JP2017119726A - 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment.SOLUTION: Provided are selected imidazo[1,2-f][1,2,4]triazinyl nucleosides, nucleoside phosphates and prodrugs thereof, where the 2' position of the nucleoside sugar is substituted with halogen and carbon substituents. The compounds, compositions and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections caused by both wild type and mutant strains of HCV.SELECTED DRAWING: None

Description

  The present invention relates generally to antiviral active compounds, more specifically to nucleosides that exhibit activity against flavivirus infections, most specifically to hepatitis C virus RNA-dependent RNA polymerase inhibitors.

  Viruses containing the flavivirus family include at least three genera that can be classified (pestiviruses, flaviviruses, and hepaciviruses) (Calisher, et al., J. Gen. Virol., 1993, 70, 37-43). . Pestiviruses cause many economically important animal diseases such as bovine viral diarrhea virus (BVDV), conventional swine fever virus (CSFV, swine fever virus) and sheep border disease (BDV), but those in human disease The importance of is not well characterized (Moennig, V., et al, Adv. Vir. Res. 1992, 48, 53-98). Flaviviruses are involved in important human diseases such as dengue and yellow fever, while hepacivirus causes human hepatitis C virus infection. Other important viral infections attributed to the Flavivirus family include West Nile virus (WNV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St. Louis encephalitis, Omsk hemorrhagic fever virus. And Zika virus. Flaviviridae virus family infections combine to cause worldwide significant mortality, morbidity and economic loss. There is therefore a need to develop effective treatments for flavivirus infections.

  Because hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 32: 98-1 12, 2000), in current antiviral research, There is a great deal of interest in developing improved treatments for chronic HCV infection (Di Beseglie, AM and Bacon, BR, Scientific American, Oct .: 80-85, (1999); Gordon , CP, et al, J. Med. Chem. 2005, 48, 1-20; Maradpour, D .; et al., Nat. Rev. Micro.2007, 5 (6), 453-463). Some HCV treatments are described by Bymock et al. in Antibiological Chemistry & Chemotherapy, 11: 2; 79-95 (2000).

  RNA-dependent RNA polymerase (RdRp) is one of the most studied subjects for the development of new HCV therapeutics. NS5B polymerase is the subject of inhibitors in early human clinical trials (Sommadossi, J., WO 01/90121 A2, US 2004/000002 A1). These enzymes have been extensively characterized at the biochemical and structural levels using selective inhibitor identification screening assays (De Clercq, E. (2001) J. Pharmacol. Exp. Ther. 297: 1-10; De Clercq, E. (2001) J. Clin. Virol. 22: 73-89). Biochemical objects such as NS5B are important in HCV therapy development because HCV is not replicated in the laboratory and cell-based assays and preclinical animal systems are difficult to develop.

  Currently, there are mainly two antiviral compounds, ribavirin (nucleoside analog) and interferon alpha (α) (IFN), which are used to treat chronic HCV infection in humans. Ribavirin alone is not effective in reducing viral RNA levels, has significant toxicity, and is known to induce anemia. Although the combination of IFN and ribavirin has been reported to be effective in the management of chronic hepatitis C (Scott, LJ, et al. Drugs 2002, 62, 507-556), continued during this treatment Less than half of patients with some genotypes have a positive benefit. Other patent applications disclosing the use of nucleoside analogues in the treatment of hepatitis C virus are WO01 / 32153, WO01 / 60315, WO02 / 057425, WO02 / 057287, WO02 / 032920, WO02 / 18404. No., WO 04/046331, WO 2008/089105 and WO 2008/41079, but additional treatment of HCV infection is still not available for patients.

  It is difficult to virologically cure chronic HCV-infected patients due to the large amount of daily virus production and the high natural susceptibility of HCV virus in chronically infected patients (Neumann, et al, Science 1998, 282, 103- 7; Fukimoto, et al., Hepatology, 1996, 24, 1351-4; Domingo, et al., Gene, 1985, 40, 1-8; Martell, et al., J. Virol. 1992, 66, 3225-. 9). Experimental antiviral nucleoside analogs have been shown to induce mutations that allow the HCV virus to survive both in vivo and in vitro (Miggliacio, et al., J. Biol. Chem. 2003, 926; Carroll, et al. , Antimicrobial Agents Chemotherapy 2009, 926; Brown, AB, Expert Opin. Investig. Drugs 2009, 18, 709-725). Therefore, agents with improved antiviral properties, particularly increased activity against virus resistant strains, improved oral bioavailability, fewer undesirable side effects and extended effective in vivo half-life (De Francesco, R Et al. (2003) Anti-Research 58: 1-16) is urgently needed.

  Nucleobase pyrrolo [1,2-f] [1,2,4] triazine, imidazo [1,5-f] [1,2,4] triazine, imidazo [1,2-f] [1,2,4 ] Carboxylide Research 2001, 331 (1), 77-82; Nucleosides & Nucleotides (Nucleosides & Nucleotides) 1996), 15 (1-3), 793-807; Tetrahedron Letters (1994), 35 (30), 5339-42; Heterocycles (1992), 34 (3), 569-74; Chem. Soc. Perkin Trans. 1 1985, 3, 621-30; Chem. Soc. Perkin Trans. 1 1984, 2, 229-38; WO2000056734; Organic Letters (2001), 3 (6), 839-842; Chem. Soc. Perkin Trans. 1 1999, 20, 2929-2936; Med. Chem. 1986, 29 (11), 2231-5. However, these compounds are not disclosed as useful for HCV treatment.

  Pyrrolo [1,2-f] [1,2,4] triazinyl, imidazo [1,5-f] [1,2,4] triazinyl, imidazo [1 having antiviral, anti-HCV, and anti-RdRp activity , 2-f] [1,2,4] triazinyl, and [1,2,4] triazolo [4,3-f] [1,2,4] triazinyl nucleobase ribosides, Babu, Y. et al. S. WO 2008/089105 and WO 2008/41079; Cho, et al. WO 2009/132123 and Franccom, et al. , WO 2010/002877. Butler, et al. WO2009 / 132135 describes antiviral pyrrolo [1,2-f] [1,2,4] triazinyl, imidazo [1,5-f] [1, which is substituted at the 1′-position of a nucleoside sugar. 2,4] triazinyl, imidazo [1,2-f] [1,2,4] triazinyl, and [1,2,4] triazolo [4,3-f] [1,2,4] triazinyl nucleoside Is disclosed.

  Provided are compounds that inhibit flavivirus family viruses. The invention also includes compounds of Formula I or Formulas IV-VI that inhibit viral nucleic acid polymerases, particularly HCV RNA-dependent RNA polymerase (RdRp), but not cellular nucleic acid polymerases. Compounds of Formula I or Formulas IV-VI were found to be effective against both wild type and S282T mutants of HCV virus. Accordingly, compounds of Formula I or Formulas IV-VI are useful for the treatment of flavivirus infections in humans and other animals.

式Ｉ
の化合物もしくはその医薬上許容可能な塩を提供し；
式中：
Ｒ^１は（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
Ｒ^２はハロゲンであり；
各Ｒ^３、Ｒ^４、もしくはＲ^５は独立して、Ｈ、ＯＲ^ａ、Ｎ（Ｒ^ａ）_２、Ｎ_３、ＣＮ、ＮＯ_２、Ｓ（Ｏ）_ｎＲ^ａ、ハロゲン、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
または隣接炭素原子上のＲ^３、Ｒ^４もしくはＲ^５の任意の２つが一緒になって−Ｏ（ＣＯ）Ｏ−であるか、またはそれらが結合している環炭素原子と一緒になって二重結合を形成しており；
Ｒ^６はＨ、ＯＲ^ａ、Ｎ（Ｒ^ａ）_２、Ｎ_３、ＣＮ、ＮＯ_２、Ｓ（Ｏ）_ｎＲ^ａ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、ハロゲン、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
各ｎは独立して、０、１、もしくは２であり；
各Ｒ^ａは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、もしくは−ＳＯ_２ＮＲ^１１Ｒ^１２であり；
Ｒ^７はＨ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、もしくは

であり；
各ＹもしくはＹ^１は独立して、Ｏ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
Ｗ^１およびＷ^２は、一緒になったときに、−Ｙ^３（Ｃ（Ｒ^ｙ）_２）_３Ｙ^３−であり；またはＷ^１もしくはＷ^２の１つはＲ^３もしくはＲ^４のいずれかと一緒になって−Ｙ^３−であり、Ｗ^１もしくはＷ^２の他方は式Ｉａであり；または
各Ｗ^１およびＷ^２は、独立して、式Ｉａ基

式Ｉａ
であり、式中：
各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、Ｎ−ＮＲ_２、Ｓ、Ｓ−Ｓ、Ｓ（Ｏ）、もしくはＳ（Ｏ）_２であり；
各Ｙ^３は独立して、Ｏ、Ｓ、もしくはＮＲであり；
Ｍ２は、０、１もしくは２であり；
各Ｒ^Ｘは独立して、Ｒ^ｙもしくは式

であり、式中
各Ｍ１ａ、Ｍ１ｃ、およびＭ１ｄは独立して、０もしくは１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１もしくは１２であり；
各Ｒ^ｙは独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、Ｒ、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）ＯＲ、−Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｎ（Ｒ）_２、−^＋Ｎ（Ｒ）_３、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−ＯＣ（＝Ｙ^１）Ｒ、−ＯＣ（＝Ｙ^１）ＯＲ、−ＯＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−ＳＣ（＝Ｙ^１）Ｒ、−ＳＣ（＝Ｙ^１）ＯＲ、−ＳＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｒ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）ＯＲ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−ＳＯ_２ＮＲ_２、−ＣＮ、−Ｎ_３、−ＮＯ_２、−ＯＲ、もしくはＷ^３であり；または同一炭素原子上の２つのＲ^ｙは一緒になったときに、３〜７個の炭素原子の炭素環を形成し；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_２〜Ｃ_２０ヘテロシクリル、Ｃ_２〜Ｃ_２０置換ヘテロシクリル、アリールアルキルもしくは置換アリールアルキルであり；
Ｗ^３は、Ｗ^４もしくはＷ^５であり；Ｗ^４はＲ、−Ｃ（Ｙ^１）Ｒ^ｙ、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^ｙ、もしくは−ＳＯ_２Ｗ^５であり；ならびにＷ^５は独立して、０〜３個のＲ^ｙ基に置換されている炭素環もしくは複素環であり；
各Ｘ^１もしくはＸ^２は独立して、Ｃ−Ｒ^１０もしくはＮであり；
各Ｒ^８は、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＣＨＯ、ＣＮ、−ＣＨ（＝ＮＲ^１１）、−ＣＨ＝ＮＮＨＲ^１１、−ＣＨ＝Ｎ（ＯＲ^１１）、−ＣＨ（ＯＲ^１１）_２、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｓ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＯＲ^１１、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキル、アリール（Ｃ_１〜Ｃ_８）アルキル、ＯＲ^１１もしくはＳＲ^１１であり；
各Ｒ^９もしくはＲ^１０は独立して、Ｈ、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＣＨＯ、ＣＮ、−ＣＨ（＝ＮＲ^１１）、−ＣＨ＝ＮＨＮＲ^１１、−ＣＨ＝Ｎ（ＯＲ^１１）、−ＣＨ（ＯＲ^１１）_２、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｓ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＯＲ^１１、Ｒ^１１、ＯＲ^１１もしくはＳＲ^１１であり；
各Ｒ^１１もしくはＲ^１２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；またはＲ^１１およびＲ^１２はそれらが共に結合している窒素と一緒になって３〜７員複素環を形成し、前記複素環の炭素原子の任意の１つは−Ｏ−、−Ｓ−もしくは−ＮＲ^ａ−に置換されていることができ；
式中、各Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^１１もしくはＲ^１２の各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルは独立して、１つもしくは複数のハロ、ヒドロキシ、ＣＮ、Ｎ_３、Ｎ（Ｒ^ａ）_２もしくはＯＲ^ａに置換されていてもよく；ならびに、前記（Ｃ_１〜Ｃ_８）アルキルのそれぞれの１個もしくは複数の非末端炭素原子は、−Ｏ−、−Ｓ−もしくは−ＮＲ^ａ−に置換されていてよい。 In one embodiment, Formula I:

Formula I
Or a pharmaceutically acceptable salt thereof;
In the formula:
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) Substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
R ² is halogen;
Each R ³ , R ⁴ , or R ⁵ is independently H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , halogen, (C ₁ -C _{8) alkyl, (C} 4 -C _{8) carbocyclylalkyl, (C} 1 -C ₈₎ substituted _{alkyl, (C} 2 -C _{8) alkenyl, (C} 2 -C ₈₎ substituted _{alkenyl, (C} 2 -C _{8) alkynyl,} be _(C 2 -C ₈₎ substituted alkynyl or aryl _(C 1 -C ₈₎ alkyl;
Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms taken together are —O (CO) O—, or taken together with the ring carbon atom to which they are attached. Forming a double bond;
R ⁶ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , -C (= O) R ¹¹ , -C (= O) OR ¹¹ ,- ^{C (= O) NR 11 R} 12, -C (= O) SR 11, -S (O) R 11, -S (O) 2 R 11, -S (O) (OR 11), - S (O ) ₂ (OR ¹¹ ), —SO ₂ NR ¹¹ R ¹² , halogen, (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ ˜C ₈ ) carbocyclylalkyl, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S ( O) R ¹¹ , —S (O) ₂ R ¹¹ , —S (O) (OR ¹¹ ), —S (O) ₂ (OR ¹¹ ), or —SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , or

Is;
Each Y or Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
W ¹ and W ² when taken together are —Y ³ (C (R ^y ) ₂ ) ₃ Y ³ —; or ^{one of} W ¹ or W ² is either R ³ or R ⁴ Taken together -Y ^3- , the other of W ¹ or W ² is of formula Ia; or each W ¹ and W ² is independently a group of formula Ia

Formula Ia
And in the formula:
Each Y ² is independently a single bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S— S, S (O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^X is independently R ^y or the formula

Where each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R ) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) _{^{2 (OR), - OC (}} = Y 1) R, -OC (= Y 1) OR, -OC (= Y 1) (N (R) 2), - SC (= Y 1) R, -SC ( = Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, -N ( R) C (= Y ¹ ) N (R) ₂ , —SO ₂ NR ₂ , —CN, —N ₃ , —NO ₂ , —OR, or W ³ ; or two R ^y on the same carbon atom Together form a carbocycle of 3 to 7 carbon atoms;
Each R is independently H, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C _{8) alkynyl, (C} 2 ~C ₈₎ substituted _alkynyl, C 6 _{-C 20 aryl,} C 6 _{-C 20} substituted _aryl, C 2 _{-C 20 heterocyclyl,} C 2 _{-C 20} substituted heterocyclyl, arylalkyl or substituted Arylalkyl;
W ³ is W ⁴ or W ⁵ ; W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ ; And W ⁵ is independently a carbocyclic or heterocyclic ring substituted with 0 to 3 R ^y groups;
Each X ¹ or X ² is independently C—R ¹⁰ or N;
Each R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, —CH (═NR ¹¹ ), —CH═ NNHR ¹¹ , —CH═N (OR ¹¹ ), —CH (OR ¹¹ ) ₂ , —C (═O) NR ¹¹ R ¹² , —C (═S) NR ¹¹ R ¹² , —C (═O) OR ¹¹ , _(C 1 ~C _{8) alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8) alkynyl, (C} 4 _{~C 8)} carbocyclylalkyl, aryl optionally substituted, is substituted heteroaryl optionally _{have, -C (= O) (C} 1 ~C 8) _{alkyl, -S (O) n (C} 1 ~C 8) alkyl, aryl _(C 1 _{~C 8)} alkyl, ^{oR 11} or SR ¹¹ ;
Each R ⁹ or R ¹⁰ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, —CH ( = NR ¹¹ ), -CH = NHNR ¹¹ , -CH = N (OR ¹¹ ), -CH (OR ¹¹ ) ₂ , -C (= O) NR ¹¹ R ¹² , -C (= S) NR ¹¹ R ¹² , -C ⁽⁼ O) be ^{oR 11,} R ^{11, oR 11} or ^{SR 11;}
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, optionally substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached together form a 3- to 7-membered heterocycle, and any of the carbon atoms of the heterocycle one -O -, - S- or -NR ^a - can be substituted on;
In the formula, each R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈₎ ) Alkynyl or aryl (C ₁ -C ₈ ) alkyl may independently be substituted with one or more halo, hydroxy, CN, N ₃ , N (R ^a ) ₂ or OR ^a ; Each one or more non-terminal carbon atoms of the (C ₁ -C ₈ ) alkyl may be substituted with —O—, —S—, or —NR ^a —.

  In another embodiment, the compounds of formula I or formulas IV-VI and their pharmaceutically acceptable salts and their racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amorphous Provides all of the quality types.

  In another embodiment, novel compounds of Formula I or Formulas IV-VI are provided that are active against infectious Flaviviridae viruses. While not wishing to be bound by theory, the compounds of the invention inhibit viral replication as they can inhibit viral RNA-dependent RNA polymerase. They are useful for the treatment of human patients infected with human viruses (such as hepatitis C).

  In another embodiment, a pharmaceutical composition comprising an effective amount of a compound of Formula I or Formula IV-VI, or a pharmaceutically acceptable salt thereof is provided in combination with a pharmaceutically acceptable diluent or carrier. .

In another embodiment, the present application provides:
a) a first pharmaceutical composition comprising a compound of formula I or formula IV-VI; or a pharmaceutically acceptable salt, solvate or ester thereof; and b) an interferon, ribavirin or analog thereof, HCV NS3 protease Inhibitors, NS5a inhibitors, α-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, renin-angiotensin antagonists, other antifibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, HCV NS5B polymerase non-nucleoside inhibitor, HCV NS5A inhibitor, TLR-7 agonist, cyclophilin inhibitor, HCV IRES inhibitor, pharmacokinetic enhancer and other HCV therapeutic agents; or mixtures thereof It is selected from the group consisting of containing a second pharmaceutical composition comprising at least one additional therapeutic agent to provide a combination of medicines.

  In another embodiment, the application includes contacting an effective amount of a compound of Formula I or Formula IV-VI; or a pharmaceutically acceptable salt, solvate, and / or ester thereof with HCV-infected cells. , A method for inhibiting HCV polymerase is provided.

  In another embodiment, the application provides an effective amount of a compound of Formula I or Formula IV-VI; or a pharmaceutically acceptable salt, solvate, and / or ester thereof; and at least one additional therapeutic agent, HCV Provided is a method for inhibiting HCV polymerase comprising contacting with an infected cell.

  In another embodiment, the present application provides a method for administering a therapeutically effective amount of a compound of Formula I or Formula IV-VI, or a pharmaceutically acceptable salt thereof to a subject in need thereof, resulting from a viral infection. A method of treating and / or preventing a disease, wherein the viral infection is dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Due to a virus selected from the group consisting of Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus and hepatitis C virus.

  In another embodiment, this application provides a method of treating HCV in a patient, wherein said patient has a therapeutically effective amount of a compound of formula I or formula IV-VI; or a pharmaceutically acceptable salt, solvate thereof, and Or administering an ester.

  In another embodiment, this application provides a method of treating HCV in a patient, wherein said patient has a therapeutically effective amount of a compound of formula I or formula IV-VI; or a pharmaceutically acceptable salt, solvate thereof, and And / or esters; and administering at least one additional therapeutic agent.

  Another aspect of the present invention is the administration to the animal of an effective amount of a compound of Formula I or Formulas IV-VI and a second compound having anti-HCV properties, ie, using them. A method for the treatment or prevention of symptoms or effects of HCV infection in an infected animal.

  In another aspect, the present invention also provides a method of inhibiting HCV comprising administering to a mammal infected with HCV an amount of a compound of Formula I or Formula IV-VI effective to inhibit HCV replication in infected cells of said mammal. To do.

  In another aspect, there is provided the use of a compound of formula I or formula IV-VI in pharmaceuticals for the treatment of flavivirus infection. In another aspect, there is provided a compound of formula I or formula IV-VI for use in the treatment of flavivirus infection. In one embodiment, the flavivirus infection is an acute or chronic HCV infection. In one embodiment of each aspect of use and compound, the treatment reduces one or more viral loads or RNA clearance in the patient.

  In another aspect, the present invention also provides processes and novel intermediates disclosed herein that are useful in the preparation of compounds of Formula I or Formulas IV-VI of the present invention.

式ＩＶの化合物もしくはその医薬上許容可能な塩であり；
式中：
Ｒ^１は（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
Ｒ^２はハロゲンであり；
各Ｒ^３、Ｒ^４、およびＲ^５は、独立して、Ｈ、ハロゲン、ＯＲ^ａ、Ｎ（Ｒ^ａ）_２、Ｎ_３、ＣＮ、ＮＯ_２、Ｓ（Ｏ）_ｎＲ^ａ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
または隣接炭素原子上のＲ^３、Ｒ^４もしくはＲ^５の任意の２つが一緒になって−Ｏ（ＣＯ）Ｏ−であるか、またはそれらが結合している環炭素原子と一緒になって二重結合を形成しており；
各ｎは独立して、０、１、もしくは２であり；
各Ｒ^ａは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、もしくは−ＳＯ_２ＮＲ^１１Ｒ^１２であり；
Ｒ^７はＨ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、もしくは

であり、
ＹはＯ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
Ｗ^１およびＷ^２は、一緒になったときに、−Ｙ^３（Ｃ（Ｒ^ｙ）_２）_３Ｙ^３−であり；またはＷ^１もしくはＷ^２の１つはＲ^３もしくはＲ^４のいずれかと一緒になって−Ｙ^３−であり、Ｗ^１もしくはＷ^２の他方は式Ｉａであり、または
各Ｗ^１およびＷ^２は、独立して、式ＩＶａ基

式ＩＶａ
であり、式中：
各Ｙ^１は独立して、Ｏ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、Ｎ−ＮＲ_２、Ｓ、Ｓ−Ｓ、Ｓ（Ｏ）、もしくはＳ（Ｏ）_２であり；
各Ｙ^３は独立して、Ｏ、Ｓ、もしくはＮＲであり；
Ｍ２は、０、１もしくは２であり；
各Ｒ^Ｘは、式ＩＶｂ基

式ＩＶｂ
であり、式中
各Ｍ１ａ、Ｍ１ｃ、およびＭ１ｄは独立して、０もしくは１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１もしくは１２であり；
各Ｒ^ｙは独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）Ｒ^１３、−Ｃ（＝Ｙ^１）ＯＲ、−Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｎ（Ｒ）_２、−^＋Ｎ（Ｒ）_３、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）_２Ｒ^１３、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−ＯＣ（＝Ｙ^１）Ｒ、−ＯＣ（＝Ｙ^１）ＯＲ、−ＯＣ（＝Ｙ^１）Ｎ（Ｒ）_２）、−ＳＣ（＝Ｙ^１）Ｒ、−ＳＣ（＝Ｙ^１）ＯＲ、−ＳＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｒ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）ＯＲ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｓ（Ｏ）_２ＮＲ^２、−ＣＮ、−Ｎ_３、−ＮＯ_２、−ＯＲ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、ヘテロアリールアルキルであり；
式中、各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、もしくはヘテロアリールアルキルは、１〜３個のＲ^２０基に置換されていてもよく；
または同一炭素原子上の２つのＲ^ｙは一緒になったときに、３〜７個の炭素原子の炭素環を形成し；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、もしくはアリールアルキルであり；
各Ｒ^８は、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＯＲ^１１もしくはＳ（Ｏ）_ｎＲ^１１であり；
各Ｒ^９は独立して、Ｈ、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＣＨＯ、ＣＮ、−ＣＨ（＝ＮＲ^１１）、−ＣＨ＝ＮＨＮＲ^１１、−ＣＨ＝Ｎ（ＯＲ^１１）、−ＣＨ（ＯＲ^１１）_２、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｓ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＯＲ^１１、Ｒ^１１、ＯＲ^１１もしくはＳ（Ｏ）_ｎＲ^１１であり；
各Ｒ^１１もしくはＲ^１２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；またはＲ^１１およびＲ^１２はそれらが共に結合している窒素と一緒になって３〜７員複素環を形成し、前記複素環の炭素原子の任意の１つは−Ｏ−、−Ｓ−もしくは−ＮＲ^ｂ−に置換されていることができ；
各Ｒ^１３は独立して、１〜３個のＲ^２０基に置換されていてもよい炭素環もしくは複素環であり；
各Ｒ^２０は独立して、ハロゲン、ＣＮ、Ｎ_３、Ｎ（Ｒ）_２、ＯＲ、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）ＯＲ、もしくはＣ（＝Ｙ^１）Ｎ（Ｒ）_２であり；
式中、各Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^１１もしくはＲ^１２の各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルは独立して、１つもしくは複数のハロ、ヒドロキシ、ＣＮ、Ｎ_３、Ｎ（Ｒ^ｂ）_２もしくはＯＲ^ｂに置換されていてもよく；ならびに、前記（Ｃ_１〜Ｃ_８）アルキルのそれぞれの１個もしくは複数の非末端炭素原子は、−Ｏ−、−Ｓ−もしくは−ＮＲ^ｂに置換されていてよく；
各Ｒ^ｂは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^２１、−Ｃ（＝Ｏ）ＯＲ^２１、−Ｃ（＝Ｏ）ＮＲ^２１Ｒ^２２、−Ｃ（＝Ｏ）ＳＲ^２１、−Ｓ（Ｏ）Ｒ^２１、−Ｓ（Ｏ）_２Ｒ^２１、−Ｓ（Ｏ）（ＯＲ^２１）、−Ｓ（Ｏ）_２（ＯＲ^２１）、もしくは−ＳＯ_２ＮＲ^２１Ｒ^２２であり；ならびに
各Ｒ^２１もしくはＲ^２２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルである、
化合物もしくはその医薬上許容可能な塩。
（項目２）
前記各ＹおよびＹ^１はＯである、項目１に記載の化合物。
（項目３）
前記Ｒ^８は、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、ＯＲ^１１またはＳ（Ｏ）_ｎＲ^１１である、項目２に記載の化合物。
（項目４）
前記Ｒ^９がＨ、ハロゲン、Ｓ（Ｏ）_ｎＲ^１１またはＮＲ^１１Ｒ^１２である、項目３に記載の化合物。
（項目５）
前記Ｒ^４がＯＲ^ａである、項目４に記載の化合物。
（項目６）
前記Ｒ^１がＣＨ_３である、項目５に記載の化合物。
（項目７）
前記Ｒ^２がＦである、項目６に記載の化合物。
（項目８）
前記Ｒ^７が、

であり；
式中、Ｙは−Ｏ−であり；Ｗ^１は式Ｉａであり、Ｗ^２はＲ^４と一緒になって−Ｏ−である、項目７に記載の化合物。
（項目９）
式Ｖ

式Ｖ
により表され、
式中、Ｒ^１がメチルまたはエチニルであり、Ｒ^４がＯＲ^ａである、項目１に記載の化合物。
（項目１０）
前記Ｒ^７がＨまたは

である、項目９に記載の化合物
（項目１１）
下記構造

の、項目１に記載の化合物。
（項目１２）
式ＶＩ

式ＶＩ
の化合物またはそれらの医薬上許容可能な塩であり；
式中：
Ｒ^４はＯＲ^ａであり；
各ｎは独立して、０、１、もしくは２であり；
各Ｒ^ａは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、もしくは−ＳＯ_２ＮＲ^１１Ｒ^１２であり；
Ｒ^７はＨ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、もしくは

であり；
Ｙは、Ο、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
Ｗ^１およびＷ^２は、一緒になったときに、−Ｙ^３（Ｃ（Ｒ^ｙ）_２）_３Ｙ^３−であり；または
Ｗ^１もしくはＷ^２の１つはＲ^４と一緒になって−Ｙ^３−であり、Ｗ^１もしくはＷ^２の他方は式Ｉａであり；または
各Ｗ^１およびＷ^２は、独立して、式ＶＩａ基

式ＶＩａ
であり、式中：
各Ｙ^１は独立して、Ｏ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、Ｎ−ＮＲ_２、Ｓ、Ｓ−Ｓ、Ｓ（Ｏ）、もしくはＳ（Ｏ）_２であり；
各Ｙ^３は独立して、Ｏ、Ｓ、もしくはＮＲであり；
Ｍ２は、０、１もしくは２であり；
各Ｒ^Ｘは、式ＶＩｂ基

式ＶＩｂ
であり、式中
各Ｍ１ａ、Ｍ１ｃ、およびＭ１ｄは独立して、０もしくは１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１もしくは１２であり；
各Ｒ^ｙは独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）Ｒ^１３、−Ｃ（＝Ｙ^１）ＯＲ、−Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｎ（Ｒ）_２、−^＋Ｎ（Ｒ）_３、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）_２Ｒ^１３、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−ＯＣ（＝Ｙ^１）Ｒ、−ＯＣ（＝Ｙ^１）ＯＲ、−ＯＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−ＳＣ（＝Ｙ^１）Ｒ、−ＳＣ（＝Ｙ^１）ＯＲ、−ＳＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｒ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）ＯＲ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−ＳＯ_２ＮＲ_２、−ＣＮ、−Ｎ_３、−ＮＯ_２、−ＯＲ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、ヘテロアリールアルキルであり；
式中、各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、もしくはヘテロアリールアルキルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、もしくはアリールアルキルであり；
各Ｒ^１１もしくはＲ^１２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
各Ｒ^１３は独立して、１〜３個のＲ^２０基に置換されていてもよい炭素環もしくは複素環であり；
各Ｒ^２０は独立して、ハロゲン、ＣＮ、Ｎ_３、Ｎ（Ｒ）_２、ＯＲ、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）ＯＲ、もしくはＣ（＝Ｙ^１）Ｎ（Ｒ）_２であり；
式中、各Ｒ^４、Ｒ^１１もしくはＲ^１２の各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルは独立して、１つもしくは複数のハロ、ヒドロキシ、ＣＮ、Ｎ_３、Ｎ（Ｒ^ｂ）_２もしくはＯＲ^ｂに置換されていてもよく；ならびに、前記（Ｃ_１〜Ｃ_８）アルキルのそれぞれの１個もしくは複数の非末端炭素原子は、−Ｏ−、−Ｓ−もしくは−ＮＲ^ｂに置換されていてよく；
各Ｒ^ｂは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^２１、−Ｃ（＝Ｏ）ＯＲ^２１、−Ｃ（＝Ｏ）ＮＲ^２１Ｒ^２２、−Ｃ（＝Ｏ）ＳＲ^２１、−Ｓ（Ｏ）Ｒ^２１、−Ｓ（Ｏ）_２Ｒ^２１、−Ｓ（Ｏ）（ＯＲ^２１）、−Ｓ（Ｏ）_２（ＯＲ^２１）、もしくは−ＳＯ_２ＮＲ^２１Ｒ^２２であり；ならびに
各Ｒ^２１もしくはＲ^２２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルである、
式ＶＩの化合物またはそれらの医薬上許容可能な塩。
（項目１３）
前記Ｒ^ａは、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、もしくは−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_６）アルキルであり；
Ｒ^７もしくはＲ^４と一緒になったＲ^７は

または

であり、式中、
ａは、Ｒ^７結合点であり；
ｂは、Ｒ^４結合点であり；
Ａｒは、フェニルもしくはナフチルであり、前記フェニルおよびナフチルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒ^ｙは独立して、（Ｃ_１〜Ｃ_８）アルキルもしくはＣ_５〜Ｃ_６カルボシクリル、前記アルキルおよびカルボシクリルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_６）アルキル、もしくはアリールアルキルであり；ならびに
各Ｒ^２０は独立して、ハロゲン、ＣＮ、Ｎ（Ｒ）_２、ＯＲ、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−Ｃ（＝Ｏ）Ｒ、−Ｃ（＝Ｏ）ＯＲ、もしくはＣ（＝Ｏ）Ｎ（Ｒ）_２である、項目１２に記載の化合物。
（項目１４）
構造

または

を有する化合物またはそれらの医薬上許容可能な塩。
（項目１５）
治療有効量の項目１に記載の化合物および医薬上許容可能な担体を含む、医薬組成物。
（項目１６）
インターフェロン、リバビリンもしくはその類似体、ＨＣＶ ＮＳ３プロテアーゼ阻害剤、ＮＳ５ａ阻害剤、α−グルコシダーゼ１阻害剤、肝保護剤、メバロン酸デカルボキシラーゼアンタゴニスト、レニン−アンギオテンシン系アンタゴニスト、エンドセリンアンタゴニスト、他の抗線維剤、ＨＣＶ ＮＳ５Ｂポリメラーゼのヌクレオシドもしくはヌクレオチド阻害剤、ＨＣＶ ＮＳ５Ｂポリメラーゼの非ヌクレオシド阻害剤、ＨＣＶ ＮＳ５Ａ阻害剤、ＴＬＲ−７アゴニスト、シクロフィリン阻害剤、ＨＣＶ ＩＲＥＳ阻害剤、薬物動態エンハンサーおよび他のＨＣＶ治療薬；またはそれらの混合物からなる群から選択される少なくとも１つの追加治療薬をさらに含む、項目１５に記載の医薬組成物。
（項目１７）
治療有効量の項目１の化合物を、それを必要としている哺乳類に投与することを含む、フラビウイルス感染治療方法。
（項目１８）
前記ウイルス感染がＣ型肝炎ウイルス感染である、項目１７に記載の方法。
（項目１９）
前記ウイルス感染がＣ型肝炎ウイルスのＳ２８２Ｔ突然変異体に起因する、項目１８に記載の方法。
（項目２０）
インターフェロン、リバビリンもしくはその類似体、ＨＣＶ ＮＳ３プロテアーゼ阻害剤、ＮＳ５ａ阻害剤、α−グルコシダーゼ１阻害剤、肝保護剤、メバロン酸デカルボキシラーゼアンタゴニスト、レニン−アンギオテンシン系アンタゴニスト、エンドセリンアンタゴニスト、他の抗線維剤、ＨＣＶ ＮＳ５Ｂポリメラーゼのヌクレオシドもしくはヌクレオチド阻害剤、ＨＣＶ ＮＳ５Ｂポリメラーゼの非ヌクレオシド阻害剤、ＨＣＶ ＮＳ５Ａ阻害剤、ＴＬＲ−７アゴニスト、シクロフィリン阻害剤、ＨＣＶ ＩＲＥＳ阻害剤、薬物動態エンハンサーおよび他のＨＣＶ治療薬；またはそれらの混合物からなる群から選択される少なくとも１つの追加治療薬を投与することをさらに含む、項目１７に記載の方法。 In another aspect, new methods of synthesis, analysis, separation, isolation, purification, characterization, and testing of the compounds of the invention are provided.
For example, the present invention provides the following items.
(Item 1)
Formula IV

A compound of formula IV or a pharmaceutically acceptable salt thereof;
In the formula:
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) Substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
R ² is halogen;
Each R ³ , R ⁴ , and R ⁵ is independently H, halogen, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , (C _1- C _{8) alkyl, (C} 4 _{~C 8) carbocyclylalkyl, (C} 1 _{~C 8)} substituted _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} substituted alkenyl, _(C 2 ~ C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms taken together are —O (CO) O—, or taken together with the ring carbon atom to which they are attached. Forming a double bond;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ ˜C ₈ ) carbocyclylalkyl, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S ( O) R ¹¹ , —S (O) ₂ R ¹¹ , —S (O) (OR ¹¹ ), —S (O) ₂ (OR ¹¹ ), or —SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S (O) R ¹¹ , S (O) ₂ R ¹¹ , —S (O) (OR ¹¹ ), —S (O) ₂ (OR ¹¹ ), —SO ₂ NR ¹¹ R ¹² , or

And
Y is O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
W ¹ and W ² when taken together are —Y ³ (C (R ^y ) ₂ ) ₃ Y ³ —; or ^{one of} W ¹ or W ² is either R ³ or R ⁴ Taken together -Y ^3- , the other of W ¹ or W ² is of formula Ia, or each W ¹ and W ² is independently a group of formula IVa

Formula IVa
And in the formula:
Each Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Each Y ² is independently a single bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S— S, S (O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^X is a group of formula IVb

Formula IVb
Where each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C _{^{(= Y 1) N (R}} ) 2, -N (R) 2, - + N (R) 3, -SR, -S (O) R, -S (O) 2 R, -S (O) 2 _{^{R 13, -S (O) (}} OR), - S (O) 2 (OR), - OC (= Y 1) R, -OC (= Y 1) OR, -OC (= Y 1) N (R _{^{) 2), - SC (=}} Y 1) R, -SC (= Y 1) OR, -SC (= Y 1) (N (R) 2), - N (R) C (= Y 1) R, _{^{-N (R) C (= Y}} 1) OR, -N (R) C (= Y 1) N (R) 2, -S (O) 2 NR 2, -CN, -N 3, -NO 2, _{-OR, (C} 1 _{~C 8) alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} A _Kiniru, C 6 _{-C 20 aryl,} C 3 _{-C 20 carbocyclyl,} C 2 _{-C 20} heterocyclyl, arylalkyl, heteroarylalkyl;
In the formula, each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl or heteroarylalkyl, it may be substituted with 1 to 3 R ²⁰ groups;
Or two R ^y on the same carbon atom together form a carbocycle of 3 to 7 carbon atoms;
Each R is _{independently, H, (C 1 ~C 8} ) _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8) alkynyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20} carbocyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;
Each R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , OR ¹¹ or S (O) _n R ¹¹ ;
Each R ⁹ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, —CH (= NR ¹¹ ), -CH = NHNR ¹¹ , -CH = N (OR ¹¹ ), -CH (OR ¹¹ ) ₂ , -C (= O) NR ¹¹ R ¹² , -C (= S) NR ¹¹ R ¹² , -C ( = O) OR ¹¹ , R ¹¹ , OR ¹¹ or S (O) _n R ¹¹ ;
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, optionally substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached together form a 3- to 7-membered heterocycle, and any of the carbon atoms of the heterocycle One may be substituted with -O-, -S- or -NR ^b- ;
Each R ¹³ is independently a carbocyclic or heterocyclic ring optionally substituted with 1 to 3 R ²⁰ groups;
Each R ²⁰ is independently halogen, CN, N ₃ , N (R) ₂ , OR, —SR, —S (O) R, —S (O) ₂ R, —S (O) (OR), ^{_{-S (O) 2 (oR)}} , - C (= Y 1) R, it is a -C ⁽⁼ Y 1) oR or ^{C (= Y 1) N (} R) 2,;
In the formula, each R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈₎ ) Alkynyl or aryl (C ₁ -C ₈ ) alkyl may independently be substituted with one or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or OR ^b ; One or more non-terminal carbon atoms of each of said (C ₁ -C ₈ ) alkyl may be substituted with —O—, —S— or —NR ^b ;
Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈₎ ^{carbocyclylalkyl, -C (= O) R 21} , -C (= O) OR 21, -C (= O) NR 21 R 22, -C (= O) SR 21, -S ( _{^{O) R 21, -S (O}} ) 2 R 21, -S (O) (oR 21), - S (O) 2 (oR 21), or be a _-SO 2 ^NR 21 ^{R 22;} and each ^{R 21} Or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl,- _{C (= O) (C 1} ~C 8) _{alkyl, -S (O) n (C} 1 ~C 8) alkyl Or aryl _(C 1 _{~C 8)} alkyl,
A compound or a pharmaceutically acceptable salt thereof.
(Item 2)
The compound according to Item 1, wherein each Y and Y ¹ is O.
(Item 3)
3. The compound according to item 2, wherein R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ¹¹ or S (O) _n R ¹¹ .
(Item 4)
4. The compound according to item 3, wherein R ⁹ is H, halogen, S (O) _n R ¹¹ or NR ¹¹ R ¹² .
(Item 5)
Item 5. The compound according to Item 4, wherein R ⁴ is OR ^a .
(Item 6)
6. The compound according to item 5, wherein R ¹ is CH ₃ .
(Item 7)
Item 7. The compound according to Item 6, wherein R ² is F.
(Item 8)
R ⁷ is

Is;
8. The compound according to item 7, wherein Y is —O—; W ¹ is formula Ia and W ² together with R ⁴ is —O—.
(Item 9)
Formula V

Formula V
Represented by
The compound according to item 1, wherein R ¹ is methyl or ethynyl, and R ⁴ is OR ^a .
(Item 10)
R ⁷ is H or

The compound according to item 9 (item 11)
The following structure

2. The compound according to item 1.
(Item 12)
Formula VI

Formula VI
Or a pharmaceutically acceptable salt thereof;
In the formula:
R ⁴ is OR ^a ;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ ˜C ₈ ) carbocyclylalkyl, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S ( O) R ¹¹ , —S (O) ₂ R ¹¹ , —S (O) (OR ¹¹ ), —S (O) ₂ (OR ¹¹ ), or —SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , or

Is;
Y is Ο, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
W ¹ and ^{W 2,} when taken _{^{together, -Y 3 (C (R y}} ) 2) 3 Y 3 - a and; or one of W ¹ or ^{W 2} together with ^{R 4} - Y ^3- and the other of W ¹ or W ² is of formula Ia; or each W ¹ and W ² is independently a group of formula VIa

Formula VIa
And in the formula:
Each Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Each Y ² is independently a single bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S— S, S (O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^X is a group of formula VIb

Formula VIb
Where each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C _{^{(= Y 1) N (R}} ) 2, -N (R) 2, - + N (R) 3, -SR, -S (O) R, -S (O) 2 R, -S (O) 2 R ¹³ , -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N ( R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R _{^{, -N (R) C (=}} Y 1) OR, -N (R) C (= Y 1) N (R) 2, -SO 2 NR 2, -CN, -N 3, -NO 2, -OR , _(C 1 ~C _{8) alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} Al _{Cycloalkenyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20 carbocyclyl,} C 2 _{-C 20} heterocyclyl, arylalkyl, heteroarylalkyl;
In the formula, each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl or heteroarylalkyl, it may be substituted with 1 to 3 R ²⁰ groups;
Each R is _{independently, H, (C 1 ~C 8} ) _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8) alkynyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20} carbocyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, optionally substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl _(C 1 ~C ₈₎ alkyl;
Each R ¹³ is independently a carbocyclic or heterocyclic ring optionally substituted with 1 to 3 R ²⁰ groups;
Each R ²⁰ is independently halogen, CN, N ₃ , N (R) ₂ , OR, —SR, —S (O) R, —S (O) ₂ R, —S (O) (OR), ^{_{-S (O) 2 (oR)}} , - C (= Y 1) R, it is a -C ⁽⁼ Y 1) oR or ^{C (= Y 1) N (} R) 2,;
Wherein each ^{R 4,} each _(C 1 _{~C 8)} of the ^{R 11} or ^{R 12} _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} alkynyl or aryl _(C 1 _{~C 8)} alkyl Each independently may be substituted with one or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or OR ^b ; and each of the (C ₁ -C ₈ ) alkyl One or more non-terminal carbon atoms may be substituted with —O—, —S— or —NR ^b ;
Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈₎ ^{carbocyclylalkyl, -C (= O) R 21} , -C (= O) OR 21, -C (= O) NR 21 R 22, -C (= O) SR 21, -S ( _{^{O) R 21, -S (O}} ) 2 R 21, -S (O) (oR 21), - S (O) 2 (oR 21), or be a _-SO 2 ^NR 21 ^{R 22;} and each ^{R 21} Or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl,- _{C (= O) (C 1} ~C 8) _{alkyl, -S (O) n (C} 1 ~C 8) alkyl Or aryl _(C 1 _{~C 8)} alkyl,
A compound of formula VI or a pharmaceutically acceptable salt thereof.
(Item 13)
R ^a is H, (C ₁ -C ₈ ) alkyl, or —C (═O) (C ₁ -C ₆ ) alkyl;
^{R 7} taken together with R ⁷ or ^{R 4} is

Or

Where
a is the R ⁷ point of attachment;
b is the R ⁴ point of attachment;
Ar is phenyl or naphthyl, and the phenyl and naphthyl may be substituted with 1 to 3 R ²⁰ groups;
Each R ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, wherein said alkyl and carbocyclyl may be substituted with 1 to 3 R ²⁰ groups;
Each R is independently H, (C ₁ -C ₆ ) alkyl, or arylalkyl; and each R ²⁰ is independently halogen, CN, N (R) ₂ , OR, —SR, —S _{(O) R, -S (O} ) 2 R, -S (O) (oR), - S (O) 2 (oR), - C (= O) R, -C (= O) oR or C, 13. A compound according to item 12, which is (═O) N (R) ₂ .
(Item 14)
Construction

Or

Or a pharmaceutically acceptable salt thereof.
(Item 15)
A pharmaceutical composition comprising a therapeutically effective amount of the compound of item 1 and a pharmaceutically acceptable carrier.
(Item 16)
Interferon, ribavirin or analogs thereof, HCV NS3 protease inhibitor, NS5a inhibitor, α-glucosidase 1 inhibitor, hepatoprotectant, mevalonate decarboxylase antagonist, renin-angiotensin antagonist, endothelin antagonist, other antifibrotic agents, Nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other HCV therapeutic agents; 16. The pharmaceutical composition according to item 15, further comprising at least one additional therapeutic agent selected from the group consisting of:
(Item 17)
A method of treating a flavivirus infection comprising administering a therapeutically effective amount of a compound of item 1 to a mammal in need thereof.
(Item 18)
18. The method according to item 17, wherein the viral infection is hepatitis C virus infection.
(Item 19)
19. A method according to item 18, wherein the viral infection is caused by the S282T mutant of hepatitis C virus.
(Item 20)
Interferon, ribavirin or analogs thereof, HCV NS3 protease inhibitor, NS5a inhibitor, α-glucosidase 1 inhibitor, hepatoprotectant, mevalonate decarboxylase antagonist, renin-angiotensin antagonist, endothelin antagonist, other antifibrotic agents, Nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other HCV therapeutic agents; 18. The method of item 17, further comprising administering at least one additional therapeutic agent selected from the group consisting of:

  Reference will now be made in detail to certain embodiments of the invention, examples illustrated in the accompanying details, structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention covers all alternatives, modifications, and equivalents, which are intended to be included within the scope of the present invention.

式ＩＩ
もしくはその医薬上許容可能な塩により表され；
式中：
Ｒ^１は（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
各Ｒ^３、Ｒ^４、もしくはＲ^５は独立して、Ｈ、ＯＲ^ａ、Ｎ（Ｒ^ａ）_２、Ｎ_３、ＣＮ、ＮＯ_２、Ｓ（Ｏ）_ｎＲ^ａ、ハロゲン、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
または隣接炭素原子上のＲ^３、Ｒ^４もしくはＲ^５の任意の２つが一緒になって−Ｏ（ＣＯ）Ｏ−であるか、またはそれらが結合している環炭素原子と一緒になって二重結合を形成しており；
Ｒ^６はＨ、ＯＲ^ａ、Ｎ（Ｒ^ａ）_２、Ｎ_３、ＣＮ、ＮＯ_２、Ｓ（Ｏ）_ｎＲ^ａ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、ハロゲン、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
各ｎは独立して、０、１、もしくは２であり；
各Ｒ^ａは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、もしくは−ＳＯ_２ＮＲ^１１Ｒ^１２であり；
Ｒ^７はＨ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、もしくは

であり；
各ＹもしくはＹ^１は独立して、Ｏ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
Ｗ^１およびＷ^２は、一緒になったときに、−Ｙ^３（Ｃ（Ｒ^ｙ）_２）_３Ｙ^３−であり；またはＷ^１もしくはＷ^２の１つはＲ^３もしくはＲ^４のいずれかと一緒になって−Ｙ^３−であり、Ｗ^１もしくはＷ^２の他方は式Ｉａであり；または
各Ｗ^１およびＷ^２は、独立して、式Ｉａ基

式Ｉａ
であり、式中：
各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、Ｎ−ＮＲ_２、Ｓ、Ｓ−Ｓ、Ｓ（Ｏ）、もしくはＳ（Ｏ）_２であり；
各Ｙ^３は独立して、Ｏ、Ｓ、もしくはＮＲであり；
Ｍ２は、０、１もしくは２であり；
各Ｒ^Ｘは独立して、Ｒ^ｙもしくは式

であり、式中
各Ｍ１ａ、Ｍ１ｃ、およびＭ１ｄは独立して、０もしくは１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１もしくは１２であり；
各Ｒ^ｙは独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、Ｒ、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）ＯＲ、−Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｎ（Ｒ）_２、−^＋Ｎ（Ｒ）_３、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−ＯＣ（＝Ｙ^１）Ｒ、−ＯＣ（＝Ｙ^１）ＯＲ、−ＯＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−ＳＣ（＝Ｙ^１）Ｒ、−ＳＣ（＝Ｙ^１）ＯＲ、−ＳＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｒ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）ＯＲ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−ＳＯ_２ＮＲ_２、−ＣＮ、−Ｎ_３、−ＮＯ_２、−ＯＲ、もしくはＷ^３であり；または同一炭素原子上の２つのＲ^ｙは一緒になったときに、３〜７個の炭素原子の炭素環を形成し；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_２〜Ｃ_２０ヘテロシクリル、Ｃ_２〜Ｃ_２０置換ヘテロシクリル、アリールアルキルもしくは置換アリールアルキルであり；
Ｗ^３は、Ｗ^４もしくはＷ^５であり；Ｗ^４はＲ、−Ｃ（Ｙ^１）Ｒ^ｙ、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^ｙ、もしくは−ＳＯ_２Ｗ^５であり；ならびにＷ^５は独立して、０〜３個のＲ^ｙ基に置換されている炭素環もしくは複素環であり；
各Ｘ^１もしくはＸ^２は独立して、Ｃ−Ｒ^１０もしくはＮであり；
各Ｒ^８は、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＣＨＯ、ＣＮ、−ＣＨ（＝ＮＲ^１１）、−ＣＨ＝ＮＮＨＲ^１１、−ＣＨ＝Ｎ（ＯＲ^１１）、−ＣＨ（ＯＲ^１１）_２、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｓ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＯＲ^１１、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキル、アリール（Ｃ_１〜Ｃ_８）アルキル、ＯＲ^１１もしくはＳＲ^１１であり；
各Ｒ^９もしくはＲ^１０は独立して、Ｈ、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＣＨＯ、ＣＮ、−ＣＨ（＝ＮＲ^１１）、−ＣＨ＝ＮＨＮＲ^１１、−ＣＨ＝Ｎ（ＯＲ^１１）、−ＣＨ（ＯＲ^１１）_２、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｓ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＯＲ^１１、Ｒ^１１、ＯＲ^１１もしくはＳＲ^１１であり；
各Ｒ^１１もしくはＲ^１２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；またはＲ^１１およびＲ^１２はそれらが共に結合している窒素と一緒になって３〜７員複素環を形成し、前記複素環の炭素原子の任意の１つは−Ｏ−、−Ｓ−もしくは−ＮＲ^ａ−に置換されていることができ；
式中、各Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^１１もしくはＲ^１２の各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルは独立して、１つもしくは複数のハロ、ヒドロキシ、ＣＮ、Ｎ_３、Ｎ（Ｒ^ａ）_２もしくはＯＲ^ａに置換されていてもよく；ならびに、前記（Ｃ_１〜Ｃ_８）アルキルのそれぞれの１個もしくは複数の非末端炭素原子は、−Ｏ−、−Ｓ−もしくは−ＮＲ^ａ−に置換されていてよい。 In another embodiment, the compound of formula I is of formula II

Formula II
Or represented by a pharmaceutically acceptable salt thereof;
In the formula:
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) Substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
Each R ³ , R ⁴ , or R ⁵ is independently H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , halogen, (C ₁ -C _{8) alkyl, (C} 4 -C _{8) carbocyclylalkyl, (C} 1 -C ₈₎ substituted _{alkyl, (C} 2 -C _{8) alkenyl, (C} 2 -C ₈₎ substituted _{alkenyl, (C} 2 -C _{8) alkynyl,} be _(C 2 -C ₈₎ substituted alkynyl or aryl _(C 1 -C ₈₎ alkyl;
Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms taken together are —O (CO) O—, or taken together with the ring carbon atom to which they are attached. Forming a double bond;
R ⁶ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , -C (= O) R ¹¹ , -C (= O) OR ¹¹ ,- ^{C (= O) NR 11 R} 12, -C (= O) SR 11, -S (O) R 11, -S (O) 2 R 11, -S (O) (OR 11), - S (O ) ₂ (OR ¹¹ ), —SO ₂ NR ¹¹ R ¹² , halogen, (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ ˜C ₈ ) carbocyclylalkyl, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S ( O) R ¹¹ , —S (O) ₂ R ¹¹ , —S (O) (OR ¹¹ ), —S (O) ₂ (OR ¹¹ ), or —SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , or

Is;
Each Y or Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
W ¹ and W ² when taken together are —Y ³ (C (R ^y ) ₂ ) ₃ Y ³ —; or ^{one of} W ¹ or W ² is either R ³ or R ⁴ Taken together -Y ^3- , the other of W ¹ or W ² is of formula Ia; or each W ¹ and W ² is independently a group of formula Ia

Formula Ia
And in the formula:
Each Y ² is independently a single bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S— S, S (O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^X is independently R ^y or the formula

Where each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R ) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) _{^{2 (OR), - OC (}} = Y 1) R, -OC (= Y 1) OR, -OC (= Y 1) (N (R) 2), - SC (= Y 1) R, -SC ( = Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, -N ( R) C (= Y ¹ ) N (R) ₂ , —SO ₂ NR ₂ , —CN, —N ₃ , —NO ₂ , —OR, or W ³ ; or two R ^y on the same carbon atom Together form a carbocycle of 3 to 7 carbon atoms;
Each R is independently H, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C _{8) alkynyl, (C} 2 ~C ₈₎ substituted _alkynyl, C 6 _{-C 20 aryl,} C 6 _{-C 20} substituted _aryl, C 2 _{-C 20 heterocyclyl,} C 2 _{-C 20} substituted heterocyclyl, arylalkyl or substituted Arylalkyl;
W ³ is W ⁴ or W ⁵ ; W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ ; And W ⁵ is independently a carbocyclic or heterocyclic ring substituted with 0 to 3 R ^y groups;
Each X ¹ or X ² is independently C—R ¹⁰ or N;
Each R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, —CH (═NR ¹¹ ), —CH═ NNHR ¹¹ , —CH═N (OR ¹¹ ), —CH (OR ¹¹ ) ₂ , —C (═O) NR ¹¹ R ¹² , —C (═S) NR ¹¹ R ¹² , —C (═O) OR ¹¹ , _(C 1 ~C _{8) alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8) alkynyl, (C} 4 _{~C 8)} carbocyclylalkyl, aryl optionally substituted, is substituted heteroaryl optionally _{have, -C (= O) (C} 1 ~C 8) _{alkyl, -S (O) n (C} 1 ~C 8) alkyl, aryl _(C 1 _{~C 8)} alkyl, ^{oR 11} or SR ¹¹ ;
Each R ⁹ or R ¹⁰ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, —CH ( = NR ¹¹ ), -CH = NHNR ¹¹ , -CH = N (OR ¹¹ ), -CH (OR ¹¹ ) ₂ , -C (= O) NR ¹¹ R ¹² , -C (= S) NR ¹¹ R ¹² , -C ⁽⁼ O) be ^{oR 11,} R ^{11, oR 11} or ^{SR 11;}
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, optionally substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached together form a 3- to 7-membered heterocycle, and any of the carbon atoms of the heterocycle one -O -, - S- or -NR ^a - can be substituted on;
In the formula, each R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈₎ ) Alkynyl or aryl (C ₁ -C ₈ ) alkyl may independently be substituted with one or more halo, hydroxy, CN, N ₃ , N (R ^a ) ₂ or OR ^a ; Each one or more non-terminal carbon atoms of the (C ₁ -C ₈ ) alkyl may be substituted with —O—, —S—, or —NR ^a —.

In one embodiment of the invention of formula II, R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is H. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ¹ is (C ₁ -C ₈ ) alkyl and R ⁶ is CN, OH, or CH ₃ .

In one embodiment of Formula II, R ³ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or _(C 2 _{~C 8)} alkynyl. In one aspect of this embodiment, R ³ is H. In another aspect of this embodiment, R ³ is H and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ³ is H and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ³ is H and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ³ is H and R ¹ is methyl. In another aspect of this embodiment, R ³ is H, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ³ is H, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ³ is H, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ³ is H, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ³ is H, R ¹ is methyl, and R ⁶ is H.

In one embodiment of Formula II, R ⁴ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ). alkenyl or _(C 2 _{~C 8)} alkynyl. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In one embodiment of Formula II, R ⁵ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ). alkenyl or _(C 2 _{~C 8)} alkynyl. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁵ is N ₃ .

In another embodiment of formula II, R ⁵ is H. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of formula II, R ⁶ is H, CN, OR ^a or CH ₃ . In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of formula II, R ⁶ is CN, OR ^a or CH ₃ . In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ .

である。この実施形態の１つの態様では、Ｒ^７はＨである。この実施形態の別の態様では、Ｒ^７は、−Ｃ（＝Ｏ）Ｒ^１１である。この実施形態の別の態様では、Ｒ^７は、−Ｃ（＝Ｏ）Ｒ^１１であり、式中、Ｒ^１１は、（Ｃ_１〜Ｃ_８）アルキルである。この実施形態の別の態様では、Ｒ^７は

である。この実施形態の別の態様では、Ｒ^６はＨである。この実施形態の別の態様では、Ｒ^６はＣＮである。この実施形態の別の態様では、Ｒ^６はＯＲ^ａである。この実施形態の別の態様では、Ｒ^６はＯＨである。この実施形態の別の態様では、Ｒ^６はＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＨまたはＯＲ^ａである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１は（Ｃ_１〜Ｃ_８）アルキル、（Ｃ₂〜Ｃ_８）アルケニルまたは（Ｃ_２〜Ｃ_８）アルキニルである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１は（Ｃ_１〜Ｃ_８）アルキルである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１は（Ｃ_１〜Ｃ_８）アルキルであり、Ｘ^１またはＸ^２の少なくとも１つはＮである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルであり、Ｘ^１またはＸ^２の少なくとも１つはＮである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１は（Ｃ_１〜Ｃ_８）アルキルであり、Ｒ^６はＣＮ、ＯＨ、またはＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルであり、Ｒ^６はＣＮ、ＯＨ、またはＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルであり、Ｒ^６はＨである。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルである。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１は（Ｃ_１〜Ｃ_８）アルキルであり、Ｘ^１またはＸ^２の少なくとも１つはＮである。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルであり、Ｘ^１またはＸ^２の少なくとも１つはＮである。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１は（Ｃ_１〜Ｃ_８）アルキルであり、Ｒ^６はＣＮ、ＯＨ、またはＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルであり、Ｒ^６はＣＮ、ＯＨ、またはＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルであり、Ｒ^６はＨである。 In one embodiment of Formula II, R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) SR ¹¹ or

It is. In one aspect of this embodiment, R ⁷ is H. In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ . In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ , wherein R ¹¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁷ is

It is. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In one embodiment of Formula II, X ¹ is N or C—R ¹⁰ . In another aspect of this embodiment, X ¹ is N. In another aspect of this embodiment, X ¹ is C—R ¹⁰ . In another aspect of this embodiment, X ² is C—H. In another aspect of this embodiment, X ¹ is N and X ² is C—H. In another aspect of this embodiment, X ¹ is C—R ¹⁰ and X ² is CH. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of Formula II, each R ⁸ is independently halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ^11, or SR ¹¹ . In another aspect of this embodiment, R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ , R ⁹ is H or halogen, and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is NH ₂ , R ⁹ is H or halogen, and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of formula II, each R ¹⁰ is independently H, halogen, CN, or optionally substituted heteroaryl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² and R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ , R ⁹ is H or halogen, and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ , R ⁹ is H or halogen, and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is (C ₁ -C ₈ ) alkyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

式ＩＩＩ
により表され、またはその医薬上許容可能な塩であり；
式中：
Ｒ^１は、ＣＨ_３、ＣＨ_２Ｆ、またはエチニルであり、残っている変数はすべて式Ｉで定義したとおりである。 In another embodiment, the compound of formula I or formula II is of formula III

Formula III
Or a pharmaceutically acceptable salt thereof;
In the formula:
R ¹ is CH ₃ , CH ₂ F, or ethynyl, and all remaining variables are as defined in Formula I.

In one embodiment of Formula III, R ⁴ is H, OR ^a , N (R ^a ) ₂ , N ₃ , CN, SR ^a , halogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ). alkenyl or _(C 2 _{~C 8)} alkynyl. In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is CH ₃ , CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of formula III, R ⁶ is H, CN, OR ^a or CH ₃ . In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of formula III, R ⁶ is CN, OR ^a or CH ₃ . In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ .

である。この実施形態の１つの態様では、Ｒ^７はＨである。この実施形態の別の態様では、Ｒ^７は、−Ｃ（＝Ｏ）Ｒ^１１である。この実施形態の別の態様では、Ｒ^７は、−Ｃ（＝Ｏ）Ｒ^１１であり、式中、Ｒ^１１は（Ｃ_１〜Ｃ_８）アルキルである。この実施形態の別の態様では、Ｒ^７は

である。この実施形態の別の態様では、Ｒ^６はＨである。この実施形態の別の態様では、Ｒ^６はＣＮである。この実施形態の別の態様では、Ｒ^６はＯＲ^ａである。この実施形態の別の態様では、Ｒ^６はＯＨである。この実施形態の別の態様では、Ｒ^６はＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＨまたはＯＲ^ａである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルであり、Ｘ^１またはＸ^２の少なくとも１つはＮである。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルであり、Ｒ^６はＣＮ、ＯＨ、またはＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＯＲ^ａであり、Ｒ^１はメチルであり、Ｒ^６はＨである。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルである。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルであり、Ｘ^１またはＸ^２の少なくとも１つはＮである。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルであり、Ｒ^６は、ＣＮ、ＯＨ、またはＣＨ_３である。この実施形態の別の態様では、Ｒ^４はＯＨであり、Ｒ^１はメチルであり、Ｒ^６はＨである。 In one embodiment of Formula III, R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) SR ¹¹ or

It is. In one aspect of this embodiment, R ⁷ is H. In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ . In another aspect of this embodiment, R ⁷ is —C (═O) R ¹¹ , wherein R ¹¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, R ⁷ is

It is. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In one embodiment of Formula III, X ¹ is N or C—R ¹⁰ . In another aspect of this embodiment, X ¹ is N. In another aspect of this embodiment, X ¹ is C—R ¹⁰ . In another aspect of this embodiment, X ² is C—H. In another aspect of this embodiment, X ¹ is N and X ² is C—H. In another aspect of this embodiment, X ¹ is C—R ¹⁰ and X ² is CH. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of Formula III, each R ⁸ is independently halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ^11, or SR ¹¹ . In another aspect of this embodiment, R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ , R ⁹ is H or halogen, and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is NH ₂ , R ⁹ is H or halogen, and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl, CH ₂ F, or ethynyl. In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

In another embodiment of formula III, each R ¹⁰ is independently H, halogen, CN, or optionally substituted heteroaryl. In another aspect of this embodiment, R ¹ is methyl. In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁹ is H, halogen, or NR ¹¹ R ¹² and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is NH ₂ and R ⁹ is H or halogen. In another aspect of this embodiment, R ⁸ is NH ₂ , R ⁹ is H or halogen, and R ¹ is methyl. In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ . In another aspect of this embodiment, R ⁸ and R ⁹ are each NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁸ is OH and R ⁹ is NH ₂ . In another aspect of this embodiment, R ⁸ is OH, R ⁹ is NH ₂ and R ¹ is methyl. In another aspect of this embodiment, R ⁶ is H. In another aspect of this embodiment, R ⁶ is CN. In another aspect of this embodiment, R ⁶ is OR ^a . In another aspect of this embodiment, R ⁶ is OH. In another aspect of this embodiment, R ⁶ is CH ₃ . In another aspect of this embodiment, R ⁴ is H or OR ^a . In another aspect of this embodiment, R ⁴ is OR ^a and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OR ^a , R ¹ is methyl, and R ⁶ is H. In another aspect of this embodiment, R ⁴ is OH and R ¹ is methyl. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is CN, OH, or CH ₃ . In another aspect of this embodiment, R ⁴ is OH, R ¹ is methyl, and R ⁶ is H.

式ＩＶ
の化合物もしくはその医薬上許容可能な塩を提供し；
式中：
Ｒ^１は（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
Ｒ^２はハロゲンであり；
各Ｒ^３、Ｒ^４、およびＲ^５は、独立して、Ｈ、ハロゲン、ＯＲ^ａ、Ｎ（Ｒ^ａ）_２、Ｎ_３、ＣＮ、ＮＯ_２、Ｓ（Ｏ）_ｎＲ^ａ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、もしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
または隣接炭素原子上のＲ^３、Ｒ^４もしくはＲ^５の任意の２つが一緒になって−Ｏ（ＣＯ）Ｏ−であるか、またはそれらが結合している環炭素原子と一緒になって二重結合を形成しており；
各ｎは独立して、０、１、もしくは２であり；
各Ｒ^ａは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、もしくは−ＳＯ_２ＮＲ^１１Ｒ^１２であり；
Ｒ^７はＨ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、もしくは

であり；
Ｙは、Ο、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
Ｗ^１およびＷ^２は、一緒になったときに、−Ｙ^３（Ｃ（Ｒ^ｙ）_２）_３Ｙ^３−であり；またはＷ^１もしくはＷ^２の１つはＲ^３もしくはＲ^４のいずれかと一緒になって−Ｙ^３−であり、Ｗ^１もしくはＷ^２の他方は式Ｉａであり；または
各Ｗ^１およびＷ^２は、独立して、式ＩＶａ基

式ＩＶａ
であり、式中：
各Ｙ^１は独立して、Ｏ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、Ｎ−ＮＲ_２、Ｓ、Ｓ−Ｓ、Ｓ（Ｏ）、もしくはＳ（Ｏ）_２であり；
各Ｙ^３は独立して、Ｏ、Ｓ、もしくはＮＲであり；
Ｍ２は、０、１もしくは２であり；
各Ｒ^Ｘは、式ＩＶｂ基

式ＩＶｂ
であり、式中
各Ｍ１ａ、Ｍ１ｃ、およびＭ１ｄは独立して、０もしくは１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１もしくは１２であり；
各Ｒ^ｙは独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）Ｒ^１３、−Ｃ（＝Ｙ^１）ＯＲ、−Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｎ（Ｒ）_２、−^＋Ｎ（Ｒ）_３、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）_２Ｒ^１３、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−ＯＣ（＝Ｙ^１）Ｒ、−ＯＣ（＝Ｙ^１）ＯＲ、−ＯＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−ＳＣ（＝Ｙ^１）Ｒ、−ＳＣ（＝Ｙ^１）ＯＲ、−ＳＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｒ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）ＯＲ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−ＳＯ_２ＮＲ_２、−ＣＮ、−Ｎ_３、−ＮＯ_２、−ＯＲ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、ヘテロアリールアルキルであり；式中、各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、もしくはヘテロアリールアルキルは、１〜３個のＲ^２０基に置換されていてもよく；または同一炭素原子上の２つのＲ^ｙは一緒になったときに、３〜７個の炭素原子の炭素環を形成し；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、もしくはアリールアルキルであり；
各Ｒ^８は、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＯＲ^１１もしくはＳ（Ｏ）_ｎＲ^１１であり；
各Ｒ^９は独立して、Ｈ、ハロゲン、ＮＲ^１１Ｒ^１２、Ｎ（Ｒ^１１）ＯＲ^１１、ＮＲ^１１ＮＲ^１１Ｒ^１２、Ｎ_３、ＮＯ、ＮＯ_２、ＣＨＯ、ＣＮ、−ＣＨ（＝ＮＲ^１１）、−ＣＨ＝ＮＨＮＲ^１１、−ＣＨ＝Ｎ（ＯＲ^１１）、−ＣＨ（ＯＲ^１１）_２、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｓ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＯＲ^１１、Ｒ^１１、ＯＲ^１１もしくはＳ（Ｏ）_ｎＲ^１１であり；
各Ｒ^１１もしくはＲ^１２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；またはＲ^１１およびＲ^１２はそれらが共に結合している窒素と一緒になって３〜７員複素環を形成し、前記複素環の炭素原子の任意の１つは−Ｏ−、−Ｓ−もしくは−ＮＲ^ｂ−に置換されていることができ；
各Ｒ^１３は独立して、１〜３個のＲ^２０基に置換されていてもよい炭素環もしくは複素環であり；
各Ｒ^２０は独立して、ハロゲン、ＣＮ、Ｎ_３、Ｎ（Ｒ）_２、ＯＲ、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）ＯＲ、もしくはＣ（＝Ｙ^１）Ｎ（Ｒ）_２であり；
式中、各Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^１１もしくはＲ^１２の各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルは独立して、１つもしくは複数のハロ、ヒドロキシ、ＣＮ、Ｎ_３、Ｎ（Ｒ^ｂ）_２もしくはＯＲ^ｂに置換されていてもよく；ならびに、前記（Ｃ_１〜Ｃ_８）アルキルのそれぞれの１個もしくは複数の非末端炭素原子は、−Ｏ−、−Ｓ−もしくは−ＮＲ^ｂに置換されていてよく；
各Ｒ^ｂは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^２１、−Ｃ（＝Ｏ）ＯＲ^２１、−Ｃ（＝Ｏ）ＮＲ^２１Ｒ^２２、−Ｃ（＝Ｏ）ＳＲ^２１、−Ｓ（Ｏ）Ｒ^２１、−Ｓ（Ｏ）_２Ｒ^２１、−Ｓ（Ｏ）（ＯＲ^２１）、−Ｓ（Ｏ）_２（ＯＲ^２１）、もしくは−ＳＯ_２ＮＲ^２１Ｒ^２２であり；
各Ｒ^２１もしくはＲ^２２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
ただし、化合物１、１ｄ、１ｅ、２、ＴＰ−１、Ａ−１、８、および２１は、除外されてもよい。 In another embodiment, Formula IV:

Formula IV
Or a pharmaceutically acceptable salt thereof;
In the formula:
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) Substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
R ² is halogen;
Each R ³ , R ⁴ , and R ⁵ is independently H, halogen, OR ^a , N (R ^a ) ₂ , N ₃ , CN, NO ₂ , S (O) _n R ^a , (C _1- C _{8) alkyl, (C} 4 _{~C 8) carbocyclylalkyl, (C} 1 _{~C 8)} substituted _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} substituted alkenyl, _(C 2 ~ C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, or aryl (C ₁ -C ₈ ) alkyl;
Or any two of R ³ , R ⁴ or R ⁵ on adjacent carbon atoms taken together are —O (CO) O—, or taken together with the ring carbon atom to which they are attached. Forming a double bond;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ ˜C ₈ ) carbocyclylalkyl, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S ( O) R ¹¹ , —S (O) ₂ R ¹¹ , —S (O) (OR ¹¹ ), —S (O) ₂ (OR ¹¹ ), or —SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , or

Is;
Y is Ο, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
W ¹ and W ² when taken together are —Y ³ (C (R ^y ) ₂ ) ₃ Y ³ —; or ^{one of} W ¹ or W ² is either R ³ or R ⁴ Taken together -Y ^3- , the other of W ¹ or W ² is of formula Ia; or each W ¹ and W ² is independently a group of formula IVa

Formula IVa
And in the formula:
Each Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Each Y ² is independently a single bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S— S, S (O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^X is a group of formula IVb

Formula IVb
Where each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C _{^{(= Y 1) N (R}} ) 2, -N (R) 2, - + N (R) 3, -SR, -S (O) R, -S (O) 2 R, -S (O) 2 R ¹³ , -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N ( R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R _{^{, -N (R) C (=}} Y 1) OR, -N (R) C (= Y 1) N (R) 2, -SO 2 NR 2, -CN, -N 3, -NO 2, -OR , _(C 1 ~C _{8) alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} Al _{Cycloalkenyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20 carbocyclyl,} C 2 _{-C 20} heterocyclyl, arylalkyl, heteroarylalkyl; wherein each _(C 1 _{~C 8) alkyl, (C} 2 -C _{8) alkenyl, (C} 2 -C _{8) alkynyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20 carbocyclyl,} C 2 _{-C 20} heterocyclyl, arylalkyl or heteroarylalkyl, are 1-3 ^{R 20} May be substituted; or two R ^y on the same carbon atom, when taken together, form a carbocycle of 3 to 7 carbon atoms;
Each R is _{independently, H, (C 1 ~C 8} ) _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8) alkynyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20} carbocyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;
Each R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , OR ¹¹ or S (O) _n R ¹¹ ;
Each R ⁹ is independently H, halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , N ₃ , NO, NO ₂ , CHO, CN, —CH (= NR ¹¹ ), -CH = NHNR ¹¹ , -CH = N (OR ¹¹ ), -CH (OR ¹¹ ) ₂ , -C (= O) NR ¹¹ R ¹² , -C (= S) NR ¹¹ R ¹² , -C ( = O) OR ¹¹ , R ¹¹ , OR ¹¹ or S (O) _n R ¹¹ ;
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, optionally substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl; or R ¹¹ and R ¹² together with the nitrogen to which they are attached together form a 3- to 7-membered heterocycle, and any of the carbon atoms of the heterocycle One may be substituted with -O-, -S- or -NR ^b- ;
Each R ¹³ is independently a carbocyclic or heterocyclic ring optionally substituted with 1 to 3 R ²⁰ groups;
Each R ²⁰ is independently halogen, CN, N ₃ , N (R) ₂ , OR, —SR, —S (O) R, —S (O) ₂ R, —S (O) (OR), ^{_{-S (O) 2 (oR)}} , - C (= Y 1) R, it is a -C ⁽⁼ Y 1) oR or ^{C (= Y 1) N (} R) 2,;
In the formula, each R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈₎ ) Alkynyl or aryl (C ₁ -C ₈ ) alkyl may independently be substituted with one or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or OR ^b ; One or more non-terminal carbon atoms of each of said (C ₁ -C ₈ ) alkyl may be substituted with —O—, —S— or —NR ^b ;
Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈₎ ^{carbocyclylalkyl, -C (= O) R 21} , -C (= O) OR 21, -C (= O) NR 21 R 22, -C (= O) SR 21, -S ( _{^{O) R 21, -S (O}} ) 2 R 21, -S (O) (oR 21), - S (O) 2 (oR 21), or be a _-SO 2 ^NR 21 ^{R 22;}
Each R ²¹ or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl;
However, compounds 1, 1d, 1e, 2, TP-1, A-1, 8, and 21 may be excluded.

であり；
式中、Ｙは、−Ｏ−であり；Ｗ^１は、式Ｉａであり、Ｗ^２はＲ^４と一緒になって−Ｏ−である。別の実施形態では、式ＩＶの化合物は、式Ｖ

により表され、
式中、Ｒ^１は、メチルまたはエチニルであり、Ｒ^４はＯＲ^ａである。この実施形態の別の態様では、Ｒ^７はＨまたは

である。 In another aspect of this embodiment, Y and Y ¹ are O. In another aspect of this embodiment, R ⁸ is halogen, NR ¹¹ R ¹² , N (R ¹¹ ) OR ¹¹ , NR ¹¹ NR ¹¹ R ¹² , OR ^11, or S (O) _n R ¹¹ . In another aspect of this embodiment, R ⁹ is H, halogen, S (O) _n R ¹¹ or NR ¹¹ R ¹² . In another aspect of this embodiment, R ⁴ is OR ^a . In another aspect of this embodiment, R ¹ is CH ₃ . In another aspect of this embodiment, R ² is F. In another aspect of this embodiment, R ⁷ is

Is;
Wherein Y is —O—; W ¹ is Formula Ia and W ² together with R ⁴ is —O—. In another embodiment, the compound of formula IV is of formula V

Represented by
In the formula, R ¹ is methyl or ethynyl, and R ⁴ is OR ^a . In another aspect of this embodiment, R ⁷ is H or

It is.

で表される。 In another aspect of this embodiment, the compound of formula V has the structure:

It is represented by

の化合物もしくはその医薬上許容可能な塩を提供し；
式中：
Ｒ^４はＯＲ^ａであり；
各ｎは独立して、０、１、もしくは２であり；
各Ｒ^ａは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、もしくは−ＳＯ_２ＮＲ^１１Ｒ^１２であり；
Ｒ^７はＨ、−Ｃ（＝Ｏ）Ｒ^１１、−Ｃ（＝Ｏ）ＯＲ^１１、−Ｃ（＝Ｏ）ＮＲ^１１Ｒ^１２、−Ｃ（＝Ｏ）ＳＲ^１１、−Ｓ（Ｏ）Ｒ^１１、−Ｓ（Ｏ）_２Ｒ^１１、−Ｓ（Ｏ）（ＯＲ^１１）、−Ｓ（Ｏ）_２（ＯＲ^１１）、−ＳＯ_２ＮＲ^１１Ｒ^１２、もしくは

であり；
ＹはＯ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
Ｗ^１およびＷ^２は、一緒になったときに、−Ｙ^３（Ｃ（Ｒ^ｙ）_２）_３Ｙ^３−であり；またはＷ^１もしくはＷ^２の１つはＲ^４と一緒になって−Ｙ^３−であり、Ｗ^１もしくはＷ^２の他方は式Ｉａであり；または
各Ｗ^１およびＷ^２は、独立して、式ＶＩａ基

であり、式中：
各Ｙ^１は独立して、Ｏ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；
各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、Ｎ−ＮＲ_２、Ｓ、Ｓ−Ｓ、Ｓ（Ｏ）、もしくはＳ（Ｏ）_２であり；
各Ｙ^３は独立して、Ｏ、Ｓ、もしくはＮＲであり；
Ｍ２は、０、１もしくは２であり；
各Ｒ^Ｘは、式ＶＩｂ基

式ＶＩｂ
であり、式中
各Ｍ１ａ、Ｍ１ｃ、およびＭ１ｄは独立して、０もしくは１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１もしくは１２であり；
各Ｒ^ｙは独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）Ｒ^１３、−Ｃ（＝Ｙ^１）ＯＲ、−Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｎ（Ｒ）_２、−^＋Ｎ（Ｒ）_３、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）_２Ｒ^１３、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−ＯＣ（＝Ｙ^１）Ｒ、−ＯＣ（＝Ｙ^１）ＯＲ、−ＯＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−ＳＣ（＝Ｙ^１）Ｒ、−ＳＣ（＝Ｙ^１）ＯＲ、−ＳＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｒ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）ＯＲ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−ＳＯ_２ＮＲ_２、−ＣＮ、−Ｎ_３、−ＮＯ_２、−ＯＲ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、ヘテロアリールアルキルであり；
式中、各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、アリールアルキル、もしくはヘテロアリールアルキルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_３〜Ｃ_２０カルボシクリル、Ｃ_２〜Ｃ_２０ヘテロシクリル、もしくはアリールアルキルであり；
各Ｒ^１１もしくはＲ^１２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
各Ｒ^１３は独立して、１〜３個のＲ^２０基に置換されていてもよい炭素環もしくは複素環であり；
各Ｒ^２０は独立して、ハロゲン、ＣＮ、Ｎ_３、Ｎ（Ｒ）_２、ＯＲ、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）ＯＲ、もしくはＣ（＝Ｙ^１）Ｎ（Ｒ）_２であり；
式中、各Ｒ^４、Ｒ^１１もしくはＲ^１２の各（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルは独立して、１つもしくは複数のハロ、ヒドロキシ、ＣＮ、Ｎ_３、Ｎ（Ｒ^ｂ）_２もしくはＯＲ^ｂに置換されていてもよく；ならびに、前記（Ｃ_１〜Ｃ_８）アルキルのそれぞれの１個もしくは複数の非末端炭素原子は、−Ｏ−、−Ｓ−もしくは−ＮＲ^ｂに置換されていてよく；
各Ｒ^ｂは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）Ｒ^２１、−Ｃ（＝Ｏ）ＯＲ^２１、−Ｃ（＝Ｏ）ＮＲ^２１Ｒ^２２、−Ｃ（＝Ｏ）ＳＲ^２１、−Ｓ（Ｏ）Ｒ^２１、−Ｓ（Ｏ）_２Ｒ^２１、−Ｓ（Ｏ）（ＯＲ^２１）、−Ｓ（Ｏ）_２（ＯＲ^２１）、もしくは−ＳＯ_２ＮＲ^２１Ｒ^２２であり；
各Ｒ^２１もしくはＲ^２２は独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_４〜Ｃ_８）カルボシクリルアルキル、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_８）アルキル、−Ｓ（Ｏ）_ｎ（Ｃ_１〜Ｃ_８）アルキルもしくはアリール（Ｃ_１〜Ｃ_８）アルキルであり；
ただし、化合物１、１ｃ、１ｄ、１ｅ、２、ＴＰ−１、Ａ−１、８、および２１は、除外されてもよい。 In another embodiment, Formula VI:

Or a pharmaceutically acceptable salt thereof;
In the formula:
R ⁴ is OR ^a ;
Each n is independently 0, 1, or 2;
Each R ^a is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ ˜C ₈ ) carbocyclylalkyl, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S ( O) R ¹¹ , —S (O) ₂ R ¹¹ , —S (O) (OR ¹¹ ), —S (O) ₂ (OR ¹¹ ), or —SO ₂ NR ¹¹ R ¹² ;
R ⁷ is H, —C (═O) R ¹¹ , —C (═O) OR ¹¹ , —C (═O) NR ¹¹ R ¹² , —C (═O) SR ¹¹ , —S (O) R ¹¹ , -S (O) ₂ R ¹¹ , -S (O) (OR ¹¹ ), -S (O) ₂ (OR ¹¹ ), -SO ₂ NR ¹¹ R ¹² , or

Is;
Y is O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
W ¹ and ^{W 2,} when taken _{^{together, -Y 3 (C (R y}} ) 2) 3 Y 3 - a and; or one of ^{W 1} or ^{W 2} together with ^{R 4} - Y ^3- and the other of W ¹ or W ² is of formula Ia; or each W ¹ and W ² is independently a group of formula VIa

And in the formula:
Each Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Each Y ² is independently a single bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S— S, S (O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^X is a group of formula VIb

Formula VIb
Where each M1a, M1c, and M1d is independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) R ¹³ , -C (= Y ¹ ) OR, -C _{^{(= Y 1) N (R}} ) 2, -N (R) 2, - + N (R) 3, -SR, -S (O) R, -S (O) 2 R, -S (O) 2 R ¹³ , -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N ( R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R _{^{, -N (R) C (=}} Y 1) OR, -N (R) C (= Y 1) N (R) 2, -SO 2 NR 2, -CN, -N 3, -NO 2, -OR , _(C 1 ~C _{8) alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} Al _{Cycloalkenyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20 carbocyclyl,} C 2 _{-C 20} heterocyclyl, arylalkyl, heteroarylalkyl;
In the formula, each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl or heteroarylalkyl, it may be substituted with 1 to 3 R ²⁰ groups;
Each R is _{independently, H, (C 1 ~C 8} ) _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8) alkynyl,} C 6 _{-C 20 aryl,} C 3 _{-C 20} carbocyclyl, C ₂ -C ₂₀ heterocyclyl, or arylalkyl;
Each R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, optionally substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl _(C 1 ~C ₈₎ alkyl;
Each R ¹³ is independently a carbocyclic or heterocyclic ring optionally substituted with 1 to 3 R ²⁰ groups;
Each R ²⁰ is independently halogen, CN, N ₃ , N (R) ₂ , OR, —SR, —S (O) R, —S (O) ₂ R, —S (O) (OR), ^{_{-S (O) 2 (oR)}} , - C (= Y 1) R, it is a -C ⁽⁼ Y 1) oR or ^{C (= Y 1) N (} R) 2,;
Wherein each ^{R 4,} each _(C 1 _{~C 8)} of the ^{R 11} or ^{R 12} _{alkyl, (C} 2 _{~C 8) alkenyl, (C} 2 _{~C 8)} alkynyl or aryl _(C 1 _{~C 8)} alkyl Each independently may be substituted with one or more halo, hydroxy, CN, N ₃ , N (R ^b ) ₂ or OR ^b ; and each of the (C ₁ -C ₈ ) alkyl One or more non-terminal carbon atoms may be substituted with —O—, —S— or —NR ^b ;
Each R ^b is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈₎ ^{carbocyclylalkyl, -C (= O) R 21} , -C (= O) OR 21, -C (= O) NR 21 R 22, -C (= O) SR 21, -S ( _{^{O) R 21, -S (O}} ) 2 R 21, -S (O) (oR 21), - S (O) 2 (oR 21), or be a _-SO 2 ^NR 21 ^{R 22;}
Each R ²¹ or R ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclyl. Alkyl, —C (═O) (C ₁ -C ₈ ) alkyl, —S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl;
However, compounds 1, 1c, 1d, 1e, 2, TP-1, A-1, 8, and 21 may be excluded.

もしくは

であり、
式中、
ａは、Ｒ^７結合点であり；
ｂは、Ｒ^４結合点であり；
Ａｒは、フェニルもしくはナフチルであり、前記フェニルおよびナフチルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒ^ｙは独立して、（Ｃ_１〜Ｃ_８）アルキルまたはＣ_５〜Ｃ_６カルボシクリルであり、前記アルキルおよびカルボシクリルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_６）アルキル、もしくはアリールアルキルであり；ならびに
各Ｒ^２０は独立して、ハロゲン、ＣＮ、Ｎ（Ｒ）_２、ＯＲ、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−Ｃ（＝Ｏ）Ｒ、−Ｃ（＝Ｏ）ＯＲ、もしくはＣ（＝Ｏ）Ｎ（Ｒ）_２である。 In another aspect of this embodiment, R ^a is H, (C ₁ -C ₈ ) alkyl, or —C (═O) (C ₁ -C ₆ ) alkyl; together with R ⁷ or R ⁴ R ⁷ is now

Or

And
Where
a is the R ⁷ point of attachment;
b is the R ⁴ point of attachment;
Ar is phenyl or naphthyl, and the phenyl and naphthyl may be substituted with 1 to 3 R ²⁰ groups;
Each R ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, wherein the alkyl and carbocyclyl may be substituted with 1 to 3 R ²⁰ groups;
Each R is independently H, (C ₁ -C ₆ ) alkyl, or arylalkyl; and each R ²⁰ is independently halogen, CN, N (R) ₂ , OR, —SR, —S _{(O) R, -S (O} ) 2 R, -S (O) (oR), - S (O) 2 (oR), - C (= O) R, -C (= O) oR or C, (= O) N (R) ₂ .

もしくは

を有する化合物により表され、またはそれらの医薬上許容可能な塩である。 In another embodiment, the compounds of formulas IV-VI have the structure

Or

Or a pharmaceutically acceptable salt thereof.

などの複素環で表すことができる。 In one embodiment of Formulas I-III and IV-VI, R ¹¹ or R ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C _2- C _{8) alkynyl, (C} 4 _{~C 8)} carbocyclylalkyl, aryl optionally substituted, optionally substituted _{heteroaryl, -C (= O) (C} 1 ~C 8) alkyl, - S (O) _n (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl. In another embodiment, R ¹¹ and R ¹² together with the nitrogen to which they are attached together form a 3-7 membered heterocyclic ring, and any one of the heterocyclic carbon atoms is —O— , -S- or -NR ^a - can be substituted in. Thus, as a non-limiting example, the —NR ¹¹ R ¹² moiety is

And can be represented by a heterocyclic ring.

In another embodiment of Formulas I-III and Formulas IV-VI, each R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² is independently (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl, said (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈₎ alkynyl or aryl _(C 1 -C ₈₎ alkyl is independently one or more of halo, ^{_{hydroxy, CN, N 3, N (}} R a) may be substituted in the ₂ or oR ^a . Thus, as a non-limiting example, R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² are —CH (NH ₂ ) CH ₃ , —CH (OH) CH ₂ CH ₃ , —CH (NH _{2) CH (CH 3) 2} , -CH 2 CF 3, - (CH 2) 2 CH (N 3) CH 3, - (CH 2) may represent a portion of such 6 NH _2.

In another embodiment of formulas I-III and formulas IV-VI, R ³ , R ⁴ , R ⁵ , R ⁶ , R ^11, or R ¹² is (C ₁ -C ₈ ) alkyl, and said (C _1- One or more non-terminal carbon atoms of each C ₈ ) alkyl may be substituted with —O—, —S— or —NR ^a —. Thus, as non-limiting examples, R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ or R ¹² are —CH ₂ OCH ₃ , —CH ₂ OCH ₂ CH ₃ , —CH ₂ OCH (CH ₃ ). ₂ , —CH ₂ SCH ₃ , — (CH ₂ ) ₆ OCH ₃ , — (CH ₂ ) ₆ N (CH ₃ ) _{2, and the} like can be represented.

および

からなる群から選択される化合物；
またはそれらの医薬上許容可能な塩もしくはエステルである。 In another embodiment, Formulas I-III are:

and

A compound selected from the group consisting of:
Or a pharmaceutically acceptable salt or ester thereof.

および

からなる群から選択される式Ｉの化合物；またはそれらの塩もしくはエステル合成に有用な化合物を提供する。 In another embodiment,

and

Compounds of formula I selected from the group consisting of: or compounds useful for the synthesis of their salts or esters are provided.

Definitions Unless otherwise stated, the following terms and phrases used in this specification shall have the following meanings.

  Where the trade name is used herein, Applicants intend to independently include the trade name product and the active pharmaceutical ingredient (s) of the trade name product.

  As used herein, “a compound of the invention” or “a compound of formula I” means a compound of formula I or a pharmaceutically acceptable salt thereof. Similarly, with respect to separable intermediates, the phrase “compound of formula (number)” means a compound of formula and pharmaceutically acceptable salts thereof.

“Alkyl” is a hydrocarbon containing straight chain, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group can be 1-20 carbon atoms (ie, C ₁ -C ₂₀ alkyl), 1-8 carbon atoms (ie, C ₁ -C ₈ alkyl), or 1-6 carbon atoms. (Ie C ₁ -C ₆ alkyl). Examples of suitable alkyl groups include methyl (Me, _-CH 3), ethyl _{(Et, -CH 2 CH 3)} , 1- propyl (n -Pr, n - _{propyl, -CH 2 CH 2 CH 3)} , 2-propyl (i -Pr, i - _{propyl, -CH (CH 3) 2)} , 1- butyl (n -Bu, n - _{butyl, -CH 2 CH 2 CH 2 CH} 3), 2- methyl-1- propyl (i -Bu, i - _{butyl, -CH 2 CH (CH 3)} 2), 2- butyl (s -Bu, s - _{butyl, -CH (CH 3) CH 2} CH 3), 2- methyl-2 - propyl (t -Bu, t - _{butyl, -C (CH 3) 3)} , 1- pentyl (n - _{pentyl, -CH 2 CH 2 CH 2 CH} 2 CH 3), 2- pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (—CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (—C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (—CH (CH ₃ ) CH (CH _{3) 2),} 3-methyl-1-butyl _{(-CH 2 CH 2 CH (CH} 3) 2), 2- methyl-1-butyl _{(-CH 2 CH (CH 3)} CH 2 CH 3), 1- Hexyl (—CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (—CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (—CH (CH ₂ CH ₃ ) ( _{CH 2 CH 2 CH 3))} , 2- methyl-2-pentyl _{(-C (CH 3) 2 CH} 2 CH 2 CH 3), 3- methyl-2-pentyl _{(-CH (CH 3) CH (} CH 3 ) _CH 2 _CH 3), 4- methyl-2-pentyl (-C _{(CH 3) CH 2 CH (} CH 3) 2), 3- methyl-3-pentyl _{(-C (CH 3) (CH} 2 CH 3) 2), 2- methyl-3-pentyl (-CH (CH _{2 CH 3) CH (CH 3)} 2), 2,3- dimethyl-2-butyl _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ , and octyl (— (CH ₂ ) ₇ CH ₃ ), but are not limited to these.

“Alkoxy” means a group having the formula —O-alkyl, wherein an alkyl group, as defined above, is attached to the parent molecule through an oxygen atom. Alkyl moiety of the alkoxy group having 1 to 20 carbon atoms _(i.e., C 1 _{-C 20} alkoxy), 1 to 12 carbon atoms _(i.e., C 1 _{-C 12} alkoxy), or 1 to 6 carbons Can have atoms (ie C ₁ -C ₆ alkoxy). Examples of suitable alkoxy groups include methoxy (—O—CH ₃ or —OMe), ethoxy (—OCH ₂ CH ₃ or —OEt), t-butoxy (—O—C (CH ₃ ) ₃ or —OtBu) However, it is not limited to these.

“Haloalkyl” is an alkyl group in which one or more hydrogen atoms of the alkyl group defined above is replaced by a halogen atom. The alkyl portion of the haloalkyl group can be from 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ haloalkyl), 1-12 carbon atoms (ie, C ₁ -C ₁₂ haloalkyl), or 1-6 carbons. Can have atoms (ie, C ₁ -C ₆ alkyl). Examples of suitable haloalkyl _{groups, -CF 3, -CHF 2, -CFH} 2, -CH 2 CF 3, but like, but not limited to.

“Alkenyl” is a hydrocarbon containing straight, secondary, tertiary or cyclic carbon atoms and having at least one unsaturation, ie, a carbon-carbon sp ² double bond. For example, an alkenyl group is 2-20 carbon atoms (ie, C ₂ -C ₂₀ alkenyl), 2-8 carbon atoms (ie, C ₂ -C ₈ alkenyl), or 2-6 carbon atoms. _(i.e., C 2 -C ₆ alkenyl) may have. Examples of suitable alkenyl groups include ethylene or vinyl (—CH═CH ₂ ), allyl (—CH ₂ CH═CH ₂ ), cyclopentenyl (—C ₅ H ₇ ), and 5-hexenyl (—CH ₂ CH _{2 CH 2 CH 2 CH = CH} 2) include, but are not limited to.

“Alkynyl” is a hydrocarbon containing straight, secondary, tertiary or cyclic carbon atoms and having at least one unsaturation, ie, a carbon-carbon sp triple bond. For example, an alkynyl group is 2-20 carbon atoms (ie, C ₂ -C ₂₀ alkynyl), 2-8 carbon atoms (ie, C ₂ -C ₈ alkyne), or 2-6 carbons. Can have atoms (ie, C ₂ -C ₆ alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylene (—C≡CH), propargyl (—CH ₂ C≡CH), and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclic carbonization having two monovalent radical centers obtained by removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of the parent alkane. Refers to hydrogen radical. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include methylene (—CH ₂ —), 1,1-ethyl (—CH (CH ₃ ) —), 1,2-ethyl (—CH ₂ CH ₂ —), 1,1-propyl. _{(-CH (CH 2 CH 3)} -), 1,2- propyl _{(-CH 2 CH (CH 3)} -), 1,3- propyl _{(-CH 2 CH 2 CH 2 -} ), 1,4- butyl (—CH ₂ CH ₂ CH ₂ CH ₂ —) and the like, but are not limited thereto.

  “Alkenylene” refers to an unsaturated, branched or straight chain or cyclic having two monovalent radical centers obtained by removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of the parent alkene. Refers to a hydrocarbon radical. For example, an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Exemplary alkenylene radicals include, but are not limited to, 1,2-ethylene (—CH═CH—).

“Alkynylene” means an unsaturated, branched or straight chain or cyclic having two monovalent radical centers obtained by removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of the parent alkyne. Refers to a hydrocarbon radical. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include acetylene (—C≡C—), propargyl (—CH ₂ C≡C—), and 4-pentynyl (—CH ₂ CH ₂ CH ₂ C≡C—). However, it is not limited to these.

“Amino” generally has the formula —N (X) ₂ , wherein each “X” is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, and the like. ) Refers to a nitrogen radical that can be regarded as an ammonia derivative. The nitrogen hybrid is approximately sp ³ . Nonlimiting examples of amino, _-NH 2, -N _(alkyl) 2, -NH (alkyl), - N _{(carbocyclyl)} 2, -NH (carbocyclyl), - N _{(heterocyclyl)} 2, -NH ( Heterocyclyl), -N (aryl) ₂ , -NH (aryl), -N (alkyl) (aryl), -N (alkyl) (heterocyclyl), -N (carbocyclyl) (heterocyclyl), -N (aryl) (hetero) Aryl), -N (alkyl) (heteroaryl) and the like. The term “alkylamino” refers to an amino group substituted with at least one alkyl group. Non-limiting examples of amino _{groups, -NH 2, -NH (CH 3} ), - N (CH 3) 2, -NH (CH 2 CH 3), - N (CH 2 CH 3) 2, - NH (phenyl), -N (phenyl) ₂ , -NH (benzyl), -N (benzyl) _2, etc. are mentioned. Substituted alkylamino generally refers to an alkylamino group as defined above with at least one substituted alkyl as defined herein attached to the amino nitrogen atom. Non-limiting examples of substituted alkylamino include —NH (alkylene-C (O) —OH), —NH (alkylene-C (O) —O-alkyl), —N (alkylene-C (O) — OH) ₂ , -N (alkylene-C (O) -O-alkyl) _{2, and the} like.

  “Aryl” means an aromatic hydrocarbon radical derived by the removal of a hydrogen atom from a carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (eg, phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp ³ carbon atom) is replaced with an aryl radical. Examples of typical arylalkyl groups include benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, naphthbenzyl, 2-naphthphenylethane-1-yl, and the like. An arylalkyl group can contain 7 to 20 carbon atoms, for example, the alkyl moiety is 1 to 6 carbon atoms, and the aryl moiety is 6 to 14 carbon atoms. is there.

“Arylalkenyl” means that one of the hydrogen atoms bonded to a carbon atom (typically a terminal carbon atom or an sp ³ carbon atom, but may also be an sp ² carbon atom) is replaced with an aryl radical Refers to a non-cyclic alkenyl radical. The aryl portion of arylalkenyl can include, for example, any aryl group disclosed herein, and the alkenyl portion of arylalkenyl can include, for example, any alkenyl group disclosed herein. it can. An arylalkenyl group can contain 8 to 20 carbon atoms, for example, the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

“Arylalkynyl” means that one of the hydrogen atoms bonded to a carbon atom (typically a terminal carbon atom or an sp ³ carbon atom, but may also be an sp carbon atom) is replaced with an aryl radical Refers to a non-cyclic alkynyl radical. The aryl portion of an arylalkynyl can include, for example, any aryl group disclosed herein, and the alkynyl portion of an arylalkynyl can include, for example, any alkynyl group disclosed herein. it can. An arylalkynyl group can contain 8 to 20 carbon atoms, for example, an alkynyl moiety is 2 to 6 carbon atoms and an aryl moiety is 6 to 14 carbon atoms.

“Substituted” in references to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, “substituted alkyl”, “substituted alkylene”, “substituted aryl”, “substituted arylalkyl” , “Substituted heterocyclyl”, and “substituted carbocyclyl”, unless otherwise specified, are alkyl, alkylene, aryl, aryl, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. It means alkyl, heterocyclyl and carbocyclyl, respectively. ^{Typical substituents, -X, -R b, -O -} , = O, -OR b, -SR b, -S -, -NR b 2, -N + R b 3, = NR b, _{-CX 3, -CN, -OCN, -SCN} , -N = C = O, -NCS, -NO, -NO 2, = N 2, -N 3, -NHC (= O) R b, -OC ( _{^{= O) R b, -NHC (}} = O) NR b 2, -S (= O) 2 -, - S (= O) 2 OH, -S (= O) 2 R b, -OS (= O) _{^{2 OR b, -S (= O}} ) 2 NR b 2, -S (= O) R b, -OP (= O) (OR b) 2, -P (= O) (OR b) 2, -P (= O) (O ⁻ ) ₂ , —P (═O) (OH) ₂ , —P (O) (OR ^b ) (O ⁻ ), —C (═O) R ^b , —C (═O) ^{X, -C (S) R b} , -C (O) OR b, -C (O) ^{-, -C (S) OR b} , -C (O) SR b, -C (S) SR b, -C (O) NR b 2, -C (S) NR b 2, -C (= NR b ) NR ^b ₂ (wherein each X is independently halogen: F, Cl, Br, or I), but is not limited to; and each R ^b is independently H, alkyl, An aryl, arylalkyl, heterocyclic ring, or protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may be similarly substituted. Unless otherwise specified, when the term “substituted” is used in conjunction with a group such as arylalkyl having two or more substitutable moieties, the substituent is an aryl moiety, an alkyl moiety, or both Can be combined.

  As used herein, the term “prodrug” refers to spontaneous chemical reaction (s), enzyme-catalyzed chemical reaction (s), photolysis, and / or metabolic chemistry upon administration to a biological system. Refers to drug substance, ie any compound that produces the active ingredient as a result of the reaction (s). Thus, a prodrug is a covalently modified analog or latent form of a therapeutically active compound.

  Substituents and other moieties of compounds of Formulas I-III and Formulas IV-VI are sufficiently stable compounds to provide pharmaceutically useful compounds that can be formulated into an acceptable and stable pharmaceutical composition. Those skilled in the art will recognize that they should be selected to provide. The definitions and substituents of the various genera and subgenera of the compounds are described and illustrated herein. It should be understood by those skilled in the art that none of the above definitions and combinations of substituents should lead to inoperable species or compounds. “Inoperable species or compounds” refers to compound structures that do not conform to the relevant scientific principles (eg, carbon atoms attached to more than four covalent bonds) or formulations into isolated and pharmaceutically acceptable dosage forms Means a compound that is too unstable to allow crystallization.

“Heteroalkyl” refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom (such as O, N, or S). For example, if the carbon atom of the alkyl group attached to the parent molecule is replaced with a heteroatom (eg, O, N, or S), the resulting heteroalkyl group is each an alkoxy group (eg, — OCH ₃ etc.), an amine (eg —NHCH ₃ , —N (CH ₃ ) ₂ etc.), or a thioalkyl group (eg —SCH ₃ ). When a non-terminal carbon atom of an alkyl group that is not bound to a parent molecule is replaced with a heteroatom (eg, O, N, or S), the resulting heteroalkyl group is each an alkyl ether (eg, — CH ₂ CH ₂ —O—CH ₃ ), alkylamines (eg —CH ₂ NHCH ₃ , —CH ₂ N (CH ₃ ) ₂ etc.), or thioalkyl ethers (eg —CH ₂ —S—CH ₃ ). When the terminal carbon atom of the alkyl group is substituted with a heteroatom (eg, O, N, or S), the resulting heteroalkyl group is each a hydroxyalkyl group (eg, —CH ₂ CH ₂ —OH). , An aminoalkyl group (eg —CH ₂ NH ₂ ), or an alkyl thiol group (eg —CH ₂ CH ₂ —SH). A heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C ₁ -C ₆ heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.

である。 As used herein, “heterocycle” or “heterocyclyl” includes, by way of non-limiting example, Paquette, Leo A .; The Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially Chapter 1, Chapter 3, Chapter 6, Chapter 7, Chapter 9 and Chapter 9; The Chemistry of HeteroCoMeter of HeteroCo "(John Wiley & Sons, New York, 1950 to present), especially 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82: 5566. In one specific embodiment of the present invention, “heterocycle” refers to one or more (eg, 1, 2, 3, or 4) carbon atoms that are heteroatoms (eg, O , N, or S) Substituted, including "carbocyclyl" as defined herein. The term “heterocycle” or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (ie, aromatic heterocycles). Substituted heterocyclyl includes heterocycles substituted with any of the substituents disclosed herein, including, for example, carbonyl groups. Non-limiting examples of carbonyl substituted heterocyclyls are:

It is.

が挙げられる。 Non-limiting examples of heterocycles include pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfurated tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl , Thiaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroiso Quinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl Thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, phthalazinyl, naphthyridinyl Quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochrominyl, chrominyl, imidazolinyl Pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolin Nyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxyindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

Is mentioned.

  As a non-limiting example, the carbon-bonded heterocycle is 2, 3, 4, 5, or 6 of pyridine, 3, 4, 5, or 6 of pyridazine, or 2 of pyrimidine. 4th, 5th, or 6th, 2nd, 3rd, 5th, or 6th of pyrazine, 2nd, 3rd, 4th, or 5th of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole Position, oxazole, imidazole or thiazole 2-position, 4-position, or 5-position, isoxazole, pyrazole, or isothiazole 3-position, 4-position, or 5-position, aziridine 2-position or 3-position, azetidine 2-position, 3rd or 4th, quinoline 2nd, 3rd, 4th, 5th, 6th, 7th or 8th, or isoquinoline 1st, 3rd, 4th, 5th, 6th They are joined by the 7-position or 8-position. Even more typically, the carbon-bonded heterocycle includes 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

  As non-limiting examples, the nitrogen-bonded heterocycle is aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazolin, 3-Pyrazoline, piperidine, piperazine, indole, indoline, 1-position of 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline. Even more typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

“Heterocyclylalkyl” is a non-substituted hydrogen atom in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp ³ carbon atom) is replaced with a heterocyclyl radical (ie, a heterocyclyl-alkylene moiety). Refers to a cyclic alkyl radical. Typical heterocyclylalkyl groups, heterocyclyl _-CH 2 -, 2-(heterocyclyl) ethan-1-yl, and the like (wherein "heterocyclyl" moieties, Principles of Modern Heterocyclic Chemistry any of the above, including those described in Including, but not limited to, a heterocyclyl group. One skilled in the art will also appreciate that a heterocyclyl group can be attached to the alkyl portion of a heterocyclylalkyl through a carbon-carbon bond or a carbon-heteroatom bond as long as the product group is chemically stable. A heterocyclylalkyl group contains 3 to 20 carbon atoms, for example, the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl portion is 2 to 14 carbon atoms. Non-limiting examples of heterocyclylalkyl include 5-membered sulfur, oxygen, and / or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethane-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, Examples include 6-membered sulfur, oxygen, and / or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridylmethyl, pyrimidylmethyl, pyrazinylmethyl and the like.

“Heterocyclylalkenyl” refers to a heterocyclyl radical in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal carbon atom or an sp ³ carbon atom, but can also be an sp ² carbon atom). That is, it refers to an acyclic alkenyl radical substituted with a heterocyclyl-alkenylene moiety. The heterocyclyl portion of the heterocyclylalkenyl group includes any heterocyclyl group described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclylalkenyl group includes any alkenyl group disclosed herein. including. One skilled in the art will also appreciate that a heterocyclyl group can be attached to the alkenyl moiety of a heterocyclylalkenyl by a carbon-carbon bond or a carbon-heteroatom bond as long as the product group is chemically stable. A heterocyclylalkenyl group contains 4 to 20 carbon atoms, for example, the alkenyl moiety of the heterocyclylalkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.

“Heterocyclylalkynyl” means that one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp ³ carbon atom, but also an sp carbon atom) is a heterocyclyl radical (ie, heterocyclyl- Refers to an acyclic alkynyl radical substituted with an alkynylene moiety. The heterocyclyl portion of the heterocyclylalkynyl group includes any heterocyclyl group described herein, including those described in Principles of Modem Heterocyclic Chemistry, and the alkynyl portion of a heterocyclylalkynyl group includes any alkynyl group disclosed herein. including. One skilled in the art will also appreciate that a heterocyclyl group can be attached to the alkynyl moiety of a heterocyclylalkynyl through a carbon-carbon bond or a carbon-heteroatom bond as long as the product group is chemically stable. A heterocyclylalkynyl group contains 4 to 20 carbon atoms, for example, the alkynyl moiety of the heterocyclylalkynyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.

  “Heteroaryl” refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, All of the aromatic rings listed in the definition of “heterocyclyl” are included, including pyridazyl, pyrimidyl, pyrazyl and the like.

  “Carbocycle” or “carbocyclyl” is saturated having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle (ie, Cycloalkyl), partially unsaturated (eg, cycloalkenyl, cycloalkadienyl, etc.) or aromatic ring. Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles are arranged as 7-12 ring atoms, for example bicyclo [4,5], [5,5], [5,6] or [6,6] systems, or bicyclo [5,6 Or 9 or 10 ring atoms arranged as a [6,6] system, or a spiro-fused ring. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohexa- 1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclocarbocycles include naphthyl, tetrahydronaphthalene, and decalin.

  “Carbocyclylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by a carbocyclyl radical as described herein. Examples of typical but not limited carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

  “Arylheteroalkyl” is a heteroalkyl, as defined herein, wherein a hydrogen atom (which can be attached to either a carbon atom or a heteroatom) is replaced with an aryl group, as defined herein. Point to. The aryl group can be attached to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, so long as the resulting aryl heteroalkyl group provides a chemically stable moiety. For example, an arylheteroalkyl group has the general formula -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl,- Can have alkylene-S-alkylene-aryl and the like. Furthermore, any alkylene moiety of the above general formula can be further substituted with any substituent as defined or exemplified herein.

“Heteroarylalkyl” refers to an alkyl group, as defined herein, in which a hydrogen atom is replaced with a heteroaryl group, as defined herein. Non-limiting examples of heteroaryl alkyl, -CH ₂ - pyridinyl, -CH ₂ - pyrrolyl, -CH ₂ - oxazolyl, -CH ₂ - indolyl, -CH ₂ - isoindolyl, -CH ₂ - purinyl, -CH ₂ - furanyl, -CH ₂ - thienyl, -CH ₂ - benzofuranyl, -CH ₂ - benzothiophenyl, -CH ₂ - carbazolyl, -CH ₂ - imidazolyl, -CH ₂ - thiazolyl, -CH ₂ - isoxazolyl, -CH ₂ - pyrazolyl, -CH ₂ - isothiazolyl, -CH ₂ - quinolyl, -CH ₂ - isoquinolyl, -CH ₂ - pyridazinyl, -CH ₂ - pyrimidyl, -CH ₂ - pyrazyl, -CH (CH ₃₎ - pyridinyl, - CH (CH ₃₎ - pyrrolyl, -CH (CH ₃₎ - oxazolyl, -CH (CH ₃ - indolyl, -CH (CH ₃₎ - isoindolyl, -CH (CH ₃₎ - purinyl, -CH (CH ₃₎ - furanyl, -CH (CH ₃₎ - thienyl, -CH (CH ₃₎ - benzofuranyl, -CH (CH ₃₎ - benzothiophenyl, -CH (CH ₃₎ - carbazolyl, -CH (CH ₃₎ - imidazolyl, -CH (CH ₃₎ - thiazolyl, -CH (CH ₃₎ - isoxazolyl, -CH (CH ₃ ) - pyrazolyl, -CH (CH ₃₎ - isothiazolyl, -CH (CH ₃₎ - quinolyl, -CH (CH ₃₎ - isoquinolyl, -CH (CH ₃₎ - pyridazinyl, -CH (CH ₃₎ - pyrimidyl, - CH (CH ₃₎ - pyrazinyl, and the like.

  The term “optionally substituted” when referring to a particular moiety (eg, an optionally substituted aryl group) of compounds of Formulas I-III and IV-VI is that all substituents are hydrogen, Or, one or more hydrogens of the moiety refers to a moiety that may be substituted by a substituent, such as those listed under the “substituted” definition, or as otherwise indicated.

Specific moieties of compounds of Formulas I-III and Formulas IV-VI (eg, the carbon atom of the (C ₁ -C ₈ ) alkyl may be substituted with —O—, —S—, or —NR ^a —) The term “optionally substituted” refers to that where one or more methylene groups of (C ₁ -C ₈ ) alkyl are 0, 1, 2, or more specific groups (eg, —O -, - S-, or -NR ^a -) by means that may be substituted.

The term “non-terminal carbon atom (s)” referring to an alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers to the intermediary between the first carbon atom of the moiety and the final carbon atom in the moiety. Refers to the carbon atom within the moiety. Thus, as non-limiting examples, within the alkyl moiety —CH ₂ (C ^* ) H ₂ (C ^* ) H ₂ CH ₃ or the alkylene moiety —CH ₂ (C ^* ) H ₂ (C ^* ) H ₂ CH ₂ C ^* atoms are considered non-terminal carbon atoms.

などの荷電を分離した基により表すこともでき、本発明を説明する目的において上記表示と同じものであるとする。 Some Y and Y ¹ alternatives are nitrogen oxides such as ⁺ N (O) (R) or ⁺ N (O) (OR). Each of these nitrogen oxides bonded to a carbon atom as shown herein is

For example, for the purpose of explaining the present invention, it is assumed that the display is the same as the above display.

  "Linker" or "link" means a chemical moiety that includes a covalent bond or chain of atoms. Linkers include repeating units of alkyloxy (eg, polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (eg, polyethyleneamino, Jeffamine ™); and diacid esters and amides (succinate, succinamide, Diglycolate, malonate, and caproamide).

  Terms such as “oxygen bond”, “nitrogen bond”, “carbon bond”, “sulfur bond”, or “phosphorus bond” form a bond between two parts by using multiple types of atoms within the part When possible, the bond formed between the parts means through a specific atom. For example, a nitrogen-bonded amino acid is bonded through the amino acid nitrogen atom rather than through the amino acid oxygen or carbon atom.

は、

と同じ意味である。 Unless otherwise specified, the carbon atoms of compounds of Formulas I-III and IV-VI shall be tetravalent. In some chemical structure representations that do not have a sufficient number of linking groups for the carbon atom to be tetravalent, the remaining carbon substituents required to be tetravalent are considered hydrogen. For example,

Is

Means the same.

  “Protecting group” refers to a moiety of a compound that masks or modifies the properties of a functional group or the properties of the entire compound. The chemical structure of the protecting group varies widely. One function of the protecting group serves as an intermediate in the synthesis of the parent drug substance. Chemical protecting groups and protection / deprotection strategies are well known in the art. “Protective Groups in Organic Chemistry”, Theodora W. See Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are designed in order, for example, in order to conceal the reactivity of certain functional groups and assist in the effectiveness of a desired chemical reaction. Often used to form and destroy in a controlled manner: protection of the functional groups of the compound is protected, including polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical methods Alter other physical properties in addition to functional group reactivity Chemically protected intermediates may be biologically active or inert alone.

  Protected compounds may also exhibit modified or in some cases optimized properties (such as cell membrane passage and resistance to enzymatic degradation or osteoclastation) in vitro and in vivo. In this role, protected compounds with the intended therapeutic effect are sometimes referred to as prodrugs. Another function of the protecting group is to convert the parent drug to a prodrug, thereby releasing the parent drug upon in vivo conversion of the prodrug. Because active prodrugs can be absorbed more effectively than the parent drug, prodrugs can have higher potency than the parent drug in vivo. Protecting groups are removed either in vitro in the case of chemical intermediates or in vivo in the case of prodrugs. In the case of chemical intermediates, it is not particularly important that the product produced after deprotection, for example an alcohol, is physiologically acceptable, but generally it is more desirable if the product is pharmacologically harmless. .

A “prodrug moiety” is a labile function that is separated from an activity-inhibiting compound during metabolism, systemically, intracellularly, by hydrolysis, by enzymatic cleavage, or by some other process. Meaning Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development , Develop. Enzymes capable of being activated by an enzyme with a phosphonate prodrug compound of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase, and phosphatase. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity in order to optimize drug delivery, bioavailability and effectiveness.

  A prodrug moiety may include an active metabolite or the drug itself.

Exemplary prodrug moieties include hydrolysis sensitive or labile acyloxymethyl esters —CH ₂ OC (═O) R ³⁰ and acyloxymethyl carbonate —CH ₂ OC (═O) OR ³⁰ , wherein R ³⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl). Acyloxyalkyl esters were first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates (Farquahar et al (1983) J. Pharm. Sci. 72: 324; further US patents). No. 4,816,570, No. 4,968,788, No. 5,663,159 and No. 5,792,756). In certain compounds of the invention, the prodrug moiety is part of a phosphate group. Acyloxyalkyl esters can be used to deliver phosphate across cell membranes and enhance oral bioavailability. Alkoxycarbonyloxyalkyl esters (carbonates), a modification close to acyloxyalkyl esters, can also enhance oral bioavailability as prodrug moieties in the combination of compounds of the present invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy (POM) —CH ₂ OC (═O) C (CH ₃ ) ₃ . An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethyl carbonate (POC) —CH ₂ OC (═O) OC (CH ₃ ) ₃ .

  The phosphate group can be a phosphate prodrug moiety. Prodrug moieties include, but are not limited to, pivaloyloxymethyl carbonate (POC) or POM groups that can be sensitive to hydrolysis. Alternatively, the prodrug moiety may be sensitive to enzyme-enhanced cleavage (such as a lactate ester or phosphonamidate ester group).

  Phosphorus aryl esters, particularly phenyl esters, have been reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498). Phenyl esters containing carboxylic acid esters in the ortho position relative to the phosphate have also been described (Khamnei and Torrance, (1996) J. Med. Chem. 39: 4109-4115). Benzyl esters have been reported to produce the parent phosphonic acid. In some cases, substituents at the ortho or para position may accelerate the hydrolysis. Benzyl analogs with acylated phenols or alkylated phenols can produce phenolic compounds by the action of enzymes (eg, esterases, oxidases, etc.), which are subsequently cleaved at the benzylic C—O bond to phosphoric acid and A quinone methide intermediate is formed. Examples of this class of prodrugs are described by Mitchell et al (1992) J. MoI. Chem. Soc. Perkin Trans. I 2345; Brook et al WO 91/19721. In addition, other benzyl prodrugs containing carboxylic ester containing groups attached to the methylene of benzyl have been described (Glazier et al WO 91/19721). Thio-containing prodrugs have been reported to be useful for intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or bonded to another thiol group to form a disulfide. De-esterification or reduction of this disulfide produces a free thio intermediate, which is subsequently decomposed to phosphoric acid and episulfide (Puch et al (1993) Antiviral Res., 22: 155-174; Benzaria et al (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al, US Pat. No. 6,312,662).

  All enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs and compounds thereof within the scope of formula I, formula II, formula III, formula IV, formula V, or formula VI It should be noted that pharmaceutically acceptable salts are included in the present invention. All such enantiomeric and diastereomeric mixtures are within the scope of this invention.

  The compounds of formulas I-III and IV-VI and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism may be due to different crystal packing (packing polymorphism) or due to different packing (conformation polymorphism) between different conformers on the same molecule. As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the present invention may exist due to different crystal packings (packing pseudopolymorphs) or due to different packings (conformational pseudopolymorphisms) between different conformers on the same molecule. May exist. The present invention includes all polymorphs and pseudopolymorphs of the compounds of Formulas I-III and Formulas IV-VI and their pharmaceutically acceptable salts.

  Compounds of formulas I-III and IV-VI and their pharmaceutically acceptable salts may also exist as amorphous solids. As used herein, an amorphous solid is a solid whose atomic position order in the solid is not a long distance. This definition applies as well when the crystal size is 2 nanometers or less. Additives (such as solvents) can be used to make the amorphous mold of the present invention. The present invention includes all amorphous forms of compounds of Formulas I-III and Formulas IV-VI and pharmaceutically acceptable salts thereof.

Contains selected substituents that make up the compounds of Formulas I-III and Formulas IV-VI, but is present to a recursive extent. In this context, “recursive substituent” means that a substituent may be listed as another example of itself. Due to the recursive nature of such substituents, theoretically, in any given embodiment, there can be a large amount of the compound. For example, R ^x includes a R ^y substituent. R ^y can be R. R can be W ³ . W ³ being able to be ^{W 4, W 4} may include a substituent containing a or ^{R y} is R. It will be appreciated by those skilled in the art of medicinal chemistry that the total number of such substituents is reasonably limited by the desired properties of the intended compound. Non-limiting examples of such properties include physical properties (such as molecular weight, solubility or log P), adaptive properties (such as activity against the intended target), and practical properties (such as ease of synthesis).

As a non-limiting example, in certain embodiments, W ³ and R ^y are recursive substituents. Typically, in certain embodiments, each recursive substitution is independently 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, It can occur 5, 4, 3, 2, 1, or 0 times. More typically, in certain embodiments, each recursive substitution can occur independently no more than 12 times. Even more typically, in certain embodiments, each recursive substitution can occur independently no more than three times. For example, in certain embodiments, W ³ occurs 0-8 times and R ^y occurs 0-6 times. Even more typically, in certain embodiments, W ³ occurs 0-6 times and R ^y occurs 0-4 times.

  Recursive substituents are an intended aspect of the invention. Those skilled in the art of medicinal chemistry understand the versatility of such substituents. To the extent that recursive substituents are present in embodiments of the present invention, the total number is determined as described above.

  The modifier “about” used with respect to a quantity includes a predetermined value and has the meaning indicated in the context (eg, including the degree of error associated with the measurement of a particular quantity).

であり得、式中、各ＹもしくはＹ^１は独立して、Ｏ、Ｓ、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、もしくはＮ−ＮＲ_２であり；Ｗ^１およびＷ^２は、一緒になったときに、−Ｙ^３（Ｃ（Ｒ^ｙ）_２）_３Ｙ^３−であり；またはＷ^１もしくはＷ^２の１つはＲ^３もしくはＲ^４のいずれかと一緒になって−Ｙ^３−であり、Ｗ^１もしくはＷ^２の他方は式Ｉａであり；または各Ｗ^１およびＷ^２は、独立して、式Ｉａ基

であり、式中：
各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、ＮＲ、^＋Ｎ（Ｏ）（Ｒ）、Ｎ（ＯＲ）、^＋Ｎ（Ｏ）（ＯＲ）、Ｎ−ＮＲ_２、Ｓ、Ｓ−Ｓ、Ｓ（Ｏ）、もしくはＳ（Ｏ）_２であり；
各Ｙ^３は独立して、Ｏ、Ｓ、もしくはＮＲであり；
Ｍ２は、０、１もしくは２であり；
各Ｒ^ｙは独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、Ｒ、−Ｃ（＝Ｙ^１）Ｒ、−Ｃ（＝Ｙ^１）ＯＲ、−Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−Ｎ（Ｒ）_２、−^＋Ｎ（Ｒ）_３、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−ＯＣ（＝Ｙ^１）Ｒ、−ＯＣ（＝Ｙ^１）ＯＲ、−ＯＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−ＳＣ（＝Ｙ^１）Ｒ、−ＳＣ（＝Ｙ^１）ＯＲ、−ＳＣ（＝Ｙ^１）（Ｎ（Ｒ）_２）、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｒ、−Ｎ（Ｒ）Ｃ（＝Ｙ^１）ＯＲ、もしくは−Ｎ（Ｒ）Ｃ（＝Ｙ^１）Ｎ（Ｒ）_２、−ＳＯ_２ＮＲ_２、−ＣＮ、−Ｎ_３、−ＮＯ_２、−ＯＲ、保護基もしくはＷ^３であり；または同一炭素原子上の２つのＲ^ｙは一緒になったときに、３〜７個の炭素原子の炭素環を形成し；
各Ｒ^Ｘは独立して、Ｒ^ｙ、保護基、もしくは式

であり、式中：
Ｍ１ａ、Ｍ１ｃ、およびＭ１ｄは独立して、０もしくは１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１もしくは１２であり；
各ＲはＨ、ハロゲン、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、（Ｃ_２〜Ｃ_８）置換アルキニル、Ｃ_６〜Ｃ_２０アリール、Ｃ_６〜Ｃ_２０置換アリール、Ｃ_２〜Ｃ_２０複素環、Ｃ_２〜Ｃ_２０置換ヘテロシクリル、アリールアルキル、置換アリールアルキルもしくは保護基であり；
Ｗ^３は、Ｗ^４もしくはＷ^５であり；Ｗ^４はＲ、−Ｃ（Ｙ^１）Ｒ^ｙ、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^ｙ、もしくは−ＳＯ_２Ｗ^５であり；ならびにＷ^５は独立して、０〜３個のＲ^ｙ基に置換されている炭素環もしくは複素環である。 Compounds of formulas I-III and IV-VI may contain a phosphate group as R ⁷ , which is a prodrug moiety

Where each Y or Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR. be _2; ^{W 1} and ^{W 2,} when taken _{^{together, -Y 3 (C (R y}} ) 2) 3 Y 3 - a and; or one of ^{W 1} or ^{W 2} is ^{R 3} or R -Y ^3- with any of ⁴ and the other of W ¹ or W ² is Formula Ia; or each W ¹ and W ² is independently a group of Formula Ia

And in the formula:
Each Y ² is independently a single bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S— S, S (O), or S (O) ₂ ;
Each Y ³ is independently O, S, or NR;
M2 is 0, 1 or 2;
Each R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R ) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) _{^{2 (OR), - OC (}} = Y 1) R, -OC (= Y 1) OR, -OC (= Y 1) (N (R) 2), - SC (= Y 1) R, -SC ( _{^{= Y 1) oR, -SC (}} = Y 1) (N (R) 2), - N (R) C (= Y 1) R, -N (R) C (= Y 1) oR or -N, (R) C (= Y ¹ ) N (R) ₂ , —SO ₂ NR ₂ , —CN, —N ₃ , —NO ₂ , —OR, a protecting group or W ³ ; or 2 on the same carbon atom one of R ^y when taken together, form a carbocyclic ring having 3 to 7 carbon atoms Tooth;
Each R ^X is independently R ^y , a protecting group, or a formula

And in the formula:
M1a, M1c, and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each R is H, halogen, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C _{8) alkynyl, (C} 2 -C ₈₎ substituted _alkynyl, C 6 _{-C 20 aryl,} C 6 _{-C 20} substituted _aryl, C 2 _{-C 20 heterocycle,} C 2 _{-C 20} substituted heterocyclyl, arylalkyl, substituted aryl Alkyl or protecting group;
W ³ is W ⁴ or W ⁵ ; W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ ; And W ⁵ is independently a carbocyclic or heterocyclic ring substituted with 0 to 3 R ^y groups.

The W ⁵ carbocycle and the W ⁵ heterocycle may be independently substituted with 0 to 3 R ^y groups. W ⁵ can be a saturated, unsaturated or aromatic ring including mono- or bicyclic carbocycles or heterocycles. W ⁵ can have 3 to 10 ring atoms, for example 3 to 7 ring atoms. W ⁵ ring is saturated if it contains 3 ring atoms, saturated or monounsaturated if it contains 4 ring atoms, saturated if it contains 5 ring atoms, or monocyclic or bicyclic unsaturated, and 6 ring atoms Is a saturated, monocyclic or bicyclic unsaturated or aromatic ring.

W ⁵ heterocycle is monocyclic or 7-10 ring members having 3-7 ring members (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S) It can be a bicyclic ring having (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). W ⁵ heteromonocyclic is a 3-6 ring atom (2-5 carbon atoms and 1-2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3-5 Carbon atoms and 1-2 heteroatoms selected from N and S). W ⁵ heterobicycles are 7-10 ring atoms (6-9 carbon atoms as well as arranged as bicyclo [4,5], [5,5], [5,6] or [6,6] systems and 1 to 2 heteroatoms selected from N, O and S); or 9 to 10 ring atoms (8 to 9 carbon atoms) arranged as a bicyclo [5,6] or [6,6] system And 1-2 heteroatoms selected from N and S). The W ⁵ heterocycle may be attached to Y ² through carbon, nitrogen, sulfur or other atoms by a stable covalent bond.

および

なども挙げられるが、これらに限定されない。 W ⁵ heterocycles include, for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. It is done. Also as an example of the W ^5,

and

However, it is not limited to these.

が挙げられる。 W ⁵ carbocycles and heterocycles may be independently substituted with 0 to 3 R groups as defined above. For example, as a substituted W ⁵ carbocycle:

Is mentioned.

が挙げられる。 Examples of substituted phenyl carbocycles include

Is mentioned.

もしくは

が挙げられ、式中、
ａは、Ｒ^７結合点であり；
ｂは、Ｒ^４結合点であり；
Ａｒは、フェニルもしくはナフチルであり、前記フェニルおよびナフチルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒ^ｙは独立して、（Ｃ_１〜Ｃ_８）アルキルもしくはＣ_５〜Ｃ_６カルボシクリル、前記アルキルおよびカルボシクリルは、１〜３個のＲ^２０基に置換されていてもよく；
各Ｒは独立して、Ｈ、（Ｃ_１〜Ｃ_６）アルキル、もしくはアリールアルキルであり；ならびに
各Ｒ^２０は独立して、ハロゲン、ＣＮ、Ｎ（Ｒ）_２、ＯＲ、−ＳＲ、−Ｓ（Ｏ）Ｒ、−Ｓ（Ｏ）_２Ｒ、−Ｓ（Ｏ）（ＯＲ）、−Ｓ（Ｏ）_２（ＯＲ）、−Ｃ（＝Ｏ）Ｒ、−Ｃ（＝Ｏ）ＯＲ、もしくはＣ（＝Ｏ）Ｎ（Ｒ）_２である。 Embodiments of R ⁷ together with R ⁷ or R ⁴ include structures

Or

In the formula,
a is the R ⁷ point of attachment;
b is the R ⁴ point of attachment;
Ar is phenyl or naphthyl, and the phenyl and naphthyl may be substituted with 1 to 3 R ²⁰ groups;
Each R ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, wherein said alkyl and carbocyclyl may be substituted with 1 to 3 R ²⁰ groups;
Each R is independently H, (C ₁ -C ₆ ) alkyl, or arylalkyl; and each R ²⁰ is independently halogen, CN, N (R) ₂ , OR, —SR, —S _{(O) R, -S (O} ) 2 R, -S (O) (oR), - S (O) 2 (oR), - C (= O) R, -C (= O) oR or C, (= O) N (R) ₂ .

の実施形態は、

などの部分構造を含み、式中、各Ｙ^２ｂは独立して、ＯまたはＮ（Ｒ）である。この実施形態の別の態様では、各Ｙ^２ｂはＯであり、各Ｒ^Ｘは独立して、

であり、式中、Ｍ１２ｃは、１、２または３であり、各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、またはＳである。この実施形態の別の態様では、Ｙ^２ｂ−Ｒ^Ｘの片方はＮＨ（Ｒ）であり、Ｙ^２ｂ−Ｒ^Ｘの他方はＯ−Ｒ^Ｘであり、式中Ｒ^Ｘは、

であり、式中、Ｍ１２ｃは２である。この実施形態の別の態様では、各Ｙ^２ｂはＯであり、各Ｒ^Ｘは独立して、

であり、式中、Ｍ１２ｃは２である。この実施形態の別の態様では、各Ｙ^２ｂはＯであり、各Ｒ^Ｘは独立して、

であり、式中、Ｍ１２ｃは１であり、Ｙ^２は、単結合、Ｏ、またはＣＲ_２である。 Of the compounds of formulas I-III and formulas IV-VI

Embodiments of

Wherein each Y ^2b is independently O or N (R). In another aspect of this embodiment, each Y ^2b is O and each R ^X is independently

Where M12c is 1, 2 or 3, and each Y ² is independently a single bond, O, CR ₂ , or S. In another aspect of this embodiment, one of Y ^2b —R ^X is NH (R), the other of Y ^2b —R ^X is O—R ^X , wherein R ^X is

Where M12c is 2. In another aspect of this embodiment, each Y ^2b is O and each R ^X is independently

Where M12c is 2. In another aspect of this embodiment, each Y ^2b is O and each R ^X is independently

, And the formula, M12c is 1, ^{Y 2} is a single bond, O or CR _2,.

の他の実施形態は、

などの部分構造を含み、式中、各Ｙ^３は独立して、ＯまたはＮ（Ｒ）である。この実施形態の別の態様では、各Ｙ^３はＯである。この実施形態の別の態様では、部分構造は

であり、式中、Ｒ^ｙは、本明細書に定義されるＷ^５である。 Of the compounds of formulas I-III and formulas IV-VI

Other embodiments are:

Wherein each Y ³ is independently O or N (R). In another aspect of this embodiment, each Y ³ is O. In another aspect of this embodiment, the substructure is

^Where R ^y is W ⁵ as defined herein.

の別の実施形態は、部分構造

を含み、式中、各Ｙ^２ｃは独立して、Ｏ、Ｎ（Ｒ^ｙ）またはＳである。 Of formulas I-III and formulas IV-VI

Another embodiment of the partial structure

Wherein each Y ^2c is independently O, N (R ^y ) or S.

の別の実施形態は、式中、Ｗ^１またはＷ^２の片方はＲ^３またはＲ^４のいずれかと一緒になって−Ｙ^３−であり、Ｗ^１またはＷ^２の他方は式Ｉａである部分構造を含む。かかる実施形態は、

または

式Ｉｂ
から選択される式Ｉｂの化合物により表される。 Of the compounds of formulas I-III and formulas IV-VI

Another embodiment is that wherein one of ^{W 1} or ^{W 2} is -Y ³ together with either ^{R 3} or ^{R 4} of the - and the other of ^{W 1} or ^{W 2} is Formula Ia portion Includes structure. Such an embodiment is

Or

Formula Ib
Represented by a compound of formula Ib selected from:

であり、式中、Ｍ１２ｃは、１、２または３であり、各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、またはＳである。式Ｉｂの実施形態の別の態様では、Ｗ^１またはＷ^２はＹ^２ｂ−Ｒ^Ｘであり；各Ｙ、Ｙ^３およびＹ^２ｂはＯであり、Ｒ^Ｘは、

であり、式中、Ｍ１２ｃは２である。式Ｉｂの実施形態の別の態様では、Ｗ^１またはＷ^２はＹ^２ｂ−Ｒ^Ｘであり：各Ｙ、Ｙ^３およびＹ^２ｂはＯであり、Ｒ^Ｘは、

であり、式中、Ｍ１２ｃは１であり、Ｙ^２は、単結合、Ｏ、またはＣＲ_２である。 In another aspect of embodiments of formula Ib, each Y and Y ³ is O. In another aspect of embodiments of formula Ib, W ¹ or W ² is Y ^2b —R ^X ; each Y, Y ³ and Y ^2b is O, and R ^X is

Where M12c is 1, 2 or 3, and each Y ² is independently a single bond, O, CR ₂ , or S. In another aspect of embodiments of formula Ib, W ¹ or W ² is Y ^2b —R ^X ; each Y, Y ³ and Y ^2b is O, and R ^X is

Where M12c is 2. In another aspect of embodiments of formula Ib, W ¹ or W ² is Y ^2b —R ^X : each Y, Y ³ and Y ^2b is O, and R ^X is

, And the formula, M12c is 1, ^{Y 2} is a single bond, O or CR _2,.

の別の実施形態は、部分構造

を含み、式中、Ｗ^５は炭素環（フェニルまたは置換フェニルなど）である。この実施形態の別の態様では、部分構造は

であり、式中、Ｙ^２ｂはＯまたはＮ（Ｒ）であり、フェニル炭素環は、０〜３個のＲ基に置換されている。この部分構造の実施形態の別の態様では、Ｒ^Ｘは、

であり、式中、Ｍ１２ｃは、１、２または３であり、各Ｙ^２は独立して、単結合、Ｏ、ＣＲ_２、またはＳである。 Of the compounds of formulas I-III and formulas IV-VI

Another embodiment of the partial structure

Wherein W ⁵ is a carbocycle (such as phenyl or substituted phenyl). In another aspect of this embodiment, the substructure is

Wherein Y ^2b is O or N (R), and the phenyl carbocycle is substituted with 0 to 3 R groups. In another aspect of this substructure embodiment, R ^X is

Where M12c is 1, 2 or 3, and each Y ² is independently a single bond, O, CR ₂ , or S.

の別の実施形態は、部分構造

または

を含む。 Of formulas I-III and formulas IV-VI

Another embodiment of the partial structure

Or

including.

  The chiral carbon in the amino acid and lactate moieties may be either in the R or S configuration or in a racemic mixture.

の別の実施形態は、部分構造

であり、式中、各Ｙ^２は独立して、−Ｏ−または−ＮＨ−である。この実施形態の別の態様では、Ｒ^ｙは、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニルまたは（Ｃ_２〜Ｃ_８）置換アルキニルである。この実施形態の別の態様では、Ｒ^ｙは、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニルもしくは（Ｃ_２〜Ｃ_８）置換アルキニルであり；ならびにＲはＣＨ_３である。この実施形態の別の態様では、Ｒ^ｙは、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_１〜Ｃ_８）置換アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）置換アルケニル、（Ｃ_２〜Ｃ_８）アルキニルまたは（Ｃ_２〜Ｃ_８）置換アルキニルであり；Ｒは、ＣＨ_３であり；ならびに各Ｙ^２は、−ＮＨ−である。この実施形態の１つの態様では、Ｗ^１およびＷ^２は独立して、窒素結合、天然アミノ酸または天然アミノ酸エステルである。この実施形態の別の態様では、Ｗ^１およびＷ^２は独立して、天然２−ヒドロキシカルボン酸または天然２−ヒドロキシカルボン酸エステルであり、前記酸またはエステルは、２−ヒドロキシ基を介してＰに結合されている。 Of formulas I-III and formulas IV-VI

Another embodiment of the partial structure

Wherein each Y ² is independently —O— or —NH—. In another aspect of this embodiment, R ^y is (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl. a _(C 2 _{~C 8)} alkynyl or _(C 2 _{~C 8)} substituted alkynyl. In another aspect of this embodiment, R ^y is (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl. , _(C 2 _{~C 8)} alkynyl or _(C 2 _{~C 8)} substituted alkynyl; and R is CH _3. In another aspect of this embodiment, R ^y is (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl. , _(C 2 _{~C 8)} alkynyl or _(C 2 _{~C 8)} substituted alkynyl; R is an CH _3; and each ^{Y 2} is -NH-. In one aspect of this embodiment, W ¹ and W ² are independently nitrogen bonds, natural amino acids or natural amino acid esters. In another aspect of this embodiment, W ¹ and W ² are independently a natural 2-hydroxycarboxylic acid or a natural 2-hydroxycarboxylic acid ester, wherein the acid or ester is P via a 2-hydroxy group. Is bound to.

の別の実施形態は、部分構造

である。 Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI

Another embodiment of the partial structure

It is.

In one aspect of this embodiment, each R ^X is independently (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, each R ^X is independently C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl.

は、

または

から選択される。 In one preferred embodiment,

Is

Or

Selected from.

の別の実施形態は、部分構造

であり、式中、Ｗ^１およびＷ^２は独立して、下表２０．１〜２０．３７および下表３０．１の式の１つから選択される。表２０．１〜２０．３７に使用される基（例えば、Ｗ^２３、Ｒ^２１など）は、別段の定めのない限り、表２０．１〜２０．３７のみに付随する。
表２０．１〜２０．３７に使用される基は、以下の定義を有する：
各Ｒ^２１は独立して、Ｈもしくは（Ｃ_１〜Ｃ_８）アルキルであり；
各Ｒ^２２は独立して、Ｈ、Ｒ^２１、Ｒ^２３もしくはＲ^２４であり、式中、各Ｒ^２４は独立して、０〜３個のＲ^２３に置換されており；
各Ｒ^２３は独立して、Ｒ^２３ａ、Ｒ^２３ｂ、Ｒ^２３ｃもしくはＲ^２３ｄであり、Ｒ^２３がヘテロ原子へ結合する場合、Ｒ^２３は、Ｒ^２３ｃもしくはＲ^２３ｄであり；
各Ｒ^２３ａは独立して、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３もしくは−ＮＯ_２であり；
各Ｒ^２３ｂは独立して、Ｙ^２１であり；
各Ｒ^２３ｃは独立して、−Ｒ^２ｘ、−Ｎ（Ｒ^２ｘ）（Ｒ^２ｘ）、−ＳＲ^２ｘ、−Ｓ（Ｏ）Ｒ^２ｘ、−Ｓ（Ｏ）_２Ｒ^２ｘ、−Ｓ（Ｏ）（ＯＲ^２ｘ）、−Ｓ（Ｏ）_２（ＯＲ^２ｘ）、−ＯＣ（＝Ｙ^２１）Ｒ^２ｘ、−ＯＣ（＝Ｙ^２１）ＯＲ^２ｘ、−ＯＣ（＝Ｙ^２１）（Ｎ（Ｒ^２ｘ）（Ｒ^２ｘ））、−ＳＣ（＝Ｙ^２１）Ｒ^２ｘ、−ＳＣ（＝Ｙ^２１）ＯＲ^２ｘ、−ＳＣ（＝Ｙ^２１）（Ｎ（Ｒ^２ｘ）（Ｒ^２ｘ））、−Ｎ（Ｒ^２ｘ）Ｃ（＝Ｙ^２１）Ｒ^２ｘ、−Ｎ（Ｒ^２ｘ）Ｃ（＝Ｙ^２１）ＯＲ^２ｘ、もしくは−Ｎ（Ｒ^２Ｘ）Ｃ（＝Ｙ^２１）（Ｎ（Ｒ^２ｘ）（Ｒ^2Ｘ））であり；
各Ｒ^２３ｄは独立して、−Ｃ（＝Ｙ^２１）Ｒ^２ｘ、−Ｃ（＝Ｙ^２１）ＯＲ^２ｘもしくは−Ｃ（＝Ｙ^２１）（Ｎ（Ｒ^２ｘ）（Ｒ^２ｘ））であり；
各Ｒ^２ｘは独立して、Ｈ、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、（Ｃ_２〜Ｃ_８）アルキニル、アリール、ヘテロアリールであり；または２つのＲ^２ｘはそれらが共に結合している窒素と一緒になって３〜７員複素環を形成し、前記複素環の炭素原子の任意の１つは−Ｏ−、−Ｓ−もしくは−ＮＲ^２１−に置換されていることができ；ならびに、前記（Ｃ_１〜Ｃ_８）アルキルのそれぞれの１個もしくは複数の非末端炭素原子は、−Ｏ−、−Ｓ−または−ＮＲ^２１−に置換されていてよく；
各Ｒ^２４は独立して、（Ｃ_１〜Ｃ_８）アルキル、（Ｃ_２〜Ｃ_８）アルケニル、もしくは（Ｃ_２〜Ｃ_８）アルキニルであり；
各Ｒ^２５は独立してＲ^２４であり、各Ｒ^２４は、０〜３個のＲ^２３基に置換されており；
各Ｒ^２５ａは独立して、（Ｃ_１〜Ｃ_８）アルキレン、（Ｃ_２〜Ｃ_８）アルケニレン、もしくは（Ｃ_２〜Ｃ_８）アルキニレンであり、前記（Ｃ_１〜Ｃ_８）アルキレン、（Ｃ_２〜Ｃ_８）アルケニレン、もしくは（Ｃ_２〜Ｃ_８）アルキニレンの任意の１つは、０〜３個のＲ^２３基に置換されており；
各Ｗ^２３は独立して、Ｗ^２４もしくはＷ^２５であり；
各Ｗ^２４は独立して、Ｒ^２５、−Ｃ（＝Ｙ^２１）Ｒ^２５、−Ｃ（＝Ｙ^２１）Ｗ^２５、−ＳＯ_２Ｒ^２５、もしくは−ＳＯ_２Ｗ^２５であり；
各Ｗ^５は独立して、０〜３個のＲ^２２基に独立して置換されている炭素環もしくは複素環であり；ならびに
各Ｙ^２１は独立して、ＯもしくはＳである。
表２０．１

表２０．２

表２０．３

表２０．４

表２０．５

表２０．６

表２０．７

表２０．８

表２０．９

表２０．１０

表２０．１１

表２０．１２

表２０．１３

表２０．１４

表２０．１５

表２０．１６

表２０．１７

表２０．１８

表２０．１９

表２０．２０

表２０．２１

表２０．２２

表２０．２３

表２０．２４

表２０．２５

表２０．２６

表２０．２７

表２０．２８

表２０．２９

表２０．３０

表２０．３１

表２０．３２

表２０．３３

表２０．３４

表２０．３５

表２０．３６

表２０．３７

表３０．１

Of formulas I-III and formulas IV-VI

Another embodiment of the partial structure

Where W ¹ and W ² are independently selected from one of the formulas in Tables 20.1-20.37 and Table 30.1 below. Groups used in Tables 20.1-20.37 (eg, W ²³ , R ^21, etc.) are only associated with Tables 20.1-10.27 unless otherwise specified.
The groups used in Tables 20.1-20.37 have the following definitions:
Each R ²¹ is independently H or (C ₁ -C ₈ ) alkyl;
Each R ²² is independently H, R ²¹ , R ²³ or R ²⁴ , wherein each R ²⁴ is independently substituted with 0-3 R ²³ ;
Each R ²³ is independently R ^23a , R ^23b , R ^23c or R ^23d , and when R ²³ is attached to a heteroatom, R ²³ is R ^23c or R ^23d ;
Each R ^23a is independently F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
Each R ^23b is independently Y ²¹ ;
Each R ^23c is independently -R ^2x , -N (R ^2x ) (R ^2x ), -SR ^2x , -S (O) R ^2x , -S (O) ₂ R ^2x , -S (O) ( OR ^2x ), -S (O) ₂ (OR ^2x ), -OC (= Y ²¹ ) R ^2x , -OC (= Y ²¹ ) OR ^2x , -OC (= Y ²¹ ) (N (R ^2x ) (R ^{2x)), - SC (=} Y 21) R 2x, -SC (= Y 21) OR 2x, -SC (= Y 21) (N (R 2x) (R 2x)), - N (R 2x) C (= Y ²¹ ) R ^2x , —N (R ^2x ) C (= Y ²¹ ) OR ^2x , or —N (R ^2X ) C (= Y ²¹ ) (N (R ^2x ) (R ^2X ));
Each R ^23d is independently -C (= Y ²¹ ) R ^2x , -C (= Y ²¹ ) OR ^2x or -C (= Y ²¹ ) (N (R ^2x ) (R ^2x ));
Each R ^2x is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl, heteroaryl; or two R ^2x are they form a 3- to 7-membered heterocyclic ring together with the nitrogen to which they are attached together, any one of the carbon atoms of the heterocyclic ring is -O -, - S- or -NR 21 ^- is replaced by the And one or more non-terminal carbon atoms of each of said (C ₁ -C ₈ ) alkyl may be substituted with —O—, —S— or —NR ²¹ —;
Each R ²⁴ is independently (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, or (C ₂ -C ₈ ) alkynyl;
Each R ²⁵ is independently R ²⁴ , each R ²⁴ is substituted with 0-3 R ²³ groups;
Each R ^25a is independently (C ₁ -C ₈ ) alkylene, (C ₂ -C ₈ ) alkenylene, or (C ₂ -C ₈ ) alkynylene, and said (C ₁ -C ₈ ) alkylene, (C _{2 to} C ₈ ) alkenylene, or any one of (C _{2 to} C ₈ ) alkynylene is substituted with 0 to 3 R ²³ groups;
Each W ²³ is independently W ²⁴ or W ²⁵ ;
Each W ²⁴ is independently R ²⁵ , —C (═Y ²¹ ) R ²⁵ , —C (= Y ²¹ ) W ²⁵ , —SO ₂ R ²⁵ , or —SO ₂ W ²⁵ ;
Each W ⁵ is independently a carbocyclic or heterocyclic ring independently substituted with 0 to 3 R ²² groups; and each Y ²¹ is independently O or S.
Table 20.1

Table 20.2

Table 20.3

Table 20.4

Table 20.5

Table 20.6

Table 20.7

Table 20.8

Table 20.9

Table 20.10

Table 20.11

Table 20.12

Table 20.13

Table 20.14

Table 20.15

Table 20.16

Table 20.17

Table 20.18

Table 20.19

Table 20.20

Table 20.21

Table 20.22

Table 20.23

Table 20.24

Table 20.25

Table 20.26

Table 20.27

Table 20.28

Table 20.29

Table 20.30

Table 20.31

Table 20.32.

Table 20.33

Table 20.34

Table 20.35

Table 20.36

Table 20.37

Table 30.1

および

が挙げられる。 R ^X embodiments include ester, carbamate, carbonate, thioester, amide, thioamide and urea groups:

and

Is mentioned.

Any reference to a compound of the invention described herein also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from appropriate bases such as alkali metals or alkaline earths (eg, Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺² and Mg ⁺² ), ammonium And NR ₄ ⁺ , where R is as defined herein. Physiologically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; ) Organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid , Polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthate, pamoate, salicylic acid , Stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine Arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, salts formed with such leucine; and (c) elemental anions such as chlorine, bromine, and salts formed with iodine. Physiologically acceptable salts of a hydroxy group compound include a combination of an anion of the compound and a suitable cation (such as Na ⁺ and NR ₄ ⁺ ).

  For therapeutic use, the salts of the active ingredients of the compounds of the present invention are physiologically acceptable, ie, salts derived from physiologically acceptable acids or bases. However, acid or base salts that are not physiologically acceptable may also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the present invention.

  Ultimately, the compositions herein should be understood to include the compounds of the present invention in combination with non-ionized and zwitterionic forms, and stoichiometric amounts of water as hydrates. .

  The compounds of the present invention exemplified in Formulas I-III and IV-VI may have asymmetric centers, such as chiral carbon or phosphorus atoms. Accordingly, the compounds of the present invention include racemic mixtures of all stereoisomers (such as enantiomers, diastereomers, and atropisomers). Furthermore, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. That is, the asymmetric centers apparent from the depiction are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures and individual optical isomers that are isolated or synthesized and substantially free of their enantiomers or diastereomeric partners are all within the scope of this invention. Racemic mixtures are separated into their respective substantially optically pure isomers via well-known techniques such as, for example, separation of diastereomeric salts formed with optically active additives (eg acids or bases). Then, it is converted back to an optically active substance. In most instances, the desired optical isomer is synthesized by a stereospecific reaction method starting with the appropriate stereoisomer of the desired starting material.

  The term “chiral” refers to molecules that have the property of non-superimposability of their mirror image partners, while the term “achiral” refers to molecules that are superimposable on their mirror image partners.

  The term “stereoisomer” refers to compounds that have the same chemical structure but differ with respect to the arrangement of atoms or groups in space.

  “Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography.

  “Enantiomers” refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The stereochemistry definitions and conventions used herein are generally described in S.H. P. Parker, Ed. McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E .; And Wilen, S .; , Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc. , New York. Many organic compounds exist in optically active forms with the ability to rotate plane-polarized planes. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its asymmetric center (s). The prefixes d and l, D and L, or (+) and (−) are used to indicate rotational signs of plane polarized light by the compound, and S, (−), or l indicates that the compound is levorotatory And a compound prefixed with R, (+) or d is dextrorotatory. In a given chemical structure, these stereoisomers are the same except that they are mirror images of each other. Certain stereoisomers are sometimes referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselection or stereospecificity during a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species lacking optical activity.

は、隣接部分構造、基、部分、または原子への共有結合部位を示す。 When a compound described herein is substituted with multiple identical designated groups, eg, “R” or “R ¹ ”, the groups may be the same or different, ie, each group independently It is understood that it will be selected. Wavy line

Indicates a covalent bond site to an adjacent partial structure, group, moiety, or atom.

  In some cases, the compounds of the invention can also exist as tautomeric isomers. Although only one of the delocalized resonance structures may be shown, it is contemplated that all such forms are within the scope of the present invention. For example, enamine tautomers can exist in purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all possible tautomeric forms are within the scope of the present invention.

に示すとおり、等価の互変異性型を有することができる。 Pyrrolo [1,2-f] [1,2,4] triazine, imidazo [1,5-f] [1,2,4] triazine, imidazo [1,2-f] [1,2,4] triazine And one skilled in the art will recognize that [1,2,4] triazolo [4,3-f] [1,2,4] triazine nucleosides can exist in tautomeric forms. For example, without limitation, structures (a) and (b)

Can have equivalent tautomeric forms.

  All possible tautomeric forms of the heterocycle in all embodiments disclosed herein are within the scope of the invention.

Method for Inhibiting HCV Polymerase Another aspect of the present invention relates to a method for inhibiting HCV polymerase activity, comprising the step of treating a sample suspected of containing HCV using the composition of the present invention.

  The compositions of the present invention can act as HCV polymerase inhibitors as intermediates for such inhibitors, or have other uses as described below. The inhibitor binds to a position on the surface or in the cavity of HCV polymerase that has a geometric shape unique to HCV polymerase. Compositions that bind to HCV polymerase can bind with varying degrees of reversibility. Compounds that bind substantially irreversibly are ideal candidates for use in this method of the invention. Compositions that bind substantially irreversibly after labeling are useful as HCV polymerase detection probes. Thus, the present invention comprises the following steps: treatment of a sample suspected of containing HCV polymerase with a composition comprising a labeled-conjugated compound of the invention; and observing sample effects on labeling activity The present invention relates to a method for detecting HCV polymerase in a sample suspected of. Suitable labels are well known in the diagnostic art and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in a conventional manner using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino.

  Within the context of the present invention, samples suspected of containing HCV polymerase include natural or artificial materials (biological; tissue or cell culture, etc.); biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, Tears, sputum, saliva, tissue samples, etc.); laboratory samples; food, water, or air samples; bioproduct samples (cell extracts, especially recombinant cells that synthesize the desired glycoprotein); Can be mentioned. Typically, the sample is suspected of being biogenic to produce HCV polymerase, often a pathogen (such as HCV). The sample can be contained in any medium containing water and an organic solvent water mixture. Samples include living organisms (such as humans) and artificial substances (such as cell culture).

  The processing step of the present invention includes adding the composition of the present invention to a sample or includes adding a composition precursor to the sample. The adding step includes any administration method described above.

  If desired, HCV polymerase activity after application of the composition can be observed by any method, including methods for detecting direct and indirect HCV polymerase activity. Quantitative, qualitative, and semi-quantitative methods for determining HCV polymerase activity are all contemplated. Typically, one of the above screening methods is applied, but any other method (such as observing the physiological properties of a living organism) is also applicable.

  Examples of the organism containing HCV polymerase include HCV virus. The compounds of the present invention are useful for the treatment or prevention of HCV infection in animals or humans.

  However, it should be noted that in screening compounds capable of inhibiting human immunodeficiency virus, enzyme assay results may not correlate with cell culture assays. Therefore, cell-based assays should be the primary screening method.

HCV polymerase inhibitor screening The compositions of the invention are screened for HCV polymerase inhibitory activity by any conventional technique for assessing enzyme activity. Within the context of the present invention, typically the composition is first screened for in vitro inhibition of HCV polymerase and then for in vivo activity of the composition exhibiting inhibitory activity. Compositions with an in vitro Ki (inhibition constant) of less than about 5 × 10 ⁻⁶ M, typically less than about 1 × 10 ⁻⁷ M, preferably less than about 5 × 10 ⁻⁸ M are preferred for in vivo use.

  Useful in vitro screening has been described in detail but is not described in detail herein. However, the examples describe suitable in vitro assays.

Pharmaceutical Formulations The compounds of the present invention are formulated using conventional carriers and excipients, which are selected according to common practice. Tablets include excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery other than oral administration. All formulations may contain excipients such as those described in “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH range of the formulation is about 3 to about 11, but is usually about 7 to 10.

  While the active ingredient can be administered alone, it may be preferable to present it as a medicament. The formulations according to the invention for both animal and human use comprise at least one active ingredient as defined above together with one or more acceptable carriers and may therefore comprise other therapeutic ingredients. The carrier (s) must be “acceptable” in the sense of being compatible with the other formulation ingredients and physiologically harmless to the recipient.

  Formulations include those suitable for the aforementioned administration routes. The formulations can conveniently be present in unit dosage form and can be prepared by any method well known in the pharmaceutical art. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared homogeneously, intimate association of the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

  Formulations of the present invention suitable for oral administration include as discrete units such as capsules and tablets each containing a predetermined amount of active ingredient; as a powder or granule; as an aqueous or non-aqueous liquid solution or suspension As a liquid; or as an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient can also be administered as a bolus, electuary or paste.

  Tablets may use one or more accessory ingredients and are made by compression or stamping. Compressed tablets may be prepared by compressing the active ingredient in a free-flow form (such as a powder or granule) in a suitable machine, binder, lubricant, inert diluent, preservative, surface active or dispersing agent. May be mixed with. Molded tablets may be made by stamping in a suitable machine a mixture of the powdered active ingredient moistened with an inert diluent. Tablets may be coated or marked and may be formulated so as to obtain a slow or controlled release of the active ingredient.

  For infections of the eye or other external tissues such as mouth and skin, the formulation preferably contains active ingredient (s), eg 0.075-20% w / w (active ingredient (one Or more) in increments of 0.1% w / w, in the range of 0.1% to 20%, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0. It is applied as a topical ointment or cream containing in an amount of 2-15% w / w, most preferably 0.5-10% w / w. When formulated as an ointment, the active ingredient may be applied with either paraffin or an ointment base that is miscible with water. Alternatively, the active ingredient can be formulated in a cream using an oil-in-water cream system.

  If desired, the cream-based aqueous phase may be, for example, at least 30% w / w polyhydric alcohol, ie two or more hydroxyl groups (propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol ( PEG 400, etc.) and mixtures thereof, topical formulations may desirably include compounds that enhance absorption or penetration of the active ingredient from the skin or other affected area, examples of such dermal penetration enhancers. , Dimethyl sulfoxide and related analogs.

  The oily phase of the emulsion of the present invention can be composed of known ingredients in a known manner. The oil phase may contain only an emulsifier (or known as an emergency), but desirably comprises a lipid or oil, or a mixture of both lipid and oil and at least one emulsifier. Preferably, a hydrophilic emulsifier is included with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oil and lipid. Overall, with or without stabilizer (s), the emulsifier (s) makes a so-called emulsifying wax, which together with oils and lipids forms a so-called emulsifying ointment base, which Form an oil-type dispersed phase of the cream formulation.

  Emulsion (emulsion and emulsion) stabilizers suitable for use in the formulations of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and lauryl. Sodium sulfate is mentioned.

  The selection of an appropriate oil or lipid for the formulation is based on obtaining the desired appearance characteristics. The cream should preferably be a non-sticky, non-staining and washable product with suitable consistency to avoid leakage from test tubes or other containers. Linear or branched, monobasic or dibasic alkyl esters such as diisodiazinate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- A branched ester mixture known as ethylhexyl palmitate or Crodamol CAP may be used, the last three being the preferred esters. These may be used alone or in combination depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

  The medicament according to the invention comprises a combination according to the invention with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The medicament containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, medicinal candy, aqueous or oily suspensions, dispersions or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the pharmaceutical composition manufacturing art, and such compositions can be used as a sweetener, flavoring agent to provide a palatable preparation. One or more agents, including colorants and preservatives. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets are also acceptable. These excipients include, for example, inert diluents (such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating and disintegrating agents (such as corn starch or alginic acid); binders (starch, gelatin) Or acacia, etc.); and a smoothing agent (such as magnesium stearate, stearic acid or talc). Tablets may be uncoated or coated by known techniques (such as microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and provide sustained activity over a longer period of time) Good. For example, a time delay material (such as glyceryl monostearate or glyceryl distearate) may be applied alone or in combination with a wax.

  Formulations for oral use may also be present as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or the active ingredient is water or an oil medium (peanut oil, liquid paraffin). Or as soft gelatin capsules mixed with olive oil or the like).

  The aqueous suspensions of the present invention contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidione, gum tragacanth and gum acacia), and dispersing or wetting agents (natural phospholipids such as lecithin) Etc.), condensation products of fatty acids and alkylene oxides (eg, polyoxyethylene stearate), condensation products of long chain fatty alcohols and ethylene oxide (eg, heptadecaethyleneoxycetanol), fatty acid and hexitol anhydride derived parts The condensation product of a typical ester and ethylene oxide (for example, polyoxyethylene sorbitan monooleate). Aqueous suspensions also contain one or more preservatives (such as ethyl or n-propyl p-hydroxy-benzoate), one or more colorants, one or more flavoring agents and one or more sweetening agents. An agent (such as sucrose or saccharin) may be included.

  Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil), or in a mineral oil (such as liquid paraffin). Oral suspensions may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (such as those described above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant (such as ascorbic acid).

  Dispersants and granules of the present invention suitable for the preparation of an aqueous suspension are active ingredients in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives by adding water. I will provide a. Suitable dispersing or wetting agents and suspending agents are exemplified by the above disclosure. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

  The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil (such as olive oil or arachis oil), a mineral oil (such as liquid paraffin), or a mixture of these. Suitable emulsifiers include natural gums (such as gum acacia and gum tragacanth), natural phospholipids (such as soy lecithin, esters or partial esters derived from fatty acids) and hexitol anhydrides (such as sorbitan monooleate), and ethylene oxide and these moieties. It may be a condensation product of a typical ester (such as polyoxyethylene sorbitan monooleate). The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring or coloring agent.

  The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butane-diol solution, prepared as a lyophilized powder. May be. Among the acceptable vehicles and solvents that can be applied are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids (such as oleic acid) can be used in the preparation of infusion solutions as well.

  The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time release agent intended for oral administration to humans is about 1-1000 mg with an appropriate and convenient amount of carrier material that can vary from about 5 to about 95% (weight: weight) of the total composition. Active substance compounds. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution intended for intravenous injection may contain about 3-500 μg of active ingredient per milliliter of solution so that a suitable volume can be injected at a rate of about 30 mL / hour.

  Formulations suitable for topical administration in the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5-20%, advantageously 0.5-10% and especially about 1.5% w / w.

  Formulations suitable for topical administration in the mouth include medicinal candy containing a flavoring base (usually sucrose and acacia or tragacanth) active ingredients; lozenges containing the active ingredient in an inert base (such as gelatin and glycerin or sucrose and acacia) As well as mouthwashes containing the active ingredients in a suitable liquid carrier.

  Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

  The particle size of formulations suitable for intrapulmonary or nasal administration is, for example, in the range of 0.1 to 500 microns (0.5, 1, 30, 35, etc.) and nasally to reach the alveolar sac. Administered by rapid inhalation or by oral inhalation. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and delivered with other therapeutic agents (such as those conventionally used in the treatment or prevention of HCV infection below).

  Formulations suitable for vaginal administration may exist as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, carriers known to be suitable in the art. .

  Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient; and suspensions Aqueous and non-aqueous sterile suspensions that may contain agents and thickeners are included.

  The formulations are present in unit dose or multi-dose containers (eg, sealed ampoules and vials) and are lyophilized (freeze-dried) requiring only the addition of a sterile liquid carrier (eg, water for injection) immediately prior to use. It can be stored in a lyophilized state. Simple injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations comprise a daily dose or unit daily sub-dose, as herein above recited, or an appropriate divided amount thereof.

  In addition to the ingredients noted above, the formulations of the present invention may include other agents conventionally used in the art with respect to the formulation type of interest, for example those suitable for oral administration may contain flavoring agents. It should be understood that it can be included.

  The present invention further provides an animal composition comprising at least one active ingredient as defined above together with an animal carrier.

  An animal carrier is a substance useful for the purpose of administering the composition, otherwise it may be a solid, liquid or gaseous substance which is inert or acceptable in the veterinary field and is compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

  The compounds of the present invention are used to provide controlled release pharmaceuticals (“controlled release agents”) that contain one or more compounds of the present invention as the active ingredient, so that the active ingredient release is less frequent, Or it is controlled and adjusted to improve the pharmacodynamics or toxicity profile of a given active ingredient.

  An effective amount of the active ingredient depends at least on the nature of the condition to be treated, toxicity, whether the compound is used prophylactically (low dose) or against active viral infections, delivery methods, and pharmaceutical dosage forms. Dependent and determined by the clinician using conventional quantification tests. About 0.0001 to about 100 mg / kg body weight / day; typically about 0.01 to about 10 mg / kg body weight / day; more typically about. 01 to about 5 mg / kg body weight / day; most typically about. It can be expected to be from 05 to about 0.5 mg / kg body weight / day. For example, a daily candidate dose for an adult human weighing about 70 kg is in the range of 1 mg to 1000 mg, preferably 5 mg to 500 mg, and may be in single or multiple dose forms.

Route of administration One or more compounds of the invention (referred to herein as active ingredients) are administered by any route appropriate to the condition being treated. Suitable routes include oral, enteral, nasal, topical (such as intraoral and sublingual), vaginal and parenteral (such as subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), Etc. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

Combination therapy The compounds of Formulas I-III and Formulas IV-VI are typically selected based on the condition being treated, the cross-reactivity of the components and the pharmacological properties of the combination. For example, when treating an infection (eg, HCV), the compositions of the invention are used in combination with other active therapeutic agents (such as those described herein).

  The compositions of the present invention are also used in combination with one or more other active ingredients. Preferably, the other active therapeutic ingredient or agent is interferon, ribavirin or analog thereof, HCV NS3 protease inhibitor, NS5a inhibitor, α-glucosidase 1 inhibitor, hepatoprotectant, mevalonate decarboxylase antagonist, renin-angiotensin System antagonists, other antifibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, A pharmacokinetic enhancer or other HCV therapeutic agent; or a mixture thereof.

More specifically, one or more compounds of the invention may be used in combination with one or more compounds selected from the group consisting of:
1) Interferons such as PEGylated rIFN-α2b (PEG-Intron), PEGylated rIFN-α2a (Pegasys), rIFN-α2b (IntronA), rIFN-α2a (Roferon-A), interferon α (MOR-22, OPC) -18, Alfaferone, Alphanative, Multiferon, Subarine), Interferon alphacon-1 (Infergen), Interferon alpha-nl (Wellferon), Interferon alpha-n3 (Alferon), Interferon-beta (Avonex, DL-8234), Interferon- Omega (omega DUROS, Biomed510), Alvin terferon α-2b (Albuferon), IFNαXL, BLX-8 3 (Locteron), DA-3021, glycosylated interferon α-2b (AVI-005), PEG-Infergen, PEG interferon lambda (PEG of IL-29), Bellerophon,
2) Ribavirin and its analogs, such as Ribavirin (Rebetol, Copegus), and Teribavirine (Viramidine),
3) HCV NS3 protease inhibitors such as boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI-1230 , MK-7090, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451, BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531 and ITMN-191 (R-7227),
4) α-Glucosidase 1 inhibitors such as celgosivir (MX-3253), Miglitol, UT-231B,
5) Hepatoprotective agents such as Emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibiline, and MitoQ,
6) Nucleoside or nucleotide inhibitors of HCV NS5B polymerase, such as R1626, R7128 (R4048), IDX184, IDX-102, PSI-7951, BCX-4678, Valopicitabine (NM-283), and MK-0608,
7) Non-nucleoside inhibitors of HCV NS5B polymerase, such as firibvir (PF-868554), ABT-333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281, VBY- 708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (Nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190,
8) HCV NS5A inhibitors such as AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052,
9) TLR-7 agonists such as imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691, and SM-360320,
10) Cyclophilin inhibitors such as DEBIO-025, SCY-635, and NIM811,
11) HCV IRES inhibitor, such as MCI-067,
12) Pharmacokinetic enhancers such as BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and roxithromycin,
13) Other HCV therapeutic agents, for example, thymosin α1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (Virostat), PYN-17 (Altyrex), KPE02003002, actiron (CPG-10101), GS-9525 , KRN-7000, Shibacil, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA971, NOV-205, Talbasin, EHC-18, VGX-410C, EMZ-702, AVI4065, BMS -650032, BMS-791325, Baviuximab, MDX-1106 (ONO-4538), Oglufanide, FK-788, and VX-497 (Merimeposib),
14) Mevalonate decarboxylase antagonists such as statins, HMGCoA synthase inhibitors (eg, hyeglucin), squalene synthesis inhibitors (eg, zaragozic acid);
15) Angiotensin II receptor antagonists such as losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan;
16) Angiotensin converting enzyme inhibitors such as captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril;
17) Other antifibrotic agents such as amiloride and 18) endothelin antagonists such as bosentan and ambrisentan.

  In yet another embodiment, the application provides a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient. And / or pharmaceutical compositions comprising the esters are disclosed.

  In accordance with the present invention, a therapeutic agent used in combination with a compound or composition of the present invention can be any agent that has a therapeutic effect when used in combination with a compound of the present invention. For example, therapeutic agents used in combination with the compounds or compositions of the present invention include interferon, ribavirin or analogs thereof, HCV NS3 protease inhibitor, NS5a inhibitor, α-glucosidase 1 inhibitor, hepatoprotectant, mevalonate Carboxylase antagonist, renin-angiotensin antagonist, other anti-fibrotic agent, endothelin antagonist, nucleoside or nucleotide inhibitor of HCV NS5B polymerase, non-nucleoside inhibitor of HCV NS5B polymerase, HCV NS5A inhibitor, TLR-7 agonist, cyclophilin inhibitor , An HCV IRES inhibitor, a pharmacokinetic enhancer or other HCV therapeutic agent; or a mixture thereof.

More specifically, the composition of one or more compounds of the invention may be used in combination with one or more compounds selected from the group consisting of:
1) Interferons such as PEGylated rIFN-α2b (PEG-Intron), PEGylated rIFN-α2a (Pegasys), rIFN-α2b (IntronA), rIFN-α2a (Roferon-A), interferon α (MOR-22, OPC) -18, Alfaferone, Alphanative, Multiferon, Subarine), Interferon alphacon-1 (Infergen), Interferon alpha-nl (Wellferon), Interferon alpha-n3 (Alferon), Interferon-beta (Avonex, DL-8234), Interferon- Omega (omega DUROS, Biomed510), Alvin terferon α-2b (Albuferon), IFNαXL, BLX-8 3 (Locteron), DA-3021, glycosylated interferon α-2b (AVI-005), PEG-Infergen, PEG interferon lambda (PEG of IL-29), Bellerophon,
2) Ribavirin and its analogs, such as Ribavirin (Rebetol, Copegus), and Teribavirine (Viramidine),
3) HCV NS3 protease inhibitors such as boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI-1230 , MK-7090, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451, BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531 and ITMN-191 (R-7227),
4) α-Glucosidase 1 inhibitors such as celgosivir (MX-3253), Miglitol, UT-231B,
5) Hepatoprotective agents such as Emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibiline, and MitoQ,
6) Nucleoside or nucleotide inhibitors of HCV NS5B polymerase, such as R1626, R7128 (R4048), IDX184, IDX-102, PSI-7951, BCX-4678, Valopicitabine (NM-283), and MK-0608,
7) Non-nucleoside inhibitors of HCV NS5B polymerase, such as firibvir (PF-868554), ABT-333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281, VBY- 708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (Nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190,
8) HCV NS5A inhibitors such as AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052,
9) TLR-7 agonists such as imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691, and SM-360320,
10) Cyclophilin inhibitors such as DEBIO-025, SCY-635, and NIM811,
11) HCV IRES inhibitor, such as MCI-067,
12) Pharmacokinetic enhancers such as BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and roxithromycin,
13) Other HCV therapeutic agents, for example, thymosin α1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (Virostat), PYN-17 (Altyrex), KPE02003002, actiron (CPG-10101), GS-9525 , KRN-7000, Shibacil, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA971, NOV-205, Talbasin, EHC-18, VGX-410C, EMZ-702, AVI4065, BMS -650032, BMS-791325, Baviuximab, MDX-1106 (ONO-4538), Oglufanide, FK-788, and VX-497 (Merimeposib),
14) Mevalonate decarboxylase antagonists such as statins, HMGCoA synthase inhibitors (eg, hyeglucin), squalene synthesis inhibitors (eg, zaragozic acid);
15) Angiotensin II receptor antagonists such as losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan;
16) Angiotensin converting enzyme inhibitors such as captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril;
17) Other antifibrotic agents such as amiloride and 18) endothelin antagonists such as bosentan and ambrisentan.

In yet another embodiment, the present application provides:
a) a first pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate or ester thereof; and b) an HIV protease inhibitor compound, an HIV non-nucleoside inhibitor of reverse transcriptase, reverse transcription HIV nucleoside inhibitor of enzyme, HIV nucleotide inhibitor of reverse transcriptase, HIV integrase inhibitor, gp41 inhibitor, CXCR4 inhibitor, gp120 inhibitor, CCR5 inhibitor, interferon, ribavirin analog, NS3 protease inhibitor, NS5a At least one additional therapeutic agent selected from the group consisting of inhibitors, α-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other HCV therapeutic agents, and combinations thereof A pharmaceutical combination comprising a second pharmaceutical composition comprising Subjected to.

  Combinations of compounds of Formulas I-III and Formulas IV-VI and additional active therapeutic agents may be selected for the treatment of patients with HCV infection and other conditions (such as HIV infection). Accordingly, the compounds of Formulas I-III and Formulas IV-VI include one or more compounds useful for HIV treatment, such as HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleosides of reverse transcriptase. Inhibitors, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, NS5a inhibitors, α -Can be used in combination with glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other HCV therapeutics.

  More specifically, one or more compounds of the invention are 1) HIV protease inhibitors such as amprenavir, atazanavir, phosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir, saquinavir Tipranavir, Brecanavir, Darunavir, TMC-126, TMC-114, Mozenavir (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423, RO0334649, KNI-272, DPC-681, DPC-684 , And GW640385X, DG17, PPL-100, 2) HIV non-nucleoside inhibitors of reverse transcriptase, such as, for example, capravirin, emivirin, delavirdine, efavirenz, nevirapine, (+) calanolide A, Travirin, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773, UK-453,061, RDEA806, 3 ) HIV nucleoside inhibitors of reverse transcriptase such as zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxyvir, elbucitabine, arobudine, MIV-210, racivir (± -FTC), D-d4FC, emtricitabine , Fodivudin thidoxyl, fosalvudin thidoxyl, aplicitivin (AVX754), amdoxivir, KP-1461, abacavir + lamivudine, abacavir + la Mivudine + zidovudine, zidovudine + lamivudine, 4) HIV nucleotide inhibitors of reverse transcriptase such as tenofovir, tenofovir disoproxil fumarate + emtricitabine, tenofovir disoproxil fumarate + emtricitabine + efavirenz, and adefovir 5) HIV integration Lase inhibitors, for example, curcumin, derivatives of curcumin, chicory acid, derivatives of chicory acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, aurintricarboxylic acid Derivative, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivative, tyrphostin, tyrphostin derivative, quercetin, quercetin derivative, S-1360, gintevir (AR-177), L-87081 , And L-870810, MK-0518 (raltegravir), BMS-707035, MK-2048, BA-011, BMS-538158, GSK364735C, 6) gp41 inhibitors such as enfuvirtide, sifvirtide, FB006M, TRI-1144, SPC3 , DES6, Locus gp41, CovX, and REP 9, 7) CXCR4 inhibitors such as AMD-070, 8) Invasion inhibitors such as SP01A, TNX-355, 9) gp120 inhibitors such as BMS-488043 and BlockAide / CR, 10) G6PD oxidase inhibitor and NADH oxidase inhibitor, eg, immunotin, 10) CCR5 inhibitor, eg, aplaviroc, bicribilok, INCB9471, PRO- 40, INCB15050, PF-232798, CCR5 mAb004, and Maraviroc, 11) Interferons such as PEGylated rIFN-α2b, PEGylated rIFN-α2a, rIFN-α2b, IFNα-2bXL, rIFN-α2a, consensus IFNα, Infergen, Lefif , Locteron, AVI-005, PEG-Infergen, PEGylated IFN-β, oral interferon α, ferron, rareferon, intermax α, r-IFN-β, Infergen + actimun, IFN-ω and DUROS, and Albuferon 12) Ribavirin analogs such as Rebetol, Copegas, VX-497, and Viramidine (Talavivirin), 13) NS5a inhibitors such as A-831, A-689, and BMS- 90052, 14) NS5b polymerase inhibitors such as NM-283, Valopicitabine, R1626, PSI-6130 (R1656), IDX184, PSI-7851, HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH -759, PF-868554, GSK625433, and XTL-2125, 15) NS3 protease inhibitors such as SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191, and BILN-2065, 16) α-glucosidase 1 inhibitors such as MX-3253 (Cergosivir) and UT-231B, 17) hepatoprotective agents such as IDN-6556, ME 3738, MitoQ, and LB-84451, 1 ) Non-nucleoside inhibitors of HCV, such as benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives, 19) Other HCV therapeutic agents such as zadaxine, nitazoxanide (Arinea), BIFN-401 ( Virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, babituximab, oglphanide, PYN-17, KPE02003002, actilon (CPG-10101), KRN-7000, Shivacil, GI-5005, ANA-975, XTL -6865, ANA 971, NOV-205, Talbasin, EHC-18, and NIM811, 19) Pharmacokinetic enhancers such as BAS-100 and SPI452, 20) RNAse H inhibition Agents, such as ODN-93 and ODN-112, 21) other anti-HIV drugs, such as VGV-1, PA-457 (bebilimato), ampligen, HRG214, cytolin, polymun, VGX-410, KD247, AMZ 0026 CYT 99007, A-221 HIV, BAY 50-4798, MDX010 (iplimumab), PBS119, ALG889, and PA-1050040 may be used in combination with one or more compounds.

  Combinations of any of the compounds of the present invention in a single dosage form for simultaneous or sequential administration to a patient with one or more other active therapeutic agents are also possible. The combination therapy may be administered as a simultaneous dosing schedule or as a continuous dosing schedule. In the case of continuous administration, it can be administered in combination two or more times.

  Co-administration of a compound of the present invention and one or more other active therapeutic agents generally results in the presence of a therapeutically effective amount of a compound of the present invention and one or more other active therapeutic agents in the body of the patient. In the form, refers to the simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents.

  Co-administration is a unit dose administration of a compound of the invention before or after administration of a unit dose of one or more other active therapeutic agents, eg, a few seconds of administration of one or more other active therapeutic agents, Administration of a compound of the invention within minutes or hours. For example, a unit dose of a compound of the invention can be administered first, and a unit dose of one or more other active therapeutic agents can be administered within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed by a unit dose of one or more other active therapeutic agents after a period of time (eg, 1-12 hours). Can be done. In other cases, a unit dose of one or more other active therapeutic agents is administered first, followed by a unit dose of a compound of the invention after a period of time (eg, 1-12 hours). May be desired.

  Combination therapy can provide “synergism” and “synergism”, that is, the effect obtained when using the active ingredients in combination is higher than the overall effect obtained when the compounds are used separately. The synergistic effect is that the active ingredients are (1) co-formulated and administered or delivered simultaneously in a formulation; (2) delivered alternately or in parallel as separate formulations; or (3) some The case can be reached with other dosing schedules. Upon delivery in alternation therapy, a synergistic effect can be reached at the time of administration or delivery of the compounds sequentially, for example as separate tablets, pills or capsules, or by different injections in separate syringes. In general, in alternation therapy, an effective amount of each active ingredient is administered sequentially, ie, sequentially, whereas in combination therapy, an effective amount of two or more active ingredients are administered together. The synergistic antiviral effect shows a higher antiviral effect than the predicted simple additive effect of the combined individual compounds.

  In yet another embodiment, the application contacts an effective amount of a compound of Formula I-III and Formula IV-VI, or a pharmaceutically acceptable salt, solvate, and / or ester thereof with HCV-infected cells. A method of inhibiting intracellular HCV polymerase comprising inhibiting HCV polymerase thereby.

  In yet another embodiment, the application provides an effective amount of a compound of Formulas I-III and Formulas IV-VI, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional Provided is a method of inhibiting intracellular HCV polymerase comprising contacting an active therapeutic agent with HCV infected cells, thereby inhibiting HCV polymerase.

  In yet another embodiment, the application provides an effective amount of a compound of Formulas I-III and Formulas IV-VI, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional Active therapeutic agents (one or more interferons, ribavirin or analogs thereof, HCV NS3 protease inhibitor, NS5a inhibitor, α-glucosidase 1 inhibitor, hepatoprotectant, mevalonate decarboxylase antagonist, renin-angiotensin antagonist, Other anti-fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV A method of inhibiting intracellular HCV polymerase comprising contacting an IRES inhibitor, a pharmacokinetic enhancer and other HCV therapeutic agent; or a mixture thereof) with an HCV-infected cell is provided.

  In yet another embodiment, the application provides a method of treating HCV in a patient, wherein a therapeutically effective amount of a compound of formula I-III and formula IV-VI, or a pharmaceutically acceptable salt, solvate thereof, and And / or administering an ester to the patient.

  In yet another embodiment, the application provides a method of treating HCV in a patient, wherein a therapeutically effective amount of a compound of formula I-III and formula IV-VI, or a pharmaceutically acceptable salt, solvate thereof, and Or / and administering at least one additional active therapeutic agent to the patient, thereby inhibiting HCV polymerase.

  In yet another embodiment, the application provides a method of treating HCV in a patient, wherein a therapeutically effective amount of a compound of formula I-III and formula IV-VI, or a pharmaceutically acceptable salt, solvate thereof, and And / or esters and at least one additional active therapeutic agent (one or more interferons, ribavirin or analogs thereof, HCV NS3 protease inhibitor, NS5a inhibitor, α-glucosidase 1 inhibitor, hepatoprotective agent, mevalonic acid Decarboxylase antagonists, renin-angiotensin antagonists, other antifibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 Administering to the patient an agonist, cyclophilin inhibitor, HCV IRES inhibitor, pharmacokinetic enhancer and other HCV therapeutic agent; or a mixture thereof.

  In yet another embodiment, this application provides the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, for the preparation of a medicament for the treatment of HCV infection in a patient.

Metabolites of the Compounds of the Invention In vivo metabolites of the compounds described herein are also within the scope of the invention to the extent that such products are novel and not obvious from the prior art. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound mainly due to enzymatic processes. Accordingly, the present invention includes novel and non-obvious compounds produced by a process comprising contacting a mammal with a compound of the present invention for a time sufficient to obtain its metabolite. Such products are typically prepared for radiolabeled (eg, ¹⁴ C or ³ H) compounds of the invention, sufficient time for metabolic action to occur (typically about 30 seconds to 30 hours). ) Parenteral administration of detectable amounts (eg, greater than about 0.5 mg / kg) to animals (such as rats, mice, guinea pigs, monkeys, or humans), as well as urine, blood or other biological samples of the conversion products Identified by isolation from. Because these products are labeled, they are easily isolated (others are isolated using antibodies that can bind to epitopes that survive in the metabolite). Metabolite structure is determined in a conventional manner, for example by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The conversion products are useful in diagnostic assays for therapeutic dosing of compounds of the present invention, even if they do not themselves have HCV polymerase inhibitory activity, unless they are found in vivo.

  Techniques and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein to be stable in the gastrointestinal tract when less than about 50 mol% of the protecting groups are deprotected in the intestinal substitute or gastric juice during 1 hour incubation at 37 ° C. Just because a compound is stable in the digestive tract does not mean that it cannot be hydrolyzed in vivo. The prodrugs of the invention are typically stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver or other metabolic organs, or general cells.

Examples Certain abbreviations and acronyms are used in the description of experimental details. Most of these will be understood by those skilled in the art, but Table 1 lists many of these abbreviations and acronyms.
Table 1

７−ブロモ−２，４−ビス−メチルスルファニル−イミダゾ［２，１−ｆ］［１，２，４］トリアジン（ＷＯ２００８１１６０６４号に従って調製、５００ｍｇ、１．７２ｍｍｏｌ）の無水ＴＨＦ懸濁液（５ｍＬ）にＢｕＬｉ（１．６Ｍヘキサン溶液、１．６１ｍＬ、２．４１ｍｍｏｌ）を−７８℃で滴下した。５分後に懸濁液は赤褐色溶液になり、次いで１ａ（ＷＯ２００６３１７２５号に従って調製、６７５ｍｇ、１．８１ｍｍｏｌ）および三フッ化ホウ素エーテラート（２．４０ｍＬ、１．８９ｍｍｏｌ）のＴＨＦ溶液（５ｍＬ）の混合物を前記混合物に滴下した。−７８℃で２時間撹拌後、飽和ＮＨ_４Ｃｌを添加して反応物をクエンチした。混合物を酢酸エチルで希釈した；有機層をブラインで洗浄して、真空濃縮した。残渣をシリカゲルカラムクロマトグラフィーにより精製し（ＥｔＯＡｃ／ヘキサン）、１ｂを濃黄色発泡体（６５０ｍｇ、６７％）として得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：δ８．１３（ｄ、２Ｈ）、８．０３（ｄ、２Ｈ）、７．８１（ｄ、１Ｈ）、７．５９（ｔ、１Ｈ）、７．４５（ｍ、３Ｈ）、７．３６（ｔ、２Ｈ）、６．４０（ｂｒｓ、１Ｈ）、６．０１（ｄｄ、１Ｈ）、４．７８（ｍ、２Ｈ）、４．６０（ｄｄ、１Ｈ）、２．６８（ｓ、３Ｈ）、２．４５（ｓ、３Ｈ）、１．６２（ｄ、３Ｈ）。^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）：δ−１６７．５．ＭＳ＝５８５．１（Ｍ＋Ｈ^＋）。 Compound Preparation Compound 1

Anhydrous THF suspension (5 mL) of 7-bromo-2,4-bis-methylsulfanyl-imidazo [2,1-f] [1,2,4] triazine (prepared according to WO200008116064, 500 mg, 1.72 mmol) BuLi (1.6 M hexane solution, 1.61 mL, 2.41 mmol) was added dropwise at −78 ° C. After 5 minutes, the suspension becomes a reddish brown solution, then a mixture of 1a (prepared according to WO200631725, 675 mg, 1.81 mmol) and boron trifluoride etherate (2.40 mL, 1.89 mmol) in THF (5 mL). It was dripped at the said mixture. After stirring at −78 ° C. for 2 hours, saturated NH ₄ Cl was added to quench the reaction. The mixture was diluted with ethyl acetate; the organic layer was washed with brine and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give 1b as a dark yellow foam (650 mg, 67%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (d, 2H), 8.03 (d, 2H), 7.81 (d, 1H), 7.59 (t, 1H), 7.45 ( m, 3H), 7.36 (t, 2H), 6.40 (brs, 1H), 6.01 (dd, 1H), 4.78 (m, 2H), 4.60 (dd, 1H), 2.68 (s, 3H), 2.45 (s, 3H), 1.62 (d, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-167.5. MS = 585.1 (M + H ^< + ^> ).

１ｂ（８２０ｍｇ、１．４０ｍｍｏｌ）のジクロロメタン溶液（２０ｍＬ）に三フッ化ホウ素エーテラート（２ｍＬ）およびトリエチルシラン（２ｍＬ）を添加し、室温で１６時間撹拌した。さらなる三フッ化ホウ素エーテラート（１ｍＬ）およびトリエチルシラン（１ｍＬ）を添加して、７日間撹拌した。混合物をジクロロメタンおよび飽和重炭酸ナトリウムで希釈した。有機層を水、飽和塩化アンモニウムおよびブラインで連続洗浄して、硫酸マグネシウム上で乾燥させて、濃縮した。残渣をシリカゲルカラムクロマトグラフィーにより精製し（ＥｔＯＡｃ／ヘキサン）、１ｃ（６０５ｍｇ、７６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：δ８．１０（ｄ、Ｊ＝７．２Ｈｚ、２Ｈ）、８．００（ｄ、Ｊ＝７．２Ｈｚ、２Ｈ）、７．６６（ｓ、１Ｈ）、７．６１（ｔ、Ｊ＝７．２Ｈｚ、１Ｈ）、７．５３（ｔ、Ｊ＝７．２Ｈｚ、１Ｈ）、７．４６（ｔ、Ｊ＝７．２Ｈｚ、２Ｈ）、７．３８（ｔ、Ｊ＝７．２Ｈｚ、２Ｈ）、５．７８（ｍ、２Ｈ）、４．８０（ｄｄ、１Ｈ）、４．６８（ｍ、１Ｈ）、４．６０（ｄｄ、１Ｈ）、２．６８（ｓ、３Ｈ）、２．６５（ｓ、３Ｈ）、１．３２（ｄ、３Ｈ）。^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）：δ−１４９．９．ＭＳ＝５６９．１（Ｍ＋Ｈ^＋）。

Boron trifluoride etherate (2 mL) and triethylsilane (2 mL) were added to a dichloromethane solution (20 mL) of 1b (820 mg, 1.40 mmol) and stirred at room temperature for 16 hours. Additional boron trifluoride etherate (1 mL) and triethylsilane (1 mL) were added and stirred for 7 days. The mixture was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was washed successively with water, saturated ammonium chloride and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give 1c (605 mg, 76%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.10 (d, J = 7.2 Hz, 2H), 8.00 (d, J = 7.2 Hz, 2H), 7.66 (s, 1H), 7 .61 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 5.78 (m, 2H), 4.80 (dd, 1H), 4.68 (m, 1H), 4.60 (dd, 1H), 2.68 (s) 3H), 2.65 (s, 3H), 1.32 (d, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-149.9. MS = 569.1 (M + H ^< + ^> ).

化合物１ｃ（６３５ｍｇ、１．１２ｍｍｏｌ）を鋼製オートクレーブに入れた。液体アンモニア（〜３０ｍＬ）を帯電し、オートクレーブを堅く密封した。混合物を５０℃で１６時間撹拌した。室温に冷却後、アンモニアを蒸発させ、固体残渣をＴＨＦ（１０ｍＬ）およびＭｅＯＨ（１０ｍＬ）に溶解させた。ナトリウムエトキシド（２５重量％、０．６３ｍＬ）を添加して、６０℃で４０分間撹拌した。混合物をＡｃＯＨにて中性化して、濃縮した。残渣をＲＰ ＨＰＬＣにより精製し、生成物１ｄ（１７５ｍｇ、４８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）：δ８．２１（ｂｒｓ、２Ｈ）、７．６０（ｓ、１Ｈ）、５．４５（ｂｒｓ、１Ｈ）、５．４３（ｄ、１Ｈ）、４．９１（ｔ、１Ｈ）、３．９２（ｍ、１Ｈ）、３．７６（ｍ、２Ｈ）、３．５７（ｍ、１Ｈ）、２．４４（ｓ、３Ｈ）、１．０９（ｄ、３Ｈ）。^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ−ｄ_６）：δ−１５３．５．ＭＳ＝３３０．１（Ｍ＋Ｈ^＋）。

Compound 1c (635 mg, 1.12 mmol) was placed in a steel autoclave. Liquid ammonia (˜30 mL) was charged and the autoclave was tightly sealed. The mixture was stirred at 50 ° C. for 16 hours. After cooling to room temperature, the ammonia was evaporated and the solid residue was dissolved in THF (10 mL) and MeOH (10 mL). Sodium ethoxide (25 wt%, 0.63 mL) was added and stirred at 60 ° C. for 40 minutes. The mixture was neutralized with AcOH and concentrated. The residue was purified by RP HPLC to give product 1d (175 mg, 48%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.21 (brs, 2H), 7.60 (s, 1H), 5.45 (brs, 1H), 5.43 (d, 1H), 4. 91 (t, 1H), 3.92 (m, 1H), 3.76 (m, 2H), 3.57 (m, 1H), 2.44 (s, 3H), 1.09 (d, 3H) ). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ): δ-153.5. MS = 330.1 (M + H ^< + ^> ).

１ｄ（１７５ｍｇ、０．５３ｍｍｏｌ）のジクロロメタン溶液（１１ｍＬ）にＭＣＰＢＡ（３７０ｍｇ、〜１．５ｍｍｏｌ）を添加して、室温で１６時間撹拌した。混合物を濃縮して粗１ｅを得、これを精製せずに次の反応に使用した．ＭＳ＝３６２．０（Ｍ＋Ｈ^＋）。

MCPBA (370 mg, ˜1.5 mmol) was added to 1d (175 mg, 0.53 mmol) in dichloromethane (11 mL) and stirred at room temperature for 16 hours. The mixture was concentrated to give crude 1e, which was used in the next reaction without purification. MS = 362.0 (M + H ^< + ^> ).

（先行反応から得た）化合物１ｅを鋼製オートクレーブに入れた。液体アンモニア（〜３０ｍＬ）を帯電し、オートクレーブを堅く密封した。混合物を１１５℃で３日間撹拌した。室温に冷却後、アンモニアを蒸発させた。固体残渣をＲＰ ＨＰＬＣにより精製し、化合物１（１０５ｍｇ、２工程中６６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、Ｄ_２Ｏ）：δ７．３１（ｓ、１Ｈ）、５．４３（ｄ、Ｊ＝２５．２Ｈｚ、１Ｈ）、４．０７（ｄｄ、Ｊ＝９．６、２３．２、１Ｈ）、３．８９（ｍ、１Ｈ）、３．８３（ｄｄ、Ｊ＝２．４、１２．８Ｈｚ、１Ｈ）、３．６７（ｄｄ、Ｊ＝４．８、１２．８Ｈｚ、１Ｈ）、１．０５（ｄ、Ｊ＝２２．８Ｈｚ、３Ｈ）。^１９Ｆ ＮＭＲ（３７６ＭＨｚ、Ｄ_２Ｏ）：δ−１５３．５．ＭＳ＝２９９．２（Ｍ＋Ｈ^＋）。

Compound 1e (obtained from the previous reaction) was placed in a steel autoclave. Liquid ammonia (˜30 mL) was charged and the autoclave was tightly sealed. The mixture was stirred at 115 ° C. for 3 days. After cooling to room temperature, the ammonia was evaporated. The solid residue was purified by RP HPLC to give compound 1 (105 mg, 66% over 2 steps). ¹ H NMR (400 MHz, D ₂ O): δ 7.31 (s, 1H), 5.43 (d, J = 25.2 Hz, 1H), 4.07 (dd, J = 9.6, 23.2) 1H), 3.89 (m, 1H), 3.83 (dd, J = 2.4, 12.8 Hz, 1H), 3.67 (dd, J = 4.8, 12.8 Hz, 1H) 1.05 (d, J = 22.8 Hz, 3H). ¹⁹ F NMR (376 MHz, D ₂ O): δ-153.5. MS = 299.2 (M + H ^< + ^> ).

化合物１（８２ｍｇ、０．２８ｍｍｏｌ）の水溶液（３４０ｍＬ）にアデノシンデアミナーゼ（Ｓｉｇｍａ−Ａｌｄｒｉｃｈ製Ａ５１６８ウシ脾臓ＩＸ型、０．１２５単位／ｍＬ水）を添加して、３７℃で４時間撹拌した。混合物を濃縮して、ＲＰ ＨＰＬＣにより精製し、化合物２（５６ｍｇ、６８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、Ｄ_２Ｏ）：δ７．３５（ｓ、１Ｈ）、５．４６（ｄ、Ｊ＝２５．２Ｈｚ、１Ｈ）、４．０８（ｄｄ、Ｊ＝９．６、２２．６、１Ｈ）、３．９３（ｍ、１Ｈ）、３．８７（ｄｄ、Ｊ＝２．４、１２．８Ｈｚ、１Ｈ）、３．７１（ｄｄ、Ｊ＝４．８、１２．８Ｈｚ、１Ｈ）、１．１２（ｄ、Ｊ＝２３．２Ｈｚ、３Ｈ）。^１９Ｆ ＮＭＲ（３７６ＭＨｚ、Ｄ_２Ｏ）：δ−１５３．４．ＭＳ＝３００．２（Ｍ＋Ｈ^＋）。 Compound 2

Adenosine deaminase (Sigma-Aldrich A5168 bovine spleen type IX, 0.125 units / mL water) was added to an aqueous solution (340 mL) of Compound 1 (82 mg, 0.28 mmol), and the mixture was stirred at 37 ° C. for 4 hours. The mixture was concentrated and purified by RP HPLC to give compound 2 (56 mg, 68%). ¹ H NMR (400 MHz, D ₂ O): δ 7.35 (s, 1H), 5.46 (d, J = 25.2 Hz, 1H), 4.08 (dd, J = 9.6, 22.6) 1H), 3.93 (m, 1H), 3.87 (dd, J = 2.4, 12.8 Hz, 1H), 3.71 (dd, J = 4.8, 12.8 Hz, 1H) 1.12 (d, J = 23.2 Hz, 3H). ¹⁹ F NMR (376 MHz, D ₂ O): δ-153.4. MS = 300.2 (M + H ^< + ^> ).

７−ブロモ−ピロロ［２，１−ｆ］［１，２，４］トリアジン−４−イルアミン（ＷＯ２００７０５６１７０号に従って調製、２．１３ｇ、１０ｍｍｏｌ）のＴＨＦ懸濁液（２０ｍＬ）にＴＭＳＣｌ（２．６６ｍＬ、２１ｍｍｏｌ）を添加して、アルゴン下で室温で１６時間撹拌した。−７８℃に冷却後、ＢｕＬｉ（１．６Ｍ、２１ｍＬ、３３ｍｍｏｌ）のヘキサン溶液を滴下した。混合物を同温で１時間撹拌した。次いで１ａ（ＷＯ２００６３１７２５号に従って調製、４．４６ｇ、１２ｍｍｏｌ）のＴＨＦ溶液（１０ｍＬ）を添加した。−７８℃で２時間撹拌後、飽和塩化アンモニウムを添加して反応物をクエンチした。混合物を酢酸エチルで抽出した。有機抽出物を真空濃縮した。残渣をシリカゲルクロマトグラフィーにより精製し（酢酸エチル／ヘキサン）、３ｂを黄色固体（１．６ｇ、３２％）として得た。ＭＳ＝５０７．１（Ｍ＋Ｈ^＋）。 Compound 3

To a suspension of 7-bromo-pyrrolo [2,1-f] [1,2,4] triazin-4-ylamine (prepared according to WO2007056170, 2.13 g, 10 mmol) in THF (20 mL) was added TMSCl (2.66 mL). , 21 mmol) and stirred at room temperature under argon for 16 hours. After cooling to −78 ° C., a hexane solution of BuLi (1.6 M, 21 mL, 33 mmol) was added dropwise. The mixture was stirred at the same temperature for 1 hour. Then 1a (prepared according to WO200631725, 4.46 g, 12 mmol) in THF (10 mL) was added. After stirring at −78 ° C. for 2 hours, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 3b as a yellow solid (1.6 g, 32%). MS = 507.1 (M + H ^< + ^> ).

Alternative method for compound 3b using 1,2-bis-[(chlorodimethyl) silanyl] ethane instead of chlorotrimethylsilane 7-Bromo-pyrrolo [2,1-f] [1,2,4] triazine-4 -To a suspension of ylamine (500 mg, 2.35 mmol) in THF (6.5 mL) was added BuLi (1.6 M hexane solution, 1.6 mL) at -78 [deg.] C. After 30 minutes, l, 2-bis-[(chlorodimethyl) silanyl] ethane (538 mg, 2.4 mmol) in THF (1.2 mL) was added. After 45 minutes, BuLi (1.6 mL) was added. After an additional 30 minutes, BuLi (1.5 mL) was added. Then, 30 minutes later, a THF solution (2 mL) of 1a (610 mg, 1.64 mmol) was added dropwise. The reaction mixture was stirred at −78 ° C. for 2 hours under argon. Acetic acid (0.7 mL) was added dropwise to quench the reaction followed by the addition of saturated ammonium chloride. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 3b (320 mg, 40%). Starting la was also recovered from the chromatography (350 mg).

化合物３ｂ（５０ｍｇ、０．１ｍｍｏｌ）およびＴＭＳＣＮ（６７μｌ、０．５ｍｍｏｌ）のアセトニトリル溶液（２．０ｍＬ）に０℃でＴＭＳＯＴｆ（９１μｌ、０．５ｍｍｏｌ）を添加した。反応混合物を室温で１時間、次いで６５℃で３日間撹拌した。反応物を飽和ＮａＨＣＯ_３で室温でクエンチし、ＣＨ_３ＣＯ_２Ｅｔで希釈した。有機相を分離して、ブラインで洗浄して、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮した。残渣をＲＰ−ＨＰＬＣにより精製し（アセトニトリル／水）、所望の化合物３ｃ（２８ｍｇ、５４％）を得た。ＭＳ＝５１６．１（Ｍ＋Ｈ^＋）。

TMSOTf (91 μl, 0.5 mmol) was added at 0 ° C. to a solution of compound 3b (50 mg, 0.1 mmol) and TMSCN (67 μl, 0.5 mmol) in acetonitrile (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then at 65 ° C. for 3 days. The reaction was quenched with saturated NaHCO ₃ at room temperature and diluted with CH ₃ CO ₂ Et. The organic phase was separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC (acetonitrile / water) to give the desired compound 3c (28 mg, 54%). MS = 516.1 (M + H ^< + ^> ).

３ｃ（５６ｍｇ、０．１１ｍｍｏｌ）のメタノール溶液（１．２ｍＬ）に水酸化アンモニウム（２８％水溶液、０．８ｍＬ）を添加して、室温で１６時間撹拌した。混合物を濃縮して、残渣をＲＰ ＨＰＬＣにより精製し（水／アセトニトリル）、化合物３（２０ｍｇ、６０％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ、Ｄ_２Ｏ）：δ７．８８（ｓ、１Ｈ）、７．０７（ｄ、１Ｈ）、６．９２（ｄ、１Ｈ）、４．１７（ｍ、２Ｈ）、４．０４（ｄｄ、１Ｈ）、３．８７（ｄｄ、１Ｈ）、１．１５（ｄ、３Ｈ）．ＭＳ＝３０８．１（Ｍ＋Ｈ^＋）。

To a methanol solution (1.2 mL) of 3c (56 mg, 0.11 mmol) was added ammonium hydroxide (28% aqueous solution, 0.8 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile) to give compound 3 (20 mg, 60%). ¹ H NMR (500 MHz, D ₂ O): δ 7.88 (s, 1H), 7.07 (d, 1H), 6.92 (d, 1H), 4.17 (m, 2H), 4.04 (Dd, 1H), 3.87 (dd, 1H), 1.15 (d, 3H). MS = 308.1 (M + H ^< + ^> ).

化合物３ｂ（６０ｍｇ、０．１２ｍｍｏｌ）のメタノール溶液（０．５ｍＬ）に水酸化アンモニウム（２８％水溶液、０．５ｍＬ）を添加して、室温で１６時間撹拌した。混合物を濃縮して、残渣をＲＰ ＨＰＬＣにより精製し（水／アセトニトリル）、化合物４（２５ｍｇ、７０％）を得た。ＭＳ＝２９９．１（Ｍ＋Ｈ^＋）。 Compound 4

To a methanol solution (0.5 mL) of compound 3b (60 mg, 0.12 mmol) was added ammonium hydroxide (28% aqueous solution, 0.5 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile) to give compound 4 (25 mg, 70%). MS = 299.1 (M + H ^< + ^> ).

１ｂの１ｃへの変換に類似した方法により化合物３ｂを化合物５ａへ変換した。次いで、３ｃの３への変換に類似した方法により化合物５ａを化合物５へ変換した。^１Ｈ ＮＭＲ（３００ＭＨｚ、Ｄ_２Ｏ）：δ７．６８（ｓ、１Ｈ）、６．７５（ｄ、Ｊ＝４．５Ｈｚ、１Ｈ）、６．６５（ｄ、Ｊ＝４．５Ｈｚ、１Ｈ）、５．６５（ｄ、Ｊ＝２５．２Ｈｚ、１Ｈ）、３．９５（ｍ、３Ｈ）、３．７４（ｄｄ、１Ｈ）、０．９８（ｄ、Ｊ＝２２．８Ｈｚ、３Ｈ）。^１９Ｆ ＮＭＲ（２８２ＭＨｚ、Ｄ_２Ｏ）：δ−１５４．２．ＭＳ＝２８３．２（Ｍ＋Ｈ^＋）。 Compound 5

Compound 3b was converted to compound 5a by a method analogous to the conversion of 1b to 1c. Compound 5a was then converted to compound 5 by a method analogous to the conversion of 3c to 3. ¹ H NMR (300 MHz, D ₂ O): δ 7.68 (s, 1H), 6.75 (d, J = 4.5 Hz, 1H), 6.65 (d, J = 4.5 Hz, 1H), 5.65 (d, J = 25.2 Hz, 1H), 3.95 (m, 3H), 3.74 (dd, 1H), 0.98 (d, J = 22.8 Hz, 3H). ¹⁹ F NMR (282 MHz, D ₂ O): δ-154.2. MS = 283.2 (M + H ^< + ^> ).

General preparation of triphosphate nucleosides:
Place the nucleoside (~ 20 mg) in a pear flask (5-15 mL). Add trimethyl phosphate (0.5-1.0 mL). Cool the solution in an ice-water bath. POCl ₃ (40-45 mg) is added and stirred at 0 ° C. until the reaction is complete (1-4 hours; reaction progress is monitored by ion exchange HPLC; analytical sample recovers ˜3 μL reaction mixture. prepared by diluting with _{1.0M Et 3 NH 2 CO 3 (} 30~50μL) Te). Then added acetonitrile or DMF solution of pyrophosphate _-Bu 3 N (250mg) and _{Bu 3 N (90~105mg) (1~1.5mL} ). The mixture is stirred at 0 ° C. for 0.3-2½ hours, then the reaction is quenched with 1.0 M Et ₃ NH ₂ CO ₃ (˜5 mL). The reaction mixture is stirred for another half hour to 1 hour while warming to room temperature. The mixture is concentrated to dryness, redissolved in water (4 mL) and purified by ion exchange HPLC. Fractions containing the desired product are concentrated to dryness, dissolved in water (~ 5 mL), concentrated to dryness and dissolved again in water (~ 5 mL). NaHCO ₃ (30-50 mg) is added and concentrated to dryness. The residue is dissolved in water and concentrated again to dryness. This process is repeated 2-5 times. The residue is then subjected to C-18 HPLC purification to give the desired product as sodium or salt. Alternatively, the crude reaction mixture is subjected first to C-18 HPLC and then to ion exchange HPLC purification to give the desired product as a triethylammonium salt.

化合物２を出発物質として使用して一般的方法により化合物ＴＰ−１を調製した。^１Ｈ ＮＭＲ（３００ＭＨｚ、Ｄ_２Ｏ）：δ７．４４（ｓ、１Ｈ）、５．４５（ｄ、Ｊ＝２５．５Ｈｚ、１Ｈ）、４．０−４．４（ｍ、４Ｈ）、３．０５（ｍ、ＮＣＨ_２ＣＨ_３）、１．１０（ｍ、ＮＣＨ_２ＣＨ_３および２’−Ｃ−ＣＨ_３）。^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、Ｄ_２Ｏ）：δ−９．５（ｄ、Ｊ＝２２．１Ｈｚ）、−１１．０（ｄ、Ｊ＝１９．９Ｈｚ）、−２３．２（ｔ、Ｊ＝２３．０Ｈｚ）。^１９Ｆ ＮＭＲ（２８２ＭＨｚ、Ｄ_２Ｏ）：δ−１５３．９。 Compound TP-1

Compound TP-1 was prepared by a general method using compound 2 as a starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.44 (s, 1H), 5.45 (d, J = 25.5 Hz, 1H), 4.0-4.4 (m, 4H), 3. _{05 (m, NCH 2 CH 3} ), 1.10 (m, NCH 2 CH 3 and _2'-C-CH 3). ³¹ P NMR (121.4 MHz, D ₂ O): δ-9.5 (d, J = 22.1 Hz), −11.0 (d, J = 19.9 Hz), −23.2 (t, J = 23.0 Hz). ¹⁹ F NMR (282 MHz, D ₂ O): δ-153.9.

化合物３を出発物質として使用して一般的方法により化合物ＴＰ−２を調製した。^１Ｈ ＮＭＲ（３００ＭＨｚ、Ｄ_２Ｏ）：δ７．８２（ｓ、１Ｈ）、７．０３（ｄ、１Ｈ）、６．９０（ｄ、１Ｈ）、４．１−４．４（ｍ、４Ｈ）、３．０５（ｍ、ＮＣＨ_２ＣＨ_３）、１．１０（ｍ、ＮＣＨ_２ＣＨ_３および２’−Ｃ−ＣＨ_３）。^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、Ｄ_２Ｏ）：δ−１０．７（ｄ、Ｊ＝１９．５Ｈｚ）、−１１．３（ｄ、Ｊ＝１９．８Ｈｚ）、−２３．１（ｔ、Ｊ＝１９．８Ｈｚ）。 Compound TP-2

Compound TP-2 was prepared by a general method using compound 3 as a starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.82 (s, 1H), 7.03 (d, 1H), 6.90 (d, 1H), 4.1-4.4 (m, 4H) _{, 3.05 (m, NCH 2 CH} 3), 1.10 (m, NCH 2 CH 3 and _2'-C-CH 3). ³¹ P NMR (121.4 MHz, D ₂ O): δ-10.7 (d, J = 19.5 Hz), −11.3 (d, J = 19.8 Hz), −23.1 (t, J = 19.8 Hz).

化合物５を出発物質として使用して一般的方法により化合物ＴＰ−３を調製した。^１Ｈ ＮＭＲ（３００ＭＨｚ、Ｄ_２Ｏ）：δ７．７３（ｓ、１Ｈ）、６．８７（ｄ、１Ｈ）、６．８２（ｄ、１Ｈ）、５．７１（ｄ、Ｊ＝２４．６Ｈｚ、１Ｈ）、４．０−４．４（ｍ、４Ｈ）、３．０５（ｍ、ＮＣＨ_２ＣＨ_３）、１．１４（ｍ、ＮＣＨ_２ＣＨ_３）、１．００（ｄ、Ｊ＝２２．８Ｈｚ、３Ｈ、２’−Ｃ−ＣＨ_３）。^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、Ｄ_２Ｏ）：δ−８．１（ｄ、Ｊ＝２２．１Ｈｚ）、−１１．１（ｄ、Ｊ＝１９．９Ｈｚ）、−２２．７（ｔ、Ｊ＝２３．０Ｈｚ）。^１９Ｆ ＮＭＲ（２８２ＭＨｚ、Ｄ_２Ｏ）：δ−１５５．６．ＭＳ＝５２０．９（Ｍ−Ｈ^＋）。 Compound TP-3

Compound TP-3 was prepared by a general method using compound 5 as a starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.73 (s, 1H), 6.87 (d, 1H), 6.82 (d, 1H), 5.71 (d, J = 24.6 Hz, _{1H), 4.0-4.4 (m, 4H} ), 3.05 (m, NCH 2 CH 3), 1.14 (m, NCH 2 CH 3), 1.00 (d, J = 22. 8Hz, 3H, 2'-C- CH 3). ³¹ P NMR (121.4 MHz, D ₂ O): δ-8.1 (d, J = 22.1 Hz), −11.1 (d, J = 19.9 Hz), −22.7 (t, J = 23.0 Hz). ¹⁹ F NMR (282 MHz, D ₂ O): δ-155.6. MS = 520.9 (M-H ^<+> ).

化合物８を出発物質として使用して一般的方法により化合物ＴＰ−８ａを調製した。^１Ｈ ＮＭＲ（３００ＭＨｚ、Ｄ_２Ｏ）：δ７．９５（ｓ、１Ｈ）、７．６８（ｓ、１Ｈ）、５．６３（ｄ、Ｊ＝２５．５Ｈｚ、１Ｈ）、４．０−４．４（ｍ、４Ｈ）、３．０５（ｍ、ＮＣＨ_２ＣＨ_３）、１．１０（ｍ、ＮＣＨ_２ＣＨ_３および２’−Ｃ−ＣＨ_３）。^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、Ｄ_２Ｏ）：δ−９．２０（ｄ、Ｊ＝２２．１Ｈｚ）、−１１．０７（ｄ、Ｊ＝１９．９Ｈｚ）、−２３．８２（ｔ、Ｊ＝２３．０Ｈｚ）。^１９Ｆ ＮＭＲ（２８２ＭＨｚ、Ｄ_２Ｏ）：δ−１５５．９．ＭＳ＝５２１．６（Ｍ−Ｈ^＋）。 Compound TP-8a

Compound TP-8a was prepared by the general method using compound 8 as the starting material. ¹ H NMR (300 MHz, D ₂ O): δ 7.95 (s, 1H), 7.68 (s, 1H), 5.63 (d, J = 25.5 Hz, 1H), 4.0-4. _{4 (m, 4H), 3.05} (m, NCH 2 CH 3), 1.10 (m, NCH 2 CH 3 and _2'-C-CH 3). ³¹ P NMR (121.4 MHz, D ₂ O): δ-9.20 (d, J = 22.1 Hz), -11.07 (d, J = 19.9 Hz), -23.82 (t, J = 23.0 Hz). ¹⁹ F NMR (282 MHz, D ₂ O): δ-155.9. MS = 521.6 (M-H ^<+> ).

ヌクレオシド（０．１ｍｍｏｌ）のトリメチル亜リン酸溶液（１．０ｍＬ）に１Ｈ−テトラゾール（４２ｍｇ、０．６ｍｍｏｌ）を添加してから、２，２−ジメチル−チオプロピオン酸Ｓ−（２−｛ジイソプロピルアミノ−［２−（２，２−ジメチル−プロピオニルスルファニル）−エトキシ］−ホスファニルオキシ｝−エチル）エステル（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８５，３８，３９４１に従って調製、９０ｍｇ、０．２ｍｍｏｌ）を０℃で添加した。２時間撹拌後、３０％過酸化水素水溶液（１４０μＬ）を混合物に添加した。次いで混合物を室温まで加温した。３０分撹拌後、１Ｍ Ｎａ_２Ｓ_２Ｏ_３水溶液（５ｍＬ）を添加して反応物をクエンチした。有機層を飽和Ｎａ_２ＣＯ_３水溶液（１０ｍＬ×２）、ブラインで洗浄して、真空濃縮した。残渣をＲＰ−ＨＰＬＣにより精製し（ＭｅＣＮ〜Ｈ_２Ｏ勾配）、プロドラッグＡを得た。 General method for preparing nucleoside prodrugs (Method A):

1H-tetrazole (42 mg, 0.6 mmol) was added to a trimethyl phosphite solution (1.0 mL) of nucleoside (0.1 mmol), and then 2,2-dimethyl-thiopropionic acid S- (2- {diisopropyl Amino- [2- (2,2-dimethyl-propionylsulfanyl) -ethoxy] -phosphanyloxy} -ethyl) ester (prepared according to J. Med. Chem., 1985, 38, 3941, 90 mg, 0.2 mmol) Added at 0 ° C. After stirring for 2 hours, 30% aqueous hydrogen peroxide (140 μL) was added to the mixture. The mixture was then warmed to room temperature. After stirring for 30 minutes, 1M Na ₂ S ₂ O ₃ aqueous solution (5 mL) was added to quench the reaction. The organic layer was washed with saturated aqueous Na ₂ CO ₃ (10 mL × 2), brine and concentrated in vacuo. The residue was purified by RP-HPLC (MeCN~H ₂ O gradient) to give the prodrug A.

化合物１を出発物質として使用してＡ方法により化合物Ａ−１を調製した。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：δ７．４２（ｓ、１Ｈ）、５．４７（ｄ、Ｊ＝２６．４Ｈｚ、１Ｈ）、４．９５（ｂｒｓ、２Ｈ）、４．５９（ｍ、２Ｈ）、４．３５（ｍ、１Ｈ、４’−Ｈ）、４．１８（ｍ、２Ｈ、５’−Ｈ）、４．１０（ｍ、４Ｈ）、３．１３（ｍ、４Ｈ）、１．２４（ｄ、３Ｈ）、１．２２（ｓ、９Ｈ）、１．１９（ｄ、９Ｈ）。^３１Ｐ ＮＭＲ（１６１．９ＭＨｚ、ＣＤＣｌ_３）：δ−１．２６．ＭＳ＝６６７．１（Ｍ＋Ｈ^＋）。 Compound A-1

Compound A-1 was prepared by Method A using Compound 1 as the starting material. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.42 (s, 1H), 5.47 (d, J = 26.4 Hz, 1H), 4.95 (brs, 2H), 4.59 (m, 2H) ), 4.35 (m, 1H, 4′-H), 4.18 (m, 2H, 5′-H), 4.10 (m, 4H), 3.13 (m, 4H), 1. 24 (d, 3H), 1.22 (s, 9H), 1.19 (d, 9H). ³¹ P NMR (161.9 MHz, CDCl ₃ ): δ-1.26. MS = 667.1 (M + H ^< + ^> ).

General method for preparing nucleoside prodrugs (Method B):
Non-limiting examples of monophosphoramidic acid prodrugs comprising the present invention can be prepared according to general scheme 1.

一般的方法は、約２〜１０等量の適切な塩基の存在下で、アミノ酸エステル塩１９ｂ、例えば、ＨＣｌ塩とアリールジクロロホスフェート１９ａを反応させて、ホスホロアミド酸１９ｃを得ることを含む。適切な塩基としては、イミダゾール、ピリジン（ルチジンおよびＤＭＡＰなど）、三級アミン（トリエチルアミンおよびＤＡＢＣＯなど）、および置換アミジン（ＤＢＮおよびＤＢＵなど）が挙げられるが、これらに限定されない。三級アミンが特に好ましい。好ましくは、各工程の生成物を再結晶またはクロマトグラフィーなしで後続工程に直接使用する。１９ａ、１９ｂ、および１９ｃの非限定的な具体例は、ＷＯ２００６／１２１８２０号に見ることができ、これは参照することによりその全体が本明細書に組み込まれる。ヌクレオシド塩基１９ｄは適切な塩基の存在下でホスホロアミド酸１９ｃと反応する。適切な塩基としては、イミダゾール、ピリジン（ルチジンおよびＤＭＡＰなど）、三級アミン（トリエチルアミンおよびＤＡＢＣＯなど）、および置換アミジン（ＤＢＮおよびＤＢＵなど）が挙げられるが、これらに限定されない。生成物Ｂは、再結晶および／またはクロマトグラフィーにより単離し得る。 Scheme 1

The general method involves reacting amino acid ester salt 19b, eg, HCl salt, with aryl dichlorophosphate 19a in the presence of about 2-10 equivalents of a suitable base to give phosphoramidic acid 19c. Suitable bases include, but are not limited to, imidazole, pyridine (such as lutidine and DMAP), tertiary amines (such as triethylamine and DABCO), and substituted amidines (such as DBN and DBU). Tertiary amines are particularly preferred. Preferably, the product of each step is used directly in the subsequent step without recrystallization or chromatography. Non-limiting examples of 19a, 19b, and 19c can be found in WO 2006/121820, which is hereby incorporated by reference in its entirety. Nucleoside base 19d reacts with phosphoramidic acid 19c in the presence of a suitable base. Suitable bases include, but are not limited to, imidazole, pyridine (such as lutidine and DMAP), tertiary amines (such as triethylamine and DABCO), and substituted amidines (such as DBN and DBU). Product B can be isolated by recrystallization and / or chromatography.

フェニルエトキシアラニニル塩化リン（１２４ｍｇ、０．４２ｍｍｏｌ；ＭｃＧｕｉｇａｎ ｅｔ ａｌ，Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９３，３６，１０４８−１０５２に従って調製）を、化合物３（２０ｍｇ、０．０６５ｍｍｏｌ）およびＮ−メチルイミダゾール（４２μＬ、０．５２ｍｍｏｌ）の無水トリメチルホスフェート溶液（０．８ｍＬ）の混合物に添加した。反応混合物は、３時間室温で撹拌してから、メタノールを添加して反応物をクエンチした。メタノール溶媒は減圧除去する。残渣を逆相ＨＰＬＣ、次いでシリカゲルカラムクロマトグラフィー（１００％酢酸エチル）により精製し、化合物Ｂ−１（１０ｍｇ、２７％）を得た。^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、ＣＤＣｌ_３）：δ−３．４２、３．７７．ＭＳ＝５６３．０（Ｍ＋Ｈ^＋）、５６１．０（Ｍ−Ｈ^＋）。 Compound B-1

Phenylethoxyalaninyl phosphorus chloride (124 mg, 0.42 mmol; prepared according to McGuigan et al, J. Med. Chem. 1993, 36, 1048-1052) was prepared from compound 3 (20 mg, 0.065 mmol) and N-methylimidazole ( 42 μL, 0.52 mmol) in a mixture of anhydrous trimethyl phosphate solution (0.8 mL). The reaction mixture was stirred for 3 hours at room temperature before methanol was added to quench the reaction. The methanol solvent is removed under reduced pressure. The residue was purified by reverse phase HPLC followed by silica gel column chromatography (100% ethyl acetate) to give compound B-1 (10 mg, 27%). ³¹ P NMR (121.4 MHz, CDCl ₃ ): δ-3.42, 3.77. MS = 563.0 (M + H ^< + ^> ), 561.0 (M-H ^<+> ).

約３．１ｍｍｏｌの４−クロロフェニル２−プロピロキシアラニニル塩化リン（ＭｃＧｕｉｇａｎ ｅｔ ａｌ，Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９３，３６，１０４８−１０５２に従って調製）を約０．５ｍｍｏｌの化合物３および約３．８ｍｍｏｌのＮ−メチルイミダゾールの約３ｍＬ無水トリメチルホスフェート溶液の混合物に添加した。反応混合物を室温で約１時間〜２４時間撹拌し、メタノールを添加して反応物をクエンチした。メタノール溶媒は減圧除去する。残渣を逆相ＨＰＬＣにより精製し、化合物Ｂ−２を得る。 Compound B-2

About 3.1 mmol of 4-chlorophenyl 2-propyloxyalaninyl phosphorus chloride (prepared according to McGuigan et al, J. Med. Chem. 1993, 36, 1048-1052) is added to about 0.5 mmol of compound 3 and about 3.8 mmol. Was added to a mixture of about 3 mL of anhydrous trimethyl phosphate in N-methylimidazole. The reaction mixture was stirred at room temperature for about 1-24 hours and methanol was added to quench the reaction. The methanol solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC to give compound B-2.

化合物Ｂ−１に使用されるものと類似の方法により化合物Ｂ−３を得た。^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、ＣＤＣｌ_３）：δ−３．５０、３．７６．ＭＳ＝５７７．２（Ｍ＋Ｈ^＋）。 Compound B-3

Compound B-3 was obtained by a method similar to that used for compound B-1. ³¹ P NMR (121.4 MHz, CDCl ₃ ): δ-3.50, 3.76. MS = 577.2 (M + H ^< + ^> ).

化合物Ｂ−１に使用されるものと類似の方法により化合物Ｂ−４を得た。^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤ_３ＯＤ）：δ２．２．ＭＳ＝６３３．４（Ｍ＋Ｈ^＋）。 Compound B-4

Compound B-4 was obtained by a method similar to that used for compound B-1. ³¹ P NMR (162 MHz, CD ₃ OD): δ 2.2. MS = 633.4 (M + H ^< + ^> ).

化合物Ｂ−１に使用されるものと類似の方法により化合物Ｂ−５を得た。^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）：δ４．１５、４．２７．ＭＳ＝５４９．３（Ｍ＋Ｈ^＋）。 Compound B-5

Compound B-5 was obtained by a method similar to that used for compound B-1. ³¹ P NMR (162 MHz, CDCl ₃ ): δ 4.15, 4.27. MS = 549.3 (M + H &lt; ⁺ &gt;).

化合物Ｂ−１に使用されるものと類似の方法により化合物Ｂ−６を得た。^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）：δ３．５０、４．０７．ＭＳ＝６１３．１（Ｍ＋Ｈ^＋）。 Compound B-6

Compound B-6 was obtained by a method similar to that used for compound B-1. ³¹ P NMR (162 MHz, CDCl ₃ ): δ 3.50, 4.07. MS = 613.1 (M + H ^< + ^> ).

化合物５を親ヌクレオシドとして使用して、化合物Ｂ−１に使用されるものと類似の方法により化合物Ｂ−７を得た。^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）：δ３．３７、３．９７．ＭＳ＝５３８．１（Ｍ＋Ｈ^＋）。 Compound B-7

Compound B-7 was obtained by a method similar to that used for Compound B-1, using Compound 5 as the parent nucleoside. ³¹ P NMR (162 MHz, CDCl ₃ ): δ 3.37, 3.97. MS = 538.1 (M + H &lt; ⁺ &gt;).

化合物５を親ヌクレオシドとして使用して、化合物Ｂ−１に使用されるものと類似の方法により化合物Ｂ−８を得た。^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）：δ３．６９、４．３９．ＭＳ＝５８８．１（Ｍ＋Ｈ^＋）。 Compound B-8

Compound B-8 was obtained by a method analogous to that used for Compound B-1, using Compound 5 as the parent nucleoside. ³¹ P NMR (162 MHz, CDCl ₃ ): δ 3.69, 4.39. MS = 588.1 (M + H ^< + ^> ).

エチルＬ−バリン塩酸塩（２．５ｇ、１３．８ｍｍｏｌ、１等量）を含むフラスコ内にＣＨ_２Ｃｌ_２（４６ｍＬ、０．３Ｍ）およびフェニルジクロロホスフェート（２．１ｍＬ、１３．８ｍｍｏｌ、１等量）を添加後に−１０℃に冷却した。１０分後、ＴＥＡ（３．８ｍＬ、１３．８ｍｍｏｌ、１当量）を反応混合物に５分間かけてゆっくりと添加した。反応を１時間進行させた後、ｐ−ニトロフェノール（１．９ｇ、１３．８ｍｍｏｌ、１等量）を反応混合物に添加してから、さらなるＴＥＡ（３．８ｍＬ、１３．８ｍｍｏｌ、１等量）を５分間かけて添加した。反応物を加温して、さらに２時間進行させた。反応物を真空濃縮して、ジエチルエーテル（２００ｍＬ）中で取り上げた。不溶性塩を濾過して、ろ液を真空濃縮した。４／１Ｈｅｘ／ＥｔＯＡｃを使用してフラッシュカラムクロマトグラフィーを行い、透明な油をＣ−１ａとして得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：ｄ８．２１（ｓ、２Ｈ）、７．４１−７．２０（ｍ、７Ｈ）、４．２２−４．０５（ｍ、３Ｈ）、２．４６（ｓ、２Ｈ）、１．９９（ｄｄ、Ｊ＝２３．０、２０．１Ｈｚ、２Ｈ）、１．６８（ｓ、１Ｈ）、１．２０−１．０５（ｍ、８Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）：ｄ−２．７９（ｄｄ、Ｊ＝２８．０、４．２Ｈｚ）。
ＬＣＭＳ ｍ／ｚ４２２．９９［Ｍ＋Ｈ^＋］。 Alternative method for the preparation of nucleoside prodrugs (Method C):

In a flask containing ethyl L-valine hydrochloride (2.5 g, 13.8 mmol, 1 eq) CH ₂ Cl ₂ (46 mL, 0.3 M) and phenyldichlorophosphate (2.1 mL, 13.8 mmol, 1 eq) The amount was cooled to −10 ° C. after addition. After 10 minutes, TEA (3.8 mL, 13.8 mmol, 1 eq) was slowly added to the reaction mixture over 5 minutes. After the reaction was allowed to proceed for 1 hour, p-nitrophenol (1.9 g, 13.8 mmol, 1 eq) was added to the reaction mixture before additional TEA (3.8 mL, 13.8 mmol, 1 eq). Was added over 5 minutes. The reaction was warmed and allowed to proceed for an additional 2 hours. The reaction was concentrated in vacuo and taken up in diethyl ether (200 mL). Insoluble salts were filtered and the filtrate was concentrated in vacuo. Flash column chromatography was performed using 4/1 Hex / EtOAc to give a clear oil as C-1a.
¹ H NMR (400 MHz, CDCl ₃ ): d8.21 (s, 2H), 7.41-7.20 (m, 7H), 4.22-4.05 (m, 3H), 2.46 (s 2H), 1.99 (dd, J = 23.0, 20.1 Hz, 2H), 1.68 (s, 1H), 1.20-1.05 (m, 8H).
³¹ P NMR (162 MHz, CDCl ₃ ): d-2.79 (dd, J = 28.0, 4.2 Hz).
LCMS m / z 422.99 [M + H ^<+ >].

化合物３（７０ｍｇ、０．２３ｍｍｏｌ、１等量）を含むフラスコ内にＴＨＦ（１ｍＬ、０．２Ｍ）およびＮＭＰ（１ｍＬ、０．２Ｍ）を添加後に０℃に冷却した。ｔ−ＢｕＭｇＣｌ（５６０μＬ、２．５等量、１Ｍ ＴＨＦ）をゆっくりと添加して、５分間撹拌後、上記フェノラートＣ−１ａ（２０７ｍｇ、０．４６ｍｍｏｌ、２等量。５００μＬのＴＨＦに溶解）を添加した。反応混合物を５０℃に加温した。反応物をＬＣＭＳによりモニタリングした。反応完了後、混合物を真空濃縮して、残渣をＨＰＬＣにより精製し、化合物Ｃ−１を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ７．８７（ｓ、１Ｈ）、７．２４−７．１０（ｍ、４Ｈ）、７．０３（ｔ、Ｊ＝７．２Ｈｚ、１Ｈ）、６．８１（ｄ、Ｊ＝４．６Ｈｚ、１Ｈ）、６．５２（ｄ、Ｊ＝４．７Ｈｚ、１Ｈ）、５．６１（ｓ、２Ｈ）、４．４６（ｄｄ、Ｊ＝２４．０、１１．４Ｈｚ、２Ｈ）、４．３３−４．１４（ｍ、２Ｈ）、４．０６（ｄｔ、Ｊ＝７．２、４．２Ｈｚ、２Ｈ）、３．８２−３．７０（ｍ、１Ｈ）、３．６３（ｔ、Ｊ＝１０．６Ｈｚ、２Ｈ）、１．９８（ｓ、１Ｈ）、１．１７（ｄｄ、Ｊ＝１４．８、７．６Ｈｚ、３Ｈ）、０．８２（ｄｄ、Ｊ＝２２．８、６．８Ｈｚ、６Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）：ｄ５．１１。
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）：ｄ−１５２．２８。
ＬＣＭＳ ｍ／ｚ５９１．２１［Ｍ＋Ｈ^＋］。 Compound C-1

In a flask containing Compound 3 (70 mg, 0.23 mmol, 1 equivalent), THF (1 mL, 0.2 M) and NMP (1 mL, 0.2 M) were added and then cooled to 0 ° C. t-BuMgCl (560 μL, 2.5 eq, 1M THF) was added slowly and after stirring for 5 min, the phenolate C-1a (207 mg, 0.46 mmol, 2 eq. dissolved in 500 μL of THF) was added. Added. The reaction mixture was warmed to 50 ° C. The reaction was monitored by LCMS. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by HPLC to give compound C-1.
¹ H NMR (400 MHz, CDCl ₃ ) d7.87 (s, 1H), 7.24-7.10 (m, 4H), 7.03 (t, J = 7.2 Hz, 1H), 6.81 ( d, J = 4.6 Hz, 1H), 6.52 (d, J = 4.7 Hz, 1H), 5.61 (s, 2H), 4.46 (dd, J = 24.0, 11.4 Hz) 2H), 4.33-4.14 (m, 2H), 4.06 (dt, J = 7.2, 4.2 Hz, 2H), 3.82-3.70 (m, 1H), 3 .63 (t, J = 10.6 Hz, 2H), 1.98 (s, 1H), 1.17 (dd, J = 14.8, 7.6 Hz, 3H), 0.82 (dd, J = 22.8, 6.8 Hz, 6H).
³¹ P NMR (162 MHz, CDCl ₃ ): d5.11.
¹⁹ F NMR (376 MHz, CDCl ₃ ): d-152.28.
LCMS m / z 591.21 [M + H ^<+ >].

化合物Ｃ−１ａに例示したものに類似した方法だが、メチオニンエステルを使用して化合物Ｃ−２ａを得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ８．１９（ｓ、２Ｈ）、７．４４−７．０３（ｍ、７Ｈ）、４．１１（ｓ、２Ｈ）、３．８１（ｄ、Ｊ＝４４．５Ｈｚ、１Ｈ）、２．０４（ｓ、３Ｈ）、１．６１（ｓ、２Ｈ）、１．２１（ｄ、Ｊ＝６．１Ｈｚ、２Ｈ）、１．０１−０．６５（ｍ、４Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ−２．００（ｄ、Ｊ＝１２．９Ｈｚ）。ＬＣＭＳ ｍ／ｚ４５５．０３［Ｍ＋Ｈ^＋］。

A method similar to that illustrated for compound C-1a but using compound methionine to give compound C-2a.
¹ H NMR (400 MHz, CDCl ₃ ) d8.19 (s, 2H), 7.44-7.03 (m, 7H), 4.11 (s, 2H), 3.81 (d, J = 44. 5 Hz, 1 H), 2.04 (s, 3 H), 1.61 (s, 2 H), 1.21 (d, J = 6.1 Hz, 2 H), 1.01-0.65 (m, 4 H) .
³¹ P NMR (162 MHz, CDCl ₃ ) d-2.00 (d, J = 12.9 Hz). LCMS m / z 455.03 [M + H ^<+ >].

化合物Ｃ−１に例示したものに類似した方法により、化合物３およびＣ−２ａを使用して化合物Ｃ−２を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ７．９６（ｄ、Ｊ＝１５．８Ｈｚ、１Ｈ）、７．４０−７．０６（ｍ、１３Ｈ）、６．９３（ｄ、Ｊ＝６．７Ｈｚ、１Ｈ）、６．７０（ｓ、１Ｈ）、５．９８（ｓ、１Ｈ）、４．５４（ｄｄ、Ｊ＝２１．６、１１．７Ｈｚ、２Ｈ）、４．３２（ｄ、Ｊ＝１２．０Ｈｚ、２Ｈ）、４．１４（ｄｔ、Ｊ＝１３．０、６．４Ｈｚ、４Ｈ）、２．４４（ｄ、Ｊ＝７．５Ｈｚ、２Ｈ）、２．００（ｄ、Ｊ＝１６．２Ｈｚ、５Ｈ）、１．８９（ｓ、２Ｈ）、１．３５−１．１３（ｍ、７Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ４．１２、３．５８。
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）ｄ−１５２．２８（ｓ）。
ＬＣＭＳ ｍ／ｚ６２３．２７［Ｍ＋Ｈ^＋］。 Compound C-2

Compound C-2 was obtained using methods 3 and C-2a in a manner similar to that illustrated for compound C-1.
¹ H NMR (400 MHz, CDCl ₃ ) d7.96 (d, J = 15.8 Hz, 1H), 7.40-7.06 (m, 13H), 6.93 (d, J = 6.7 Hz, 1H ), 6.70 (s, 1H), 5.98 (s, 1H), 4.54 (dd, J = 21.6, 11.7 Hz, 2H), 4.32 (d, J = 12.0 Hz) 2H), 4.14 (dt, J = 13.0, 6.4 Hz, 4H), 2.44 (d, J = 7.5 Hz, 2H), 2.00 (d, J = 16.2 Hz, 5H), 1.89 (s, 2H), 1.35-1.13 (m, 7H).
_{^{31 P NMR (162MHz, CDCl 3}} ) d4.12,3.58.
¹⁹ F NMR (376 MHz, CDCl ₃ ) d-152.28 (s).
LCMS m / z 623.27 [M + H ^<+ >].

化合物Ｃ−１ａに例示したものに類似した方法だが、トリプトファンエステルを使用して化合物Ｃ−３ａを得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ８．１８−８．０３（ｍ、３Ｈ）、７．２９−７．０８（ｍ、８Ｈ）、７．３６−６．９８（ｍ、３Ｈ）、４．４１−４．１１（ｍ、１Ｈ）、４．１５−３．９５（ｍ ２Ｈ）、３．６８−３．８０（ｍ、１Ｈ）、３．３３−３．０４（ｍ、２Ｈ）、１．０６−１．１７（ｍ、３Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ−２．８７、−２．９９。
ＬＣＭＳ ｍ／ｚ５１０．０３［Ｍ＋Ｈ^＋］。

A method similar to that illustrated for Compound C-1a but using tryptophan ester gave Compound C-3a.
¹ H NMR (400 MHz, CDCl ₃ ) d8.18-8.03 (m, 3H), 7.29-7.08 (m, 8H), 7.36-6.98 (m, 3H), 4. 41-4.11 (m, 1H), 4.15-3.95 (m 2H), 3.68-3.80 (m, 1H), 3.33-3.04 (m, 2H), 1 .06-1.17 (m, 3H).
³¹ P NMR (162 MHz, CDCl ₃ ) d-2.87, -2.99.
LCMS m / z 510.03 [M + H ^<+ >].

化合物Ｃ−１に例示したものに類似した方法により、化合物３およびＣ−３ａを使用して化合物Ｃ−３を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ８．２７（ｓ、１Ｈ）、７．８４（ｓ、１Ｈ）、７．４７（ｓ、１Ｈ）、７．３６−６．７７（ｍ、１１Ｈ）、６．５７（ｓ、１Ｈ）、４．４０−３．９６（ｍ、６Ｈ）、３．２０（ｓ、４Ｈ）、２．６０（ｓ、１Ｈ）、１．３０−１．０４（ｍ、６Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ４．０２、３．７５
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）ｄ−１５２．１３。
ＬＣＭＳ ｍ／ｚ６７８．３２［Ｍ＋Ｈ^＋］。 Compound C-3

Compound C-3 was obtained using a method similar to that illustrated for Compound C-1 using Compound 3 and C-3a.
¹ H NMR (400 MHz, CDCl ₃ ) d8.27 (s, 1H), 7.84 (s, 1H), 7.47 (s, 1H), 7.36-6.77 (m, 11H), 6 .57 (s, 1H), 4.40-3.96 (m, 6H), 3.20 (s, 4H), 2.60 (s, 1H), 1.30-1.04 (m, 6H) ).
³¹ P NMR (162 MHz, CDCl ₃ ) d4.02, 3.75
¹⁹ F NMR (376 MHz, CDCl ₃ ) d-152.13.
LCMS m / z 678.32 [M + H ^<+ >].

化合物Ｃ−１ａに例示したものに類似した方法により、フェニルアラニンエステルを置換することにより化合物Ｃ−４ａを得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ８．１５（ｔ、Ｊ＝８．７Ｈｚ、２Ｈ）、７．４３−７．１１（ｍ、１０Ｈ）、７．０４（ｄｄｄ、Ｊ＝１１．４、６．７、２．９Ｈｚ、２Ｈ）、４．３２（ｄｄｄ、Ｊ＝１５．３、１１．３、６．１Ｈｚ、４Ｈ）、４．１５−３．９９（ｍ、７Ｈ）、３．７４（ｔｄ、Ｊ＝１１．０、５．０Ｈｚ、８Ｈ）、３．０１（ｄ、Ｊ＝５．７Ｈｚ、２Ｈ）、１．１７（ｔｄ、Ｊ＝７．１、５．２Ｈｚ、２Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ−２．９７、−２．９９。
ＬＣＭＳ ｍ／ｚ４７１．０３［Ｍ＋Ｈ^＋］。

Compound C-4a was obtained by substituting phenylalanine ester by a method similar to that exemplified for compound C-1a.
¹ H NMR (400 MHz, CDCl ₃ ) d8.15 (t, J = 8.7 Hz, 2H), 7.43-7.11 (m, 10H), 7.04 (ddd, J = 11.4, 6 .7, 2.9 Hz, 2H), 4.32 (ddd, J = 15.3, 11.3, 6.1 Hz, 4H), 4.15-3.99 (m, 7H), 3.74 ( td, J = 11.0, 5.0 Hz, 8H), 3.01 (d, J = 5.7 Hz, 2H), 1.17 (td, J = 7.1, 5.2 Hz, 2H).
³¹ P NMR (162 MHz, CDCl ₃ ) d-2.97, -2.99.
LCMS m / z 471.03 [M + H ^<+ >].

化合物Ｃ−１に例示したものに類似した方法により、化合物３およびＣ−４ａを使用して化合物Ｃ−４を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ７．９２（ｄ、Ｊ＝１３．２Ｈｚ、１Ｈ）、７．４６−６．９７（ｍ、１７Ｈ）、６．９１（ｓ、１Ｈ）、６．７５（ｓ、１Ｈ）、４．１０（ｄｄ、Ｊ＝２９．６、１９．２Ｈｚ、８Ｈ）、２．９７（ｓ、３Ｈ）、１．３２−１．０５（ｍ、７Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ５．１１。
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）ｄ−１５２．３４（ｓ）。
ＬＣＭＳ ｍ／ｚ６３９．２４［Ｍ＋Ｈ^＋］。 Compound C-4

Compound C-4 was obtained using a method similar to that illustrated for compound C-1 using compound 3 and C-4a.
¹ H NMR (400 MHz, CDCl ₃ ) d7.92 (d, J = 13.2 Hz, 1H), 7.46-6.97 (m, 17H), 6.91 (s, 1H), 6.75 ( s, 1H), 4.10 (dd, J = 29.6, 19.2 Hz, 8H), 2.97 (s, 3H), 1.32-1.05 (m, 7H).
³¹ P NMR (162 MHz, CDCl ₃ ) d 5.11.
¹⁹ F NMR (376 MHz, CDCl ₃ ) d-152.34 (s).
LCMS m / z 639.24 [M + H ^<+ >].

化合物Ｃ−１ａに例示したものに類似した方法だが、プロリンエステルを使用して化合物Ｃ−５ａを得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ８．２０（ｄ、Ｊ＝７．８Ｈｚ、２Ｈ）、７．４５−７．０８（ｍ、７Ｈ）、４．３７（ｔｄ、Ｊ＝８．０、３．８Ｈｚ、２Ｈ）、４．１７−３．９８（ｍ、２Ｈ）、３．６１−３．３４（ｍ、２Ｈ）、２．２１−１．７７（ｍ、３Ｈ）、１．１９（ｔｄ、Ｊ＝７．１、３．８Ｈｚ、３Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ−３．９２、−３．９６。
ＬＣＭＳ ｍ／ｚ４２０．９８［Ｍ＋Ｈ^＋］。

A method similar to that illustrated for compound C-1a but using proline ester gave compound C-5a.
¹ H NMR (400 MHz, CDCl ₃ ) d8.20 (d, J = 7.8 Hz, 2H), 7.45-7.08 (m, 7H), 4.37 (td, J = 8.0, 3 .8 Hz, 2H), 4.17-3.98 (m, 2H), 3.61-3.34 (m, 2H), 2.21-1.77 (m, 3H), 1.19 (td J = 7.1, 3.8 Hz, 3H).
³¹ P NMR (162 MHz, CDCl ₃ ) d-3.92, -3.96.
LCMS m / z 420.98 [M + H ^<+ >].

化合物Ｃ−１に例示したものに類似した方法により、化合物３およびＣ−５ａを使用して化合物Ｃ−５を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ７．９５（ｄ、Ｊ＝４．５Ｈｚ、１Ｈ）、７．３９−７．１０（ｍ、４Ｈ）、６．９２（ｄｄ、Ｊ＝１６．０、４．６Ｈｚ、１Ｈ）、６．６９（ｓ、１Ｈ）、６．０３（ｂｓ、２Ｈ）、４．４６−４．３６（ｍ、１Ｈ）、４．３６−３．９６（ｍ、４Ｈ）、３．３７（ｄ、Ｊ＝５８．９Ｈｚ、２Ｈ）、２．２６−１．６６（ｍ、４Ｈ）、１．３９−１．１２（ｍ、８Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ３．４７、２．７５。
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）ｄ−１５２．３６。
ＬＣＭＳ ｍ／ｚ５８９．１４［Ｍ＋Ｈ^＋］。 Compound C-5

Compound C-5 was obtained using a method similar to that illustrated for Compound C-1 using Compound 3 and C-5a.
¹ H NMR (400 MHz, CDCl ₃ ) d7.95 (d, J = 4.5 Hz, 1H), 7.39-7.10 (m, 4H), 6.92 (dd, J = 16.0, 4 .6 Hz, 1H), 6.69 (s, 1H), 6.03 (bs, 2H), 4.46-4.36 (m, 1H), 4.36-3.96 (m, 4H), 3.37 (d, J = 58.9 Hz, 2H), 2.26 to 1.66 (m, 4H), 1.39-1.12 (m, 8H).
³¹ P NMR (162 MHz, CDCl ₃ ) d3.47, 2.75.
¹⁹ F NMR (376 MHz, CDCl ₃ ) d-152.36.
LCMS m / z 589.14 [M + H ^<+ >].

化合物Ｃ−１に例示したものに類似した方法により、化合物３およびＣ−１ａのスルホン類似体を使用して化合物Ｃ−６を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ７．９３（ｓ、１Ｈ）、７．８９（ｓ、１Ｈ）、７．３５−７．０１（ｍ、５Ｈ）、６．９３（ｄ、Ｊ＝２．８Ｈｚ、１Ｈ）、６．５８（ｄ、Ｊ＝２．８Ｈｚ、１Ｈ）、５．７９（ｂｓ、２Ｈ）、４．３０（ｓ、６Ｈ）、４．１１（ｄ、Ｊ＝７．０Ｈｚ、６Ｈ）、３．１０−２．８４（ｍ、３Ｈ）、２．７５（ｓ、３Ｈ）、２．５４（ｓ、６Ｈ）、１．３１−１．１５（ｍ、６Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ３．３９、３．３３。
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）ｄ−１５２．４０
ＬＣＭＳ ｍ／ｚ６５５．２４［Ｍ＋Ｈ^＋］。

Compound C-6 was obtained by a method similar to that illustrated for Compound C-1 using Compound 3 and the sulfone analog of C-1a.
¹ H NMR (400 MHz, CDCl ₃ ) d7.93 (s, 1H), 7.89 (s, 1H), 7.35-7.01 (m, 5H), 6.93 (d, J = 2. 8 Hz, 1 H), 6.58 (d, J = 2.8 Hz, 1 H), 5.79 (bs, 2 H), 4.30 (s, 6 H), 4.11 (d, J = 7.0 Hz, 6H), 3.10-2.84 (m, 3H), 2.75 (s, 3H), 2.54 (s, 6H), 1.31-1.15 (m, 6H).
³¹ P NMR (162 MHz, CDCl ₃ ) d3.39, 3.33.
¹⁹ F NMR (376 MHz, CDCl ₃ ) d-152.40
LCMS m / z 655.24 [M + H ^<+ >].

化合物８（２００ｍｇ、０．７１ｍｍｏｌ）のＴＨＦ溶液（１ｍＬ）およびＮＭＰ（１ｍＬ）にｔｅｒｔ−ブチルマグネシウムクロライド（１．０ＭのＴＨＦ溶液、１．０６ｍＬ、１．０６ｍｍｏｌ）をアルゴン雰囲気下で０℃で添加した。１５分後、化合物３０ｄ−１（２８０ｍｇ、０．７１ｍｍｏｌ）をＴＨＦ溶液として添加した。５分後、反応混合物を室温に加温し、２時間撹拌した。反応混合物を０℃に冷却して、ＭｅＯＨでクエンチして、濃縮した。反応物をシリカゲルクロマトグラフィー、次いでＲＰ ＨＰＬＣにより精製し、ＰＤ−Ａ−８ｂ（２２５ｍｇ、５９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：ｄ８．０９（２ｓ、１Ｈ）、７．５４（２ｓ、１Ｈ）、７．３１−７．１２（ｍ、５Ｈ）、５．６６（ｄｄ、１Ｈ）、４．５２−４．４５（ｍ、２Ｈ）、４．１９−４．０３（ｍ、４Ｈ）、３．８７−３．６９（ｍ、１Ｈ）、１．３５−１．１５（ｍ、９Ｈ）。
^３１Ｐ ＮＭＲ（１６１ＭＨｚ、ＣＤＣｌ_３）：ｄ４．１４（ｓ）、３．５５（ｓ）。
ＬＣ／ＭＳ＝５３９（Ｍ＋Ｈ^＋）。
保持時間：１．９４分間
ＬＣ：Ｔｈｅｒｍｏ Ｅｌｅｃｔｒｏｎ Ｓｕｒｖｅｙｏｒ ＨＰＬＣ
ＭＳ：Ｆｉｎｎｉｇａｎ ＬＣＱ Ａｄｖａｎｔａｇｅ ＭＡＸ質量分析計
カラム：Ｐｈｅｎｏｍｅｎｅｘ社製Ｐｏｌａｒ ＲＰ ３０ｍｍ×４．６ｍｍ
溶媒：０．１％ギ酸−アセトニトリル溶液、０．１％ギ酸−水
勾配：０分間〜０．１分間５％ＡＣＮ、０．１分間〜１．９５分間５％〜１００％ＡＣＮ、１．９５分間〜３．５分間１００％ＡＣＮ、３．５分間〜３．５５分間１００％〜５％ＡＣＮ、３．５５分間〜４分間５％ＡＣＮ。 Compound PD-A-8b

Compound 8 (200 mg, 0.71 mmol) in THF (1 mL) and NMP (1 mL) were added tert-butylmagnesium chloride (1.0 M THF solution, 1.06 mL, 1.06 mmol) at 0 ° C. under an argon atmosphere. Added. After 15 minutes, compound 30d-1 (280 mg, 0.71 mmol) was added as a THF solution. After 5 minutes, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ° C., quenched with MeOH and concentrated. The reaction was purified by silica gel chromatography followed by RP HPLC to give PD-A-8b (225 mg, 59%). ¹ H NMR (400 MHz, CDCl ₃ ): d8.09 (2s, 1H), 7.54 (2s, 1H), 7.31-7.12 (m, 5H), 5.66 (dd, 1H), 4.52-4.45 (m, 2H), 4.19-4.03 (m, 4H), 3.87-3.69 (m, 1H), 1.35-1.15 (m, 9H) ).
³¹ P NMR (161 MHz, CDCl ₃ ): d4.14 (s), 3.55 (s).
LC / MS = 539 (M + H ^< + ^> ).
Retention time: 1.94 minutes LC: Thermo Electron Surveyor HPLC
MS: Finnigan LCQ Advantage MAX mass spectrometer Column: Polar RP 30 mm × 4.6 mm manufactured by Phenomenex
Solvent: 0.1% formic acid-acetonitrile solution, 0.1% formic acid-water gradient: 5% ACN for 0 min to 0.1 min, 5% to 100% ACN for 0.1 min to 1.95 min, 1.95 Minute to 3.5 minutes 100% ACN, 3.5 minutes to 3.55 minutes 100% to 5% ACN, 3.55 minutes to 4 minutes 5% ACN.

３０ｄ−２に類似した形でアラニンエチルエステル塩酸塩をアラニンイソプロピルエステル塩酸塩に代えて、化合物３０ｄ−１を３０ａから調製した。 Preparation of 30d-1

Compound 30d-1 was prepared from 30a substituting alanine ethyl ester hydrochloride for alanine isopropyl ester hydrochloride in a manner similar to 30d-2.

ＰＤ−Ａ−８ｂに類似した形で（Ｓ）−３０ｄ−２を３０ｄ−１に代えて化合物（Ｓ）−ＰＤ−Ａ−８ｃを調製した。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：ｄ８．１４（ｓ、１Ｈ）、７．６０（ｓ、１Ｈ）、７．１−７．３（ｍ、５Ｈ）、５．６６（ｄｄ、１Ｈ）、５．０２（ｍ、１Ｈ）、４．５０（ｍ、１Ｈ）、４．４０（ｍ、１Ｈ）、４．１−４．３（ｍ、２Ｈ）、３．９８（ｍ、１Ｈ）、３．７８（ｍ、１Ｈ）、３．１８（ｂｒｓ、１Ｈ）、１．１５−１．４（ｍ、１２Ｈ）。^３１Ｐ ＮＭＲ（１６１ＭＨｚ、ＣＤＣｌ_３）：ｄ３．７０（ｓ）。
ＬＣ／ＭＳ＝５５３（Ｍ＋Ｈ^＋）。 Compound (S) -PD-A-8c

Compound (S) -PD-A-8c was prepared by replacing (S) -30d-2 with 30d-1 in a similar manner to PD-A-8b. ¹ H NMR (400 MHz, CDCl ₃ ): d8.14 (s, 1H), 7.60 (s, 1H), 7.1-7.3 (m, 5H), 5.66 (dd, 1H), 5.02 (m, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.1-4.3 (m, 2H), 3.98 (m, 1H), 3 .78 (m, 1H), 3.18 (brs, 1H), 1.15-1.4 (m, 12H). ³¹ P NMR (161 MHz, CDCl ₃ ): d3.70 (s).
LC / MS = 553 (M + H ^< + ^> ).

アラニンイソプロピルエステル塩酸塩（７．９５ｇ、４７．４ｍｍｏｌ）をジクロロメタン（１００ｍＬ）に懸濁した。化合物３１ａ（１０ｇ、４７．４ｍｍｏｌ）を添加した。次いでトリエチルアミン（１３．２ｍＬ、９５ｍｍｏｌ）を１５分間滴下した（内部反応温度；−１０℃〜−３℃）。反応が（リンＮＭＲにより）ほぼ完了時、ｐ−ニトロフェノール（６．２９ｇ、４５．０ｍｍｏｌ）を固体部分として添加した。生成スラリーにトリエチルアミン（６．２８ｍＬ、４５ｍｍｏｌ）を１５分間添加した。次いで混合物を室温まで加温した。反応完了時、ＭＴＢＥ（１００ｍＬ）を添加した。白色沈殿物を濾過により除去した。濾過ケーキをＭＴＢＥ（３×５０ｍＬ）で洗浄した。ろ液および洗浄物を併合して、濃縮した。残渣をシリカゲルカラムクロマトグラフィーにより精製し（０〜５０％酢酸エチル／ヘキサン）、ジアステレオマー混合物１：１比として化合物３０ｄ−２（１４．１ｇ、７７％）を得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）：δ８．２２（２ｄ、２Ｈ）、７．２−７．４（ｍ、７Ｈ）、５．０（ｍ、１Ｈ）、４．０９（ｍ、１Ｈ）、３．９６（ｍ、１Ｈ）、１．３９（２ｄ、３Ｈ）、１．２２（ｍ、６Ｈ）．ＭＳ＝４０９．０（Ｍ＋Ｈ^＋）、４０７．２（Ｍ−Ｈ^＋）。 Preparation of (S) -30d-2

Alanine isopropyl ester hydrochloride (7.95 g, 47.4 mmol) was suspended in dichloromethane (100 mL). Compound 31a (10 g, 47.4 mmol) was added. Then, triethylamine (13.2 mL, 95 mmol) was added dropwise for 15 minutes (internal reaction temperature; −10 ° C. to −3 ° C.). When the reaction was nearly complete (by phosphorus NMR), p-nitrophenol (6.29 g, 45.0 mmol) was added as a solid portion. Triethylamine (6.28 mL, 45 mmol) was added to the resulting slurry for 15 minutes. The mixture was then warmed to room temperature. When the reaction was complete, MTBE (100 mL) was added. The white precipitate was removed by filtration. The filter cake was washed with MTBE (3 × 50 mL). The filtrate and washings were combined and concentrated. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to give compound 30d-2 (14.1 g, 77%) as a 1: 1 ratio of diastereomeric mixture.
¹ H NMR (300 MHz, CDCl ₃ ): δ 8.22 (2d, 2H), 7.2-7.4 (m, 7H), 5.0 (m, 1H), 4.09 (m, 1H), 3.96 (m, 1H), 1.39 (2d, 3H), 1.22 (m, 6H). MS = 409.0 (M + H ^< + ^> ), 407.2 (M-H ^<+> ).

２つのジアステレオマーを以下の条件下でキラルカラムクロマトグラフィーにより分離した；
カラム：キラルパックＩＣ、２×２５ｃｍ
溶媒系：７０％ヘプタンおよび３０％イソプロパノール（ＩＰＡ）
流速：６ｍＬ／分。
流速負荷容量：１．０ｍＬ
負荷試料の濃度：７０％ヘプタンおよび３０％ＩＰＡ中１５０ｍｇ／ｍＬ
（Ｓ）−化合物３０ｄ−２：保持時間４３分間。^３１Ｐ ＮＭＲ（１６２．１ＭＨｚ、ＣＤＣｌ_３）：δ−２．９９（ｓ）。
（Ｒ）−化合物３０ｄ−２：保持時間６２分間。^３１Ｐ ＮＭＲ（１６２．１ＭＨｚ、ＣＤＣｌ_３）：δ−３．０２（ｓ）。 Separation of two diastereomers of compound 30d-2

The two diastereomers were separated by chiral column chromatography under the following conditions;
Column: Chiral Pack IC, 2 × 25cm
Solvent system: 70% heptane and 30% isopropanol (IPA)
Flow rate: 6 mL / min.
Flow rate load capacity: 1.0 mL
Load sample concentration: 150 mg / mL in 70% heptane and 30% IPA
(S) -Compound 30d-2: Retention time 43 minutes. ³¹ P NMR (162.1 MHz, CDCl ₃ ): δ-2.99 (s).
(R) -Compound 30d-2: Retention time 62 minutes. _{^{31 P NMR (162.1MHz, CDCl 3}} ): δ-3.02 (s).

  Alternatively, the two diastereomers were separated by crystallization according to the following method;

  Compound 30d-2 was dissolved in diethyl ether (-10 mL / gram). Hexane was then added with stirring until the solution became cloudy. Seed crystals (-10 mg / gram compound 30d-2) were added to promote crystallization. The resulting suspension was gently stirred for 16 hours, cooled to ˜0 ° C., stirred for an additional 2 hours and filtered to recover the crystalline material (35% -35% yield of crystalline material). The crystalline material includes ˜95% (S) -compound 30d-2 and ˜5% (R) -compound 30d-2. Recrystallization gave 99% of the diastereomerically pure (S) isomer.

、および

As an example, the following PD-A compound is made by a general method.

,and

General method for preparing nucleoside prodrugs (Method D):
Non-limiting examples of 3′-O-acyclic monophosphoroamidic acid prodrugs comprising the invention can be prepared according to General Scheme 2.

一般的方法は、ＰＤ−Ａ（Ｒ^４＝ＯＨ）とカルボン酸または活性化したカルボキシレート（アシルクロライドまたは無水酸など）との反応を含み、これは一般に当業者に知られている（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，２００６，４９，６６１４ ａｎｄ Ｏｒｇａｎｉｃ Ｌｅｔｔｅｒｓ，２００３，６，８０７）。Ｒ^８＝ＮＨ_２の場合、アミノ基の保護が必要となり得る。簡単に述べると、化合物ＰＤ−Ａのアセトニトリル溶液（２ｍＬ）にＮ，Ｎ−ジメチルホルムアミドジメチルアセタル（〜１．１当量）を添加して、室温で１時間撹拌する。６−アミノ基の保護完了後、混合物を濃縮して乾燥させる。残渣にＤＣＣ（〜４当量）などの脱水剤、アセトニトリルおよびカルボン酸（〜２当量）を添加する。混合物を室温で２４〜４８時間撹拌する。水（０．２ｍＬ）およびトリフルオロ酢酸（０．１ｍＬ）を０℃で添加して、室温で６４時間撹拌する。重炭酸ナトリウムを０℃で添加する。混合物を室温で半時間撹拌して、濾過する。ろ液を濃縮して、残渣をシリカゲルカラムクロマトグラフィーにより精製し、化合物ＰＤ−Ｂを得る。アシルクロライドまたは無水酸を使用する場合、適切な塩基（トリエチルアミンなど）を脱水剤の代わりに添加する。 Scheme 2

The general method involves the reaction of PD-A (R ⁴ ═OH) with a carboxylic acid or activated carboxylate (such as an acyl chloride or anhydride), which is generally known to those skilled in the art (Journal of Medicinal Chemistry, 2006, 49, 6614 and Organic Letters, 2003, 6, 807). When R ⁸ = NH ₂ , protection of the amino group may be necessary. Briefly, N, N-dimethylformamide dimethylacetal (˜1.1 eq) is added to a solution of compound PD-A in acetonitrile (2 mL) and stirred at room temperature for 1 hour. After protection of the 6-amino group is complete, the mixture is concentrated to dryness. To the residue is added a dehydrating agent such as DCC (~ 4 eq), acetonitrile and carboxylic acid (~ 2 eq). The mixture is stirred at room temperature for 24-48 hours. Add water (0.2 mL) and trifluoroacetic acid (0.1 mL) at 0 ° C. and stir at room temperature for 64 hours. Sodium bicarbonate is added at 0 ° C. The mixture is stirred for half an hour at room temperature and filtered. The filtrate is concentrated and the residue is purified by silica gel column chromatography to give compound PD-B. If an acyl chloride or anhydride is used, a suitable base (such as triethylamine) is added instead of the dehydrating agent.

ＰＤ−Ａ−８ｂ（１００ｍｇ、０．１９ｍｍｏｌ）のＤＣＭ溶液（１．０ｍＬ）にＮ，Ｎ−ジメチルホルムアミド−ジメチルアセタル（２５μＬ、０．１９ｍｍｏｌ）をアルゴン雰囲気下で室温で添加した。３０分後、反応混合物を濃縮した。反応物をＤＣＭ中で取り上げ、濃縮した。このプロセスを２回反復した。生成した残渣をＴＨＦ（１．０ｍＬ）中で取り上げ、アルゴン雰囲気下で０℃に冷却した。溶液にトリエチルアミン（７９μＬ、０．５７ｍｍｏｌ）およびＤＭＡＰ（５ｍｇ、０．０４ｍｍｏｌ）を添加した。５分後、塩化イソブチリル（６０μＬ、０．５７ｍｍｏｌ）を添加した。１０分後、反応物を室温に加温し、３時間撹拌した。混合物を０℃に冷却して、５％ＴＦＡ水溶液でクエンチしてから、室温で４時間撹拌した。反応混合物を酢酸エチルで抽出した（３回）。併合有機層を硫酸ナトリウムで乾燥させて、濾過し、濃縮した。残渣をＲＰ ＨＰＬＣにより精製し（アセトニトリル／水）、ＰＤ−Ｂ−８ｉ（７１ｍｇ、６１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：ｄ８．１７（２ｓ、１Ｈ）、７．６６（２ｓ、１Ｈ）、７．３４−７．１４（ｍ、５Ｈ）、５．６９（ｄｄ、１Ｈ）、５．５６−５．４３（ｍ、１Ｈ）、４．５５−４．０１（ｍ、５Ｈ）、３．７９−３．６９（ｍ、１Ｈ）、２．７０−２．６４（ｍ、１Ｈ）、１．３７−１．１７（ｍ、１５Ｈ）。^３１Ｐ ＮＭＲ（１６１ＭＨｚ、ＣＤＣｌ_３）：ｄ２．９９（ｓ）、２．８８（ｓ）。
ＬＣ／ＭＳ＝６０９（Ｍ＋Ｈ^＋）。
保持時間：２．２１分間
ＬＣ：Ｔｈｅｒｍｏ Ｅｌｅｃｔｒｏｎ Ｓｕｒｖｅｙｏｒ ＨＰＬＣ
ＭＳ：Ｆｉｎｎｉｇａｎ ＬＣＱ Ａｄｖａｎｔａｇｅ ＭＡＸ質量分析計
カラム：Ｐｈｅｎｏｍｅｎｅｘ社製Ｐｏｌａｒ ＲＰ ３０ｍｍ×４．６ｍｍ
溶媒：０．１％ギ酸−アセトニトリル溶液、０．１％ギ酸−水
勾配：０分間〜０．１分間５％ＡＣＮ、０．１分間〜１．９５分間５％〜１００％ＡＣＮ、１．９５分間〜３．５分間１００％ＡＣＮ、３．５分間〜３．５５分間１００％〜５％ＡＣＮ、３．５５分間〜４分間５％ＡＣＮ。 Compound PD-B-8i

N, N-dimethylformamide-dimethylacetal (25 μL, 0.19 mmol) was added to a solution (1.0 mL) of PD-A-8b (100 mg, 0.19 mmol) in DCM at room temperature under an argon atmosphere. After 30 minutes, the reaction mixture was concentrated. The reaction was taken up in DCM and concentrated. This process was repeated twice. The resulting residue was taken up in THF (1.0 mL) and cooled to 0 ° C. under an argon atmosphere. To the solution was added triethylamine (79 μL, 0.57 mmol) and DMAP (5 mg, 0.04 mmol). After 5 minutes, isobutyryl chloride (60 μL, 0.57 mmol) was added. After 10 minutes, the reaction was warmed to room temperature and stirred for 3 hours. The mixture was cooled to 0 ° C. and quenched with 5% aqueous TFA and then stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate (3 times). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by RP HPLC (acetonitrile / water) to give PD-B-8i (71 mg, 61%). ¹ H NMR (400 MHz, CDCl ₃ ): d8.17 (2s, 1H), 7.66 (2s, 1H), 7.34-7.14 (m, 5H), 5.69 (dd, 1H), 5.56-5.43 (m, 1H), 4.55-4.01 (m, 5H), 3.79-3.69 (m, 1H), 2.70-2.64 (m, 1H) ), 1.37-1.17 (m, 15H). _{^{31 P NMR (161MHz, CDCl 3}} ): d2.99 (s), 2.88 (s).
LC / MS = 609 (M + H ^< + ^> ).
Retention time: 2.21 minutes LC: Thermo Electron Surveyor HPLC
MS: Finnigan LCQ Advantage MAX mass spectrometer Column: Polar RP 30 mm × 4.6 mm manufactured by Phenomenex
Solvent: 0.1% formic acid-acetonitrile solution, 0.1% formic acid-water gradient: 5% ACN for 0 min to 0.1 min, 5% to 100% ACN for 0.1 min to 1.95 min, 1.95 Minute to 3.5 minutes 100% ACN, 3.5 minutes to 3.55 minutes 100% to 5% ACN, 3.55 minutes to 4 minutes 5% ACN.

、および

As an example, the following PD-B compound is prepared by a general method.

,and

General method for preparing nucleoside prodrugs (Method E):
Non-limiting examples of 3 ′, 5′-cyclic monophosphoramidic acid prodrugs comprising the present invention can be prepared according to general scheme 3.

スキーム３は、化合物ＰＤ−Ｃの調製に有用であり得る化学プロセスを例証する。したがって、Ａｒが電子求引基（ｐ−ニトロまたはｐ−クロロ基など）に置換されている場合に、塩基の存在下でＰＤ−Ａ１をＰＤ−Ｃに変換する（Ｅｕｒｏｐｅａｎ Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，２００９，４４，３７６９）。あるいは、Ｂｉｏｏｒｇａｎｉｃ ａｎｄ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ，２００７，１７，２４５２に従って化合物４０を化合物４１へ変換し、これを、次いでアミノ酸エステル塩と結合させて、ＰＤ−Ｃを形成する。 Scheme 3

Scheme 3 illustrates a chemical process that may be useful for the preparation of compound PD-C. Thus, when Ar is substituted with an electron withdrawing group (such as p-nitro or p-chloro group), PD-A1 is converted to PD-C in the presence of a base (European Journal of Medicinal Chemistry, 2009). , 44, 3769). Alternatively, compound 40 is converted to compound 41 according to Bioorganic and Medicinal Chemistry Letters, 2007, 17, 2452, which is then coupled with an amino acid ester salt to form PD-C.

ＰＤ−Ａ−８ｐのＤＭＳＯ溶液を室温でカリウムｔ−ブトキシド（〜１当量）を用いて処理し、反応混合物を約１０分間〜約２時間撹拌する。次いで混合物を０℃に冷却して、１Ｎ ＨＣｌを用いて、〜ｐＨ６に中性化する。混合物をＨＰＬＣにより精製し、化合物ＰＤ−Ｃ−８ｑを得る。 Compound PD-C-8q

A solution of PD-A-8p in DMSO is treated with potassium t-butoxide (˜1 eq) at room temperature and the reaction mixture is stirred for about 10 minutes to about 2 hours. The mixture is then cooled to 0 ° C. and neutralized to ˜pH 6 using 1N HCl. The mixture is purified by HPLC to give compound PD-C-8q.

化合物ＰＤ−Ｃ−８ｓ

化合物ＰＤ−Ｃ−８ｔ

Additionally, by way of example, the following PD-C compound is made by a general method.
Compound PD-C-8r

Compound PD-C-8s

Compound PD-C-8t

化合物８をＰＯ（ＯＭｅ）_３（０．１〜０．５Ｍ溶液）に溶解させて、アルゴン下で０℃に冷却する。この撹拌溶液にＰＯＣｌ_３（１．０〜５．０当量）を滴下して、反応混合物を室温に約２〜１６時間加温する。生成した溶液をアセトニトリルおよび０．０５〜０．５Ｍ ＫＯＨの急速に撹拌した水溶液に滴下する。添加完了時、溶媒を減圧除去する。生成した残渣を水に溶解させ、ＨＰＬＣにより精製し、化合物４１−１を得る。 Compound PD-D-8u

Compound 8 is dissolved in PO (OMe) ₃ (0.1-0.5 M solution) and cooled to 0 ° C. under argon. To this stirred solution, POCl ₃ (1.0-5.0 eq) is added dropwise and the reaction mixture is allowed to warm to room temperature for about 2-16 hours. The resulting solution is added dropwise to a rapidly stirred aqueous solution of acetonitrile and 0.05-0.5 M KOH. When the addition is complete, the solvent is removed under reduced pressure. The resulting residue is dissolved in water and purified by HPLC to give compound 41-1.

化合物４１−１のＤＣＭおよびＰＯ（ＯＭｅ）_３溶液を調製して、０℃に冷却する。この溶液に塩化オキサリル（１．０〜５．０当量）、次いで触媒量のＤＭＦを添加する。混合物を約１０分間〜約ｌ時間撹拌する。活性化が完了時、大量の２−プロパノールを反応混合物に添加して、撹拌し、室温に加温する。溶媒を減圧除去して、生成した粗物質を前段階ＨＰＬＣにより精製し、化合物ＰＤ−Ｄ−８ｕを得る。

Prepare a solution of compound 41-1 in DCM and PO (OMe) ₃ and cool to 0 ° C. To this solution is added oxalyl chloride (1.0-5.0 eq) followed by a catalytic amount of DMF. The mixture is stirred for about 10 minutes to about 1 hour. When activation is complete, a large amount of 2-propanol is added to the reaction mixture, stirred and allowed to warm to room temperature. The solvent is removed in vacuo and the resulting crude material is purified by preparative HPLC to give compound PD-D-8u.

化合物ＰＤ−Ｄ−８ｕに類似した形で２−アミノプロパンを２−プロパノールに代えて化合物ＰＤ−Ｅ−８ｖを化合物４１−１から調製する。 Compound PD-E-8v

Compound PD-E-8v is prepared from compound 41-1, substituting 2-propanol for 2-propanol in a manner similar to compound PD-D-8u.

化合物２０に類似した形で化合物８を化合物１８に代えて化合物ＰＤ−Ｆ−８ｗを調製する。 Compound PD-F-8w

Compound PD-F-8w is prepared by replacing Compound 8 with Compound 18 in a manner similar to Compound 20.

約９０ｍＭ化合物８のＴＨＦ溶液を約−７８℃に冷却して、約２．２〜約５等量のｔ−ブチルマグネシウムクロライド（約１ＭのＴＨＦ溶液）を添加する。混合物を約０℃に約３０分間加温し、再び約−７８℃に冷却する。（２Ｓ）−２−｛［クロロ（ｌ−フェノキシ）ホスホリル］アミノ｝エチルイソ酪酸塩（ＷＯ２００８０８５５０８号）（１ＭのＴＨＦ溶液、約２等量）の溶液を滴下する。冷却をやめ、反応物を約１〜約２４時間撹拌する。反応物を水でクエンチして、混合物を酢酸エチルで抽出する。抽出物を乾燥および蒸発させ、残渣をクロマトグラフィーにより精製し、化合物ＰＤ−Ｇ−８ｘを得る。 Compound PD-G-8x

The THF solution of about 90 mM compound 8 is cooled to about −78 ° C. and about 2.2 to about 5 equivalents of t-butyl magnesium chloride (about 1 M THF solution) is added. The mixture is warmed to about 0 ° C. for about 30 minutes and cooled again to about −78 ° C. A solution of (2S) -2-{[chloro (l-phenoxy) phosphoryl] amino} ethyl isobutyrate (WO20080885508) (1M THF solution, approximately 2 equivalents) is added dropwise. Remove cooling and stir the reaction for about 1 to about 24 hours. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The extract is dried and evaporated and the residue is purified by chromatography to give compound PD-G-8x.

化合物４（約０．０４ｍｍｏｌ）および無水ＭｅＯＨ（約５ｍＬ）を酢酸（約５ｍＬ）で処理して、反応物を室温で一晩撹拌する。飽和ＮａＨＣＯ_３を添加して、反応混合物を中性化し、ＨＰＬＣ系（アセトニトリル−Ｈ_２Ｏ）を使用して粗物質を精製し、６を得る。 Compound 6

Compound 4 (about 0.04 mmol) and anhydrous MeOH (about 5 mL) are treated with acetic acid (about 5 mL) and the reaction is stirred at room temperature overnight. Saturated NaHCO ₃ is added to neutralize the reaction mixture and the crude material is purified using an HPLC system (acetonitrile-H ₂ O) to give 6.

乾燥したアルゴンで置換した丸底フラスコ（５０ｍＬ）に化合物３ｂ（約０．３９ｍｍｏｌ）および無水ジクロロメタン（約１０ｍＬ）を添加する。フラスコを乾燥氷／アセトン浴（〜−７８℃）に入れ、溶液を約１０分間撹拌する。ＢＦ_３−Ｅｔ_２Ｏ（約０．１０ｍＬ）を滴下して、反応物を約１０分間撹拌する。次いで、ＡｌＭｅ_３（約１．１６ｍｍｏｌ、２．０Ｍのトルエン溶液）を添加する。数分後、乾燥氷／アセトン浴を除去して、反応混合物を室温〜約４５℃で約４時間〜約４日間撹拌する。ピリジン（約２ｍＬ）のＭｅＯＨ溶液（約１０ｍＬ）を添加して、溶媒を減圧除去する。粗物質をクロマトグラフィーにより精製し、水酸化アンモニウムのメタノール溶液でほぼ室温で約１６時間処理する。混合物を濃縮して、残渣をＨＰＬＣにより精製し、７を得る。 Compound 7

To a dry argon-substituted round bottom flask (50 mL) is added compound 3b (about 0.39 mmol) and anhydrous dichloromethane (about 10 mL). Place the flask in a dry ice / acetone bath (˜−78 ° C.) and stir the solution for about 10 minutes. BF ₃ -Et ₂ O was added dropwise (approximately 0.10 mL), the reaction is stirred for about 10 minutes. AlMe ₃ (about 1.16 mmol, 2.0 M toluene solution) is then added. After a few minutes, the dry ice / acetone bath is removed and the reaction mixture is stirred at room temperature to about 45 ° C. for about 4 hours to about 4 days. Add pyridine (about 2 mL) in MeOH (about 10 mL) and remove the solvent in vacuo. The crude material is purified by chromatography and treated with ammonium hydroxide in methanol at about room temperature for about 16 hours. The mixture is concentrated and the residue is purified by HPLC to give 7.

７−ブロモイミダゾ［１，２−ｆ］［１，２，４］トリアジン−４−アミン（ＡＣＳ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ，２０１０，１，２８６に従って得た；３７５ｍｇ、１．７５ｍｍｏｌ）のＴＨＦ懸濁液（（４．０ｍＬ）に１，２−ビス−［（クロロジメチル）シラニル］エタン（４５２ｍｇ、２．１０ｍｍｏｌ）をアルゴン雰囲気下で添加した。６０分後、反応物を−７８℃に冷却して、ＢｕＬｉ（１．６ＭのＴＨＦ溶液、３．８ｍＬ、６．１０ｍｍｏｌ）を添加した。１０分後、−７８℃で、１ａ（ＷＯ２００６３１７２５号に従って得た、７８２ｍｇ、２．１０ｍｍｏｌ）のＴＨＦ溶液（１．０ｍＬ）を滴下した。反応混合物を−７８℃で１時間撹拌した。飽和塩化アンモニウム水溶液を添加して、０℃に加温した。全固体が溶解性となるまで水を添加した。混合物を酢酸エチルで抽出した。有機抽出物を硫酸ナトリウムで乾燥させて、濾過し、真空濃縮した。残渣をシリカゲルクロマトグラフィーにより精製し（酢酸エチル／ヘキサン）、８ｂ（６０６ｍｇ、５９％）を黄色固体として得た。
ＬＣ／ＭＳ＝５０８（Ｍ＋Ｈ^＋）
保持時間：２．１７〜２．２６分間
ＬＣ：Ｔｈｅｒｍｏ Ｅｌｅｃｔｒｏｎ Ｓｕｒｖｅｙｏｒ ＨＰＬＣ
ＭＳ：Ｆｉｎｎｉｇａｎ ＬＣＱ Ａｄｖａｎｔａｇｅ ＭＡＸ質量分析計
カラム：Ｐｈｅｎｏｍｅｎｅｘ社製Ｐｏｌａｒ ＲＰ ３０ｍｍ×４．６ｍｍ
溶媒：０．１％ギ酸−アセトニトリル溶液、０．１％ギ酸−水
勾配：０分間〜０．１分間５％ＡＣＮ、０．１分間〜１．９５分間５％〜１００％ＡＣＮ、１．９５分間〜３．５分間１００％ＡＣＮ、３．５分間〜３．５５分間１００％〜５％ＡＣＮ、３．５５分間〜４分間５％ＡＣＮ。 Compound 8

A suspension of 7-bromoimidazo [1,2-f] [1,2,4] triazine-4-amine (obtained according to ACS Medicinal Chemistry Letters, 2010, 1,286; 375 mg, 1.75 mmol) in THF ( (4.0 mL) was added 1,2-bis-[(chlorodimethyl) silanyl] ethane (452 mg, 2.10 mmol) under an argon atmosphere.After 60 minutes, the reaction was cooled to -78.degree. BuLi (1.6 M THF solution, 3.8 mL, 6.10 mmol) was added, and after 10 min at −78 ° C. 1a (782 mg, 2.10 mmol obtained according to WO200631725) in THF solution (1. The reaction mixture was stirred for 1 hour at −78 ° C. Saturated aqueous ammonium chloride was added to bring the reaction mixture to 0 ° C. Water was added until all solids were soluble The mixture was extracted with ethyl acetate The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo The residue was purified by silica gel chromatography. (Ethyl acetate / hexane), 8b (606 mg, 59%) was obtained as a yellow solid.
LC / MS = 508 (M + H ⁺ )
Retention time: 2.17-2.26 minutes LC: Thermo Electron Surveyor HPLC
MS: Finnigan LCQ Advantage MAX mass spectrometer Column: Polar RP 30 mm × 4.6 mm manufactured by Phenomenex
Solvent: 0.1% formic acid-acetonitrile solution, 0.1% formic acid-water gradient: 5% ACN for 0 min to 0.1 min, 5% to 100% ACN for 0.1 min to 1.95 min, 1.95 Minute to 3.5 minutes 100% ACN, 3.5 minutes to 3.55 minutes 100% to 5% ACN, 3.55 minutes to 4 minutes 5% ACN.

化合物８ｂ（５１０ｍｇ、１．３９ｍｍｏｌ）のジクロロエタン溶液（１０．０ｍＬ）に０℃でアルゴン雰囲気下、トリエチルシラン（１．７７ｍＬ、１１．０９ｍｍｏｌ）、次いでＢＦ_３・Ｅｔ_２Ｏ（１．４１ｍＬ、１１．０９ｍｍｏｌ）を添加した。反応混合物を５５℃で１６時間撹拌した。反応物を０℃に冷却して、飽和ＮａＨＣＯ_３水溶液でクエンチした。反応物をＤＣＭ、次いでＥｔＯＡｃで抽出した。併合有機相を硫酸ナトリウム上で乾燥させて、濾過し、濃縮した。残渣をシリカゲルクロマトグラフィーにより精製し（酢酸エチル／ヘキサン）、８ｃ（４５３ｍｇ、６４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）：ｄ８．１０−７．９４（ｍ、５Ｈ）、７．６−７．３３（ｍ、７Ｈ）、５．９１（ｄｄ、１Ｈ）、５．７８（ｄ、Ｊ＝２４．６Ｈｚ、１Ｈ）、４．８７（ｄｄ、１Ｈ）、４．７０（ｍ、１Ｈ）、４．５８（ｄｄ、１Ｈ）、１．３１（ｄ、Ｊ＝２２．４Ｈｚ、３Ｈ）。
ＬＣ／ＭＳ＝４９１（Ｍ^＋）。
保持時間：２．３６分間
ＬＣ：Ｔｈｅｒｍｏ Ｅｌｅｃｔｒｏｎ Ｓｕｒｖｅｙｏｒ ＨＰＬＣ
ＭＳ：Ｆｉｎｎｉｇａｎ ＬＣＱ Ａｄｖａｎｔａｇｅ ＭＡＸ質量分析計
カラム：Ｐｈｅｎｏｍｅｎｅｘ社製Ｐｏｌａｒ ＲＰ ３０ｍｍ×４．６ｍｍ
溶媒：０．１％ギ酸−アセトニトリル溶液、０．１％ギ酸−水
勾配：０分間〜０．１分間５％ＡＣＮ、０．１分間〜１．９５分間５％〜１００％ＡＣＮ、１．９５分間〜３．５分間１００％ＡＣＮ、３．５分間〜３．５５分間１００％〜５％ＡＣＮ、３．５５分間〜４分間５％ＡＣＮ。

Triethylsilane (1.77 mL, 11.09 mmol) and then BF ₃ .Et ₂ O (1.41 mL, 11) in a dichloroethane solution (10.0 mL) of compound 8b (510 mg, 1.39 mmol) at 0 ° C. under an argon atmosphere. .09 mmol) was added. The reaction mixture was stirred at 55 ° C. for 16 hours. The reaction was cooled to 0 ° C. and quenched with saturated aqueous NaHCO ₃ . The reaction was extracted with DCM then EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 8c (453 mg, 64%). ¹ H NMR (400 MHz, CDCl ₃ ): d8.10-7.94 (m, 5H), 7.6-7.33 (m, 7H), 5.91 (dd, 1H), 5.78 (d , J = 24.6Hz, 1H), 4.87 (dd, 1H), 4.70 (m, 1H), 4.58 (dd, 1H), 1.31 (d, J = 22.4Hz, 3H ).
LC / MS = 491 (M ^<+> ).
Retention time: 2.36 minutes LC: Thermo Electron Surveyor HPLC
MS: Finnigan LCQ Advantage MAX mass spectrometer Column: Polar RP 30 mm × 4.6 mm manufactured by Phenomenex
Solvent: 0.1% formic acid-acetonitrile solution, 0.1% formic acid-water gradient: 5% ACN for 0 min to 0.1 min, 5% to 100% ACN for 0.1 min to 1.95 min, 1.95 Minute to 3.5 minutes 100% ACN, 3.5 minutes to 3.55 minutes 100% to 5% ACN, 3.55 minutes to 4 minutes 5% ACN.

８ｃ（５００ｍｇ、０１．０２ｍｍｏｌ）のＴＨＦ溶液（５．０ｍＬ）に水酸化リチウム（１２２ｍｇ、５．０９ｍｍｏｌ）を水溶液（５．０ｍＬ）として添加し、室温でｌ時間撹拌した。反応物を０℃に冷却して、１Ｎ ＨＣｌ水溶液（５．１ｍＬ）で中性化した。混合物を濃縮して、残渣をＲＰ ＨＰＬＣにより精製し（水／アセトニトリル）、化合物８（１８５ｍｇ、６４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤ_３ＯＤ）：ｄ７．９７（ｓ、１Ｈ）、７．６３（ｓ、１Ｈ）、５．５４（ｄ、Ｊ＝２４．８Ｈｚ、１Ｈ）、４．０３（ｄｄ、１Ｈ）、３．８８（ｍ、１Ｈ）、３．７１（ｄｄ、１Ｈ）、１．８０（ｄ、Ｊ＝２２．１Ｈｚ、３Ｈ）。
ＬＣ／ＭＳ＝２８４（Ｍ＋Ｈ^＋）。
保持時間：１．０６分間
ＬＣ：Ｔｈｅｒｍｏ Ｅｌｅｃｔｒｏｎ Ｓｕｒｖｅｙｏｒ ＨＰＬＣ
ＭＳ：Ｆｉｎｎｉｇａｎ ＬＣＱ Ａｄｖａｎｔａｇｅ ＭＡＸ質量分析計
カラム：Ｐｈｅｎｏｍｅｎｅｘ社製Ｐｏｌａｒ ＲＰ ３０ｍｍ×４．６ｍｍ
溶媒：０．１％ギ酸−アセトニトリル溶液、０．１％ギ酸−水
勾配：０分間〜０．１分間５％ＡＣＮ、０．１分間〜１．９５分間５％〜１００％ＡＣＮ、１．９５分間〜３．５分間１００％ＡＣＮ、３．５分間〜３．５５分間１００％〜５％ＡＣＮ、３．５５分間〜４分間５％ＡＣＮ。

To a THF solution (5.0 mL) of 8c (500 mg, 01.02 mmol) was added lithium hydroxide (122 mg, 5.09 mmol) as an aqueous solution (5.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0 ° C. and neutralized with 1N aqueous HCl (5.1 mL). The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile) to give compound 8 (185 mg, 64%). ¹ H NMR (400 MHz, CD ₃ OD): d7.97 (s, 1H), 7.63 (s, 1H), 5.54 (d, J = 24.8 Hz, 1H), 4.03 (dd, 1H), 3.88 (m, 1H), 3.71 (dd, 1H), 1.80 (d, J = 22.1 Hz, 3H).
LC / MS = 284 (M + H ^< + ^> ).
Retention time: 1.06 minutes LC: Thermo Electron Surveyor HPLC
MS: Finnigan LCQ Advantage MAX mass spectrometer Column: Polar RP 30 mm × 4.6 mm manufactured by Phenomenex
Solvent: 0.1% formic acid-acetonitrile solution, 0.1% formic acid-water gradient: 5% ACN for 0 min to 0.1 min, 5% to 100% ACN for 0.1 min to 1.95 min, 1.95 Minute to 3.5 minutes 100% ACN, 3.5 minutes to 3.55 minutes 100% to 5% ACN, 3.55 minutes to 4 minutes 5% ACN.

化合物１ｅ（先行反応工程から得た粗生物）をＥｔＯＨに溶解させた。反応がほぼ完了するまで過剰水素化ホウ素ナトリウムを部分的に添加した。混合物を酢酸にて中性化した。混合物を濃縮して、固体残渣をシリカゲルカラムクロマトグラフィーにより精製し（０〜１０％ＭｅＯＨ／ジクロロメタン）、化合物２７（２１０ｍｇ、２工程中５０％）を得た。 Alternative method for compound 8

Compound 1e (crude product obtained from the previous reaction step) was dissolved in EtOH. Excess sodium borohydride was partially added until the reaction was nearly complete. The mixture was neutralized with acetic acid. The mixture was concentrated and the solid residue was purified by silica gel column chromatography (0-10% MeOH / dichloromethane) to give compound 27 (210 mg, 50% over 2 steps).

ラネーニッケル（約５００ｍｇ）をＨ_２Ｏで洗浄することにより中性化し、１ｄ（約１００ｍｇ）のエタノール溶液（約１０ｍＬ）に添加した。次いで、反応が完了するまで混合物を８０℃に加熱した。触媒を濾過により除去し、溶液を真空濃縮した。混合物を濃縮して、残渣をＨＰＬＣにより精製し、８を得た。 Further alternatives to compound 8

Raney nickel (about 500 mg) was neutralized by washing with H ₂ O and added to a 1d (about 100 mg) ethanol solution (about 10 mL). The mixture was then heated to 80 ° C. until the reaction was complete. The catalyst was removed by filtration and the solution was concentrated in vacuo. The mixture was concentrated and the residue was purified by HPLC to give 8.

化合物３（１２０ｍｇ、０．３９ｍｍｏｌ、１等量）を含むフラスコ内にＰＯ（ＯＭｅ）_３（１．５ｍＬ、０．２５Ｍ）を添加して、０℃に冷却後にＰＯＣｌ_３（１２５μＬ、１．３７ｍｍｏｌ、３．５等量）を添加した。反応混合物を５時間撹拌後に反応物を水でクエンチした。これをＨＰＬＣにより直接精製し、一リン酸化合物９を得た。
ＬＣＭＳ ｍ／ｚ３８７．９５［Ｍ＋Ｈ^＋］。 Compound 9

PO (OMe) ₃ (1.5 mL, 0.25 M) was added into a flask containing Compound 3 (120 mg, 0.39 mmol, 1 equivalent), and after cooling to 0 ° C., POCl ₃ (125 μL, 1.37 mmol). 3.5 equivalents) was added. After stirring the reaction mixture for 5 hours, the reaction was quenched with water. This was directly purified by HPLC to obtain monophosphate compound 9.
LCMS m / z 387.95 [M + H ^<+ >].

化合物９（３０ｍｇ、０．０７８ｍｍｏｌ、１等量）を含むフラスコ内にＮＭＰ（０．８ｍＬ、０．１Ｍ）を添加してから、ＴＥＡ（４３μＬ、０．３１ｍｍｏｌ、４等量）、テトラブチルアンモニウムブロミド（２５ｍｇ、０．０７８ｍｍｏｌ、１等量）を添加し、続いて炭酸クロロメチルイソプロピル（６０μＬ、０．３８ｍｍｏｌ、５等量）を添加した。反応混合物を５０℃に加熱して、一晩撹拌した。ＨＰＬＣにより直接精製し、化合物１０を得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ７．９８（ｓ、１Ｈ）、７．０１（ｄ、Ｊ＝４．７Ｈｚ、１Ｈ）、６．７２（ｄ、Ｊ＝４．７Ｈｚ、１Ｈ）、６．０４（ｂｓ、２Ｈ）、５．７４−５．６１（ｍ、４Ｈ）、４．９１（ｄｄｔ、Ｊ＝１２．６、９．４、６．３Ｈｚ、２Ｈ）、４．６４−４．２８（ｍ、４Ｈ）、１．３７−１．１９（ｍ、１５Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ−４．０６。
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＣＤＣｌ_３）ｄ−７６．５８、−１５１．９５ ＴＦＡ塩。
ＬＣＭＳ ｍ／ｚ６２０．０３［Ｍ＋Ｈ^＋］。 Compound 10

NMP (0.8 mL, 0.1 M) was added to a flask containing compound 9 (30 mg, 0.078 mmol, 1 equivalent), then TEA (43 μL, 0.31 mmol, 4 equivalents), tetrabutylammonium. Bromide (25 mg, 0.078 mmol, 1 eq) was added followed by chloromethyl isopropyl carbonate (60 μL, 0.38 mmol, 5 eq). The reaction mixture was heated to 50 ° C. and stirred overnight. Purification directly by HPLC gave compound 10.
¹ H NMR (400 MHz, CDCl ₃ ) d7.98 (s, 1H), 7.01 (d, J = 4.7 Hz, 1H), 6.72 (d, J = 4.7 Hz, 1H), 6. 04 (bs, 2H), 5.74-5.61 (m, 4H), 4.91 (ddt, J = 12.6, 9.4, 6.3 Hz, 2H), 4.64-4.28 (M, 4H), 1.37-1.19 (m, 15H).
³¹ P NMR (162 MHz, CDCl ₃ ) d-4.06.
¹⁹ F NMR (376 MHz, CDCl ₃ ) d-76.58, -151.95 TFA salt.
LCMS m / z 620.03 [M + H ^<+ >].

化合物Ｂ−２のＤＭＳＯ溶液を約３モル等量のカリウムｔ−ブトキシドで約１５分間〜２４時間処理する。反応物を１Ｎ ＨＣｌでクエンチして、逆相ＨＰＬＣにより化合物１１を単離する。 Compound 11

A DMSO solution of compound B-2 is treated with about 3 molar equivalents of potassium t-butoxide for about 15 minutes to 24 hours. The reaction is quenched with 1N HCl and compound 11 is isolated by reverse phase HPLC.

化合物１ｂ（約１ｍｍｏｌ）を鋼製オートクレーブに入れる。反応器に液体アンモニア（約３０ｍＬ）を入れ、混合物を約０℃〜５０℃で約１６時間撹拌する。アンモニアを蒸発させて、残渣を精製し、１２ａを得る。１２ａ（約１００ｍｇ）のエタノール溶液（約１０ｍＬ）をラネーニッケル（約５００ｍｇ）で処理し、Ｈ_２Ｏで洗浄することにより中性化する。次いで、反応が完了するまで混合物を約３５〜約８０℃に加熱する。触媒を濾過により除去し、溶液を真空濃縮する。混合物を濃縮して、残渣をＨＰＬＣにより精製し、１２ｂを得る。化合物１２ｂ（約５０ｍｇ）およびＴＭＳＣＮ（約０．５ｍｍｏｌ）のアセトニトリル溶液（約２．０ｍＬ）に約０℃でＴＭＳＯＴｆ（約０．５ｍｍｏｌ）を添加する。反応混合物を室温で約１時間、次いで６５℃で約３日間撹拌する。反応物を飽和ＮａＨＣＯ_３で室温でクエンチし、ＣＨ_３ＣＯ_２Ｅｔで希釈する。有機相を分離して、ブラインで洗浄して、Ｎａ_２ＳＯ_４上で乾燥させて、濾過し、濃縮する。残渣をＲＰ−ＨＰＬＣにより精製してから、メタノール（約１ｍＬ）に溶解させる。水酸化アンモニウム（２８％水溶液、約０．８ｍＬ）を添加して、混合物をほぼ室温で１６時間撹拌する。混合物を濃縮して、残渣をＲＰ ＨＰＬＣにより精製し、１２を得る。 Compound 12

Compound 1b (about 1 mmol) is placed in a steel autoclave. Charge the reactor with liquid ammonia (about 30 mL) and stir the mixture at about 0 ° C. to 50 ° C. for about 16 hours. Ammonia is evaporated and the residue is purified to give 12a. A solution of 12a (about 100 mg) in ethanol (about 10 mL) is treated with Raney nickel (about 500 mg) and neutralized by washing with H ₂ O. The mixture is then heated to about 35 to about 80 ° C. until the reaction is complete. The catalyst is removed by filtration and the solution is concentrated in vacuo. The mixture is concentrated and the residue is purified by HPLC to give 12b. TMSOTf (about 0.5 mmol) is added at about 0 ° C. to a solution of compound 12b (about 50 mg) and TMSCN (about 0.5 mmol) in acetonitrile (about 2.0 mL). The reaction mixture is stirred at room temperature for about 1 hour and then at 65 ° C. for about 3 days. The reaction is quenched with saturated NaHCO ₃ at room temperature and diluted with CH ₃ CO ₂ Et. The organic phase is separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by RP-HPLC and then dissolved in methanol (ca. 1 mL). Ammonium hydroxide (28% aqueous solution, about 0.8 mL) is added and the mixture is stirred at about room temperature for 16 hours. The mixture is concentrated and the residue is purified by RP HPLC to give 12.

化合物１２を出発物質として使用して化合物９と同じ方法により化合物１３を調製する。 Compound 13

Compound 13 is prepared by the same method as compound 9 using compound 12 as starting material.

約１〜約５等量のＤＣＣのピリジン溶液を用いた化合物１３処理により化合物１４を調製し、反応物を約１〜約２４時間加熱還流する。従来のイオン交換および逆相ＨＰＬＣにより化合物１４を単離する。 Compound 14

Compound 14 is prepared by treatment of Compound 13 with about 1 to about 5 equivalents of a DCC solution of DCC and the reaction is heated to reflux for about 1 to about 24 hours. Compound 14 is isolated by conventional ion exchange and reverse phase HPLC.

約０．４ｍｍｏｌ化合物１４のＤＭＦ溶液約１０ｍＬを約０．８ｍｍｏｌのＤＩＰＥＡおよび約０．８ｍｍｏｌの炭酸クロロメチルイソプロピルで処理する（ＷＯ２００７／０２７２４８号）。反応物を約２５〜約８０℃に約１５分間〜約２４時間加熱する。溶媒を真空除去し、残渣をＨＰＬＣにより精製し、化合物１５を得る。 Compound 15

About 10 mL of a DMF solution of about 0.4 mmol compound 14 is treated with about 0.8 mmol DIPEA and about 0.8 mmol chloromethyl isopropyl carbonate (WO 2007/027248). The reaction is heated to about 25 to about 80 ° C. for about 15 minutes to about 24 hours. The solvent is removed in vacuo and the residue is purified by HPLC to give compound 15.

化合物３（約０．２２ｍｍｏｌ）を無水ピリジン（約２ｍＬ）に溶解させて、クロロトリメチルシラン（約０．１７ｍＬ）を添加する。混合物を約０℃〜約２５℃で約１〜約２４時間撹拌する。さらなるクロロトリメチルシラン（約０．１ｍＬ）を添加して、反応物を約１〜約２４時間撹拌する。４，４’−ジメトキシトリチルクロライド（約０．６６ｍｍｏｌ）およびＤＭＡＰ（約０．１１〜約０．２２ｍｍｏｌ）を連続添加する。混合物を約１〜約２４時間撹拌する。ＴＢＡＦ（１．０Ｍ、約０．２２ｍＬ）のＴＨＦ溶液を添加して、反応物を約１〜約２４時間撹拌する。混合物を酢酸エチルと水の間で分配する。酢酸エチル層を乾燥させて、濃縮する。残渣をクロマトグラフィーにより精製し、化合物１６を得る。 Compound 16

Compound 3 (about 0.22 mmol) is dissolved in anhydrous pyridine (about 2 mL) and chlorotrimethylsilane (about 0.17 mL) is added. The mixture is stirred at about 0 ° C. to about 25 ° C. for about 1 to about 24 hours. Additional chlorotrimethylsilane (about 0.1 mL) is added and the reaction is stirred for about 1 to about 24 hours. 4,4′-Dimethoxytrityl chloride (about 0.66 mmol) and DMAP (about 0.11 to about 0.22 mmol) are added sequentially. The mixture is stirred for about 1 to about 24 hours. TBAF (1.0 M, about 0.22 mL) in THF is added and the reaction is stirred for about 1 to about 24 hours. Partition the mixture between ethyl acetate and water. The ethyl acetate layer is dried and concentrated. The residue is purified by chromatography to give compound 16.

約１．２５ｍｍｏｌの化合物１６および約１．９ｍｍｏｌのトリエチルアンモニウム２−（２，２−ジメチル−３−（トリチルオキシ）プロパノイルチオ）エチルホスフィネート（ＷＯ２００８０８２６０１号）の混合物を無水ピリジン（約１９ｍＬ）に溶解させる。ピバロイルクロライド（約２．５ｍｍｏｌ）を約−３０〜約０℃で滴下し、溶液を約３０分間〜約２４時間撹拌する。反応物を塩化メチレンで希釈し、塩化アンモニウム水溶液（約０．５Ｍ）にて中性化する。塩化メチレン相を蒸発させ、残渣を乾燥させ、クロマトグラフィーにより精製し、化合物１７を得る。 Compound 17

Dissolve a mixture of about 1.25 mmol of compound 16 and about 1.9 mmol of triethylammonium 2- (2,2-dimethyl-3- (trityloxy) propanoylthio) ethyl phosphinate (WO2008082601) in anhydrous pyridine (about 19 mL) Let Pivaloyl chloride (about 2.5 mmol) is added dropwise at about −30 to about 0 ° C. and the solution is stirred for about 30 minutes to about 24 hours. The reaction is diluted with methylene chloride and neutralized with aqueous ammonium chloride (ca. 0.5 M). The methylene chloride phase is evaporated and the residue is dried and purified by chromatography to give compound 17.

約０．４９ｍｍｏｌ化合物１７の無水炭素四塩化物溶液（約５ｍＬ）にベンジルアミン（約２．４５ｍｍｏｌ）を滴下する。反応混合物を約１〜約２４時間撹拌する。溶媒を蒸発させ、残渣をクロマトグラフィーにより精製し、化合物１８を得る。 Compound 18

About 0.49 mmol Compound 17 in anhydrous carbon tetrachloride (about 5 mL) is added dropwise with benzylamine (about 2.45 mmol). The reaction mixture is stirred for about 1 to about 24 hours. The solvent is evaporated and the residue is purified by chromatography to give compound 18.

約２ｍｍｏｌ化合物１８の塩化メチレン溶液（約１０ｍＬ）をトリフルオロ酢酸水溶液（９０％、約１０ｍＬ）で処理する。反応混合物を約２５〜約６０℃で約１〜約２４時間撹拌する。反応混合物をエタノールで希釈して、揮発性物質を蒸発させ、残渣をクロマトグラフィーにより精製し、化合物２０を得る。 Compound 20

About 2 mmol of compound 18 in methylene chloride (about 10 mL) is treated with aqueous trifluoroacetic acid (90%, about 10 mL). The reaction mixture is stirred at about 25 to about 60 ° C. for about 1 to about 24 hours. The reaction mixture is diluted with ethanol, volatiles are evaporated, and the residue is purified by chromatography to give compound 20.

約９０ｍＭ化合物２のＴＨＦ溶液を約−７８℃に冷却して、約２．２〜約５等量のｔ−ブチルマグネシウムクロライド（約１ＭのＴＨＦ溶液）を添加する。混合物を約０℃に約３０分間加温し、再び約−７８℃に冷却する。
（２Ｓ）−２−｛［クロロ（１−フェノキシ）ホスホリル］アミノ｝プロピルピバロエート溶液（ＷＯ２００８０８５５０８号）（１ＭのＴＨＦ溶液、約２等量）を滴下する。冷却をやめ、反応物を約１〜約２４時間撹拌する。反応物を水でクエンチして、混合物を酢酸エチルで抽出する。抽出物を乾燥させ、蒸発させ、残渣をクロマトグラフィーにより精製し、化合物２１を得る。 Compound 21

Cool the THF solution of about 90 mM Compound 2 to about −78 ° C. and add about 2.2 to about 5 equivalents of t-butylmagnesium chloride (about 1 M THF solution). The mixture is warmed to about 0 ° C. for about 30 minutes and cooled again to about −78 ° C.
(2S) -2-{[Chloro (1-phenoxy) phosphoryl] amino} propyl pivaloate solution (WO20080885508) (1M THF solution, approximately 2 equivalents) is added dropwise. Remove cooling and stir the reaction for about 1 to about 24 hours. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The extract is dried and evaporated and the residue is purified by chromatography to give compound 21.

Ｃ−１ａ調製に類似した方法により化合物２２ａを得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）ｄ８．１１（ｄ、Ｊ＝９．０Ｈｚ、２Ｈ）、８．０２（ｓ、１Ｈ）、７．４８（ｔ、Ｊ＝７．５Ｈｚ、２Ｈ）、７．４２−７．２５（ｍ、４Ｈ）、７．２１（ｄｔ、Ｊ＝１４．９、５．５Ｈｚ、２Ｈ）、７．０８（ｔ、Ｊ＝７．３Ｈｚ、２Ｈ）、５．１７−５．０３（ｍ、２Ｈ）、４．９９（ｄｄ、Ｊ＝１６．５、９．７Ｈｚ、２Ｈ）、３．４４（ｓ、１Ｈ）、３．３５−３．２１（ｍ、２Ｈ）、３．１９（ｄ、Ｊ＝９．２Ｈｚ、１Ｈ）、３．００−２．８０（ｍ、２Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ_３）ｄ４．２７。
ＬＣＭＳ ｍ／ｚ４５２．０９［Ｍ＋Ｈ^＋］。 Compound 22

Compound 22a was obtained by a method analogous to C-1a preparation.
¹ H NMR (400 MHz, CDCl ₃ ) d8.11 (d, J = 9.0 Hz, 2H), 8.02 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7. 42-7.25 (m, 4H), 7.21 (dt, J = 14.9, 5.5 Hz, 2H), 7.08 (t, J = 7.3 Hz, 2H), 5.17-5 .03 (m, 2H), 4.99 (dd, J = 16.5, 9.7 Hz, 2H), 3.44 (s, 1H), 3.35-3.21 (m, 2H), 3 .19 (d, J = 9.2 Hz, 1H), 3.00-2.80 (m, 2H).
³¹ P NMR (162 MHz, CDCl ₃ ) d 4.27.
LCMS m / z 452.09 [M + H ^<+ >].

化合物３および２２ａを使用してＣ−１調製に類似した方法により化合物２２ｂを得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤ_３ＯＤ）ｄ７．７６（ｄ、Ｊ＝６．３Ｈｚ、１Ｈ）、７．３８（ｔ、Ｊ＝８．２Ｈｚ、１Ｈ）、７．２７−７．１２（ｍ、４Ｈ）、７．０６−６．８１（ｍ、３Ｈ）、６．７４（ｄｄ、Ｊ＝４．６、３．５Ｈｚ、１Ｈ）、４．９５−４．７９（ｍ、１Ｈ）、４．３５−３．９０（ｍ、４Ｈ）、３．２３（ｄｔ、Ｊ＝３．２、１．６Ｈｚ、３Ｈ）、３．１８−３．０５（ｍ、２Ｈ）、２．８２（ｄｔ、Ｊ＝１４．７、７．３Ｈｚ、２Ｈ）、１．１５（ｄ、Ｊ＝２２．４Ｈｚ、３Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤ_３ＯＤ）ｄ１０．７６、１０．７１。
ＬＣＭＳ ｍ／ｚ６２０．０５［Ｍ＋Ｈ^＋］。

Compound 22b was obtained by a method analogous to C-1 preparation using compounds 3 and 22a.
¹ H NMR (400 MHz, CD ₃ OD) d7.76 (d, J = 6.3 Hz, 1H), 7.38 (t, J = 8.2 Hz, 1H), 7.27-7.12 (m, 4H), 7.06-6.81 (m, 3H), 6.74 (dd, J = 4.6, 3.5 Hz, 1H), 4.95-4.79 (m, 1H), 4. 35-3.90 (m, 4H), 3.23 (dt, J = 3.2, 1.6 Hz, 3H), 3.18-3.05 (m, 2H), 2.82 (dt, J = 14.7, 7.3 Hz, 2H), 1.15 (d, J = 22.4 Hz, 3H).
³¹ P NMR (162 MHz, CD ₃ OD) d10.76, 10.71.
LCMS m / z 620.05 [M + H ^<+ >].

２２ｂ（５０ｍｇ、０．０８ｍｍｏｌ、１等量）を含むフラスコ内にエタノール（４ｍＬ）、続いてＰｄ（ＯＨ）_２（５６ｍｇ、０．０８ｍｍｏｌ、１等量）およびギ酸アンモニウム（４２ｍｇ、０．６４ｍｍｏｌ、８等量）を添加した。反応物を８０℃に約１時間加熱した。固体を濾過して、物質をＨＰＬＣにより精製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ_６）ｄ１０．７２（ｓ、１Ｈ）、７．９１（ｓ、１Ｈ）、７．９５−７．８９（ｂｓ、２Ｈ）、７．４１（ｄ、Ｊ＝７．７Ｈｚ、１Ｈ）、７．２６（ｄ、Ｊ＝８．１Ｈｚ、１Ｈ）、７．１９−６．６６（ｍ、３Ｈ）、４．２０−３．７５（ｍ、３Ｈ）、２．９９（ｄｄ、Ｊ＝１６．５、９．６Ｈｚ、２Ｈ）、２．８９−２．７０（ｍ、２Ｈ）、２．４８−２．５８（ｍ、８Ｈ）、１．１０（ｄ、Ｊ＝２２．３Ｈｚ、３Ｈ）。
^３１Ｐ ＮＭＲ（１６２ＭＨｚ、ＤＭＳＯ−ｄ_６）ｄ７．４９。
^１９Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ−ｄ_６）ｄ−１５４．８９。
ＬＣＭＳ ｍ／ｚ５３０．２１［Ｍ＋Ｈ^＋］。 Compound 22

Ethanol (4 mL) in a flask containing 22b (50 mg, 0.08 mmol, 1 eq) followed by Pd (OH) ₂ (56 mg, 0.08 mmol, 1 eq) and ammonium formate (42 mg, 0.64 mmol, 8 equivalents) was added. The reaction was heated to 80 ° C. for about 1 hour. The solid was filtered and the material was purified by HPLC.
¹ H NMR (400 MHz, DMSO-d ₆ ) d10.72 (s, 1H), 7.91 (s, 1H), 7.95-7.89 (bs, 2H), 7.41 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.19-6.66 (m, 3H), 4.20-3.75 (m, 3H), 2. 99 (dd, J = 16.5, 9.6 Hz, 2H), 2.89-2.70 (m, 2H), 2.48-2.58 (m, 8H), 1.10 (d, J = 22.3 Hz, 3H).
³¹ P NMR (162 MHz, DMSO-d ₆ ) d7.49.
¹⁹ F NMR (376 MHz, DMSO-d ₆ ) d-154.89.
LCMS m / z 530.21 [M + H ^<+ >].

化合物３（２５０ｍｇ、０．８２ｍｍｏｌ）をＰＯ（ＯＭｅ）_３（５ｍＬ、０．１６Ｍ）に溶解させて、アルゴン下で０℃に冷却した。この撹拌溶液にＰＯＣｌ_３（０．３２ｍＬ、４．１ｍｍｏｌ）をゆっくりと滴下して、反応混合物を室温に１６時間加温した。生成した溶液をアセトニトリル（４００ｍＬ）および０．０８Ｍ ＫＯＨ水溶液（３００ｍＬ）の急速に撹拌した溶液に滴下した。添加完了時、反応進行をＬＣＭＳにより確認した。反応完了時、溶媒を減圧除去した。生成固体残渣を水に溶解させ、ＨＰＬＣにより精製し、１４０ｍｇの化合物２３を得た（収率；４７％）。
^１Ｈ−ＮＭＲ（４００ＭＨｚ；ＣＤ_３ＯＤ）：ｄ８．１５（ｓ、１Ｈ）、７．４０（ｄ、１Ｈ；Ｊ＝４．８Ｈｚ）、７．０９（ｄ、１Ｈ；Ｊ＝４．８Ｈｚ）、４．６４（ｄｄ、１Ｈ；Ｊ＝２４Ｈｚ、７．２Ｈｚ）、４．５０−４．３６（ｍ、３Ｈ）、１．３２（ｄ、３Ｈ；Ｊ＝２２Ｈｚ）。
^１９Ｆ−ＮＭＲ（３７６ＭＨｚ；ＣＤ_３ＯＤ）：ｄ−１５３．１１。
^３１Ｐ−ＮＭＲ（１６２ＭＨｚ；ＣＤ_３ＯＤ）：ｄ−２．２０。ＭＳ［Ｍ＋Ｈ^＋］＝３７０．２。 Compound 23

Compound 3 (250 mg, 0.82 mmol) was dissolved in PO (OMe) ₃ (5 mL, 0.16 M) and cooled to 0 ° C. under argon. To this stirred solution was slowly added POCl ₃ (0.32 mL, 4.1 mmol) and the reaction mixture was allowed to warm to room temperature for 16 h. The resulting solution was added dropwise to a rapidly stirred solution of acetonitrile (400 mL) and 0.08 M aqueous KOH (300 mL). When the addition was complete, the reaction progress was confirmed by LCMS. Upon completion of the reaction, the solvent was removed under reduced pressure. The resulting solid residue was dissolved in water and purified by HPLC to give 140 mg of compound 23 (yield; 47%).
¹ H-NMR (400 MHz; CD ₃ OD): d8.15 (s, 1H), 7.40 (d, 1H; J = 4.8 Hz), 7.09 (d, 1H; J = 4.8 Hz) 4.64 (dd, 1H; J = 24 Hz, 7.2 Hz), 4.50-4.36 (m, 3H), 1.32 (d, 3H; J = 22 Hz).
¹⁹ F-NMR (376 MHz; CD ₃ OD): d-153.11.
³¹ P-NMR (162 MHz; CD ₃ OD): d-2.20. MS [M + H ^<+ >] = 370.2.

化合物２３（７ｍｇ、０．０２ｍｍｏｌ）のＤＣＭ溶液（２ｍＬ）およびＰＯ（ＯＭｅ）_３（１ｍＬ）を調製して、０℃に冷却した。この溶液に塩化オキサリル（１０μＬ）、続いてＤＭＦ（２μＬ）を添加した。混合物を１分間撹拌後に一部を取り出し、ＭｅＯＨ中でクエンチしてから、活性化をＬＣＭＳにより確認した。後続量の塩化オキサリル（１０μＬ）およびＤＭＦ（２μＬ）を活性化が完了するまで添加した。この時点で、大量の２−プロパノール（５ｍＬ）を反応混合物に添加して、撹拌し、室温に加温した。反応完了後、溶媒を減圧除去し、生成した粗物質を前段階ＨＰＬＣにより精製し、５．５ｍｇの化合物２４を得た（収率７０％）。
^１Ｈ−ＮＭＲ（４００ＭＨｚ；ＤＭＳＯ−ｄ_６）：ｄ８．２６（ｂｒ、１Ｈ）、８．１５（ｂｒ、１Ｈ）、７．９７（ｓ、１Ｈ）、７．００（ｄ、１Ｈ；Ｊ＝４．４Ｈｚ）、６．８８（ｄ、１Ｈ；Ｊ＝４．４Ｈｚ）、４．５９−４．５１（ｍ、２Ｈ）、４．３７−４．２５（ｍ、２Ｈ）、１．２３（ｄ、３Ｈ；Ｊ＝２２．８Ｈｚ）。^１９Ｆ−ＮＭＲ（３７６ＭＨｚ；ＣＤ_３ＯＤ）：ｄ−１５１．７２。
^３１Ｐ−ＮＭＲ（１６２ＭＨｚ；ＣＤ_３ＯＤ）：ｄ−５．６９。
ＭＳ［Ｍ＋Ｈ^＋］＝４１２．０。 Compound 24

A solution of compound 23 (7 mg, 0.02 mmol) in DCM (2 mL) and PO (OMe) ₃ (1 mL) was prepared and cooled to 0 ° C. To this solution was added oxalyl chloride (10 μL) followed by DMF (2 μL). A portion of the mixture was removed after stirring for 1 minute and quenched in MeOH before activation was confirmed by LCMS. Subsequent amounts of oxalyl chloride (10 μL) and DMF (2 μL) were added until activation was complete. At this point, a large amount of 2-propanol (5 mL) was added to the reaction mixture, stirred and allowed to warm to room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the resulting crude material was purified by pre-stage HPLC to obtain 5.5 mg of compound 24 (yield 70%).
¹ H-NMR (400 MHz; DMSO-d ₆ ): d8.26 (br, 1H), 8.15 (br, 1H), 7.97 (s, 1H), 7.00 (d, 1H; J = 4.4 Hz), 6.88 (d, 1H; J = 4.4 Hz), 4.59-4.51 (m, 2H), 4.37-4.25 (m, 2H), 1.23 ( d, 3H; J = 22.8 Hz). ¹⁹ F-NMR (376 MHz; CD ₃ OD): d-151.72.
³¹ P-NMR (162 MHz; CD ₃ OD): d-5.69.
MS [M + H ^<+ >] = 412.0.

化合物２４に類似した形でアラニンのヘプチルエステルを２−プロパノールに代えて化合物２５を化合物２３から調製した（収率５．３％）。
^１Ｈ−ＮＭＲ（４００ＭＨｚ；ＣＤ_３ＯＤ）：ｄ７．９１（ｓ、１Ｈ）、６．９８（ｄ、１Ｈ；Ｊ＝４．８Ｈｚ）、６．９２（ｄ、１Ｈ；Ｊ＝４．８Ｈｚ）、５．２９（ｄｄ、１Ｈ；Ｊ＝２４．４Ｈｚ、８．８Ｈｚ）、４．６６−４．６０（ｍ、２Ｈ）、４．４８−４．４０（ｍ、１Ｈ）、４．１５−４．１１（ｍ、３Ｈ）、３．９２（ｄｄ、１Ｈ；Ｊ＝９．６Ｈｚ、７．２Ｈｚ）、１．６７−１．６４（ｍ、３Ｈ）、１．４０−１．２７（ｍ、１５Ｈ）、０．９１−０．８７（ｍ、６Ｈ）。
^１９Ｆ−ＮＭＲ（３７６ＭＨｚ；ＣＤ_３ＯＤ）：ｄ−１５１．４６。^３１Ｐ−ＮＭＲ（１６２ＭＨｚ；ＣＤ_３ＯＤ）：ｄ７．３６。
ＭＳ［Ｍ＋Ｈ^＋］＝５３９．４。 Compound 25

Compound 25 was prepared from Compound 23 (yield 5.3%) by replacing the heptyl ester of alanine with 2-propanol in a manner similar to Compound 24.
¹ H-NMR (400 MHz; CD ₃ OD): d7.91 (s, 1H), 6.98 (d, 1H; J = 4.8 Hz), 6.92 (d, 1H; J = 4.8 Hz) 5.29 (dd, 1H; J = 24.4 Hz, 8.8 Hz), 4.66-4.60 (m, 2H), 4.48-4.40 (m, 1H), 4.15- 4.11 (m, 3H), 3.92 (dd, 1H; J = 9.6 Hz, 7.2 Hz), 1.67-1.64 (m, 3H), 1.40-1.27 (m 15H), 0.91-0.87 (m, 6H).
¹⁹ F-NMR (376 MHz; CD ₃ OD): d-151.46. ³¹ P-NMR (162 MHz; CD ₃ OD): d 7.36.
MS [M + H ^<+ >] = 539.4.

化合物１０の調製に類似した形で化合物２６を化合物２２から調製する。 Compound 26

Compound 26 is prepared from compound 22 in a manner analogous to the preparation of compound 10.

Antiviral Activity Another aspect of the present invention relates to a method for inhibiting viral infection comprising the step of processing a sample or subject suspected of requiring such inhibition using the composition of the present invention.

  Within the context of the present invention, samples suspected of containing virus include natural or artificial materials (biological; tissue or cell culture, etc.); biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears) Fluids, sputum, saliva, tissue samples, etc.); laboratory samples; food, water, or air samples; bioproduct samples (cell extracts, particularly recombinant cells that synthesize the desired glycoprotein), etc. It is done. Typically, the sample is suspected of containing a living organism that induces a viral infection, often a pathogen (such as a tumor virus). The sample can be contained in any medium containing water and an organic solvent water mixture. Samples include living organisms (such as humans) and artificial substances (such as cell culture).

  If desired, the antiviral activity of a compound of the present invention after application of the composition can be observed by any method, including methods for direct and indirect detection of such activity. Quantitative, qualitative, and semi-quantitative methods for determining such activity are all contemplated. Typically, one of the above screening methods is applied, but any other method (such as observing the physiological properties of a living organism) is also applicable.

  The antiviral activity of the compounds of the present invention can be measured using known standard screening protocols. For example, the antiviral activity of a compound can be measured using the following general protocol.

Cell-based flavivirus immunodetection assay BHK21 or A549 cells are trypsinized and counted, Hams F-12 medium (A549 cells) or RPMI-1640 medium supplemented with 2% fetal bovine serum (FBS) and 1% penicillin / streptomycin Dilute to 2 × 10 ⁵ cells / mL with (BHK21 cells). Distribute 2 × 10 ⁴ cells into wells of a clear 96 well tissue culture plate and place overnight at 37 ° C., 5% CO ₂ . The next day, cells are infected with virus at a superinfection degree of infection (MOI) of 0.3 in the presence of various concentrations of test compound for 1 hour at 37 ° C. and an additional 48 hours at 5% CO ₂ . Cells are washed once with PBS and fixed with cold methanol for 10 minutes. After washing twice with PBS, the immobilized cells are blocked with PBS containing 1% FBS and 0.05% Tween-20 for 1 hour at room temperature. The primary antibody solution (4G2) is then added at a concentration of 1:20 to 1: 100 in PBS containing 1% FBS and 0.05% Tween-20 for 3 hours. Cells are then washed 3 times with PBS and then incubated with horseradish peroxidase (HRP) conjugated anti-mouse IgG (Sigma, 1: 2000 dilution) for 1 hour. After washing 3 times with PBS, 50 microliters of 3,3 ′, 5,5′-tetramethylbenzidine (TMB) substrate solution (Sigma) is added to each well for 2 minutes. The reaction is stopped by adding 0.5M sulfuric acid. Read plate at 450 nm absorbance for viral load quantification. After measurement, the cells are washed 3 times with PBS and then incubated with propidium iodide for 5 minutes. Plates are read in a Tecan Safari ™ reader (erection 537 nm, release 617 nm) for cell number quantification. Dose response curves are plotted from mean absorbance versus log of test compound concentration. EC ₅₀ is calculated by nonlinear regression analysis. A positive control (such as N-nonyl-deoxynojirimycin) can be used.

Cell-based flavivirus cytopathic effect assay For examination of West Nile virus or Japanese encephalitis virus, BHK21 cells were trypsinized and concentration of 4 × 10 ⁵ cells / mL in RPMI-1640 medium supplemented with 2% FBS and 1% penicillin / streptomycin. Dilute to For dengue virus testing, Huh7 cells are trypsinized and diluted to a concentration of 4 × 10 ⁵ cells / mL in DMEM medium supplemented with 5% FBS and 1% penicillin / streptomycin. Distribute 50 microliter cell suspension (2 × 10 ⁴ cells) to each well in a 96-well optical bottom PIT polymer base plate (Nunc). Cells are grown overnight in culture medium at 37 ° C., 5% CO ₂ and then MOI = 0 in West Nile virus (eg B956 strain) or Japanese encephalitis virus (eg Nakayama strain) in the presence of various concentrations of test compound. .3 or dengue virus (eg DEN-2 NGC strain) with MOI = 1. Plates containing virus and compound are further incubated at 37 ° C., 5% CO ₂ for 72 hours. At the end of the incubation, 100 microliter CellTiter-Glo ™ reagent is added to each well. The contents are mixed for 2 minutes on an orbital shaker to induce cell lysis. The plate is incubated for 10 minutes at room temperature to stabilize the luminescent signal. Record the luminescence readings using a plate reader. A positive control (such as N-nonyl-deoxynojirimycin) can be used.

Antiviral activity in a dengue-infected mouse model.
Compounds are tested in vivo in a dengue virus-infected mouse model (Schul et al. J. Infectious Dis. 2007; 195: 665-74). 6-10 week old AG129 mice (B & K Universal Ltd, Hll, UK) are housed individually in a ventilated cage. Mice are injected intraperitoneally with 0.4 mL TSV01 dengue virus 2 suspension. Blood samples are collected by retroorbital puncture under isoflurane anesthesia. Blood samples were collected at a final concentration of 0.4% in a test tube containing sodium citrate and immediately centrifuged at 6000 g for 3 minutes to obtain plasma. Plasma (20 microliters) is diluted with 780 microliters RPMI-1640 medium and briefly frozen in liquid nitrogen for plaque assay analysis. The remaining plasma is stored for cytokine and NS1 protein level determination. Mice develop dengue viremia, which rises over several days and peaks 3 days after infection.

  For antiviral activity testing, a compound of the present invention is added to a vehicle fluid such as 10% ethanol, 30% PEG300 and 60% D5W (5% dextrose in water; or 6N HCl (1.5 eq): 1N NaOH (pH 3 Adjusted to 0.5): dissolved in 100 mM citrate buffer, pH 3.5 (0.9% v / v: 2.5% v / v: 96.6% v / v). 10 week-old AG129 mice are classified into 6 groups of 6 animals each, and all mice are infected with the above dengue virus (day 0) .In 1 group, 0.2 mg / kg of the compound of the invention is 0 at 200 mL / mouse. Start on the day (first dose just before dengue infection) and take oral gavage twice a day (once in the morning and once in the evening) for 3 consecutive days. 1 mg / kg, 5 mg / kg and 25 mg / kg compounds are administered by oral gavage of 200 microliters / mouse in the same manner as the above group (2R, 3R, 4R, 5R) -2- (2-amino-6-hydroxy-purine A positive control such as -9-yl) -5-hydroxymethyl l-3-methyl-tetrahydro-furan-3,4-diol may be used, and a further group is treated with vehicle fluid only.

  On the third day after infection, approximately 100 microliters of blood sample (anticoagulated with sodium citrate) is collected from the mice by retroorbital puncture under isoflurane anesthesia. Plasma is obtained from each blood sample by centrifugation in liquid nitrogen and easy freezing for infectious disease assay analysis. The collected plasma samples are analyzed by the infectious disease assay described in Schul et al. Cytokines are also analyzed as described by Schul. NS1 protein levels are analyzed using the Platelia ™ kit (BioRad Laboratories). Antiviral effects are indicated by reduced cytokine levels and / or NS1 protein levels.

  Typically, administration of 5-50 mg / kg twice a day of a compound of the invention results in about 5-100 times, more typically 10-60 times, most typically 20-20 times viremia. Decrease by 30 times.

HCV IC ₅₀ Determination Assay Protocol: Wild type or S282T (Miglicaccio, et al, J. Biol. Chem. 2003, 49164-49170; Klumpp, et al, J. Biol. Chem. 2006, 3793-3799) mutants. Either polymerase enzyme was used in this assay. 28 μL polymerase mixture (final concentration: 50 mM Tris-HCl pH 7.5, 10 mM KCL, 5 mM MgCl ₂ , 1 mM DTT, 10 mM EDTA, 4 ng / μL RNA template, and 75 nM HCVΔ21 NS5b polymerase) was added to the assay plate; NS5b polymerase assay (40 μL) was made by adding 4 μL of diluted compound. It was added polymerase and compound mixtures of nucleotide substrate after preincubation for 10 min at 35 ° C. _{(K M} of 33P-alpha labeled competitor nucleotides, and 0.5mM of the remaining three nucleotides) 8 [mu] L. The assay plate was covered and incubated at 35 ° C. for 90 minutes. The reaction was then vacuum filtered through a 96 well DEAE-81 filter plate. Then, a plurality capacity 0.125M NaHP0 _4, water, and the filter plate and vacuum washed with ethanol to remove not incorporated label. Plates were then counted on TopCount to assess product synthesis levels relative to background controls. IC50 values are determined using a prism fit program.

Preferably, the compounds described herein inhibited NS5b polymerase with an IC _{50 of} less than 1000 μM, more preferably less than ₁₀₀ μM, and most preferably less than 10 μM. For example, the IC ₅₀ of compound TP-1 for both HCV polymerase wild-type and S282T mutant enzymes is 0.15 μM. In Table 2 below, 2'-methylguanidine triphosphate and (2R, 3R, 4R, 5R) -2- (4-aminopyrrolo [1,2-f] [1,2,4] triazine-7- Yl) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyl-tetrahydrofuran-2-carbonitrile triphosphate compared to the activity obtained with the wild-type and S282T mutant enzymes TP-1 and TP-2 activity against both are shown. Unexpectedly, when pyrrolo [1,2-f] [1,2,4] triazin-7-yl nucleoside 2′OH is replaced with 2′F, activity against a resistant S282T HCV mutant of the virus is unexpectedly observed. Is given.

HCV EC ₅₀ determination Replicon cells were seeded in 96-well plates at a density of 8 × 10 ³ cells / well in 100 μL culture medium excluding Geneticin. Compounds were serially diluted with 100% DMSO and then added to the cells at a 1: 200 dilution to a final concentration of 0.5% DMSO and a total volume of 200 μL. After incubating the plates at 37 ° C. for 3 days, the culture medium was removed and the cells were lysed in the lysis buffer provided by Promega's luciferase assay system. According to the manufacturer's instructions, 100 μL of luciferase substrate was added to the lysed cells and luciferase activity was measured with a TopCount luminometer. Preferably, the EC50 of the compounds described herein is less than 1000 μΜ, more preferably less than 100 μΜ, and most preferably less than 10 μΜ. Representative activities of compounds of formula I are shown in Table 3 below.

  The cytotoxicity of the compounds of the invention can be determined using the following general protocol.

Metabolic effects test:
Applicants monophosphate prodrugs of nucleoside analogs X ¹ position is nitrogen, X ^1-position was observed that are likely to have higher activity than the counterpart is carbon. This difference in activity correlates with the amount of active triphosphate analog of the intracellular compound. This can be quantified by a metabolic test that quantifies the intracellular concentration of the triphosphate analog. Higher intracellular concentrations of triphosphate metabolites correlate with enhanced activity prodrugs.

For example, by comparison of the prodrug Compound B-7 and prodrug Compound PD-A-8b, activity is shown to be increased when X ¹ position is nitrogen. This is because, in Table 3, the HCV EC ₅₀ of the compound is 0.68 μΜ compared with 63 to 73 μΜ of Compound B-7 when X ¹ position is nitrogen (Compound PD-A-8b). I can observe. Activation of the prodrug analog PD-A-8b (relative to its triphosphate analog TP-8a), as seen in Table 4, is the counterpart B of the prodrug whose X ¹ position is carbon. It was found that the efficiency was more than two orders of magnitude higher than observed for -7 (relative to its triphosphate analog TP-3).

Experiment:
Huh-luc / neo replicon cells containing HCV genotype 1b subgenomic replicons in Dulbecco's modified Eagle's medium containing glutamax supplemented with 10% heat-inactivated fetal bovine serum, penicillin-streptomycin, and G418 disulfate solution Maintained. Cells were transferred to 12-well tissue culture plates by trypsinization and grown to confluency (0.88 × 10 ⁶ cells / well). Cells were treated with 10 μΜ nucleosides or 10 μΜ prodrugs for 24 hours. After 24 hours, the cells were washed twice with 2.0 mL ice-cold 0.9% sodium chloride saline. The cells were then scraped into 0.5 mL 70% methanol (MeOH) and frozen overnight to facilitate nucleotide metabolite extraction. The extracted cellular material in 70% MeOH was transferred into a test tube and dried. After drying, the sample was resuspended with 1 mM ammonium phosphate pH 8.5 containing an internal standard (100 nM Cl ATP). Intracellular levels of triphosphate nucleosides were quantified based on a formal standard curve by liquid chromatography coupled with tandem mass spectrometry.

result

Cytotoxic cell culture assay (CC50 determination):
The assay is based on assessment of the cytotoxic effects of test compounds using metabolic substrates.
CC50 determination assay protocol:
MT-2 cells are maintained in RPMI-1640 medium supplemented with 1.5% fetal bovine serum and antibiotics.
2. Cells are distributed into 96-well plates (20,000 cells in 100 μL medium / well) and various concentrations of test compound are added three times (100 μL / well). Includes untreated control.
3. Cells are incubated at 37 ° C. for 5 days.
4). Prepare a 2 mg / mL XTT solution (6 mL / assay plate) in phosphate buffered saline pH 7.4 in the dark. Heat the solution in a 55 ° C. water bath for 5 minutes. Add 50 [mu] L of N-methylphenazonium methosulphate (5 [mu] g / mL) for every 6 mL XTT solution.
5. Remove 100 μL medium from each well on the assay plate and add 100 μL XTT substrate solution to each well. Incubate for 45-60 minutes at 37 ° C. in a CO ₂ incubator.
6). Add 20 μL of 2% Triton X-100 to each well to prevent XTT metabolic conversion.
7. Subtract background at 650 nm and read absorbance at 450 nm.
8). The absorbance percentage is plotted against the untreated control, and the CC50 value is estimated as the drug concentration that inhibits cell growth by 50%. Consider absorbance directly proportional to cell growth.

  All publications, patents, and patent documents cited herein are hereby incorporated by reference as if individually incorporated. The invention has been described with reference to various specific and preferred embodiments and techniques. However, those skilled in the art will appreciate that many changes and modifications may be made and remain within the spirit and scope of the invention.

Claims (1)

2'-fluoro substituted carbanucleoside analogs for antiviral therapy and the like.