautomeric structure:

には以下の名が与えられる：
（Ｓ）−６，６’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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’−｛３−［４−（ベンジルオキシ）フェニル］シクロプロパン−１，２−ジイル｝ビス｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンゾイミダゾール｝（ＡＣＤ Ｎａｍｅ ｖ１２）。

Is given the following name:
(S) -6,6 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [ d] imidazole) (Chemdraw v9);
6,6 ′-{3- [4- (benzyloxy) phenyl] cyclopropane-1,2-diyl} bis {2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazole} (ACD Name v12).

  Tautomeric structure:

には以下の名が与えられる：
（Ｓ）−６，６’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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−（２−［４−（ベンジルオキシ）フェニル］−３−｛２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンゾイミダゾール−６−イル｝シクロプロピル）−２−［（２Ｓ）−ピロリジン−２−イル］−１Ｈ−ベンゾイミダゾール（ＡＣＤ Ｎａｍｅ ｖ１２）。

Is given the following name:
(S) -6,6 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [ d] imidazole) (Chemdraw v9);
5- (2- [4- (Benzyloxy) phenyl] -3- {2-[(2S) -pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopropyl) -2-[(2S ) -Pyrrolidin-2-yl] -1H-benzimidazole (ACD Name v12).

  Certain compounds in the following examples were purified using reverse phase HPLC. Purification was performed using either a C18 or C8 reverse phase column. Compounds were eluted using a gradient of about 10-100% acetonitrile in 0.1% aqueous trifluoroacetic acid; about 60-100% methanol in 10 mM aqueous ammonium acetate; or about 10-95% methanol in 10 mM aqueous ammonium acetate. . For purifications performed with trifluoroacetic acid, the product thus obtained may be in the form of a trifluoroacetate salt. The compound can be characterized as the trifluoroacetate salt or as the free base after neutralization, extraction and isolation.

  Certain compounds in the following examples may be used in automated purification systems (eg, Isco CombiFlash®) using normal phase silica gel chromatography such as conventional flash chromatography or prepacked silica gel columns (55 or 35 μm silica gel, Isco gold columns). ), Analogix Intelliflash). The compound can also be purified by preparative thin layer chromatography. Typical solvents for silica gel chromatography include ethyl acetate in hexane, diethyl ether in hexane, tetrahydrofuran in hexane, ethyl acetate in methylene chloride, methanol in methylene chloride, methanol in methylene chloride containing ammonium hydroxide, acetone in hexane and Examples include methylene chloride in hexane.

  Representative compounds contemplated as part of the present invention:

ジメチル（［２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタ−１−エン−１，３−ジイル］ビス｛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］｝）ビスカルバメート；

Dimethyl ([2- (4-tert-butylphenyl) cyclopent-1-ene-1,3-diyl] bis {benzene-4,1-diylcarbamoyl (2S) pyrrolidine-2,1-diyl [(2S)- 3-methyl-1-oxobutane-1,2-diyl]}) biscarbamate;

ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタ−３−エン−１，３−ジイル）ビス（４，１−フェニレン）ビス（アザンジイル）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）ジカルバメート；

Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(2- (4-tert-butylphenyl) cyclopent-3-ene -1,3-diyl) bis (4,1-phenylene) bis (azanediyl) bis (oxomethylene)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1- Diyl) dicarbamate;

ジメチル（［２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタン−１，３−ジイル］ビス｛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］｝）ビスカルバメート；

Dimethyl ([2- (4-tert-butylphenyl) cyclopentane-1,3-diyl] bis {benzene-4,1-diylcarbamoyl (2S) pyrrolidine-2,1-diyl [(2S) -3-methyl -1-oxobutane-1,2-diyl]}) biscarbamate;

ジメチル（［２−（４−シクロプロピルフェニル）シクロペンタ−１−エン−１，３−ジイル］ビス｛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］｝）ビスカルバメート；

Dimethyl ([2- (4-cyclopropylphenyl) cyclopent-1-ene-1,3-diyl] bis {benzene-4,1-diylcarbamoyl (2S) pyrrolidine-2,1-diyl [(2S) -3 -Methyl-1-oxobutane-1,2-diyl]}) biscarbamate;

ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（２−（４−シクロプロピルフェニル）シクロペンタ−３−エン−１，３−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）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）ジカルバメート；

Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(2- (4-cyclopropylphenyl) cyclopent-3-ene- 1,3-diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl ) Dicarbamate;

ジメチル（［２−（４−シクロプロピルフェニル）シクロペンタン−１，３−ジイル］ビス｛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］｝）ビスカルバメート；

Dimethyl ([2- (4-cyclopropylphenyl) cyclopentane-1,3-diyl] bis {benzene-4,1-diylcarbamoyl (2S) pyrrolidine-2,1-diyl [(2S) -3-methyl- 1-oxobutane-1,2-diyl]}) biscarbamate;

ジメチル（［２−（４−ｔｅｒｔ−ブチルフェニル）シクロヘキサ−１−エン−１，３−ジイル］ビス｛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］｝）ビスカルバメート；
ジメチル（［２−（４−ｔｅｒｔ−ブチルフェニル）シクロヘキサン−１，３−ジイル］ビス｛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］｝）ビスカルバメート；

Dimethyl ([2- (4-tert-butylphenyl) cyclohex-1-ene-1,3-diyl] bis {benzene-4,1-diylcarbamoyl (2S) pyrrolidine-2,1-diyl [(2S)- 3-methyl-1-oxobutane-1,2-diyl]}) biscarbamate;
Dimethyl ([2- (4-tert-butylphenyl) cyclohexane-1,3-diyl] bis {benzene-4,1-diylcarbamoyl (2S) pyrrolidine-2,1-diyl [(2S) -3-methyl- 1-oxobutane-1,2-diyl]}) biscarbamate;

メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［２−（４−ｔｅｒｔ−ブチルフェニル）−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンタ−１−エン−１−イル］−１Ｈ−ベンゾイミダゾール−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｝カルバメート；
ジメチル（２Ｓ，２’Ｓ）−１，１^’−（（２Ｓ，２’Ｓ）−２，２’−（６，６’−（２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタ−３−エン−１，３−ジイル）ビス（１Ｈ−ベンゾ［ｄ］イミダゾール−６，２−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）ジカルバメート；
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛５−［２−（４−ｔｅｒｔ−ブチルフェニル）−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンチル］−１Ｈ−ベンゾイミダゾール−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｝カルバメート；
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［２−（４−シクロプロピルフェニル）−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンタ−１−エン−１−イル］−１Ｈ−ベンゾイミダゾール−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｝カルバメート；
メチル［（２Ｓ）−１−（２−｛６−［５−（４−シクロプロピルフェニル）−４−｛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−ベンゾイミダゾール−６−イル｝シクロペンタ−１−エン−１−イル］−１Ｈ−ベンゾイミダゾール−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］カルバメート；
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［２−（４−シクロプロピルフェニル）−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンチル］−１Ｈ−ベンゾイミダゾール−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｝カルバメート；

Methyl {(2S) -1-[(2S) -2- {5- [2- (4-tert-butylphenyl) -3- {2-[(2S) -1-{(2S) -2- [ (Methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopent-1-en-1-yl] -1H-benzimidazol-2-yl} pyrrolidine -1-yl) -3-methyl-1-oxobutan-2-yl} carbamate;
Dimethyl (2S, 2'S) -1,1 ^' -((2S, 2'S) -2,2'-(6,6 '-(2- (4-tert-butylphenyl) cyclopent-3-ene -1,3-diyl) bis (1H-benzo [d] imidazole-6,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl ) Dicarbamate;
Methyl {(2S) -1-[(2S) -2- {5- [2- (4-tert-butylphenyl) -3- {2-[(2S) -1-{(2S) -2- [ (Methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopentyl] -1H-benzimidazol-2-yl} pyrrolidin-1-yl] -3- Methyl-1-oxobutan-2-yl} carbamate;
Methyl {(2S) -1-[(2S) -2- {6- [2- (4-cyclopropylphenyl) -3- {2-[(2S) -1-{(2S) -2-[( Methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopent-1-en-1-yl] -1H-benzimidazol-2-yl} pyrrolidine- 1-yl] -3-methyl-1-oxobutan-2-yl} carbamate;
Methyl [(2S) -1- (2- {6- [5- (4-cyclopropylphenyl) -4- {2-[(2S) -1- {2-[(methoxycarbonyl) amino] -3- Methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopent-1-en-1-yl] -1H-benzimidazol-2-yl} pyrrolidin-1-yl) -3-methyl -1-oxobutan-2-yl] carbamate;
Methyl {(2S) -1-[(2S) -2- {6- [2- (4-cyclopropylphenyl) -3- {2-[(2S) -1-{(2S) -2-[( Methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopentyl] -1H-benzimidazol-2-yl} pyrrolidin-1-yl] -3-methyl -1-oxobutan-2-yl} carbamate;

メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［２−（４−ｔｅｒｔ−ブチルフェニル）−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンタ−１−エン−１−イル］−５−フルオロ−１Ｈ−ベンゾイミダゾール−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｝カルバメート；
メチル［（２Ｓ）−１−（２−｛６−［２−（４−ｔｅｒｔ−ブチルフェニル）−３−｛５−フルオロ−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−ベンゾイミダゾール−６−イル｝シクロペンタ−３−エン−１−イル］−５−フルオロ−１Ｈ−ベンゾイミダゾール−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］カルバメート；
メチル｛（２Ｓ）−１−［（２Ｓ）−２−｛６−［２−（４−ｔｅｒｔ−ブチルフェニル）−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンチル］−５−フルオロ−１Ｈ−ベンゾイミダゾール−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｝カルバメート；
メチル［（２Ｓ）−１−｛（２Ｓ）−２−［６−（２−［３−フルオロ−４−（ピペリジン−１−イル）フェニル］−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンタ−１−エン−１−イル）−１Ｈ−ベンゾイミダゾール−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］カルバメート；
メチル［（２Ｓ）−１−｛（２Ｓ）−２−［６−（５−［３−フルオロ−４−（ピペリジン−１−イル）フェニル］−４−｛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−ベンゾイミダゾール−６−イル｝シクロペンタ−１−エン−１−イル）−１Ｈ−ベンゾイミダゾール−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］カルバメート；
メチル［（２Ｓ）−１−｛（２Ｓ）−２−［６−（２−［３−フルオロ−４−（ピペリジン−１−イル）フェニル］−３−｛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−ベンゾイミダゾール−６−イル｝シクロペンチル）−１Ｈ−ベンゾイミダゾール−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］カルバメート；

Methyl {(2S) -1-[(2S) -2- {6- [2- (4-tert-butylphenyl) -3- {5-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopent-1-en-1-yl] -5-fluoro-1H- Benzoimidazol-2-yl} pyrrolidin-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate;
Methyl [(2S) -1- (2- {6- [2- (4-tert-butylphenyl) -3- {5-fluoro-2-[(2S) -1- {2-[(methoxycarbonyl)] Amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopent-3-en-1-yl] -5-fluoro-1H-benzimidazol-2-yl} pyrrolidine -1-yl) -3-methyl-1-oxobutan-2-yl] carbamate;
Methyl {(2S) -1-[(2S) -2- {6- [2- (4-tert-butylphenyl) -3- {5-fluoro-2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopentyl] -5-fluoro-1H-benzimidazol-2-yl} pyrrolidine -1-yl] -3-methyl-1-oxobutan-2-yl} carbamate;
Methyl [(2S) -1-{(2S) -2- [6- (2- [3-fluoro-4- (piperidin-1-yl) phenyl] -3- {2-[(2S) -1- {(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopent-1-en-1-yl) -1H- Benzoimidazol-2-yl] pyrrolidin-1-yl} -3-methyl-1-oxobutan-2-yl] carbamate;
Methyl [(2S) -1-{(2S) -2- [6- (5- [3-fluoro-4- (piperidin-1-yl) phenyl] -4- {2-[(2S) -1- {(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopent-1-en-1-yl) -1H- Benzoimidazol-2-yl] pyrrolidin-1-yl} -3-methyl-1-oxobutan-2-yl] carbamate;
Methyl [(2S) -1-{(2S) -2- [6- (2- [3-fluoro-4- (piperidin-1-yl) phenyl] -3- {2-[(2S) -1- {(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-6-yl} cyclopentyl) -1H-benzimidazol-2-yl] pyrrolidine -1-yl} -3-methyl-1-oxobutan-2-yl] carbamate;

メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛４−［２−（４−ｔｅｒｔ−ブチルフェニル）−３−（４−｛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−イミダゾール−５−イル）フェニル）シクロペンタ−１−エン−１−イル］フェニル｝−１Ｈ−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｝カルバメート；および
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛４−［５−（４−ｔｅｒｔ−ブチルフェニル）−４−（４−｛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−イミダゾール−５−イル｝フェニル）シクロペンタ−１−エン−１−イル］フェニル｝−１Ｈ−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｝カルバメート；
メチル｛（２Ｓ）−１−［（２Ｓ）−２−（５−｛４−［２−（４−ｔｅｒｔ−ブチルフェニル）−３−（４−｛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−イミダゾール−５−イル｝フェニル）シクロペンチル］フェニル｝−１Ｈ−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｝カルバメート。

Methyl {(2S) -1-[(2S) -2- (5- {4- [2- (4-tert-butylphenyl) -3- (4- {2-[(2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-imidazol-5-yl) phenyl) cyclopent-1-en-1-yl] phenyl} -1H -Imidazol-2-yl) pyrrolidin-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate; and methyl {(2S) -1-[(2S) -2- (5- {4- [5- (4-tert-Butylphenyl) -4- (4- {2-[(2S) -1-{(2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidine- 2-yl] -1H-imidazol-5-yl} Eniru) cyclopent-1-en-1-yl] phenyl}-1H-imidazol-2-yl) pyrrolidin-1-yl] -3-methyl-1-oxobutan-2-yl} carbamate;
Methyl {(2S) -1-[(2S) -2- (5- {4- [2- (4-tert-butylphenyl) -3- (4- {2-[(2S) -1-{( 2S) -2-[(methoxycarbonyl) amino] -3-methylbutanoyl} pyrrolidin-2-yl] -1H-imidazol-5-yl} phenyl) cyclopentyl] phenyl} -1H-imidazol-2-yl) pyrrolidine -1-yl] -3-methyl-1-oxobutan-2-yl} carbamate.

Intermediate synthesis

（Ｓ）−ｔｅｒｔ−ブチル２−（４−ブロモ−１Ｈ−イミダゾール−２−イル）ピロリジン−１−カルボキシレート
中間体１Ａ
（Ｓ）−ｔｅｒｔ−ブチル２−ホルミルピロリジン−１−カルボキシレート
窒素でパージしたオーブン乾燥した５００ｍＬ３ツ口フラスコに、塩化オキサリル（５．３２ｍＬ、６０．８ｍｍｏｌ）および無水ジクロロメタン（１２５ｍＬ）を加え、溶液を−７８℃に冷却した。無水ＤＭＳＯ（７．３０ｍＬ、１０３ｍｍｏｌ）の無水ジクロロメタン（２５ｍＬ）中溶液を定圧添加漏斗から２０分間かけて滴下添加した。（Ｓ）−ｔｅｒｔ−ブチル２−（ヒドロキシメチル）ピロリジン−１−カルボキシレート（９．４１ｇ、４６．８ｍｍｏｌ）の無水ジクロロメタン（５０ｍＬ）中溶液を定圧添加漏斗から２０分間かけて滴下添加し、次いで反応混合物を−７８℃で３０分間撹拌した。トリエチルアミン（３２．６ｍＬ、２３４ｍｍｏｌ）を注射器により５分間かけて滴下添加し、粘稠性白色混合物を氷水浴中で３０分間撹拌した。反応を１０％（ｗ／ｖ）クエン酸水溶液（３０ｍＬ）でクエンチした。混合物を分液漏斗中、Ｅｔ_２Ｏ（５５０ｍＬ）と１０％（ｗ／ｖ）クエン酸水溶液との間で分配した。層を分離し、有機相を水およびブラインで洗浄した。有機相を無水Ｎａ_２ＳＯ_４で脱水し、濾過し、濃縮して、黄色油状物（９．４ｇ）を得、これを次の反応に直接使用した。

(S) -tert-butyl 2- (4-bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate intermediate 1A
(S) -tert-butyl 2-formylpyrrolidine-1-carboxylate To an oven-dried 500 mL three-necked flask purged with nitrogen, oxalyl chloride (5.32 mL, 60.8 mmol) and anhydrous dichloromethane (125 mL) were added and the solution Was cooled to -78 ° C. A solution of anhydrous DMSO (7.30 mL, 103 mmol) in anhydrous dichloromethane (25 mL) was added dropwise from a constant pressure addition funnel over 20 minutes. A solution of (S) -tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate (9.41 g, 46.8 mmol) in anhydrous dichloromethane (50 mL) was added dropwise from a constant pressure addition funnel over 20 minutes, then The reaction mixture was stirred at −78 ° C. for 30 minutes. Triethylamine (32.6 mL, 234 mmol) was added dropwise via syringe over 5 minutes and the viscous white mixture was stirred in an ice-water bath for 30 minutes. The reaction was quenched with 10% (w / v) aqueous citric acid (30 mL). The mixture was partitioned between Et ₂ O (550 mL) and 10% (w / v) aqueous citric acid in a separatory funnel. The layers were separated and the organic phase was washed with water and brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a yellow oil (9.4 g) that was used directly in the next reaction.

Intermediate 1B
(S) -tert-Butyl 2- (1H-imidazol-2-yl) pyrrolidine-1-carboxylate The product from Intermediate 1A (20 g, 100 mmol) was dissolved in methanol (50.2 mL) and ammonium hydroxide. (50.2 mL) was added. To this solution, glyoxal (40% aqueous solution; 24.08 mL, 211 mmol) was added dropwise over 10 minutes. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, diluted with 50 mL of water and then extracted with ethyl acetate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give a tan solid. The solid was treated with ether and concentrated. The solid was then triturated with 2: 1 diethyl ether: hexane (150 mL) to give 17 g of solid, which was used directly in the next reaction. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 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
(S) -tert-Butyl 2- (4,5-dibromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate N-bromosuccinimide (108 mmol) was obtained from intermediate 1B (12.05 g). To a cooled (0 ° C.) solution in dichloromethane (200 mL). The mixture was stirred in an ice bath for 2 hours, then concentrated, dissolved in ethyl acetate (250 mL), washed with water (3 × 150 mL) and brine (1 × 100 mL), dried (MgSO ₄ ), Concentration gave a dark dark residue. The residue was mixed with dichloromethane / hexane (1: 1) and concentrated therefrom to give a brown solid (ca. 19 g). The solid was triturated with ether (ca. 100 mL) and filtered to isolate a tan solid (13.23 g, 65% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 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, 2.55 Hz, 1H), 10.82 (s, 1H); MS (DCI +) m / z 394/396/398 (M + H) ) ⁺ .

Intermediate 1D
(S) -tert-butyl 2- (4-bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate product from intermediate 1C in a 1 L round bottom flask equipped with a condenser and 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 at reflux for 16 hours. The reaction mixture was cooled to room temperature and dioxane and a small amount of water were removed by rotary evaporation. The residue was extracted with dichloromethane. The combined organic phases were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated by rotary evaporation and coevaporated with 2: 1 hexane / dichloromethane (100 mL) to give a beige color. Foam (4.38 g) was obtained. Dissolve the foam in dichloromethane (2 mL), add hexane (2 mL), load the resulting solution onto a column and purify by silica gel flash chromatography eluting with 30% to 80% ethyl acetate / hexane to give the title The compound was obtained as a white solid (3.48 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.48 (s, 9H), 1.83-2.33 (m, 3H), 2.79-3.02 (m, 1H), 3.37 (dd , J = 7.10, 5.37 Hz, 2H), 4.88 (dd, J = 0.59, 2.49 Hz, 1H), 6.92 (s, 1H), 10.70 (br s, 1H) ); MS (ESI +) m / z 316/318 (M + H) ⁺ .

（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）に溶解した（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）を加え、続いてクロロギ酸メチル（７５ｍＬ、９７３ｍｍｏｌ）を１時間かけて滴下添加し、これにより溶液の昇温が生じた。添加後、混合物を６０℃で２２時間加熱し、次いで冷却し、ジクロロメタン（４００ｍＬ）で抽出した。得られた水層を氷浴中で冷却し、次いでｐＨが２となるまで１２Ｎ塩酸を滴下添加した。得られた混合物を０℃で２時間撹拌し、次いで得られた固体を真空濾過により集め、真空乾燥機中で乾燥して、標題化合物８０ｇ（９４％）を無色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ １２．５０（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）。

(S) -2- (methoxycarbonylamino) -3-methylbutanoic acid To (S) -2-amino-3-methylbutanoic acid (57 g, 487 mmol) dissolved in dioxane (277 mL), 2N aqueous sodium hydroxide solution (803 mL, 1606 mmol) was added, followed by dropwise addition of methyl chloroformate (75 mL, 973 mmol) over 1 hour, which caused the solution to warm. After the addition, the mixture was heated at 60 ° C. for 22 hours, then cooled and extracted with dichloromethane (400 mL). The resulting aqueous layer was cooled in an ice bath and then 12N hydrochloric acid was added dropwise until the pH was 2. The resulting mixture was stirred at 0 ° C. for 2 hours, then the resulting solid was collected by vacuum filtration and dried in a vacuum dryer to give 80 g (94%) of the title compound as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 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 = 7.0 Hz, 6H).

メチル（Ｓ）−１−（（Ｓ）−２−（５−ブロモ−１Ｈ−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−イルカルバメート
中間体４Ａ
（Ｓ）−５−ブロモ−２−（ピロリジン−２−イル）−１Ｈ−イミダゾール塩酸塩
中間体１Ｄ（５．０ｇ、１５．８ｍｍｏｌ）の４Ｍ ＨＣｌ／ジオキサン（４０ｍＬ）中混合物を１時間撹拌した。混合物を濃縮して、標題化合物３．９９ｇ（１００％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ２１７（Ｍ＋Ｈ）^＋。

Methyl (S) -1-((S) -2- (5-bromo-1H-imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-ylcarbamate intermediate 4A
A 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) pyrrolidin-1-yl) -3-methyl-1-oxobutan-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 × 300 mL). The organic phase was washed with H ₂ O and brine. The organic phase was then dried (MgSO ₄ ), filtered and concentrated. Purification by chromatography (silica gel, 75% EtOAc in hexanes) gave 5.2 g (88%) of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 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 = 1.52 Hz, 1H), 7.26 (d, J = 8.46 Hz, 1H), 12.01 (s, 1H); MS (ESI) m / z 373 (M + H) ⁺ .

（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）を周囲温度にてジクロロメタン（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）を少量ずつ添加して処理した。混合物を１８時間撹拌し、次いで水で希釈し、酢酸エチル中に抽出し、濃縮して、標題化合物を得た。

(2S, 4S) -1- (tert-Butoxycarbonyl) -4- (tert-Butyldimethylsilyloxy) pyrrolidine-2-carboxylic acid (2S, 4S) -1- (tert-Butoxycarbonyl) -4-hydroxypyrrolidine 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 to give tert-butylchlorodimethylsilane (7 .61 g, 50.5 mmol) was added in small portions. The mixture was stirred for 18 hours, then diluted with water, extracted into ethyl acetate and concentrated to give the title compound.

（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１３℃に冷却し、（Ｌ）−プロリンベンジルエステル塩酸塩（２０７ｇ、８５６ｍｍｏｌ）を入れた。次いでトリエチルアミン（１０９ｇ、１０７９ｍｍｏｌ）を３０分で入れた。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１５℃に冷却し、６．７％ＮａＨＣＯ_３１５００ｍＬを１．５時間で入れ、続いて水１２００ｍＬを６０分かけて加えた。混合物を室温で３０分間撹拌し、次いで濾過し、水／ＤＭＦ混合物（１：２、２５０ｍＬ）で洗浄し、次いで水（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）−ベンジル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−カルボキシレート２８２ｇを白色固体として得た（９０％）。
（Ｓ）−ベンジル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−カルボキシレート（４０ｇ）および５％Ｐｄ／アルミナを、Ｐａｒｒ（登録商標）反応器に入れ、続いてＴＨＦ（１６０ｍＬ）を入れた。反応器を密閉し、窒素でパージ（２０ｐｓｉｇで６回）し、続いて水素パージした（３０ｐｓｉｇで６回）。反応器を、水素で３０ｐｓｉｇに加圧し、室温で約１５時間撹拌した。得られたスラリー液をＧＦ／Ｆフィルターで濾過し、濃縮して、約１３５ｇの溶液にした。ヘプタン（１２０ｍＬ）を加え、固体が形成するまで溶液を撹拌した。さらに２−３時間後、追加のヘプタン（２４０ｍＬ）を滴下添加し、約１時間スラリー液を撹拌し、次いで濾過した。固体を乾燥して、標題化合物（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−カルボン酸を得た。

(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 the 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. Then triethylamine (109 g, 1079 mmol) was charged in 30 minutes. The resulting suspension was mixed at room temperature for 1.5 hours. The reaction mixture was cooled to 15 ° C. and 1500 mL of 6.7% NaHCO ₃ was added over 1.5 hours, followed by the addition of 1200 mL of water over 60 minutes. The mixture was stirred at room temperature for 30 minutes, then filtered, washed with a water / DMF mixture (1: 2, 250 mL) and then with water (1500 mL). The wet cake was dried at 55 ° C. for 24 hours to give 282 g of the product (S) -benzyl 1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylate white Obtained as a solid (90%).
(S) -Benzyl 1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylate (40 g) and 5% Pd / alumina were added to a Parr® reactor. Followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6 times at 20 psig) followed by hydrogen (6 times at 30 psig). The reactor was pressurized to 30 psig with hydrogen and stirred at room temperature for about 15 hours. The resulting slurry was filtered through a GF / F filter and concentrated to a solution of about 135 g. Heptane (120 mL) was added and the solution was stirred until a solid formed. After an additional 2-3 hours, additional heptane (240 mL) was added dropwise and the slurry was stirred for about 1 hour and then filtered. The solid was dried to give the title compound (S) -1-((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylic acid.

Intermediate 11A
To a flask containing N- (4-bromo-5-fluoro-2-nitrophenyl) -2,2,2-trifluoroacetamide trifluoroacetic anhydride (10.0 mL, 70.5 mmol) at 0 ° C. Bromo-3-fluoroaniline (2.0 g, 10.5 mmol) was added and stirring was 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 warmed to 25 ° C. The solution was concentrated and the residue was dissolved in EtOAc, washed with 10% NaHCO ₃ , brine, dried (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) was added to CH. ₃ OH (30 mL) was added followed by 1.0 M K ₂ CO ₃ (10.5 mL, 10.5 mmol) and the solution was stirred for 30 min (Charifson, PS et al., J. Med. Chem. 2008, 51, 5243-5263). The solution was diluted with H ₂ O and stirred for 1 hour. The resulting orange 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 To a solution in H ₂ O (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol) and the mixture was heated at 95 ° C. for 4 h. The cooled mixture was diluted with EtOH, filtered through diatomaceous earth until no color was passed through the filter, 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). N-bromosuccinimide (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, rinsed with water and dried to constant weight to give the title compound (4.78 g, 67%). . ¹ H NMR (400 MHz, CDCL ₃ ) δ ppm 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 stirred at reflux for 12 hours. The mixture was cooled to room temperature, poured into water and adjusted to pH 5 with saturated sodium bicarbonate solution. The resulting solid was filtered and rinsed thoroughly with ethyl acetate. The filtrate was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% EtOAc in hexanes to give the title compound (3.32 g, 79%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.94 (d, 1H), 6.51 (d, J = 7.0, 1H), 3.87 (br s, 2H), 3.46 (br s , 2H).

Intermediate 13
4-Bromo-3-methylbenzene-1,2-diamine intermediate 13A
N- (3-Bromo-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide 3-Bromo-2-methylaniline (1.0 g, 5.37 mmol) in CH ₂ Cl ₂ (4 To a solution in 0.0 mL) was added trifluoroacetic anhydride (2.0 mL, 14.2 mmol) 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 had formed. The mixture was concentrated in vacuo and the residue was partitioned between water and CH ₂ Cl ₂ (twice). The organic layers were combined and dried over Na ₂ SO ₄ . The desiccant was filtered off and the crude product was purified by crystallization from aqueous EtOH to give the title compound (1.3 g, 74%).

Intermediate 13B
3-bromo-2-methyl-6-nitroaniline N- (3-bromo-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide (1.3 g, 3.97 mmol) in CH ₃ 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 with the addition of 1N HCl, and the mixture was extracted with CH ₂ Cl ₂ (3 times). The combined extracts were dried over Na ₂ SO ₄ , the desiccant was filtered off and the solvent was removed in vacuo to give the title compound as a yellow solid (0.57 g, 62%).

Intermediate 13C
4-Bromo-3-methylbenzene-1,2-diamine To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin (II) chloride ( 1.48 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 adjusted to pH> 7 by adding 1N aqueous NaOH. The resulting mixture was extracted with CH ₂ Cl ₂ (twice) and the combined extracts were dried over Na ₂ SO ₄ . The desiccant was filtered off and the solvent removed in vacuo 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 To a solution in H ₂ O (1.5 mL) was added iron powder (0.6 g, 10.6 mmol) and ammonium chloride (0.17 g, 3.2 mmol). 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 washed with EtOH until no further color passed through the filter. The filtrate is concentrated and the residue is 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%) as a brown wax. Obtained as a solid.

Intermediate 15
4-Bromo-3-fluorobenzene-1,2-diamine intermediate 15A
3-Fluoro-2-nitroaniline To a pressure tube was added 1,3-difluoro-2-nitrobenzene (2.8 mL, 26.4 mmol) and 7N NH _{3 in} CH ₃ OH (10 mL, 70 mmol). The tube was sealed and the mixture was stirred at room temperature for 5 days. The solution was diluted with H ₂ O and extracted with CH ₂ Cl ₂ and the combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an oil. The oil was triturated with hexane and the resulting orange solid was collected by filtration to give the title compound (2.1 g, 51%).

Intermediate 15B
4-Bromo-3-fluoro-2-nitroaniline To a solution of 3-fluoro-2-nitroaniline (2.1 g, 13.4 mmol) in DMF (30 mL) at 0 ° C. was added N-bromosuccinimide (2.4 g, A solution of 13.4 mmol) in DMF (20 mL) was added. The resulting solution was stirred at 0 ° C. for 30 minutes and then warmed 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 (3.1 g, 97%).

Intermediate 15C
4-Bromo-3-fluorobenzene-1,2-diamine To a solution of 4-bromo-3-fluoro-2-nitroaniline (3.0 g, 12.8 mmol) in THF (30 mL) was added EtOH (30 mL) and H. ₂ O (10 mL) was added, followed by iron powder (3.6 g, 63.8 mmol) and ammonium chloride (1.0 g, 19.2 mmol). 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 no further color passed through the filter. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% EtOAc in hexanes to give the title compound (2.2 g, 84%).

General procedure 20

スキームＸＩに一般的に上記した通り、ジアミン（ＸＩ−１）は２ステップでベンゾイミダゾール（ＸＩ−３）に変換できる。

As generally described above in Scheme XI, diamine (XI-1) can be converted to benzimidazole (XI-3) in two steps.

Description of general procedure 20. General procedure 20A
(S) -tert-butyl 2- (6-bromo-5-fluoro-1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate 4-bromo-5-fluorobenzene-1,2-diamine To a solution of (1.7 g, 8.4 mmol) in DMSO (42 mL) was added (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.8 g, 8.4 mmol) followed by 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 twice with toluene to give the crude product, which was purified by flash chromatography (0-50% EtOAc / hexanes) to give the title compound (2.5 g, 6.4 mmol, 77%) Got.

(S) -tert-butyl 2- (5-bromo-6-fluoro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate (S) -tert-butyl 2- (6-bromo-5-fluoro-1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate (2.5 g, 6.4 mol) in THF (32 mL) To the medium solution was added sodium hydride (0.27 g, 6.8 mmol) 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 to quench the reaction. The mixture was diluted with EtOAc, washed with 1N HCl, H ₂ O and brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give an oil. The oil was purified by flash chromatography (0-30% EtOAc / hexanes) to give the title compound (2.9 g, 5.7 mmol, 89%).

The following compounds of general formula (XI-3) can be made according to general procedure 20, starting from the appropriate diamine:
(S) -tert-butyl 2- (5-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate;
(S) -tert-butyl 2- (5-bromo-4-methyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate ;
(S) -tert-butyl 2- (5-bromo-4-chloro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate ;
(S) -tert-butyl 2- (5-bromo-4-fluoro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate ;
(S) -tert-butyl 2- (6-bromo-3-((2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b] pyridin-2-yl) pyrrolidine-1-carboxylate ;
(S) -tert-butyl 2- (5-bromo-7-methyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate ;
(S) -tert-butyl 2- (5-bromo-6-methyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate ;
(S) -tert-butyl 2- (5-bromo-6- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine- 1-carboxylate;
(S) -tert-butyl 2- (5-bromo-7- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine- 1-carboxylate;
(S) -tert-butyl 2- (5-bromo-6-methoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate ;
(S) -tert-butyl 2- (5-bromo-7-methoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) pyrrolidine-1-carboxylate And (S) -methyl 5-bromo-2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole -7-carboxylate.

［実施例１］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）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）ジカルバメート

[Example 1]
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4-methoxyphenyl) cyclopropane-1,2- Diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate

実施例１Ａ
（２Ｒ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（（Ｅ）−エテン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
４，４’−ジアミノスチルベン二塩酸塩（０．５ｇ、２．３８ｍｍｏｌ）のジメチルスルホキシド（１０ｍＬ）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（１．０２４ｇ、４．７６ｍｍｏｌ）、Ｏ−（７−アザベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルウロニウムヘキサフルオロホスフェート（ＨＡＴＵ）（１．８０８ｇ、４．７６ｍｍｏｌ）およびヒューニッヒ塩基（１．６６ｍＬ、９．５１ｍｍｏｌ）を加え、混合物を室温で３時間撹拌した。次いで１Ｎ塩酸水溶液（２０ｍＬ）を反応混合物に加え、続いてジクロロメタン（２０ｍＬで２回）で抽出した。有機抽出物を乾燥し、濾過し、濃縮した。残留物をクロマトグラフィー（シリカゲル、ジクロロメタン中メタノール）により精製して、標題化合物１．０９ｇ、（７６％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ６０４（Ｍ＋Ｈ）^＋。

Example 1A
(2R, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-((E) -ethene-1,2-diyl) bis (4,1-phenylene)) bis (azanediyl) bis ( Oxomethylene) dipyrrolidine-1-carboxylate 4,4′-diaminostilbene dihydrochloride (0.5 g, 2.38 mmol) in dimethyl sulfoxide (10 mL) was added to (S) -1- (tert-butoxycarbonyl). Pyrrolidine-2-carboxylic acid (1.024 g, 4.76 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) (1.808 g, 4.76 mmol) and Hunig's base (1.66 mL, 9.51 mmol) were added and the mixture was stirred at room temperature for 3 hours. 1N aqueous hydrochloric acid (20 mL) was then added to the reaction mixture followed by extraction with dichloromethane (2 × 20 mL). The organic extract was dried, filtered and concentrated. The residue was purified by chromatography (silica gel, methanol in dichloromethane) to give 1.09 g, (76%) of the title compound. MS (ESI) m / z 604 (M + H) ^<+> .

実施例１Ｂ
（４−メトキシフェニル）（トリブチルスタンニル）メチルメチルカルボネート
−７８℃に冷却した乾燥テトラヒドロフラン（８０ｍＬ）に、リチウムジイソプロピルアミドの溶液（ヘプタン／テトラヒドロフラン／エチルベンゼン中２．０Ｍ、１８．３６ｍＬ、３７．５ｍｍｏｌ）を加え、続いて水素化トリ−ｎ−ブチルスズ（９．８１ｍＬ、３７．５ｍｍｏｌ）を滴下添加した。５分後、混合物を氷水浴中に０．５時間置き、次いで−７８℃に再度冷却した。４−メトキシベンズアルデヒド（４．４５ｍＬ、３７．５ｍｍｏｌ）を滴下添加し、反応混合物をこの温度で１．５時間撹拌した。その後、クロロギ酸メチル（３．４１ｍＬ、４４．１ｍｍｏｌ）を滴下添加し、冷却浴を除去し、混合物を室温で終夜撹拌した。次いで飽和塩化アンモニウム水溶液（１００ｍＬ）を加え、続いて酢酸エチルで抽出した。有機抽出物を乾燥し、濾過し、濃縮した。残留物をクロマトグラフィー（シリカゲル、ヘキサン中酢酸エチル）により精製して、標題化合物６．７ｇ（３８％）を得た。

Example 1B
(4-Methoxyphenyl) (tributylstannyl) methyl methyl carbonate in dry tetrahydrofuran (80 mL) cooled to -78 ° C. and a solution of lithium diisopropylamide (2.0 M in heptane / tetrahydrofuran / ethylbenzene, 18.36 mL, 37. 5 mmol) was added followed by dropwise addition of tri-n-butyltin hydride (9.81 mL, 37.5 mmol). After 5 minutes, the mixture was placed in an ice-water bath for 0.5 hour and then cooled again to -78 ° C. 4-Methoxybenzaldehyde (4.45 mL, 37.5 mmol) was added dropwise and the reaction mixture was stirred at this temperature for 1.5 hours. Then methyl chloroformate (3.41 mL, 44.1 mmol) was added dropwise, the cooling bath was removed and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution (100 mL) was then added followed by extraction with ethyl acetate. The organic extract was dried, filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate in hexane) to give 6.7 g (38%) of the title compound.

実施例１Ｃ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
実施例１Ａの生成物（１００ｍｇ、０．１６５ｍｍｏｌ）および実施例１Ｂからの生成物（２４１ｍｇ、０．４９６ｍｍｏｌ）を部分的にジクロロメタン（５ｍＬ）に溶解し、次いで混合物を−２５℃に冷却した。三フッ化ホウ素エーテレート（０．０６３ｍＬ、０．４９６ｍｍｏｌ）を加え、得られた混合物を１時間撹拌した。次いで溶液を室温に加温し、０．５Ｎ塩酸水溶液（１０ｍＬ）を加え、続いてジクロロメタン（１０ｍＬで２回）で抽出した。有機抽出物を乾燥し、濾過し、濃縮した。残留物をクロマトグラフィー（シリカゲル、ジクロロメタン中メタノール）により精製して、標題化合物０．１１５ｇ（９６％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ７２５（Ｍ＋Ｈ）^＋。

Example 1C
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(3- (4-methoxyphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (Azandiyl) bis (oxomethylene) dipyrrolidine-1-carboxylate The product of Example 1A (100 mg, 0.165 mmol) and the product from Example 1B (241 mg, 0.496 mmol) were partially dichloromethane (5 mL). And then the mixture was cooled to -25 ° C. Boron trifluoride etherate (0.063 mL, 0.496 mmol) was added and the resulting mixture was stirred for 1 hour. The solution was then warmed to room temperature and 0.5N aqueous hydrochloric acid (10 mL) was added followed by extraction with dichloromethane (2 × 10 mL). The organic extract was dried, filtered and concentrated. The residue was purified by chromatography (silica gel, methanol in dichloromethane) to give 0.115 g (96%) of the title compound. MS (ESI) m / z 725 (M + H) ^<+> .

実施例１Ｄ
（２Ｓ，２’Ｓ）−Ｎ，Ｎ’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−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１Ｃの生成物（１１５ｍｇ、０．１５９ｍｍｏｌ）をジオキサン（１．５ｍＬ）およびジオキサン中塩酸（４．０Ｎ、０．６ｍＬ、２．３８ｍｍｏｌ）に溶解し、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／ｚ５４８（Ｍ＋Ｈ）^＋。

Example 1D
(2S, 2'S) -N, N '-(4,4'-(3- (4-methoxyphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) dipyrrolidine-2- Carboxamide The product of Example 1C (115 mg, 0.159 mmol) was dissolved in dioxane (1.5 mL) and hydrochloric acid in dioxane (4.0 N, 0.6 mL, 2.38 mmol) and the mixture was stirred at room temperature for 4 hours. . The mixture was then concentrated to give the title compound as the hydrochloride salt. MS (ESI) m / z 548 (M + H) ^<+> .

実施例１Ｅ
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）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）ジカルバメート
実施例１Ｄからの生成物（８３ｍｇ、０．１５８ｍｍｏｌ）、（Ｓ）−２−（メトキシカルボニルアミノ）−３−メチルブタン酸（５５ｍｇ、０．３１６ｍｍｏｌ）、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（６７ｍｇ、０．３４８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール水和物（５３ｍｇ、０．３４８ｍｍｏｌ）および４−メチルモルホリン（１．３８ｍＬ、１．２７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）に溶解し、混合物を室温で３時間撹拌した。その後、１Ｎ塩酸水溶液（１０ｍＬ）を加え、続いてジクロロメタン（１０ｍＬで２回）で抽出した。合わせた有機抽出物を乾燥し、濾過し、濃縮した。残留物をクロマトグラフィー（シリカゲル、ジクロロメタン中メタノール）により精製して、標題化合物６０ｍｇ（４５％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ ９．９６（ｓ，１Ｈ）、９．８７（ｓ，１Ｈ）、７．９６（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ）、７．７０（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ）、７．５５（ｍ，２Ｈ）、７．３２（ｍ，４Ｈ）、６．９８（ｍ，４Ｈ）、６．７２（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ）、４．４３（ｍ，１Ｈ）、４．３９（ｍ，１Ｈ）、４．０２（ｍ，２Ｈ）、３．６５（ｓ，３Ｈ）、３．６２（ｍ，２Ｈ）、３．５３（ｓ，３Ｈ）、３．５２（ｓ，３Ｈ）、２．８７（ｍ，１Ｈ）、２．７０（ｍ，２Ｈ）、２．１５（ｍ，２Ｈ）、１．９０（ｍ，８Ｈ）、０．９０（ｍ，１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ ８３９（Ｍ＋Ｈ）^＋。

Example 1E
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4-methoxyphenyl) cyclopropane-1,2- Diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate Product from Example 1D (83 mg, 0.158 mmol), (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (55 mg, 0.316 mmol), N- (3-dimethylaminopropyl) -N ′ -Ethylcarbodiimide hydrochloride (67 mg, 0.348 mmol), 1-hydroxybenzotriazole hydrate (53 mg, 0.348 mmol) and 4-methylmorpholine (1.38 mL) , 1.27 mmol) was dissolved in N, N-dimethylformamide (3 mL) and the mixture was stirred at room temperature for 3 h. Thereafter, 1N aqueous hydrochloric acid solution (10 mL) was added, followed by extraction with dichloromethane (2 × 10 mL). The combined organic extracts were dried, filtered and concentrated. The residue was purified by chromatography (silica gel, methanol in dichloromethane) to give 60 mg (45%) of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.96 (s, 1H), 9.87 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.70 (d , J = 8.5 Hz, 1H), 7.55 (m, 2H), 7.32 (m, 4H), 6.98 (m, 4H), 6.72 (d, J = 8.6 Hz, 2H) ), 4.43 (m, 1H), 4.39 (m, 1H), 4.02 (m, 2H), 3.65 (s, 3H), 3.62 (m, 2H), 3.53 (S, 3H), 3.52 (s, 3H), 2.87 (m, 1H), 2.70 (m, 2H), 2.15 (m, 2H), 1.90 (m, 8H) , 0.90 (m, 12H); MS (ESI) m / z 839 (M + H) ⁺ .

［実施例２］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）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）ジカルバメート

[Example 2]
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4- (benzyloxy) phenyl) cyclopropane-1 , 2-diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) Dicarbamate

実施例２Ａ
（４−（ベンジルオキシ）フェニル）（トリブチルスタンニル）メチルメチルカルボネート
リチウムジイソプロピルアミド（ヘプタン／テトラヒドロフラン／エチルベンゼン中２．０Ｍ、１０．５ｍＬ、２１ｍｍｏｌ）、水素化トリ−ｎ−ブチルスズ（５．５５ｍＬ、２１ｍｍｏｌ）、４−ベンジルオキシベンズアルデヒド（４．２４ｇ、２０ｍｍｏｌ）およびクロロギ酸メチル（１．８６ｍＬ、２４ｍｍｏｌ）の溶液を、実施例１Ｂに記載した方法を用いて処理して、標題化合物４．６ｇ（４１％）を得た。

Example 2A
(4- (Benzyloxy) phenyl) (tributylstannyl) methyl methyl carbonate lithium diisopropylamide (2.0 M in heptane / tetrahydrofuran / ethylbenzene, 10.5 mL, 21 mmol), tri-n-butyltin hydride (5.55 mL) , 21 mmol), 4-benzyloxybenzaldehyde (4.24 g, 20 mmol) and methyl chloroformate (1.86 mL, 24 mmol) were treated using the method described in Example 1B to give 4.6 g of the title compound. (41%) was obtained.

実施例２Ｂ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
実施例２Ａからの生成物（０．３４ｇ、０．６ｍｍｏｌ）、実施例１Ａからの生成物（０．１２ｇ、０．２ｍｍｏｌ）および三フッ化ホウ素エーテレート（０．０７６ｍＬ、０．６ｍｍｏｌ）を、実施例１Ｃに記載した方法を用いて処理して、標題化合物１０８ｍｇ（６７％）を得た。

Example 2B
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene) )) Bis (azanediyl) bis (oxomethylene) dipyrrolidine-1-carboxylate Product from Example 2A (0.34 g, 0.6 mmol), Product from Example 1A (0.12 g, 0.2 mmol) And boron trifluoride etherate (0.076 mL, 0.6 mmol) were treated using the method described in Example 1C to afford 108 mg (67%) of the title compound.

実施例２Ｃ
（２Ｓ，２’Ｓ）−Ｎ，Ｎ’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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２Ｂからの生成物（１００ｍｇ、０．１２５ｍｍｏｌ）を、実施例１Ｄに記載した方法を用いて処理して、標題化合物７５ｍｇ（１００％）を得た。

Example 2C
(2S, 2'S) -N, N '-(4,4'-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) dipyrrolidine 2-Carboxamide The product from Example 2B (100 mg, 0.125 mmol) was treated using the method described in Example 1D to give 75 mg (100%) of the title compound.

実施例２Ｄ
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）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）ジカルバメート
実施例２Ｃからの生成物（７５ｍｇ、０．１２５ｍｍｏｌ）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（４６ｍｇ、０．２６３ｍｍｏｌ）を、実施例１Ｅに記載した方法を用いて処理して、標題化合物７０ｍｇ（５９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）ｄ ｐｐｍ ０．８８（ｔ，Ｊ＝６．０７Ｈｚ，６Ｈ）０．９３（ｔ，Ｊ＝７．２６Ｈｚ，６Ｈ）１．７７−２．２０（ｍ，１０Ｈ）、２．７０（ｄ，Ｊ＝５．８６Ｈｚ，２Ｈ）、２．９０（ｔ，Ｊ＝５．７５Ｈｚ，１Ｈ）、３．５２（ｓ，３Ｈ）、３．５３（ｓ，３Ｈ）、３．５７−３．６７（ｍ，２Ｈ）、３．７５−３．８５（ｍ，２Ｈ）、４．０３（ｑ，Ｊ＝８．３５Ｈｚ，２Ｈ）、４．３９（ｄｄ，Ｊ＝７．９２，４．８８Ｈｚ，１Ｈ）、４．４４（ｄｄ，Ｊ＝８．１３，４．７７Ｈｚ，１Ｈ）、４．９９（ｓ，２Ｈ）、６．８０（ｄ，Ｊ＝８．５７Ｈｚ，２Ｈ）、６．９８（ｄｄ，Ｊ＝８．７８，２．２８Ｈｚ，４Ｈ）、７．２６−７．４２（ｍ，１１Ｈ）、７．５３（ｄ，Ｊ＝８．５７Ｈｚ，２Ｈ）、９．８７（ｓ，１Ｈ）、９．９６（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ ９１５（Ｍ＋Ｈ）^＋。

Example 2D
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4- (benzyloxy) phenyl) cyclopropane-1 , 2-diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) Dicarbamate The product from Example 2C (75 mg, 0.125 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (46 mg, 0.263 mmol) were prepared according to the method described in Example 1E. To give 70 mg (59%) of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) d ppm 0.88 (t, J = 6.07 Hz, 6H) 0.93 (t, J = 7.26 Hz, 6H) 1.77-2.20 (m , 10H), 2.70 (d, J = 5.86 Hz, 2H), 2.90 (t, J = 5.75 Hz, 1H), 3.52 (s, 3H), 3.53 (s, 3H) ), 3.57-3.67 (m, 2H), 3.75-3.85 (m, 2H), 4.03 (q, J = 8.35 Hz, 2H), 4.39 (dd, J = 7.92, 4.88 Hz, 1H), 4.44 (dd, J = 8.13, 4.77 Hz, 1H), 4.99 (s, 2H), 6.80 (d, J = 8. 57 Hz, 2H), 6.98 (dd, J = 8.78, 2.28 Hz, 4H), 7.26-7.42 (m, 11H), 7.53 (d, J = 8. 7Hz, 2H), 9.87 (s , 1H), 9.96 (s, 1H); MS (ESI) m / z 915 (M + H) +.

［実施例３］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−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））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）ジカルバメート

[Example 3]
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(4,4'-(3- (4-methoxyphenyl) cyclo Propane-1,2-diyl) bis (4,1-phenylene)) bis (1H-imidazole-4,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane -2,1-diyl) dicarbamate

実施例３Ａ
（Ｅ）−１，２−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）エタン
（Ｅ）−１，２−ビス（４−ブロモフェニル）エテン（１０ｇ、２９．６ｍｍｏｌ）、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）（１６．５３ｇ、６５．１ｍｍｏｌ）、酢酸カリウム（８．７１ｇ、８９ｍｍｏｌ）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）、ジクロロメタンとの錯体（２．４２ｇ、２．９６ｍｍｏｌ）のジオキサン（５５０ｍＬ）中溶液を、１００℃で１８時間加熱した。次いで混合物を珪藻土を通して濾過し、濾液を濃縮し、残留物を酢酸エチルに溶解し、ブラインで抽出した。有機抽出物を少容量に濃縮し、シリカゲルのショートパッドに通し、次いで濃縮して、標題化合物９．６ｇ（７５％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ４３３（Ｍ＋Ｈ）^＋。

Example 3A
(E) -1,2-bis (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethane (E) -1,2-bis (4 -Bromophenyl) ethene (10 g, 29.6 mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (16.53 g, 65.1 mmol), potassium acetate (8.71 g, 89 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), complex with dichloromethane (2.42 g, 2 .96 mmol) in dioxane (550 mL) was heated at 100 ° C. for 18 h. The mixture was then filtered through diatomaceous earth, the filtrate was concentrated and the residue was dissolved in ethyl acetate and extracted with brine. The organic extract was concentrated to a small volume, passed through a short pad of silica gel and then concentrated to give 9.6 g (75%) of the title compound. MS (ESI) m / z 433 (M + H) ^<+> .

実施例３Ｂ
２，２’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン）
実施例３Ａからの生成物（１．０ｇ、２．３１ｍｍｏｌ）、実施例１Ｂからの生成物（１．１８ｇ、２．４３ｍｍｏｌ）および三フッ化ホウ素エーテレート（０．３０８ｍＬ、２．４３ｍｍｏｌ）を、実施例１Ｃに記載した方法を用いて処理して、標題化合物１００ｍｇ（８％）を得た。

Example 3B
2,2 ′-(4,4 ′-(3- (4-methoxyphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (4,4,5,5-tetramethyl -1,3,2-dioxaborolane)
The product from Example 3A (1.0 g, 2.31 mmol), the product from Example 1B (1.18 g, 2.43 mmol) and boron trifluoride etherate (0.308 mL, 2.43 mmol) were Work up using the method described in Example 1C to give 100 mg (8%) of the title compound.

Example 3C
(S) -tert-butyl 2-formylpyrrolidine-1-carboxylate Oxalyl chloride (5.32 mL, 60.8 mmol) and anhydrous dichloromethane (125 mL) were combined under nitrogen and the solution was cooled to −78 ° C. A solution of anhydrous dimethyl sulfoxide (7.30 mL, 103 mmol) in anhydrous dichloromethane (25 mL) was added dropwise over 20 minutes. A solution of (S) -tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate (9.41 g, 46.8 mmol) in anhydrous dichloromethane (50 mL) was added dropwise over 20 minutes and then the reaction mixture was added. Stir at −78 ° C. for 30 minutes. Triethylamine (32.6 mL, 234 mmol) was then added dropwise over 5 minutes and the reaction mixture was stirred in an ice-water bath for 30 minutes. The reaction was quenched with 10% (w / v) aqueous citric acid (30 mL) and the resulting mixture was partitioned between diethyl ether (550 mL) and 10% (w / v) aqueous citric acid. The organic phase was subsequently washed with water and brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the title compound (9.4 g), which was used directly in the next reaction.

Example 3D
(S) -tert-butyl 2- (1H-imidazol-2-yl) pyrrolidine-1-carboxylate The product from Example 3C (20 g, 100 mmol) was dissolved in methanol (50.2 mL) and ammonium hydroxide. (50.2 mL) was added. To this solution, glyoxal (40% in water; 24.08 mL, 211 mmol) was added dropwise over 10 minutes. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, diluted with 50 mL of water and then extracted with ethyl acetate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was treated with ether and concentrated. The solid was then triturated with 2: 1 diethyl ether: hexane (150 mL) to give 17 g of solid, which was used directly in the next reaction.

Example 3E
(S) -tert-Butyl 2- (4,5-dibromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate N-bromosuccinimide (108 mmol) was prepared from the product from Example 3D (12.05 g 50.8 mmol) in dichloromethane (200 mL) was added to a cooled solution (0 ° C.). The reaction mixture was stirred in an ice bath for 2 hours and then concentrated. The residue was dissolved in ethyl acetate (250 mL) and the resulting solution was extracted with water (3 × 150 mL) and brine (1 × 100 mL). The organic phase was dried (MgSO ₄ ) and concentrated. The residue was treated with dichloromethane / hexane (1: 1) to give a brown solid (ca. 19 g). The solid was triturated with diethyl ether (ca. 100 mL) and the title compound was collected by filtration (13.23 g, 65% yield).

実施例３Ｆ
（Ｓ）−ｔｅｒｔ−ブチル２−（５−ブロモ−１Ｈ−イミダゾール−２−イル）ピロリジン−１−カルボキシレートまたは（Ｓ）−ｔｅｒｔ−ブチル２−（４−ブロモ−１Ｈ−イミダゾール−２−イル）ピロリジン−１−カルボキシレート
実施例３Ｅからの生成物（６．２５ｇ、１５．８２ｍｍｏｌ）をジオキサン（２００ｍＬ）および水（２００ｍＬ）に溶解した。亜硫酸ナトリウム（２２．３８ｇ、１７４ｍｍｏｌ）の水（２００ｍＬ）中溶液を加え、反応混合物を１６時間還流下で加熱した。反応混合物を室温に冷却し、減圧下で濃縮し、ジクロロメタンで抽出した。合わせた有機抽出物をブライン（５０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で脱水し、濾過し、減圧下で濃縮し、２：１ヘキサン／ジクロロメタン（１００ｍＬ）との共蒸発を行って、粗製の標題化合物（４．３８ｇ）を得た。粗生成物をジクロロメタン（２ｍＬ）に溶解し、ヘキサン（２ｍＬ）を加えた。溶液を３０％から８０％酢酸エチル／ヘキサンで溶離するシリカゲルフラッシュクロマトグラフィーにより精製して、標題化合物（３．４８ｇ、収率７０％）を得た。

Example 3F
(S) -tert-butyl 2- (5-bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate or (S) -tert-butyl 2- (4-bromo-1H-imidazol-2-yl) ) Pyrrolidine-1-carboxylate The product from Example 3E (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 reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and extracted with dichloromethane. The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and coevaporated with 2: 1 hexane / dichloromethane (100 mL) to give crude. Of the title compound (4.38 g). The crude product was dissolved in dichloromethane (2 mL) and hexane (2 mL) was added. The solution was purified by silica gel flash chromatography eluting with 30% to 80% ethyl acetate / hexanes to give the title compound (3.48 g, 70% yield).

実施例３Ｇ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−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−カルボキシレート
実施例３Ｂからの生成物（１００ｍｇ、０．１８１ｍｍｏｌ）、実施例３Ｆからの生成物（１７２ｍｇ、０．５４３ｍｍｏｌ）、［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）、ジクロロメタンとの錯体（１４．８ｍｇ、０．０１８ｍｍｏｌ）および炭酸ナトリウムの溶液（水中１．０Ｍ、０．５４３ｍＬ、０．５４３ｍｍｏｌ）を、エタノール（１．５ｍＬ）およびトルエン（１．５ｍＬ）の溶液中８５℃で１８時間加熱した。水（１０ｍＬ）を加え、続いて酢酸エチル（１０ｍＬで２回）で抽出した。合わせた有機洗液を乾燥し、濾過し、濃縮した。残留物をクロマトグラフィー（シリカゲル、ジクロロメタン中メタノール）により精製して、標題化合物７０ｍｇ（５０％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ７７１（Ｍ＋Ｈ）^＋。

Example 3G
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(4,4 ′-(3- (4-methoxyphenyl) cyclopropane-1,2-diyl) bis (4 1-phenylene)) bis (1H-imidazole-4,2-diyl)) dipyrrolidine-1-carboxylate product from Example 3B (100 mg, 0.181 mmol), product from Example 3F (172 mg, 0 .543 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), a complex with dichloromethane (14.8 mg, 0.018 mmol) and a solution of sodium carbonate (1.0 M in water, 0. 543 mL, 0.543 mmol) was heated in a solution of ethanol (1.5 mL) and toluene (1.5 mL) at 85 ° C. for 18 hours. Water (10 mL) was added followed by extraction with ethyl acetate (2 × 10 mL). The combined organic washings were dried, filtered and concentrated. The residue was purified by chromatography (silica gel, methanol in dichloromethane) to give 70 mg (50%) of the title compound. MS (ESI) m / z 771 (M + H) ^<+> .

実施例３Ｈ
（Ｓ）−４，４’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−イミダゾール）
実施例３Ｇからの生成物（７０ｍｇ、０．０９１ｍｍｏｌ）を、実施例１Ｄに記載した方法を用いて処理して、標題化合物５２ｍｇ（１００％）を得た。

Example 3H
(S) -4,4 ′-(4,4 ′-(3- (4-methoxyphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (2-((S) -Pyrrolidin-2-yl) -1H-imidazole)
The product from Example 3G (70 mg, 0.091 mmol) was treated using the method described in Example 1D to give 52 mg (100%) of the title compound.

実施例３Ｉ
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（４，４’−（３−（４−メトキシフェニル）シクロプロパン−１，２−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））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）ジカルバメート
実施例３Ｈからの生成物（５０ｍｇ、０．０８８ｍｍｏｌ）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（３０ｍｇ、０．１７１ｍｍｏｌ）を、実施例１Ｅに記載した方法を用いて処理して、標題化合物３１ｍｇ（４０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ １４．５（ｂｓ，２Ｈ）、７．９８（ｂｓ，１Ｈ）、７．９０（ｂｓ，１Ｈ）、７．７８（ｍ，２Ｈ）、７．６４（ｍ，４Ｈ）、７．２９（ｔ，Ｊ＝７．８Ｈｚ，２Ｈ）、７．１８（ｍ，２Ｈ）、７．０５（ｍ，２Ｈ）、６．７２（ｍ，２Ｈ）、５．０９（ｍ，２Ｈ）、４．０７（ｍ，２Ｈ）、３．８３（ｍ，４Ｈ）、３．５４（ｓ，３Ｈ）、３．５３（ｓ，６Ｈ）、３．１８（ｍ，１Ｈ）、２．９２（ｍ，２Ｈ）、２．３５（ｍ，２Ｈ）、２．０１（ｍ，８Ｈ）、０．８８（ｍ，１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ ８８５（Ｍ＋Ｈ）^＋。

Example 3I
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(4,4'-(3- (4-methoxyphenyl) cyclo Propane-1,2-diyl) bis (4,1-phenylene)) bis (1H-imidazole-4,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane -2,1-Diyl) dicarbamate The product from Example 3H (50 mg, 0.088 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (30 mg, 0.171 mmol) were run. Work up using the method described in Example 1E to give 31 mg (40%) of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 14.5 (bs, 2H), 7.98 (bs, 1H), 7.90 (bs, 1H), 7.78 (m, 2H), 7. 64 (m, 4H), 7.29 (t, J = 7.8 Hz, 2H), 7.18 (m, 2H), 7.05 (m, 2H), 6.72 (m, 2H), 5 .09 (m, 2H), 4.07 (m, 2H), 3.83 (m, 4H), 3.54 (s, 3H), 3.53 (s, 6H), 3.18 (m, 1H), 2.92 (m, 2H), 2.35 (m, 2H), 2.01 (m, 8H), 0.88 (m, 12H); MS (ESI) m / z 885 (M + H) ⁺ .

［実施例４］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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））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）ジカルバメート

[Example 4]
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(4,4'-(3- (4- (benzyloxy)) Phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (1H-imidazole-4,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl- 1-oxobutane-2,1-diyl) dicarbamate

実施例４Ａ
２，２’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン）
実施例３Ａからの生成物（０．２５ｇ、０．５７８ｍｍｏｌ）、実施例２Ａからの生成物（１．６２ｇ、２．８９ｍｍｏｌ）および三フッ化ホウ素エーテレート（０．３６７ｍＬ、２．８９ｍｍｏｌ）を、実施例１Ｃに記載した方法を用いて処理して、標題化合物１５０ｍｇ（４１％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ６２９（Ｍ＋Ｈ）^＋。

Example 4A
2,2 ′-(4,4 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolane)
The product from Example 3A (0.25 g, 0.578 mmol), the product from Example 2A (1.62 g, 2.89 mmol) and boron trifluoride etherate (0.367 mL, 2.89 mmol) were Work up using the method described in Example 1C to give 150 mg (41%) of the title compound. MS (ESI) m / z 629 (M + H) ^<+> .

実施例４Ｂ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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−カルボキシレート
実施例４Ａからの生成物（１５０ｍｇ、０．２３９ｍｍｏｌ）、実施例３Ｆからの生成物（３０３ｍｇ、０．９５５ｍｍｏｌ）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）、ジクロロメタンとの錯体（２４．４ｍｇ、０．０３ｍｍｏｌ）を、実施例３Ｇに記載した方法を用いて処理して、標題化合物１３０ｍｇ（６４％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ８４７（Ｍ＋Ｈ）^＋。

Example 4B
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(4,4 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (1H-imidazole-4,2-diyl)) dipyrrolidine-1-carboxylate product from Example 4A (150 mg, 0.239 mmol), product from Example 3F ( 303 mg, 0.955 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), a complex with dichloromethane (24.4 mg, 0.03 mmol) was prepared according to the method described in Example 3G. To give 130 mg (64%) of the title compound. MS (ESI) m / z 847 (M + H) ^<+> .

実施例４Ｃ
（Ｓ）−４，４’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（２−（（Ｓ）−ピロリジン−２−イル）−１Ｈ−イミダゾール）
実施例４Ｂからの生成物（１２５ｍｇ、０．１４８ｍｍｏｌ）を、実施例１Ｄに記載した方法を用いて処理して、標題化合物９５ｍｇ（１００％）を得た。

Example 4C
(S) -4,4 ′-(4,4 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (2- ( (S) -pyrrolidin-2-yl) -1H-imidazole)
The product from Example 4B (125 mg, 0.148 mmol) was treated using the method described in Example 1D to give 95 mg (100%) of the title compound.

実施例４Ｄ
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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））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）ジカルバメート
実施例４Ｃからの生成物（９５ｍｇ、０．１４８ｍｍｏｌ）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（５２ｍｇ、０．２９６ｍｍｏｌ）を、実施例１Ｅに記載した方法を用いて処理して、標題化合物５７ｍｇ（４０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ １４．６（ｂｓ，２Ｈ）、７．９９（ｂｓ，１Ｈ）、７．９３（ｂｓ，１Ｈ）、７．７９（ｄ，Ｊ＝７．９Ｈｚ，２Ｈ）、７．５９（ｄ，Ｊ＝７．９Ｈｚ，２Ｈ）、７．５６（ｍ，２Ｈ）、７．３１（ｍ，７Ｈ）、７．２０（ｍ，２Ｈ）、７．０４（ｍ，２Ｈ）、６．８１（ｍ，２Ｈ）、５．１４（ｍ，２Ｈ）、４．９９（ｓ，２Ｈ）、４．１０（ｍ，２Ｈ）、３．８３（ｍ，４Ｈ）、３．５４（ｓ，３Ｈ）、３．５３（ｓ，６Ｈ）、３．２０（ｍ，１Ｈ）、２．９５（ｍ，２Ｈ）、２．３５（ｍ，２Ｈ）、２．０５（ｍ，８Ｈ）、０．９１（ｍ，１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ ９６１（Ｍ＋Ｈ）^＋。

Example 4D
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(4,4'-(3- (4- (benzyloxy)) Phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (1H-imidazole-4,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl- 1-oxobutane-2,1-diyl) dicarbamate The product from Example 4C (95 mg, 0.148 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (52 mg, 0.296 mmol) Was treated using the method described in Example 1E to give 57 mg (40%) of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 14.6 (bs, 2H), 7.9 (bs, 1H), 7.93 (bs, 1H), 7.79 (d, J = 7.9 Hz) , 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.56 (m, 2H), 7.31 (m, 7H), 7.20 (m, 2H), 7.04 ( m, 2H), 6.81 (m, 2H), 5.14 (m, 2H), 4.99 (s, 2H), 4.10 (m, 2H), 3.83 (m, 4H), 3.54 (s, 3H), 3.53 (s, 6H), 3.20 (m, 1H), 2.95 (m, 2H), 2.35 (m, 2H), 2.05 (m , 8H), 0.91 (m, 12H); MS (ESI) m / z 961 (M + H) ⁺ .

［実施例５］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（５，５’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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）ジカルバメート

[Example 5]
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(5,5 '-(3- (4- (benzyloxy) phenyl) cyclopropane-1 , 2-Diyl) bis (1H-benzo [d] imidazole-5,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) di Carbamate

実施例５Ａ
ｔｅｒｔ−ブチル４−ブロモ−１，２−フェニレンジカルバメート
４−ブロモ−１，２−ジアミノベンゼン（５．６１ｇ、３０ｍｍｏｌ）および飽和重炭酸ナトリウム溶液（１００ｍＬ）のテトラヒドロフラン（１５０ｍＬ）中懸濁液を、二炭酸ジ−ｔｅｒｔ−ブチル（１７．５ｇ、８０ｍｍｏｌ）で処理し、続いて窒素下で３日間撹拌した。混合物を酢酸エチルで希釈し、水（２回）および飽和塩化ナトリウム溶液で抽出した。脱水（Ｎａ_２ＳＯ_４）し、真空で濃縮して、粗生成物を褐色油状物として得た。この物質を酢酸エチルに溶解し、Ｄａｒｃｏ Ｇ−６０で処理した。混合物を珪藻土を通して濾過し、赤色濾液をＤａｒｃｏ Ｇ−６０で再度処理し、珪藻土を通して濾過した。濾液を真空で濃縮して、桃色固体を得、これをヘキサンで摩砕し、濾取した。真空乾燥機中５０℃で１８時間乾燥した後、これらの手順により、標題化合物（１０．２３ｇ、８８％）を極薄い桃色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．７６（ｓ，１Ｈ）、７．３２（ｓ，１Ｈ）、７．２４（ｍ，１Ｈ）、６．７３（ｓ，１Ｈ）、６．５４（ｓ，１Ｈ）、１．５２（ｓ，９Ｈ）、１．５１（ｓ，９Ｈ）；ＭＳ（ＥＳＩ−）ｍ／ｚ（相対存在率）３８５（１００，Ｍ−Ｈ）、３８７（９２）。

Example 5A
A suspension of tert-butyl 4-bromo-1,2-phenylenedicarbamate 4-bromo-1,2-diaminobenzene (5.61 g, 30 mmol) and saturated sodium bicarbonate solution (100 mL) in tetrahydrofuran (150 mL). , Treated with di-tert-butyl dicarbonate (17.5 g, 80 mmol), followed by stirring under nitrogen for 3 days. The mixture was diluted with ethyl acetate and extracted with water (twice) and saturated sodium chloride solution. Dehydrated (Na ₂ SO ₄ ) and concentrated in vacuo to give the crude product as a brown oil. This material was dissolved in ethyl acetate and treated with Darco G-60. The mixture was filtered through diatomaceous earth and the red filtrate was treated again with Darco G-60 and filtered through diatomaceous earth. The filtrate was concentrated in vacuo to give a pink solid that was triturated with hexane and collected by filtration. After drying in a vacuum dryer at 50 ° C. for 18 hours, these procedures yielded the title compound (10.23 g, 88%) as a very light pink solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.76 (s, 1H), 7.32 (s, 1H), 7.24 (m, 1H), 6.73 (s, 1H), 6.54 ( s, 1H), 1.52 (s, 9H), 1.51 (s, 9H); MS (ESI-) m / z (relative abundance) 385 (100, MH), 387 (92).

実施例５Ｂ
ｔｅｒｔ−ブチル４−（（トリメチルシリル）エチニル）−１，２−フェニレンジカルバメート
マイクロ波管中、実施例５Ａの化合物（２．０ｇ、５．１６ｍｍｏｌ）のトリエチルアミン（１７ｍＬ）中溶液を、２０分間窒素スパージすることにより脱気した。次いで溶液をビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリド（１８１ｍｇ、０．２６ｍｍｏｌ）およびヨウ化銅（Ｉ）（９８ｍｇ、０．５２ｍｍｏｌ）で処理し、続いてさらに１０分間窒素でスパージした。混合物をトリメチルシリルアセチレン（１．０９ｍＬ、７６１ｍｇ、７．７５ｍｍｏｌ）で処理した。マイクロ波管を密閉し、混合物を７０℃で１８時間加温した。混合物を冷却し、酢酸エチルで希釈し、水および飽和塩化ナトリウム溶液で抽出した。溶液を脱水（Ｎａ_２ＳＯ_４）し、３−（メルカプトプロピル）シリカゲルと共に１時間撹拌した。濾過し、真空で濃縮して油状物を得、これをヘキサン中０−２０％酢酸エチルで溶離する１２０ｇシリカゲルカートリッジ上でクロマトグラフィーにかけた。これらの手順により、標題化合物（１．６５ｇ、７９％）を白色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．５６（ｍ，２Ｈ）、７．２７（ｓ，１Ｈ）、６．７７（ｓ，１Ｈ）、６．５６（ｓ，１Ｈ）、１．５２（ｓ，１８Ｈ）、０．２３（ｍ，９Ｈ）；ＭＳ（ＥＳＩ＋） ｍ／ｚ（相対存在率）４０５（８，Ｍ＋Ｈ）^＋、４２１（３６，Ｍ＋ＮＨ_４）^＋、８２６（１００，２Ｍ＋ＮＨ_４）^＋。

Example 5B
tert-Butyl 4-((trimethylsilyl) ethynyl) -1,2-phenylenedicarbamate In a microwave tube, a solution of the compound of Example 5A (2.0 g, 5.16 mmol) in triethylamine (17 mL) is nitrogenated for 20 minutes. Degassed by sparging. The solution was then treated with bis (triphenylphosphine) palladium (II) chloride (181 mg, 0.26 mmol) and copper (I) iodide (98 mg, 0.52 mmol), followed by sparging with nitrogen for an additional 10 minutes. The mixture was treated with trimethylsilylacetylene (1.09 mL, 761 mg, 7.75 mmol). The microwave tube was sealed and the mixture was warmed at 70 ° C. for 18 hours. The mixture was cooled, diluted with ethyl acetate and 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. Filtration and concentration in vacuo gave an oil that was chromatographed on a 120 g silica gel cartridge eluting with 0-20% ethyl acetate in hexane. These procedures gave the title compound (1.65 g, 79%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.56 (m, 2H), 7.27 (s, 1H), 6.77 (s, 1H), 6.56 (s, 1H), 1.52 ( s, 18H), 0.23 (m, 9H); MS (ESI +) m / z (relative abundance) 405 (8, M + H) ⁺ , 421 (36, M + NH ₄ ) ⁺ , 826 (100, 2M + NH ₄ ) ⁺ .

実施例５Ｃ
ｔｅｒｔ−ブチル４−エチニル−１，２−フェニレンジカルバメート
実施例５Ｂの化合物（１．６８ｇ、４．１６ｍｍｏｌ）の２：１メタノール−テトラヒドロフラン中溶液を、炭酸カリウム（４０２ｍｇ、２．９１ｍｍｏｌ）で処理し、続いて室温で３時間撹拌した。溶液を酢酸エチルで希釈し、水および飽和塩化ナトリウム溶液で抽出した。脱水（Ｎａ_２ＳＯ_４）し、真空で濃縮して油状物を得、これをヘキサン中５−４０％酢酸エチルで溶離する１２０ｇシリカゲルカートリッジ上でクロマトグラフィーにかけた。これらの手順により、標題化合物（１．２１ｇ、８８％）を白色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．５８（ｓ，２Ｈ）、７．２６（ｍ，１Ｈ）、６．８０（ｓ，１Ｈ）、６．５６（ｓ，１Ｈ）、３．０２（ｓ，１Ｈ）、１．５１（ｓ，１８Ｈ）。ＭＳ＋ＥＳＩ ｍ／ｚ（相対存在率）３３３（１６，Ｍ＋Ｈ）^＋、３５０（１００，Ｍ＋ＮＨ_４）^＋、６８２（３８，２Ｍ＋ＮＨ_４）^＋。

Example 5C
tert-Butyl 4-ethynyl-1,2-phenylenedicarbamate A solution of the compound of Example 5B (1.68 g, 4.16 mmol) in 2: 1 methanol-tetrahydrofuran was treated with potassium carbonate (402 mg, 2.91 mmol). And then stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate and extracted with water and saturated sodium chloride solution. Dry (Na ₂ SO ₄ ) and concentrate in vacuo to give an oil that was chromatographed on a 120 g silica gel cartridge eluting with 5-40% ethyl acetate in hexane. These procedures gave the title compound (1.21 g, 88%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.58 (s, 2H), 7.26 (m, 1H), 6.80 (s, 1H), 6.56 (s, 1H), 3.02 ( s, 1H), 1.51 (s, 18H). MS + ESI m / z (relative abundance) 333 (16, M + H) ⁺ , 350 (100, M + NH ₄ ) ⁺ , 682 (38, 2M + NH ₄ ) ⁺ .

実施例５Ｄ
（Ｅ）−３，４−ビス（ｔｅｒｔ−ブトキシカルボニルアミノ）スチリルボロン酸
ボランメチルスルフィド錯体（３８４μＬ、３０７ｍｇ、４．０４ｍｍｏｌ）の乾燥テトラヒドロフラン（０．６７ｍＬ）中溶液を、０℃にて（１Ｒ）−（＋）−α−ピネン（１．２８ｍＬ、１．１０ｇ、８．０９ｍｍｏｌ）で処理し、続いて室温に３時間加温した。乳白色溶液を−４０℃に冷却し、実施例５Ｃの化合物（１．１２ｇ、３．３７ｍｍｏｌ）の乾燥テトラヒドロフラン（７ｍＬ；添加漏斗を濯ぐために２ｍＬ使用した）中溶液で１０分かけて滴下処理し、続いて室温に２時間加温した。混合物を０℃に冷却し、アセトアルデヒド（２．６６ｍＬ、２．０８ｇ、４７．２ｍｍｏＬ）で処理し、続いて室温に加温し、次いで還流下で１８時間加温した。混合物を室温に冷却し、真空で濃縮して、油状物を得た。この物質を水（５．０ｍＬ、２８０ｍｍｏｌ）およびテトラヒドロフラン（２ｍＬ）で処理し、続いて周囲温度で３時間撹拌した。混合物を酢酸エチルで希釈し、水および飽和塩化ナトリウム溶液で抽出した。脱水（Ｎａ_２ＳＯ_４）し、真空で濃縮して油状物を得、これはα−ピネン様の臭気がした。この物質をヘキサンで摩砕し、濾取した。真空乾燥機中５０℃で２時間乾燥した後、これらの手順により、標題化合物（６９９ｍｇ、５５％）を淡黄色粉体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ ８．５２（ｍ，３Ｈ）、７．７５（ｓ，２Ｈ）、７．４７（ｍ，２Ｈ）、７．１８（ｍ，３Ｈ）、６．００（ｄ，Ｊ＝１８．４Ｈｚ，１Ｈ）、１．４７（ｓ，１８Ｈ）；ＭＳ（ＥＳＩ−）ｍ／ｚ（相対存在率）３７７（１００，Ｍ−Ｈ）⁻。

Example 5D
(E) A solution of 3,4-bis (tert-butoxycarbonylamino) styrylboronic acid borane methyl sulfide complex (384 μL, 307 mg, 4.04 mmol) in dry tetrahydrofuran (0.67 mL) at 0 ° C. (1R )-(+)-Α-Pinene (1.28 mL, 1.10 g, 8.09 mmol) followed by warming to room temperature for 3 hours. The milky white solution was cooled to −40 ° C. and treated dropwise over 10 minutes with a solution of the compound of Example 5C (1.12 g, 3.37 mmol) in dry tetrahydrofuran (7 mL; 2 mL used to rinse the addition funnel). Subsequently, the mixture was warmed to room temperature for 2 hours. The mixture was cooled to 0 ° C. and treated with acetaldehyde (2.66 mL, 2.08 g, 47.2 mmol) followed by warming to room temperature then warming to reflux for 18 hours. The mixture was cooled to room temperature and concentrated in vacuo to give an oil. This material was treated with water (5.0 mL, 280 mmol) and tetrahydrofuran (2 mL), followed by stirring at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate and extracted with water and saturated sodium chloride solution. Dehydrated (Na ₂ SO ₄ ) and concentrated in vacuo to give an oil that had an α-pinene-like odor. This material was triturated with hexane and collected by filtration. After drying in a vacuum dryer at 50 ° C. for 2 hours, these procedures gave the title compound (699 mg, 55%) as a pale yellow powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.52 (m, 3H), 7.75 (s, 2H), 7.47 (m, 2H), 7.18 (m, 3H), 6. 00 (d, J = 18.4 Hz, 1H), 1.47 (s, 18H); MS (ESI−) m / z (relative abundance) 377 (100, MH) ⁻ .

実施例５Ｅ
（Ｅ）−ｔｅｒｔ−ブチル４，４’−（エテン−１，２−ジイル）ビス（ベンゼン−４，２，１−トリイル）テトラカルバメート
マイクロ波管中、実施例５Ｄの化合物（８６６ｍｇ、２．２９ｍｍｏｌ）、実施例５Ａの化合物（７３９ｍｇ、１．９１ｍｍｏｌ）、リン酸三カリウム（８１０ｍｇ、３．８２ｍｍｏｌ）およびＣｙｔｅｃ（登録商標）ＰＡ−Ｐｈ（Ｇ．Ａｄｊａｂｅｎｇら、Ｏｒｇ．Ｌｅｔｔ．２００３年、５巻、９５３頁；Ｇ．Ａｄｊａｂｅｎｇら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．２００４年、６９巻、５０８２頁）（５６ｍｇ、０．１９ｍｍｏｌ）の４：１テトラヒドロフラン−水（９．５ｍＬ）中懸濁液を、３０分間窒素スパージすることにより脱気した。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）（３５ｍｇ、０．０３８ｍｍｏｌ）で処理し、続いてさらに５分間脱気した。マイクロ波管を密閉し、混合物を８０℃で１８時間加温した。混合物を冷却し、酢酸エチルで希釈し、水、１Ｎリン酸三カリウム溶液および飽和塩化ナトリウム溶液で抽出した。溶液を脱水（Ｎａ_２ＳＯ_４）し、３−（メルカプトプロピル）シリカゲルと共に１時間撹拌した。濾過し、真空で濃縮した後、残留物をヘキサン中１０−７０％酢酸エチルで溶離する１２０ｇシリカゲルカートリッジ上でクロマトグラフィーにかけた。これらの手順により油状物を得、これをジクロロメタン−ヘキサンから結晶化し、真空乾燥機中５０℃で１８時間乾燥した後、標題化合物（７９４ｍｇ、６５％）を白色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．６２（ｓ，２Ｈ）、７．４７（ｓ，２Ｈ）、７．２５（ｄｄ，Ｊ＝１０．２，１．４Ｈｚ，２Ｈ）、６．９６（ｓ，１Ｈ）、６．７１（ｓ，４Ｈ）、１．５３（ｓ，１８Ｈ）、１．５２（ｓ，１８Ｈ）；ＭＳ（ＥＳＩ−）ｍ／ｚ（相対存在率）６３９（１００，Ｍ−Ｈ）⁻。

Example 5E
(E) -tert-Butyl 4,4 ′-(ethene-1,2-diyl) bis (benzene-4,2,1-triyl) tetracarbamate The compound of Example 5D (866 mg, 2. 29 mmol), the compound of Example 5A (739 mg, 1.91 mmol), tripotassium phosphate (810 mg, 3.82 mmol) and Cytec® PA-Ph (G. Adjabeng et al., Org. Lett. 2003, 5 Vol. 953; G. Adjabeng et al., J. Org. Chem. 2004, 69, 5082) (56 mg, 0.19 mmol) in 4: 1 tetrahydrofuran-water (9.5 mL) Degassed by nitrogen sparging for 30 minutes. The mixture was treated with tris (dibenzylideneacetone) dipalladium (0) (35 mg, 0.038 mmol) followed by degassing for an additional 5 minutes. The microwave tube was sealed and the mixture was warmed at 80 ° C. for 18 hours. The mixture was cooled, diluted with ethyl acetate and extracted with water, 1N tripotassium phosphate solution and saturated sodium chloride solution. The solution was dehydrated (Na ₂ SO ₄ ) and stirred with 3- (mercaptopropyl) silica gel for 1 hour. After filtration and concentration in vacuo, the residue was chromatographed on a 120 g silica gel cartridge eluting with 10-70% ethyl acetate in hexane. These procedures gave an oil that was crystallized from dichloromethane-hexane and dried in a vacuum oven at 50 ° C. for 18 hours to give the title compound (794 mg, 65%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.62 (s, 2H), 7.47 (s, 2H), 7.25 (dd, J = 10.2, 1.4 Hz, 2H), 6.96 (S, 1H), 6.71 (s, 4H), 1.53 (s, 18H), 1.52 (s, 18H); MS (ESI-) m / z (relative abundance) 639 (100, M−H) ⁻ .

実施例５Ｆ
ｔｅｒｔ−ブチル４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（ベンゼン−４，２，１−トリイル）テトラカルバメート
実施例５Ｅの化合物（７９４ｍｇ、１．２４ｍｍｏｌ）および実施例２Ａの化合物（３．４８ｇ、６．２０ｍｍｏｌ）の３：１（乾燥）ジクロロメタン−トルエン（２０ｍＬ）中溶液を、−２５℃にて三フッ化ホウ素エーテレート（７８５μＬ、８７９ｍｇ、６．２０ｍｍｏｌ）で処理し、続いて−２５℃で１時間撹拌した。混合物を５ｍＬ飽和重炭酸ナトリウム溶液を加えることによりクエンチし、続いて周囲温度に加温した。混合物を酢酸エチルで希釈し、飽和重炭酸ナトリウム溶液で抽出した。脱水（Ｎａ_２ＳＯ_４）し、真空で濃縮して琥珀色油状物を得、これをヘキサン中１０−６０％酢酸エチルで溶離する３２０ｇシリカゲルカートリッジ上でクロマトグラフィーにかけた。これらの手順により、標題化合物（５２０ｍｇ、５０％）を灰白色の硬い泡状物として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．３３（ｍ，１５Ｈ）、６．９８（ｍ，４Ｈ）、６．７６（ｍ，４Ｈ）、６．６３（ｍ，４Ｈ）、４．９８（ｓ，２Ｈ）、２．７２（ｄ，Ｊ＝７．５Ｈｚ，１Ｈ）、２．６８（ｔ，Ｊ＝９．８Ｈｚ，２Ｈ）、１．５０（ｍ，９Ｈ）、１．４９（ｓ，９Ｈ）、１．４８（ｓ，１８Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対存在率）８５４（１００，Ｍ＋ＮＨ_４）^＋。

Example 5F
tert-Butyl 4,4 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (benzene-4,2,1-triyl) tetracarbamate Compound of Example 5E (794 mg , 1.24 mmol) and the compound of Example 2A (3.48 g, 6.20 mmol) in 3: 1 (dry) dichloromethane-toluene (20 mL) were added boron trifluoride etherate (785 μL, 879 mg, 6.20 mmol) followed by stirring at −25 ° C. for 1 hour. The mixture was quenched by adding 5 mL saturated sodium bicarbonate solution followed by warming to ambient temperature. The mixture was diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution. Dried _(Na 2 SO _4), to give an amber oil was concentrated in vacuo, which was chromatographed on 320g silica gel cartridge, eluting with 10-60% ethyl acetate in hexane. These procedures afforded the title compound (520 mg, 50%) as an off-white hard foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.33 (m, 15H), 6.98 (m, 4H), 6.76 (m, 4H), 6.63 (m, 4H), 4.98 ( s, 2H), 2.72 (d, J = 7.5 Hz, 1H), 2.68 (t, J = 9.8 Hz, 2H), 1.50 (m, 9H), 1.49 (s, 9H), 1.48 (s, 18H); MS (ESI +) m / z (relative abundance) 854 (100, M + NH ₄ ) ⁺ .

実施例５Ｇ
４，４’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ジベンゼン−１，２−ジアミン
実施例５Ｆの化合物（５２０ｍｇ、０．６２ｍｍｏｌ）を、塩化水素のジオキサン中溶液（４Ｎ、１５ｍＬ）に溶解し、続いて室温で２時間撹拌した。混合物をエーテルで希釈し、固体を濾取し、続いてエーテルで洗浄した。空気乾燥した後、固体を真空乾燥機中５０℃で１８時間乾燥した。これらの手順により、標題化合物（２８３ｍｇ、７８％）を淡褐色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ ７．３９（ｍ，１１Ｈ）、６．９８（ｍ，８Ｈ）、６．８１（ｍ，９Ｈ）、６．５１（ｍ，２Ｈ）、５．００（ｓ，２Ｈ）、２．７６（ｍ，１Ｈ）、２．６１（ｍ，２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対存在率）４３７（１００，Ｍ＋Ｈ）^＋、８７３（５０，２Ｍ＋Ｈ）^＋。

Example 5G
4,4 ′-(3- (4- (Benzyloxy) phenyl) cyclopropane-1,2-diyl) dibenzene-1,2-diamine The compound of Example 5F (520 mg, 0.62 mmol) was added to hydrogen chloride. Dissolved in a solution in dioxane (4N, 15 mL) followed by stirring at room temperature for 2 hours. The mixture was diluted with ether and the solid was collected by filtration followed by washing with ether. After air drying, the solid was dried in a vacuum dryer at 50 ° C. for 18 hours. These procedures gave the title compound (283 mg, 78%) as a light brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.39 (m, 11H), 6.98 (m, 8H), 6.81 (m, 9H), 6.51 (m, 2H), 5. 00 (s, 2H), 2.76 (m, 1H), 2.61 (m, 2H); MS (ESI +) m / z (relative abundance) 437 (100, M + H) ⁺ , 873 (50, 2M + H) ) ⁺ .

実施例５Ｈ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（５，５’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（２−アミノ−５，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
および
（２Ｓ）−ｔｅｒｔ−ブチル２−（２−アミノ−４−（２−（４−アミノ−３−（（Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピロリジン−２−カルボキサミド）フェニル）−３−（４−（ベンジルオキシ）フェニル）シクロプロピル）フェニルカルバモイル）ピロリジン−１−カルボキシレート
実施例５Ｇの化合物（２０９ｍｇ、０．３６ｍｍｏｌ）、１−（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−プロリン（１５８ｍｇ、０．７４ｍｍｏｌ）およびＯ−（７−アザベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルウロニウムヘキサフルオロホスフェート（ＨＡＴＵ、２８０ｍｇ、０．７４ｍｍｏｌ）の乾燥ジメチルスルホキシド（１．８ｍＬ）中溶液を、ジイソプロピルエチルアミン（６２７μＬ、４６４ｍｇ、３．５９ｍｍｏｌ）で処理し、続いて室温で２時間撹拌した。混合物を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。脱水（Ｎａ_２ＳＯ_４）し、真空で濃縮して、褐色固体を得、これを次のステップに直接使用した。

Example 5H
(2S, 2 ′S) -tert-butyl 2,2 ′-(5,5 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (2-amino-5) , 1-phenylene)) bis (azanediyl) bis (oxomethylene) dipyrrolidine-1-carboxylate and (2S) -tert-butyl 2- (2-amino-4- (2- (4-amino-3-(( S) -1- (tert-Butoxycarbonyl) pyrrolidine-2-carboxamido) phenyl) -3- (4- (benzyloxy) phenyl) cyclopropyl) phenylcarbamoyl) pyrrolidine-1-carboxylate Compound of Example 5G (209 mg , 0.36 mmol), 1- (tert-butoxycarbonyl) -L-proline (158 mg, 0.74 mmol) and O- (7- A solution of azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU, 280 mg, 0.74 mmol) in dry dimethyl sulfoxide (1.8 mL) was diluted with diisopropylethylamine. (627 μL, 464 mg, 3.59 mmol) followed by stirring at room temperature for 2 hours. The mixture was diluted with ethyl acetate and extracted with water (3 times) and saturated sodium chloride solution. Dehydrated (Na ₂ SO ₄ ) and concentrated in vacuo to give a brown solid that was used directly in the next step.

実施例５Ｉ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（５，５’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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−カルボキシレート
実施例５Ｈの化合物のトルエン（２ｍＬ）およびテトラヒドロフラン（０．５ｍＬ）中懸濁液を氷酢酸（１５０μＬ）で処理し、続いて７０℃で１時間加温した。混合物を冷却し、トルエンを用いて真空で（３回）濃縮して、酢酸を除去した。得られた固体をジクロロメタン中３−１２％メタノールで溶離する８０ｇシリカゲルカートリッジ上でクロマトグラフィーにかけた。これらの手順により油状物を得、これはエーテル−ヘキサンで摩砕すると固化した。固体を濾取し、ヘキサンで洗浄した。真空乾燥機中５０℃で２４時間乾燥した後、これらの手順により、標題化合物（５９ｍｇ、実施例５Ｇから２１％）を淡黄色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．３３（ｍ，５Ｈ）、６．９２（ｍ，２Ｈ）、６．７２（ｄ，Ｊ＝８．５，１Ｈ）、５．０９（ｍ，１Ｈ）、４．９４（ｓ，１Ｈ）、３．４０（ｓ，２Ｈ）、３．０４（ｓ，１Ｈ）、２．９２（ｄ，Ｊ＝８．４，１Ｈ）、２．７８（ｍ，０．５Ｈ）、２．１７（ｓ，２Ｈ）、２．００（ｓ，１Ｈ）、１．６２（ｓ，４Ｈ）、１．５１（ｓ，９Ｈ）、１．５０（ｓ，９Ｈ）、１．３０（ｍ，２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対存在率）７９５（１００，Ｍ＋Ｈ）^＋、７９６（４４）、１５８９（５２，２Ｍ＋Ｈ）^＋。

Example 5I
(2S, 2 ′S) -tert-butyl 2,2 ′-(5,5 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (1H-benzo [d ] Imidazole-5,2-diyl)) dipyrrolidine-1-carboxylate A suspension of the compound of Example 5H in toluene (2 mL) and tetrahydrofuran (0.5 mL) was treated with glacial acetic acid (150 μL) followed by 70. Warm for 1 hour at ° C. The mixture was cooled and concentrated in vacuo with toluene (3 times) to remove acetic acid. The resulting solid was chromatographed on an 80 g silica gel cartridge eluting with 3-12% methanol in dichloromethane. These procedures gave an oil that solidified upon trituration with ether-hexane. The solid was collected by filtration and washed with hexane. After drying in a vacuum dryer at 50 ° C. for 24 hours, these procedures gave the title compound (59 mg, 21% from Example 5G) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.33 (m, 5H), 6.92 (m, 2H), 6.72 (d, J = 8.5, 1H), 5.09 (m, 1H) ), 4.94 (s, 1H), 3.40 (s, 2H), 3.04 (s, 1H), 2.92 (d, J = 8.4, 1H), 2.78 (m, 0.5H), 2.17 (s, 2H), 2.00 (s, 1H), 1.62 (s, 4H), 1.51 (s, 9H), 1.50 (s, 9H), 1.30 (m, 2H); MS (ESI +) m / z (relative abundance) 795 (100, M + H) ⁺ , 796 (44), 1589 (52, 2M + H) ⁺ .

実施例５Ｊ
（Ｓ）−５，５’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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）
実施例５Ｉの化合物（５９ｍｇ、０．０７４ｍｍｏｌ）を、メタノール（４ｍＬ）を含む塩化水素のジオキサン中溶液（４Ｎ、６ｍＬ）に溶解し、続いて室温で１時間撹拌した。混合物を真空で濃縮し、続いて高真空下で乾燥した。生成物を次のステップに直接使用した。

Example 5J
(S) -5,5 ′-(3- (4- (benzyloxy) phenyl) cyclopropane-1,2-diyl) bis (2-((S) -pyrrolidin-2-yl) -1H-benzo [ d] imidazole)
The compound of Example 51 (59 mg, 0.074 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4N, 6 mL) containing methanol (4 mL), followed by stirring at room temperature for 1 hour. The mixture was concentrated in vacuo followed by drying under high vacuum. The product was used directly for the next step.

実施例５Ｋ
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（５，５’−（３−（４−（ベンジルオキシ）フェニル）シクロプロパン−１，２−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）ジカルバメート
実施例５Ｊの化合物（５５ｍｇ、０．０７４ｍｍｏｌ）、Ｎ−（メトキシカルボニル）−Ｌ−バリン（３３ｍｇ、０．１９ｍｍｏｌ）、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（３６ｍｇ、０．１９ｍｍｏｌ）および１−ヒドロキシベンゾトリアゾール（２８ｍｇ、０．１９ｍｍｏｌ）の乾燥Ｎ，Ｎ−ジメチルホルムアミド（４００μＬ）中溶液を、０℃にてＮ−メチルモルホリン（１６３μＬ、１５０ｍｇ、１．４９ｍｍｏｌ）で処理した。溶液を０℃で３０分間撹拌し、室温に２時間加温した。次いで溶液を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。脱水（Ｎａ_２ＳＯ_４）し、真空で濃縮して油状物を得、これをジクロロメタン中１−１２％メタノールで溶離する１０ｇシリカゲルカートリッジ上でクロマトグラフィーにかけた。これらの手順により、クロロホルム−ヘキサンで濃縮した後、標題化合物（３５ｍｇ、５２％）を灰白色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １０．４４（ｓ，１Ｈ）、１０．２６（ｓ，１Ｈ）、７．６８（ｓ，１Ｈ）、７．５３（ｍ，１Ｈ）、７．３０（ｍ，１０Ｈ）、６．９３（ｍ，４Ｈ）、６．７０（ｄ，Ｊ＝６．７，２Ｈ）、５．４１（ｍ，５Ｈ）、４．９３（ｓ，２Ｈ）、４．３３（ｍ，２Ｈ）、３．８５（ｍ，２Ｈ）、３．７０（ｓ，６Ｈ）、３．６３（ｓ，４Ｈ）、３．０８（ｓ，２Ｈ）、２．８３（ｍ，３Ｈ）、２．３７（ｓ，２Ｈ）、２．１８（ｍ，４Ｈ）、１．９４（ｍ，３Ｈ）、１．２４（ｍ，２Ｈ）、１．０５（ｍ，２Ｈ）、０．８６（ｍ，１２Ｈ）；ＭＳ（ＥＳＩ＋）ｍ／ｚ（相対存在率）９０９（１００，Ｍ＋Ｈ）^＋。

Example 5K
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(5,5 '-(3- (4- (benzyloxy) phenyl) cyclopropane-1 , 2-Diyl) bis (1H-benzo [d] imidazole-5,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) di Carbamate Compound of Example 5J (55 mg, 0.074 mmol), N- (methoxycarbonyl) -L-valine (33 mg, 0.19 mmol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride ( A solution of 36 mg, 0.19 mmol) and 1-hydroxybenzotriazole (28 mg, 0.19 mmol) in dry N, N-dimethylformamide (400 μL) was added at 0 ° C. Hollin (163μL, 150mg, 1.49mmol) was treated with. The solution was stirred at 0 ° C. for 30 minutes and warmed to room temperature for 2 hours. The solution was then diluted with ethyl acetate and extracted with water (3 times) and saturated sodium chloride solution. Dry (Na ₂ SO ₄ ) and concentrate in vacuo to give an oil that was chromatographed on a 10 g silica gel cartridge eluting with 1-12% methanol in dichloromethane. These procedures gave the title compound (35 mg, 52%) as an off-white solid after concentration with chloroform-hexane. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.44 (s, 1H), 10.26 (s, 1H), 7.68 (s, 1H), 7.53 (m, 1H), 7.30 ( m, 10H), 6.93 (m, 4H), 6.70 (d, J = 6.7, 2H), 5.41 (m, 5H), 4.93 (s, 2H), 4.33 (M, 2H), 3.85 (m, 2H), 3.70 (s, 6H), 3.63 (s, 4H), 3.08 (s, 2H), 2.83 (m, 3H) 2.37 (s, 2H), 2.18 (m, 4H), 1.94 (m, 3H), 1.24 (m, 2H), 1.05 (m, 2H), 0.86 ( m, 12H); MS (ESI +) m / z (relative abundance) 909 (100, M + H) ⁺ .

［実施例６］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（３−（４−シクロヘキシルフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）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）ジカルバメート

[Example 6]
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4-cyclohexylphenyl) cyclopropane-1,2- Diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate

実施例６Ａ
（２Ｓ，２’Ｓ）−Ｎ，Ｎ’−（４，４’−（３−（４−ヒドロキシフェニル）シクロプロパン−１，２−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２Ｂからの生成物（８５０ｍｇ、１．０６ｍｍｏｌ）に、三臭化ホウ素（ジクロロメタン中１．０Ｍ、２．３４ｍＬ、２．３４ｍｍｏｌ）のジクロロメタン（２５ｍＬ）中溶液を室温で０．２５時間加えた。次いでメタノール（２５ｍＬ）を溶液に加え、混合物を濃縮して、標題化合物５４０ｍｇ（７６％）をビス臭化水素酸塩として得た。ＭＳ（ＥＳＩ）ｍ／ｚ５１１（Ｍ＋Ｈ）^＋。

Example 6A
(2S, 2'S) -N, N '-(4,4'-(3- (4-hydroxyphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) dipyrrolidine-2- Carboxamide The product from Example 2B (850 mg, 1.06 mmol) was added to a solution of boron tribromide (1.0 M in dichloromethane, 2.34 mL, 2.34 mmol) in dichloromethane (25 mL) at room temperature for 0.25 hours. added. Methanol (25 mL) was then added to the solution and the mixture was concentrated to give 540 mg (76%) of the title compound as the bishydrobromide salt. MS (ESI) m / z 511 (M + H) ^<+> .

実施例６Ｂ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（３−（４−ヒドロキシフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
実施例６Ａからの生成物のビス臭化水素酸塩（６００ｍｇ、０．８９３ｍｍｏｌ）に、ジオキサン（２５ｍＬ）およびメタノール（３ｍＬ）中の二炭酸ジ−ｔｅｒｔ−ブチル（４８７ｍｇ、２．２３ｍｍｏｌ）およびトリエチルアミン（２．４９ｍＬ、１７．８６ｍｍｏｌ）を加え、混合物を室温で１時間撹拌した。次いで混合物を濃縮した。１Ｎ ＨＣｌの溶液（１０ｍＬ）を残留物に加え、続いてジクロロメタン（１０ｍＬで２回）で抽出した。有機抽出物を乾燥し、濾過し、濃縮した。次いで残留物をクロマトグラフィー（シリカゲル、ジクロロメタン中メタノール）により精製して、標題化合物４２５ｍｇ（６７％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ７１１（Ｍ＋Ｈ）^＋。その代わりに、Ｒａｎｅｙ（登録商標）ニッケルおよび高圧環境下での水素を用いることにより、実施例２Ｂの生成物中のベンジル基を除去して、実施例６Ｂ（ｔｅｒｔ−ブトキシカルボニル基を除去していない。）を得ることができる。

Example 6B
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(3- (4-hydroxyphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (Azandiyl) bis (oxomethylene) dipyrrolidine-1-carboxylate The product bishydrobromide salt from Example 6A (600 mg, 0.893 mmol) was added to dicarbonate in dioxane (25 mL) and methanol (3 mL). Di-tert-butyl (487 mg, 2.23 mmol) and triethylamine (2.49 mL, 17.86 mmol) were added and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated. A solution of 1N HCl (10 mL) was added to the residue followed by extraction with dichloromethane (2 × 10 mL). The organic extract was dried, filtered and concentrated. The residue was then purified by chromatography (silica gel, methanol in dichloromethane) to give 425 mg (67%) of the title compound. MS (ESI) m / z 711 (M + H) ^<+> . Instead, the benzyl group in the product of Example 2B was removed to remove Example 6B (the tert-butoxycarbonyl group) by using Raney® nickel and hydrogen under high pressure. Not.) Can be obtained.

実施例６Ｃ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（３−（４−（トリフルオロメチルスルホニルオキシ）フェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
ジクロロメタン（３ｍＬ）に溶解した実施例６Ｂからの生成物（５０ｍｇ、０．０７ｍｍｏｌ）に、トリエチルアミン（０．０９８ｍＬ、０．７０２ｍｍｏｌ）を加えた。次いでトリフルオロメタンスルホン酸無水物（０．０５９ｍＬ、０．３５２ｍｍｏｌ）のジクロロメタン（２ｍＬ）中溶液を、室温で滴下添加した。１時間後、１Ｎ ＨＣｌの溶液（５ｍＬ）を加え、続いてジクロロメタン（１０ｍＬ）で抽出した。有機抽出物を乾燥し、濾過し、濃縮して、標題化合物６０ｍｇ（１００％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ８４３（Ｍ＋Ｈ）^＋。

Example 6C
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(3- (4- (trifluoromethylsulfonyloxy) phenyl) cyclopropane-1,2-diyl) bis (4 1-phenylene)) bis (azanediyl) bis (oxomethylene) dipyrrolidine-1-carboxylate The product from Example 6B (50 mg, 0.07 mmol) dissolved in dichloromethane (3 mL) was added to triethylamine (0.098 mL, 0 .702 mmol) was added. A solution of trifluoromethanesulfonic anhydride (0.059 mL, 0.352 mmol) in dichloromethane (2 mL) was then added dropwise at room temperature. After 1 hour, a solution of 1N HCl (5 mL) was added followed by extraction with dichloromethane (10 mL). The organic extract was dried, filtered and concentrated to give 60 mg (100%) of the title compound. MS (ESI) m / z 843 (M + H) ^<+> .

実施例６Ｄ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（３−（４−シクロヘキセニルフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
ジメトキシエタン（３ｍＬ）および水（１ｍＬ）中の実施例６Ｃからの生成物（６０ｍｇ、０．０７０ｍｍｏｌ）、１−シクロヘキセン−イル−ボロン酸ピナコールエステル（１６．３ｍｇ、０．０７８ｍｍｏｌ）、重炭酸ナトリウム（２９．９ｍｇ、０．３５６ｍｍｏｌ）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）（１３ｍｇ、０．０１８ｍｍｏｌ）を８０℃で１７時間加熱した。次いで水（５ｍＬ）を混合物に加え、続いて酢酸エチル（５ｍＬで２回）で抽出した。有機抽出物を乾燥し、濾過し、濃縮した。次いで残留物をクロマトグラフィー（シリカゲル、ヘキサン中酢酸エチル）により精製して、標題化合物２０ｍｇ（３６％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ７７６（Ｍ＋Ｈ）^＋。

Example 6D
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(3- (4-cyclohexenylphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) Bis (azanediyl) bis (oxomethylene) dipyrrolidine-1-carboxylate product from Example 6C (60 mg, 0.070 mmol), 1-cyclohexenyl-boronic acid in dimethoxyethane (3 mL) and water (1 mL) Pinacol ester (16.3 mg, 0.078 mmol), sodium bicarbonate (29.9 mg, 0.356 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (13 mg, 0.018 mmol) ) At 80 ° C. for 17 hours. Water (5 mL) was then added to the mixture followed by extraction with ethyl acetate (2 x 5 mL). The organic extract was dried, filtered and concentrated. The residue was then purified by chromatography (silica gel, ethyl acetate in hexane) to give 20 mg (36%) of the title compound. MS (ESI) m / z 776 (M + H) ^<+> .

実施例６Ｅ
（２Ｓ，２’Ｓ）−ｔｅｒｔ−ブチル２，２’−（４，４’−（３−（４−シクロヘキシルフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）ビス（オキソメチレン）ジピロリジン−１−カルボキシレート
メタノール（３ｍＬ）中の実施例６Ｄからの生成物（２０ｍｇ、０．０２６ｍｍｏｌ）に、１０％パラジウム炭素（１１ｍｇ、０．１０３ｍｍｏｌ）を加え、混合物を水素雰囲気（風船）下に置いた。室温で２４時間水素化した後、混合物を珪藻土を通して濾過し、濾過ケーキをメタノールで洗浄した。濾液を濃縮して、標題化合物２０ｍｇ（１００％）を得た。ＭＳ（ＥＳＩ）ｍ／ｚ７７８（Ｍ＋Ｈ）^＋。

Example 6E
(2S, 2 ′S) -tert-butyl 2,2 ′-(4,4 ′-(3- (4-cyclohexylphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (Azandiyl) bis (oxomethylene) dipyrrolidine-1-carboxylate To the product from Example 6D (20 mg, 0.026 mmol) in methanol (3 mL) was added 10% palladium on carbon (11 mg, 0.103 mmol), The mixture was placed under a hydrogen atmosphere (balloon). After hydrogenation at room temperature for 24 hours, the mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The filtrate was concentrated to give 20 mg (100%) of the title compound. MS (ESI) m / z 778 (M + H) ^<+> .

実施例６Ｆ
（２Ｓ，２’Ｓ）−Ｎ，Ｎ’−（４，４’−（３−（４−シクロヘキシルフェニル）シクロプロパン−１，２−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６Ｆからの生成物（２０ｍｇ、０．０２６ｍｍｏｌ）を、実施例１Ｄに記載した方法を用いて処理して、標題化合物１５ｍｇ（１００％）を得た。

Example 6F
(2S, 2'S) -N, N '-(4,4'-(3- (4-cyclohexylphenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) dipyrrolidine-2- Carboxamide The product from Example 6F (20 mg, 0.026 mmol) was treated using the method described in Example 1D to give 15 mg (100%) of the title compound.

実施例６Ｇ
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（３−（４−シクロヘキシルフェニル）シクロプロパン−１，２−ジイル）ビス（４，１−フェニレン））ビス（アザンジイル）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）ジカルバメート
実施例６Ｆからの生成物（１５ｍｇ、０．０２６ｍｍｏｌ）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（９ｍｇ、０．０５２ｍｍｏｌ）を、実施例１Ｅに記載した方法を用いて処理して、標題化合物９ｍｇ（４０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δｐｐｍ ９．９６（ｓ，１Ｈ）、９．８７（ｓ，１Ｈ）、７．５３（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ）、７．３３（ｍ，５Ｈ）、６．９８（ｍ，５Ｈ）、４．４３（ｍ，１Ｈ）、４．３９（ｍ，１Ｈ）、４．０２（ｍ，２Ｈ）、３．８０（ｍ，４Ｈ）、３．６１（ｍ，２Ｈ）、３．５４（ｍ，６Ｈ）、２．９０（ｍ，１Ｈ）、２．７４（ｍ，１Ｈ）、２．６８（ｍ，１Ｈ）、２．１２（ｍ，２Ｈ）、１．８０（ｍ，１４Ｈ）、１．２６（ｍ，５Ｈ）、０．８８（ｍ，１２Ｈ）；ＭＳ（ＥＳＩ）ｍ／ｚ ８９１（Ｍ＋Ｈ）^＋。

Example 6G
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4-cyclohexylphenyl) cyclopropane-1,2- Diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate The product from Example 6F (15 mg, 0.026 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (9 mg, 0.052 mmol) were treated using the method described in Example 1E. This gave 9 mg (40%) of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.96 (s, 1H), 9.87 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.33 (m , 5H), 6.98 (m, 5H), 4.43 (m, 1H), 4.39 (m, 1H), 4.02 (m, 2H), 3.80 (m, 4H), 3 .61 (m, 2H), 3.54 (m, 6H), 2.90 (m, 1H), 2.74 (m, 1H), 2.68 (m, 1H), 2.12 (m, 2H), 1.80 (m, 14H), 1.26 (m, 5H), 0.88 (m, 12H); MS (ESI) m / z 891 (M + H) ⁺ .

［実施例７］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタ−３−エン−１，３−ジイル）ビス（４，１−フェニレン）ビス（アザンジイル）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）ジカルバメート

[Example 7]
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(2- (4-tert-butylphenyl) cyclopent-3-ene -1,3-diyl) bis (4,1-phenylene) bis (azanediyl) bis (oxomethylene)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1- Diyl) dicarbamate

実施例７Ａ
３−メトキシシクロペンタ−２−エノン
１，３−シクロペンタンジオン（１５．０ｇ、１５３ｍｍｏｌ）およびＩ_２（１．１６４ｇ、４．５９ｍｍｏｌ）のメタノール（１５０ｍＬ）中混合物を２５℃で１６時間撹拌した。溶媒を減圧下で除去した。残留物を酢酸エチル（２００ｍＬ）に溶解し、Ｎａ_２Ｓ_２Ｏ_３水溶液（１００ｍＬ）、水（１００ｍＬ）およびブライン（１００ｍＬ）で順次洗浄した。有機層をＮａ_２ＳＯ_４で脱水し、濾過し、真空で濃縮した。残留物をさらに精製せずに次のステップに使用した。ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ１１３（Ｍ＋Ｈ）^＋。

Example 7A
3-Methoxycyclopent-2-enone A mixture of 1,3-cyclopentanedione (15.0 g, 153 mmol) and I ₂ (1.164 g, 4.59 mmol) in methanol (150 mL) was stirred at 25 ° C. for 16 hours. . The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed sequentially with aqueous Na ₂ S ₂ O ₃ (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was used in the next step without further purification. LC / MS (ESI) m / z 113 (M + H) ^<+> .

実施例７Ｂ
２−ブロモ−３−メトキシシクロペンタ−２−エノン
実施例７Ａ（５００ｍｇ、４．４６ｍｍｏｌ）およびＮ−ブロモスクシンイミド（７９４ｍｇ、４．４６ｍｍｏｌ）のジクロロメタン（５ｍＬ）中混合物を２５℃で１６時間撹拌した。混合物を真空で濃縮した。残留物をシリカカラム（ジクロロメタン／メタノール＝２００：１、ｖ／ｖ）上で精製して、標題化合物（６５０ｍｇ、３．４０ｍｍｏｌ、収率７６％）を固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ４．１２（ｓ，３Ｈ）、２．７９−２．８２（ｍ，２Ｈ）、２．６２−２．６５（ｍ，２Ｈ）；ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ １９１（Ｍ＋Ｈ）^＋。

Example 7B
2-Bromo-3-methoxycyclopent-2-enone A mixture of Example 7A (500 mg, 4.46 mmol) and N-bromosuccinimide (794 mg, 4.46 mmol) in dichloromethane (5 mL) was stirred at 25 ° C. for 16 hours. . The mixture was concentrated in vacuo. The residue was purified on a silica column (dichloromethane / methanol = 200: 1, v / v) to give the title compound (650 mg, 3.40 mmol, 76% yield) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.12 (s, 3H), 2.79-2.82 (m, 2H), 2.62-2.65 (m, 2H); LC / MS (ESI ) M / z 191 (M + H) ⁺ .

実施例７Ｃ
２−（４−ｔｅｒｔ−ブチルフェニル）−３−メトキシシクロペンタ−２−エノン
実施例７Ｂ（４４０ｍｇ、２．３０３ｍｍｏｌ）、４−ｔｅｒｔ−ブチルフェニルボロン酸（４９２ｍｇ、２．７６ｍｍｏｌ）、［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）、ジクロロメタンとの錯体（１８８ｍｇ、０．２３０ｍｍｏｌ）およびＫ_２ＣＯ_３（６３７ｍｇ、４．６１ｍｍｏｌ）の１，４−ジオキサン（２ｍＬ）および水（０．５ｍＬ）中混合物を１００℃で１６時間撹拌した。混合物を酢酸エチル（１００ｍＬ）で希釈し、ブライン（３０ｍＬで４回）で洗浄した。有機層をＮａ_２ＳＯ_４で脱水し、濾過し、真空で濃縮した。残留物をカラムクロマトグラフィー（シリカゲル上、石油エーテル／酢酸エチル＝５：１、ｖ／ｖで溶離）により精製して、標題化合物（４４５ｍｇ、１．８２１ｍｍｏｌ、収率７９％）を白色固体として得た。ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ２４５（Ｍ＋Ｈ）^＋。

Example 7C
2- (4-tert-Butylphenyl) -3-methoxycyclopent-2-enone Example 7B (440 mg, 2.303 mmol), 4-tert-butylphenylboronic acid (492 mg, 2.76 mmol), [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), complex with dichloromethane (188 mg, 0.230 mmol) and K ₂ CO ₃ (637 mg, 4.61 mmol) of 1,4-dioxane (2 mL) and The mixture in water (0.5 mL) was stirred at 100 ° C. for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (4 × 30 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with petroleum ether / ethyl acetate = 5: 1, v / v) to give the title compound (445 mg, 1.821 mmol, 79% yield) as a white solid. It was. LC / MS (ESI) m / z 245 (M + H) ^<+> .

実施例７Ｄ
３−ブロモ−２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタ−２−エノン
実施例７Ｃ（２４５ｍｇ、１．００３ｍｍｏｌ）の１，２−ジクロロエタン（５ｍＬ）中溶液に、ＰＢｒ_３（０．１４２ｍＬ、１．５０４ｍｍｏｌ）を加えた。得られた混合物を１時間加熱還流し、次いで周囲温度に冷却し、砕いた氷上に注ぎ入れた。有機層を分離し、飽和ＮａＨＣＯ_３水溶液（５ｍＬ）で洗浄し、ＭｇＳＯ_４で脱水した。溶媒を減圧下で除去し、残留物をカラムクロマトグラフィー（シリカゲル上、ジクロロメタン／メタノール＝２００：１、ｖ／ｖで溶離）により精製して、標題化合物（２００ｍｇ、０．６８２ｍｍｏｌ、収率６８．０％）を薄黄色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．３８（ｓ，４Ｈ）、３．００−３．０３（ｍ，２Ｈ）、２．６２−２．６５（ｍ，２Ｈ）、１．２６（ｓ，９Ｈ）；ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ ２９３（Ｍ＋Ｈ）^＋。

Example 7D
3-Bromo-2- (4-tert-butylphenyl) cyclopent-2-enone To a solution of Example 7C (245 mg, 1.003 mmol) in 1,2-dichloroethane (5 mL) was added PBr ₃ (0.142 mL, 1 .504 mmol) was added. The resulting mixture was heated to reflux for 1 hour, then cooled to ambient temperature and poured onto crushed ice. The organic layer was separated, washed with saturated aqueous NaHCO ₃ (5 mL) and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, eluting with dichloromethane / methanol = 200: 1, v / v) to give the title compound (200 mg, 0.682 mmol, yield 68. 0%) was obtained as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.38 (s, 4H), 3.00-3.03 (m, 2H), 2.62-2.65 (m, 2H), 1.26 (s , 9H); LC / MS (ESI) m / z 293 (M + H) ⁺ .

実施例７Ｅ
ｔｅｒｔ−ブチル４−（２−（４−ｔｅｒｔ−ブチルフェニル）−３−オキソシクロペンタ−１−エニル）フェニルカルバメート
実施例７Ｄ（８８ｍｇ、０．３００ｍｍｏｌ）、ｔｅｒｔ−ブチル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）フェニルカルバメート（１０５ｍｇ、０．３３０ｍｍｏｌ）、［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）、ジクロロメタンとの錯体（２４．５１ｍｇ、０．０３０ｍｍｏｌ）およびＫ_２ＣＯ_３（８３ｍｇ、０．６００ｍｍｏｌ）の１，４−ジオキサン（２ｍＬ）および水（０．５ｍＬ）中混合物を１００℃で１６時間撹拌した。混合物を酢酸エチル（３０ｍＬ）で希釈し、ブライン（１０ｍＬで４回）で洗浄した。有機層をＮａ_２ＳＯ_４で脱水し、濾過し、真空で濃縮した。残留物を分取薄層クロマトグラフィー（石油エーテル／酢酸エチル＝２：１、ｖ／ｖで溶離）により精製して、標題化合物（６０ｍｇ、０．１４８ｍｍｏｌ、収率４９．３％）を白色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ７．２８−７．３６（ｍ，６Ｈ）、７．１４（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）、６．５２（ｓ，１Ｈ）、３．００−３．０３（ｍ，２Ｈ）、２．６６−２．６９（ｍ，２Ｈ）、１．５１（ｓ，９Ｈ）、１．３２（ｓ，９Ｈ）；ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ ４０６（Ｍ＋Ｈ）^＋。

Example 7E
tert-Butyl 4- (2- (4-tert-butylphenyl) -3-oxocyclopent-1-enyl) phenylcarbamate Example 7D (88 mg, 0.300 mmol), tert-butyl 4- (4,4,4) 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbamate (105 mg, 0.330 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), dichloromethane A mixture of the complex with (24.51 mg, 0.030 mmol) and K ₂ CO ₃ (83 mg, 0.600 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 100 ° C. for 16 h. . The mixture was diluted with ethyl acetate (30 mL) and washed with brine (4 × 10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (eluting with petroleum ether / ethyl acetate = 2: 1, v / v) to give the title compound (60 mg, 0.148 mmol, 49.3% yield) as a white solid Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.28-7.36 (m, 6H), 7.14 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H), 3.00 −3.03 (m, 2H), 2.66-2.69 (m, 2H), 1.51 (s, 9H), 1.32 (s, 9H); LC / MS (ESI) m / z 406 (M + H) ⁺ .

実施例７Ｆ
ｔｅｒｔ−ブチル４−（２−（４−ｔｅｒｔ−ブチルフェニル）−３−ヒドロキシシクロペンチル）フェニルカルバメート
実施例７Ｅ（２０ｍｇ、０．０４９ｍｍｏｌ）および１０％パラジウム炭素（５．２５ｍｇ、０．０４９ｍｍｏｌ）のメタノール（４ｍＬ）中混合物を水素雰囲気（風船）下２５℃で１６時間撹拌した。混合物を濾過し、濾液を真空で濃縮した。残留物をさらに精製せずに次のステップに直接使用した。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ６．６７−７．２５（ｍ，８Ｈ）、６．２６（ｓ，１Ｈ）、４．５３（ｂｒｓ，１Ｈ）、３．５２（ｂｒｓ，１Ｈ）、３．２９（ｂｒ，１Ｈ）、１．８２−２．２４（ｍ，４Ｈ）、１．４５（ｓ，９Ｈ）、１．２０（ｓ，９Ｈ）；ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ ４０８（Ｍ−Ｈ）⁻。

Example 7F
tert-Butyl 4- (2- (4-tert-butylphenyl) -3-hydroxycyclopentyl) phenylcarbamate Example 7E (20 mg, 0.049 mmol) and 10% palladium on carbon (5.25 mg, 0.049 mmol) in methanol The mixture in (4 mL) was stirred at 25 ° C. under a hydrogen atmosphere (balloon) for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was used directly in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.67-7.25 (m, 8H), 6.26 (s, 1H), 4.53 (brs, 1H), 3.52 (brs, 1H), 3.29 (br, 1H), 1.82-2.24 (m, 4H), 1.45 (s, 9H), 1.20 (s, 9H); LC / MS (ESI) m / z 408 (M−H) ⁻ .

実施例７Ｇ
ｔｅｒｔ−ブチル４−（２−（４−ｔｅｒｔ−ブチルフェニル）−３−オキソシクロペンチル）フェニルカルバメート
粗製の実施例７Ｆ（２６３ｍｇ、０．６４１ｍｍｏｌ）およびデス−マーチンペルヨージナン（２９９ｍｇ、０．７０５ｍｍｏｌ）のジクロロメタン（４ｍＬ）中混合物を２５℃で３０分間撹拌した。混合物を酢酸エチル（３０ｍＬ）で希釈し、飽和ＮａＨＣＯ_３溶液（１０ｍＬで４回）で洗浄し、次いで飽和Ｎａ_２Ｓ_２Ｏ_４溶液（１０ｍＬで４回）で洗浄した。有機層をＮａ_２ＳＯ_４で脱水し、濾過し、真空で濃縮した。残留物を分取薄層クロマトグラフィー（ジクロロメタン／メタノール＝２００：１、ｖ／ｖで溶離）により精製して、標題化合物（６０ｍｇ、０．１４７ｍｍｏｌ、収率２２．９７％）を薄黄色油状物として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ ＣＤＣｌ_３）δｐｐｍ ７．１８−７．２０（ｍ，４Ｈ）、７．０５（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ）、６．８９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）、６．３３（ｓ，１Ｈ）、３．３２−３．４２（ｍ，２Ｈ）、２．５７−２．６３（ｍ，１Ｈ）、２．３３−２．４１（ｍ，２Ｈ）、１．９５−１．９８（ｍ，１Ｈ）、１．４４（ｓ，９Ｈ）、１．１８（ｓ，９Ｈ）；ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ ４０６（Ｍ−Ｈ）⁻。

Example 7G
tert-Butyl 4- (2- (4-tert-butylphenyl) -3-oxocyclopentyl) phenylcarbamate Crude Example 7F (263 mg, 0.641 mmol) and Dess-Martin periodinane (299 mg, 0.705 mmol) Of dichloromethane in dichloromethane (4 mL) was stirred at 25 ° C. for 30 min. The mixture was diluted with ethyl acetate (30 mL) and washed with saturated NaHCO ₃ solution (4 × 10 mL) and then with saturated Na ₂ S ₂ O ₄ solution (4 × 10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (eluting with dichloromethane / methanol = 200: 1, v / v) to give the title compound (60 mg, 0.147 mmol, yield 22.97%) as a pale yellow oil. Got as. ¹ H NMR (400 MHz CDCl ₃ ) δ ppm 7.18-7.20 (m, 4H), 7.05 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H) ), 6.33 (s, 1H), 3.32-3.42 (m, 2H), 2.57-2.63 (m, 1H), 2.33-2.41 (m, 2H), 1.95-1.98 (m, 1H), 1.44 (s, 9H), 1.18 (s, 9H); LC / MS (ESI) m / z 406 (M-H) ⁻ .

実施例７Ｈ
３−（４−アミノフェニル）−２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタノン
実施例７Ｇ（１．３ｇ、３．１９ｍｍｏｌ）のジクロロメタン（１２ｍＬ）およびトリフルオロ酢酸（４ｍＬ）中混合物を周囲温度で１時間撹拌した。混合物を酢酸エチル（１００ｍＬ）で希釈し、飽和ＮａＨＣＯ_３溶液（３０ｍＬで３回）およびブライン（３０ｍＬ）で洗浄した。有機層をＮａ_２ＳＯ_４で脱水し、濾過し、真空で濃縮した。残留物を分取薄層クロマトグラフィー（石油エーテル／酢酸エチル＝２：１、ｖ／ｖ）により精製して、標題化合物（５８６ｍｇ、１．９０６ｍｍｏｌ、収率５９．８％）を固体として得た。ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ３０８（Ｍ＋Ｈ）^＋。

Example 7H
3- (4-Aminophenyl) -2- (4-tert-butylphenyl) cyclopentanone Example 7G (1.3 g, 3.19 mmol) in dichloromethane (12 mL) and trifluoroacetic acid (4 mL) was mixed with ambient Stir at temperature for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO ₃ solution (3 × 30 mL) and brine (30 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 2: 1, v / v) to give the title compound (586 mg, 1.906 mmol, 59.8% yield) as a solid. . LC / MS (ESI) m / z 308 (M + H) ^<+> .

実施例７Ｉ
２−（４−ｔｅｒｔ−ブチルフェニル）−３−（４−（２，５−ジメチル−１Ｈ−ピロール−１−イル）フェニル）シクロペンタノン
実施例７Ｈ（３００ｍｇ、０．９７６ｍｍｏｌ）、ヘキサン−２，５−ジオン（１３４ｍｇ、１．１７１ｍｍｏｌ）およびｐ−トルエンスルホン酸（１．８５６ｍｇ、９．７６μｍｏｌ）のトルエン（２ｍＬ）中混合物を１１０℃で１時間撹拌した。混合物を真空で濃縮した。残留物をさらに精製せずに次のステップに直接使用した。ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ３８６（Ｍ＋Ｈ）^＋。

Example 7I
2- (4-tert-butylphenyl) -3- (4- (2,5-dimethyl-1H-pyrrol-1-yl) phenyl) cyclopentanone Example 7H (300 mg, 0.976 mmol), hexane-2 , 5-dione (134 mg, 1.171 mmol) and p-toluenesulfonic acid (1.856 mg, 9.76 μmol) in toluene (2 mL) were stirred at 110 ° C. for 1 hour. The mixture was concentrated in vacuo. The residue was used directly in the next step without further purification. LC / MS (ESI) m / z 386 (M + H) ^<+> .

実施例７Ｊ
５−（４−ｔｅｒｔ−ブチルフェニル）−４−（４−（２，５−ジメチル−１Ｈ−ピロール−１−イル）フェニル）シクロペンタ−１−エニルトリフルオロメタンスルホネート
粗製の実施例７Ｉ（３７６ｍｇ、０．９７６ｍｍｏｌ）のテトラヒドロフラン（１０ｍＬ）中溶液に、リチウムビス（トリメチルシリル）アミド（１．１７１ｍＬ、１．１７１ｍｍｏｌ、テトラヒドロフラン）を−７８℃で滴下添加した。周囲温度で３０分間撹拌した後、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（４１８ｍｇ、１．１７１ｍｍｏｌ）を、−７８℃で反応混合物に一度に加えた。次いで混合物を室温に加温し、終夜撹拌した。反応を飽和ＮＨ_４Ｃｌ溶液でクエンチした。有機層を分離し、真空で濃縮した。残留物を分取薄層クロマトグラフィー（石油エーテル／酢酸エチル＝２０：１、ｖ／ｖで溶離）により精製して、標題化合物（３００ｍｇ、０．５８０ｍｍｏｌ、収率５９．４％）を油状物として得た。ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ５１８（Ｍ＋Ｈ）^＋。

Example 7J
5- (4-tert-Butylphenyl) -4- (4- (2,5-dimethyl-1H-pyrrol-1-yl) phenyl) cyclopent-1-enyl trifluoromethanesulfonate Crude Example 7I (376 mg, 0 Lithium bis (trimethylsilyl) amide (1.171 mL, 1.171 mmol, tetrahydrofuran) was added dropwise at −78 ° C. to a solution of .976 mmol) in tetrahydrofuran (10 mL). After stirring for 30 minutes at ambient temperature, 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl) sulfonyl] methanesulfonamide (418 mg, 1.171 mmol) was added to the reaction mixture at −78 ° C. Added at once. The mixture was then warmed to room temperature and stirred overnight. The reaction was quenched with saturated NH ₄ Cl solution. The organic layer was separated and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (eluting with petroleum ether / ethyl acetate = 20: 1, v / v) to give the title compound (300 mg, 0.580 mmol, 59.4% yield) as an oil. Got as. LC / MS (ESI) m / z 518 (M + H) ^<+> .

実施例７Ｋ
ｔｅｒｔ−ブチル４−（５−（４−ｔｅｒｔ−ブチルフェニル）−４−（４−（２，５−ジメチル−１Ｈ−ピロール−１−イル）フェニル）シクロペンタ−１−エニル）フェニルカルバメート
実施例７Ｊ（３７３ｍｇ、０．７２１ｍｍｏｌ）、ｔｅｒｔ−ブチル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）フェニルカルバメート（２５３ｍｇ、０．７９３ｍｍｏｌ）、Ｋ_２ＣＯ_３（２９９ｍｇ、２．１６２ｍｍｏｌ）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）、ジクロロメタンとの錯体（５８．８ｍｇ、０．０７２ｍｍｏｌ）の１，４−ジオキサン（４ｍＬ）および水（１ｍＬ）中混合物を１００℃で１６時間加熱した。混合物を真空で濃縮し、残留物をカラムクロマトグラフィー（シリカゲル上、ジクロロメタン／石油エーテル＝２：１、ｖ／ｖで溶離）により精製して、標題化合物（３８６ｍｇ、０．６８８ｍｍｏｌ、収率９５％）を固体として得た。ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ５６１（Ｍ＋Ｈ）^＋。

Example 7K
tert-Butyl 4- (5- (4-tert-butylphenyl) -4- (4- (2,5-dimethyl-1H-pyrrol-1-yl) phenyl) cyclopent-1-enyl) phenylcarbamate Example 7J (373 mg, 0.721 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbamate (253 mg, 0.793 mmol), K ₂ CO ₃ (299 mg, 2.162 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), a complex with dichloromethane (58.8 mg, 0.072 mmol) of 1,4-dioxane (4 mL ) And water (1 mL) were heated at 100 ° C. for 16 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, eluting with dichloromethane / petroleum ether = 2: 1, v / v) to give the title compound (386 mg, 0.688 mmol, 95% yield). ) Was obtained as a solid. LC / MS (ESI) m / z 561 (M + H) ^<+> .

実施例７Ｌ
ｔｅｒｔ−ブチル４−（４−（４−アミノフェニル）−５−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタ−１−エニル）フェニルカルバメート
実施例７Ｋ（４７５ｍｇ、０．８４７ｍｍｏｌ）、ヒドロキシルアミン塩酸塩（３５３ｍｇ、５．０８ｍｍｏｌ）およびＫＯＨ（１４３ｍｇ、２．５４ｍｍｏｌ）のエタノール（６ｍＬ）および水（２ｍＬ）中混合物を６５℃で４８時間撹拌した。混合物を真空で濃縮した。残留物を酢酸エチル（２０ｍＬ）で希釈し、ブライン（６ｍＬで２回）で洗浄した。有機層をＮａ_２ＳＯ_４で脱水し、濾過し、濃縮した。残留物をさらに精製せずに次のステップに直接使用した。ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ４８３（Ｍ＋Ｈ）^＋。

Example 7L
tert-Butyl 4- (4- (4-aminophenyl) -5- (4-tert-butylphenyl) cyclopent-1-enyl) phenylcarbamate Example 7K (475 mg, 0.847 mmol), hydroxylamine hydrochloride (353 mg , 5.08 mmol) and KOH (143 mg, 2.54 mmol) in ethanol (6 mL) and water (2 mL) were stirred at 65 ° C. for 48 h. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL) and washed with brine (2 x 6 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used directly in the next step without further purification. LC / MS (ESI) m / z 483 (M + H) ^<+> .

実施例７Ｍ
４，４’−（２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタ−３−エン−１，３−ジイル）ジアニリン
粗製の実施例７Ｌ（３７２ｍｇ、０．７７１ｍｍｏｌ）のジクロロメタン（３ｍＬ）およびトリフルオロ酢酸（１ｍＬ）中混合物を室温で１６時間撹拌した。混合物をＮａＨＣＯ_３水溶液で中和し、ジクロロメタン（１０ｍＬで２回）で抽出した。有機層をＮａ_２ＳＯ_４で脱水し、濾過し、濃縮した。残留物をカラムクロマトグラフィー（シリカゲル上、ジクロロメタン／メタノール＝５０：１、ｖ／ｖで溶離）により精製して、標題化合物（２４０ｍｇ、０．６２７ｍｍｏｌ、収率８１％）を褐色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，メタノール−ｄ_４）δｐｐｍ ７．１２（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ）、６．９８（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ）、６．８９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）、６．８６（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）、６．５７（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）、６．４３（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）、６．１２（ｓ，１Ｈ）、４．４９（ｓ，１Ｈ）、３．０２−３．０５（ｍ，１Ｈ）、２．８７−２．９３（ｍ，１Ｈ）、２．４１−２．４５（ｍ，１Ｈ）、１．１６（ｓ，９Ｈ）；ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ ３８３（Ｍ＋Ｈ）^＋。

Example 7M
4,4 ′-(2- (4-tert-Butylphenyl) cyclopent-3-ene-1,3-diyl) dianiline Crude Example 7L (372 mg, 0.771 mmol) in dichloromethane (3 mL) and trifluoroacetic acid The mixture in (1 mL) was stirred at room temperature for 16 hours. The mixture was neutralized with aqueous NaHCO ₃ and extracted with dichloromethane (2 × 10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica gel, eluting with dichloromethane / methanol = 50: 1, v / v) to give the title compound (240 mg, 0.627 mmol, 81% yield) as a brown solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.12 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 6.43 (d, J = 8.4 Hz, 2H) ), 6.12 (s, 1H), 4.49 (s, 1H), 3.02-3.05 (m, 1H), 2.87-2.93 (m, 1H), 2.41- 2.45 (m, 1H), 1.16 (s, 9H); LC / MS (ESI) m / z 383 (M + H) ⁺ .

Example 7N
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(2- (4-tert-butylphenyl) cyclopent-3-ene -1,3-diyl) bis (4,1-phenylene) bis (azanediyl) bis (oxomethylene)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1- Diyl) dicarbamate Intermediate 9 (103 mg, 0.376 mmol), Example 7M (80 mg, 0.188 mmol), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP®), 215 mg, 0.414 mmol) and diisopropylethylamine (0.197 mL, 1.129 mmol) in N, N-dimethylformamide (2 mL) Medium mixture was stirred at ambient temperature for 16 hours. The mixture was then preparative HPLC (instrument: Gilson 281 (PHG008); column: Waters Xbridge ™ OBD ™ C18 19 ^* 250 mm, 10 μm; mobile phase A: water (10 ppm NH ₄ HCO ₃ ) B: acetonitrile, gradient: 8 32-80% B in minutes, stopped in 15 minutes; flow rate (mL / min) 30.00; detection wavelength (nm) 214/254; retention time (min) 7.6; injection number 2.00; Purified (%) 17.82) to give the title compound (30 mg, 0.034 mmol, 8.94% yield) as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.02-7.47 (m, 12H), 6.43 (s, 1H), 4.49-4.57 (m, 2H), 4.20 -4.27 (m, 3H), 3.93-3.98 (m, 2H), 3.65-3.75 (m, 8H), 3.06-3.15 (m, 1H), 2 .63-2.67 (m, 2H), 2.03-2.31 (m, 10H), 1.27 (s, 9H), 0.95-1.06 (m, 12H); LC / MS (ESI) m / z 891 (M + H) ^<+> .

［実施例８］
ジメチル（２Ｓ，２’Ｓ）−１，１’−（（２Ｓ，２’Ｓ）−２，２’−（４，４’−（２−（４−ｔｅｒｔ−ブチルフェニル）シクロペンタン−１，３−ジイル）ビス（４，１−フェニレン）ビス（アザンジイル）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）ジカルバメート
実施例７Ｎ（５０ｍｇ、０．０５６ｍｍｏｌ）および１０％パラジウム炭素（５．９７ｍｇ、０．０５６ｍｍｏｌ）のメタノール（１ｍＬ）中混合物を水素（風船）下３０℃で１６時間撹拌した。混合物を濾過し、濾液を真空で濃縮した。残留物を分取ＨＰＬＣ（装置：Ｗａｔｅｒｓ２７６７ＰＨＷ００３；カラム：Ｂｏｓｔｏｎ Ｃ１８ １０μｍ ２１^＊２５０ｍｍ；移動相Ａ：水（０．０５％ＮＨ_４ＨＣＯ_３）；Ｂ：アセトニトリル、勾配：８分で５５−８５％Ｂ、１４分で停止；流量（ｍＬ／分）３０．００；検出波長（ｎｍ）２１４／２５４；保持時間（分）８．１８；注入数２．００；粗製試料の純度（％）７０）により精製して、標題化合物（３１ｍｇ、０．０３５ｍｍｏｌ、収率６１．９％）を白色固体として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，メタノール−ｄ_４）δｐｐｍ ６．７０−７．３７（ｍ，１２Ｈ）、４．５１−４．５３（ｍ，２Ｈ）、４．２０−４．２３（ｍ，２Ｈ）、３．９５−３．９８（ｍ，２Ｈ）、３．４９−３．７３（ｍ，１０Ｈ）、３．１５−３．１８（ｍ，１Ｈ）、２．０１−２．５５（ｍ，１４Ｈ）、１．１８−１．２２（ｍ，９Ｈ）、０．９６−１．０５（ｍ，１２Ｈ）；ＬＣ／ＭＳ（ＥＳＩ）ｍ／ｚ ８９３（Ｍ＋Ｈ）^＋。

[Example 8]
Dimethyl (2S, 2 ′S) -1,1 ′-((2S, 2 ′S) -2,2 ′-(4,4 ′-(2- (4-tert-butylphenyl) cyclopentane-1, 3-Diyl) bis (4,1-phenylene) bis (azanediyl) bis (oxomethylene)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) di Carbamate A mixture of Example 7N (50 mg, 0.056 mmol) and 10% palladium on carbon (5.97 mg, 0.056 mmol) in methanol (1 mL) was stirred under hydrogen (balloon) at 30 ° C. for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (instrument: Waters 2767 PHW003; column: Boston C18 10 μm 21 ^* 250 mm; mobile phase A: water (0.05% NH ₄ HCO ₃ ); B: acetonitrile, gradient: 55-85% B in 8 minutes. Flow rate (mL / min) 30.00; Detection wavelength (nm) 214/254; Retention time (min) 8.18; Injection number 2.00; Crude sample purity (%) 70) Purification gave the title compound (31 mg, 0.035 mmol, 61.9% yield) as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 6.70-7.37 (m, 12H), 4.51-4.53 (m, 2H), 4.20-4.23 (m, 2H) 3.95-3.98 (m, 2H), 3.49-3.73 (m, 10H), 3.15-3.18 (m, 1H), 2.01-2.55 (m, 14H), 1.18-1.22 (m, 9H), 0.96-1.05 (m, 12H); LC / MS (ESI) m / z 893 (M + H) ^<+> .

The title compounds of Examples 2, 3, 4 and 6 exhibited EC ₅₀ values of less than about 0.1 nM in the HCV 1b-Con1 replicon assay in the presence of 5% FBS. The title compounds of Examples 1, 5 and 8 exhibited EC ₅₀ values of about 0.1 to about 1 nM in the HCV 1b-Con1 replicon assay in the presence of 5% FBS. The title compound of Example 7 exhibited an EC ₅₀ value of about 1 to about 5 nM in the HCV 1b-Con1 replicon assay in the presence of 5% FBS.

  The present invention also contemplates pharmaceutically acceptable salts of each compound in Example 1-8, as well as pharmaceutically acceptable salts of each compound described below.

  Similarly, the following compounds of formula I or their pharmaceutically acceptable salts can be similarly prepared according to the schemes and procedures described above,

式中、Ａは表１ａから選択され、Ｂは表１ｂから選択され、Ｄは表２から選択され、ＹおよびＺは各々独立に表３から選択され、

Wherein A is selected from Table 1a, B is selected from Table 1b, D is selected from Table 2, Y and Z are each independently selected from Table 3;

は表４から選択され、Ａ、Ｂ、ＤおよびＸは各々独立に１つまたは複数のＲ_Ａで場合によって置換されており、ＤはＪで場合によって置換されており、Ｊ、Ｌ_１、Ｌ_２、Ｌ_３およびＲ_Ａは上記した通りである。好ましくは、Ｌ_１、Ｌ_２およびＬ_３は結合である。

Are selected from Table 4, A, B, D and X are each independently optionally substituted with one or more R _A , D is optionally substituted with J, J, L ₁ , L ₂ , L ₃ and R _A are as described above. Preferably L ₁ , L ₂ and L ₃ are a bond.

Table 1a. A

Table 1b. B

Table 2. D

Table 3. Y and Z

Table 3. Y and Z (continued)

Table 3. Y and Z (continued)

Table 4.

  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 placed under the translational control of poliovirus IRES instead of HCV IRES, and HuH-7 cells are used to support replicon replication.

  The inhibitory activity of the compounds of the present invention can be assessed using various assays known in the art. For example, two stable subgenomic replicon cell lines can be used for compound characterization in cell culture, one from genotype 1a-H77 and the other from genotype 1b-Con1, which are each University of Texas Medical Branch, Galveston, TX or Apath, LLC, St. Obtained from Louis, MO. The replicon construct can be a bicistronic subgenomic replicon. The genotype 1a replicon construct contains the NS3-NS5B coding region (1a-H77) from the H77 strain of HCV. The replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. These two coding regions separated by FMDV2a protease contain the first cistron of the bicistronic replicon construct, and the second cistron contains 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 HCV 5'UTR, 3'UTR and NS3-NS5B coding regions are derived from the 1b-Con1 strain and the adaptive mutations are K1609E, K1846T and Y3005C. Furthermore, the 1b-Con1 replicon construct contains a poliovirus IRES between the HCV IRES and the luciferase gene. The replicon cell line is in Dulbecco's modified Eagle medium (DMEM) containing 10% (v / v) fetal bovine serum (FBS), penicillin 100 IU / ml, streptomycin 100 mg / ml (Invitrogen) and G418 200 mg / ml (Invitrogen). Can be maintained.

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 seeded in 96-well plates at a density of 5000 cells / well in 100 μl DMEM containing 5% FBS. The next day, the compound can be diluted with dimethyl sulfoxide (DMSO) to produce a 200-fold stock solution in a series of 8 semi-log dilutions. The dilution series can then be further diluted 100-fold with media containing 5% FBS. Medium containing inhibitor is added to an 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, the medium from cell culture plates can be replaced with DMEM containing 40% human plasma and 5% FBS overnight. 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. Luciferin solution (100 μl, Promega) can be added to each well and luciferase activity can be measured using a Victor II luminometer (Perkin-Elmer). The percent inhibition of HCV RNA replication can be calculated for each compound concentration, and EC ₅₀ values can be calculated using a non-linear regression curve and GraphPad Prism 4 software fitting a four parameter logistic equation. Using the assays described above or similar cell-based replicon assays, representative compounds of the present invention showed significant inhibitory activity against HCV replication.

The invention also features a pharmaceutical composition comprising a compound of the invention. The pharmaceutical composition of the invention may comprise one or more compounds of the invention, each of which is of formula I (or I _A , I _B , I _C , I _D , I _E , I _F or I _G ).

  The invention further features a pharmaceutical composition comprising a pharmaceutically acceptable salt, solvate or prodrug of a compound of the invention. Without being limited, pharmaceutically acceptable salts can be zwitterionic or derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable salt is one that retains the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation or allergic response and has a reasonable benefit / risk ratio. Effective in the intended application and not biologically or otherwise undesirable.

  The invention further features a pharmaceutical composition comprising a compound of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. By way of example and not limitation, these other therapeutic agents include antiviral drugs (eg, anti-HIV drugs, anti-HBV drugs or HCV protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, IRES inhibitors or NS5A inhibitors Other anti-HCV drugs such as drugs), antibacterial drugs, antifungal drugs, immunomodulators, anticancer or chemotherapeutic agents, anti-inflammatory agents, antisense RNA, siRNA, antibodies or drugs for treating cirrhosis or liver inflammation You can choose from. Specific examples of these other therapeutic agents include ribavirin, α-interferon, β-interferon, pegylated interferon-α, pegylated interferon-λ, ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Devio-025, NIM -811, R7128, R1626, R4048, T-1106, PSI-7851 (Pharmacase) (nucleoside polymerase inhibitor), PSI-938 (Pharmacase) (nucleoside polymerase inhibitor), PF-008685554, ANA-598, IDX184 (nucleoside) Polymerase inhibitor), IDX102, IDX375 (non-nucleoside polymerase inhibitor), GS-9190 (non-nucleoside polymerase inhibitor), VCH-759, V H-916, MK-3281, BCX-4678, MK-3281, VBY708, ANA598, GL59728, GL60667, BMS-790052 (NS5A inhibitor), BMS-793125 (protease inhibitor), BMS-6500032, BMS-824393, GS-9132, ACH-1095 (protease inhibitor), AP-H005, A-831 (Arrow Therapeutics) (NS5A inhibitor), A-689 (Arrow Therapeutics) (NS5A inhibitor), INX08189 (Inhibitex) (polymerase inhibition) Drug), AZD2836, telaprevir (protease inhibitor), boceprevir (protease inhibitor), ITMN-191 (Intermune / Roche), B -201335 (protease inhibitor), VBY-376, VX-500 (Vertex) (protease inhibitor), PHX-B, ACH-1625, IDX136, IDX316, VX-813 (Vertex) (protease inhibitor), SCH900518 ( Schering-Plough), TMC-435 (Tibotec) (protease inhibitor), ITMN-191 (Intermune, Roche) (protease inhibitor), MK-7909 (Merck) (protease inhibitor), IDX-PI (Novartis), BI-201335 (Boehringer Ingelheim), R7128 (Roche) (nucleoside polymerase inhibitor), MK-3281 (Merck), MK-0608 (Merck (Nucleoside polymerase inhibitors), PF-868554 (Pfizer) (non-nucleoside polymerase inhibitors), PF-4886991 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset), PPI-461 (Presidio) (NS5A) Inhibitors), BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), Albuferon (Novartis), ABT-450 (Abbott / Entanta) (protease inhibitor), ABT-333 ( Abbott) (non-nucleoside polymerase inhibitor), ABT-072 (Abbott) (non-nucleoside polymerase inhibitor), ritonavir, another sitok Such as, but not limited to, ROM P450 monooxygenase inhibitors or any combination thereof.

  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 drugs. For example, a pharmaceutical composition of the invention can be a compound of the invention having the formula I, I _A , I _B , I _C , I _D , I _E , I _F or I _G (or salts, solvates or pros thereof). Drug) and HCV polymerase inhibitors (such as nucleoside or non-nucleoside polymerase inhibitors), HCV protease inhibitors, HCV helicase inhibitors, CD81 inhibitors, cyclophilin inhibitors, IRES inhibitors or NS5A inhibitors Drugs 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 an anti-HBV drug, anti-HIV drug or anti-hepatitis A. Including one or more other antiviral drugs, such as drugs, anti-hepatitis D drugs, anti-hepatitis E drugs or anti-hepatitis G drugs. Examples of anti-HBV drugs include, but are not limited to, adefovir, lamivudine and tenofovir. Examples of anti-HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanocin, stavudine, tenofovir, zalcitabine, abacavir , Efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249 or other HIV protease, reverse transcriptase, integrase or fusion inhibitor, etc. It is not a thing. As will be apparent to those skilled in the art, any other desired antiviral agent can also be included in the pharmaceutical composition of the present invention.

In a preferred embodiment, the pharmaceutical composition of the invention comprises a compound of the invention (eg a compound of formula I, I _A , I _B , I _C , I _D , I _E , I _F or I _G or preferably the Examples A compound selected from 1-8 or a salt, solvate or prodrug thereof) and an HCV protease inhibitor. 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 A compound selected from Examples 1-8 or a salt, solvate or prodrug thereof) and an HCV polymerase inhibitor (eg, a non-nucleoside polymerase inhibitor or preferably a nucleoside polymerase inhibitor). In yet another preferred embodiment, the pharmaceutical composition of the invention comprises (1) a compound of the invention (eg of formula I, I _A , I _B , I _C , I _D , I _E , I _F or I _G Compound or preferably a compound selected from Examples 1-8 or a salt, solvate or prodrug thereof), (2) an HCV protease inhibitor and (3) an HCV polymerase inhibitor (eg, a non-nucleoside polymerase inhibitor) Or preferably a nucleoside polymerase inhibitor). Non-limiting examples of protease and polymerase inhibitors are described above.

  The pharmaceutical composition of the invention typically comprises a pharmaceutically acceptable carrier or excipient. Examples of suitable pharmaceutically acceptable carriers / excipients include saccharides (eg lactose, glucose or sucrose), starches (eg corn starch or potato starch), cellulose or derivatives thereof (eg Sodium carboxymethylcellulose, ethylcellulose or cellulose acetate), oils (eg peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (eg propylene glycol), buffers (eg hydroxylated) Magnesium or aluminum hydroxide), agar, alginic acid, powdered tragacanth, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol or phosphate buffer, etc. Also limited to Not. Lubricants, colorants, mold release agents, coating agents, sweeteners, flavoring or fragrances, preservatives or antioxidants can also be included in the pharmaceutical composition of the present invention.

  The pharmaceutical compositions of the present invention can be formulated based on their route of administration using methods well known in the art. For example, sterile injectable preparations can be prepared as sterile injectable aqueous or oleaginous suspension using suitable dispersing or wetting agents and suspending agents. Suppositories for rectal administration are solid at room temperature but liquid at rectal temperature, so appropriate non-irritating excipients and drugs such as cocoa butter or polyethylene glycols that melt in the rectum to release the drug Can be prepared by mixing. Solid dosage forms for oral administration can be capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Solid dosage forms may also contain other materials in addition to an inert diluent such as a lubricant. In the case of capsules, tablets and pills, the dosage forms can also contain buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents commonly used in the art. Liquid dosage forms may also contain wetting agents, emulsifying agents, suspending agents, sweetening, flavoring or perfuming agents. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes as described in US Pat. No. 6,703,403. For pharmaceutical formulations applicable to the present invention, see, for example, Hoover, John E. et al. , REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, PA: 1975) and Lachman, L .; Ed., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker, New York, NY, 1980).

  Any of the compounds described herein or pharmaceutically acceptable salts thereof can be used to prepare the pharmaceutical compositions of the present invention.

In a preferred embodiment, a compound of the invention (eg a compound of formula I, I _A , I _B , I _C , I _D , I _E , I _F or I _G or preferably a compound selected from Examples 1-8) Or a salt, solvate or prodrug thereof) formulated with a solid dispersant capable of molecularly dispersing the compound of the present invention in an amorphous base containing a pharmaceutically acceptable hydrophilic polymer. Turn into. The base can 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 evaporation techniques. Extrusion and spray drying are preferred. In one example, the compounds of the invention are formulated with a solid dispersion comprising copovidone and vitamin E TPGS. In another example, the compound of the invention is formulated with a solid dispersion comprising copovidone and Span20.

The solid dispersant described herein can comprise at least 30% by weight of a pharmaceutically acceptable hydrophilic polymer or a combination of such hydrophilic polymers. Preferably, the solid dispersant comprises at least 40% by weight of a 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.) pharmaceutically acceptable hydrophilic polymer or combination of such polymers. The solid dispersion described herein can also comprise at least 1% by weight of a pharmaceutically acceptable surfactant or a combination of such surfactants. Preferably, the solid dispersion comprises at least 2% by weight of a pharmaceutically acceptable surfactant or a combination of such surfactants. More preferably, the solid dispersant comprises 4 wt% to 20 wt% surfactant, such as 5 wt% to 10 wt% surfactant. Furthermore, the solid dispersants described herein can comprise at least 1% by weight, preferably at least 5%, such as at least 10% of a compound 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 , I _F or I _G or preferably a compound selected from Examples 1-8 or a salt, solvate or prodrug thereof). The solid dispersant can also be mixed with other excipients such as mannitol / aerosil (99: 1) and the weight ratio of solid dispersant to other excipients ranges from 5: 1 to 1: 5 1: 1 is preferred. In another example, the solid dispersant is 5% of a compound of the invention (eg, Formula I, I _A , I _B) molecularly dispersed in an amorphous base comprising 5% Span20 and 90% copovidone. , I _C , I _D , I _E , I _F or I _G or preferably a compound selected from Examples 1-8 or a salt, solvate or prodrug thereof). The solid dispersant can also be mixed with other excipients such as mannitol / aerosil (99: 1) and the solid dispersant can be mixed with other excipients such as mannitol / aerosil (99: 1). They can also be mixed and the weight ratio of solid dispersant to other excipients can range from 5: 1 to 1: 5, with 1: 1 being preferred.

  Various additives can also be included in or mixed with the solid dispersant. For example, at least one additive selected from flow regulators, binders, lubricants, fillers, disintegrants, plasticizers, colorants or stabilizers may be used when compressing the solid dispersion into tablets. Can be used. These additives can be mixed with a solid dispersant pulverized or milled before compression molding. The disintegrant promotes the rapid disintegration of the compression agent in the stomach and keeps the released granules separated from each other. Examples of suitable disintegrants include, but are not limited to, crosslinked polymers such as crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose 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 Potato or corn starch, isomalt or polyvinyl alcohol, but is not limited thereto. Examples of suitable flow control agents 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, 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 attack by microorganisms.

  The invention further features a method of using a compound of the 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 disappearance of the activity being inhibited (eg, viral replication). In many cases, representative compounds of the present invention produce HCV virus replication (eg, in the HCV replicon assay described above) at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, It can be reduced by 80%, 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, one or more compounds of the invention (or salts, solvates or prodrugs thereof) are used to inhibit HCV genotype 1a replication. In another embodiment, one or more compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit HCV genotype 1b replication. In yet another embodiment, one or more compounds of the invention (or their salts, solvates or prodrugs) are used to inhibit replication of both HCV genotypes 1a and 1b.

  The invention also features a method of using a compound of the invention (or a salt, solvate or prodrug thereof) in treating HCV infection. The method typically involves administering a therapeutically effective amount of a compound of the invention (or a salt, solvate or prodrug thereof) or a pharmaceutical composition comprising the same to an HCV patient in the blood or liver of the patient. Including reducing HCV virus levels. As used herein, the term “treating” refers to retrograde, alleviation, progression inhibition or one or more symptoms of a disorder or condition to which such term applies or such disorder or condition or It refers to prevention. The term “treatment” refers to the act of treating. In one embodiment, the method comprises administering to a HCV patient a therapeutically effective amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof) or pharmaceutical compositions comprising the same. Reducing the level of HCV virus in the patient's blood or liver.

The compounds of the invention (or salts, solvates or prodrugs thereof) may be used as a single active pharmaceutical agent or other anti-HCV, anti-HIV, anti-HBV, anti-hepatitis A, anti-hepatitis D It can be administered in combination with another desired drug, such as a drug, an anti-hepatitis E drug, an anti-hepatitis G drug or other antiviral drug. Any of the compounds described herein or pharmaceutically acceptable salts thereof can be used in the methods of the invention. In one embodiment, the invention provides a compound of the invention (eg, a compound of formula I, I _A , I _B , I _C , I _D , I _E , I _F or I _G or preferably Examples 1-8). Or a salt, solvate or prodrug thereof), interferon and ribavirin, which are administered to a patient with HCV. The interferon is preferably α-interferon, more preferably pegylated interferon-α such as PEGASYS (peginterferon α-2a).

  The compounds of the invention (or salts, solvents or prodrugs thereof) can be administered to a patient in single or divided doses. A typical daily dose can range from 0.1 to 200 mg / kg body weight, such as, but not limited to, 0.25 to 100 mg / kg body weight. Single dose compositions can include these amounts or their submultiples that constitute a daily dose. Preferably, each dose comprises a sufficient amount of a compound of the invention effective to reduce the HCV viral load in the patient's blood or liver. The amount of active ingredient or combined active ingredients in preparing a single dosage form can vary depending on the host treated and the particular mode of administration. The specific dose level for any particular patient is subject to the activity, age, weight, general health, sex, diet, time of administration, route of administration, excretion rate, concomitant medications and therapies of the specific compound used Obviously, it depends on a variety of factors such as the severity of the particular disease.

  The invention further features a method of using the pharmaceutical composition of the invention in treating HCV infection. The method typically includes reducing the level of HCV virus in the patient's blood or liver by administering a pharmaceutical composition of the invention to the patient. Any of the pharmaceutical compositions described herein can be used in the methods of the invention.

  Furthermore, the invention features the use of a compound or salt of the invention in the manufacture of a medicament for the treatment of HCV infection. Any of the compounds described herein or pharmaceutically acceptable salts thereof can be used to make the medicaments of the present invention.

The compounds of the present invention can also be substituted with isotopes. Preferred isotopic substitution includes substitution with stable or non-radioactive isotopes such as deuterium, ¹³ C, ¹⁵ N or ¹⁸ O. Incorporation of heavy atoms, such as replacement of hydrogen with deuterium, can produce isotope effects that can alter the pharmacokinetics of the drug. In one example, at least 5 mol% (eg, at least 10 mol%) of hydrogen in the compounds of the invention is replaced with deuterium. In another example, at least 25 mole percent hydrogen in the compounds of the present invention is replaced with deuterium. In a further 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 enrichment thereof can be accomplished either by exchange of protons with deuterium or synthesis of molecules using enriched or substituted starting materials, but is not limited thereto. Other methods known in the art can also be used for isotope substitution.

  The foregoing description of the present invention has been provided by way of illustration and description, and is not intended to be exhaustive or limited to the details disclosed. Modifications and variations are possible or can be obtained from the practice of the invention in light of the above teachings. Therefore, it should be noted that the scope of the present invention is defined by the appended claims and equivalents thereof.

Claims (6)

A compound of formula I, or a pharmaceutically acceptable salt thereof,

In the formula:
X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl, and is optionally substituted with one or more _RA ;
L ₁ and L ₂ are each independently a bond; or C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ each optionally substituted independently with one or more R _L for each occurrence It is selected from -C ₆ alkynylene;
L ₃ is a bond or —L _S —K—L _S ′ —, and K is a 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 is _C 5 -C ₆ carbocyclic ring, 6-membered heterocyclic ring from a 5-membered,

Or

And optionally substituted with one or more _RA ;
B is _C 5 -C ₆ carbocyclic ring, 6-membered heterocyclic ring from a 5-membered,

Or

And optionally substituted with one or more _RA ;
D _is selected from C 5 -C ₆ carbocyclic ring or a 5 6 membered membered heterocyclic ring, and either being optionally substituted with one or more _{R A;} or D is _C 5 -C ₆ carbocyclic ring or Is a 5- to 6-membered heterocyclic ring, and is substituted with J and optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocyclic ring or a 3- to 6-membered ring As well as optionally substituted with one or more _RA ;
Z ₁ is independently selected from O, S, NH or CH ₂ for each occurrence ;
Z ₂ is independently selected from N or CH for each occurrence;
Z ₃ is independently selected from N or CH for each occurrence;
Z ₄ is independently selected from O, S, NH or CH ₂ for each occurrence ; and
W ₁ , W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are each independently selected from CH or N for each occurrence ;
Y is

Where -T- _RD is

And
Or Y

And
Where L _{Y ′} is C ₁ -C ₆ alkylene and R _D is —O—C ₁ -C ₆ alkyl;
Z is

Where -T- _RD is

And
Or
Z is

And
Where L _{Y ′} is C ₁ -C ₆ alkylene and R _D is —O—C ₁ -C ₆ alkyl;
R _A is independently halogen at each occurrence, nitro, oxo, selected phosphonoxy, phosphono, thioxo, cyano or -L _S -R _E, 2 two adjacent R _A is bonded atoms and their they are attached Optionally combined with any atom between the atoms in question to form a carbocyclic or heterocyclic ring;
R _B and R _B ′ are each independently for each occurrence, hydrogen; or each is independently for each occurrence halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3 C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with one or more substituents selected from membered to 12-membered carbocyclic or heterocyclic rings; or Selected from 3- to 12-membered carbocycles or heterocycles; each 3- to 12-membered carbocycle or heterocycle in R _B or R _B ′ is independently halogen, hydroxy, mercapto, amino for each occurrence , carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl C ₂ -C _{6 alkenyl,} optionally in the C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} one or more substituents selected from C 2 -C ₆ haloalkenyl or _C 2 -C ₆ haloalkynyl Has been replaced ;
R _E is independently for each occurrence —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 (R _S R _S '), -N (R _S ) 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 (R _S ) 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, - _{(O) N (R S)} C (O) -R S '; or,
Each C ₁ optionally substituted with one or more substituents independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano for each occurrence -C _{6 alkyl,} C 2 -C ₆ alkenyl or _C 2 -C ₆ alkynyl; or
A C ₃ -C ₁₂ carbocyclic or 3 12-membered membered heterocyclic ring, each of which is independently halogen at each occurrence, 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, -N (R S R S} ') or with one or more substituents selected from R _F is substituted by a halogen wherein each R _F is, independently at each occurrence, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, _cyano, C 1 -C ₆ alkyl, _{C 2} - _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 2 -C _{6 haloalkenyl,} C 2 -C _{6 haloalkynyl,} from _{C (O) OR S, -N} (R S R S ') is one or more _C 3 _{-C 12} carbocyclic or 3 12-membered membered heterocyclic ring optionally substituted with substituents _selected, the 12-membered C 3 _{-C 12} carbocyclic or 3-membered Selected from heterocycles;
R _F independently for each occurrence contains 0, 1, 2, 3, 4 or 5 heteroatoms, each selected from O, S or N, and optionally substituted with one or more R _L C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl; or-(R _X -R _Y ) _Q- (R _X -R _Y ') (Q is 0, 1, 2, 3 or 4, and each Rx is independently O, S or N (R _B ) and each R _Y is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C independently optionally substituted with one or more substituents selected from phosphono, thioxo, formyl or cyano _2- C ₆ alkynylene, wherein each R _Y 'is independently one or more selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano Selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, independently substituted with substituents;
R _L is independently halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, —O—R _S , —S—R _S , —C (O) R _S , —OC (O) R _S , for each occurrence. _{-C (O) oR S, -N} (R S R S '), - S (O) R S, -SO 2 R S, -C (O) N (R S R S') or -N (R _S ) C (O) R _S ′; or each occurrence independently of halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₁ -C ₆ alkyl, Optionally with one or more substituents selected from 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 haloalkynyl. Replaced That _C 3 _{-C 12} is selected from heterocycles 12 membered carbocyclic or 3 members;
L _S and L _S ′ are each independently a bond for each occurrence; or C ₁ -C ₆ alkylene, C ₂ -C ₆ , each optionally substituted with one or more R _L independently for each occurrence alkenylene, or it is selected from _C 2 -C ₆ alkynylene;
R _S , R _S ′ and R _S ″ are each independently for each occurrence,
Hydrogen; or
One or more of each occurrence independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, 3 to 12 membered carbocyclic or heterocyclic ring C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl optionally substituted with a substituent of: or-(R _G -R _H ) _n- (R _G -R _H ') (each n is independently 0, 1, 2, 3 or 4; each _{R G} is independently O, S or n _{(R B);} each _{R H} is independently each halogen, hydroxy, mercapto 1 selected from amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or a 3 to 12 membered carbocyclic or heterocyclic ring C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene optionally substituted with one or more substituents; and each R _H 'is independently halogen, hydroxy Optionally substituted with one or more substituents selected from, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or a 3 to 12 membered carbocyclic or heterocyclic ring C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl); or a 3 to 12 membered carbocyclic or heterocyclic ring;
Selected from
Each 3- to 12-membered carbocyclic or heterocyclic ring in R _S , R _S ′ or R _S ″ is independently halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, for each occurrence From 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 haloalkynyl A compound optionally substituted with one or more selected substituents, or a pharmaceutically acceptable salt thereof. A is _C 5 -C ₆ carbocyclic ring, 6-membered heterocyclic ring from a 5-membered,

Or

And optionally substituted with one or more _RA ;
B is _C 5 -C ₆ carbocyclic ring, 6-membered heterocyclic ring from a 5-membered,

Or

And optionally substituted with one or more _RA ;
D _is, C 5 -C ₆ is selected from the heterocyclic 6-membered carbon ring or a 5-, and either being optionally substituted with one or more _{R A;} or D is _C 5 -C ₆ carbocyclic ring or Is a 5- to 6-membered heterocyclic ring, and is substituted with J and optionally substituted with one or more R _A , where J is a C ₃ -C ₆ carbocyclic ring or a 3- to 6-membered ring As well as optionally substituted with one or more _RA ;
Z ₁ is independently selected from O, S, NH or CH ₂ for each occurrence;
A claim wherein Z ₂ is independently selected from N or CH for each occurrence; and W ₁ , W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are each independently selected from CH or N for each occurrence 2. A compound or salt according to 1. A heterocyclic 6-membered A and B is C ₅ -C ₆ carbocyclic ring or 5-membered independently and is optionally substituted with one or more R _A independently; and D is C ₅ -C ₆ are selected from carbocyclic or 5 6 membered membered heterocyclic ring, and either being optionally substituted with one or more R _a; or D is a C ₅ -C ₆ carbocyclic ring or 5-membered 6 Is a membered heterocycle, and is substituted with J and optionally substituted with one or more R _A , wherein J is a C ₃ -C ₆ carbocycle or a 3 to 6 membered heterocycle 2. _A compound or salt according to claim 1 present and optionally substituted with one or more _RA . The compound is:
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4-methoxyphenyl) cyclopropane-1,2- Diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1- (diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate ;
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4- (benzyloxy) phenyl) cyclopropane-1 , 2-diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) Dicarbamate;
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(4,4'-(3- (4-methoxyphenyl) cyclo Propane-1,2-diyl) bis (4,1-phenylene)) bis (1H-imidazole-4,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane -2,1-diyl) dicarbamate;
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(4,4'-(3- (4- (benzyloxy)) Phenyl) cyclopropane-1,2-diyl) bis (4,1-phenylene)) bis (1H-imidazole-4,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl- 1-oxobutane-2,1-diyl) dicarbamate;
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(5,5 '-(3- (4- (benzyloxy) phenyl) cyclopropane-1 , 2-Diyl) bis (1H-benzo [d] imidazole-5,2-diyl)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) di Carbamate;
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(3- (4-cyclohexylphenyl) cyclopropane-1,2- Diyl) bis (4,1-phenylene)) bis (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate;
Dimethyl (2S, 2'S) -1,1 '-((2S, 2'S) -2,2'-(4,4 '-(2- (4-tert-butylphenyl) cyclopent-3-ene -1,3-diyl) bis (4,1-phenylene) bis (azanediyl) bis (oxomethylene)) 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'-(4,4 '-(2- (4-tert-butylphenyl) ) Cyclopentane-1,3-diyl) bis (4,1-phenylene) bis (azanediyl) bis (oxomethylene)) bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2) , 1-diyl) dicarbamate selected from the group consisting of ,Compound. A pharmaceutical composition comprising the compound or salt according to claim 1 or 4 . A pharmaceutical composition comprising a compound or salt according to claim 1 or 4 and another anti-HCV agent.