JP4738172B2 - Antiinfectives - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an HCV (hepatitis C virus) polymerase inhibiting compound and a composition including a therapeutically effective amount of the compound. <P>SOLUTION: This invention relates to the compound having formula (I). This invention also relates to methods for inhibiting HCV polymerase, inhibiting HCV viral replication, and treating or preventing HCV infection. Processes for making the compounds and the synthetic intermediates employed in the processes, are also provided. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention provides novel anti-infective agents. Specifically, the present invention provides HCV polymerase inhibitory compounds, as well as compositions comprising a therapeutically effective amount of the compounds. The present invention also provides methods for inhibiting hepatitis C virus (HCV) polymerase, methods for inhibiting HCV virus replication, and methods for treating or preventing HCV infection. Also provided are methods for producing the compounds and synthetic intermediates used in the methods.

  Infection with hepatitis C virus (HCV) is a major cause of human liver disease worldwide. Over 85% of all infected people are chronically infected. Chronic HCV infection represents 30% of all cirrhosis, end-stage liver disease and liver cancer in the United States. The CDC estimates that the number of deaths from HCV will increase to 38,000 per year by 2010.

  Initial treatment consisted of interferon alone, but the combination of interferon α-2b and ribavirin over 24 or 48 weeks is now the most effective approved treatment for the treatment of chronic HCV infection. However, there are many side effects associated with this therapy (flu-like symptoms from interferon, leukemia, thrombocytopenia and depression, and anemia induced by ribavirin). Furthermore, this treatment is not very effective against infections caused by HVCV genotype 1, which accounts for about 75% of all HCV infections.

  Based on the above contents, it is strongly desired to identify compounds having the ability to inhibit HCV. The present invention provides novel anti-infective agents that are HCV polymerase inhibitors.

  The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt form, stereoisomer or tautomer thereof.

式中、
Ａは、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環からなる群から選択される単環式または二環式環であり；
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^２およびＲ^３は独立に、水素、アルケニル、アルキニル、アルコキシアルキル、アルコキシカルボニル、アルキル、アリール、アリールアルキル、ヘテロアリール、複素環、ヘテロアリールアルキル、シアノ、ハロ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａおよびＲ_ａＣ（Ｏ）−からなる群から選択され；Ｒ^２およびＲ^３は独立に、独立にＲ_ａ、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ^２およびＲ^３が、それらが結合している炭素原子と一体となって、アリール、シクロアルキル、ヘテロアリールおよび複素環からなる群から選択される５員または６員環を形成しており、前記アリール、シクロアルキル、ヘテロアリールおよび複素環は（Ｒ^６）_ｍで置換されていても良く；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は独立に、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１、２、３または４であり；
ただし、Ａが下記のもの：

Where
A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, selected from the group consisting of R _f R _g C═N— and R _k O—; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro , Haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c ,- _{S (O) R c, -S} (O) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C ( O) N It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _c R _e;
R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _{b), R a R b NC} (O) -, - SR a, -S (O) R a, -S (O) 2 R a , and _R a C (O) - is selected from the group consisting of; ^{R 2} And R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, — (alkyl) (OR _k ), — (alkyl) (NR _a R _b ), —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and From —C (O) NR _a R _b Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of;
Alternatively, R ² and R ³ together with the carbon atom to which they are attached form a 5- or 6-membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl and heterocycle And the aryl, cycloalkyl, heteroaryl and heterocycle may be substituted with (R ⁶ ) _m ;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently, independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substituents selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Is replaced by;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Where A is:

以外の単環式環であり、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではなく；
さらには、Ａが下記のもの：

R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, Cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N ( R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, heteroaryl, _{heterocyclealkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R _a , —C (O) OR _a and — When C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, hetero Not arylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl;
In addition, A is:

であり、Ｒ^４がヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、未置換アルキル、ハロまたは−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ、および−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

R ⁴ is hydroxy or R _e S—, R ⁵ is hydrogen, unsubstituted alkyl, halo or —OR _k and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl , Heteroaryl, heterocyclic alkyl, —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _{When a is} —C (O) OR and —C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl , (Cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl.

  The present invention also provides a process for producing the compounds of the present invention and intermediates used in the process.

  The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a compound or combination of compounds of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

  The present invention also provides a method for the treatment or prevention of an infection caused by an RNA-containing virus comprising the step of administering the pharmaceutical composition of the present invention to a patient in need of such treatment.

  The present invention further comprises a method of inhibiting the replication of an RNA-containing virus comprising the step of contacting said virus with a therapeutically effective amount of a compound or combination of compounds of the present invention or a pharmaceutically acceptable salt thereof. I will provide a.

  The present invention further provides a method for the treatment or prevention of infections caused by RNA-containing viruses, comprising the step of administering the pharmaceutical composition of the present invention to a patient in need of such treatment. .

  As used herein, the following terms have the meanings indicated:

  As used herein, the singular forms “a”, “an” and “the” are intended to include the plural unless the context clearly indicates otherwise. .

  As used herein, the term “alkyl” is derived from a straight or branched saturated hydrocarbon having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Refers to the group Examples of alkyl groups include butyl, methyl, 2-methylbutyl and the like.

  As used herein, the term “alkenyl” is a straight chain of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms having at least one carbon-carbon double bond. Or refers to a branching group. Examples of alkenyl groups include allyl, propenyl, 3-methyl-2-butenyl and the like.

  As used herein, the term “alkynyl” is a straight chain of 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms having at least one carbon-carbon triple bond. Or a branched hydrocarbon. Examples of alkynyl groups include ethynyl, 2-methyl-3-butynyl, 3-pentynyl and the like.

  The term “alkoxy” as used herein refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include tert-butoxy, methoxy, isopropoxy and the like.

  The term “alkoxyalkoxy” as used herein, means an alkoxy group, as de? Ned herein, appended to the parent molecular moiety through another alkoxy group, as de? Ned herein.

  Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy and methoxymethoxy.

  The term “alkoxyalkoxyalkyl” as used herein, means an alkoxyalkoxy group, as de? Ned herein, appended to the parent molecular moiety through an alkyl group, as de? Ned herein. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy) methyl, and 2- (2-methoxyethoxy) ethyl. is not.

  The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with at least one alkoxy group.

  The term “alkoxycarbonyl” as used herein refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl groups include tert-butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl and the like.

  The term “alkoxycarbonylalkyl” as used herein refers to an alkoxycarbonyl group attached to the parent molecular moiety through an alkyl group.

  The term “alkylcarbonyl” as used herein refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of alkylcarbonyl groups include acyl, butanoyl, 2,2-dimethylpropanoyl and the like.

  The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonyl group, as de? Ned herein, appended to the parent molecular moiety through an alkyl group, as de? Ned herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

  The term “alkylsulfanyl” as used herein refers to an alkyl group attached to the parent molecular moiety through a sulfur atom. Examples of alkylsulfanyl groups include methylsulfanyl, (1-methylethyl) sulfanyl, (2-methylpropyl) sulfanyl and the like.

  The term “alkylsulfanylalkyl” as used herein refers to an alkylsulfanyl group attached to the parent molecular moiety through an alkyl group.

  The term “alkylsulfinyl” as used herein refers to an alkyl group attached to the parent molecular moiety through a —S (O) — group.

  The term “alkylsulfinylalkyl” as used herein refers to an alkylsulfinyl group attached to the parent molecular moiety through an alkyl group.

The term “alkylsulfonyl” as used herein refers to an alkyl group attached to the parent molecular moiety through a —S (O) ₂ — group.

  The term “alkylsulfonylalkyl” as used herein refers to an alkylsulfonyl group attached to the parent molecular moiety through an alkyl group.

The term “aryl” as used herein refers to a phenyl group or a bicyclic or tricyclic hydrocarbon fused ring system in which one or more rings is a phenyl group. A bicyclic fused ring system has a phenyl group fused to a monocyclic cycloalkenyl group as defined herein, a monocyclic cycloalkyl group as defined herein, or another phenyl group. Examples of tricyclic fused ring systems include bicyclic fused ring systems fused to a monocyclic cycloalkenyl group as defined herein, a monocyclic cycloalkyl group as defined herein, or another phenyl group. There is. Examples of aryl groups include anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl and the like. The aryl groups of the present invention may be attached to the parent molecular moiety through any substitutable carbon atom of the group. The aryl groups of the present invention are independently alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —SO ₂ OR _a , —SO ₂ NR _a R _b , —NR _{a ^{R b, -N (R 3)}} C (O) R a, -N (R e) C (O) OR a, -N (R e) C (O) NR a R b, -N (R e) SO ₂ R _a , —N (R _e ) SO ₂ NR _a R _b , —N (R _e ) SO ₂ N (R _e ) C (O) OR _a , —C (O) R _a , —C (O ) OR _a , —C (O) NR _a R _b cycloalkyl, cycloalkenyl, heterocycle, second aryl group and heteroary Optionally substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of: alkenyl, alkenyl and alkynyl each independently, independently cyano, formyl, halo , Nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , — SR _a , —SOR _a , —SO ₂ R _a , —SO ₂ OR _a , —SO ₂ NR _a R _b , —NR _a R _b , —N (R _e ) C (O) R _a , —N (R ,) C (O) OR _a , —N (R _e ) C (O) NR _a R _b , —N (R _e ) SO ₂ R _a , —N (R _e ) SO ₂ NR _a R _b , —N _{(R e) SO 2 N (} R e) C (O) OR a, -C (O) R a, -C (O) OR a, -C ( ) NR a _{R b,} cycloalkyl, cycloalkenyl, heterocycle are substituted with a second aryl group and 0, 1, 2 or 3 substituents selected from the group consisting of heteroaryl; R _a, R _b and R _e are as defined herein; the second aryl group, heteroaryl, cycloalkyl, cycloalkenyl and heterocycle are independently —OH, —O (alkyl), alkyl, alkenyl. , alkynyl, cyano, formyl, halo, haloalkoxy, haloalkyl, _{nitro, -NH 2, -N (H)} ( alkyl), - N _{(alkyl) 2, -C (O) OH} , -C (O) O ( Alkyl), —C (O) NH ₂ , —C (O) N (H) (alkyl), —C (O) N (alkyl) ₂ and 0, 1, 2, or 3 selected from the group consisting of oxo Pieces It may be substituted with a substituent.

  The term “arylalkenyl” as used herein refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

  The term “arylalkoxy” as used herein refers to an arylalkyl group attached to the parent molecular moiety through an oxygen atom.

  The term “arylalkyl” as used herein refers to an aryl group attached to the parent molecular moiety through an alkyl group.

  The term “arylcarbonyl” as used herein refers to an aryl group attached to the parent molecular moiety through a carbonyl group.

  The term “arylcarbonylalkyl” as used herein, means an arylcarbonyl group, as de? Ned herein, appended to the parent molecular moiety through an alkyl group, as de? Ned herein.

  The term “aryloxy” as used herein refers to an aryl group attached to the parent molecular moiety through an oxygen atom.

  The term “aryloxyalkyl” as used herein refers to an aryloxy group attached to the parent molecular moiety through an alkyl atom.

  The term “arylsulfanyl” as used herein refers to an aryl group attached to the parent molecular moiety through a sulfur atom.

  The term “arylsulfanylalkyl” as used herein refers to an arylsulfanyl group attached to the parent molecular moiety through an alkyl group.

  The term “arylsulfonyl” as used herein refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.

  The term “arylsulfonylalkyl” as used herein refers to an arylsulfonyl group attached to the parent molecular moiety through an alkyl group.

The term “carboxy” as used herein refers to —CO ₂ H.

  The term “carboxyalkyl” as used herein refers to a carboxy group attached to the parent molecular moiety through an alkyl group.

  The term “cyano” as used herein refers to —CN.

  The term “cyanoalkyl” as used herein refers to a cyano group attached to the parent molecular moiety through an alkyl group.

As used herein, the term “cycloalkenyl” refers to a non-aromatic, partially unsaturated monocyclic, bicyclic or tricyclic ring having 3 to 14 carbon atoms and 0 heteroatoms. Refers to the formula ring system. Examples of cycloalkenyl groups include cyclohexenyl, octahydronaphthalenyl, norbornylenyl and the like. The cycloalkenyl groups of the present invention are independently alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O ) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —SO ₂ OR _a , —SO ₂ NR _a R _b , —NR _{a R b, -N (R e} ) C (O) R a, -N (R e) C (O) OR a, -N (R e) C (O) NR a R b, -N (R e ) SO ₂ R _a , —N (R _e ) SO ₂ NR _a R _b , —N (R _e ) SO ₂ N (R _e ) C (O) OR _a , —C (O) R _a , —C ( O) OR _a , —C (O) NR _a R _b cycloalkyl, second cycloalkenyl, heterocycle, aryl, heteroa Optionally substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of reel and ethylenedioxy; said alkyl, alkenyl and alkynyl are each independently, independently cyano, Formyl, halo, nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _{b, -SR a, -SOR a,} -SO 2 R a, -SO 2 OR a, -SO 2 NR a R b, -NR a R b, -N (R e) C (O) R a, - N (R _e ) C (O) OR _a —N (R _e ) C (O) NR _a R _b , —N (R _e ) SO ₂ R _a , —N (R _e ) SO ₂ N R _a R _b , _{-N (R e) SO 2 N} (R e) C (O) OR a, -C (O) R a, - _{(O) OR a, -C (} O) NR a R b, cycloalkyl, a second cycloalkenyl, heterocycle, aryl and 0, 1, 2 or 3 substituents selected from the group consisting of heteroaryl R _a , R _b and R _e are as defined herein; and said cycloalkyl, said second cycloalkenyl, said heterocycle, said aryl and said heteroaryl are independently- OH, —O (alkyl), alkyl, alkenyl, alkynyl, cyano, formyl, halo, oxo, haloalkoxy, haloalkyl, nitro, oxo, —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , -C (O) OH, -C (O) O ( _{alkyl), - C (O) NH} 2, the -C (O) N (H) ( alkyl) and -C (O) N _{(alkyl) 2} It may be substituted with 0, 1, 2 or 3 substituents selected from that group.

  The term “cycloalkenylalkyl” as used herein refers to a cycloalkenyl group attached to the parent molecular moiety through an alkyl group.

The term “cycloalkyl” as used herein refers to a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring system having 3 to 14 carbon atoms and 0 heteroatoms. . Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [3.1.1] heptyl, 6,6-dimethylbicyclo [3.1.1] heptyl, adamantyl and the like. The cycloalkyl groups of the present invention are independently alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O ) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —SO ₂ OR _a , —SO ₂ NR _a R _b , —NR _{a R b, -N (R e} ) C (O) R a, -N (R e) C (O) OR a, -N (R e) C (O) NR a R b, -N (R e —N (R _e ) SO ₂ N (R _e ) C (O) OR _a , —C (O) R _a , —C (O) OR _a , —C (O) NR _a R _b , second cyclo Selected from the group consisting of alkyl, cycloalkenyl, heterocycle, aryl, heteroaryl and ethylenedioxy May be substituted with 1, 2, 3, 4 or 5 substituents; said alkyl, respectively alkenyl and alkynyl are independently cyano independently, formyl, halo, nitro, oxo, _-OR a, _{-OC (O) R a, -OC} (O) OR a, -OC (O) NR a R b, -OSO 2 R a, -OSO 2 NR a R b, -SR a, -SOR a, -SO ₂ R _a , —SO ₂ 0R _a , —SO ₂ NR _a R _b , —NR _a R _b , —N (R _e ) C (O) R _a , —N (R _e ) C (O) OR _a , -N (R _e ) C (O) NR _a R _b , -N (R _e ) SO ₂ R _a -N (R _e ) SO ₂ NR _a R _b , -N (R _e ) SO ₂ N (R _{e ) C (O) OR a,} -C (O) R a, -C (O) OR a, -C (O) NR a R b, a second Sik Defined R _a, R _b and R _e are herein; alkyl, cycloalkenyl, heterocycle, aryl and 0, 1, 2 or 3 substituents selected from the group consisting of heteroaryl and substituted The second cycloalkyl, the cycloalkenyl, the heterocycle, the aryl and the heteroaryl are independently —OH, —O (alkyl), alkyl, alkenyl, alkynyl, cyano, formyl, halo. , haloalkoxy, haloalkyl, nitro, _{oxo, -NH 2, -N (H)} ( alkyl), - N _{(alkyl) 2, -C (O) OH} , -C (O) O ( alkyl), - C ( Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of O) NH ₂ , —C (O) N (H) (alkyl) and —C (O) N (alkyl) ₂ May be.

  The term “cycloalkylalkenyl” as used herein refers to a cycloalkyl group attached to the parent molecular moiety through an alkenyl group.

  The term “cycloalkylalkyl” as used herein refers to a cycloalkyl group attached to the parent molecular moiety through an alkyl group.

  The term “formyl” as used herein refers to —CHO.

  The term “formylalkyl” as used herein refers to a formyl group attached to the parent molecular moiety through an alkyl group.

  As used herein, the terms “halo” and “halogen” refer to F, Cl, Br and I.

  The term “haloalkoxy” as used herein refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

  The term “haloalkoxyalkyl” as used herein refers to a haloalkoxy group attached to the parent molecular moiety through an alkyl group.

  The term “haloalkyl” as used herein refers to an alkyl group substituted by 1, 2, 3 or 4 halogen atoms.

As used herein, the term “heteroaryl” is an aromatic 5- or 6-membered ring in which at least one atom is selected from the group consisting of N, O, and S, with the remaining atoms being carbon. Point to. The term “heteroaryl” includes bicyclic systems in which a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocyclic group, as defined herein, or another Heteroaryl groups are also included. The term “heteroaryl” includes a tricyclic system in which the bicyclic system is fused to a phenyl group, a monocyclic cycloalkyl group as defined herein, a heterocyclic group as defined herein, or another Of heteroaryl groups. The heteroaryl group is attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Examples of heteroaryl groups include benzothienyl, benzoxazolyl, benzimidazolyl, benzooxadiazolyl, dibenzofuranyl, dihydrobenzothiazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, Examples include oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, triazinyl and the like. The heteroaryl groups of the present invention are independently alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O ) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —SO ₂ OR _a , —SO ₂ NR _a R _b , —NR _{a R b, -N (R e} ) C (O) R a, -N (R e) C (O) OR a, -N (R e) C (O) NR a R b, -N (R e ) SO ₂ R _a , —N (R _e ) SO ₂ NR _a R _b , —N (R _e ) SO ₂ N (R _e ) C (O) OR _a , —C (O) R _a , —C ( _{O) oR a, -C (O} ) NR a R b, cycloalkyl, cycloalkenyl, heterocycle, aryl and a second f Optionally substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of roaryl groups; said alkyl, alkenyl and alkynyl are each independently, independently cyano, formyl, halo , Nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , — SR _a , —SOR _a , —SO ₂ R _a , —SO ₂ 0R _a , —SO ₂ NR _a R _b , —NR _a R _b , ￣N (R _e ) C (O) R _a —N (R _e ) C (O) OR _a , —N (R _e ) C (O) NR _a R _b , —N (R _e ) SO ₂ R _a , —N (R _e ) SO ₂ NRR _b , —N (R _{e) ) SO 2 N (R e)} C (O) OR a, -C (O) R a -C (O) OR a, -C O) NR a _{R b,} cycloalkyl, cycloalkenyl, heterocycle, is substituted with aryl and second 0, 1, 2 or 3 substituents selected from the group consisting of heteroaryl group; R _a , R _b and R _e are as defined herein, and the second heteroaryl group, the aryl, the cycloalkyl, the cycloalkenyl and the heterocycle are independently, —OH, —O (alkyl), alkyl, alkenyl, alkynyl, cyano, formyl, halo, haloalkoxy, haloalkyl, _nitro, -NH 2, -N (H) (alkyl), - N _(alkyl) 2, -C (O) OH, -C (O) O _{(alkyl), - C (O) NH} 2, -C (O) N (H) ( alkyl), - C (O) N ( _alkyl) is selected from the group consisting of _2, and oxo It may be substituted with 0, 1, 2 or 3 substituents that. Furthermore, the nitrogen heteroatom may be quaternized or oxidized to N-oxide. Furthermore, the nitrogen-containing ring may be N-protected.

  The term “heteroarylalkenyl” as used herein refers to a heteroaryl group attached to the parent molecular moiety through an alkenyl group.

  The term “heteroarylalkyl” as used herein refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.

  The term “heteroarylsulfonyl” as used herein refers to a heteroaryl group attached to the parent molecular moiety through a sulfonyl group.

  The term “heteroarylsulfonylalkyl” as used herein refers to a heteroarylsulfonyl group attached to the parent molecular moiety through an alkyl group.

The term “heterocycle” as used herein refers to cyclic, non-aromatic saturated or partially unsaturated 3, 4 having at least one atom selected from the group consisting of oxygen, nitrogen and sulfur. Refers to a 5, 6 or 7 membered ring. The term “heterocycle” includes a heterocycle attached to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another monocyclic heterocyclic group. Also included are fused bicyclic systems. The term “heterocycle” includes fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another monocyclic heterocyclic group. Also included are tricyclic systems. The heterocyclic groups of the present invention are attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Examples of heterocyclic groups include benzoxazinyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridyl There are dinyl, piperidinyl, thiomorpholinyl, tetrahydropyranyl and the like. The heterocyclic groups of the present invention are independently alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O ) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —SO ₂ O R _a , —SO ₂ NR _a R _b , —NR _{a R b, -N (R e} ) C (O) R a, -N (R e) C (O) OR a, -N (R e) C (O) NR a R b, -N (R e ) SO ₂ R _a , —N (R _e ) SO ₂ NR _a R _b , —N (R _e ) SO ₂ N (R _e ) C (O) OR _a , —C (O) R _a , —C ( _{O) OR a, -C (O} ) NR a R b, cycloalkyl, cycloalkenyl, a second heterocycle, aryl, heteroaryl And optionally substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of ethylenedioxy; said alkyl, alkenyl and alkynyl are each independently, independently cyano, formyl , Halo, nitro, oxo, —OR _a , —OC (O) R _a , —OC (O) OR _a , —OC (O) NR _a R _b , —OSO ₂ R _a , —OSO ₂ NR _a R _b , —SR ² , —SOR _a , —SO ₂ R _a , —SO ₂ 0R _a , —SO ₂ NR _a R _b , —NR _a R _b , —N (R _e ) C (O) R _a , —N (R _e ) C (O) OR _a , —N (R _e ) C (O) NR _a R _b , —N (R _e ) SO ₂ R _a , —N (R _e ) SO ₂ NR _a R _b , _{-N (R e) SO 2 N} (R e) C (O) OR a, -C (O) R a, -C (O _{OR a, -C (O) NR} a R b, cycloalkyl, cycloalkenyl, substituted with a second heterocycle, aryl and 0, 1, 2 or 3 substituents selected from the group consisting of heteroaryl R _a , R _b and R _e are as defined herein; the cycloalkyl, cycloalkenyl, the second heterocycle, the aryl and the heteroaryl are independently —OH , —O (alkyl), alkyl, alkenyl, alkynyl, cyano, formyl, halo, haloalkoxy, haloalkyl, nitro, oxo, —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —C (O) OH, -C (O ) O ( _{alkyl), - C (O) NH} 2, -C (O) N (H) ( alkyl), and -C (O) N _(alkyl) group consisting of ₂ Or May be substituted with 0, 1, 2 or 3 substituents selected from Further, the nitrogen heteroatom may be quaternized or oxidized to N-oxide. Furthermore, the nitrogen-containing heterocycle may be N-protected.

  The term “heterocyclic alkenyl” as used herein refers to a heterocyclic group attached to the parent molecular moiety through an alkenyl group.

  The term “heterocyclic alkyl” as used herein refers to a heterocyclic group attached to the parent molecular moiety through an alkyl group.

  The term “heterocyclic carbonyl” as used herein, means a heterocycle, as de? Ned herein, appended to the parent molecular moiety through a carbonyl group, as de? Ned herein.

  Representative examples of heterocyclic carbonyl include, but are not limited to, pyrrolidinylcarbonyl and piperazin-1-ylcarbonyl.

  The term “hydroxy” as used herein refers to —OH.

  The term “hydroxyalkyl” as used herein refers to an alkyl group substituted with at least one hydroxy group.

The term “nitro” as used herein refers to —NO ₂ .

  The term “nitroalkyl” as used herein refers to an alkyl group substituted with at least one nitro group.

  The term “oxo” as used herein refers to ═O.

  The term “sulfanyl” as used herein refers to —S—.

  The term “sulfinyl” as used herein refers to —SO—.

The term “sulfonyl” as used herein refers to —SO ₂ —.

  Alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkynyl, alkylsulfanyl, alkylsulfanylalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkyl Sulfonylalkyl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, arylsulfanylalkyl, arylsulfonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloal Kishiarukiru, haloalkyl, heteroarylalkenyl, it is clear that heteroarylalkyl, heteroalkyl sulfonyl alkyl, heterocycloalkenyl, heterocyclealkyl, hydroxyalkyl and nitroalkyl may be substituted.

  In a first embodiment, the present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt form, stereoisomer or tautomer thereof.

式中、
Ａは、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環からなる群から選択される単環式または二環式環であり；
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^２およびＲ^３は独立に、水素、アルケニル、アルキニル、アルコキシアルキル、アルコキシカルボニル、アルキル、アリール、アリールアルキル、ヘテロアリール、複素環、ヘテロアリールアルキル、シアノ、ハロ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａおよびＲ_ａＣ（Ｏ）−からなる群から選択され；Ｒ^２およびＲ^３は独立に、独立にＲ_ａ、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ^２およびＲ^３が、それらが結合している炭素原子と一体となって、アリール、シクロアルキル、ヘテロアリールおよび複素環からなる群から選択される５員または６員環を形成しており、前記アリール、シクロアルキル、ヘテロアリールおよび複素環は（Ｒ^６）_ｍで置換されていても良く；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は独立に、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１、２、３または４であり；
ただし、Ａが下記のもの：

Where
A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, selected from the group consisting of R _f R _g C═N— and R _k O—; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro , Haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c ,- _{S (O) R c, -S} (O) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C ( O) N It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _c R _e;
R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _{b), R a R b NC} (O) -, - SR a, -S (O) R a, -S (O) 2 R a , and _R a C (O) - is selected from the group consisting of; ^{R 2} And R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, — (alkyl) (OR _k ), — (alkyl) (NR _a R _b ), —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and From —C (O) NR _a R _b Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of;
Alternatively, R ² and R ³ together with the carbon atom to which they are attached form a 5- or 6-membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl and heterocycle And the aryl, cycloalkyl, heteroaryl and heterocycle may be substituted with (R ⁶ ) _m ;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently, independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substituents selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Is replaced by;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Where A is:

以外の単環式環であり、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではなく；
さらには、Ａが下記のもの：

R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, Cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N ( R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, heteroaryl, _{heterocyclealkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R _a , —C (O) OR _a and — When C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, hetero Not arylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl;
In addition, A is:

であり、Ｒ^４がヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、未置換アルキル、ハロまたは−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ、および−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

R ⁴ is hydroxy or R _e S—, R ⁵ is hydrogen, unsubstituted alkyl, halo or —OR _k and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl , Heteroaryl, heterocyclic alkyl, —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _{When a is} —C (O) OR and —C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl , (Cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl.

  For example, the present invention provides a compound of formula (I) wherein A is a monocyclic ring selected from the group consisting of aryl and heteroaryl.

  For example, the present invention provides a compound of formula (I) wherein A is a bicyclic ring selected from the group consisting of heterocycle and heteroaryl.

  For example, in the present invention, A is naphthyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzoisoxazolyl, benzoxazinyl, benzothia Provided are compounds of formula (I) selected from the group consisting of diazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and naphthyridinyl, cinnolinyl and pteridinyl.

For example, the present invention provides that R ² and R ³ together with the carbon atom to which they are attached are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl A compound of formula (I) is provided that forms a 5- or 6-membered ring selected from the group consisting of: phenyl, pyridyl, pyridazinyl and pyrimidinyl.

For example, the present invention provides a compound of formula (I) wherein R ² and R ³ together with the carbon atom to which they are attached form a cycloalkyl ring.

For example, the present invention provides a compound of formula (I) wherein R ² and R ³ together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring.

For example, the invention provides that R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N ( R _a ) (R _b ), R _a R _b NC (O) —, —SR _a , —S (O) R _a , —S (O) ₂ R _a and R _a C (O) — R ² and R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl,-(alkyl) (OR _k ),-(alkyl) (NR _a R _{b), - SR a, -S} (O) R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R a, -C ( O) OR _a and -C (O) Provided is a compound of formula (I) substituted with 0, 1, 2, or 3 substituents selected from the group consisting of NR _a R _b .

For example, in the present invention, R ⁴ is hydroxy, halo, —NH ₂ , —NH (alkyl), —N (alkyl) ₂ , —N (H) NH ₂ , —N ₃ , —N (H) (hydroxyalkyl) Or a compound of formula (I) which is R _c S—.

For example, the present invention provides that A is aryl; R ² and R ³ together with the carbon atom to which they are attached, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl A compound of formula (I) is provided that forms a 5- or 6-membered ring selected from the group consisting of:, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, tetrazolyl, cyclopentyl and cyclohexyl.

For example, the present invention provides that A is phenyl; R ² and R ³ together with the carbon atom to which they are attached, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl A compound of formula (I) is provided that forms a 5- or 6-membered ring selected from the group consisting of:, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, tetrazolyl, cyclopentyl and cyclohexyl.

For example, the present invention provides compounds of formula (I) wherein A is phenyl; R ² and R ³ are pyridyl together with the carbon atom to which they are attached.

For example, the present invention provides compounds of formula (I) wherein A is phenyl; and R ² and R ³ are thienyl together with the carbon atom to which they are attached.

For example, the present invention provides that A is heteroaryl; R ² and R ³ together with the carbon atom to which they are attached phenyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl A compound of formula (I) is provided that forms a 5- or 6-membered ring selected from the group consisting of: imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, tetrazolyl, cyclopentyl and cyclohexyl.

For example, the invention provides that A is thienyl; R ² and R ³ together with the carbon atom to which they are attached phenyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, Provided is a compound of formula (I) forming a 5- or 6-membered ring selected from the group consisting of imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, tetrazolyl, cyclopentyl and cyclohexyl.

For example, the present invention provides compounds of formula (I) wherein A is thienyl; R ² and R ³ together with the carbon atom to which they are attached form a phenyl ring.

For example, the invention provides compounds of formula (I) wherein A is thienyl; R ² and R ³ are pyridyl together with the carbon atom to which they are attached.

For example, the present invention provides that A is pyridyl; R ² and R ³ together with the carbon atom to which they are attached, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl There is provided a compound of formula (I) which forms a 5 or 6 member selected from the group consisting of: imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, tetrazolyl, cyclopentyl and cyclohexyl.

For example, the present invention provides compounds of formula (I) wherein A is pyridyl; R ² and R ³ together with the carbon atom to which they are attached form a pyridyl ring.

For example, the invention provides that A is phenyl, thienyl, pyridyl, imidazolyl, benzoxazolyl, benzoxazinyl or benzimidazolyl; R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, Alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _b ), R _a R _b NC (O) —, —SR _a , —S (O ) R _a , —S (O) ₂ R _a and R _a C (O) —; R ² and R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo , Cyano, nitro, haloalkyl,-(alkyl) (OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O ) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and —C (O) NR Provided is a compound of formula (I) substituted with 0, 1, 2, or 3 substituents selected from the group consisting of _a R _b .

For example, the present invention provides that R ² and R ³ together with the carbon atom to which they are attached are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl Forming a 5- or 6-membered ring selected from the group consisting of, phenyl, pyridyl, pyridazinyl and pyrimidinyl; R ⁴ is hydroxy. In an even more preferred embodiment, the invention provides that A is pyridyl, phenyl, thienyl, imidazolyl, benzoxazolyl, benzimidazolyl or benzoxazinyl; and R ² and R ³ are the carbon atom to which they are attached; Together, they form a 5- or 6-membered ring selected from phenyl, thienyl, pyrazolyl, pyridyl, pyrimidinyl or pyridazinyl; provided is a compound of formula (I) wherein R ⁴ is hydroxy.

For example, the present invention provides compounds of formula (I) wherein A is pyridyl; R ² and R ³ together with the carbon atom to which they are attached form a pyridyl ring; and R ⁴ is hydroxyl I will provide a.

For example, the invention provides that A is pyridyl, phenyl, thienyl, imidazolyl, benzoxazolyl, benzimidazolyl or benzoxazinyl; R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl , Alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _b ), R _a R _b NC (O) —, —SR _a , —S ( O) R _a , —S (O) ₂ R _a and R _a C (O) — are selected; R ² and R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, Halo, cyano, nitro, haloalkyl,-(alkyl) (OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S ( O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and —C (O) Provided are compounds of formula (I), substituted with 0, 1, 2 or 3 substituents selected from the group consisting of NR _a R _b ; wherein R ⁴ is hydroxy.

For example, the invention provides that A is pyridyl, phenyl, thienyl, imidazolyl, benzimidazolyl, benzoxazolyl or benzoxazinyl; R ² and R ³ together with the carbon atom to which they are attached; Forming a 5- or 6-membered ring selected from the group consisting of phenyl, pyridyl, thienyl, pyrimidinyl, pyrazolyl, pyridazinyl, cyclohexyl or cyclopentyl; R ⁴ is hydroxy; R ¹ is hydrogen, alkenyl, alkoxyalkyl , Alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkenyl, cycloalkylalkyl, formi Rualkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic alkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl - _to provide a compound of a formula selected from R _f R g C = N- and _R k group consisting O- (I).

Examples of compounds of the first embodiment of the invention of formula (I) include
1- [2- (1-Cyclohexen-1-yl) ethyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1, 8-naphthyridin-2 (1H) -one;
[3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridin-1 (2H) -yl] acetic acid ethyl;
1- (3-anilinopropyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H ) -On;
3- [3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridin-1 (2H) -yl ] Propanal;
1- [3- (Dimethylamino) propyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -on;
1- (3-[[2- (Dimethylamino) ethyl] (methyl) amino] propyl} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl)- 4-hydroxy-1,8-naphthyridin-2 (1H) -one;
1- (2-Aminoethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON;
1- [3- (Diethylamino) propyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 ( 1H) -on;
1- (Benzyloxy) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one ;
1- (Benzyloxy) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one ;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-isobutoxy-1,8-naphthyridin-2 (1H) -one;
1-benzyl-4-chloro-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one;
1-butyl-4-chloro-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one;
4-amino-1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one;
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- (methylamino) -1,8-naphthyridin-2 (1H) -one ;
1-butyl-4- (dimethylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one ;
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydrazino-1,8-naphthyridin-2 (1H) -one;
4-azido-1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one;
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(2-hydroxyethyl) amino] -1,8-naphthyridine-2 (1H) -on;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -N ′-(2-phenylethyl) sulfamide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylic acid benzyl 2,2-dioxide;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] sulfamide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-propyldiazathian-1-carboxylate benzyl 2,2-dioxide;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -N'-propylsulfamide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylate methyl 2,2-dioxide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylate allyl 2,2-dioxide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylic acid 2-propynyl 2,2-dioxide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylic acid 2-cyanoethyl 2,2-dioxide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylate 2- (trimethylsilyl) ethyl 2,2-dioxide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylic acid benzyl 2,2-dioxide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylate methyl 2,2-dioxide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-methyldiazathian-1-carboxylate benzyl 2,2-dioxide;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -N'-methylsulfamide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylic acid 2-aminoethyl 2,2-dioxide;
N-cyclopentyl-N ′-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1, 2,4-benzothiadiazin-7-yl] sulfamide;
N-cyclobutyl-N ′-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1, 2,4-benzothiadiazin-7-yl] sulfamide;
N [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl] -N '-(4-piperidinyl) sulfamide;
N- (2-hydroxyethyl) -N '-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide -4H-1,2,4-benzothiadiazin-7-yl] sulfamide;
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl] amino} sulfonyl) amino] propanamide;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-azetidinesulfonamide;
3-hydroxy-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] -1-azetidinesulfonamide;
3-Amino-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] -1-pyrrolidinesulfonamide;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-piperidinesulfonamide;
N-benzyl-N ′-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1, 2,4-benzothiadiazin-7-yl] sulfamide;
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl] amino} sulfonyl) amino] ethyl benzoate;
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl] amino} sulfonyl) amino] benzoic acid;
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo.-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] amino} sulfonyl) amino] benzamide;
N- (2-aminoethyl) -N '-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide -4H-1,2,4-benzothiadiazin-7-yl] sulfamide;
1-({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4 -Benzothiadiazin-7-yl] amino} sulfonyl) -3-piperidinecarboxylate;
(2S) -1-({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1 , 2,4-Benzothiadiazin-7-yl] amino} sulfonyl) -2-pyrrolidinecarboxylate;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-pyrrolidinesulfonamide;
3-hydroxy-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] -1-piperidinesulfonamide;
N- (2-furylmethyl) -3- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide- 4H-1,2,4-benzothiadiazin-7-yl] diazathian-1-carboxamide 2,2-dioxide;
4-Amino-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one ;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (isobutylamino) thieno [3,2-b] pyridine-5 (4H ) -On;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(3S) -3-methylcyclopentyl] amino} thieno [3 2-b] pyridin-5 (4H) -one;
4-{[1-Cyclopropylethyl] amino} -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b ] Pyridin-5 (4H) -one;
4- (Butylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On;
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(2-ethylbutyl) amino] -7-hydroxythieno [3,2-b] pyridine -5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (pentylamino) thieno [3,2-b] pyridine-5 (4H ) -On;
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methylbutyl) amino] thieno [3,2-b] pyridine -5 (4H) -one;
4-[(3,3-Dimethylbutyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2- b] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methylbenzyl) amino] thieno [3,2-b] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(2-methylbenzyl) amino] thieno [3,2-b] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(4-methylbenzyl) amino] thieno [3,2-b] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methylbut-2-enyl) amino] thieno [3,2 -B] pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (propylamino) thieno [3,2-b] pyridine-5 (4H ) -On;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(pyridin-4-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(pyridin-3-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(pyridin-2-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methoxybenzyl) amino] thieno [3,2-b] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(3-furylmethyl) amino] -7-hydroxythieno [3,2-b] Pyridin-5 (4H) -one;
3-({[6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-5-oxothieno [3,2-b] pyridine-4 ( 5H) -yl] amino} methyl) benzonitrile;
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(thien-3-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one;
4- (Cyclobutylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H) -on;
4- (Benzylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On;
4-[(Cyclohexylmethyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine- 5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(1,3-thiazol-5-ylmethyl) amino] thieno [3 , 2-b] pyridin-5 (4H) -one;
4-[(3-Bromobenzyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] Pyridin-5 (4H) -one;
4- (Cyclohexylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On;
4- (Cyclopentylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On;
4- (Cycloheptylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H) -on;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(1R, 3S) -3-methylcyclohexyl] amino} thieno [ 3,2-b] pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(1R, 3R) -3-methylcyclohexyl] amino} thieno [ 3,2-b] pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(1-ethylpropyl) amino] -7-hydroxythieno [3,2-b] Pyridin-5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4 {[1-phenylethyl] amino} thieno [3,2-b] pyridine -5 (4H) -one;
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(1R) -1-methylbutyl] amino} thieno [3,2 -B] pyridin-5 (4H) -one;
4- (Cyclobutylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H) -on;
4-[(Cyclopropylmethyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine -5 (4H) -one;
2-({3- [4- (cyclohexylamino) -7-hydroxy-5-oxo-4,5-dihydrothieno [3,2-b] pyridin-6-yl] -1,1-dioxide-4H-1 , 2,4-benzothiadiazin-7-yl} oxy) acetamide;
N-(({3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-thieno [2,3-e ] [1,2,4] thiadiazin-7-yl} methyl) urea;
1-benzyl-4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} Quinolin-2 (1H) -one;
1-benzyl-4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] quinoline-2 (1H) -on;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxylic acid 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1 , 1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- (2-hydroxyethyl) -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -2-hydroxy-1- (aminocarbonyl) ethyl] -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
N- (2-amino-2-oxoethyl) -3- (1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [ 1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [S) -2-hydroxy-1-methylethyl] -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N, N-bis (2-hydroxyethyl) -4H-thieno [2,3-e] [ 1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxy-1- (hydroxymethyl) ethyl] -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
1-benzyl-4-hydroxy-3- (7-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-3-yl) quinolin-2 (1H) -one;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- (3-hydroxypropyl) -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(2S) -2,3-dihydroxypropyl] -4H-thieno [2,3- e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -1- (hydroxymethyl) propyl] -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxybutyl] -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -4H-thieno [2 , 3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
1-Benzyl-3- [1,1-dioxide-7- (piperazin-1-ylcarbonyl) -4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -4- Hydroxyquinolin-2 (1H) -one;
N- [5- (aminocarbonyl) pyridin-2-yl] -3- (1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-7-yl] methyl carbamate;
[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-7-yl] methylaminocarbonyl carbamate;
3- [7- (Azidomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-benzyl-4-hydroxyquinoline-2 ( 1H) -on;
3- [7- (Aminomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-benzyl-4-hydroxyquinoline-2 (1H) -on;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} methanesulfonamide;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} nicotinamide;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} morpholine-4-carboxamide;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} -2-hydroxyacetamide;
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-3-yl} quinolin-2 (1H) -one;
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazine- 3-yl] quinolin-2 (1H) -one;
N-[{1-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2,3-e ] [1,2,4] thiadiazin-7-yl) methyl] methanesulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] ethanesulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] propane-1-sulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] propane-2-sulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] benzenesulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] -1-phenylmethanesulfonamide;
1-butyl-4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} -1,8-naphthyridin-2 (1H) -one; 1-butyl-4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1 , 2,4] thiadiazin-3-yl] -1,8-naphthyridin-2 (1H) -one;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine -7-carboxylate methyl 1,1-dioxide;
4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} -1- ( 3-methylbutyl) -1,8-naphthyridin-2 (1H) -one;
4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1- (3-methylbutyl ) -1,8-naphthyridin-2 (1H) -one;
1-benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2 (1H) -pyridinone;
1-benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6-dimethyl-2 (1H) -pyridinone;
1-benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-methyl-5-phenyl-2 (1H) -pyridinone;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6-dimethyl-1- (3-methylbutyl) -2 (1H)- Pyridinone;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (2-ethylbutyl) -4-hydroxy-5,6-dimethyl-2 (1H)- Pyridinone;
1-benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-phenyl-2 (1H) -pyridinone;
1,5-dibenzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-methyl-2 (1H) -pyridinone;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (2-ethylbutyl) -4-hydroxy-6-methyl-5-phenyl-2 (1H ) -Pyridinone;
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -2 (1H) -pyridinone;
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydropyridin-3-yl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} methanesulfonamide;
N- [3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7- Yl] methanesulfonamide;
N- [3- (4-Hydroxy-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadiazin-7-yl] methanesulfone An amide;
N- [3- (4-Hydroxy-1-isopentyl-5,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] methanesulfonamide;
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7- Yl] diazathian-1-carboxylic acid benzyl 2,2-dioxide;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7- Yl] sulfamide;
N- {3- [1- (cyclobutylmethyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} methanesulfonamide;
N- {3- [5-Bromo-1- (cyclobutylmethyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl] -1,1-dioxide-4H-1,2,4 -Benzothiadiazin-7-yl} methanesulfonamide;
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-5-vinyl-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadia Din-7-yl] methanesulfonamide; and 3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-propoxyquinoline-2 (1H ) -One; or these pharmaceutically acceptable salt forms, stereoisomers or tautomers, but are not limited thereto.

  In a second embodiment, the present invention provides a compound of formula (II) below or a pharmaceutically acceptable salt form, stereoisomer or tautomer of that compound.

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は独立に、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１、２、３または４であり；
ただし、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, selected from the group consisting of R _f R _g C═N— and R _k O—; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro , Haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c ,- _{S (O) R c, -S} (O) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C ( O) N It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _c R _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently, independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Where R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N (R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, hetero aryl, heterocyclic _{alkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R a, -C (O) oR _a and -C (O) NR If a R _b, R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl Not heterocyclic alkenyl and heterocyclic alkyl.

For example, the present invention provides a compound of formula (II) wherein R ⁴ is hydroxy.

For example, the invention includes R ⁴ is hydroxy; R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo Alkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl A compound of formula (II) selected from the group consisting of-, R _a R _b NC (O) alkyl-, R _f R _g C = N- and R _k O- is provided.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, C ₃ alkenyl, C ₄ alkenyl, C ₅ alkenyl, C ₃ alkynyl, C ₄ alkynyl, C ₅ Alkynyl, furyl (C ₁ -C ₂ alkyl)-, thienyl (C ₁ -C ₂ alkyl)-, phenyl (C ₁ -C ₂ alkyl)-, pyridinyl (C ₁ -C ₂ alkyl)-, thiazolyl (C ₁ -C ₂ alkyl) -, isoxazolyl _(C 1 -C ₂ alkyl) -, naphthyl _(C 1 -C ₂ alkyl), benzothienyl _(C 1 -C ₂ alkyl) -, indolyl _(C 1 -C ₂ alkyl) - , _(C 3 -C _{7 cycloalkyl) (C} 1 _{~C 2} alkyl) _{-, (C} 5 -C _{6 cycloalkenyl) (C} 1 _{~C 2} alkyl) _-, C 3 ~C ₇ Shi Roarukiru, _{(phenylalkyl) O -, (C 1 ~C} 6 _{alkyl) O -, ((C 3} ~C 6 cycloalkyl) alkyl) O-, phenyl _{CH = N-, NH 2, (} C 1 ~C 7 _{alkyl) N (H) -, (} C 1 ~C 7 _{alkenyl) N (H) -, (} C 3 ~C 7 _{cycloalkyl) N (H) -, (} (C 3 ~C 7 cycloalkyl) alkyl) N (H)-, (phenylalkyl) N (H)-, (thienylmethyl) N (H)-, (thiazolylmethyl) N (H)-, (furylmethyl) N (H)-, (pyridinylmethyl) N (H )-, (Tetrahydropyran) N (H)-, (benzyl) N (H)-, (tetrahydronaphthalenyl) N (H)-; each R ¹ is alkyl, hydroxy, oxo , Halo, cyano, nitro, haloalkyl, From the group consisting of haloalkoxy, phenyl, piperazinyl, morpholinyl, carboxy, —C (O) O (alkyl), —NH ₂ , —NH (alkyl), —N (alkyl) ₂ , —O alkyl, —O-phenyl Provided are compounds of formula (II) substituted with 0, 1, 2, or 3 substituents selected.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is ((1-isopropyl) butyl) N (H)-, ((2-chloro-1,3-thiazol-5-yl) methyl) N ( H)-, ((2-methyl-1,3-thiazol-4-yl) methyl) N (H)-, ((3-methylthien-2-yl) methyl) N (H)-, ((3- (Trifluoromethyl) cyclohexyl) N (H)-, ((5-chlorothien-2-yl) methyl) N (H)-, ((pyridin-3-yl) methyl) N (H)-, (1,2 , 3,4-Tetrahydronaphthalen-2-yl) N (H)-, (1,3-thiazol-2-ylmethyl) N (H)-, (1,3-thiazol-5-ylmethyl) N (H) -, (1-cyclohexen-1-yl) ethyl, (1-cyclopropylethyl) N (H -, (1-ethylbutyl) N (H)-, (1-ethylpropyl) N (H)-, (1-methylbutyl) N (H)-, (1-phenylethyl) N (H)-, (1 -Propylbutyl) N (H)-, (1-thien-3-ylethyl) N (H)-, (2- (1H-indol-3-yl) ethyl, (2- (dimethylamino) ethyl) (methyl ) Aminopropyl, (2-bromobenzyl) N (H)-, (2-chloro-1,3-thiazol-5-yl) methyl, (2-chloro-4-pyridinyl) methyl, (2-ethyl-3) -Methylbutyl) N (H)-, (2-ethylbutyl) N (H)-, (2-furylmethyl) N (H)-, (2-methyl-1,2-thiazol-4-yl) methyl, 2-methyl-1,3-thiazol-4-yl) methyl, (2-methyl-1 , 3-thiazol-5-yl) methyl, ((2-methylphenyl) methyl) N (H)-, (3,3-dimethylbutyl) N (H)-, (3,5-dimethyl-4-isoxazolyl) ) Methyl, (3,5-dimethylcyclohexyl) N (H)-, (3-bromobenzyl) N (H)-, (3-cyanobenzyl) N (H)-, (3-ethylcyclopentyl) N (H )-, (3-furylmethyl) N (H)-, ((3-methoxyphenyl) methyl) N (H)-, (3-methylbenzyl) N (H)-, (3-methylbut-2-enyl) ) N (H)-, (3-methylbutyl) N (H)-, (3-methylcyclohexyl) N (H)-, (3-methylcyclopentyl) N (H)-, (3-trifluoromethyl) benzyl , ((4-Bromophenyl) methyl) N (H) , (4-isopropylcyclohexyl) N (H)-, ((4-methoxyphenyl) methyl) N (H)-, ((4-methylphenyl) methyl) N (H)-, (5-bromo-2- Thienyl) methyl, (5-bromo-3-pyridinyl) methyl, (5-carboxy-2-furyl) methyl, (5-chloro-2-thienyl) methyl, (5-ethoxycarbonyl-2-furyl) methyl, ( 5-methyl-2-thienyl) methyl, (5-methyl-3-isoxazolyl) methyl, (5-methyl-3-pyridinyl) methyl, (5-nitro-2-furyl) methyl, (5-phenyl-2- Thienyl) methyl, (5-tert-butyl-2-thienyl) methyl, (6,6-dimethylbicyclo [3.1.1] hept-2-yl) methyl, (6-ethoxy-2-pyridinyl) Methyl, (6-methyl-2-pyridinyl) methyl, (cyclopropylmethyl) N (H)-, (pyridin-2-ylmethyl) N (H)-, (pyridin-3-ylmethyl) N (H)-, (Pyridin-4-ylmethyl) N (H)-, (tetrahydro-2H-pyran-4-yl) N (H)-, (thien-2-ylmethyl) N (H)-, (thien-3-ylmethyl) N (H)-, 1,1'-biphenyl-4-ylmethyl, 1,3-thiazol-4-ylmethyl, 1-adamantylmethyl, 1-benzothien-2-ylmethyl, 1-ethylpropyl, 1-naphthylmethyl, 1-neopentyl, 1-phenylethyl, 2- (1,3-dioxolan-2-yl) ethyl, 2- (3-thienyl) ethyl, 2,3-dihydroxypropyl, 2-aminoethyl, 2- Cyanobenzyl, 2-cyclohexylethyl, (2-methylphenyl) methyl, 2-methylbutyl, 2-naphthylmethyl, 2-phenylethyl, 2-phenylpropyl, 2-pyridinylmethyl, 3- (4-methyl-1-piperazinyl) Propyl, 3- (4-morpholinyl) propyl, 3- (diethylamino) propyl, 3- (dimethylamino) propyl, 3-anilinopropyl, 3-bromobenzyl, 3-butenyl, 3-chlorobenzyl, 3-cyanobenzyl 3-ethylbutyl, 3-fluorobenzyl, 3-hydroxybutyl, 3-hydroxypropyl, 3-iodobenzyl, 3-methoxybenzyl, 3-methoxycarbonylbenzyl, 3-methyl-2-butenyl, 3-methylbenzyl, 3 -Methylbutyl, 3-nitrobenzyl, 3-phen Xibenzyl, 3-pyridinylmethyl, 3-thienylmethyl, 4-bromobenzyl, 4-cyanobenzyl, 4-methoxybenzyl, 4-methyl-3-pentenyl, 4-methylbenzyl, 4-methylpentyl, 4-pyridinylmethyl, 4- tert- butyl benzyl, -NH _2, phenylmethyl, (phenylmethyl) N (H) -, benzyloxy, (butyl) N (H) -, (cyclobutyl) N (H) -, cyclobutylmethyl, cycloheptyl, (Cycloheptyl) N (H)-, cyclohexyl, (cyclohexyl) N (H)-, cyclohexylmethyl, cyclopentyl, (cyclopentyl) N (H)-, cyclopropylmethyl, cyclopropylethyl, hydrogen, isobutoxy, (isobutyl) N (H)-, (isopropyl) N (H)-, n-butyl Selected from the group consisting of til, pentyl, (pentyl) N (H)-, (phenylmethylene) N (H)-, prop-2-enyl, propane-3-al, propoxy and (propyl) N (H)- A compound of formula (II) is provided.

  In a third embodiment, the present invention provides a compound of the following formula (III) or a pharmaceutically acceptable salt form, stereoisomer or tautomer of the compound.

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２、または３個の置換基で置換されており；
ｍは０、１または２であり；
ｎは０、１、２、３または４であり；
ただし、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C═N— and R _k O— are selected from the group consisting of; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl , haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S ( _{O) R c, -S (O} ) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
Where R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N (R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, hetero aryl, heterocyclic _{alkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R a, -C (O) oR _a and -C (O) NR If a R _b, R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl Not heterocyclic alkenyl and heterocyclic alkyl.

For example, the present invention provides a compound of formula (III) wherein R ⁴ is hydroxy.

For example, the invention includes R ⁴ is hydroxy; R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo Alkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl Provided is a compound of formula (III) selected from the group consisting of-, R _a R _b NC (O) alkyl-, R _f R _g C = N- and R _k O-.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is ((1-isopropyl) butyl) N (H)-, ((2-chloro-1,3-thiazol-5-yl) methyl) N (H )-, ((2-methyl-1,3-thiazol-4-yl) methyl) N (H)-, ((3-methylthien-2-yl) methyl) N (H)-, ((3-tri Fluoromethyl) cyclohexyl) N (H)-, ((5-chlorothien-2-yl) methyl) N (H)-, ((pyridin-3-yl) methyl) N (H)-, (1,2, 3,4-tetrahydronaphthalen-2-yl) N (H)-, (1,3-thiazol-2-ylmethyl) N (H)-, (1,3-thiazol-5-ylmethyl) N (H)- , (1-cyclohexen-1-yl) ethyl, (1-cyclopropylethyl) N (H) , (1-ethylbutyl) N (H)-, (1-ethylpropyl) N (H)-, (1-methylbutyl) N (H)-, (1-phenylethyl) N (H)-, (1- Propylbutyl) N (H)-, (1-thien-3-ylethyl) N (H)-, (2- (1H-indol-3-yl) ethyl, (2- (dimethylamino) ethyl) (methyl) Aminopropyl, ((2-bromophenyl) methyl) N (H)-, (2-chloro-1,3-thiazol-5-yl) methyl, (2-chloro-4-pyridinyl) methyl, (2-ethyl) -3-methylbutyl) N (H)-, (2-ethylbutyl) N (H)-, (2-furylmethyl) N (H)-, (2-methyl-1,2-thiazol-4-yl) methyl , (2-methyl-1,3-thiazol-4-yl) methyl, (2-methyl Til-1,3-thiazol-5-yl) methyl, (2-methylbenzyl) N (H)-, (3,3-dimethylbutyl) N (H)-, (3,5-dimethyl-4-isoxazolyl) ) Methyl, (3,5-dimethylcyclohexyl) N (H)-, (3-bromobenzyl) N (H)-, (3-cyanobenzyl) N (H)-, (3-ethylcyclopentyl) N (H )-, (3-furylmethyl) N (H)-, (3-methoxybenzyl) N (H)-, (3-methylbenzyl) N (H)-, (3-methylbut-2-enyl) N ( H)-, (3-methylbutyl) N (H)-, (3-methylcyclohexyl) N (H)-, (3-methylcyclopentyl) N (H)-, (3-trifluoromethyl) benzyl, (( 4-bromophenyl) methyl) N (H)-, (4-i Propylcyclohexyl) N (H)-, ((4-methoxyphenyl) methyl) N (H)-, ((4-methylphenyl) methyl) N (H)-, (5-bromo-2-thienyl) methyl, (5-bromo-3-pyridinyl) methyl, (5-carboxy-2-furyl) methyl, (5-chloro-2-thienyl) methyl, (5-ethoxycarbonyl-2-furyl) methyl, (5-methyl- 2-thienyl) methyl, (5-methyl-3-isoxazolyl) methyl, (5-methyl-3-pyridinyl) methyl, (5-nitro-2-furyl) methyl, (5-phenyl-2-thienyl) methyl, (5-tert-butyl-2-thienyl) methyl, (6,6-dimethylbicyclo [3.1.1] hept-2-yl) methyl, (6-ethoxy-2-pyridinyl) methyl, ( -Methyl-2-pyridinyl) methyl, (cyclopropylmethyl) N (H)-, (pyridin-2-ylmethyl) N (H)-, (pyridin-3-ylmethyl) N (H)-, (pyridine-4) -Ylmethyl) N (H)-, (tetrahydro-2H-pyran-4-yl) N (H)-, (thien-2-ylmethyl) N (H)-, (thien-3-ylmethyl) N (H) -, 1,1'-biphenyl-4-ylmethyl, 1,3-thiazol-4-ylmethyl, 1-adamantylmethyl, 1-benzothien-2-ylmethyl, 1-ethylpropyl, 1-naphthylmethyl, 1-neopentyl, 1-phenylethyl, 2- (1,3-dioxolan-2-yl) ethyl, 2- (3-thienyl) ethyl, 2,3-dihydroxypropyl, 2-aminoethyl, (2-cyanophen Nyl) methyl, 2-cyclohexylethyl, (2-methylphenyl) methyl, 2-methylbutyl, 2-naphthylmethyl, 2-phenylethyl, 2-phenylpropyl, 2-pyridinylmethyl, 3- (4-methyl-1-piperazinyl) ) Propyl, 3- (4-morpholinyl) propyl, 3- (diethylamino) propyl, 3- (dimethylamino) propyl, 3-anilinopropyl, (3-bromophenyl) methyl, 3-butenyl, (3-chlorophenyl) Methyl, (3-cyanophenyl) methyl, 3-ethylbutyl, (3-fluorophenyl) methyl, 3-hydroxybutyl, 3-hydroxypropyl, (3-iodophenyl) methyl, (3-methoxyphenyl) methyl, (3 -Methoxycarbonylphenyl) methyl, 3-methyl-2-butenyl (3-methylphenyl) methyl, 3-methylbutyl, (3-nitrophenyl) methyl, 3-phenoxybenzyl, 3-pyridinylmethyl, 3-thienylmethyl, (4-bromophenyl) methyl, (4-cyanophenyl) methyl, (4-methoxyphenyl) methyl, 4-methyl-3-pentenyl, (4-methylphenyl) methyl, 4-methylpentyl, 4-pyridinylmethyl, (4-tert-butylphenyl) methyl, -NH _2, phenylmethyl, (Phenylmethyl) N (H)-, (phenylethyl) N (H)-, benzyloxy, (butyl) N (H)-, (cyclobutyl) N (H)-, cyclobutylmethyl, cycloheptyl, (cyclo Heptyl) N (H)-, cyclohexyl, (cyclohexyl) N (H)-, cyclohexylmethyl, Clopentyl, (cyclopentyl) N (H)-, cyclopropylethyl, cyclopropylmethyl, isobutoxy, (isobutyl) N (H)-, (isopropyl) N (H)-, n-butyl, pentyl, (pentyl) N ( A compound of formula (III) selected from the group consisting of H)-, (phenylmethylene) N (H)-, prop-2-enyl, propan-3-al, propoxy and (propyl) N (H)- provide.

  In a fourth embodiment, the present invention provides a compound of formula (IV) below or a pharmaceutically acceptable salt form, stereoisomer or tautomer of that compound.

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２、または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１、２、３または４であり；
ただし、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, selected from the group consisting of R _f R _g C═N— and R _k O—; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro , Haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c ,- _{S (O) R c, -S} (O) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C ( O) N It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _c R _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Where R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N (R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, hetero aryl, heterocyclic _{alkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R a, -C (O) oR _a and -C (O) NR If a R _b, R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl Not heterocyclic alkenyl and heterocyclic alkyl.

For example, the present invention provides a compound of formula (IV) wherein R ⁴ is hydroxy.

For example, the invention provides a compound of formula (IV), wherein R ⁴ is hydroxy; R ¹ is selected from the group consisting of R _a R _b N—, R _f R _g C═N—, and R _k O— To do.

For example, the invention provides that R ⁴ is hydroxy; R ¹ is alkyl O—, (cycloalkyl) O—, (arylalkyl) O—, aryl CH═N—, —NH ₂ , alkyl N (H) —, Alkenyl (H)-, cycloalkyl N (H)-, (cycloalkylalkyl) N (H)-, (heteroarylalkyl) N (H)-, (arylalkyl) N (H)-and (heterocycle) Provided is a compound of formula (IV) selected from the group consisting of N (H)-.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is (C ₃ -C ₇ alkyl) O—, (C ₃ -C ₆ cycloalkyl) O—, (phenylalkyl) O—, phenyl CH═N— , (C ₃ -C ₇ alkyl) N (H)-, (C ₃ -C ₇ alkenyl) N (H)-, (C ₃ -C ₇ cycloalkyl) N (H)-, ((C ₃ -C ₇ cycloalkyl) C ₁ -C ₂ alkyl) N (H)-, (thienylmethyl) N (H)-, (thiazolylmethyl) N (H)-, (furylmethyl) N (H)-, (pyridinylmethyl) N Selected from the group consisting of (H)-, (tetranaphthalenyl) N (H)-, (tetrahydropyranyl) N (H)-and (phenylalkyl) N (H)-; (phenylalkyl) O- , Phenyl CH = N-, (thienylmethyl) N (H)- (Thiazolylmethyl) N (H)-, (furylmethyl) N (H)-, (pyridinylmethyl) N (H)-and (phenylalkyl) N (H)-are each independently phenyl, thienyl, thiazolyl, furyl and pyridinyl. And selected from the group consisting of nitro, cyano, hydroxyl, alkoxy, —NH ₂ , —N (H) (alkyl), —N (alkyl) 2, alkyl, halo, haloalkyl, carboxy, acetyl and alkyloxycarbonyl. Provided are compounds of formula (IV) substituted with 0, 1 or 2 substituents.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is (phenylmethyl) N (H)-, (1-phenylethyl) N (H)-, (cyclopropylmethyl) N (H)-, (cyclohexyl) Methyl) N (H)-, (1-cyclopropylethyl) N (H)-, phenyl CH = N-, propyl O-, (1-propylbutyl) N (H)-, (isobutyl) N (H) -, (Isopropyl) N (H)-, (1-ethylpropyl) N (H)-, (1-ethylbutyl) N (H)-, (2-ethylbutyl) N (H)-, (1-isopropylbutyl) ) N (H)-, (1-methylbutyl) N (H)-, (3-methylbutyl) N (H)-, (3,3-dimethylbutyl) N (H)-, (propyl) N (H) -, (Butyl) N (H)-, (pentyl) N (H)-, (2-ethyl 3-methylbutyl) N (H)-, (3-methylbut-2-enyl) N (H)-, (cyclobutyl) N (H)-, (cyclopentyl) N (H)-, (cyclohexyl) N (H) -, (Cycloheptyl) N (H)-, (thienylmethyl) N (H)-, (furylmethyl) N (H)-, (thiazolylmethyl) N (H)-, (pyridinylmethyl) N (H)-, Selected from the group consisting of (tetrahydronaphthalenyl) N (H)-and (tetrahydropyranyl) N (H)-; (phenylmethyl) O-, phenyl CH = N-, (thienylmethyl) N (H) -, (Thiazolylmethyl) N (H)-, (furylmethyl) N (H)-, (pyridinylmethyl) N (H)-, (phenylmethyl) N (H)-and (1-phenylethyl) N (H) -Phenyl, thieny Le, thiazolyl, furyl and pyridinyl each independently, nitro, cyano, hydroxyl, _methoxy, -NH 2, -N (H) (alkyl), - N (alkyl) 2, methyl, halo, halomethyl, carboxy, acetyl, and Provided is a compound of formula (IV) substituted with 0, 1 or 2 substituents selected from the group consisting of alkyloxycarbonyl.

Examples of compounds of the fourth embodiment of the invention of formula (IV) include
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(1E) -phenylmethylene] amino} -2 (1H)- Quinolinone;
1-amino-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2 (1H) -quinolinone;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-propoxyquinolin-2 (1H) -one;
1- (benzylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
1-amino-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1-propylbutyl) amino] quinolin-2 (1H) -one ;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(1-ethylpropyl) amino] -4-hydroxyquinolin-2 (1H) -one ;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (pentylamino) quinolin-2 (1H) -one;
1- (cyclohexylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(2-methyl-1,3-thiazol-4-yl) Methyl] amino} quinolin-2 (1H) -one;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (isopropylamino) quinolin-2 (1H) -one;
1- (cyclobutylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
1- (cyclopentylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[3-methylcyclopentyl] amino} quinolin-2 (1H) -one ;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (tetrahydro-2H-pyran-4-ylamino) quinoline-2 (1H) -ON;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl)-{[1-ethylbutyl] amino} -4-hydroxyquinolin-2 (1H) -one;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(3R) -3-methylcyclohexyl] amino} quinoline-2 ( 1H) -on;
1- (cycloheptylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[3-ethylcyclopentyl] amino} -4-hydroxyquinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-isopropylbutyl] amino} quinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-phenylethyl] amino} quinolin-2 (1H) -one ;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-thien-3-ylethyl] amino} quinoline-2 (1H ) -On;
1-{[3,5-dimethylcyclohexyl] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline-2 (1H) -ON;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(4-isopropylcyclohexyl) amino] quinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [1,2,3,4-tetrahydronaphthalen-2-ylamino] quinoline -2 (1H) -one;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[3- (trifluoromethyl) cyclohexyl] amino} quinoline-2 ( 1H) -on;
1- (butylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(3-methylbutyl) amino] quinolin-2 (1H) -one;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(3-furylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(2-furylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(thien-2-ylmethyl) amino] quinoline-2 (1H)- on;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1,3-thiazol-2-ylmethyl) amino] quinoline-2 (1H) -on;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[(2R) -2-ethyl-3-methylbutyl] amino} -4-hydroxyquinoline -2 (1H) -one;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(4-methylbenzyl) amino] quinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(3-methylbenzyl) amino] quinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2-methylbenzyl) amino] quinolin-2 (1H) -one ;
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1 {[(3-methylthien-2-yl) methyl] amino} quinoline-2 (1H) -on;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(4-methoxybenzyl) amino] quinolin-2 (1H) -one ;
1-{[(5-chlorothien-2-yl) methyl] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline- 2 (1H) -one;
1-{[(2-Chloro-1,3-thiazol-5-yl) methyl] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one;
1-[(3-Bromobenzyl) amino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one ;
1-[(4-Bromobenzyl) amino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one ;
1-[(2-Bromobenzyl) amino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one ;
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(pyridin-3-ylmethyl) amino] quinoline-2 (1H)- on;
3-({[3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxoquinolin-1 (2H) -yl] amino} Methyl) benzonitrile;
2-({3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl} oxy) acetamide;
2-({3- [1- (Cyclopentylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) acetamide;
2-({3- [1- (cyclohexylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) acetamide;
2-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl) oxy] acetamide;
2-({3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2-benzothiazine-7- Yl} oxy) acetamide;
2-({3- [1- (Butylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) acetamide;
2-[(3- {4-hydroxy-1-[(3-methylbutyl) amino] -2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl) oxy] acetamide;
3- (8-amino-7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (isobutylamino) quinoline-2 (1H ) -On;
2-({8-amino-3- [4-hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl} oxy) acetamide;
2-({3- [4-Hydroxy-2-oxo-1- (propylamino) -1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) acetamide;
2-({3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) propanamide;
2-({3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) butanamide;
8-Amino-3- [4-hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-ylmethanesulfonate;
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- (7-hydroxy-8-nitro-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) quinoline -2 (1H) -one;
3- (7- {2-[(3S) -3-Aminopyrrolidin-1-yl] -2-oxoethoxy} -1,1-dioxide-4H-1,2,4-benzothiadiazine-3- Yl) -1-[(cyclopropylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one;
2-[(3-{-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4 -Benzothiadiazin-7-yl) oxy] -N-ethylacetamide;
[(3-{-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl) oxy] acetic acid;
3- {7- [2- (3-Aminopyrrolidin-1-yl) -2-oxoethoxy] -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl} -1 -[(Cyclopropylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one;
3- (8-Amino-7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(cyclopropylmethyl) amino] -4-hydroxyquinoline -2 (1H) -one;
2-[(8-amino-3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H- 1,2,4-benzothiadiazin-7-yl) oxy] acetamide;
[(8-amino-3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1, 2,4-benzothiadiazin-7-yl) oxy] acetonitrile;
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- [7- (2-hydroxyethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] Quinolin-2 (1H) -one;
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- [7- (1H-imidazol-2-ylmethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazine-3 -Yl] quinolin-2 (1H) -one;
1-[(Cyclopropylmethyl) amino] -3- [1,1-dioxide-7- (1,3-thiazol-2-ylmethoxy) -4H-1,2,4-benzothiadiazin-3-yl ] -4-hydroxyquinolin-2 (1H) -one;
1-[(Cyclopropylmethyl) amino] -3- [7- (4,5-dihydro-1H-imidazol-2-ylmethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazine -3-yl] -4-hydroxyquinolin-2 (1H) -one;
2-{[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl) oxy] methyl} -1,3-thiazole-4-carbonitrile;
3- [7- (2-Aminoethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1-[(cyclopropylmethyl) amino] -4-hydroxy Quinolin-2 (1H) -one;
N- {2-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1 , 2,4-benzothiadiazin-7-yl) oxy] ethyl} methanesulfonamide;
3- {7-[(5-Bromopyridin-2-yl) oxy] -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl} -4-hydroxy-1- ( Isobutylamino) quinolin-2 (1H) -one;
4-hydroxy-1- (isobutylamino) -3- {7-[(3-nitropyridin-2-yl) oxy] -1,1-dioxide-4H-1,2,4-benzothiadiazine-3 -Yl} quinolin-2 (1H) -one;
tert-Butyl 3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4 -Benzothiadiazine-7-yl carbamate;
3- (7-amino-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(cyclopropylmethyl) amino] -4-hydroxyquinoline-2 (1H ) -On;
2-chloro-6-({3- [4-hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl} oxy) methyl isonicotinate;
N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} methanesulfonamide;
N- (3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4 -Benzothiadiazin-7-yl) methanesulfonamide;
N- {1-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl} -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl) methanesulfonamide;
2-{[3- (1-Amino-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7 -Yl] oxy} acetamide;
N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} ethanesulfonamide;
3- {3- [1- (Cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Din-7-yl} diazathian-1-carboxylic acid benzyl 2,2-dioxide;
N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Din-7-yl} -N′-methylsulfamide; and N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1 , 1-dioxide-4H-1,2,4-benzothiadiazin-7-yl} sulfamide;
Alternatively, these pharmaceutically acceptable salt forms, stereoisomers, tautomers and the like are not limited thereto.

  In a fifth embodiment, the present invention provides a compound of the following formula (Va) or a pharmaceutically acceptable salt form, stereoisomer or tautomer of the compound:

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２、または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ただし、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C═N— and R _k O— are selected from the group consisting of; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl , haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S ( _{O) R c, -S (O} ) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
Where R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N (R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, hetero aryl, heterocyclic _{alkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R a, -C (O) oR _a and -C (O) NR If a R _b, R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl Not heterocyclic alkenyl and heterocyclic alkyl.

For example, the present invention provides a compound of formula (Va) wherein R ⁴ is hydroxy.

For example, the invention includes R ⁴ is hydroxy; R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo Alkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl A compound of formula (Va) selected from the group consisting of-, R _a R _b NC (O) alkyl-, R _f R _g C = N- and R _k O- is provided.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is C ₁ -C ₇ alkyl, phenyl-C ₁ -C ₂ alkyl-, heteroaryl-C ₁ -C ₂ alkyl-, ((C ₃ -C _{6 cycloalkyl)} C 1 -C ₂ alkyl) _{-, (C} 1 ~C _{7 alkyl) O -, (C 3 ~C} 7 cycloalkyl) O-, phenyl _-C 1 -C ₂ alkyl -O -, - NH ₂ , (C ₁ -C ₇ alkyl) N (H)-, (C ₃ -C ₇ cycloalkyl) N (H)-, ((C ₃ -C ₇ cycloalkyl) C ₁ -C ₂ alkyl) N (H )-, (Heterocycle) N (H)-, (heteroarylalkyl) N (H)-, (arylalkyl) N (H)-. A compound of formula (Va) is provided.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is isopropyl, 3-methylbutyl, butyl, isobutyl, phenylmethyl, thienylmethyl, cyclobutylmethyl, cyclopropylethyl, —NH ₂ , (isopropyl) N (H) Selected from the group consisting of-, (isobutyl) N (H)-, (3-methylbutyl) N (H)-, (cyclobutyl) N (H)-and (cyclopropylmethyl) N (H)-; Methyl and said thienylmethyl are independently unsubstituted or from alkyl, alkenyl, alkynyl, haloalkyl, halo, cyano, nitro, —NH ₂ , —N (H) alkyl, —N (alkyl) ₂ , hydroxy and alkoxy Providing a compound of formula (Va) substituted with 1, 2 or 3 substituents selected from the group consisting of .

  In a sixth embodiment, the present invention provides a compound of the following formula (Vb) or a pharmaceutically acceptable salt form, stereoisomer or tautomer thereof.

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２、または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ただし、Ｒ^４がヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、未置換アルキル、ハロまたは−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C═N— and R _k O— are selected from the group consisting of; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl , haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S ( _{O) R c, -S (O} ) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
Provided that R ⁴ is hydroxy or R _e S—, R ⁵ is hydrogen, unsubstituted alkyl, halo or —OR _k , R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, Heteroaryl, heterocyclic alkyl, —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, Not (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl.

For example, the present invention provides a compound of formula (Vb) wherein R ⁴ is hydroxy.

For example, the invention provides that R ⁴ is hydroxyl; R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo Alkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl A compound of formula (Vb) selected from the group consisting of-, R _a R _b NC (O) alkyl-, R _f R _g C = N- and R _k O- is provided.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is C ₁ -C ₇ alkyl, phenyl-C ₁ -C ₂ alkyl-, heteroaryl-C ₁ -C ₂ alkyl-, ((C ₃ -C _{6 cycloalkyl)} C 1 -C ₂ alkyl) _{-, (C} 1 ~C _{7 alkyl) O -, (C 3 ~C} 7 cycloalkyl) O-, phenyl _-C 1 -C ₂ alkyl -O -, - NH ₂ , (C ₁ -C ₇ alkyl) N (H)-, (C ₃ -C ₇ cycloalkyl) N (H)-, ((C ₃ -C ₇ cycloalkyl) C ₁ -C ₂ alkyl) N (H )-, (Heterocycle) N (H)-, (heteroarylalkyl) N (H)-, (arylalkyl) N (H)-. A compound of formula (Vb) is provided.

For example, in the present invention, R ⁴ is hydroxy; R ¹ is isopropyl, 3-methylbutyl, butyl, isobutyl, phenylmethyl, thienylmethyl, cyclobutylmethyl, cyclopropylethyl, —NH ₂ , (isopropyl) N (H) Selected from the group consisting of-, (isobutyl) N (H)-, (3-methylbutyl) N (H)-, (cyclobutyl) N (H)-and (cyclopropylmethyl) N (H)-; Methyl and said thienylmethyl are independently unsubstituted or from alkyl, alkenyl, alkynyl, haloalkyl, halo, cyano, nitro, —NH ₂ , —N (H) alkyl, —N (alkyl) ₂ , hydroxy and alkoxy Providing a compound of formula (Vb) substituted with 1, 2 or 3 substituents selected from the group consisting of .

  In a seventh embodiment, the present invention provides a compound of the following formula (VIa) or a pharmaceutically acceptable salt form, stereoisomer or tautomer of the compound:

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２、または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ただし、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C═N— and R _k O— are selected from the group consisting of; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl , haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S ( _{O) R c, -S (O} ) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
Where R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N (R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, hetero aryl, heterocyclic _{alkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R a, -C (O) oR _a and -C (O) NR If a R _b, R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl Not heterocyclic alkenyl and heterocyclic alkyl.

For example, the present invention provides a compound of formula (VIa) wherein R ⁴ is hydroxy.

For example, the invention includes R ⁴ is hydroxy; R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo Alkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl A compound of formula (VIa) selected from the group consisting of-, R _a R _b NC (O) alkyl-, R _f R _g C = N- and R _k O- is provided.

For example, the invention includes R ⁴ is hydroxy; R ¹ is hydrogen, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkenyl, (C ₃ -C ₇ cycloalkyl) (C ₁ -C ₂ alkyl)-, (C ₅ -C ₆ cycloalkenyl) (C ₁ -C ₂ alkyl)-, C ₃ -C ₇ cycloalkyl, phenyl-C ₁ -C ₂ alkyl-, furyl (C ₁ -C ₂ alkyl)-, thienyl ( C ₁ -C ₂ alkyl) -, phenyl _(C 1 -C ₂ alkyl) -, pyridinyl _(C 1 -C ₂ alkyl) -, thiazolyl _(C 1 -C ₂ alkyl) -, isoxazolyl _(C 1 -C ₂ alkyl ) -, naphthyl _(C 1 -C ₂ alkyl), benzothienyl _(C 1 -C ₂ alkyl) -, indolyl _(C 1 -C ₂ alkyl) -, phenyl _{N (H) (C 1 ~C} 6 alkyl) - , ( ₁ -C _{7 alkyl) O -, (C 3 ~C} 6 cycloalkyl) O -, _((phenyl) C 1 -C ₂ alkyl) O-, phenyl _{CH = N-, NH 2, (} C 1 ~C 7 _{alkyl) N (H) -, (} C 1 ~C 7 _{alkenyl) N (H) -, (} C 3 ~C 7 _{cycloalkyl) N (H) -, (} (C 3 ~C 7 _{cycloalkyl) C} 1 ~ C ₂ alkyl) N (H) -, ( ( _phenyl) C 1 -C ₂ alkyl) N (H) -, (thienylmethyl) N (H) -, (thiazolylmethyl) N (H) -, (furylmethyl) N (H)-, (pyridinylmethyl) N (H)-, (tetrahydropyran) N (H)-, (benzyl) N (H)-, (tetrahydronaphthalenyl) N (H)- Each R ¹ is alkyl, hydroxy, oxo, halo, cyano, nitro, Haloalkyl, hydroxyl, alkoxy, haloalkoxy, phenyl, piperazinyl, morpholinyl, carboxy, -C (O) O (alkyl), _- NH 2, -NH (alkyl), - N _{(alkyl) 2,} - alkyl, -O- Provided is a compound of formula (VIa) substituted with 0, 1, 2 or 3 substituents selected from the group consisting of phenyl.

For example, the invention provides that R ⁴ is hydroxy; R ¹ is phenylmethyl, phenylethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, (5-chloro- thien-2-yl) methyl - _{(C 3} alkyl) N (H) -, ( C 4 alkyl) N (H) -, ( C 5 alkyl) N (H) -, (cyclobutyl) N (H) - and There is provided a compound of formula (VIa) selected from the group consisting of (cyclopropylmethyl) N (H)-.

  In an eighth embodiment, the present invention provides a compound of formula (VIb) below or a pharmaceutically acceptable salt form, stereoisomer or tautomer of that compound.

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２、または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ただし、Ｒ^４がヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、未置換アルキル、ハロまたは−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C═N— and R _k O— are selected from the group consisting of; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl , haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S ( _{O) R c, -S (O} ) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
Provided that R ⁴ is hydroxy or R _e S—, R ⁵ is hydrogen, unsubstituted alkyl, halo or —OR _k , R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, Heteroaryl, heterocyclic alkyl, —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, Not (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl.

For example, the invention includes R ⁴ is hydroxy; R ¹ is hydrogen, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkenyl, (C ₃ -C ₇ cycloalkyl) (C ₁ -C ₂ alkyl)-, (C ₅ -C ₆ cycloalkenyl) (C ₁ -C ₂ alkyl)-, C ₃ -C ₇ cycloalkyl, phenyl-C ₁ -C ₂ alkyl-, furyl (C ₁ -C ₂ alkyl)-, thienyl ( C ₁ -C ₂ alkyl) -, phenyl _(C 1 -C ₂ alkyl) -, pyridinyl _(C 1 -C ₂ alkyl) -, thiazolyl _(C 1 -C ₂ alkyl) -, isoxazolyl _(C 1 -C ₂ alkyl ) -, naphthyl _(C 1 -C ₂ alkyl), benzothienyl _(C 1 -C ₂ alkyl) -, indolyl _(C 1 -C ₂ alkyl) -, phenyl _{N (H) (C 1 ~C} 6 alkyl) - , ( ₁ -C _{7 alkyl) O -, (C 3 ~C} 6 cycloalkyl) O -, _((phenyl) C 1 -C ₂ alkyl) O-, phenyl _{CH = N-, NH 2, (} C 1 ~C 7 _{alkyl) N (H) -, (} C 1 ~C 7 _{alkenyl) N (H) -, (} C 3 ~C 7 _{cycloalkyl) N (H) -, (} (C 3 ~C 7 _{cycloalkyl) C} 1 ~ C ₂ alkyl) N (H) -, ( ( _phenyl) C 1 -C ₂ alkyl) N (H) -, (thienylmethyl) N (H) -, (thiazolylmethyl) N (H) -, (furylmethyl) N (H)-, (pyridinylmethyl) N (H)-, (tetrahydropyran) N (H)-, (benzyl) N (H)-, (tetrahydronaphthalenyl) N (H)- Each R ¹ is alkyl, hydroxy, oxo, halo, cyano, nitro, Haloalkyl, hydroxyl, alkoxy, haloalkoxy, phenyl, piperazinyl, morpholinyl, carboxy, -C (O) O (alkyl), _- NH 2, -NH (alkyl), - N _{(alkyl) 2,} - alkyl, -O- Provided is a compound of formula (VIb) substituted with 0, 1, 2, or 3 substituents selected from the group consisting of phenyl.

For example, the invention provides that R ⁴ is hydroxy; R ¹ is phenylmethyl, phenylethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, (5-chloro- thien-2-yl) methyl - _{(C 3} alkyl) N (H) -, ( C 4 alkyl) N (H) -, ( C 5 alkyl) N (H) -, (cyclobutyl) N (H) - and There is provided a compound of formula (VIb) selected from the group consisting of (cyclopropylmethyl) N (H)-.

  In a ninth embodiment, the present invention provides a compound of the following formula (VII) or a pharmaceutically acceptable salt form, stereoisomer or tautomer of the compound:

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２、または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２、または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１、２、３または４であり；
ただし、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり；Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルまたは複素環アルキルではない。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C═N— and R _k O— are selected from the group consisting of; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl , haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S ( _{O) R c, -S (O} ) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _e;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Where R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N (R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k ; R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, hetero aryl, heterocyclic _{alkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R a, -C (O) oR _a and -C (O) NR If a R _b, R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl Is not heterocyclic alkenyl or heterocyclic alkyl.

For example, the present invention provides a compound of formula (VII) wherein R ⁴ is hydroxy.

For example, the invention includes R ⁴ is hydroxy; R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo Alkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl -, R _a R _b NC (O) alkyl-, R _f R _g C = N- and R _k O- are selected from the group of formula (VII).

For example, in the present invention, R ⁴ is hydroxy; R ¹ is hydrogen, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkenyl, furyl (C ₁ -C ₂ alkyl)-, thienyl (C ₁ -C ₂ alkyl) ) -, phenyl _(C 1 -C ₂ alkyl) -, pyridinyl _(C 1 -C ₂ alkyl) -, thiazolyl _(C 1 -C ₂ alkyl) -, isoxazolyl _(C 1 -C ₂ alkyl) -, naphthyl (C ₁ -C ₂ alkyl), benzothienyl _(C 1 -C ₂ alkyl) -, indolyl _(C 1 -C ₂ alkyl) _{-, (C} 3 -C _{7 cycloalkyl) (C} 1 -C ₂ alkyl) -, ( C ₅ -C _{6 cycloalkenyl) (C} 1 -C ₂ alkyl) _-, C 3 -C ₇ cycloalkyl, phenyl _{N (H) (C 1 ~C} 6 alkyl) -, (phenylalkyl) O -, (C _{1 to} C ₇ alkyl) O—, (C ₃ -C ₆ cycloalkyl) O—, phenyl CH═N—, NH ₂ , (C ₁ -C ₇ alkyl) N (H) —, (C ₁ -C ₇ alkenyl) N _{(H) -, (C 3} ~C 7 _{cycloalkyl) N (H) -, (} (C 3 ~C 7 _cycloalkyl) C 1 -C ₂ alkyl) N (H) -, (thienylmethyl) N (H )-, (Thiazolylmethyl) N (H)-, (furylmethyl) N (H)-, (pyridinylmethyl) N (H)-, (tetrahydropyran) N (H)-, (phenylalkyl) N (H)- , (Tetrahydronaphthalenyl) N (H) —; each R ¹ is alkyl, hydroxy, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, phenyl, piperazinyl, morpholinyl, carboxy, —C (O) O (alkyl), _- NH 2, -NH (alkyl), - N _(alkyl) 2, substituted by -O-alkyl, 0, 1, 2 or 3 substituents selected from the group consisting of -O- phenyl Provided is a compound of formula (VII)

For example, in the present invention, R ⁴ is hydroxy; R ¹ is C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, phenylmethyl, (5-chloro-thien-2-yl) methyl-, —NH ₂ , (C ₃ alkyl) N (H) -, ( C 4 alkyl) N (H) -, ( C 5 alkyl) N (H) -, (cyclobutyl) N (H) - and (cyclopropylmethyl) N (H) - A compound of formula (VII) selected from the group consisting of:

  In a tenth embodiment, the present invention provides a compound of the following formula (VIII) or a pharmaceutically acceptable salt form, stereoisomer or tautomer of the compound:

式中、
ＸはＮＨ、Ｎ（アルキル）、ＯまたはＳであり；
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^２およびＲ^３は独立に、水素、アルケニル、アルキニル、アルコキシアルキル、アルコキシカルボニル、アルキル、アリール、アリールアルキル、ヘテロアリール、複素環、ヘテロアリールアルキル、シアノ、ハロ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａおよびＲ_ａＣ（Ｏ）−からなる群から選択され；Ｒ^２およびＲ^３は独立に、独立にＲ_ａ、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ^２およびＲ^３が、それらが結合している炭素原子と一体となって、アリール、シクロアルキル、ヘテロアリールおよび複素環からなる群から選択される５員または６員環を形成しており、前記アリール、シクロアルキル、ヘテロアリールおよび複素環は（Ｒ^６）_ｍで置換されていても良く；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は独立に、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^７は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^７は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１または２である。

Where
X is NH, N (alkyl), O or S;
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C═N— and R _k O— are selected from the group consisting of; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl , haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S ( _{O) R c, -S (O} ) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _e;
R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _{b), R a R b NC} (O) -, - SR a, -S (O) R a, -S (O) 2 R a , and _R a C (O) - is selected from the group consisting of; ^{R 2} And R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, — (alkyl) (OR _k ), — (alkyl) (NR _a R _b ), —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and From —C (O) NR _a R _b Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of;
Alternatively, R ² and R ³ together with the carbon atom to which they are attached form a 5- or 6-membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl and heterocycle And the aryl, cycloalkyl, heteroaryl and heterocycle may be substituted with (R ⁶ ) _m ;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently, independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R ⁷ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-R a R b NSO 2 N (} R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) -, _{k OC (O) -, R} k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P ( O) selected from the group consisting of O— and —OR _k ; each R ⁷ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle , Arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _d ), -SR _c , -S (O) R _c , -S (O) _{2 R c, -OR c, -N (} R c) (R d), - C (O) R c, -C (O) oR c and - (O) _NR c 0 is selected from the group consisting of _{R d} , 1, 2 or 3 It has been replaced by a substituent;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substituents selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Is replaced by;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1 or 2.

For example, the present invention provides that R ² and R ³ together with the carbon atom to which they are attached form a 5 or 6 membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl and heterocycle. A compound of formula (VIII) is provided wherein said aryl, cycloalkyl, heteroaryl and heterocycle are optionally substituted with (R ⁶ ) _m .

For example, the present invention provides that R ² and R ³ together with the carbon atom to which they are attached are selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, cyclopentyl, cyclohexyl and thienyl. A compound of formula (VIII) is provided which forms a member ring.

For example, the present invention relates to a 5 or 6 member selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, cyclopentyl, cyclohexyl and thienyl, together with the carbon atom to which R ² and R ³ are attached. Providing a compound of formula (VIII) wherein a ring is formed; and R ⁴ is hydroxy.

For example, the present invention relates to a 5 or 6 member selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, cyclopentyl, cyclohexyl and thienyl, together with the carbon atom to which R ² and R ³ are attached. Forming a ring; R ⁴ is hydroxy; R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cyclo Alkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxy A formula selected from the group consisting of alkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _f R _g C = N- and R _k O- VIII) is provided.

For example, the invention relates to a 5 or 6 member selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, cyclopentyl, cyclohexyl and thienyl, together with the carbon atom to which R ² and R ³ are attached. Forming a ring; R ⁴ is hydroxy; R ¹ is C ₁ -C ₇ alkyl, (C ₃ -C ₆ cycloalkyl) C ₁ -C ₂ alkyl)-, phenyl-C ₁ -C ₂ alkyl-, Heteroaryl-C ₁ -C ₂ alkyl-, ((phenyl) C ₁ -C ₂ alkyl) O—, (C ₃ -C ₇ alkyl) O—, (C ₃ -C ₆ cycloalkyl) O—, (( _phenyl) C 1 -C _{2 alkyl) N (H) -, (} C 3 ~C 6 _{cycloalkyl) N (H) -, (} (C 3 ~C 6 _cycloalkyl) C 1 -C ₂ alkyl) N ( H) - and _(C 1 -C ₇ alkyl) N (H) - to provide a formula selected from the group consisting of the compounds of (VIII).

For example, the invention relates to a 5 or 6 member selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, cyclopentyl, cyclohexyl and thienyl, together with the carbon atom to which R ² and R ³ are attached. Forming a ring; R ⁴ is hydroxy; R ¹ is C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, phenylmethyl, phenylethyl, (5-chloro-thien-2-yl) methyl, cyclobutylmethyl, Cyclopropylmethyl, cyclopropylethyl, (cyclopropylmethyl) N (H)-, (cyclobutyl) N (H)-, (cyclopentyl) N (H)-, (cyclohexyl) N (H)-, (phenylmethyl) _{N (H) -, (C} 3 alkyl) N (H) -, ( C 4 alkyl) N (H) - and _{(C 5} alkyl L) A compound of formula (VIII) is selected from the group consisting of N (H)-.

Examples of compounds of the tenth embodiment of the invention of formula (VIII) include
3- (1,1-Dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl) -4-hydroxy-1- (isobutylamino ) Quinolin-2 (1H) -one;
3- [8- (Chloromethyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] -4- Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
3- {3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H- [1,3] oxazolyl [5 4-h] [1,2,4] benzothiadiazin-8-yl} propanoic acid;
3- (8-{[(2-Aminoethyl) amino] methyl} -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazine -3-yl) -4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
{3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H- [1,3] oxazolo [5,4- h] [1,2,4] benzothiadiazin-8-yl} methyl acetate;
4-hydroxy-3- (8-{[(3R) -3-hydroxypyrrolidin-1-yl] methyl} -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1 , 2,4] benzothiadiazin-3-yl) -1- (isobutylamino) quinolin-2 (1H) -one;
3- [1,1-Dioxide-8- (pyridinium-1-ylmethyl) -4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] -1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-4-one;
3- [1,1-Dioxide-8- (pyrrolidin-1-ylmethyl) -4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] -4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
3- [8- (3-Aminophenyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl]- 4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
3- [8- (Aminomethyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] -4- Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
4-hydroxy-3- [8- (hydroxymethyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl ] -1- (isobutylamino) quinolin-2 (1H) -one;
3- {8-[(Butylamino) methyl] -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl} -4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
3- [9- (Butylamino) -1,1-dioxide-4H, 8H- [1,4] oxazino [2,3-h] [1,2,4] benzothiadiazin-3-yl]- 4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one;
4-Hydroxy-1- (3-methylbutyl) -3- (8-methyl-1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadia Din-3-yl) -1,8-naphthyridin-2 (1H) -one;
3- [1,1-Dioxide-8- (trifluoromethyl) -4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl] -4-hydroxy -1- (3-methylbutyl) -1,8-naphthyridin-2 (1H) -one;
4-hydroxy-3- (8-hydroxy-1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl) -1- ( 3-methylbutyl) -1,8-naphthyridin-2 (1H) -one;
4-Hydroxy-1- (3-methylbutyl) -3- (8-methyl-1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazine- 3-yl) -1,8-naphthyridin-2 (1H) -one;
3- [1,1-Dioxide-8- (pentafluoroethyl) -4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl] -4-hydroxy -1- (3-methylbutyl) -1,8-naphthyridin-2 (1H) -one;
3- [8- (Chloromethyl) -1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl] -4-hydroxy- 1- (3-methylbutyl) -1,8-naphthyridin-2 (1H) -one;
{3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4,7-dihydroimidazo [ 4,5-h] [1,2,4] benzothiadiazin-8-yl} acetonitrile;
{3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4,7-dihydroimidazo [ 4,5-h] [1,2,4] benzothiadiazin-8-yl} methyl acetate;
3- (9,9-dioxide-6H- [1,2,5] thiadiazolo [3,4-h] [1,2,4] benzothiadiazin-7-yl) -4-hydroxy-1- ( 3-methylbutyl) -1,8-naphthyridin-2 (1H) -one;
3- (8-amino-1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl) -4-hydroxy-1- ( 3-methylbutyl) -1,8-naphthyridin-2 (1H) -one; and 4-hydroxy-3- [8- (hydroxymethyl) -1,1-dioxide-4,9-dihydroimidazo [4,5- h] [1,2,4] benzothiadiazin-3-yl] -1- (3-methylbutyl) -1,8-naphthyridin-2 (1H) -one or a pharmaceutically acceptable salt form thereof, Examples include, but are not limited to, stereoisomers or tautomers.

  In an eleventh embodiment, the present invention provides a therapeutically effective amount of formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or a combination of compounds or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier.

  In a twelfth embodiment, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va) together with one or more host immunomodulators and a pharmaceutically acceptable carrier. ), (Vb), (VIa), (VIb), (VII) or (VIII) or a combination of compounds or a pharmaceutically acceptable salt form thereof.

  For example, the present invention provides one or more host immunomodulators and pharmaceuticals selected from the group consisting of interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants. A therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) together with an acceptable carrier Alternatively, provided is a pharmaceutical composition comprising a combination of compounds or a pharmaceutically acceptable salt form thereof.

  In a thirteenth embodiment, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV) together with one or more second antiviral agents and a pharmaceutically acceptable carrier. , (Va), (Vb), (VIa), (VIb), (VII) or a compound combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof.

  For example, the invention includes a therapeutically effective amount of formula (I) together with one or more second antiviral agents and pharmaceutically acceptable carriers that inhibit HCV replication by inhibiting host cell functions associated with viral replication. ), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a compound combination of (VIII) or a pharmaceutically acceptable product thereof A pharmaceutical composition comprising a salt form is provided.

  For example, the present invention provides a therapeutically effective amount of Formula (I), together with one or more second antiviral agents and pharmaceutically acceptable carriers that target HCV replication by targeting viral genomic proteins. II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof A pharmaceutical composition is provided.

  In a fourteenth embodiment, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators, one or more second antiviral agents and a pharmaceutically acceptable carrier. Offer things.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Selected from the group consisting of: a compound of or a combination of compounds or pharmaceutically acceptable salt forms thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants. Wherein the pharmaceutical composition comprises one or more host immunomodulators, one or more second antiviral agents, and a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Selected from the group consisting of: a compound of or a combination of compounds or pharmaceutically acceptable salt forms thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants. A pharmaceutical composition comprising one or more host immunomodulators, one or more second antiviral agents that inhibit HCV replication by inhibiting host cell functions associated with viral replication, and a pharmaceutically acceptable carrier I will provide a.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Selected from the group consisting of: a compound of or a combination of compounds or pharmaceutically acceptable salt forms thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants. Provided is a pharmaceutical composition comprising one or more host immunomodulators, one or more second antiviral agents that inhibit HCV replication by targeting viral genome proteins and a pharmaceutically acceptable carrier .

  In a fifteenth embodiment, the present invention provides a therapeutically effective amount of formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immune modulators, one or more agents that treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation And a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Selected from the group consisting of: a compound of or a combination of compounds or pharmaceutically acceptable salt forms thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants. There is provided a pharmaceutical composition comprising one or more host immunomodulators, one or more agents that treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation, and a pharmaceutically acceptable carrier.

  In a sixteenth embodiment, the present invention provides therapeutically effective amounts of Formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or (VIII) or a pharmaceutically acceptable salt form thereof, one or more second antiviral agents, one or more to treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation And a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, one or more second antiviral agents that inhibit HCV replication by inhibiting host cell functions associated with viral replication, cirrhosis and liver Pharmaceutical compositions comprising one or more agents that treat or ameliorate symptoms of HCV infection, such as inflammation, and a pharmaceutically acceptable carrier are provided.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, one or more second antiviral agents that inhibit HCV replication by targeting viral genome proteins, cirrhosis and liver inflammation, etc. Pharmaceutical compositions comprising one or more agents that treat or ameliorate symptoms of HCV infection and a pharmaceutically acceptable carrier are provided.

  In a seventeenth embodiment, the present invention provides therapeutically effective amounts of Formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or (VIII) or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators, one or more second antiviral agents, cirrhosis and liver inflammation Pharmaceutical compositions comprising one or more agents that treat or ameliorate symptoms and a pharmaceutically acceptable carrier are provided.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, selected from the group consisting of interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants A pharmaceutical comprising one or more host immunomodulators, one or more second antiviral agents, one or more agents that treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation, and a pharmaceutically acceptable carrier A composition is provided.

  In an eighteenth embodiment, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and antigens and adjuvants One or more host immunomodulators selected from the group consisting of: one or more second antiviral agents that inhibit HCV replication by inhibiting host cell functions associated with viral replication, cirrhosis and liver inflammation, etc. A pharmaceutical composition comprising one or more agents that treat or ameliorate symptoms of HCV infection and a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a compound or combination of compounds of formula (Va), (Vb), (VIa), (VIb), (VII) or (VIII) or a pharmaceutically acceptable salt form thereof. One or more host immunomodulators selected from the group consisting of: vaccines comprising interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and antigens and adjuvants, targeting proteins of the viral genome A pharmaceutical comprising one or more second antiviral agents that inhibit HCV replication, one or more agents that treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation, and a pharmaceutically acceptable carrier A composition is provided.

  In a nineteenth embodiment, the present invention provides a therapeutically effective amount of a compound or a combination of compounds (Va), (Vb), (VIa), (VIb), (VII) or (VIII) or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising a salt form, one or more host immunomodulators, one or more agents that treat a patient for a disease caused by hepatitis B (HBV) infection, and a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, selected from the group consisting of interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants There is provided a pharmaceutical composition comprising one or more host immunomodulators to be treated, one or more agents for treating a patient for a disease caused by hepatitis B (HBV) infection, and a pharmaceutically acceptable carrier.

  In a twentieth embodiment, the present invention provides therapeutically effective amounts of Formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, one or more second antiviral agents, one or more treating a patient for a disease caused by hepatitis B (HBV) infection And a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of formula (I), (II), (III), (IV), (Va), (Vb), (VIa) (VIb), (VII) or (VIII) Compound or combination of compounds or pharmaceutically acceptable salt form thereof, one or more second antiviral agents that inhibit HCV replication by inhibiting host cell functions associated with viral replication, hepatitis B (HBV) ) A pharmaceutical composition comprising one or more agents for treating a patient for a disease caused by an infection and a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) One or more second antiviral agents that inhibit HCV replication by targeting a compound of the present invention or a combination of compounds, or a pharmaceutically acceptable salt form thereof, and a protein of the viral genome, hepatitis B (HBV) infection A pharmaceutical composition comprising one or more agents for treating a patient for a disease caused by and a pharmaceutically acceptable carrier is provided.

  In a twenty-first embodiment, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or (VIII) or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators, one or more second antiviral agents, caused by hepatitis B (HBV) infection Pharmaceutical compositions comprising one or more agents for treating a patient for a disease and a pharmaceutically acceptable carrier are provided.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, selected from the group consisting of interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants A pharmaceutical comprising one or more host immunomodulators, one or more second antiviral agents, one or more agents for treating a patient for a disease caused by hepatitis B (HBV) infection, and a pharmaceutically acceptable carrier A composition is provided.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, selected from the group consisting of interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants One or more host immunomodulators, one or more second antiviral agents that inhibit HCV replication by inhibiting host cell functions associated with viral replication, diseases caused by hepatitis B (HBV) infection A pharmaceutical composition comprising one or more agents for treating a patient and a pharmaceutically acceptable carrier is provided.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Selected from the group consisting of a compound or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokine, vaccine and vaccine comprising antigen and adjuvant. One or more host immunomodulators, one or more second antiviral agents that inhibit HCV replication by targeting viral genome proteins, treating patients for diseases caused by hepatitis B (HBV) infection A pharmaceutical composition comprising one or more agents and a pharmaceutically acceptable carrier.

  Preferably, the medicament for treating a patient for a disease caused by hepatitis B (HBV) infection in said pharmaceutical composition is selected from the group consisting of L-deoxythymidine, adefovir, lamivudine and tenfovir. it can.

  In a twenty-second embodiment, the invention provides therapeutically effective amounts of Formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or (VIII) compounds or combinations of compounds or pharmaceutically acceptable salt forms thereof and one or more drugs and pharmaceutically acceptable for treating patients for diseases caused by human immunodeficiency virus (HIV) infection Pharmaceutical compositions comprising a carrier are provided.

  In a twenty-third embodiment, the present invention provides therapeutically effective amounts of Formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators, one or more treating a patient for a disease caused by human immunodeficiency virus (HIV) infection Pharmaceutical compositions comprising a drug and a pharmaceutically acceptable carrier are provided.

  For example, the present invention provides a therapeutically effective amount of a compound or combination of compounds of formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants. There is provided a pharmaceutical composition comprising one or more host immunomodulators, one or more agents for treating a patient for a disease caused by human immunodeficiency virus (HIV) infection, and a pharmaceutically acceptable carrier.

  In a twenty-fourth embodiment, the present invention provides therapeutically effective amounts of Formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or (VIII) compound or combination of compounds or pharmaceutically acceptable salt form thereof, one or more second antiviral agents, treating a patient for a disease caused by human immunodeficiency virus (HIV) infection 1 There is provided a pharmaceutical composition comprising the above drug and a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) One or more second antiviral agents that inhibit HCV replication by inhibiting host cell functions associated with viral replication, human immunodeficiency virus, or a combination of the compounds or a pharmaceutically acceptable salt form thereof (HIV) A pharmaceutical composition comprising one or more agents for treating a patient for a disease caused by an infection and a pharmaceutically acceptable carrier is provided.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) One or more second antiviral agents that inhibit HCV replication by targeting a compound of the present invention or a combination of compounds or pharmaceutically acceptable salt forms thereof and proteins of the viral genome, human immunodeficiency virus (HIV) Pharmaceutical compositions comprising one or more agents for treating a patient for a disease caused by an infection and a pharmaceutically acceptable carrier are provided.

  In a twenty-fifth embodiment, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or (VIII) compound or combination of compounds or pharmaceutically acceptable salt form thereof, one or more host immunomodulators, one or more second antiviral agents, caused by human immunodeficiency virus (HIV) infection There is provided a pharmaceutical composition comprising one or more agents for treating a patient for a disease and a pharmaceutically acceptable carrier.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, selected from the group consisting of interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants One or more host immunomodulatory agents, one or more second antiviral agents, one or more agents that treat a patient for a disease caused by human immunodeficiency virus (HIV) infection, and a pharmaceutically acceptable carrier A pharmaceutical composition is provided.

  In a twenty-sixth embodiment, the present invention provides therapeutically effective amounts of Formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII ) Or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and antigens and adjuvants One or more host immunomodulators selected from the group consisting of: one or more second antiviral agents that inhibit HCV replication by inhibiting host cell functions associated with viral replication, human immunodeficiency virus (HIV) A pharmaceutical composition comprising one or more agents for treating a patient for a disease caused by and a pharmaceutically acceptable carrier Subjected to.

  For example, the present invention provides a therapeutically effective amount of a formula (I), (II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) Or a combination thereof, or a pharmaceutically acceptable salt form thereof, selected from the group consisting of interferon-α, PEGylated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants One or more host immunoregulatory agents, one or more second antiviral agents that inhibit HCV replication by targeting viral genomic proteins, patients for diseases caused by human immunodeficiency virus (HIV) infection There is provided a pharmaceutical composition comprising one or more agents for treating and a pharmaceutically acceptable carrier.

  Agents for treating patients for diseases caused by human immunodeficiency virus (HIV) infection in the above pharmaceutical compositions include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, Fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249 or these There can be any combination, but it is not limited to these.

  In a twenty-seventh embodiment, the present invention provides a method for the treatment or prevention of an infection caused by an RNA-containing virus, wherein any pharmaceutical composition disclosed herein is administered to a patient in need of such treatment. A method is provided comprising the step of administering.

  In a twenty-eighth embodiment, the present invention provides a method of inhibiting replication of an RNA-containing virus, wherein said virus is treated with a therapeutically effective amount of formula (I), (II), (III), (IV), (Va ), (Vb), (VIa), (VIb), (VII) or (VIII) or a combination of compounds or a pharmaceutically acceptable salt.

  In a twenty-ninth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by an RNA-containing virus, wherein the therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. , (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt thereof A method having steps is provided.

  For example, the present invention provides a method for the treatment or prevention of infections caused by RNA-containing viruses, wherein a therapeutically effective amount of formula (I), (II), (III), Administering a compound of (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) or a combination of compounds or a pharmaceutically acceptable salt thereof, Provided is a method wherein the RNA-containing virus is hepatitis C virus.

  In a thirtieth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a compound combination of (VIII) and one or more host immunomodulators A method having steps is provided.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) compounds or combinations of compounds and interferon-α, PEGylated interferon-α, interferon-β, interferon -Providing a method comprising the step of administering one or more host immune modulators selected from the group consisting of vaccines comprising gamma, cytokines, vaccines and antigens and adjuvants.

  In a thirty-first embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) a compound or combination of compounds and one or more second antiviral agents A method is provided comprising the step of administering.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) compounds or combinations of compounds and inhibiting host cell functions associated with viral replication A method is provided comprising administering one or more second antiviral agents that inhibit replication.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. Inhibits HCV replication by targeting a compound or combination of compounds, and viral genome, and a protein of the viral genome, (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) A method comprising administering one or more second antiviral agents.

  In a thirty-second embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a compound combination of (VIII), one or more host immunomodulators and one or more A method comprising administering a second antiviral agent.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a compound combination of (VIII), interferon-α, PEGylated interferon-α, interferon-β, interferon -Providing a method comprising administering one or more host immune modulators selected from the group consisting of gamma, cytokines, vaccines and vaccines comprising antigens and adjuvants and one or more second antiviral agents.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a compound combination of (VIII), interferon-α, PEGylated interferon-α, interferon-β, interferon One or more host immune modulators selected from the group consisting of vaccines comprising γ, cytokines, vaccines and antigens and adjuvants and one or more which inhibits HCV replication by inhibiting host cell functions associated with viral replication A method is provided comprising the step of administering a second antiviral agent.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a compound combination of (VIII), interferon-α, PEGylated interferon-α, interferon-β, interferon One or more second that inhibits HCV replication by targeting one or more host immune modulators selected from the group consisting of gamma, cytokines, vaccines and vaccines comprising antigens and adjuvants and proteins of the viral genome A method is provided comprising the step of administering an antiviral agent.

  In a thirty-third embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form, one or more A method comprising administering a host immunomodulator, one or more agents that treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation, and a pharmaceutically acceptable carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEG One or more host immunomodulators selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, symptoms of HCV infection such as cirrhosis and liver inflammation A method is provided comprising administering one or more agents to be treated or ameliorated and a pharmaceutically acceptable carrier.

  In a thirty-fourth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, There is provided a method comprising administering one or more second antiviral agents, one or more agents that treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation, and a pharmaceutically acceptable carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, associated with viral replication One or more second antiviral agents that inhibit HCV replication by inhibiting host cell function, one or more agents that treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation, and pharmaceutically acceptable A method is provided comprising the step of administering a carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, a protein of the viral genome Administration of one or more second antiviral agents that inhibit HCV replication by targeting, one or more agents that treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation and a pharmaceutically acceptable carrier A method comprising the steps of:

  In a thirty-fifth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, Administering one or more host immunomodulators, one or more second antiviral agents, one or more agents that treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation, and a pharmaceutically acceptable carrier. A method is provided.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG Interferon-alpha, interferon-beta, interferon-gamma, cytokines, vaccines and one or more host immunomodulators selected from the group consisting of vaccines comprising antigens and adjuvants, one or more second antiviral agents, cirrhosis and Administering one or more drugs that treat or ameliorate symptoms of HCV infection, such as liver inflammation, and a pharmaceutically acceptable carrier A method including the step.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG One or more host immunoregulatory agents selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, inhibiting host cell functions associated with viral replication One or more second antiviral agents that inhibit HCV replication in the treatment of symptoms of HCV infection such as cirrhosis and liver inflammation Other provides a method comprising administering one or more agents and a pharmaceutically acceptable carrier to improve.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG HCV by targeting one or more host immunomodulators selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, proteins of the viral genome One or more second antiviral agents that inhibit replication, treat symptoms of HCV infection such as cirrhosis and liver inflammation or A method including the step of administering one or more agents and a pharmaceutically acceptable carrier for good.

  In a thirty-sixth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, A method is provided comprising administering one or more agents and a pharmaceutically acceptable carrier to treat a patient for a disease caused by hepatitis B (HBV) infection.

  In a thirty-seventh embodiment, the present invention provides a method of treating or preventing an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), ( II), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof There is provided a method comprising administering one or more host immunomodulators, one or more agents for treating a patient for a disease caused by hepatitis B (HBV) infection, and a pharmaceutically acceptable carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG Interferon-α; one or more host immunomodulators selected from the group consisting of interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants, for diseases caused by hepatitis B (HBV) infection A method is provided comprising administering one or more agents for treating a patient and a pharmaceutically acceptable carrier.

  In a thirty-eighth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, There is provided a method comprising administering one or more second antiviral agents, one or more agents for treating a patient for a disease caused by hepatitis B (HBV) infection, and a pharmaceutically acceptable carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, associated with viral replication One or more second antiviral agents that inhibit HCV replication by inhibiting host cell function, one or more agents that treat patients for diseases caused by hepatitis B (HBV) infection, and pharmaceutically acceptable A method is provided comprising the step of administering a carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, a protein of the viral genome Administering one or more second antiviral agents that inhibit HCV replication by targeting, one or more agents that treat the patient for diseases caused by hepatitis B (HBV) infection, and a pharmaceutically acceptable carrier A method comprising the steps of:

  In a thirty-ninth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (II), (III ), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, one or more hosts Providing a method comprising administering an immunomodulator, one or more second antiviral agents, one or more agents treating a patient for a disease caused by hepatitis B (HBV) infection and a pharmaceutically acceptable carrier To do.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG One or more host immunomodulators, one or more second antiviral agents, type B selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants Administering one or more drugs and a pharmaceutically acceptable carrier to treat the patient for a disease caused by hepatitis (HBV) infection To provide a method with.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG One or more host immunoregulatory agents selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, inhibiting host cell functions associated with viral replication One or more second antiviral agents that inhibit HCV replication in diseases caused by hepatitis B (HBV) infection There is provided a method including the step of administering one or more agents and a pharmaceutically acceptable carrier for treating a patient.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG HCV by targeting one or more host immunomodulators selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, proteins of the viral genome About one or more second antiviral agents that inhibit replication, diseases caused by hepatitis B (HBV) infection A method including the step of administering one or more agents and a pharmaceutically acceptable carrier to treat people.

  Agents that treat patients for diseases caused by hepatitis B (HBV) infection can be, but are not limited to, for example, L-deoxythymidine, adefovir, lamivudine, and tenfovir, or combinations thereof.

  In a fortieth embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, A method is provided comprising administering one or more agents and a pharmaceutically acceptable carrier to treat a patient for a disease caused by a human immunodeficiency virus (HIV) infection.

  In a forty-first embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, Methods are provided comprising administering one or more host immunomodulators, one or more agents for treating a patient for a disease caused by a human immunodeficiency virus (HIV) infection, and a pharmaceutically acceptable carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG Disease caused by human immunodeficiency virus (HIV) infection, one or more host immunomodulators selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants A method comprising administering one or more agents for treating a patient and a pharmaceutically acceptable carrier. To.

  In a forty-second embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, There is provided a method comprising administering one or more second antiviral agents, one or more agents for treating a patient for a disease caused by human immunodeficiency virus (HIV) infection, and a pharmaceutically acceptable carrier.

  For example, the invention is a method of treating or preventing an infection caused by hepatitis C virus, wherein a therapeutically effective amount of a compound or combination of compounds of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) or a pharmaceutically acceptable salt form thereof, a host involved in virus replication One or more second antiviral agents that inhibit HCV replication by inhibiting cellular function, one or more agents that treat patients for diseases caused by human immunodeficiency virus (HIV) infection, and pharmaceutically acceptable A method is provided comprising the step of administering a carrier.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, a protein of the viral genome One or more second antiviral agents that inhibit HCV replication by targeting, one or more agents that treat a patient for a disease caused by human immunodeficiency virus (HIV) infection, and a pharmaceutically acceptable carrier A method is provided comprising the step of administering.

  In a forty-third embodiment, the present invention provides a method for the treatment or prevention of an infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II) for a patient in need of such treatment. ), (III), (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, Administering one or more host immunomodulators, one or more second antiviral agents, one or more agents that treat the patient for a disease caused by human immunodeficiency virus (HIV) infection, and a pharmaceutically acceptable carrier. A method is provided.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG One or more host immunomodulators, one or more second antiviral agents, human immunity selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants One or more drugs and a pharmaceutically acceptable carrier for treating a patient for a disease caused by a deficiency virus (HIV) infection It provides a method with Azukasuru stage.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG One or more host immunoregulatory agents selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, inhibiting host cell functions associated with viral replication Caused by immunodeficiency virus (HIV), one or more second antiviral agents that inhibit HCV replication in A method including the step of administering one or more agents and a pharmaceutically acceptable carrier to treat the patient for patient.

  For example, the present invention is a method of treating or preventing infection caused by hepatitis C virus, wherein a therapeutically effective amount of formula (I), (II), (III) for a patient in need of such treatment. , (IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEG HCV by targeting one or more host immunomodulators selected from the group consisting of conjugated interferon-α, interferon-β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, proteins of the viral genome One or more second antiviral agents that inhibit replication, caused by human immunodeficiency virus (HIV) infection A method including the step of administering one or more agents and a pharmaceutically acceptable carrier to treat the patient for patient.

  Drugs for treating patients for diseases caused by human immunodeficiency virus (HIV) infections are ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine , Didanosine, stavudine, tenofovir, sarcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof However, it is not limited to these.

  In a forty-fourth embodiment, the present invention relates to formulas (I), (II), (III), (IV) for the manufacture of a medicament for the treatment or prevention of infections caused by RNA-containing viruses in a patient. , (Va), (Vb), (VIa), (VIb), (VII) or (VIII) or a combination of compounds or a therapeutically acceptable salt thereof.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va), for the manufacture of a medicament for the treatment or prevention of infections caused by RNA-containing viruses in a patient. Use of a compound of (Vb), (VIa), (VIb), (VII) or (VIII) or a combination of compounds or a therapeutically acceptable salt thereof, wherein said RNA-containing virus is hepatitis C virus Provides some use.

  In a forty-fifth embodiment, the present invention relates to formula (I), (II), (III), (IV) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a combination thereof or a therapeutically acceptable salt thereof and the use of one or more host immunomodulators I will provide a.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a therapeutically acceptable salt thereof and interferon-α, PEGylated interferon-α, interferon-β There is provided the use of one or more host immune modulators selected from the group consisting of vaccines comprising interferon-γ, cytokines, vaccines and antigens and adjuvants.

  In a forty-sixth embodiment, the present invention relates to the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient, in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a combination thereof, or a therapeutically acceptable salt thereof and one or more second antiviruses Provide the use of the agent.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds, or a therapeutically acceptable salt thereof and host cell function associated with viral replication The use of one or more second antiviral agents that inhibit HCV replication is provided.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a therapeutically acceptable salt thereof and a viral genome protein to target HCV replication Use of one or more second antiviral agents that inhibit

  In a forty-seventh embodiment, the present invention relates to the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient, in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds, or a combination thereof, or a therapeutically acceptable salt thereof, one or more host immunomodulators and Use of one or more second antiviral agents is provided.

  For example, the present invention provides a compound or combination of compounds of formula (I), (II), (III), (III) in the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) or a therapeutically acceptable salt thereof, interferon-α, PEGylated interferon-α, interferon-β, There is provided the use of one or more host immune modulators and one or more second antiviral agents selected from the group consisting of interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or (VIII) compounds or combinations of compounds or therapeutically acceptable salts thereof, interferon-α, PEGylated interferon-α, interferon-β Inhibiting HCV replication by inhibiting one or more host immunomodulators selected from the group consisting of vaccines comprising interferon-γ, cytokines, vaccines and antigens and adjuvants and host cell functions associated with viral replication 1 The use of the second antiviral agent is provided.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or (VIII) compounds or combinations of compounds or therapeutically acceptable salts thereof, interferon-α, PEGylated interferon-α, interferon-β One or more first inhibitors that inhibit replication of HCV by targeting one or more host immunomodulators selected from the group consisting of interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants and viral genome proteins Provides the use of two antiviral agents.

  In a forty-eighth embodiment, the present invention relates to the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient, wherein the formula (I), (11), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds, or a combination thereof, or a therapeutically acceptable salt thereof, one or more host immunomodulators and Provided is the use of one or more agents to treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immunomodulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants and one or more to treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation Provide drug use.

  In a forty-ninth embodiment, the present invention relates to the manufacture of a medicament for treating or preventing an infection caused by hepatitis C virus in a patient for formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more second anti-antibodies Viral agents and use of one or more agents to treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation are provided.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, inhibiting host cell functions related to viral replication There is provided the use of one or more second antiviral agents that inhibit HCV replication and one or more agents that treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds, or a pharmaceutically acceptable salt form thereof, by targeting a protein of the viral genome. One or more second antiviral agents that inhibit replication treat or ameliorate symptoms of HCV infection, such as cirrhosis and liver inflammation, and use of one or more agents is provided.

  In a fiftieth embodiment, the present invention relates to formulas (I), (II), (1II), (1) in manufacturing a medicament for treating or preventing an infection caused by hepatitis C virus in a patient. IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators There is provided the use of one or more second antiviral agents and one or more agents to treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation.

  For example, the present invention provides a compound or combination of compounds of formula (I), (II), (III), (III) in the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon-β HCV infections such as one or more host immunomodulators, one or more second antiviral agents selected from the group consisting of, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants, and one or more second antiviral agents, and cirrhosis and liver inflammation Use of one or more agents to treat or ameliorate the symptoms of

  In another preferred embodiment, the present invention relates to the preparation of a medicament for treating or preventing an infection caused by hepatitis C virus in a patient in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon One or more host immunomodulators selected from the group consisting of vaccines comprising α, interferon-β, interferon-γ, cytokines, vaccines and antigens and adjuvants, HCV by inhibiting host cell functions associated with viral replication One or more second antiviral agents that inhibit the replication of HCV and diseases of HCV infection such as cirrhosis and liver inflammation The provides the use of one or more agents that treat or ameliorate.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immunomodulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, one or more that inhibits HCV replication by targeting viral genome proteins A second antiviral agent and one or more to treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation It provides for the use of the drug.

  In a fifty-first embodiment, the present invention relates to the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient, in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) compounds or combinations of compounds or pharmaceutically acceptable salt and hepatitis B (HBV) infections thereof The use of one or more drugs to treat a patient for a disease caused by is provided.

  In a fifty-second embodiment, the present invention relates to the preparation of a medicament for treating or preventing an infection caused by hepatitis C virus in a patient in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators And the use of one or more drugs to treat patients for diseases caused by hepatitis B (HBV) infection.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immune modulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants and one or more to treat patients for diseases caused by hepatitis B (HBV) infection Provide drug use.

  In a thirty-third embodiment, the present invention relates to the manufacture of a medicament for treating or preventing an infection caused by hepatitis C virus in a patient, in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more second anti-antibodies Provided is the use of one or more agents to treat patients for diseases caused by viral agents and hepatitis B (HBV) infection.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, inhibiting host cell functions related to viral replication Provides for the use of one or more second antiviral agents that inhibit HCV replication and one or more agents that treat patients for diseases caused by hepatitis B (HBV) infection.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds, or a pharmaceutically acceptable salt form thereof, by targeting a protein of the viral genome. One or more second antiviral agents that inhibit replication and the use of one or more agents to treat a patient for a disease caused by hepatitis B (HBV) infection are provided.

  In a 54th embodiment, the present invention relates to the manufacture of a medicament for treating or preventing an infection caused by hepatitis C virus in a patient, in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators One or more second antiviral agents and use of one or more agents to treat a patient for a disease caused by hepatitis B (HBV) infection are provided.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- caused by one or more host immune modulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, one or more second antiviral agents and hepatitis B (HBV) infection The use of one or more drugs to treat the patient for the disease is provided.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immunomodulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, inhibiting HCV replication by inhibiting host cell functions related to viral replication Heal patients for diseases caused by one or more second antiviral agents and hepatitis B (HBV) infection It provides the use of one or more agents that.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immunomodulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, more than inhibit HCV replication by targeting viral genome proteins Treat patients for diseases caused by second antiviral agents and hepatitis B (HBV) infection It provides for the use of more drugs.

  Agents that treat patients for diseases caused by hepatitis B (HBV) infection can be, but are not limited to, for example, L-deoxythymidine, adefovir, lamivudine, and tenfovir, or combinations thereof.

  In a 55th embodiment, the present invention relates to the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient, wherein the formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof and human immunodeficiency virus (HIV) ) Provide for the use of one or more drugs to treat the patient for diseases caused by infection;

  In a fifty-sixth embodiment, the present invention relates to the preparation of a medicament for treating or preventing infection caused by hepatitis C virus in a patient, in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators And the use of one or more agents to treat patients for diseases caused by human immunodeficiency virus (HIV) infection.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immune modulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants and one or more to treat patients for diseases caused by human immunodeficiency virus (HIV) infection Provides the use of drugs.

  In a 57th embodiment, the present invention relates to the manufacture of a medicament for treating or preventing an infection caused by hepatitis C virus in a patient in formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more second anti-antibodies Provided is the use of one or more agents to treat patients for diseases caused by viral agents and human immunodeficiency virus (HIV) infection.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, inhibiting host cell functions related to viral replication The use of one or more second antiviral agents that inhibit HCV replication and the use of one or more agents to treat patients for diseases caused by human immunodeficiency virus (HIV) infection.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds, or a pharmaceutically acceptable salt form thereof, by targeting a protein of the viral genome. One or more second antiviral agents that inhibit replication and use of one or more agents to treat a patient for a disease caused by a human immunodeficiency virus (HIV) infection are provided.

  In a fifty-eighth embodiment, the present invention relates to the preparation of a medicament for treating or preventing an infection caused by hepatitis C virus in a patient for formula (I), (II), (III), ( IV), (Va), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, one or more host immunomodulators One or more second antiviral agents and use of one or more agents to treat a patient for a disease caused by a human immunodeficiency virus (HIV) infection are provided.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- by one or more host immunomodulators, one or more second antiviral agents and human immunodeficiency virus (HIV) infection selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines comprising antigens and adjuvants The use of one or more drugs to treat the patient for the disease caused is provided.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immunomodulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, inhibiting HCV replication by inhibiting host cell functions related to viral replication About diseases caused by one or more second antiviral agents and human immunodeficiency virus (HIV) The provides the use of one or more agents that therapist.

  For example, the present invention relates to formulas (I), (II), (III), (IV), (Va) for the manufacture of a medicament for treating or preventing infection caused by hepatitis C virus in a patient. ), (Vb), (VIa), (VIb), (VII) or a combination of compounds or a pharmaceutically acceptable salt form thereof, interferon-α, PEGylated interferon-α, interferon- one or more host immunomodulators selected from the group consisting of β, interferon-γ, cytokines, vaccines and vaccines including antigens and adjuvants, one or more that inhibits HCV replication by targeting viral genome proteins About a disease caused by a second antiviral agent and human immunodeficiency virus (HIV) infection The provides the use of one or more agents that treat.

  Drugs for treating patients for diseases caused by human immunodeficiency virus (HIV) infections are ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine , Didanosine, stavudine, tenofovir, sarcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof However, it is not limited to these.

  In a 59th embodiment, the invention provides a compound having the following formula (I):

［式中、
Ａは、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環からなる群から選択される単環式または二環式環であり；
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^２およびＲ^３は独立に、水素、アルケニル、アルキニル、アルコキシアルキル、アルコキシカルボニル、アルキル、アリール、アリールアルキル、ヘテロアリール、複素環、ヘテロアリールアルキル、シアノ、ハロ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａおよびＲ_ａＣ（Ｏ）−からなる群から選択され；Ｒ^２およびＲ^３は独立に、独立にＲ_ａ、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ^２およびＲ^３が、それらが結合している炭素原子と一体となって、アリール、シクロアルキル、ヘテロアリールおよび複素環からなる群から選択される５員または６員環を形成しており、前記アリール、シクロアルキル、ヘテロアリールおよび複素環は（Ｒ^６）_ｍで置換されていても良く；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は独立に、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１、２、３または４であり；
ただし、Ａが下記のもの：

[Where:
A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, selected from the group consisting of R _f R _g C═N— and R _k O—; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro , Haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c ,- _{S (O) R c, -S} (O) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C ( O) N It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _c R _e;
R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _{b), R a R b NC} (O) -, - SR a, -S (O) R a, -S (O) 2 R a , and _R a C (O) - is selected from the group consisting of; ^{R 2} And R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, — (alkyl) (OR _k ), — (alkyl) (NR _a R _b ), —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and From —C (O) NR _a R _b Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of;
Alternatively, R ² and R ³ together with the carbon atom to which they are attached form a 5- or 6-membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl and heterocycle And the aryl, cycloalkyl, heteroaryl and heterocycle may be substituted with (R ⁶ ) _m ;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently, independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substituents selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Is replaced by;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Where A is:

以外の単環式環であり、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではなく；
さらには、Ａが下記のもの：

R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, Cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N ( R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, heteroaryl, _{heterocyclealkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R _a , —C (O) OR _a and — When C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, hetero Not arylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl;
In addition, A is:

であり、Ｒ^４がヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、未置換アルキル、ハロまたは−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ、および−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。］またはその化合物の製薬上許容される塩型、立体異性体または互変異体の製造方法において、
（ａ）塩基存在下に下記式（２６）の化合物：

R ⁴ is hydroxy or R _e S—, R ⁵ is hydrogen, unsubstituted alkyl, halo or —OR _k and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl , Heteroaryl, heterocyclic alkyl, —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _{When a is} —C (O) OR and —C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl , (Cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl. Or a pharmaceutically acceptable salt form, stereoisomer or tautomer thereof,
(A) A compound of the following formula (26) in the presence of a base:

を二硫化炭素およびメチル化剤と接触させて、下記式（２７）の化合物：

Is contacted with carbon disulfide and a methylating agent to give a compound of the following formula (27):

を得る段階；ならびに
（ｂ）前記式（２７）の化合物を下記式（１３）の化合物：

(B) converting the compound of the formula (27) into a compound of the following formula (13):

と接触させる段階
を有する方法を提供する。

A method comprising the steps of:

  In a 60th embodiment, the present invention provides a compound having the following formula (I):

［式中、
Ａは、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環からなる群から選択される単環式または二環式環であり；
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^２およびＲ^３は独立に、水素、アルケニル、アルキニル、アルコキシアルキル、アルコキシカルボニル、アルキル、アリール、アリールアルキル、ヘテロアリール、複素環、ヘテロアリールアルキル、シアノ、ハロ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａおよびＲ_ａＣ（Ｏ）−からなる群から選択され；Ｒ^２およびＲ^３は独立に、独立にＲ_ａ、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ^２およびＲ^３が、それらが結合している炭素原子と一体となって、アリール、シクロアルキル、ヘテロアリールおよび複素環からなる群から選択される５員または６員環を形成しており、前記アリール、シクロアルキル、ヘテロアリールおよび複素環は（Ｒ^６）_ｍで置換されていても良く；
Ｒ^４は、アルコキシ、アリールアルコキシ、アリールオキシ、ハロ、ヒドロキシ、Ｒ_ａＲ_ｂＮ−、Ｎ_３−、Ｒ_ｅＳ−からなる群から選択され；Ｒ^４は独立に、独立にハロ、ニトロ、シアノ、−ＯＨ、−ＮＨ_２、および−ＣＯＯＨからなる群から選択される０、１または２個の置換基で置換されており；
Ｒ^５は各場合で独立に、アルケニル、アルコキシ、アルキル、アルキニル、アリール、アリールアルキル、アリールカルボニル、アリールオキシ、アジドアルキル、ホルミル、ハロ、ハロアルキル、ハロカルボニル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、シクロアルキル、シアノ、シアノアルキル、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａ（Ｏ）ＳＮ（Ｒ_ｆ）アルキル−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＳＯ_２Ｎ（Ｒ_ｆ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）アルキル−、Ｒ_ｋＯアルキル−、Ｒ_ａＲ_ｂＮＳＯ_２−、Ｒ_ａＲ_ｂＮＳＯ_２アルキル−、（Ｒ_ｂＯ）（Ｒ_ａ）Ｐ（Ｏ）Ｏ−および−ＯＲ_ｋからなる群から選択され；各Ｒ^５は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
ｎは０、１、２、３または４であり；
ただし、Ａが下記のもの：

[Where:
A is a monocyclic or bicyclic ring selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocycle;
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, selected from the group consisting of R _f R _g C═N— and R _k O—; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro , Haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c ,- _{S (O) R c, -S} (O) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C ( O) N It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _c R _e;
R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _{b), R a R b NC} (O) -, - SR a, -S (O) R a, -S (O) 2 R a , and _R a C (O) - is selected from the group consisting of; ^{R 2} And R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, — (alkyl) (OR _k ), — (alkyl) (NR _a R _b ), —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and From —C (O) NR _a R _b Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of;
Alternatively, R ² and R ³ together with the carbon atom to which they are attached form a 5- or 6-membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl and heterocycle And the aryl, cycloalkyl, heteroaryl and heterocycle may be substituted with (R ⁶ ) _m ;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ —, R _e S—; R ⁴ is independently, independently halo, nitro, cyano, -OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is independently in each case alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclic alkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S-, R _a R _b N alkyl-, R _a (O) SN (R _f )-, R _a SO ₂ N (R _f )-, R _a (O) SN (R _f ) alkyl-, R _a SO ₂ N _{(R f)} alkyl _{-, R a R b NSO 2} N (R f) -, R a R b NSO 2 N (R f) alkyl _{-, R a R b NC (} O) - _{R k OC (O) -,} R k OC (O) alkyl -, _{R k} O-alkyl _{-, R a R b NSO 2} -, R a R b NSO 2 alkyl _{-, (R b O) (} R a) P (O) selected from the group consisting of O— and —OR _k ; each R ⁵ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, hetero ring, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) ₂ R _c , —OR _c , —N (R _c ) (R _d ), —C (O) R _c , —C (O) OR _c and —C (O) NR _c R _d 0, 1, 2, or 3 It is substituted with a substituent;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substituents selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Is replaced by;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Where A is:

以外の単環式環であり、Ｒ^４がアルコキシ、アリールオキシ、ヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、アルケニル、アルコキシ、アルキル、アルキニル、アリール、ハロ、ヘテロアリール、複素環アルキル、シクロアルキル、シアノ、ニトロ、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＳ−、Ｒ_ａ（Ｏ）Ｓ−、Ｒ_ａ（Ｏ）_２Ｓ−、Ｒ_ａＳＯ_２Ｎ（Ｒ_ｆ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ｋＯＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＳＯ_２−または−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではなく；
さらには、Ａが下記のもの：

R ⁴ is alkoxy, aryloxy, hydroxy or R _e S—, and R ⁵ is hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, halo, heteroaryl, heterocyclic alkyl, Cycloalkyl, cyano, nitro, R _a R _b N—, R _a C (O) —, R _a S—, R _a (O) S—, R _a (O) ₂ S—, R _a SO ₂ N ( R _f ) —, R _a R _b NC (O) —, R _k OC (O) —, R _a R _b NSO ₂ — or —OR _k , and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl, heteroaryl, _{heterocyclealkyl, -SR a, -S (O)} R a, -S (O) 2 R a, -OR k, -N (R a) (R b), - C (O) R _a , —C (O) OR _a and — When C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, heteroaryl, hetero Not arylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl;
In addition, A is:

であり、Ｒ^４がヒドロキシまたはＲ_ｅＳ−であり、Ｒ^５が水素、未置換アルキル、ハロまたは−ＯＲ_ｋであり、Ｒ^６が水素、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、アリール、ヘテロアリール、複素環アルキル、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ、および−Ｃ（Ｏ）ＮＲ_ａＲ_ｂである場合、Ｒ^１は水素、アルケニル、アルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環アルケニルおよび複素環アルキルではない。］またはその化合物の製薬上許容される塩型、立体異性体または互変異体の製造方法において、
（ａ）塩基存在下に下記式（２６）の化合物：

R ⁴ is hydroxy or R _e S—, R ⁵ is hydrogen, unsubstituted alkyl, halo or —OR _k and R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, halo, cyano, nitro, aryl , Heteroaryl, heterocyclic alkyl, —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _{When a is} —C (O) OR and —C (O) NR _a R _b , R ¹ is hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, (cycloalkyl) alkenyl , (Cycloalkyl) alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocyclic alkenyl and heterocyclic alkyl. Or a pharmaceutically acceptable salt form, stereoisomer or tautomer thereof,
(A) A compound of the following formula (26) in the presence of a base:

をトリス（メチルチオ）メチル・メチルサルフェートと接触させて、下記式（２７）の化合物：

Is contacted with tris (methylthio) methyl methylsulfate to give a compound of the following formula (27):

を得る段階；ならびに
（ｂ）前記式（２７）の化合物を下記式（１３）の化合物：

(B) converting the compound of the formula (27) into a compound of the following formula (13):

と接触させる段階
を有する方法を提供する。

A method comprising the steps of:

  In a sixty first embodiment, the present invention provides a compound having the following formula (IX) or a pharmaceutically acceptable salt form, tautomer or stereoisomer of the compound:

式中、
Ｒ^１は、水素、アルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、（シクロアルキル）アルケニル、（シクロアルキル）アルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−およびＲ_ｋＯ−からなる群から選択され；Ｒ^１は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｅ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｅ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｅからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ^２およびＲ^３は独立に、水素、アルケニル、アルキニル、アルコキシアルキル、アルコキシカルボニル、アルキル、アリール、アリールアルキル、ヘテロアリール、複素環、ヘテロアリールアルキル、シアノ、ハロ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａおよびＲ_ａＣ（Ｏ）−からなる群から選択され；Ｒ^２およびＲ^３は独立に、独立にＲ_ａ、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ^２およびＲ^３が、それらが結合している炭素原子と一体となって、アリール、シクロアルキル、ヘテロアリールおよび複素環からなる群から選択される５員または６員環を形成しており、前記アリール、シクロアルキル、ヘテロアリールおよび複素環は（Ｒ^６）_ｍで置換されていても良く；
Ｒ^６は各場合で独立に、アルキル、アルケニル、アルキニル、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、複素環アルキル、−（アルキル）（ＯＲ_ｋ）、−（アルキル）（ＮＲ_ａＲ_ｂ）、−ＳＲ_ａ、−Ｓ（Ｏ）Ｒ_ａ、−Ｓ（Ｏ）_２Ｒ_ａ、−ＯＲ_ｋ、−Ｎ（Ｒ_ａ）（Ｒ_ｂ）、−Ｃ（Ｏ）Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａおよび−Ｃ（Ｏ）ＮＲ_ａＲ_ｂからなる群から選択され；各Ｒ^６は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、ハロアルキル、シアノ、ニトロ、−ＯＲ_ａ、−ＮＲ_ａＲ_ｂ、−ＳＲ_ａ、−ＳＯＲ_ａ、−ＳＯ_２Ｒ_ａ、−Ｃ（Ｏ）ＯＲ_ａ、−Ｃ（Ｏ）ＮＲ_ａＲ_ｂおよび−ＮＣ（Ｏ）Ｒ_ａからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ａおよびＲ_ｂは各場合で独立に、水素、アルケニル、アルキル、アルキルスルファニルアルキル、アリール、アリールアルケニル、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルアルケニル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキルカルボニル、ニトロアルキル、Ｒ_ｃＲ_ｄＮ−、Ｒ_ｋＯ−、Ｒ_ｋＯアルキル−、Ｒ_ｃＲ_ｄＮアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）アルキル−、Ｒ_ｃＳＯ_２−、Ｒ_ｃＳＯ_２アルキル−、Ｒ_ｃＣ（Ｏ）−、Ｒ_ｃＣ（Ｏ）アルキル−、Ｒ_ｃＯＣ（Ｏ）−、Ｒ_ｃＯＣ（Ｏ）アルキル−、Ｒ_ｃＲ_ｄＮアルキルＣ（Ｏ）−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）−、Ｒ_ｅＲ_ｄＮＣ（Ｏ）Ｏアルキル−、Ｒ_ｃＲ_ｄＮＣ（Ｏ）Ｎ（Ｒ_ｅ）アルキル−からなる群から選択され；Ｒ_ａおよびＲ_ｂは、アルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２ＲＣ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１または２個の置換基で置換されており；
あるいは、Ｒ_ａおよびＲ_ｂはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−アルキルＳＯ_２ＮＲ_ｃＲ_ｄ、−アルキルＣ（Ｏ）ＮＲ_ｃＲ_ｄ、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲｃＲｄからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｃおよびＲ_ｄは各場合で独立に、水素、−ＮＲ_ｆＲ_ｈ、−ＯＲ_ｆ、−ＣＯ（Ｒ_ｆ）、−ＳＲ_ｆ、−ＳＯＲ_ｆ、−ＳＯ_２Ｒ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）ＯＲ_ｆ、アルケニル、アルキル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、アリール、アリールアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環および複素環アルキルからなる群から選択され；各Ｒ_ｃおよびＲ_ｄは独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆ、−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−Ｃ（Ｏ）Ｎ（Ｈ）ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−Ｎ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈ、−Ｎ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈ、−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＯＲ_ｆ、−アルキルＮ（Ｒ_ｅ）ＳＯ_２ＮＲ_ｆＲ_ｈおよび−アルキルＮ（Ｒ_ｅ）Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｃおよびＲ_ｄはそれらが結合している窒素原子と一体となって、ヘテロアリールおよび複素環からなる群から選択される３〜６員環を形成しており；前記ヘテロアリールおよび複素環は独立に、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｆ）、−（アルキル）（ＮＲ_ｆＲ_ｈ）、−ＳＲ_ｆ、−Ｓ（Ｏ）Ｒ_ｆ、−Ｓ（Ｏ）_２Ｒ_ｆ、−ＯＲ_ｆ、−Ｎ（Ｒ_ｆ）（Ｒ_ｈ）、−Ｃ（Ｏ）Ｒ_ｆ、−Ｃ（Ｏ）ＯＲ_ｆおよび−Ｃ（Ｏ）ＮＲ_ｆＲ_ｈからなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｅは、水素、アルケニル、アルキルおよびシクロアルキルからなる群から選択され；
Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは各場合で独立に、水素、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、シクロアルケニルアルキル、複素環、複素環アルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群から選択され；各Ｒ_ｆ、Ｒ_ｇおよびＲ_ｈは独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−ＳＯ_２アルキル、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＮ（アルキル）_２、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
あるいは、Ｒ_ｆおよびＲ_ｇはそれらが結合している炭素原子と一体となって、シクロアルキル、シクロアルケニルおよび複素環からなる群から選択される３〜７員環を形成しており；
あるいは、Ｒ_ｆおよびＲ_ｈはそれらが結合している窒素原子と一体となって、複素環およびヘテロアリールからなる群から選択される３〜７員環を形成しており；前記複素環およびヘテロアリールはそれぞれ独立に、独立にアルキル、アルケニル、アルキニル、シアノ、ハロ、オキソ、ニトロ、アリール、アリールアルキル、シクロアルキル、シクロアルケニル、複素環、ヘテロアリール、ヘテロアリールアルキル、−ＯＨ、−Ｏ（アルキル）、−ＮＨ_２、−Ｎ（Ｈ）（アルキル）、−Ｎ（アルキル）_２、−Ｓ（アルキル）、−Ｓ（アルキル）、−Ｓ（Ｏ）（アルキル）、−アルキル−ＯＨ、−アルキル−Ｏ−アルキル、−アルキルＮＨ_２、−アルキルＮ（Ｈ）（アルキル）、−アルキルＳ（アルキル）、−アルキルＳ（Ｏ）（アルキル）、−アルキルＳＯ_２アルキル、−アルキルＮ（アルキル）_２、−Ｎ（Ｈ）Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（アルキル）、−Ｃ（Ｏ）アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｎ（Ｈ）（アルキル）および−Ｃ（Ｏ）Ｎ（アルキル）_２からなる群から選択される０、１、２または３個の置換基で置換されており；
Ｒ_ｋは、水素、アルケニル、アルキル、アリール、アリールアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＯアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル、Ｒ_ａＳ−、Ｒ_ａＳ（Ｏ）−、Ｒ_ａＳＯ_２−、Ｒ_ａＳアルキル−、Ｒ_ａ（Ｏ）Ｓアルキル−、Ｒ_ａＳＯ_２アルキル−、Ｒ_ａＯＣ（Ｏ）−、Ｒ_ａＯＣ（Ｏ）アルキル−、Ｒ_ａＣ（Ｏ）−、Ｒ_ａＣ（Ｏ）アルキル−からなる群から選択され；各Ｒ_ｋは、独立にアルキル、アルケニル、アルキニル、オキソ、ハロ、シアノ、ニトロ、ハロアルキル、ハロアルコキシ、アリール、ヘテロアリール、複素環、アリールアルキル、ヘテロアリールアルキル、アルコキシアルコキシアルキル、−（アルキル）（ＯＲ_ｃ）、−（アルキル）（ＮＲ_ｃＲ_ｄ）、−ＳＲ_ｃ、−Ｓ（Ｏ）Ｒ_ｃ、−Ｓ（Ｏ）_２Ｒ_ｃ、−ＯＲ_ｃ、−Ｎ（Ｒ_ｃ）（Ｒ_ｄ）、−Ｃ（Ｏ）Ｒ_ｃ、−Ｃ（Ｏ）ＯＲ_ｃおよび−Ｃ（Ｏ）ＮＲ_ｃＲ_ｄからなる群から選択される０、１、２または３個の置換基で置換されており；
ｍは０、１、２、３または４であり；
Ｒ^１１およびＲ^１２は独立にアルキル、アルケニルおよびアルキニルからなる群から選択される。

Where
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, hetero Arylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic al Kill, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, selected from the group consisting of R _f R _g C═N— and R _k O—; R ¹ is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro , Haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c ,- _{S (O) R c, -S} (O) 2 R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C ( O) N It is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of _c R _e;
R ² and R ³ are independently hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N (R _a ) (R _{b), R a R b NC} (O) -, - SR a, -S (O) R a, -S (O) 2 R a , and _R a C (O) - is selected from the group consisting of; ^{R 2} And R ³ are independently R _a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, — (alkyl) (OR _k ), — (alkyl) (NR _a R _b ), —SR _a , —S (O) R _a , —S (O) ₂ R _a , —OR _k , —N (R _a ) (R _b ), —C (O) R _a , —C (O) OR _a and From —C (O) NR _a R _b Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of;
Alternatively, R ² and R ³ together with the carbon atom to which they are attached form a 5- or 6-membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl and heterocycle And the aryl, cycloalkyl, heteroaryl and heterocycle may be substituted with (R ⁶ ) _m ;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, Halo, haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and -NC (O) _{R a} It is substituted with 0, 1, 2 or 3 substituents selected from Ranaru group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} k O-, R k O alkyl _{-, R} c R _d N-alkyl _{-, R c R d NC (} O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R c O (O) alkyl _{-, R} c R _d N alkyl _{C (O) -, R c} R d NC (O) -, R e R d NC (O) O -alkyl _{-, R c R d NC (} O) N ( R _e ) selected from the group consisting of alkyl-; R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, hetero arylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NRR d), - SR} c, -S (O) R c, -S (O) 2 RC, -OR c, - _{N (R c) (R d} ), - C (O) R c, -C (O) oR c and _{-C (O) NR c R d} 0,1 or 2 substituents selected from the group consisting of Substituted with a group;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S ( _{O) 2 R c, -OR c} , -N (R c) (R d), - or _{C (O) R c, -C} (O) oR c and -C (O) NRcRd 0, 1, 2 or 3 substituents selected from the group consisting of which is substituted by;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroarylalkyl, heterocycle and heterocyclealkyl; , Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxy Alkyl, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substituents selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Is replaced by;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) ( OR _f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h) Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: -C (O) R _f , -C (O) OR _f and -C (O) NR _f R _h Ri;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, selected from the group consisting of heteroarylalkyl; Heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- al Kill, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N _{(H) C (O) NH} 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of -C (O) N (H) (alkyl) and -C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl _{), - NH 2, -N (} H) ( alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl ) - alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0 is selected from the group consisting of _{(alkyl) 2,} Substituted with 1, 2 or 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2 or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4;
R ¹¹ and R ¹² are independently selected from the group consisting of alkyl, alkenyl and alkynyl.

Examples of the compound of the 61st embodiment of the invention of formula (IX) or a pharmaceutically acceptable salt form, tautomer or stereoisomer of the compound include:
1-benzyl-3- (bis (methylthio) methylene) -1H-quinoline-2,4 (1H, 3H) -dione;
3- [bis (methylthio) methylene] -1-butyl-1,8-naphthyridine-2,4 (1H, 3H) -dione;
3- [bis (methylthio) methylene] -1- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) quinoline-2,4 (1H, 3H) -dione;
3- [bis (methylthio) methylene] -1-[(cyclopropylmethyl) amino] quinoline-2,4 (1H, 3H) -dione;
3- [bis (methylthio) methylene] -1- (3-methylbutyl) pyridine-2,4 (1H, 3H) -dione;
1-benzyl-3- [bis (methylthio) methylene] pyridine-2,4 (1H, 3H) -dione;
3- [bis (methylthio) methylene] -1- (cyclobutylamino) quinoline-2,4 (1H, 3H) -dione; and 3- [bis (methylthio) methylene] -1- (cyclobutylmethyl) pyridine- 2,4 (1H, 3H) -dione and the like, but are not limited thereto.

  The compounds of the present invention can have asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the present invention include racemic mixtures, mixtures of diastereomers, mixtures of enantiomers, and compounds of the present invention that are substantially free of enantiomers and their enantiomers or other diastereomers. Including the individual optical isomers, such as a single diastereomer, are included in the present invention. “Substantially free” is greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound. More preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 98% free of other enantiomers or diastereomers of the compound, most preferably Means greater than about 99% free of other enantiomers or diastereomers of the compound.

  Furthermore, compounds containing possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double bonds are also encompassed by the present invention.

  Individual stereoisomers of the compounds of the present invention can be prepared by any of a number of methods that are within the knowledge of one of ordinary skill in the art. The methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in a mixture of enantiomers, followed by chromatographic separation of diastereomers and individual enantiomers. Regeneration, enzymatic resolution, etc.

  Stereospecific synthesis involves the use of appropriate chiral raw materials and synthetic reactions that do not cause racemization at the chiral center and inversion of stereochemistry.

  Diastereomeric mixtures of compounds resulting from a given synthesis reaction can often be separated by chromatographic methods known to those skilled in the art.

  Chromatographic resolution of enantiomers can be performed on chiral chromatography resins. Chromatographic columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto a column containing a chiral stationary phase. The enantiomers are then separated by HPLC.

  Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with a chiral auxiliary. The resulting diastereomers can then be separated by column chromatography. This method is particularly useful when the compound to be separated is a salt with a chiral auxiliary or a carboxyl, amino or hydroxyl group that forms a covalent bond. Chirally pure amino acids, organic carboxylic acids or organic sulfonic acids are particularly useful as chiral auxiliary. Once diastereomers are separated by chromatography, the individual enantiomers can be regenerated. In many cases, non-help, the chiral auxiliary can be recovered and used again.

  Enzymes such as esterases, phospholases and lipases can be useful for resolution of the enantiomer derivatives in the enantiomeric mixture. For example, an ester derivative of a carboxyl group in a compound to be separated can be produced. Certain enzymes selectively hydrolyze only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.

  The compounds of the present invention may exhibit tautomeric or structural isomerism. Since the figures herein may represent only one possible tautomeric or structural isomer form, it should be understood that the present invention covers any tautomeric form that has the ability to inhibit hepatitis C. Or includes structural isomer forms or mixtures thereof and is not limited to one tautomeric form or structural isomer form used in the figures.

  Furthermore, solvates and hydrates of the compounds of the present invention are included in the present invention.

Any variable (eg, R ¹ , R ² , R ³ , m, n, etc.) is present more than ^once in any substituent or compound of the invention or any other formula herein , Its definition in each case is independent of its definition in any other case. In addition, combinations of substituents are permissible when such combinations result in stable compounds. A stable compound is a compound that can be isolated from the reaction mixture with a useful degree of purity.

  The compounds of the present invention can exist as pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” is soluble or dispersible in water or oil and is used to treat a disease without causing undue toxicity, irritation and allergic response. Represents an acid or base salt or zwitterionic form of a compound of the invention that is suitable, has a reasonable benefit / risk ratio, and is effective in the intended use. The salt can be prepared separately during the final isolation and purification of the compound or by reacting a basic group (eg, a nitrogen-containing group) with a suitable acid. Typical acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate Salt, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic acid Salt, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate Salt, 3-phenylpropionate, picrate, pivalic acid, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutami Salts, bicarbonate salts, and the like p- toluenesulfonate and undecanoate. Further, the amino groups in the compounds of the present invention are chloride, bromide and methyl iodide, ethyl, propyl and butyl; dimethyl sulfate, diethyl, dibutyl and diamyl; chloride, bromide and decyl iodide, lauryl, myristyl and stearyl; And quaternization with benzyl bromide and phenethyl. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as oxalic acid, maleic acid, succinic acid and citric acid. There are organic acids such as acids.

  Base addition salts react with suitable bases such as metal cation hydroxides, carbonates or bicarbonates, or ammonia or organic primary, secondary or tertiary amines with acidic groups (eg carboxy groups or enols). Can be produced during the final isolation and purification of the compound. Pharmaceutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine. Non-toxic such as N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine Quaternary amine cations. Other representative organic amines useful for the formation of basic addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

  Preferred salts of the compounds of the present invention include monosodium salt, disodium salt, triethylamine salt, trifluoroacetate and hydrochloride.

  The compounds of the present invention can also exist as pharmaceutically acceptable prodrugs. The term “pharmaceutically acceptable prodrug” is suitable for use in contact with a patient's tissue without causing undue toxicity, irritation and allergic response, and has a reasonable benefit / risk ratio; It refers to a prodrug or zwitterionic form that is effective in the intended application. A “prodrug” is a compound of the formula (I), (II), (III), (IV), (V), (Va), (V) in vivo when such prodrug is administered to a mammalian subject. Vb), (VIa), (VIb), (VII) or (VIII) are considered to be covalently bonded carriers that release the active parent drug. Prodrugs of compounds of formula (I), (II), (III), (IV), (V), (Va), (Vb), (VIa), (VIb), (VII) or (VIII) are The compound is produced by modifying a functional group present in the compound so that the modification is cleaved in a normal operation or in vivo to be a parent compound. Prodrugs include compounds in which a hydroxy, amine, carboxy, or sulfhydryl group is attached to a group that cleaves to form a free hydroxyl, amino, carboxy, or sulfhydryl group, respectively, when administered to a mammalian subject. . Examples of prodrugs include formulas (I), (II), (III), (IV), (V), (Va), (Vb), (VIa), (VIb), (VII) and (VIII) The acetic acid, formic acid and benzoic acid derivatives of the hydroxy, carboxy and amine functional groups in the compounds of

  According to the therapeutic method and pharmaceutical composition of the present invention, the compound can be administered alone or in combination with other antiviral agents. When the compound is used, the specific pharmaceutically effective dosage level for a particular patient is the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition used Depending on factors such as the patient's age, weight, general health, sex and diet; time of administration; route of administration; excretion rate of the compound used; duration of treatment; and drugs used in combination or co-administered with the compound used; Determined. The compound can be administered orally, parenterally, osmotic (nasal spray), rectal, vaginal or topical in a unit dosage form containing carriers, adjuvants, diluents, vehicles or combinations thereof. The term “parenteral” includes infusion and subcutaneous, intravenous, intramuscular and intrasternal injection.

  An aqueous or oily suspension of the compound for parenteral administration can be formulated with a dispersing, wetting or suspending agent. An injectable formulation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents used are water, saline, Ringer's solution, buffers, fatty acids such as monoglycerides, diglycerides, oleic acid and fixed oils such as monoglycerides or diglycerides.

  The antiviral effect of a parenterally administered compound can be prolonged by reducing its absorption rate. One way to delay absorption of a particular compound is to administer an injection depot containing a suspension of the compound in crystalline, amorphous or other water-insoluble form. The absorption rate of the compound depends on its dissolution rate, which depends on its physical state. Another way to delay absorption of a particular compound is to administer an injectable depot preparation containing the compound as an oil-based solution or suspension. Yet another method of delaying the absorption of a particular compound is to use a microcapsule group of said compound entrapped in a biodegradable polymer such as a liposome, microemulsion or polylactide-polyglycolide, polyorthoester or polyanhydride. An injectable depot preparation containing the material is administered. Depending on the ratio of drug to polymer and its composition, the rate of drug release can be controlled.

  Transdermal patches can also provide sustained release of the compound. The absorption rate can be delayed by using a rate controlling membrane or by trapping the compound in a polymer substrate or gel. Conversely, absorption can be increased using absorption enhancers.

  Solid preparations for oral administration include capsules, tablets, pills, powders or granules. In those solid formulations, the active compounds are sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, tableting lubricants and tableting aids such as magnesium stearate or microcrystalline cellulose, etc. The diluent may be included. Capsules, tablets and pills can also contain buffering agents, and tablets and pills can be manufactured with enteric coatings or other controlled-release coatings. Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or mixtures thereof. The propellant can further include conventional propellants such as chlorofluorohydrocarbons or their replacements.

  Liquid preparations for oral administration include emulsions, fine emulsions, solutions, suspensions, sprays and elixirs containing an inert diluent such as water. These compositions can also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening, flavoring and perfuming agents.

  Topical formulations include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers. Their formulations also include animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Excipients such as can also be included. Suppositories for rectal or vaginal administration are obtained by mixing the compound with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at room temperature but fluid in the rectum or vagina. Can be manufactured. Ophthalmic preparations such as eye drops, eyeball ointments, powders, and liquids are also contemplated to be within the scope of the present invention.

  The compounds of the present invention inhibit HCV RNA-dependent RNA polymerase, an enzyme essential for HCV virus replication. The compound can also be administered as a single active pharmaceutical agent or in combination with one or more drugs to treat symptoms associated with hepatitis C infection or HCV infection. Other drugs that are administered in combination with the compounds of the present invention include therapies for diseases caused by HCV infection that suppress HCV viral replication by direct or indirect mechanisms. For example, host immunomodulators (eg, interferon-α, PEGylated interferon-α, CpG oligonucleotides, etc.) or antiviral compounds that inhibit host cell functions such as inosine monophosphate dehydrogenase (eg, ribavirin), etc. There are drugs. In addition, there are cytokines that regulate immune function. In addition, there are vaccines including combinations of HCV antigens or antigen adjuvants that act against HCV. In addition, it interacts with host cell components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiation translation step of HCV virus replication, or a membrane protein viroporin such as HCVP7 Some drugs block the maturation and release of viral particles by family-oriented drugs. Other agents that are administered in combination with the compounds of the present invention include agents that inhibit HCV replication by targeting viral genome proteins involved in virus replication or combinations of such agents. These agents include, for example, other HCV RNA-dependent RNA polymerase inhibitors such as the nucleoside polymerase inhibitors described in WO 0190121 (A2) or US 6348587 B1 or WO 0160315 or WO 0132153, or described in eg EP 1 16196 A1 or WO 0204425 There are other inhibitors such as benzimidazole polymerase inhibitors, or inhibitors of HCV protease such as peptidomimetic type inhibitors such as BILN2061, or non-nucleoside inhibitors such as inhibitors of HCV helicase, etc. It is not limited to these.

  Other agents administered in combination with the compounds of the present invention include agents that inhibit replication of other viruses in superinfected individuals or combinations of such agents. The drugs include, for example, therapy for diseases caused by hepatitis B (HBV) infection such as adefovir, lamivudine, LdT (1-deoxythymidine) and tenofovir, or for example protease inhibitors (ritonavir, lopinavir, indinavir, nelfinavir, saquinavir) Amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir); reverse transcriptase inhibitors (zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125); By human immunodeficiency virus (HIV) infection such as integrase inhibitors (L-870812, S-1360); or invasion inhibitors (enfuvirtide (T-20), T-1249) And the like therapy of diseases caused, but not limited thereto.

  Other drugs administered in combination with the compounds of the present invention include drugs or combinations of such drugs that treat or ameliorate symptoms of HCV infection such as cirrhosis and liver inflammation.

  When administered in combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or within a given time period, or the therapeutic agents can be administered as a single unit formulation .

  The total daily dose of the compound administered to the host in single or divided doses can be an amount of about 0.1 to about 200 mg / kg, or preferably about 0.25 to about 100 mg / kg. Single dose compositions may contain those amounts or fractions of that constituting a daily dose.

Measurement of physiological activity
HCV polymerase inhibition assay: biochemical IC ₅₀ :
A two-fold serial dilution of the inhibitor (partial inhibition assay) or a relatively narrow range of dilutions (ICB) containing the IC ₅₀ of the inhibitor was added to 20 mM Tris-Cl (pH 7.5), 5 mM MgCl. ₂ , 50 mM NaCl, 1 mM dithiothreitol, 1 mM ethylenediaminetetraacetic acid (EDTA), 300 μM GTP and 150-300 nM NS5B (HCV strain 1B (J4, Genbank accession number AF0524747, or H77, Genbank accession number AF011751) ) At room temperature for 15 minutes. The reaction was initiated by adding 20 μM CTP, 20 μM ATP, 1 μM 3H-UTP (10 mCi / μmol), 150 nM template RNA and 0.4 U / μL RNase inhibitor (RNasin, Promega) and allowed to proceed for 2-4 hours at room temperature. It was. The reaction volume was 50 μL. The reaction was stopped by adding 1 volume of 4 mM spermine in 10 mM Tris-Cl (pH 8.0), 1 mM EDTA. After incubating for at least 15 minutes at room temperature, the precipitated RNA was captured by filtration through a GF / B filter (Millipore) in a 96-well format. The filter plate was washed twice with 200 μL each of 2 mM spermine, 10 mM Tris-Cl (pH 8.0), 1 mM EDTA and ethanol. After air drying, 30 μL of Microscint 20 scintillation cocktail (Packard) was added to each well and retained cpm was measured by scintillation counting. IC ₅₀ values were calculated by a two-variable non-linear regression equation using uninhibited and fully inhibited control samples to determine the minimum and maximum values of the curve. A tight binding assay was performed on compounds that showed an IC ₅₀ value of less than 0.15 μM in the partial inhibition assay to more accurately determine the IC ₅₀ value. Retention cpm was plotted against inhibitor concentration and applied to Equation 1 using non-linear regression (Ref 1) to obtain IC ₅₀ values.

Holding cpm = A [square {(IC ₅₀ + I _t −E _t ) ² +4 IC ₅₀ E _t } − (IC ₅₀ + I _t −E _t )] Equation 1
_Where A = V _max [S] / 2 (K _m + [S]); I _t = total inhibitor concentration; E _t = total enzyme activity concentration.

  References: Morrison, J. F. and S. R. Stone., 1985, "Approaches to the study and analysis of the inhibition of enzymes by slow- and tight-binding inhibitors.", Comments Mol. Cell. Biophys. 2: 347-368.

  The sequence of the template RNA used is as follows.

上記の方法によって試験を行った場合、本発明の化合物は０．００２μＭ〜５００μＭの範囲のＩＣ_５０でＨＣＶポリメラーゼ１Ｂを阻害する。

When tested by the above method, the compounds of the invention inhibit HCV polymerase 1B with an IC ₅₀ in the range of 0.002 μM to 500 μM.

Evaluation of HCV inhibitors in HCV replication: cell culture EC ₅₀
For cell lines and assays, the literature (Ikeda M., Yi M., Li K., Lemon SM., J. Virol 2002 Mar; 76 (6): 2997-3006 and Blight KJ, Kolykhalov, with the following changes: A., Rice CM, Science 2000 Dec, 290: 1972-1974).

(RNA assay)
Replicon cells were plated in DMEM medium containing 5% fetal calf serum at 3 × 10 ³ cells / well in 96 well plates. On day 1, the medium was removed and replaced with fresh medium containing 8 serial 2-fold dilutions of the compound. The final concentration of DMSO in the medium was 0.5%. The untreated control medium was treated in the same way except that no inhibitor was added to the medium. Plates were incubated at 37 ° C. in a CO ₂ incubator. On the fourth day, after removing the medium, 100 μL of cell lysis buffer (RTL) (Qiagen) was added to each well. RNA was purified according to the method recommended by the manufacturer (Qiagen RNAeasy) and eluted with 200 μL of water. HCV RNA levels were quantified from a portion of the purified RNA (5 μL from 200 μL) by real-time RT-PCR. Primers and probes are derived from specific sequences in the 5'UTR region. The RT-PCR reaction was performed at 48 ° C. for 30 minutes, followed by 40 cycles set at 95 ° C. for 15 seconds, 54 ° C. for 30 seconds and 72 ° C. for 40 seconds. The percent reduction of HCV RNA in the presence of compound was calculated and the 50% inhibitory concentration (IC ₅₀ ) was calculated by non-linear regression using the Prism program.

When tested in the above manner, compounds of the invention inhibit replicon production with an EC ₅₀ in the range of 0.002 μM to> 100 μM.

Cytotoxicity assay Cytotoxicity assays were performed on replicon cells. That is, HCV replicon cells were plated in a 96-well plate in DMEM medium containing 5% FCS at 3 × 10 ³ cells / well. On day 1, the medium was removed and replaced with fresh medium containing 8 serial 2-fold dilutions of the compound. The final concentration of DMSO in the medium was 0.5%. All experiments were performed in duplicate. An untreated control medium was treated in the same manner except that no inhibitor was added to the medium. Plates were incubated at 37 ° C. in a CO ₂ incubator. On the fourth day, a stock solution of the tetrazolium salt MTT (4 mg / mL in PBS, Sigma catalog number M2128) was added to each well at 25 μL / well. The plate was further incubated for 4 hours and treated with 50% per well with 20% SDS + 0.02N HCl to lyse the cells. After incubation overnight, the optical density was measured by reading the plate at a wavelength of 570/650 nm. The resulting decrease in formazan blue color compared to the control was calculated and the cytopathic effect described as 50% toxic concentration (TC ₅₀ ) was calculated by non-linear regression analysis using the prism program.

When tested by the above assay, compounds of the present invention showed a CPE reduction with a TC ₅₀ ranging from 6.6 μM to> 100 μM.

  Cellular assays for drugs targeting hepatitis C are not yet available because infectious viruses cannot be made in persistent cell lines. The hepatitis C virus genome encodes a large polyprotein that produces the functional components necessary to synthesize progeny RNA after processing. A selectable cell line that produces high and persistent levels of subgenomic HCV RNA (replicon) has been derived from human liver cancer cells (Huh7) according to the methods described in the literature above. The mechanism of RNA replication in these cell lines appears to be the same as full-length HCV RNA replication in infected hepatocytes. The compounds and methods of the present invention are inhibitors of HCV RNA replication in the replicon assay system described above. It is the basis for asserting their potential as therapeutics in treating diseases caused by hepatitis C virus infection.

Synthetic Methods Abbreviations used in the schemes and examples below are DMF = N, N-dimethylformamide, DMSO = dimethylsulfoxide and THF = tetrahydrofuran.

A better understanding of the compounds and methods of the present invention will be gained in the context of the following synthetic scheme showing how the compounds of the present invention can be made. The raw materials can be obtained from commercial sources or prepared by well-established literature methods known to those skilled in the art. Groups A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined above unless otherwise noted below.

  The present invention includes compounds having formula (I) as prepared by synthetic or metabolic methods. The production of the compounds of the present invention by metabolic methods includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

合成図式１に示したように、式（２）の化合物を、加熱条件下でオキシ塩化リンの存在下に式（３）の化合物と反応させて、式（４）の化合物を得ることができる。式（４）の化合物を、ジメチルアセトアミド、ジメチルホルムアミド、ＴＨＦなど（これらに限定されるものではない）の溶媒中にて水素化ナトリウム、水素化カリウム、リチウムヘキサメチルジシラジドなどの塩基と反応させ、次にＲ^１−Ｘ（Ｒ^１はアルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルケニル、シクロアルキルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−またはＲ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−であり；ＸはＢｒ、Ｃｌ、Ｉ、ＣＦ_３Ｓ（Ｏ）_２−、ＣＨ_３Ｓ（Ｏ）_２−またはトシルである）を加えることで、式（５）の化合物を得る。

As shown in Synthesis Scheme 1, the compound of formula (2) can be reacted with the compound of formula (3) in the presence of phosphorus oxychloride under heating conditions to give the compound of formula (4). . Reaction of a compound of formula (4) with a base such as sodium hydride, potassium hydride, lithium hexamethyldisilazide in a solvent such as, but not limited to, dimethylacetamide, dimethylformamide, THF, etc. R ¹ -X (R ¹ is alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, arylalkenyl, arylalkyl, arylsulfanylalkyl Arylsulfonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkenyl, cycloalkylalkyl , Haloalkoxyalkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heteroarylsulfonyl alkyl, heterocycloalkenyl, heterocyclealkyl, hydroxyalkyl, _nitroalkyl, R a _{R b} N-alkyl _{-, R a R b NC (} O) Alkyl-, R _a R _b NC (O) O alkyl- or R _a R _b NC (O) NR _c alkyl-; X is Br, Cl, I, CF ₃ S (O) ₂ —, CH ₃ S (O) _2- or tosyl) is added to obtain a compound of formula (5).

別法として、式（６）の化合物を、加熱条件下において適宜に炭酸カリウムなどの塩基および臭化銅などの触媒の存在下に式（７）の化合物（Ｒ^１はアルケニル、アルコキシアルキル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルフィニルアルキル、アルキルスルホニルアルキル、アルキニル、アリール、アリールアルケニル、アリールアルキル、アリールスルファニルアルキル、アリールスルホニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルケニル、シクロアルキルアルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルケニル、ヘテロアリールアルキル、ヘテロアリールスルホニルアルキル、複素環、複素環アルケニル、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ａＲ_ｂＮ−、Ｒ_ａＲ_ｂＮアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）アルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）Ｏアルキル−、Ｒ_ａＲ_ｂＮＣ（Ｏ）ＮＲ_ｃアルキル−、Ｒ_ｆＲ_ｇＣ＝Ｎ−またはＲ_ｋＯ−である）で処理して、式（８）の化合物を得ることができる。式（８）の化合物を、加熱条件下に１，２−ジクロロエタン、四塩化炭素、１，４−ジオキサンまたはそれらの混合物（それらに限定されるものではない）などの溶媒中にて、ホスゲン、ジホスゲン、トリホスゲンなど（それらに限定されるものではない）の試薬で処理して、式（５）の化合物を得ることができる。

Alternatively, the compound of formula (6) can be converted to a compound of formula (7) (R ¹ is alkenyl, alkoxyalkyl, alkoxy, optionally in the presence of a base such as potassium carbonate and a catalyst such as copper bromide under heating conditions. Carbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenyl Alkyl, cycloalkyl, cycloalkylalkenyl, cycloalkylalkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroaryl Reel alkenyl, heteroarylalkyl, heteroarylsulfonylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic alkyl, hydroxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC ( O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl-, R _f R _g C = N- or R _k O-). A compound of formula (8) can be obtained. The compound of formula (8) is heated in a solvent such as, but not limited to, 1,2-dichloroethane, carbon tetrachloride, 1,4-dioxane or mixtures thereof under heating conditions, Treatment with a reagent such as, but not limited to, diphosgene, triphosgene, etc. can provide a compound of formula (5).

さらに、式（９）の化合物を、加熱条件下に水、トルエン、ベンゼンなど（それらに限定されるものではない）の溶媒中、水酸化カリウム、ピリジン、水酸化リチウムなどの塩基存在下において、ホスゲン、ジホスゲン、トリホスゲン、カルボニルジイミダゾール、クロルギ酸エチルなど（それらに限定されるものではない）の試薬と反応させて、式（５）の化合物を得ることもできる。

Furthermore, the compound of formula (9) is heated in a solvent such as, but not limited to, water, toluene, benzene and the like in the presence of a base such as potassium hydroxide, pyridine, lithium hydroxide. Reaction with reagents such as, but not limited to, phosgene, diphosgene, triphosgene, carbonyldiimidazole, ethyl chloroformate and the like can also provide compounds of formula (5).

式（５）の化合物を、ＴＨＦ、ジエチルエーテル、メチルｔｅｒｔ−ブチルエーテルなど（それらに限定されるものではない）の溶媒中、水素化ナトリウム、水素化カリウム、リチウムヘキサメチルジシラジドなどの塩基存在下に式（１０）の化合物で処理し、次に酢酸、ジクロロ酢酸または硫酸などの酸で処理して、Ｒ^４がヒドロキシである式（Ｉ）の化合物の代表的なものである式（１１）の化合物を得ることができる。

The presence of a base such as sodium hydride, potassium hydride, lithium hexamethyldisilazide in a solvent such as (but not limited to) THF, diethyl ether, methyl tert-butyl ether, etc. Treatment with a compound of formula (10) below, followed by treatment with an acid such as acetic acid, dichloroacetic acid or sulfuric acid, is representative of a compound of formula (I) wherein R ⁴ is hydroxy. ) Can be obtained.

式（５）の化合物を、水素化ナトリウム、水素化カリウムなどの塩基で前処理しておいたマロン酸ジエチルと、ジメチルアセトアミド、ジメチルホルムアミド、ＴＨＦなどの溶媒中加熱条件下で反応させることで、式（１２）の化合物を得ることができる。式（１２）の化合物を、トルエン、メシチレン、ベンゼンなどの溶媒中、加熱条件下で式（１３）の化合物で処理することで、式（１４）の化合物を得ることができる。式（１４）の化合物を、水中にて水酸化ナトリウム、水酸化カリウム、水酸化リチウムなどの塩基で加熱条件下で処理することで、式（１１）の化合物を得ることができる。

By reacting the compound of formula (5) with diethyl malonate pretreated with a base such as sodium hydride or potassium hydride in a solvent such as dimethylacetamide, dimethylformamide or THF under heating conditions, A compound of formula (12) can be obtained. The compound of formula (14) can be obtained by treating the compound of formula (12) with a compound of formula (13) under heating conditions in a solvent such as toluene, mesitylene, or benzene. A compound of formula (11) can be obtained by treating a compound of formula (14) with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide in water.

あるいは、式（８）の化合物を、塩化メチレン、クロロホルム、四塩化炭素などの溶媒中、トリエチルアミン、ジイソプロピルエチルアミン、ピリジンなどの塩基存在下クロロマロン酸エチルで処理して、式（１５）の化合物を得ることができる。あるいは、式（８）の化合物を、ベンゼン、トルエンなどの溶媒中、加熱条件下にクロロマロン酸エチルで処理して、式（１５）の化合物を得ることができる。式（１５）の化合物を、エタノール中ナトリウムエトキシドで処理して、式（１２）の化合物を得ることができる。

Alternatively, the compound of formula (8) is treated with ethyl chloromalonate in a solvent such as methylene chloride, chloroform, carbon tetrachloride and the like in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc. Obtainable. Alternatively, the compound of formula (8) can be treated with ethyl chloromalonate in a solvent such as benzene or toluene under heating conditions to give the compound of formula (15). A compound of formula (15) can be treated with sodium ethoxide in ethanol to give a compound of formula (12).

合成図式７には、Ｒ^４がハロである式（Ｉ）の化合物を製造を示している。式（１１）の化合物を、アルコールを塩化物に変換するのに一般に用いられる当業者には公知の試薬で処理することができる。例えば、式（１１）の化合物を、塩化メチレン、クロロホルムおよびベンゼンなど（それらに限定されるものではない）の溶媒存在下または非存在下にてＰＣＩ_５、ＰＣＩ_３、ＰＯＣｌ_３または塩化チオニルなど（これらに限定されるものではない）の試薬で処理して、Ｒ^４が塩素である化合物を代表する式（Ｉ）の化合物を得ることができる。ＰＢｒ_３またはＤＡＳＴを用いて同様の変換を行って、前記アルコールを、Ｒ^４がそれぞれ臭素およびフッ素である相当する式（Ｉ）の化合物に変換することが可能である。あるいは、Ｒ^４がヨウ素である式（Ｉ）の化合物は、（ａ）塩化メチレン、アセトニトリル、四塩化炭素、クロロホルムなど（それらに限定されるものではない）の溶媒中トリエチルアミン、ピリジンまたはジイソプロピルエチルアミンなどのアミン塩基存在下に、メタンスルホニルクロライドまたは無水メタンスルホニルなどのメシル化試薬と式（１１）の化合物を反応させ、（ｂ）そうして得られたメシレートをＮ−ヨードコハク酸イミドで処理することで製造することができる。

Synthesis Scheme 7 illustrates the preparation of compounds of formula (I) where R ⁴ is halo. The compound of formula (11) can be treated with reagents known to those skilled in the art commonly used to convert alcohols to chlorides. For example, a compound of formula (11) can be transformed into PCI ₅ , PCI ₃ , POCl ₃ or thionyl chloride in the presence or absence of a solvent such as, but not limited to, methylene chloride, chloroform and benzene ( (But not limited to these), compounds of formula (I) that are representative of compounds in which R ⁴ is chlorine can be obtained. Similar transformations can be performed using PBr ₃ or DAST to convert the alcohol to the corresponding compound of formula (I) where R ⁴ is bromine and fluorine, respectively. Alternatively, the compound of formula (I) wherein R ⁴ is iodine is (a) triethylamine, pyridine or diisopropylethylamine in a solvent such as (but not limited to) methylene chloride, acetonitrile, carbon tetrachloride, chloroform, etc. Reacting a compound of formula (11) with a mesylation reagent such as methanesulfonyl chloride or anhydrous methanesulfonyl in the presence of an amine base of (b), and treating the resulting mesylate with N-iodosuccinimide. Can be manufactured.

合成図式８に示したように、式（１６）の化合物を、加熱条件下にてメタノール、エタノールなどの極性溶媒中、式Ｒ_ａＲ_ｂＮＨ（Ｒ_ａおよびＲ_ｂは本明細書で定義の通りである）を有するアミンで処理することで、Ｒ^４がＲ_ａＲ_ｂＮ−である式（Ｉ）の化合物の代表的なものである式（１７）の化合物に変換して、式（１７）の化合物を得ることができる。

As shown in Synthesis Scheme 8, the compound of formula (16) is heated in a polar solvent such as methanol, ethanol, etc. under heating conditions, with the formula R _a R _b NH (R _a and R _b are as defined herein). Is converted to a compound of formula (17), which is representative of compounds of formula (I) where R ⁴ is R _a R _b N—. The compound of 17) can be obtained.

式（１８）の化合物（Ｒ^１がＯ−Ｓｉ（イソプロピル）_３または何らかの他の容易に脱離されるエーテル保護基である式（Ｉ）の化合物の代表的なもの）を、フッ素含有試薬で処理して、式（１９）の化合物を得ることができる。式（１９）の化合物のヒドロキシルアミン部分を、ジメチルホルムアミドなどの溶媒中の水素化ナトリウム、またはＴＨＦ、ジオキサンなど（それらに限定されるものではない）の溶媒中のリチウムヘキサメチルジシラジドなどの塩基で処理し、次にＲ_ｋ−Ｘ（Ｒ_ｋはアルコキシアルキル、アルコキシカルボニル、アルコキシカルボニルアルキル、アルキル、アルキルカルボニルアルキル、アルキルスルファニルアルキル、アルキルスルホニルアルキル、アリール、アリールアルキル、アリールスルファニルアルキル、カルボキシアルキル、シアノアルキル、シクロアルケニル、シクロアルケニルアルキル、シクロアルキル、シクロアルキルアルキル、ホルミルアルキル、ハロアルコキシアルキル、ハロアルキル、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、ニトロアルキル、Ｒ_ｃＲ_ｄＮアルキル−またはＲ_ｃＲ_ｄＮＣ（Ｏ）アルキルであり；ＸはＢｒ、Ｃｌ、Ｉ、ＣＦ_３Ｓ（Ｏ）_２−、ＣＨ_３Ｓ（Ｏ）_２−またはトシルである）を加えることで、Ｒ^１がＲ_ｋＯ−と定義される式（Ｉ）の化合物の代表的なものである式（２０）の化合物を得ることができる。

Treating a compound of formula (18) (representative of a compound of formula (I) where R ¹ is O—Si (isopropyl) ₃ or some other easily removed ether protecting group) with a fluorine-containing reagent. Thus, the compound of the formula (19) can be obtained. The hydroxylamine moiety of the compound of formula (19) can be replaced with sodium hydride in a solvent such as dimethylformamide, or lithium hexamethyldisilazide in a solvent such as but not limited to THF, dioxane, etc. Treatment with base, then R _k -X, where R _k is alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl, arylsulfanylalkyl, carboxyalkyl , Cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, hetero Reel alkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, _nitroalkyl, R c _{R d} N alkyl - or _R c _R d NC (O) is alkyl; X is _{Br, Cl, I, CF 3} S (O) _2- , CH ₃ S (O) ₂ — or tosyl) of formula (20), wherein R ¹ is representative of compounds of formula (I) defined as R _k O— A compound can be obtained.

式（２１）の化合物を、水酸化カリウム、水酸化ナトリウムなど（それらに限定されるものではない）の塩基水溶液で処理して、式（２２）の化合物を得ることができる。式（２２）の化合物を、ＴＨＦ、ＤＭＳＯ、ＤＭＦ、ジオキサン、エーテル、塩化メチレンなどから選択される適切な溶媒または溶媒混合物中にて水素化ナトリウムなどの金属水素化物、有機リチウム試薬（例：ｔ−ＢｕＬｉ、ｎ−ＢｕＬｉまたはｓ−ＢｕＬｉ）またはリチウムヘキサメチルジシラジドで処理し、次にＲ_ａＸ（Ｘは、Ｂｒ、Ｃｌ、Ｉ、ＣＦ_３Ｓ（Ｏ）_２−、ＣＨ_３Ｓ（Ｏ）_２−またはトシルである）を加えることで、Ｒ^１が−ＮＨＲ_ａである式（Ｉ）の化合物の代表的なものである式（２３）の化合物を得ることができる。

The compound of formula (21) can be treated with an aqueous base solution such as but not limited to potassium hydroxide, sodium hydroxide and the like to give a compound of formula (22). The compound of formula (22) is converted into a metal hydride such as sodium hydride, an organolithium reagent (eg t -BuLi, n-BuLi or s-BuLi) or lithium hexamethyldisilazide, then R _a X (X is Br, Cl, I, CF ₃ S (O) ₂ —, CH ₃ S ( O) ₂ -or tosyl) can be added to obtain a compound of formula (23) which is representative of compounds of formula (I) where R ¹ is -NHR _a .

あるいは、式（２２）の化合物を、加熱条件下で、溶媒非存在下またはジメチルアセトアミド、テトラヒドロフラン、ジオキサンなど（それらに限定されるものではない）の溶媒存在下に構造Ｒ_ｆＲ_ｇＣ（Ｏ）のアルデヒドまたはケトンで処理することで、式（２４）の化合物を得ることができる。式（２４）の化合物を、水素およびパラジウムなどの触媒で、あるいは水素化ホウ素リチウム、水素化シアノホウ素ナトリウムなどの金属水素化物で還元することで式（２５）の化合物を得る。

Alternatively, the compound of formula (22) can be converted to the structure R _f R _g C (O ) Or an aldehyde or ketone, a compound of formula (24) can be obtained. The compound of formula (25) is obtained by reducing the compound of formula (24) with a catalyst such as hydrogen and palladium or with a metal hydride such as lithium borohydride or sodium cyanoborohydride.

式（１２）の化合物を、加熱条件下で水酸化カリウムなどの塩基水溶液と反応させて、式（２６）の化合物を得ることができる。式（２６）の化合物を、Ｎ，Ｎ−ジメチルホルムアミド、テトラヒドロフラン、ジエチルエーテル、またはメチルｔｅｒｔ−ブチルエーテルなど（これらに限定されるものではない）の溶媒または溶媒混合物中にて塩基と反応させ、次にほぼ室温〜約７０℃の温度で二硫化炭素によって処理することができる。その塩基の例には、水素化ナトリウム、水素化カリウム、リチウムジイソプロピルアミド、ナトリウムヘキサメチルジシラジドおよびリチウムヘキサメチルジシラジドなどがあるが、これらに限定されるものではない。次に、約２５℃の温度でメチル化試薬で処理することで、式（２７）の化合物を得る。メチル化剤の例には、ヨウ化メチル、トリフ酸メチル、硫酸ジメチルなどがあるが、これらに限定されるものではない。

A compound of formula (12) can be obtained by reacting a compound of formula (12) with an aqueous base such as potassium hydroxide under heating conditions. The compound of formula (26) is reacted with a base in a solvent or solvent mixture such as, but not limited to, N, N-dimethylformamide, tetrahydrofuran, diethyl ether, or methyl tert-butyl ether, and Can be treated with carbon disulfide at temperatures from about room temperature to about 70 ° C. Examples of the base include, but are not limited to, sodium hydride, potassium hydride, lithium diisopropylamide, sodium hexamethyldisilazide and lithium hexamethyldisilazide. Next, the compound of Formula (27) is obtained by treating with a methylating reagent at a temperature of about 25 ° C. Examples of methylating agents include, but are not limited to, methyl iodide, methyl triflate, dimethyl sulfate, and the like.

  Alternatively, the compound of formula (26) is reacted with tris (methylthio) methyl methylsulfate in the presence of a base in a solvent such as 1,4-dioxane or dimethylacetamide at a temperature of about 25 ° C. to about 150 ° C. A compound of formula (27) can be obtained. Examples of bases include imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole, 4-nitroimidazole, pyridine, N, N-dimethylaminopyridine, 1,2,4-triazole. , Organic amines such as, but not limited to, pyrrole, 3-methylpyrrole, triethylamine, diisopropylethylamine or N-methylmorpholine.

  A compound such as (13) in a solvent or solvent mixture such as (but not limited to) toluene, benzene, dioxane or tetrahydrofuran at a temperature of about 50 ° C. to about 150 ° C. To give a compound of formula (11).

ＸがＩ、Ｂｒ、ＣｌまたはＦである式（２９）の化合物を、加熱条件下でエタノールなどの溶媒中にて炭酸ナトリウムなどの塩基存在下に、ベンゼンメチルチオールなどのアルキルチオールで処理することで、式（３０）の化合物を得ることができる。塩酸または酢酸中にて塩素ガスで（３０）を処理することで、式（３１）の化合物を得る。塩化メチレン、テトラヒドロフランまたはジオキサンなど（それらに限定されるものではない）の溶媒中の式（３１）の化合物を、アンモニアまたは水酸化アンモニウムで処理して、式（３２）の化合物を得る。適宜に加熱条件下での酢酸中の鉄粉を用い、加熱条件下にメタノールまたはエタノールなど含水アルコール系溶媒中の鉄粉および塩化アンモニウムで式（３２）の化合物を還元して、式（１３）の化合物を得る。

Treating a compound of formula (29) wherein X is I, Br, Cl or F with an alkylthiol such as benzenemethylthiol in the presence of a base such as sodium carbonate in a solvent such as ethanol under heating conditions; Thus, the compound of the formula (30) can be obtained. By treating (30) with chlorine gas in hydrochloric acid or acetic acid, a compound of formula (31) is obtained. Treatment of a compound of formula (31) in a solvent such as but not limited to methylene chloride, tetrahydrofuran or dioxane with ammonia or ammonium hydroxide provides a compound of formula (32). Using iron powder in acetic acid under heating conditions as appropriate, reducing the compound of formula (32) with iron powder and ammonium chloride in a hydroalcoholic solvent such as methanol or ethanol under heating conditions, To obtain a compound of

式（３３）の化合物を、冷却条件下にて溶媒としての硫酸の存在下に硝酸アンモニウムで処理することで、式（３４）の化合物を得ることができる。加熱条件下でメタノールまたはエタノールなどの含水アルコール系溶媒中にて、鉄粉および塩化アンモニウムで式（３４）の化合物を還元することで、式（３５）の化合物を得る。あるいはその還元は、加熱条件下で酢酸または希塩酸など（それらに限定されるものではない）の酸中、鉄粉で式（３５）の化合物を処理することで行うこともできる。加熱条件下に式（３６）のオルトエステルで式（３５）の化合物を処理することで、式（３７）の化合物を得る。

The compound of formula (34) can be obtained by treating the compound of formula (33) with ammonium nitrate in the presence of sulfuric acid as a solvent under cooling conditions. The compound of formula (35) is obtained by reducing the compound of formula (34) with iron powder and ammonium chloride in a hydroalcoholic solvent such as methanol or ethanol under heating conditions. Alternatively, the reduction can also be carried out by treating the compound of formula (35) with iron powder in an acid such as but not limited to acetic acid or dilute hydrochloric acid under heating conditions. The compound of formula (37) is obtained by treating the compound of formula (35) with the orthoester of formula (36) under heating conditions.

式（３５）の化合物を、加熱条件下に臭化シアンで処理して、式（３８）の化合物を得ることができる。ジメチルアセトアミド、Ｎ，Ｎ−ジメチルホルムアミド、メタノール、塩化メチレン、テトラヒドロフランまたはアセトニトリルなどから選択される適切な溶媒または溶媒混合物中にて、トリエチルアミン、ピリジンなどのアミン塩基または炭酸セシウムまたは炭酸カリウムなどの無機塩基の存在下に、Ｒ^８Ｘ（ＸはＢｒ、ＣｌまたはＩである）、Ｒ^８ＣＯ_２ＣｌまたはＲ^８ＳＯ_２Ｃｌで式（３８）の化合物を処理することで、式（３９）の化合物が得られる。

A compound of formula (35) can be treated with cyanogen bromide under heating conditions to give a compound of formula (38). In a suitable solvent or solvent mixture selected from dimethylacetamide, N, N-dimethylformamide, methanol, methylene chloride, tetrahydrofuran, acetonitrile or the like, an amine base such as triethylamine, pyridine, or an inorganic base such as cesium carbonate or potassium carbonate Compound of formula (39) by treatment of compound of formula (38) with R ⁸ X (X is Br, Cl or I), R ⁸ CO ₂ Cl or R ⁸ SO ₂ Cl in the presence of Is obtained.

冷却条件下、追加の溶媒の存在下または非存在下にて、硫酸または無水トリフルオロ酢酸中のトリフルオロ酢酸などの酸存在下に、式（４０）の化合物を硝酸アンモニウムまたは硝酸カリウムでニトロ化して、式（４１）の化合物を得ることができる。加熱条件下で、メタノールまたはエタノールなどの含水アルコール系溶媒中にて鉄粉および塩化アンモニウムによって式（４１）の化合物を還元することで、式（４２）の化合物が得られる。あるいは、式（４２）の化合物の還元は、加熱条件下、酢酸または希塩酸など（それらに限定されるものではない）の酸中において鉄粉を用いても行うことができる。式（４２）の化合物は、上記のような個々の条件を用い、（ａ）ニトロ化および（ｂ）段階（ｂ）の生成物の還元によって式（４４）の化合物に変換することができる。式（４４）の化合物を、加熱条件下に式（３６）のオルトエステルで処理することで、式（４５）の化合物を得ることができる。

Nitration of a compound of formula (40) with ammonium nitrate or potassium nitrate in the presence of an acid such as trifluoroacetic acid in sulfuric acid or trifluoroacetic anhydride in the presence or absence of an additional solvent under cooling conditions; A compound of formula (41) can be obtained. The compound of the formula (42) is obtained by reducing the compound of the formula (41) with iron powder and ammonium chloride in a hydroalcoholic solvent such as methanol or ethanol under heating conditions. Alternatively, the reduction of the compound of the formula (42) can be performed using iron powder in an acid such as acetic acid or dilute hydrochloric acid under heating conditions (but not limited thereto). The compound of formula (42) can be converted to the compound of formula (44) by (a) nitration and reduction of the product of step (b) (b) using the individual conditions as described above. A compound of formula (45) can be obtained by treating a compound of formula (44) with an ortho ester of formula (36) under heating conditions.

塩化メチレン、テトラヒドロフランまたはジオキサンなどの溶媒またはそれらの溶媒混合物中、ピリジン単独などの塩基またはトリエチルアミン、ジイソプロピルエチルアミンなどのアミン塩基存在下に、式（４２）の化合物を、式Ｒ_ａＳＯ_２Ｃｌのスルホニルクロライドでスルホニル化して、式（４６）の化合物を得ることができる。あるいは、塩化メチレン、テトラヒドロフランまたはジオキサンなどの溶媒または溶媒混合物中、トリエチルアミンまたはジイソプロピルエチルアミンなど（それらに限定されるものではない）のアミン塩基の存在下に、式（４２）の化合物を式（４９）の化合物でスルファモイル化して、式（４７）の化合物を得ることができる。式（４９）の化合物は、当業界で公知の条件でクロロスルホニルイソシアネートおよび２−クロロエタノールを処理することで得ることができる。式（４７）の化合物は、加熱条件下に塩化メチレン、ＴＨＦまたはアセトニトリルなどの溶媒または溶媒混合物中にて式Ｒ_ａＲ_ｂＮＨ（Ｒ_ａおよびＲ_ｂは本明細書で定義の通りである）を有するアミンでさらに処理して、式（４８）の化合物を得ることができる。塩化メチレン、テトラヒドロフランまたはジオキサンなどの溶媒または溶媒混合物中、トリエチルアミンまたはジイソプロピルエチルアミンなどのアミン塩基存在下に、式（４２）の化合物を式（５４）の化合物でスルファモイル化して、式（４８）の化合物を得ることができる。式（５４）の化合物は、塩化スルフリルで式Ｒ_ａＲ_ｂＮＨのアミンを処理することで、あるいは（ａ）式Ｒ_ａＲ_ｂＮＨのアミンをクロロスルホン酸で処理し、そして（ｂ）当業界で公知の条件にて段階（ａ）の生成物を五塩化リンなどの塩素化剤と接触させることで得ることができる。

In the presence of a base such as pyridine alone or an amine base such as triethylamine, diisopropylethylamine in a solvent such as methylene chloride, tetrahydrofuran or dioxane or a mixture thereof, the compound of formula (42) is converted to a sulfonyl of formula R _a SO ₂ Cl. Sulfonylation with chloride can give the compound of formula (46). Alternatively, a compound of formula (42) is converted to a compound of formula (49) in the presence of an amine base such as but not limited to triethylamine or diisopropylethylamine in a solvent or solvent mixture such as methylene chloride, tetrahydrofuran or dioxane. The compound of the formula (47) can be obtained by sulfamoylation with the compound of The compound of formula (49) can be obtained by treating chlorosulfonyl isocyanate and 2-chloroethanol under conditions known in the art. The compound of formula (47) is of formula R _a R _b NH (where R _a and R _b are as defined herein) in a solvent or solvent mixture such as methylene chloride, THF or acetonitrile under heating conditions. Further treatment with an amine having can yield the compound of formula (48). Compound of formula (42) is sulfamoylated with compound of formula (54) in the presence of an amine base such as triethylamine or diisopropylethylamine in a solvent or solvent mixture such as methylene chloride, tetrahydrofuran or dioxane. Can be obtained. The compound of formula (54) can be prepared by treating an amine of formula R _a R _b NH with sulfuryl chloride or (a) treating an amine of formula R _a R _b NH with chlorosulfonic acid and (b) It can be obtained by contacting the product of step (a) with a chlorinating agent such as phosphorus pentachloride under conditions known in the industry.

Similarly, ^{R 5} is - Compound alkyl NH ₂ in which formula (11), using the conditions in the conversion to a compound of formula (48) of a compound formula (42), ^{R 5} is - alkyl NHSO ₂ NR _a It can be converted to a compound of formula (11) which is R _b . R ⁵ is - compound of formula (11) alkyl NH _2, by using the conditions for converting the compound of formula (42) to the compound of formula (46), ^{R 5} is - alkyl NHSO ₂ R _a Can be converted to the compound of formula (11).

塩化メチレン、テトラヒドロフラン、ジエチルエーテル、ベンゼンまたはアセトニトリルなどの溶媒または溶媒混合物中、ピリジン、トリエチルアミンまたはジイソプロピルエチルアミンなどのアミン塩基の存在下に、式（４２）の化合物を式ＲＣＯＣ（Ｏ）ＮＨＳＯ_２Ｃｌ（５０）のスルファモイルクロライドでスルファモイル化して、式（５１）の化合物を得ることができる。式（５０）の化合物は、塩化メチレン、四塩化炭素、ジエチルエーテル、ベンゼンまたはトルエンなどの溶媒または溶媒混合物中、式Ｒ_ｃＯＨのアルコールをクロロスルホニルイソシアネートで処理することで製造することができる。塩化メチレンまたはテトラヒドロフランなどの溶媒または溶媒混合物中、トリ−ｎ−ブチルホスフィンまたはトリフェニルホスフィンなどおよびジイソプロピルアゾジカルボキシレート、１，１′−（アザジカルボニル）ピペリジンまたはジエチルアゾジカルボキシレートなどの存在下に、式（５１）の化合物をさらに、式Ｒ_ａＯＨを有するアルコールで処理することで、式（５２）の化合物を得ることができる。あるいは、Ｒ_ａがメチルである式（５２）の化合物は、当業界で公知の条件で、ヨウ化メチル、硫酸ジメチル、トリメチルシリルジアゾメタンなど（これらに限定されるものではない）のメチル化剤で式（５１）の化合物をメチル化することで得ることができる。式（５２）の化合物の式（５３）の化合物への変換は、トリフルオロ酢酸または塩酸などの酸との反応によって、あるいは水素ガス下にパラジウム／炭素などの水素化分解によって行うことができる。

In the presence of an amine base such as pyridine, triethylamine or diisopropylethylamine in a solvent or solvent mixture such as methylene chloride, tetrahydrofuran, diethyl ether, benzene or acetonitrile, the compound of formula (42) is converted to the formula RCOC (O) NHSO ₂ Cl ( The compound of formula (51) can be obtained by sulfamoylation with sulfamoyl chloride of 50). The compound of formula (50) can be prepared by treating an alcohol of formula R _c OH with chlorosulfonyl isocyanate in a solvent or solvent mixture such as methylene chloride, carbon tetrachloride, diethyl ether, benzene or toluene. Presence of tri-n-butylphosphine or triphenylphosphine and the like and diisopropyl azodicarboxylate, 1,1 '-(azadicarbonyl) piperidine or diethylazodicarboxylate in a solvent or solvent mixture such as methylene chloride or tetrahydrofuran A compound of formula (52) can be obtained by further treating the compound of formula (51) with an alcohol having the formula R _a OH. Alternatively, the compound of formula (52) wherein R _a is methyl is a methylating agent such as (but not limited to) methyl iodide, dimethyl sulfate, trimethylsilyldiazomethane, etc., under conditions known in the art. It can be obtained by methylating the compound of (51). Conversion of the compound of formula (52) to the compound of formula (53) can be carried out by reaction with an acid such as trifluoroacetic acid or hydrochloric acid, or by hydrogenolysis of palladium / carbon or the like under hydrogen gas.

Similarly, ^{R 5} is - compound of formula (11) alkyl NH ₂ is the conditions in the conversion to a compound of formula (51) of a compound formula (42), ^{R 5} is - alkyl NHSO ₂ NHCOOR _c It can be converted to a compound of formula (11).

R ⁵ is - alkyl NH ₂ compound of formula (11), the conditions used in the conversion from (51) to (52), ^{R 5} is - alkyl _{NHSO 2 N (R a) COOR} c wherein It can convert into the compound of (11).

R ⁵ is - compounds of alkyl NH ₂ Formula (11), the conditions used in the conversion from the (52) to (53), ^{R 5} is - alkyl NHSO ₂ NR _a R _b in which formula (11) Can be converted to

  In the following, the invention will be described in the context of certain preferred embodiments, but the scope of the invention is not limited thereto. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the claims. Accordingly, the following examples, including preferred embodiments, illustrate preferred practice of the present invention, and these examples are intended to illustrate certain preferred embodiments of the present invention. It will be apparent that they have been presented to provide what is believed to be the most useful and easily understood description of the procedures and conceptual aspects of

  The compounds of the present invention were named by ACD / Chem Sketch version 5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or given names consistent with the ACD nomenclature.

Example 1
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 1A
The 2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione title compound is converted to 2,3-pyridine according to the procedure described in the literature (Synthesis, 1982, 972-973). Prepared from a carboxylic anhydride (11.4 g, 76 mmol) and trimethylsilyl azide (11.0 mL, 80 mmol) as a white solid (7.27 g, 58%).

Example 1B
Suspension of 1-butyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione sodium hydride (95%, 0.96 g, 40 mmol) in dimethylacetamide (60 mL) The liquor is reacted with the product of Example 1A (5.7 g, 34.7 mmol) under stirring at 10 ° C. under nitrogen for 1 hour and then treated with n-butyl bromide (5.2 g, 38 mmol). The mixture was further stirred for 16 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with hexane and ethyl acetate (3: 1) to give the title compound as a white solid (2.5 g, 33% yield).

Example 1C
(1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) in ethyl acetate literature (Chemistry of Heterocyclic Compounds, 1998, 34 (7), 791-795) The title compound was prepared as a white solid in 2-step from 2-aminobenzenesulfonamide following the described procedure (46% yield).

Example 1D
1-Butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one Example 1B Of sodium hydride (95% 0.10 g, 4.0 mmol). The reaction was heated to reflux for 3 hours, cooled to 0 ° C., and glacial acetic acid (2 mL) was added dropwise thereto. The mixture was heated to reflux for 2 hours, cooled to room temperature, and diluted with aqueous hydrochloric acid (0.1 M, 10 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (0.130 g, 33%). MS (ESI-) m / z 397 (MH) ^- .

  While stirring a suspension of the title compound (0.130 g, 0.326 mmol) in acetonitrile and water (1: 1, 4 mL) with aqueous sodium hydroxide (1 M, 0.326 mL, 0.326 mmol) for about 30 minutes, When reacted, a clear solution was observed. The solution was lyophilized to give the sodium salt.

Example 2
1-[(5-Chloro-2-thienyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8- Naphthyridin-2 (1H) -one
Example 2A
Instead of 1-[(5-chloro-2-thienyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide 2-chloro The title compound was prepared according to the procedure of Example 1B using -5-chloromethylthiophene (0.195 g, 52%).

Example 2B
1- (5-Chloro-2-thienyl) 1-[(5-chloro-2-thienyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazine-3- Yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D substituting the product of Example 2A for the product of Example 1B (0 167 g, 58%). MS (ESI-) m / z 471/473 (M-H) < ^- >.

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 3
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (2-ethylbutyl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 3A
Ethyl 2 -[(2-ethylbutyl) amino] nicotinate 2-ethyl chloronicotinate (0.646 g, 3.48 mmol) and 2 -ethylbutylamine (0.74 g, 7.31 mmol) were added in a sealed tube at 130 ° C. Reacted for hours. The reaction mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride (2 x 50 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (19: 1) to give the title compound (0.665 g, 76%).

Example 3B
1- (2-Ethylbutyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 3A (0.664 g, 2.65 mmol) and diphosgene A solution of (1.57 g, 7.96 mmol) in 1,2-dichloroethane (13 mL) and 1,4-dioxane (1.3 mL) was reacted at 80 ° C. for 16 hours. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with hexane / ethyl acetate (9: 1) to give the title compound (0.235 g, 36 %).

Example 3C
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-8-naphthyridin-2 (1H) -one Example instead of the product of Example 1B The title compound was prepared according to the procedure of Example 1D using 3B product (0.041 g, 38%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 4
1- [1-[(5-Bromo-2-thienyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1 , 8-Naphthyridin-2 (1H) -one
Example 4A
Instead of 1-[(5-bromo-2-thienyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide 2-bromo The title compound was prepared according to the procedure of Example 1B using -5-chloromethylthiophene (0.229 g, 55%).

Example 4B
1-[(5-Bromo-2-thienyl) methyl] -3- (1,1-dioxide-4H-12,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine- 2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 4A in place of the product of Example 1B (0.208 g, 60%). MS (ESI-) m / z 515/517 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 5
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbenzyl) -1,8-naphthyridine-2 (1H) -ON
Example 5A
1- (3-Methylbenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Performed using n-butyl bromide instead of 3-methylbenzyl bromide The title compound was prepared according to the procedure of Example 1B (0.305 g, 62%). MS (DCI) m / z 269 (M + H) ^<+> .

Example 5B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbenzyl) -1,8-naphthyridine-2- (1H ) -On The title compound was prepared according to the procedure of Example 1D using the product of Example 5A in place of the product of Example 1B (0.112 g, 72%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 6
3- (1,1-dioxide-4H-1,2,3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3 -Nitrobenzyl) -1,8-naphthyridin-2 (1H) -one
Example 6A
Substituting 3-nitrobenzyl bromide for 1- (3-nitrobenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.147 g, 28%). MS (DCI) m / z 300 (M + H) ^<+> .

Example 6B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-nitrobenzyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 6A, the title compound was prepared according to the procedure of example 1D (0.032g, 42%). MS (ESI-) m / z476 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 7
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-thienylmethyl) -1,8-naphthyridine-2 (1H) -ON
Example 7A
Instead of 1- (3-thienylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, using 3- (bromomethyl) thiophene The title compound was prepared according to the procedure of Example 1B (0.170 g, 52%).

Example 7B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-thienylmethyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 7A, the title compound was prepared according to the procedure of example 1D (0.135g, 48%). MS (ESI-) m / z 437 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 8
1- (3-Chlorobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 8A
Substituting 3-chlorobenzyl bromide for 1- (3-chlorobenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.405 g, 77%). MS (DCI) m / z 289 (M + H) ^<+> .

Example 8B
1- (3-Chlorobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 8A, the title compound was prepared according to the procedure of example 1D (0.050g, 45%). MS (ESI-) m / z465 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 9
1- (3-Bromobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 9A
Substituting 3-bromobenzyl bromide for 1- (3-bromobenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.500 g, 82%). MS (DCI) m / z 333 (M + H) ^<+> .

Example 9B
1- (3-Bromobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 9A, the title compound was prepared according to the procedure of example 1D (0.050g, 45%). MS (ESI-) m / z465 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 10
1-[(2-Chloro-1,3-thiazol-5-yl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- Hydroxy-1.8-naphthyridin-2 (1H) -one
Example 10A
1-[(2-Chloro-1,3-thiazol-5-yl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using 2-chloro-5-bromomethylthiazole instead of (0.360 g, 60%).

Example 10B
1-[(2-Chloro-1,3-thiazol-5-yl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- Hydroxy-1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 10A in place of the product of Example 1B (0.136 g, 60 %).

Example 11
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -3- (3-fluorobenzyl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 11A
Substituting 3-fluorobenzyl bromide for 1- (3-fluorobenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.382 g, 76%). MS (DCI) m / z 273 (M + H) ^<+> .

Example 11B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (3-fluorobenzyl) -4-hydroxy-1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 11A, the title compound was prepared according to the procedure of example 1D (0.040g, 37%). MS (ESI-) m / z 449, (M-H) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 12
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -1,8-naphthyridine-2 (1H)- on
Example 12A
1- (3-Methylbutyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione sodium hydride (95%, 0.048 g, 2.0 mmol) in dimethyl A suspension of acetamide (2 mL) was reacted with the product of Example 1A (0.3 g, 1.83 mmol) at 20 ° C. under nitrogen. The reaction mixture was stirred for 1/2 hour, then treated with 1-bromo-3-methylbutane (0.3 g, 2.0 mmol) and stirred for an additional 16 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with hexane and ethyl acetate (3: 1) to give the title compound as a white solid (0.218 g, 51%).

Example 12B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -1,8-naphthyridine-2 (1H)- On a solution of the product of Example 12A (0.216 g, 0.92 mmol) and the product of Example 1C (0.247 g, 0.922 mmol) in dehydrated THF (7.5 mL) at 20 ° C. under nitrogen. Sodium hydride (95%, 0.089 g, 3.7 mmol) was added. The reaction was heated to reflux for 3 hours, cooled to 20 ° C., and glacial acetic acid (2.4 mL) was added dropwise. The resulting mixture was heated to reflux for 1 hour, cooled to 25 ° C., and diluted with aqueous hydrochloric acid (0.5 M, 35 mL). The resulting precipitate was collected by filtration, washed with water and dehydrated. The crude product was purified by flash column chromatography on silica gel eluting with hexane and ethyl acetate (3: 1) to give the title compound as a white solid (0.031 g, 20%). MS (ESI-) m / z411 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 13
1- (Cyclobutylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 13A
Example 1B substituting bromomethyl-cyclobutane for 1- (cyclobutylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of (0.255 g, 60%). MS (DCI) m / z 233 (M + H) ^<+> .

Example 13B
1- (Cyclobutylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 13A in place of the product of On Example 1B (0.120 g, 52%). MS (ESI-) m / z 409 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 14
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-methyl-2-thienyl) methyl] -1,8- Naphthyridin-2 (1H) -one
Example 14A
2-bromomethyl instead of 1-[(5-methyl-2-thienyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using -5-methylthiophene (0.181 g, 54%).

Example 14B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-methyl-2-thienyl) methyl] -1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 14A in place of the product of Example 1B (0.172 g, 58%). MS (ESI-) m / z451 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 15
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 15A
1-Benzyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione The title compound according to the procedure of Example 1B using benzyl bromide instead of n-butyl bromide Was produced (0.393 g, 51%). MS (DCI) m / z 255 (M + H) ^<+> .

Example 15B
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 15A in place of the product of (0.217 g, 62%). MS (ESI-) m / z 431 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 16
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-methyl-3-pyridinyl) methyl] -1,8- Naphthyridin-2 (1H) -one
Example 16A
3-chloro instead of 1-[(5-methyl-3-pyridinyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using methyl-5-methylpyridine (0.080 g, 24%).

Example 16B
3- (1.1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-methyl-3-pyridinyl) methyl] -1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 16A in place of the product of Example 1B (0.013 g, 13%). MS (ESI-) m / z446 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 17
1-[(2-Chloro-4-pyridinyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8- Naphthyridin-2 (1H) -one
Example 17A
4-Bromomethyl instead of 1-[(2-chloro-4-pyridinyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using 2-chloropyridine (0.219 g, 62%).

Example 17B
1-[(2-Chloro-4-pyridinyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 17A in place of the product of Example 1B (0.255 g, 73%). MS (ESI-) m / z 466/468 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 18
1-[(5-Bromo-3-pyridinyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8- Naphthyridin-2 (1H) -one
Example 18A
A solution of di-tert-butyl (5-bromo-3-pyridinyl) methylimidodicarbonate 5-bromo-3-chloromethylpyridinium hydrochloride (716 mg, 4.189 mmol) in dehydrated DMF (15 mL) at 0 ° C. under nitrogen. , Triethylamine (0.65 mL, 4.61 mmol), tetrabutylammonium bromide (273 mg, 0.838 mmol) and potassium di-tert-butylimidodicarbonate (1.284 g, 5.027 mmol). The reaction was heated to 50 ° C. to 55 ° C. for 3.5 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (2 × 50 mL) and saturated aqueous sodium chloride solution. The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated on a rotary evaporator. The residue was purified by flash column chromatography on silica gel using 6% ethyl acetate / methylene chloride to give the title compound as a colorless oil (0.980 g, 60%).

Example 18B
(5-Bromo-3-pyridinyl) methylamine The product of Example 18A (0.98 g, 2.53 mmol) was treated with trifluoroacetic acid and methylene chloride (1: 1 volume ratio, 20 mL) at room temperature for 2 hours. did. The solvent was removed by rotary evaporator and the resulting oil was washed with benzene / methylene chloride (3 times) to give a waxy solid. The salt was dissolved in dehydrated methanol (20 mL) and stirred with Amberlite IRA-400 (OH) resin (10 g) for 2 hours. The resin was removed by vacuum filtration and washed thoroughly with dehydrated methanol. The filtrate was concentrated by rotary evaporator to give the title compound (0.415 g, 88%).

Example 18C
2-{[(5-Bromo-3-pyridinyl) methyl] amino} ethyl nicotinate The title compound was prepared according to the procedure of Example 3A using the product of Example 18B instead of 2-ethylbutylamine (0 116 g, 68%).

Example 18D
1-[(5-Bromo-3-pyridinyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Performed in place of the product of Example 3A Purification by flash column chromatography using the product of Example 18C and eluting with 10% ethyl acetate / methylene chloride to prepare the title compound according to the procedure of Example 3B (0.057 g, 51%).

Example 18E
1-[(5-Bromo-3-pyridinyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 18D in place of the product of Example 1B (0.037 g, 43%). MS (ESI-) m / z 510/512 (M-H) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 19
1- (cyclohexylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 19A
Example 1B substituting (bromomethyl) cyclohexane for 1- (cyclohexylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of (0.05 g, 11%).

Example 19B
1- (cyclohexylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 19A instead of the product of Example 1B (0.025 g, 30%). MS (ESI-) m / z 437 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 20
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2S) -2-methylbutyl] -1,8-naphthyridine-2 (1-on
Example 20A
2-{[(2S) -2-Methylbutyl] amino} ethyl nicotinate The title compound was prepared according to the procedure of Example 3A, substituting (S)-(−)-2- methylbutylamine for 2-ethylbutylamine. (1.6 g, 77%).

Example 20B
1-[(2S) -2-Methylbutyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example 20A instead of the product of Example 3A The title compound was prepared using the product according to the procedure of Example 3B (0.400 g, 68%). MS (DCI) m / z252 ( M + NH 4) +.

Example 20C
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2S) -2-methylbutyl] -1,8-naphthyridine-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 20B in place of the product of Example 1B (0.116 g, 43%). MS (ESI-) m / z411 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 21
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-methylbenzyl) -1,8-naphthyridine-2 (1H) -ON
Example 21A
Using 4-methylbenzyl bromide instead of 1- (4-methylbenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.402 g, 82%). MS (DCI) m / z 269 (M + H) ^<+> .

Example 21B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-methylbenzyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 21A, the title compound was prepared according to the procedure of example 1D (0.099g, 60%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 22
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-nitro-2-furyl) methyl] -1,8- Naphthyridin-2 (1H) -one
Example 22A
2-bromomethyl instead of 1-[(5-nitro-2-furyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using -5-nitrofuran (0.120 g, 34%).

Example 22B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-nitro-2-furyl) methyl] -1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 21A in place of the product of Example 1B (0.040 g, 21%). _{MS (DCI / NH 3) m} / z468 (M + H) +. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 23
1- (1-benzothien-2-ylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 23A
2-chloromethyl-benzo instead of 1- (1-benzothien-2-ylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide [B] The title compound was prepared according to the procedure of Example 1B using thiophene (0.160 g, 42%).

Example 23B
1- (1-benzothien-2-ylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -On The title compound was prepared according to the procedure of Example 1D using the product of Example 23A in place of the product of Example 1B (0.148 g, 60%). MS (ESI-) m / z 487 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 24
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methoxybenzyl) -1,8-naphthyridine-2 (1H) -ON
Example 24A
Substituting 3-methoxybenzyl bromide for 1- (3-methoxybenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.446 g, 86%). MS (DCI) m / z 285 (M + H) ^<+> .

Example 24B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methoxybenzyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 24A, the title compound was prepared according to the procedure of example 1D (0.086g, 53%). MS (ESI-) m / z 461 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 25
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-iodobenzyl) -1,8-naphthyridine-2 (1H) -ON
Example 25A
Instead of 1- (3-iodobenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, using 3-iodobenzyl bromide, The title compound was prepared according to the procedure of Example 1B (0.614 g, 88%). MS (DCI) m / z 381 (M + H) ^<+> .

Example 25B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methoxybenzyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 25A, the title compound was prepared according to the procedure of example 1D (0.176g, 60%). MS (ESI-) m / z 557 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 26
1-[(3,5-dimethyl-4-isoxazolyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1, 8-Naphthyridin-2 (1H) -one
Example 26A
4 instead of 1-[(3,5-dimethyl-4-isoxazolyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using chloromethyl-3,5-dimethylisoxazole (0.199 g, 60%).

Example 26B
1-[(3,5-dimethyl-4-isoxazolyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1, 8-Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 26A in place of the product of Example 1B (0.187 g, 63%).

The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 27
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [2- (3-thienyl) ethyl] -1,8-naphthyridine- 2 (1H) -on
Example 27A
Instead of 1- [2- (3-thienyl) ethyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide 3- (2- The title compound was prepared according to the procedure of Example 1B using (bromoethyl) thiophene (0.156 g, 46%).

Example 27B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [2- (3-thienyl) ethyl] -1,8-naphthyridine- 2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 27A in place of the product of Example 1B (0.123 g, 48%). MS (ESI-) m / z451 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 28
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-pyridinylmethyl) -1,8-naphthyridine-2 (1H)- on
Example 28A
Instead of 1- (4-pyridinylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide using 4- (chloromethyl) pyridine The title compound was prepared according to the procedure of Example 1B (0.089 g, 29%).

Example 28B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-pyridinylmethyl) -1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 28A in place of the product of On Example 1B (0.034 g, 19%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 29
1- (4-Bromobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 29A
Using 4-bromobenzyl bromide instead of 1- (4-bromobenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (1.460 g, 72%). MS (DCI) m / z 333 (M + H) ^<+> .

Example 29B
1- (4-Bromobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 29A, the title compound was prepared according to the procedure of example 1D (0.060g, 59%). MS (ESI-) m / z 509 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 30
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-neopentyl-1,8-naphthyridin-2 (1H) -one
Example 30A
The title compound was prepared according to the procedure of Example 3A using 2,2-dimethylpropylamine instead of ethyl 2- (neopentylamino) nicotinate 2-ethylbutylamine (0.407 g, 57%).

Example 30B
1-Neopentyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example substituting the product of Example 30A for the product of Example 3A The title compound was prepared according to the procedure of 3B (0.182 g, 89%).

Example 30C
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-neopentyl-1,8-naphthyridin-2 (1H) -one Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 30B instead of the product of (0.070 g, 22%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 31
1-{[(1S, 2R, 5S) -6,6-Dimethylbicyclo [3.1.1] hept-2-yl] methyl} -3- (1,1-dioxide-4H-1,2,4 -Benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 31A
2-({[(1S, 2R, 5S) -6,6-dimethylbicyclo [3.1.1] hept-2-yl] methyl} amino) (-)-in place of ethyl nicotinate 2-ethylbutylamine The title compound was prepared according to the procedure of Example 3A using cis-myrtanylamine (0.604 g, 40%). MS (ESI +) m / z 303 (M + H) ^<+> .

Example 31B
1-{[(1S, 2R, 5S) -6,6-Dimethylbicyclo [3.1.1] hept-2-yl] methyl} -2H-pyrido [2,3-d] [1,3] oxazine -2,4 (1H) -Dione The title compound was prepared according to the procedure of Example 3B using the product of Example 31A in place of the product of Example 3A (0.570 g, 95%).

Example 31C
1-{[(1S, 2R, 5S) -6,6-Dimethylbicyclo [3.1.1] hept-2-yl] methyl} -3- (1,1-dioxide-4H-1,2,4 -Benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one Substitute the product of Example 1D by substituting the product of Example 31B for the product of Example 1B. The title compound was prepared according to the procedure (0.050 g, 21%). MS (ESI-) m / z 477 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 32
3-({[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H) -Yl] methyl} benzonitrile
Example 32A
3-[(2,4-Dioxo-2H-pyrido [2,3-d] [1,3] oxazin-1 (4H) -yl) methyl] benzonitrile 3-cyanobenzyl bromide instead of n-butyl bromide Was used to prepare the title compound according to the procedure of Example 1B (0.363 g, 71%). MS (DCI) m / z 280 (M + H) ^<+> .

Example 32B
3-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- [Il] methyl} benzonitrile The title compound was prepared according to the procedure of Example 1D using the product of Example 32A in place of the product of Example 1B (0.024 g, 22%). MS (ESI-) m / z 456 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 33
3- (1.1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-pyridinylmethyl) -1,8-naphthyridine-2 (1H)- on
Example 33A
Substituting 3- (bromomethyl) pyridine for 1- (3-pyridinylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.153 g, 49%).

Example 33B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-pyridinylmethyl) -1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 33A in place of the product of On Example 1B (0.098 g, 41%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 34
1- (1-adamantylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 34A
2-[(1-adamantylmethyl) amino] nicotinic acid 2-chloronicotinic acid was used instead of 2-chloronicotinic acid, and 1-adamantanemethylamine was used instead of 2-ethylbutylamine. The title compound was prepared according to the procedure (0.185 g, 79%).

Example 34B
1- (1-adamantylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 34A was substituted for the product of Example 3A. The title compound was prepared according to the procedure of Example 3B (0.025 g, 20%).

Example 34C
1- (1-adamantylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 34B, the title compound was prepared according to the procedure of example 1D (0.018g, 47%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 35
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [3- (trifluoromethyl) benzyl] -1,8-naphthyridine 2 (1H) -on
Example 35A
Instead of 1- [3- (trifluoromethyl) benzyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide 3- (trifluoro The title compound was prepared according to the procedure of Example 1B using methyl) benzyl bromide (0.250 g, 42%).

Example 35B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [3- (trifluoromethyl) benzyl] -1,8-naphthyridine 2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 35A in place of the product of Example 1B (0.22 g, 57%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 36
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2-methyl-1,3-thiazol-5-yl) methyl ] -1,8-naphthyridine-2 (1H) -one
Example 36A
1-[(2-Methyl-1,3-thiazol-5-yl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using 2-methyl-5-chloromethylthiazole instead of (0.300 g, 54%).

Example 36B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2-methyl-1,3-thiazol-5-yl) methyl ] -1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 36A in place of the product of Example 1B (0.123 g, 25 %).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 37
1- (2-Cyclohexylethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 37A
Instead of 1- (2-cyclohexylethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, 1-bromo-2-cyclohexylethane was used. The title compound was prepared according to the procedure of Example 1B (0.196 g, 39%).

Example 37B
1- (2-Cyclohexylethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) - using the product of example 37A in place of the product of one example 1B, the title compound was prepared according to the procedure of example 1D (0.030g, 18% after column purification). MS (ESI-) m / z451 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 38
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-methoxybenzyl) -1,8-naphthyridine-2 (1H) -ON
Example 38A
Using 4-methoxybenzyl chloride instead of 1- (4-methoxybenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.364 g, 70%). MS (DCI) m / z 285 (M + H) ^<+> .

Example 38B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-methoxybenzyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 38A, the title compound was prepared according to the procedure of example 1D (0.098g, 51%). MS (ESI-) m / z 461 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 39
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-methylbenzyl) -1,8-naphthyridine-2 (1H) -ON
Example 39A
Substituting 2-methylbenzyl bromide for 1- (2-methylbenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.353 g, 72%). MS (DCI) m / z 269 (M + H) ^<+> .

Example 39B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-methylbenzyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 39A, the title compound was prepared according to the procedure of example 1D (0.165g, 62%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 40
1- (Cyclopropylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 40A
1- (Cyclopropylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Performed using (bromomethyl) cyclopropane instead of n-butyl bromide The title compound was prepared according to the procedure of Example 1B (0.278 g, 70%).

Example 40B
1- (Cyclopropylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-naphthyridin-2 (1H) -one Example 1D The product of Example 40A Example 1B (0.06 g, after 20% column purification) was used instead of the title compound prepared according to the procedure of MS (ESI-) m / z 395 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 41
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (1,3-thiazol-4-ylmethyl) -1,8-naphthyridine -2 (1H) -ON
Example 41A
4- (chloro ) instead of 1- (1,3-thiazol-4-ylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using (methyl) thiazole (0.049 g, 15%).

Example 41B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (1.3-thiazol-4-ylmethyl) -1,8-naphthyridine -(1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 41A in place of the product of Example 1B (0.046 g, 59%). MS (ESI-) m / z438 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 42
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-phenyl-2-thienyl) methyl] -1,8- Naphthyridin-2 (1H) -one The product of Example 4B (100 mg, 0.193 mmol), phenylboronic acid (49 mg, 0.387 mmol), 2M aqueous Na ₂ CO ₃ (0.45 mL), pure ethanol (0. 5 mL) and tetrakis (triphenylphosphine) palladium (14 mg, 0.012 mmol) in N ₂ blown in DMF (2 mL) was heated to reflux for 2.5 h, cooled to 0 ° C., and H ₂ O (15 mL), adjusted to pH 3 with 1N HCl and extracted with ethyl acetate (3 × 25 mL). The combined extracts were washed with saturated NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel using 3% ethyl acetate / methylene chloride to give the title compound (0.039 g, 40%). MS (ESI-) m / z 513 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 43
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-methyl-3-pentenyl) -1,8-naphthyridine-2 (1H) -ON
Example 43A
Instead of 1- (4-methyl-3-pentenyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide 5-bromo-2- The title compound was prepared according to the procedure of Example 1B using methyl-2-pentene (0.157 g, 35%).

Example 43B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (4-methyl-3-pentenyl) -1,8-naphthyridine-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 43A in place of the product of Example 1B (0.030 g, 20% after recrystallization). MS (ESI-) m / z 423 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 44
4- [3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridin-1 (2H) -yl ] Methylbenzonitrile
Example 44A
4-[(2,4-dioxo-2H-pyrido [2,3-d] [1,3] oxazin-1 (4H) -yl) methyl] benzonitrile 4-cyanobenzyl bromide instead of n-butyl bromide Was used to prepare the title compound according to the procedure of Example 1B (1.02 g, 60%). MS (DCI) m / z 280 (M + H) ^<+> .

Example 44B
4-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- Yl] methylbenzonitrile The title compound was prepared according to the procedure of Example 1D using the product of Example 44A in place of the product of Example 1B (0.197 g, 60%). MS (ESI-) m / z 456 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 45
1- [2- (1-Cyclohexen-1-yl) ethyl 1-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1, 8-Naphthyridin-2 (1H) -one
Example 45A
2-{[2- (1-Cyclohexen-1-yl) ethyl] amino} ethyl nicotinate The title compound according to the procedure of Example 3A substituting 2- (1-cyclohexenyl) ethylamine for 2-ethylbutylamine (2.2 g, 80%). MS (DCI) m / z 275 (M + H) ^<+> .

Example 45B
1- [2- (1-Cyclohexen-1-yl) ethyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione in place of the product of Example 3A The title compound was prepared according to the procedure of Example 3B using the product of Example 45A (0.493 g, 91%). MS (DCI) m / z290 ( M + NH 4) +.
Example 45C
1- [2- (1-Cyclohexen-1-yl) ethyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1, 8-Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 45B in place of the product of Example 1B (0.048 g, 14%). MS (ESI-) m / z 449 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 46
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2-methyl-1,3-thiazol-4-yl) methyl ] -1,8-naphthyridine-2 (1H) -one
Example 46A
1-[(2-Methyl-1,3-thiazol-4-yl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using 4-chloromethyl-2-methylthiazole instead of (0.087 g, 26%).

Example 46B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2-methyl-1,3-thiazol-4-yl) methyl ] -1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 46A in place of the product of Example 1B (0.078 g, 56 %). _{MS (DCI / NH 3) m} / z454 (M + H) +. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 47
2-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- Yl] methyl} benzonitrile
Example 47A
2-[(2,4-Dioxo-2H-pyrido [2,3-d] [1,3] oxazin-1 (4H) -yl) methyl] benzonitrile 2-cyanobenzyl bromide instead of n-butyl bromide Was used to prepare the title compound according to the procedure of Example 1B (0.332 g, 65%). MS (DCI) m / z 280 (M + H) ^<+> .

Example 47B
2-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- Yl] methylbenzonitrile The title compound was prepared according to the procedure of Example 1D using the product of Example 47A in place of the product of Example 1B (0.183 g, 66%). MS (ESI-) m / z 456 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 48
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-methyl-3-isoxazolyl) methyl] -1,8- Naphthyridin-2 (1H) -one
Example 48A
3-chloro in place of 1-[(5-methyl-3-isoxazolyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using methyl-5-methylisoxazole (0.047 g, 15%).

Example 48B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(5-methyl-3-isoxazolyl) methyl] -1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 48A in place of the product of Example 1B (0.051 g, 67%). MS (ESI-) m / z 436 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 49
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (1-naphthylmethyl) -1,8-naphthyridine-2 (1H) -ON
Example 49A
Using 1- ( bromomethyl) naphthalene instead of 1- (2-naphthylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B (0.391 g, 71%). MS (DCI) m / z 305 (M + H) ^<+> .

Example 49B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (1-naphthylmethyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 49A, the title compound was prepared according to the procedure of example 1D (0.087g, 60%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 50
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-pyridinylmethyl) -1,8-naphthyridine-2 (1H)- on
Example 50A
Substituting 2- (bromomethyl) pyridine for 1- (2-pyridinylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, The title compound was prepared according to the procedure of Example 1B (0.060 g, 19%).

Example 50B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-pyridinylmethyl) -1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 50A in place of the product of On Example 1B (0.072 g, 72%). MS (ESI-) m / z 432 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 51
1- (4-tert-butylbenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 ( 1H)-ON
Example 51A
4- (tert-butyl) instead of 1- (4-tert-butylbenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using benzyl bromide (0.410 g, 72%). MS (DCI) m / z 311 (M + H) ^<+> .

Example 51B
1- (4-tert-butylbenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 ( 1H) -On The title compound was prepared according to the procedure of Example 1D using the product of Example 51A in place of the product of Example 1B (0.109 g, 70%). MS (ESI-) m / z 487 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 52
[3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridin-1 (2H) -yl] acetic acid ethyl
Example 52A
(2,4-Dioxo-2H-pyrido [2,3-d] [1,3] oxazin-1 (4H) -yl) ethyl acetate Example 1B using ethyl bromoacetate instead of n-butyl bromide The title compound was prepared according to the procedure of (0.174 g, 43%).

Example 52B
[3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridin-1 (2H) -yl] acetic acid The title compound was prepared according to the procedure of Example 1D using the product of Example 52A in place of the product of ethyl Example 1B (0.200 g, 52%).

Example 53
[3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridin-1 (2H) -yl] acetic acid To a suspension of the product of Example 52B in 1: 1 THF: methanol (6 mL) was added 0.5N aqueous lithium hydroxide (6 mL). The mixture was stirred at room temperature for 2 hours, adjusted to pH 3 with 1.0 N HCl and filtered. The filter cake was washed with water and dehydrated to give the title compound (0.133 g, 86%).

Example 54
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-phenoxybenzyl) -1,8-naphthyridine-2 (1H) -ON
Example 54A
Instead of 1- (3-phenoxybenzyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide, using 3-phenoxybenzyl chloride, The title compound was prepared according to the procedure of Example 1B (0.190 g, 31%). MS (DCI) m / z 347 (M + H) ^<+> .

Example 54B
3- (1,1-dioxide-4H-1,2,3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3 -Phenoxybenzyl) -1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D, substituting the product of Example 54A for the product of Example 1B (0. . 063g, 52%) MS ( ESI-) m / z523 (M-H) -. it was prepared sodium salt of the title compound according to the procedure of example 1D.

Example 55
1-allyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 55A
1-Allyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Substituting allyl bromide for n-butyl bromide according to the procedure of Example 1B The compound was prepared (5.12 g, 82%).

Example 55B
1-allyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 55A in place of the product of (1.4 g, 34.5%).

Example 56
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-naphthylmethyl) -1,8-naphthyridine-2 (1H) -ON
Example 56A
Using 2- (bromomethyl) naphthalene instead of 1- (2-naphthylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B (0.417 g, 75%). MS (DCI) m / z 305 (M + H) ^<+> .

Example 56B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-naphthylmethyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 56A, the title compound was prepared according to the procedure of example 1D (0.022g, 42%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 57
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1R) -1-phenylethyl] -1,8-naphthyridine 2 (1H) -on
Example 57A
2-{[(1R) -1-phenylethyl] amino} ethyl nicotinate The title compound according to the procedure of Example 3A, substituting (R)-(+)-α-methylbenzylamine for 2-ethylbutylamine (2.23 g, 82%). MS (DCI) m / z 271 (M + H) ^<+> .

Example 57B
1-[(1R) -1-phenylethyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example 57A instead of the product of Example 3A The title compound was prepared according to the procedure of Example 3B using the product of (0.250 g, 62%).

Example 57C
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1R) -1-phenylethyl] -1,8-naphthyridine 2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 57B in place of the product of Example 1B (0.080 g, 36%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 58
1-[(5-tert-butyl-2-thienyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1, 8-Naphthyridin-2 (1H) -one
Example 58A
2 instead of 1-[(5-tert-butyl-2-thienyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using -bromomethyl-5-tert-butylthiophene (0.098 g, 25%).

Example 58B
1-[(5-tert-butyl-2-thienyl) methyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1, 8-Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 58A in place of the product of Example 1B (0.082 g, 54%). MS (ESI-) m / z 493 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 59
1- (1,1′-biphenyl-4-ylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8- Naphthyridin-2 (1H) -one
Example 59A
4-phenyl instead of 1- (1,1′-biphenyl-4-ylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using benzyl chloride (0.119 g, 20%). MS (DCI) m / z 331 (M + H) ^<+> .

Example 59B
1- (1,1′-biphenyl-4-ylmethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 59A in place of the product of Example 1B (0.061 g, 50%). MS (ESI-) m / z507 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 60
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [2- (1H-indol-3-yl) methyl] -1, 8-Naphthyridin-2 (1H) -one
Example 60A
2-{[2- (1H-Indol-3-yl) ethyl] amino} ethyl nicotinate The title compound was prepared according to the procedure of Example 3A using tryptamine instead of 2-ethylbutylamine (1.24 g, 80%). MS (DCI) m / z 310 (M + H) ^<+> .

Example 60B
1- [2- (1H-Indol-3-yl) ethyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione in place of the product of Example 3A The title compound was prepared according to the procedure of Example 3B using the product of Example 60A (0.164 g, 53%). MS (DCI) m / z325 ( M + NH 4) +.

Example 60C
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -1, 8-Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 60B instead of the product of Example 1B (0.140 g, 54%). MS (ESI-) m / z484 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 61
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(6-ethoxy-2-pyridinyl) methyl] -4-hydroxy-1,8- Naphthyridin-2 (1H) -one
Example 61A
2-bromomethyl instead of 1-[(6-chloro-2-pyridinyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using -6-chloropyridine (0.159 g, 45%).

Example 61B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(6-ethoxy-2-pyridinyl) methyl] -4-hydroxy-1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 61A in place of the product of Example 1B (0.109 g, 42%). MS (ESI-) m / z476 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 62
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7-methyl-1,8-naphthyridine-2 (1H)- on
Example 62A
2- (benzylamino) -6-methylnicotinic acid phenylmethanaminium 2-chloro-6-methyl-nicotinic acid is used instead of 2-chloro-nicotinic acid ethyl ester, and benzylamine is used instead of 2-ethylbutylamine. The title compound was prepared as the benzylamine salt using the procedure of Example 3A (0.480 g, 46%).

Example 62B
1-Benzyl-7-methyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 62A was used in place of the product of Example 3A The title compound was prepared according to the procedure of Example 3B (0.150 g, 50%).

Example 62C
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7-methyl-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 62B instead of the product of On Example 1B (0.53 g, 51%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 63
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(6-methyl-2-pyridinyl) methyl] -1,8- Naphthyridin-2 (1H) -one
Example 63A
2-bromomethyl instead of 1-[(6-methyl-2-pyridinyl) methyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using -6-methylpyridine (0.088 g, 27%).

Example 63B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(6-methyl-2-pyridinyl) methyl] -1,8- Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 63A in place of the product of Example 1B (0.081 g, 40%). MS (ESI-) m / z446 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 64
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (1-ethylpropyl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 64A
Ethyl 2-[(1-ethylpropyl) amino] nicotinate The title compound was prepared according to the procedure of Example 3A using 2-ethylbutylamine instead of 2-ethylbutylamine (1.45 g, 88%). .

Example 64B
1- (1-Ethylpropyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 64A was substituted for the product of Example 3A. The title compound was prepared according to the procedure of Example 3B (0.120 g, 57%).

Example 64C
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (1-ethylpropyl) -4-hydroxy-1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 64B, the title compound was prepared according to the procedure of example 1D (0.030g, 15%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 65
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1S) -1-phenylethyl] -1,8-naphthyridine 2 (1H) -on
Example 65A
2-{[(1S) -1-phenylethyl] amino} ethyl nicotinate The title compound was prepared according to the procedure of Example 3A, substituting (S)-(-methylbenzylamine for 2-ethylbutylamine ( 2.2 g, 81%) MS (DCI) m / z 271 (M + H) ⁺ .

Example 65B
1-[(1S) -1-phenylethyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example 65A instead of the product of Example 3A The title compound was prepared according to the procedure of Example 3B using the product of (0.320 g, 80%).

Example 65C
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1S) -1-phenylethyl] -1,8-naphthyridine 2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 65B in place of the product of Example 1B (0.122 g, 36%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 66
2- {2- [3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H ) -Yl] ethyl} -1H-isoindole-1,3 (2H) -dione
Example 66A
1- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 The title compound was prepared according to the procedure of Example 1B using N- (2-bromoethyl) phthalimide instead of (1H) -dione n-butyl bromide (0.121 g, 20%).

Example 66B
2- {2- [3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H ) -Yl] ethyl} -1H-isoindole-1,3 (2H) -dione The title compound was prepared according to the procedure of Example 1D, substituting the product of Example 65B for the product of Example 1B. (0.085 g, 46%).

Example 67
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-hydroxypropyl) -1,8-naphthyridine-2 (1H) On solution of the product of Example 73 in THF (5 mL) was reacted with sodium borohydride (0.022 g, 0.58 mmol) at 0 ° C. for 30 minutes. The solution was poured into water and extracted with ethyl acetate. Waters using a gradient of 10% to 100% acetonitrile / 0.1% TFA in water over 12 min (15 min elution time) at a flow rate of 70 mL / min over 12 min (15 min elution time), the extract was dried over sodium sulfate. Purification by preparative HPLC on a (Waters) Symmetry C8 column (40 mm × 100 mm, particle size 7 μm) gave the title compound.

Example 68
1-cyclopentyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 68A
Ethyl 2- (cyclopentylamino) nicotinate The title compound was prepared according to the procedure of Example 3A using cyclopentylamine in place of 2-ethylbutylamine (0.231 g, 67%).

Example 68B
1-cyclopentyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example 68A using the product of Example 68A instead of the product of Example 3A The title compound was prepared according to the procedure for 3B (0.130 g, 56%).

Example 68C
1-cyclopentyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 68B instead of the product of (0.133 g, 60%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 69
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- [2- (1,3-dioxolan-2-yl) ethyl] -4-hydroxy- 1,8-naphthyridine-2 (1H) -one
Example 69A
Instead of 1- [2- (1,3-dioxolan-2-yl) ethyl] -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide The title compound was prepared according to the procedure of Example 1B using 2- (2-bromomethyl) -1,3-dioxolane (0.86 g, 53%).

Example 69B
3- (1,1-dioxide-4H-1,4-benzothiadiazin-3-yl) -1- [2- (1,3-dioxolan-2-yl) ethyl] -4-hydroxy-1, 8-Naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 69A in place of the product of Example 1B (0.89 g, 62%).

Example 70
1- (2,3-dihydroxypropyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 ( 1H) -one The product of Example 55B (1.08 g, 0.028 mol) was mixed with osmium tetroxide (0.0007 mol) and N— in 1: 1 solution of water and THF (50 mL) at room temperature for 18 hours. Reacted with methylmorpholine N-oxide (4.96 g, 0.043 mol). The reaction mixture was treated with sodium sulfite and diluted with water. The product precipitated from the aqueous mixture and was collected by vacuum filtration to give the title compound as a white solid (1.09 g, 93%).

Example 71
1-cycloheptyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 71A
Ethyl 2- (cycloheptylamino) nicotinate The title compound was prepared according to the procedure of Example 3A using cycloheptylamine instead of 2-ethylbutylamine (1.01 g, 83%).

Example 71B
1-Cycloheptyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Performed using the product of Example 71A instead of the product of Example 3A The title compound was prepared according to the procedure of Example 3B (0.205 g, 55%).

Example 71C
1-cycloheptyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 71B in place of the product of 1B (0.041 g, 15%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 72
1- (3-anilinopropyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H ) -On a solution of the product of Example 73 (0.090 g, 0.23 mmol) and aniline (0.15 mL, 0.23 mmol) in THF (6 mL) at room temperature for 24 hours, sodium triacetoxyborohydride (0 .08 g, 0.38 mmol) and glacial acetic acid (0.025 mL, 0.43 mmol). The solvent was removed under reduced pressure and the resulting solid was subjected to waters symmetry using a gradient of 10% to 100% acetonitrile / 0.1% aqueous TFA over 12 minutes (15 minutes elution time) at a flow rate of 70 mL / min. Purification by preparative HPLC on a C8 column (40 mm × 100 mm, particle size 7 μm) gave the title compound. _{MS (DCI / NH 3) m} / z476 (M + H) +. The title compound was dissolved in 1,4-dioxane (6 mL) and 4M HCl in dioxane (2 mL). After stirring at room temperature for 3 hours, the mixture was filtered and the filter cake was dried to obtain the hydrochloride.

Example 73
3- [3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridin-1 (2H) -yl ] propanal example 69B the product of (0.65 g, 0.15 mmol) with stirring water (3 mL) and glacial acetic acid (12 mL) suspension at room temperature, it was added dropwise sulfuric acid (1 mL). The mixture was heated to 60 ° C. for 1 hour and diluted with water. The mixture was filtered and the filter cake was washed with water and dried to give the title compound (0.455 g, 78%).

Example 74
4-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- Yl] methyl} methyl benzoate
Example 74A
4-[(2,4-dioxo-2H-pyrido [2,3-d] [1,3] oxazin-1 (4H) -yl) methyl] methyl benzoate instead of n-butyl bromide 4- (bromomethyl ) The title compound was prepared according to the procedure of Example 1B using methyl benzoate (1.5 g, 75%). MS (DCI) m / z 313 (M + H) ^<+> .

Example 74B
4-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- Yl] methyl} methyl benzoate The title compound was prepared according to the procedure of Example 1D using the product of Example 74A in place of the product of Example 1B (0.130 g, 37%).

Example 75
5-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- Yl] methyl} -2-furoic acid ethyl ester
Example 75A
Instead of ethyl 5-[(2,4-dioxo-2H-pyrido [2,3-d] [1,3] oxazinoxazin-1 (4H) -yl) methyl] -2-furoate n-butyl bromide The title compound was prepared according to the procedure of Example 1B using ethyl 5-chloromethyl-2-furancarboxylate (0.073 g, 19%).

Example 75B
5-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- Yl] methyl} -2-ethyl furoate The title compound was prepared according to the procedure of Example 1D using the product of Example 75A in place of the product of Example 1B (0.074 g, 69%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 76
1- [3- (Dimethylamino) propyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -one A solution of the product of Example 73 (0.085 g, 0.21 mmol) and dimethylamine (2.0 M THF solution 0.110 mL, 0.22 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 1 hour. Reacted with sodium triacetoxyborohydride (0.06 g, 0.28 mmol). The solvent was removed under reduced pressure and the resulting solid was triturated with methanol and dimethyl sulfoxide (1: 1), filtered and dried to give the product, the title compound (0.56 g, 61%). It was. _{(DCI / NH 3) m /} z428 (M + H) +. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 77
1- {3-[[2- (Dimethylamino) ethyl] (methyl) amino] propyl} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl)- The title compound was prepared according to the procedure of Example 72 using N, N, N-trimethylethylenediamine in place of 4-hydroxy-1,8-naphthyridin-2 (1H) -oneaniline . _{MS (DCI / NH 3) m} / z485 (M + H) +. The dihydrochloride of the title compound was prepared according to the procedure of Example 72.

Example 78
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [3- (4-methyl-1-piperazinyl) propyl] -1, The title compound was prepared according to the procedure of Example 72 using 4-methylpiperazine in place of 8-naphthyridine-2 (1H) -one aniline. MS (ESI-) m / z450 ( M-H) -. The dihydrochloride of the title compound was prepared according to the procedure of Example 72.

Example 79
1- (2-Aminoethyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) On solution of Example 66 (45.0 mg, 0.087 mmol) in pure ethanol (1.5 mL), N, N-dimethylformamide (0.8 mL) and dimethyl sulfoxide (1.0 mL) at room temperature. Treated with hydrazine monohydrate (13.42 mg, 0.261 mmol). The mixture was heated to reflux at 80 ° C. for 5 hours, cooled to room temperature and concentrated. The concentrate was purified by C8 HPLC column eluting with 20% to 80% acetonitrile / water [containing 1% trifluoroacetic acid] to give the TFA salt of the title compound (0.010 g, 23%).

Example 80
1- [3- (Diethylamino) propyl] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 ( The title compound was prepared according to the procedure of Example 72 substituting diethylamine for 1H) -onaniline. _{MS (DCI / NH 3) m} / z456 (M + H) +. The hydrochloride salt of the title compound was prepared according to the procedure of Example 72.

Example 81
1-cyclohexyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 81A
Ethyl 2- (cyclohexylamino) nicotinate The title compound was prepared according to the procedure of Example 3A using cyclohexylamine instead of 2-ethylbutylamine (1.92 g, 61%).

Example 81B
1-Cyclohexyl-2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example 1 substituting the product of Example 81A for the product of Example 3A The title compound was prepared according to the procedure of 3B (0.171 g, 35%).

Example 81C
1-Cyclohexyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 81B in place of the product of (0.073 g, 26%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 82
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [3- (4-morpholinyl) propyl] -1,8-naphthyridine The title compound was prepared according to the procedure of Example 72 using morpholine instead of 2 (1H) -onaniline (0.053 g, 60%). MS (ESI-) m / z450 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 83
5-{[3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxo-1,8-naphthyridine-1 (2H)- [Il] methyl} -2-furoic acid A solution of the product of Example 75B (23 mg, 0.046 mmol) in THF (1 mL) was treated with 1 N NaOH (0.2 mL) at room temperature. After 3 hours, the mixture was treated with H ₂ O (5 mL), adjusted to pH 4 with 1N HCl, and extracted with ethyl acetate (2 × 25 mL). The extract was washed with saturated NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting solid was passed through a Waters Symmetry C8 column (25 mm × 100 mm, 25 mm × 100 mm, using a gradient of 10% to 100% acetonitrile / 0.1% TFA aqueous solution over 8 minutes (10 minutes elution time) at a flow rate of 40 mL / min. Purification by preparative HPLC with a particle size of 7 μm gave the title compound (0.039 g, 83%).

Example 84
1-Benzyl-3- (7-bromo-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 84A
The title compound was prepared from 4-bromoaniline using the procedure described in the 2-amino-5-bromobenzenesulfonamide literature (JCS Perkin 1, 1979, 1043).

Example 84B
1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate sodium hydride (60%, 0.118 g, 2.95 mmol) in anhydrous dimethylacetamide (6 mL ) Diethyl malonate (0.472 g, 2.95 mmol) was added dropwise over 5 minutes to the intermediate slurry at 0 ° C. under N ₂ . The mixture was stirred at room temperature for 1 hour, reacted with the product of Example 15A (0.50 g, 1.97 mmol) and heated at 120 ° C. for 3 hours. The mixture was cooled to room temperature, partitioned between ethyl acetate and cold water and adjusted to pH 5 with 1M HCl. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from methanol to give the title compound as a white solid (0.439 g, 68%).

Example 84C
N- [2- (aminosulfonyl) -4-bromophenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide The product of Example 84B ( 0.065 g, 0.20 mmol) was reacted with the product of Example 84A (0.050 g, 0.20 mmol) under reflux in toluene (4 mL) for 3 hours. The reaction was cooled and the resulting precipitate was collected by filtration and dried to give the title compound as an off-white solid (0.074 g, 70%).

Example 84D
1-Benzyl-3- (7-bromo-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- A mixture of the product of On Example 84C (0.074 g, 0.14 mmol) in aqueous potassium hydroxide (10%, 5 mL) was heated to reflux for 16 hours, cooled to room temperature, and adjusted to pH 3 with 6M HCl. The mixture was filtered and the filter cake was washed with water, triturated with tetrahydrofuran / water, filtered and dried in vacuo to give the title compound (0.060 g, 84%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 85
1-Benzyl-3- (1,1-dioxide-7-phenyl-2H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 85A
N- [3- (aminosulfonyl) -1,1′-biphenyl-4-yl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2 The title compound was prepared according to the procedure of Example 84C using 2-amino-5-phenylbenzenesulfonamide instead of amino-5-bromobenzenesulfonamide (0.084 g, 79%).

Example 85B
1-Benzyl-3- (1,1-dioxide-7-phenyl-2H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 85A in place of the product of On Example 84C (0.055 g, 69%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 86
1-Benzyl-3- (7-cyclohexyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 86A
A solution of 2-amino-5-cyclohexylbenzenesulfonamide 4-cyclohexylaniline (0.877 g, 5.0 mmol, 1.0 equiv) in nitroethane (5 mL) was cooled to −40 ° C. and chlorosulfonyl isocyanate (0.87 g , (0.523 mL, 6.15 mmol, 1.23 eq) was added dropwise, warmed to 0 ° C., treated with aluminum trichloride (0.85 g, 6.35 mmol, 1.27 eq), 110 ° C. The mixture was filtered and the filter cake was washed with cold water, dissolved in 50% H ₂ SO ₄ (25 mL) and heated to reflux for 4 hours. Cool to room temperature, pour into 200 mL ice water and carefully neutralize with 40% NaOH to pH 7. The reaction mixture is acetic acid. Extract with ethyl (3 × 100 mL) and wash the combined extracts with brine, dry (MgSO ₄ ), filter and concentrate to give 0.40 g (31% yield) of the desired product. It was.

Example 86B
N- [2- (aminosulfonyl) -4-cyclohexylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound was prepared according to the procedure of Example 84C using the product of Example 86A instead of benzenesulfonamide (0.081 g, 76%).

Example 86C
1-Benzyl-3- (7-cyclohexyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 86B in place of the product of On Example 84C (0.040 g, 53%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 87
1-Benzyl-3- (7-tert-butyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H )-ON
Example 87A
N- [2- (aminosulfonyl) -4-tert-butylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5 The title compound was prepared according to the procedure of Example 84C using 2-amino-5-tert-butylbenzenesulfonamide instead of bromobenzenesulfonamide (0.072 g, 79%).

Example 87B
1-Benzyl-3- (7-tert-butyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H ) -On The title compound was prepared according to the procedure of Example 84D using the product of Example 87A in place of the product of Example 84C (0.040 g, 100%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 88
1-Benzyl-4-hydroxy-3- (7-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- on
Example 88A
N- [2- (aminosulfonyl) -4-methylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound was prepared according to the procedure of Example 84C using 2-amino-5-methylbenzenesulfonamide instead of benzenesulfonamide (0.075 g, 90%).

Example 88B
1-Benzyl-4-hydroxy-3- (7-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 88A instead of the product of On Example 84C (0.031 g, 42%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 89
1-butyl-3- (6-chloro-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 89A
Slurry in dehydrated DMA (15 mL) in ethyl 1-butyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate NaH (95%, 0.44 g, 18.2 mmol) To the solution, diethyl malonate (2.9 g, 18.2 mmol) was added dropwise at 10 ° C. under N ₂ over 10 minutes. The mixture was stirred at room temperature for 30 minutes, treated with the product of Example 1B (2.0 g, 9.1 mmol) and heated at 120 ° C. for 3 hours. The mixture was cooled to room temperature, partitioned between ethyl acetate and cold water and the pH adjusted to 5 with 1M HCl. The organic layer was washed twice with 100 mL water, twice with 100 mL saturated brine, dried (Na ₂ SO ₄ ), filtered and the filtrate concentrated under reduced pressure. The residue was recrystallized from hexane / ethyl acetate to give the desired compound as a white solid (1.84 g, 70% yield). MS (APCI +) m / z 291 (M + H) ^<+> .

Example 89B
N- [2- (Aminosulfonyl) -4-chlorophenyl] -1-butyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide Product of Example 89A (87 mg , 0.3 mmol) and 2-amino-4-chlorobenzenesulfonamide (62 mg, 0.3 mmol) in toluene (5 mL) at reflux for 16 hours, cooled, and the resulting precipitate was collected by filtration and dried. To give the desired amide as an off-white solid (80 mg, 59% yield). MS (APCI +) m / z 451 (M + H) ^<+> .

Example 89C
1-butyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate Example substituting the product of Example 89B for the product of Example 84B The title compound was prepared according to the procedure for 84C (0.037 g, 53%). MS (ESI-) m / z 431 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 90
1-Benzyl-3- (8-bromo-5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 90A
N- [2- (aminosulfonyl) -3-bromo-6-methylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino The title compound was prepared according to the procedure of Example 84C using 2-amino-6-bromo-3-methylbenzenesulfonamide instead of -5-bromobenzenesulfonamide to give the crude title compound (0. 1 g, 98%).

Example 90B
1-Benzyl-3- (8-bromo-5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -one The title compound was prepared according to the procedure of Example 84D, substituting the product of Example 90A for the product of Example 84C. The crude product was purified by column chromatography on silica gel eluting with methylene chloride and methanol (98: 2) to give the title compound as a white solid (0.03 g, 31% yield). MS (ESI-) m / z 525 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 91
1-Benzyl-3- (8-fluoro-5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -ON
Example 91A
N- [2- (aminosulfonyl) -3-fluoro-6-methylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino The title compound was prepared according to the procedure of Example 84C using 2-amino-6-fluoro-3-methylbenzenesulfonamide instead of -5-bromobenzenesulfonamide to give the crude title compound (0. 120 g, 100%).

Example 91B
1-Benzyl-3- (8-fluoro-5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -one The title compound was prepared according to the procedure of Example 84D, substituting the product of Example 91A for the product of Example 84C. The crude product was purified by column chromatography on silica gel eluting with methylene chloride and methanol (98: 2) to give as a white solid (0.05 g, 44% yield). MS (ESI-) m / z 463 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 92
1-Benzyl-4-hydroxy-3- (5-isopropyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- on
Example 92A
N- [2- (aminosulfonyl) -6-isopropylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound is purified after chromatography on silica gel (4: 1 hexane / ethyl acetate as eluent) according to the procedure of Example 84C using 2-amino-3-isopropylbenzenesulfonamide instead of benzenesulfonamide. Prepared (0.050 g, 55%).

Example 92B
1-Benzyl-4-hydroxy-3- (5-isopropyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 92A in place of the product of On Example 84C (0.038 g, 75%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 93
1-Benzyl-4-hydroxy-3- (5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- on
Example 93A
N- [2- (aminosulfonyl) -6-methylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound was prepared according to the procedure of Example 84C using 2-amino-3-methylbenzenesulfonamide instead of benzenesulfonamide (0.059 g, 100%).

Example 93B
1-Benzyl-4-hydroxy-3- (5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- The title compound was obtained after silica gel chromatography (98: 2 methylene chloride / methanol as eluent) according to the procedure of Example 84D using the product of Example 93A in place of the product of On Example 84C. (0.015 g, 25%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 94
1-Benzyl-3- (5-bromo-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) 4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 94A
N- [2- (aminosulfonyl) -6-bromophenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound was obtained after silica gel chromatography (2: 1 hexane / ethyl acetate as eluent) according to the procedure of Example 84C using 2-amino-3-methylbenzenesulfonamide instead of benzenesulfonamide. (0.080 g, 25%).

Example 94B
1-benzyl-3- (5-bromo-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 84D using the product of Example 94A in place of the product of Example 84C (0.040 g, 54%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 95
1-Benzyl-3- (1,1-dioxide-5-propyl-2H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 95A
N- [2- (aminosulfonyl) -6-propylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound was prepared according to the procedure of Example 84C using 2-amino-3-propylbenzenesulfonamide instead of benzenesulfonamide (0.062 g, 59%).

Example 95B
1-Benzyl-3- (1,1-dioxide-5-propyl-2H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 95A instead of the product of On Example 84C (0.029 g, 50%). MS (ESI-) m / z 473 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 96
1-Benzyl-3- (5-ethyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- on
Example 96A
N- [2- (aminosulfonyl) -6-ethylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound was prepared according to the procedure of Example 84C using 2-amino-3-ethylbenzenesulfonamide instead of benzenesulfonamide (0.070 g, 74%).

Example 96B
1-Benzyl-3- (5-ethyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 96A in place of the product of On Example 84C (0.060 g, 93%). MS (ESI-) m / z459 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 97
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -2H-1,2,4-benzothiadiazine-5-carbonitrile 1 , 1-dioxide A solution of the product of Example 94B (0.329 g, 0.643 mmol) and CuCN (0.29 g, 3.21 mmol) in dehydrated DMF (5 mL) was heated at 145 ° C. under N ₂ for 22 hours. . The reaction was cooled to room temperature, diluted with CH ₂ Cl ₂ (50 mL) and 1N aqueous HCl (10 mL) and stirred vigorously for 15 min. The layers were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 50 mL). The organic extract was washed with 1N aqueous HCl (20 mL) and saturated aqueous NaCl, and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration by rotary evaporator, the residue was purified by silica gel flash chromatography (2.5 × 14 cm, 5% EtOAc / CH ₂ Cl ₂ ) to give the title compound (0.136 g, 46%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 98
1-butyl-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-2 (1H) -quinolinone
Example 98A
Treatment of 3-nitropyridine-2- thiol 3-nitro-2-chloro-pyridine (50 g, 0.0317 mol) with thiourea (24 g, 0.0317 mol) for several hours under reflux in 200 mL of ethanol gave 2 -Mercapto-3-nitropyridine was prepared. After allowing the reaction mixture to cool, 7.19 mL of KOH solution (42.8 g of water (115 mL) solution) was added and the resulting mixture was heated to reflux for 3 hours. The crude reaction mixture was cooled to room temperature and concentrated under reduced pressure to 50% of its volume. After diluting with 300 mL of water, the product was isolated by vacuum filtration as an orange-red solid that was used without further purification.

Example 98B
3 from 2-mercapto-3-nitropyridine according to the procedure described in the 3-aminopyridine-2-sulfonamide literature (R. Lejeune and co-workers, J. Pharm. Belg., 39, 217-224, 1984). The title compound (3-aminopyrid-2-yl) sulfonamide was prepared in stages (80% yield).

Example 98C
Instead of N- [2- (aminosulfonyl) pyridin-3-yl] -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide 2-amino-4-chlorobenzenesulfonamide The title compound was prepared according to the procedure of Example 89B using 3-amino-pyridine-2-sulfonamide.

Example 98D
1-butyl-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-2 (1H) -quinolinone Example 84C The title compound was prepared as a white solid according to the procedure of Example 84D using the product of Example 98C instead of the product of (0.065 g, 22%).

Example 99
1-Benzyl-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-2 (1H) -quinolinone
Example 99A
1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate 1-benzyl-1H-benzo [d] [1,3] oxazine instead of the product of Example 15A The title compound was prepared according to the procedure of Example 84B using 2,4-dione.

Example 99B
N- [2- (Aminosulfonyl) pyridin-3-yl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide Example 99A instead of the product of Example 84B The title compound was prepared according to the procedure of Example 84C using (3-amino-pyrid-2-yl) sulfonamide instead of 2-amino-5-bromobenzenesulfonamide. The product was obtained as an off-white solid.

Example 99C
1-Benzyl-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-2 (1H) -quinolinone Example 84C The title compound was prepared according to the procedure of Example 84D using the product of Example 99B instead of the product of (0.076 g, 38%).

Real 施例100
1-Benzyl-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H )-ON
Example 100A
N- [2- (aminosulfonyl) pyridin-3-yl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide 2-amino-5-bromo The title compound was prepared according to the procedure of Example 84C using 3-amino-pyridine-2-sulfonamide instead of benzenesulfonamide.

Real 施例100B
1-Benzyl-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H ) -On Using the product of Example 100A in place of the product of Example 84C, the title compound was prepared according to the procedure of Example 84D to give reverse phase HPLC (water / acetonitrile / 0.1% NH ₄ OAc). The title compound was obtained as a white solid after purification by (gradient) (0.053 g, 10%).

Example 101
5-chloro-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -2 (1H) -Quinolinone
Example 101A
Water of 5-chloro-2H-3,1-benzoxazine-2,4 (1H) -dione potassium hydroxide (1.68 g, 30 mmol) and 2-amino-6-chlorobenzoic acid (3.43 g, 20 mmol) A 20% phosgene solution in toluene (16.8 mL, 32 mmol) was added dropwise to the (25 mL) solution at 0 ° C., resulting in precipitation. The mixture was stirred for 1 hour and the solid was collected by filtration, washed with water and dried to give the title compound (3.6 g, 91%).

Example 101B
1-Bromo-3-methylbutane was used instead of 5-chloro-1- (3-methylbutyl) -2H-3,1-benzoxazine-2,4 (1H) -dione n-butyl bromide. The title compound was prepared according to the procedure of Example 1B using the product of Example 101A in place of the product (0.610 g, 45%). MS (DCI) m / z285 ( M + NH 4) +.

Example 101C
Ethyl 5-chloro-4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydroquinoline-3-carboxylate Instead of the product of Example 1B, the product of Example 101B was used. The title compound was prepared according to the procedure of Example 89A (0.600 g, 80%).

Example 101D
N- [2- (Aminosulfonyl) pyridin-3-yl] -5-chloro-4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydroquinoline-3-carboxamide Example 101C The product (0.170 g, 0.50 mmol) was reacted with the product of Example 98A (0.086 g, 0.50 mmol) in toluene (6 mL) under reflux for 16 hours. The reaction was cooled and the resulting precipitate was collected by filtration and dried to give the title compound (0.200 g, 86%).

Example 101E
5-chloro-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -2 (1H) -Quinolinone The title compound was prepared according to the procedure of Example 84D using the product of Example 101D instead of the product of Example 84C (0.200 g, 98%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 102
1-Benzyl-3- (1,1-dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-5-methyl-2 (1H)- Quinolinone
Example 102A
1-Benzyl- (4-methyl) benzo [2,3-d] [1,3] oxazine-2,4-dione Instead of n-butyl bromide, benzyl bromide was used instead of the product of Example 1A. The title compound was prepared according to the procedure of Example 1B using (4-methyl) benzo [2,3-d] [1,3] oxazine-2,4-dione (0.67 g, 60%).

Example 102B
Ethyl 1-benzyl-4-hydroxy-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate Example 84A substituting the product of Example 102A for the product of Example 15A The title compound was prepared according to the procedure of (0.71 g, 89%).

Example 102C
N- [2- (Aminosulfonyl) pyridin-3-yl] -1-benzyl-4-hydroxy-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide in place of the product of Example 84B The title compound was prepared according to the procedure of Example 84C using the product of Example 102B, substituting the product of Example 98A for 2-amino-5-bromobenzenesulfonamide (0.163 g, 41 %).

Example 102D
1-Benzyl-3- (1,1-dioxide-4H-pyrido [3,2-3] [1,2,4] thiadiazin-3-yl) -4-hydroxy-5-methyl-2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 102C in place of the product of quinolinone Example 84C (0.064 g, 41%). MS (ESI +) m / z 447 (M + H) < ^- >. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 103
3- (1,1-Dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1-[(2-methyl-1,3-thiazole -5-yl) methyl-2 (1H) -quinolinone
Example 103A
1-[(2-Methyl-1,3-thiazol-5-yl) methyl] -2H-3,1-benzoxazine-2,4 (1H) -dione Isatoic anhydride in place of the product of Example 1A And the title compound was prepared according to the procedure of Example 1B using 2-methyl-5-chloromethylthiazole instead of n-butyl bromide (0.410 g, 73%).

Example 103B
1-[(2-Methyl-1,3-thiazol-5-yl) methyl] -2,4-dioxo-1,2,3,4-tetrahydroquinoline-3-carboxylate To the product of Example 15B The title compound was prepared according to the procedure of Example 84A using the product of Example 103A instead (0.132 g, 25%).

Example 103C
N- [2- (aminosulfonyl) pyridin-3-yl] -1-[(2-methyl-1,3-thiazol-5-yl) methyl] -2,4-dioxo-1,2,3,4 -Tetrahydroquinoline-3-carboxamide Substituting the product of Example 99A for the product of Example 84B and substituting 3-amino-pyridine-2-sulfonamide for 2-amino-5-bromobenzenesulfonamide The title compound was prepared according to the method described in the procedure of Example 84C (0.148 g, 79%).

Example 103D
3- (1,1-Dioxide-4H-pyrido [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1-[(2-methyl-1,3-thiazole -5-yl) methyl-2 (1H) -quinolinone The title compound was prepared according to the procedure of Example 84D, substituting the product of Example 103C for the product of Example 84C (0.033 g, 68% ).

Example 104
1-Benzyl-4-hydroxy-3- (7-methyl-1,1-dioxide-4H-pyrido [2,3-e] [1,2,4] thiadiazin-3-yl) -2 (1H)- Quinolinone
Example 104A
(2-Amino-5-methylpyrid-3-yl) sulfonyl chloride from 2-amino-5-picoline by the method described in literature (Weller, H ,. N., US Pat. No. 5,378,704). 5-Methylpyrid-3-yl) sulfonyl chloride was prepared.

Example 104B
2-Amino-5-methylpyridine-3-sulfonamide The product of Example 104A was reacted with concentrated ammonium hydroxide at room temperature overnight. The reaction mixture was concentrated to give the title compound as a light yellow solid in quantitative yield.

Example 104C
N- [3- (aminosulfonyl) -5-methylpyridin-2-yl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide 2-amino-5-bromobenzene The title compound was prepared according to the procedure of Example 84C using the product of Example 104B instead of the sulfonamide.

Example 104D
1-Benzyl-4-hydroxy-3- (7-methyl-1,1-dioxide-4H-pyrido [2,3-e] [1,2,4] thiadiazin-3-yl) -2 (1H)- The title compound was prepared according to the procedure of Example 84D using the product of Example 104C in place of the product of quinolinone Example 84C (0.20 g, 35%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 105
1-butyl-4-hydroxy-3- (7-methyl-1,1-dioxide-4H-pyrido [2,3-e] [1,2,4] thiadiazin-3-yl) -1,8-naphthyridine -2 (1H) -ON
Example 105A
Ethyl 3-{[3- (aminosulfonyl) -5-methylpyridin-2-yl] amino} -3-oxopropanoate The product of Example 104B (1.0 g, 0.0053 mol) in THF containing 5 mL of pyridine. A solution in (10 mL) was treated with ethyl 3-chloro-3-oxopropionate (0.97 g, 0.0064 mol) at room temperature for several hours. The reaction mixture was concentrated to half the initial volume and diluted with water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound as an off-white solid (1.19 g, 75% yield).

Example 105C
(7-Methyl-1,1-dioxide-4H-pyrido [2,3-e] [1,2,4] thiadiazin-3-yl) ethyl acetate Product of Example 105A (0.363 g, 0.0012 mol) ) In ethanol (20 mL) was reacted with sodium carbonate (0.350 g, 0.0033 mol). The reaction mixture was heated to reflux for 2 hours. After cooling, the reaction mixture was diluted with methylene chloride and filtered to remove excess sodium carbonate and concentrated. The residue was purified by chromatography on silica gel using ethyl acetate / hexane (1: 1) and then 4% methanol / methylene chloride as the mobile phase to give the title compound as a white solid (0.296 g, Yield 87%).

Example 105D
1-butyl-4-hydroxy-3- (7-methyl-1,1-dioxide-4H-pyrido [2,3-e] [1,2,4] thiadiazin-3-yl) -1,8-naphthyridine -(1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 105C instead of the product of Example 1C (0.065 g, 58% yield).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 106
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-thienylmethyl) -1,8-naphthyridine-2 (1H) -ON
Example 106A
Instead of 1- (thien-2-ylmethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione n-butyl bromide 2- (bromomethyl) -thiophene The title compound was prepared according to the procedure of Example 1B (0.165 g, 51%).

Example 106B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-thienylmethyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 106A, the title compound was prepared according to the procedure of example 1D (0.162g, 60%). MS (ESI-) m / z 437 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 107
1- (Benzyloxy) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 107A
2-[(Benzyloxy) amino] nicotinic acid ethyl 2-chloro-nicotinic acid ethyl ester (4.55 g, 24.6 mmol), O-benzylhydroxyamine hydrochloride (7.85 g, 49.2 mmol) and N, N A solution of diisopropylethylamine (6.36 g, 49.2 mmol) in 1,4-dioxane (10 mL) was reacted in a sealed tube at 120 ° C. for 48 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was re-extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (9: 1) to give the title compound (3.5 g, 53%). MS (DCI) m / z 273 (M + H) ^<+> .

Example 107B
2-[(Benzyloxy) (3-ethoxy-3-oxopropanoyl) amino] ethyl nicotinate of the product of Example 107A (1.2 g, 4.4 mmol) and triethylamine (0.49 g, 4.8 mmol) To a methylene chloride (25 mL) solution, ethyl chloromalonate (0.73 g, 4.8 mmol) was added dropwise, stirred for 2 hours, partitioned between ethyl acetate and water, and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3: 1) to give the title compound (1.1 g, 65%). MS (DCI) m / z 387 (M + H) ^<+> .

Example 107C
Ethyl 1- (benzyloxy) -4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate The product of Example 107B (0.386 g, 1.0 mmol) in ethanol ( The 5 mL) solution was treated with 21% sodium ethoxide / ethanol (0.324 g, 1.0 mmol), stirred for 30 minutes, partitioned between ethyl acetate and 5% aqueous HCl and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0:28 g, 82%). MS (DCI) m / z 341 (M + H) ^<+> .

Example 107D
N- [2- (Aminosulfonyl) phenyl] -1- (benzyloxy) -4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide Product of Example 107C (340 mg , 0.82 mmol) and 2-aminobenzenesulfonamide (141 mg, 0.82 mmol) in toluene (10 mL) at reflux and cooled for 16 h, and the resulting precipitate was collected by filtration and dried to give the title compound (340 mg, 89%) was obtained. MS (DCI) m / z 467 (M + H) ^<+> .

Example 107E
1- (Benzyloxy) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 84D using the product of Example 107D in place of the product of Example 84C to give the title compound (0.082 g, 87%). MS (ESI-) m / z 447 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 108
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -8- (2-ethylbutyl) -5-hydroxy-2- (methylsulfanyl) pyrido [2,3 -D] pyrimidin-7 (8H) -one
Example 108A
4-[(2-Ethylbutyl) amino] -2- (methylthio) pyrimidine-5-carboxylate methyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (0.40 g, 1.72 mmol) at room temperature. Reacted with 1-amino-2-ethylbutane (0.175 g, 1.72 mmol) and triethylamine (0.60 mL, 4.32 mmol) for 18 hours. The reaction was partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (0.50 g, 98%).

Example 108B
4-[(2-Ethylbutyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid A solution of the product of Example 108A (0.50 g, 1.68 mmol) in water and ethanol (1: 2) was stirred at room temperature. And reacted with sodium hydroxide (0.22 g, 5.50 mmol) for 3 h. The reaction solution was concentrated under reduced pressure to remove ethanol, and neutralized with an aqueous hydrochloric acid solution (1M). The resulting precipitate was collected by filtration and dried to give the title compound (0.41 g, 91%).

Example 108C
1- (2-Ethylbutyl) -7- (methylthio) -2H-pyrimido [4,5-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 108B (0.41 g, 1.52 mmol) was reacted with ethyl chloroformate (0.445 mL, 4.65 mmol) and pyridine (0.405 mL, 5.56 mmol) in toluene (8 mL) at 90 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate and filtered. Concentration of the filtrate gave the title compound (0.394 g, 88%).

Example 108D
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -8- (2-ethylbutyl) -5-hydroxy-2- (methylsulfanyl) pyrido [2,3 -D] pyrimidin-7 (8H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 108C instead of the product of Example 1B (0.153 g, 24%). MS (ESI-) m / z472 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 109
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -8- (2-ethylbutyl) -5-hydroxypyrido [2,3-d] pyrimidine-7 (8H) -On The product of Example 108D (0.15 g, 0.30 mmol) was reacted with an excess of Raney nickel (slurry in water, 2 mL) in ethanol (5 mL) and heated at 60 ° C. for 1 h. The mixture was filtered through celite, washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound.

Example 110
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one
Example 110A
2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione following the procedure described in the literature (Fabis and co-workers, Tetrahedron, 1998, 54, 10789-10800) The compound was prepared.

Example 110B
1-Benzyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A (0.137 g, 0.81 mmol) was added at room temperature for 20 hours. Was reacted with benzyl bromide (0.10 mL, 0.85 mmol) and potassium carbonate (0.134 g, 0.97 mmol) in dimethylformamide (5 mL). The reaction mixture was diluted with water and the resulting precipitate was collected by filtration and dried to give the title compound (0.165 g, 80%).

Example 110C
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 110B in place of the product of Example 1B (0.137 g, 49%). MS (ESI-) m / z438 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 111
4-Butyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one
Example 111A
1-Butyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione Benzyl bromide was used in place of n-butyl bromide according to the procedure of Example 110B. (0.059 g, 22%).

Example 111B
4-Butyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 111A in place of the product of Example 1B (0.050 g, 47%).

Example 112
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (4-pyridinylmethyl) thieno [3,2-b] pyridine-5 ( 4H)-ON
Example 112A
1- (Pyridin-4-ylmethyl) -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A instead of the product of Example 1A And the title compound was prepared according to the procedure of Example 1B using 4-bromomethylpyridine hydrobromide instead of n-butyl bromide (0.205 g, 80%).

Example 112B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (4-pyridinylmethyl) thieno [3,2-b] pyridine-5 ( 4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 112A instead of the product of Example 1B (0.155 g, 45%).

Example 113
1- (3-Bromobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6,7,8-tetrahydro- 2 (1H) -quinolinone
Example 113A
5,6,7,8-Tetrahydro-2H-3,1-benzoxazine-2,4 (1H) -dione 2-aminocyclohex-1-ene-1-carboxylic acid instead of the product of Example 3A The title compound was prepared according to the procedure of Example 3B using ethyl (0.960 g, 97%). MS (ESI-) m / z 166 (M-H) ^<+> .

Example 113B
1- (3-Bromobenzyl) -5,6,7,8-tetrahydro-2H-3,1-benzoxazine-2,4 (1H) -dione Production of Example 113A instead of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using 3-bromobenzyl bromide instead of n-butyl bromide (0.049 g, 46%). MS (ESI-) m / z 334 (M-H) ^<+> .

Example 113C
1- (3-Bromobenzyl) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6,7,8-tetrahydro- 2 (1H) -Quinolinone The title compound was prepared according to the procedure of Example 1D using the product of Example 113B in place of the product of Example 1B (0.021 g, 34%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 114
5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7- (4-pyridinylmethyl) thieno [2,3-b] pyridine-6 ( 7H)-ON
Example 114A
The title compound was prepared by the method of 2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione (Fabis and coworkers, Tetrahedron 1998, 54, 10789-10800).

Example 114B
1- (Pyridin-4-ylmethyl) -2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 114A instead of the product of Example 1A And the title compound was prepared according to the procedure of Example 1B using 4-bromomethylpyridine hydrobromide instead of n-butyl bromide (0.22 g, 95%).

Example 114C
5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7- (4-pyridinylmethyl) thieno [2,3-b] pyridine-6 ( 7H) -On The title compound was prepared according to the procedure of Example 1D using the product of Example 114B in place of the product of Example 1B (0.047 g, 13%).

Example 115
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (3-pyridinylmethyl) thieno [3,2-b] pyridine-5 ( 4H)-ON
Example 115A
1- (Pyridin-3-ylmethyl) -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A instead of the product of Example 1A And the title compound was prepared according to the procedure of Example 1B using 3-bromomethylpyridine hydrobromide instead of n-butyl bromide (0.28 g, 90%).

Example 115B
6- (1,1-dioxide-4H-1,2,6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (3 -Pyridinylmethyl) thieno [3,2-b] pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D substituting the product of Example 115A for the product of Example 1B ( 0.237 g, 50%) MS (DCI / NH ₃ ) m / z 439 (M + H) ⁺ The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 116
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxythieno [2,3-b] pyridin-6 (7H) -one
Example 116A
1-Benzyl-2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example 110B substituting the product of Example 114A for the product of Example 110A The title compound was prepared according to the procedure of (0.26 g, 100%).

Example 116B
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxythieno [2,3-b] pyridin-6 (7H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 116A in place of the product of Example 1B (0.144 g, 38%). MS (ESI-) m / z 436 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 117
4- (Cyclopropylmethyl) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H)-ON
Example 117A
1- (Cyclopropylmethyl) -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A was used in place of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using bromomethylcyclopropane instead of n-butyl bromide (0.23 g, 87%).

Example 117B
4- (Cyclopropylmethyl) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H) -On The title compound was prepared according to the procedure of Example 1D using the product of Example 117A in place of the product of Example 1B (0.252 g, 60%). MS (ESI-) m / z400 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 118
5- (1,1-dioxide-4H-1,2,5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7- (3 -Methylbutyl) thieno [2,3-b] pyridin-6 (7H) -one
Example 118A
1- (3-Methylbutyl) -2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 114A was used in place of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using isobutyl bromide instead of n-butyl bromide (0.074 g, 35%).

Example 118B
5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7- (3-methylbutyl) thieno [2,3-b] pyridine-6 ( 7H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 118A in place of the product of Example 1B (0.063 g, 49%). MS (ESI-) m / z416 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 119
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-2-phenylthieno [3,2-b] pyridine-5 ( 4H)-ON
Example 119A
Methyl 6-phenyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione 3-amino-5-phenylthiophene-2-carboxylate (0.25 g, 1. 07 mmol) in water (6 mL) was reacted with potassium hydroxide (0.12 g, 2.14 mmol) at 90 ° C. for 24 h. The reaction solution was cooled to 0 ° C., and phosgene (1.9 M toluene solution, 0.70 mL, 1.40 mmol) was added dropwise. After stirring at room temperature for 1 hour, the resulting solid was collected by filtration, washed with excess water and dried to give the title compound as a tan solid (0.175 g, 65%).

Example 119B
1-Benzyl-6-phenyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 [1,3] oxazine-2,4 (1H) -dione To the product of Example 1A The title compound was prepared according to the procedure of Example 1B using the product of Example 119A instead (0.19 g, 80%).

Example 119C
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-2-phenylthieno [3,2-b] pyridine-5 ( 4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 119B in place of the product of Example 1B (0.062 g, 22%). MS (ESI-) m / z512 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 120
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-3-methylthieno [3,2-b] pyridine-5 (4H )-ON
Example 120A
7-methyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione instead of methyl 3-amino-5-phenylthiophene-2-carboxylate 3-amino- The title compound was prepared according to the procedure of Example 119A using methyl 4-methylthiophene-2-carboxylate.

Example 120B
1-Benzyl-7-methyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 120A was used in place of the product of Example 110A The title compound was prepared according to the procedure of Example 110B (0.22 g, 73%). _{MS (DCI / NH 3) m} / z291 (M + NH 4) +.

Example 120C
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-3-methylthieno [3,2-b] pyridine-5 (4H ) -On The title compound was prepared according to the procedure of Example 1D using the product of Example 120B instead of the product of Example 1B (0.110 g, 30%). MS (ESI-) m / z450 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 121
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6,7,8-tetrahydro-2 (1H)- Quinolinone
Example 121A
1-Benzyl-5,6,7,8-tetrahydro-2H-3,1-benzoxazine-2,4 (IH) -dione The product of Example 113A was used instead of the product of Example 1A, and n The title compound was prepared according to the procedure of Example 1B using benzyl bromide instead of butyl bromide (0.620 g, 67%). MS (ESI-) m / z256 ( M-H) -.

Example 121B
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6,7,8-tetrahydro-2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 121A in place of the product of quinolinone Example 1B (0.039 g, 37%). MS (ESI-) m / z 434 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 122
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2 (1H) -pyridinone
Example 122A
The title compound was prepared by the method described in 2H-1,3-oxazine-2,6 (3H) -dione literature (Warren and coworkers, Journal of Organic Chemistry, 1975, 40 (6), 743-746).

Example 122B
3-Benzyl-2H-1,3-oxazine-2,6 (3H) -dione The title compound was prepared according to the procedure of Example 110B, substituting the product of Example 122A for the product of Example 110A. (0.156 g, 25%).

Example 122C
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2 (1H) -pyridinone instead of the product of Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 122B (0.13 g, 5%).

Example 123
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6-dimethyl-2 (1H) -pyridinone
Example 123A
According to the method described in 4,5-dimethyl-2H-1,3-oxazine-2,6 (3H) -dione literature (Washburne, et. Al., Tetrahedron Letters 1976, 17 (4), 243-246), The title compound was prepared. _{MS (DCI / NH 3) m} / z204 (M + H) +.

Example 123B
3-Benzyl-4,5-dimethyl-2H-1,3-oxazine-2,6 (3H) -dione Substituting the product of Example 123A for the product of Example 1A and substituting n-butyl bromide The title compound was prepared according to the procedure of Example 1B using benzyl bromide (0.109 g, 27%).

Example 123C
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6-dimethyl-2 (1H) -pyridinone Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 123B in place of the product of (0.070 g, 36%). MS (ESI-) m / z408 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 124
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-3-methylthieno [2,3-b] pyridine-6 (7H )-ON
Example 124A
According to the procedure of 5-methyl-2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione (Fabis and co-workers, Tetrahedron, 1998, 54, 10789-10800) The title compound was prepared. MS (ESI-) m / z 182 (MH) ^- .

Example 124B
1-Benzyl-5-methyl-2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 124A was used in place of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using benzyl bromide instead of n-butyl bromide (0.075 g, 50%). _{MS (DCI / NH 3) m} / z291 (M + NH 4) +.

Example 124C
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-3-methylthieno [2,3-b] pyridine-6 (7H ) -On The title compound was prepared according to the procedure of Example 1D using the product of Example 124B in place of the product of Example 1B (0.025 g, 23%). MS (ESI-) m / z450 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 125
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (3-methylbutyl) thieno [3,2-b] pyridine-5 ( 4H)-ON
Example 125A
1- (3-Methylbutyl) -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A was used in place of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using 1-bromo-3-methylbutane instead of n-butyl bromide (0.246 g, 68%).

Example 125B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (3-methylbutyl) thieno [3,2-b] pyridine-5 ( 4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 125A in place of the product of Example 1B (0.223 g, 52%). MS (ESI-) m / z416 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 126
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- (2-ethylbutyl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H)-ON
Example 126A
1- (2-Ethylbutyl) -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A was used in place of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using 1-bromo-2-ethylbutane instead of n-butyl bromide (0.116 g, 31%). _{MS (DCI / NH 3) m} / z271 (M + NH 4) +.

Example 126B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- (2-ethylbutyl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 126A in place of the product of Example 1B (0.052 g, 26%). MS (ESI-) m / z430 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 127
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-methyl-5-phenyl-2 (1H) -pyridinone
Example 127A
4-Methyl-5-phenyl-2H-1,3-oxazine-2,6 (3H) -dione 2-phenylacetoacetate ethyl (1.0 g, 4.85 mmol) and urethane (0.43 g, 4.85 mmol) Was heated undiluted with phosphorous oxychloride (3 mL) at 90 ° C. for 3 hours. Excess trial was removed under reduced pressure and the resulting residue was triturated with benzene and filtered. The solid was triturated with diethyl ether, filtered and dried to give 0.818 g (83%).

Example 127B
3-Benzyl-4-methyl-5-phenyl-2H-1,3-oxazine-2,6 (3H) -dione n-butyl bromide substituting the product of Example 127A for the product of Example 1A The title compound was prepared according to the procedure of Example 1B using benzyl bromide instead of (0.257 g, 71%).

Example 127C
1-benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-methyl-5-phenyl-2 (1H) -pyridinone The title compound was prepared according to the procedure of Example 1D using the product of Example 127B instead of the product of Example 1B (0.022 g, 5%). MS (ESI-) m / z 470 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 128
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6-dimethyl-1- (3-methylbutyl) -2 (1H)- Pyridinone
Example 128A
4,4,5-Dimethyl-3- (3-methylbutyl) -2H-1,3-oxazine-2,6 (3H) -dione The product of Example 123A was used instead of the product of Example 1A. The title compound was prepared according to the procedure of Example 1B using 1-bromo-3-methylbutane instead of n-butyl bromide (0.224 g, 60%).

Example 128B
3- (1,1-dioxide-4H-1.2,4-benzothiadiazin-3-yl) -4-hydroxy-5,6-dimethyl-1- (3-methylbutyl) -2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 128A in place of the product of pyridinone Example 1B (0.132 g, 32%). MS (ESI-) m / z 388 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 129
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (2-ethylbutyl) -4-hydroxy-5,6-dimethyl-2 (1H)- Pyridinone
Example 129A
3- (2-Ethylbutyl) -4,5-dimethyl-2H-1,3-oxazine-2,6 (3H) -dione The product of Example 123A was used instead of the product of Example 1A, and n- The title compound was prepared according to the procedure of Example 1B using 1-bromo-2-ethyl-butane instead of butyl bromide (0.181 g, 45%).

Example 129B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (2-ethylbutyl) -4-hydroxy-5,6-dimethyl-2 (1H)- The title compound was prepared according to the procedure of Example 1D using the product of Example 129A in place of the product of pyridinone Example 1B (0.027 g, 9%). MS (ESI-) m / z402 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 130
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-phenyl-2 (1H) -pyridinone
Example 130A
4-phenyl-2H-1,3-oxazine-2,6,4-phenyl-2H-1,3-oxazine-2,6 (3H) -dione Instead of ethyl 2-phenylacetoacetate, ethyl benzoyl acetate was used. The title compound was prepared according to the procedure of Example 127A to give the desired product (0.99 g, 47%).

Example 130B
3-Benzyl-4-phenyl-2H-1,3-oxazine-2,6 (3H) -dione The product of Example 130A was used instead of the product of Example 1A, and benzyl was used instead of n-butyl bromide. The title compound was prepared according to the procedure of Example 1B using bromide (0.223 g, 78%).

Example 130C
1-Benzyl-3 (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-phenyl-2 (1H) -pyridinone Product of Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 130B instead (0.021 g, 6%). MS (ESI-) m / z 456 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 131
5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7- (3-methyl-2-butenyl) thieno [2,3-b] Pyridin-6 (7H) -one
Example 131A
1- (3-Methylbut-2-enoyl-2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione Production of Example 114A instead of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using 1-bromo-3-methyl-but-2-ene in place of n-butyl bromide (0.23 g, 82%).

Example 131B
5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-7- (3-methyl-2-butenyl) thieno [2,3-b] Pyridin-6 (7H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 131A in place of the product of Example 1B (0.178 g, 44%). MS (ESI-) m / z414 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 132
1,5-dibenzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-methyl-2 (1H) -pyridinone
Example 132A
5-Benzyl-4-methyl-2H-1,3-oxazine-2,6 (3H) -dione Example using 2-benzyl-3-oxo-butyric acid ethyl ester instead of ethyl 2-phenylacetoacetate The title compound was prepared according to the procedure at 127A to give the desired product. _{MS (DCI / NH 3) m} / z218 (M + H) +.

Example 132B
3,5-Dibenzyl-4-methyl-2H-1,3-oxazine-2,6 (3H) -dione The product of Example 132A was used in place of the product of Example 1A and replaced with n-butyl bromide The title compound was prepared according to the procedure of Example 1B using benzyl bromide (0.215 g, 76%).

Example 132C
1,5-dibenzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-methyl-2 (1H) -pyridinone Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 132B instead of the product of (0.051 g, 15%). MS (ESI-) m / z484 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 133
3- (1,1-Dioxide-4H-1,2,3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (2-ethylbutyl)- 4-Hydroxy-6-methyl-5-phenyl-2 (1H) -pyridinone
Example 133A
3- (2-Ethylbutyl) -4-methyl-5-phenyl-2H-1,3-oxazine-2,6 (3H) -dione The product of Example 127A was used instead of the product of Example 1A. The title compound was prepared according to the procedure of Example 1B using 1-bromo-2-ethylbutane instead of n-butyl bromide (0.145 g, 41%). _{MS (DCI / NH 3) m} / z288 (M + H) +.

Example 133B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (2-ethylbutyl) -4-hydroxy-6-methyl-5-phenyl-2 (1H ) -Pyridinone The title compound was prepared according to the procedure of Example 1D using the product of Example 133A in place of the product of Example 1B (0.019 g, 8%). MS (ESI-) m / z 464 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 134
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-pentylthieno [3,2-b] pyridin-5 (4H) -one
Example 134A
1-pentyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione Substituting the product of Example 110A for the product of Example 1A, n-butyl The title compound was prepared according to the procedure of Example 1B using n-pentyl bromide instead of bromide (0.205 g, 72%).

Example 134B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-pentylthieno [3,2-b] pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 134A in place of the product of Example 1B (0.189 g, 53%). MS (ESI-) m / z416 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 135
5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-3-methyl-7- (3-methylbutyl) thieno [2,3-b] Pyridin-6 (7H) -one
Example 135A
According to the procedure of 5-methyl-2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione (Fabis and co-workers, Tetrahedron, 1998, 54, 10789-10800) The title compound was prepared from 2-amino-4-methyl-thiophene-3-carboxylic acid ethyl ester.

Example 135B
5-Methyl-1--3-methylbutyl) -2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione Production of Example 135A instead of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using isopentyl bromide instead of n-butyl bromide (0.048 g, 30%).

Example 135C
5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-3-methyl-7- (3-methylbutyl) thieno [2,3-b] Pyridin-6 (7H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 135B instead of the product of Example 1B (0.043 g, 52%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 136
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (4-methylpentyl) thieno [3,2-b] pyridine-5 (4H) -ON
Example 136A
1- (4-Methylpentyl) -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A was substituted for the product of Example 1A. The title compound was prepared according to the procedure of Example 1B using 1-bromo-4-methyl-pentane instead of n-butyl bromide (0.110 g, 61%).

Example 136B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (4-methylpentyl) thieno [3,2-b] pyridine-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 136A in place of the product of Example 1B (0.064 g, 34%). MS (ESI-) m / z430 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 137
4- (3-Butenyl) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H)-ON
Example 137A
1-but-3-enyl-2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 110A was used in place of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using 4-bromo-but-1-ene instead of n-butyl bromide (0.09 g, 56%).

Example 137B
4- (3-Butenyl) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 137A in place of the product of Example 1B (0.062 g, 38%). MS (ESI-) m / z399.9 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 138
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-phenyl-1,7-dihydro-6H-pyrazolo [3 , 4-b] pyridin-6-one
Example 138A
Ethyl 5- (benzylamino) -1-phenyl-1H-pyrazole-4-carboxylate substituting ethyl 5-amino-1-phenyl-4-pyrazole-carboxylate for n-butyl instead of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using benzyl bromide instead of bromide (0.990 g, 83%). MS (ESI-) m / z320 ( M-H) -.

Example 138B
Ethyl 5- [benzyl (3-ethoxy-3-oxopropanoyl) amino] -1-phenyl-1H-pyrazole-4-carboxylate (Rowley and co-workers, J. Med. Chem., 1993, 36, 3386-3396), the title compound was prepared from the product of Example 138A and ethyl malonyl chloride (51% yield). MS (ESI-) m / z 434 (MH) ^- .

Example 138C
7-Benzyl-4-hydroxy-6-oxo-1-phenyl-6,7-dihydro-1H-pyrazolo [3,4-b] pyridine-5-carboxylate methyl literature (Rowley and co-workers, J. Med Chem., 1993, 36, 3386-3396), the title compound was prepared from the product of Example 138B and sodium methoxide. MS (ESI-) m / z 374 (MH) ^- .

Example 138D
N- [2- (aminosulfonyl) phenyl] -7-benzyl-4-hydroxy-6-oxo-1-phenyl-6,7-dihydro-1H-pyrazolo [3,4-b] pyridine-5-carboxamide Prepare the title compound according to the procedure of Example 84C using the product of Example 138C in place of the product of Example 84B and using 2-aminobenzenesulfonamide in place of 2-amino-5-bromobenzenesulfonamide. (0.014 g, 61%). MS (ESI +) m / z 516 (M + H) ^<+> .

Example 138E
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-phenyl-1,7-dihydro-6H-pyrazolo [3 , 4-b] pyridin-6-one The title compound was prepared according to the procedure of Example 84D using the product of Example 138D in place of the product of Example 84C (0.061 g, 84%). MS (ESI-) m / z 496 (M-H) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 139
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -2,7-dihydroxy [1,3] thiazolo [4,5-b] pyridine -5 (4H) -ON
Example 139A
4- (Benzylamino) -2- (methylthio) -1,3-thiazole-5-carboxylate methyl 4-amino-2-methylthio-5-thiazolecarboxylate instead of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using benzyl bromide instead of n-butyl bromide (0.411 g, 57%). MS (ESI +) m / z 295 (M + H) ^<+> .

Example 139B
4- [Benzyl (3-ethoxy-3-oxopropanoyl) amino] -2- (methylthio) -1,3-thiazole-5-carboxylate product of Example 139A instead of the product of Example 138A Was used to prepare the title compound according to the procedure of Example 138B (0.147 g, 30%). MS (ESI +) m / z 409 (M + H) ^<+> .

Example 139C
4-Benzyl-7-hydroxy-2- (methylthio) -5-oxo-4,5-dihydro [1,3] thiazolo [4,5-b] ethyl pyridine-6-carboxylate To the product of Example 138B The title compound was prepared according to the procedure of Example 138C using the product of Example 139B instead (0.111 g, 82%). MS (ESI-) m / z 375 (MH) ^- .

Example 139D
N- [2- (aminosulfonyl) phenyl] -4-benzyl-7-hydroxy-2- (methylthio) -5-oxo-4,5-dihydro [1,3] thiazolo [4,5-b] pyridine- 6-Carboxamide Following the procedure of Example 84C, substituting the product of Example 139C for the product of Example 84B and substituting 2-aminobenzenesulfonamide for 2-amino-5-bromobenzenesulfonamide. The title compound was prepared (0.114 g, 75%). MS (ESI-) m / z501 ( M-H) -.

Example 139E
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -2,7-dihydroxy [1,3] thiazolo [4,5-b] pyridine -5 (4H) -one The title compound was prepared according to the procedure of Example 84D using the product of Example 139D instead of the product of Example 84C (0.108 g, 60%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 140
4-[(2-Chloro-1,3-thiazol-5-yl) methyl] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7- Hydroxythieno [3,2-b] pyridin-5 (4H) -one
Example 140A
1-[(2-Chloro-1,3-thiazol-5-yl) methyl] -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione of Example 1A The title compound was prepared according to the procedure of Example 1B using the product of Example 104A in place of the product and 2-chloro-5-bromomethylthiazole in place of n-butyl bromide (0.341 g, 75%).

Example 140B
4-[(2-Chloro-1,3-thiazol-5-yl) methyl] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7- Hydroxythieno [3,2-b] pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 140A in place of the product of Example 1B (0. 134 g, 40%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 141
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(5-methyl-3-pyridinyl) methyl] thieno [3,2 -B] Pyridin-5 (4H) -one
Example 141A
1-[(5-Methylpyridin-3-yl) methyl] -2H-thieno [3,2-c] [1,3] oxazine-2,4 (1H) -dione in place of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using the product of Example 110A and substituting 3-methyl-5-chloromethylpyridine for n-butyl bromide (0.255 g, 38%).

Example 141B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (5-methyl-3-pyridinyl) methyl] thieno [3,2- b] Pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 141A in place of the product of Example 1B (0.175 g, 43%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 142
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(2-methyl-1,3-thiazol-5-yl) methyl ] Thieno [3,2-b] pyridin-5 (4H) -one
Example 142A
1-[(2-Methyl-1,3-thiazol-5-yl) methyl] -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione of Example 1A The title compound was prepared according to the procedure of Example 1B using the product of Example 110A in place of the product and 2-methyl-5-chloromethylthiazole in place of n-butyl bromide (0.308 g, 55%).

Example 142B
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(2-methyl-1,3-thiazol-5-yl) methyl ] Thieno [3,2-b] pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D substituting the product of Example 142A for the product of Example 1B (0. 151 g, 40%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 143
4-[(5-Chloro-2-thienyl) methyl] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2 -B] Pyridin-5 (4H) -one
Example 143A
1-[(5-Chlorothien-2-yl) methyl] -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione Performed instead of the product of Example 1A The title compound was prepared according to the procedure of Example 1B using the product of Example 110A and substituting 2-chloro-5-chloromethylthiophene for n-butyl bromide (0.601 g, 100%).

Example 143B
4-[(5-Chloro-2-thienyl) methyl] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2 -B ] Pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 143A instead of the product of Example 1B (0.115 g, 12%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 144
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(2-methyl-1,3-thiazol-4-yl) methyl ] Thieno [3,2-b] pyridin-5 (4H) -one
Example 144A
1-[(2-Methyl-1,3-thiazol-4-yl) methyl] -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione of Example 1A The title compound was prepared according to the procedure of Example 1B using the product of Example 110A instead of the product and 2-methyl-4-chloromethylthiazole hydrochloride instead of n-butyl bromide (0 .200 g, 36%).

Example 144B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(2-methyl-1,3-thiazol-4-yl) methyl ] Thieno [3,2-b] pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D substituting the product of Example 144A for the product of Example 1B (0. 127 g, 38%).

Example 145
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-2- (methylsulfanyl) [1,3] thiazolo [4 5-b] Pyridin-5 (4H) -one
Example 145A
4-Benzyl-2- (methylthio) -5H- [1,3] thiazolo [4,5-d] [1,3] oxazine-5,7 (4H) -dione Performed in place of the product of Example 3A The title compound was prepared according to the procedure of Example 3B using the product of Example 139A (0.048 g, 92%). _{MS (DCI / NH 3) m} / z324 (M + NH 4) +.

Example 145B
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-2- (methylsulfanyl) [1,3] thiazolo [4 5-b] Pyridin-5 (4H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 145A instead of the product of Example 1B (0.037 g, 51%). . MS (ESI) m / z 485 (M + H) ^<+> . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 146
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-2- (methylsulfonyl) [1,3] thiazolo [4 5-b] The product of Example 145B and 3-chloroperbenzoic acid according to the procedure of the pyridin-5 (4H) -one literature (Leysen and co-workers, J. Heterocyclic Chem., 1984, 21, 401-406). The title compound was prepared from the acid as a white solid.

Example 147
2-Amino-4-benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy [1,3] thiazolo [4,5-b ] Pyridin-5 (4H) -one The product of Example 146 (0.011 g, 0.02 mmol) was added to ammonia (0.5 M solution in dioxane, 1.3 mL, 0) in a pressure tube at 70 ° C. for 17 hours. .64 mmol). The reaction was cooled and the resulting precipitate was collected by filtration and dried to give the title compound as a white solid (0.009 g, 100%).

Example 148
4-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy [1,3] thiazolo [4,5-b] pyridine-5 (4H) -one The product of Example 147 (0.0085 g, 0.019 mmol) was combined with tert-butyl nitrite (5CIL, 0.037 mmol) in DMF (0.3 mL) at 60 ° C. for 1 hour. Reacted. The reaction was cooled and the crude mixture was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (1: 1) to give the title compound as a yellow solid (0.0045 g, 54%). .

759163 Example 149
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-phenylpropyl) -1,8-naphthyridine-2 (1H) -ON
Example 149A
Ethyl 2 -[(2-phenylpropyl) amino] nicotinate The title compound was prepared according to the procedure of Example 3A using (±) -β-methylphenethylamine instead of 2-ethyl-butylamine (0.44 g, 58%).

Example 149B
1- (2-Phenylpropyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 149A was substituted for the product of Example 3A The title compound was prepared according to the procedure of Example 3B (0.44 g, 99%).

Example 149C
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-phenylpropyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 149B, the title compound was prepared according to the procedure of example 1D (0.045g, 62%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 150
8-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -5-hydroxy-2- (methylsulfanyl) pyrido [2,3-d] pyrimidine -7 (8H) -ON
Example 150A
4- (Benzylamino) -2- (methylthio) pyrimidine-5-carboxylate The title compound was prepared according to the procedure of Example 108A substituting benzylamine for 1-amino-2-ethyl-butane (0 .97 g, 92%).

Example 150B
4- (Benzylamino) -2- (methylthio) pyrimidine-5-carboxylic acid The title compound was prepared according to the procedure of Example 108B, substituting the product of Example 150A for the product of Example 108A (0 185 g, 78%).

Example 150C
1-Benzyl-7- (methylthio) -2H-pyrimido [4,5-d] [1,3] oxazine-2,4 (1H) -dione The product of Example 150B instead of the product of Example 108B Was used to prepare the title compound according to the procedure of Example 108C (0.145 g, 72%). _{MS (DCI / NH 3) m} / z302 (M + H) +.

Example 150D
8-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -5-hydroxy-2- (methylsulfanyl) pyrido [2,3-d] pyrimidine -7 (8H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 150C in place of the product of Example 1B (0.042 g, 18%). MS (ESI-) m / z 478 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 151
8-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -5-hydroxypyrido [2,3-d] pyrimidine-7 (8H)- The title compound was prepared according to the procedure of Example 109 using the product of Example 151D instead of the product of On Example 108D (0.019 g, 58%).

Example 152
3- (1,1-dioxide-4H-1,2,3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3 -Hydroxybutyl) -2 (1H) -quinolinone A solution of the product of Example 73 (0.12 g, 0.30 mmol) in tetrahydrofuran (6 mL) was added with 3.0 M methylmagnesium bromide (0.11 mL, 0.33 mmol)- Treated at 50 ° C. and stirred for 1 hour at room temperature The solution was diluted with 1N HCl and water and filtered The resulting solid was triturated with methylene chloride and filtered The filtrate was concentrated to give the title compound. (0.050 g, 40%) was obtained.

Example 153
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxythieno [3,4-b] pyridin-2 (1H) -one
Example 153A
Ethyl 4- aminothiophene-5-carboxylate instead of methyl 4H-thieno [3,4-d] [1,3] oxazine-2,4 (1H) -dione 3-amino-5-phenylthiophene-carboxylate The title compound was prepared according to the procedure of Example 119A using the hydrochloride salt (0.86 g, 50%).

Example 153B
1-Benzyl-4H-thieno [3,4-d] [1,3] oxazine-2,4 (1H) -dione Substituting the product of Example 153A for the product of Example 1A, n-butyl The title compound was prepared according to the procedure of Example 1B using benzyl bromide instead of bromide (0.33 g, 91%).

Example 153C
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxythieno [3,4-b] pyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 153B instead of the product of Example 1B (0.028 g, 5%).

Example 154
4-[(5-Bromo-2-thienyl) methyl] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2 -B] Pyridin-5 (4H) -one
Example 154A
1-[(5-Bromothien-2-yl) methyl] -2H-thieno [3,2-d] [1,3] oxazine-2,4 (1H) -dione Performed in place of the product of Example 1A Using the product of Example 110A and substituting 2-bromo-5-bromomethyl-thiophene for n-butyl bromide, the title compound was prepared according to the procedure of Example 1B (0.25 g, 82%).

Example 154B
4-[(5-Bromo-2-thienyl) 4-[(5-bromo-2-thienyl) methyl] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazine-3 -Yl) -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one The title compound according to the procedure of Example 1D, substituting the product of Example 154A for the product of Example 1B (0.219 g, 58%). MS (ESI-) m / z 521 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 155
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -2 (1H) -pyridinone
Example 155A
4: 1 of 1-butyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 2-hydroxy-nicotinic acid (0.50 g, 3.59 mmol) and potassium hydroxide (0.40 g, 7.13 mmol) 1-iodobutane (0.74 mL, 6.42 mmol) was added to a methanol: water (6 mL) solution at room temperature. The solution was heated at 60 ° C. for 30 minutes, cooled to room temperature, diluted with water and 1N HCl. The resulting solid was filtered and dried to give the title compound (0.27 g, 39%).

Example 155B
N- [2- (Aminosulfonyl) phenyl] -1-butyl-2-oxo-1,2-dihydropyridine-3-carboxamide The product of Example 155A and 2-aminobenzenesulfonamide (0.24 g, 1.39 mmol) ) In tetrahydrofuran (8 mL) at room temperature, TBTU (O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate) and triethylamine (0.58 mL). 4.15 mmol). After 18 hours, the mixture was poured into water, extracted with ethyl acetate, dehydrated with sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure at a flow rate of 70 mL / min for 12 minutes (15 minutes). Elution time) Purification by preparative HPLC on a Waters Symmetry C8 column (40 mm × 100 mm, particle size 7 μm) using a gradient from 10% to 100% acetonitrile / 0.1% aqueous TFA to give the title compound.

Example 155C
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -2 (1H) -pyridinone 12 according to the procedure of Example 84D at a flow rate of 70 mL / min. Purified by preparative HPLC on a Waters Symmetry C8 column (40 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile / 0.1% aqueous TFA in water (15 minutes elution time). The title compound was prepared. _{MS (DCI / NH 3) m} / z332 (M + H) +. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 156
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2,4-diol Example 73 product (0.12 g, 0 .30 mmol) in tetrahydrofuran (6 mL) was reacted with 3.0 M methylmagnesium bromide (0.11 mL, 0.33 mmol) at −50 ° C. and stirred at room temperature for 1 hour. The solution was diluted with 1N HCl and filtered. The resulting solid was triturated with methylene chloride and filtered to give the product.

Example 157
1- (Benzyloxy) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one
Example 157A
2-[(Benzyloxy) amino] nicotinic acid ethyl 2-chloro-nicotinic acid ethyl ester (4.55 g, 24.6 mmol), O-benzylhydroxyamine hydrochloride (7.85 g, 49.2 mmol) and N, N A solution of diisopropylethylamine (6.36 g, 49.2 mmol) in 1,4-dioxane (10 mL) was reacted in a sealed tube at 120 ° C. for 48 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was re-extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (9: 1) to give the title compound (3.5 g, 53%). MS (DCI) m / z 273 (M + H) ^<+> .

Example 157B
2-[(Benzyloxy) (3-ethoxy-3-oxopropanoyl) amino] ethyl nicotinate of the product of Example 157A (1.2 g, 4.4 mmol) and triethylamine (0.49 g, 4.8 mmol) To a methylene chloride (25 mL) solution, ethyl chloromalonate (0.73 g, 4.8 mmol) was added dropwise, stirred for 2 hours, partitioned between ethyl acetate and water, and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3: 1) to give the title compound (1.1 g, 65%). MS (DCI) m / z 387 (M + H) ^<+> .

Example 157C
Ethyl 1- (benzyloxy) -4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate The product of Example 157B (0.386 g, 1.0 mmol) in ethanol ( The 5 mL) solution was treated with 21% sodium ethoxide in ethanol (0.324 g, 1.0 mmol), stirred for 30 minutes, partitioned between ethyl acetate and 5% aqueous HCl and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.28 g, 82%). MS (DCI) m / z 341 (M + H) ^<+> .

Example 157D
N- [2- (Aminosulfonyl) phenyl] -1- (benzyloxy) -4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide instead of the product of Example 84B The title compound was prepared according to the procedure of Example 84C using the product of Example 157C and substituting 2-aminosulfonamide for the product of Example 84A (340 mg, 89% yield). MS (DCI) m / z 467 (M + H) ^<+> .

Example 157E
1- (Benzyloxy) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one The title compound was prepared according to the procedure of Example 84D using the product of Example 157D instead of the product of Example 84C (0.082 g, 87%). MS (ESI-) m / z 447 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 158
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-isobutoxy-1,8-naphthyridin-2 (1H) -one
Example 158A
The title compound was prepared according to the procedure of Example 157A using O-isobutylhydroxylamine hydrochloride in place of ethyl 2- (isobutoxyamino) nicotinate O-benzylhydroxyamine hydrochloride (0.372 g, 34%) . MS (DCI) m / z 239 (M + H) ^<+> .

Example 158B
2-[(3-Ethoxy-3-oxopropanoyl) (isobutoxy) amino] ethyl nicotinate The title compound was prepared according to the procedure of Example 157B, substituting the product of Example 158A for the product of Example 157A. Prepared (0.230 g, 42%). MS (DCI) m / z 353 (M + H) ^<+> .

Example 158C
Using the product of Example 158B in place of the product of ethyl 4-hydroxy-1-isobutoxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate 157B of Example 157C The title compound was prepared according to the procedure (0.200 g, 99%). MS (DCI) m / z 307 (M + H) ^<+> .

Example 158D
N- [2- (aminosulfonyl) phenyl] -4-hydroxy-1-isobutoxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide Example 84B instead of the product of Example The title compound was prepared according to the procedure of Example 84C using 158C product and substituting 2-aminosulfonamide for the product of Example 84A (0.225 g, 86%). MS (DCI) m / z 433 (M + H) ^<+> .

Example 158E
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-isobutoxy-1,8-naphthyridin-2 (1H) -one Example 84C The title compound was prepared according to the procedure of Example 84D using the product of Example 158D in place of the product of (0.200 g, 93%). MS (ESI-) m / z 413 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 159
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,5-naphthyridin-2 (1H) -one
Example 159A
According to the procedure of 2H-pyrido [3,2-d] [1,3] oxazine-2,4 (1H) -dione literature (Le Count, DJ and co-workers, Synthesis, 1982, 972-973), 2, The title compound was prepared from 3-pyridinecarboxylic anhydride (11.4 g, 76 mmol) and trimethylsilyl azide (11.0 mL, 80 mmol) as a small by-product (0.50 g, 4%).

Example 159B
1-Butyl-2H-pyrido [3,2-d] [1,3] oxazine-2,4 (1H) -dione Example using the product of Example 159A instead of the product of Example 1A The title compound was prepared according to the procedure of 1B (0.12 g, 35%).

Example 159C
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,5-naphthyridin-2 (1H) -one Example 1B The title compound was prepared according to the procedure of Example 1D using the product of Example 159B in place of the product of (0.053 g, 25%). MS (ESI-) m / z 397 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 160
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,5-naphthyridin-2 (1H) -one
Example 160A
1-Benzyl-2H-pyrido [3,2-d] [1,3] oxazine-2,4 (1H) -dione Substituting the product of Example 159A for the product of Example 1A, n-butyl The title compound was prepared according to the procedure of Example 1B using benzyl bromide instead of bromide (0.92 g, 60%).

Example 160B
1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate Example substituting the product of Example 160A for the product of Example 1B The title compound was prepared according to the procedure for 89A (0.110 g, 23%). MS (DCI) m / z 325 (M + H) ^<+> .

Example 160C
N- [2- (aminosulfonyl) phenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide Example 89A instead of the product of Example 89A The title compound was prepared according to the procedure of Example 89B using 160B product and using 2-aminobenzenesulfonamide instead of 2-amino-4-chlorobenzenesulfonamide (0.12 g, 86%). MS (ESI-) m / z 449 (MH) ^- .

Example 160D
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,5-naphthyridin-2 (1H) -one Example 84B The title compound was prepared according to the procedure of Example 84C using the product of Example 160C instead of the product of (0.120 g, 99%). MS (ESI-) m / z 431 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 161
1-Benzyl-4-chloro-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8 -naphthyridin-2 (1H) -one literature (Stadlbauer , W. and co-workers, Journal of Heterocyclic Chemistry, 35, 1998, 627-636). The title compound was prepared from the product of Example 15B and phosphoryl chloride (2.07 g, 88%).

Example 162
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(1E) -phenylmethylene] amino} -2 (1H)- Quinolinone
Example 162A
2-[(2E) -2-benzylidenehydrazino] benzoic acid (Fischer, E. and co-workers, Chem. Ber., 35, 1902, 2318) according to the procedure of 2-hydrazinobenzoic acid hydrochloride (1 The title compound was prepared from .89 g (10.0 mmol) and benzaldehyde (1.06 g, 10.0 mmol) (2.4 g, quantitative yield). MS (DCI) m / z 241 (M + H) ^<+> .

Example 162B
1-{[(1E) -Phenylmethylene] amino} -2H-3,1-benzoxazine-2,4 (1H) -dione The product of Example 162A (1.2 g, 5.0 mmol) and potassium hydroxide To a solution of (0.336 g, 6.0 mmol) in water (15 mL) at 0 ° C., 20% phosgene in toluene (3.5 mL, 6.5 mmol) was added dropwise, stirred for 1 hour, treated with 1M NaOH. The pH was adjusted to 10 and extracted 3 times with 30 mL of ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.32 g, 24%). MS (DCI) m / z 267 (M + H) ^<+> .

Example 162C
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(1E) -phenylmethylene] amino} -2 (1H)- instead of the product of the quinolinone example 1B using the product of example 162B, the title compound was prepared according to the procedure of example 1D (0.110g, 49%). MS (ESI-) m / z443 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 163
1-amino-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2 (1H) -quinolinone The product of Example 162C (0. A solution of 075 g, 0.17 mmol) in 10% aqueous potassium hydroxide (5 mL) was refluxed for 2 hours, cooled, and treated with 12M HCl to pH 3, resulting in precipitation. The solid was collected by filtration, washed repeatedly with water and dried to constant weight to give the desired product (0.050 g, 83%). MS (ESI-) m / z 355 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 164
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-phenylethyl) -1,8-naphthyridine-2 (1H) -ON
Example 164A
Ethyl 2-[(2-phenylethyl) amino] nicotinate The title compound was prepared according to the procedure of Example 3A using phenethylamine in place of 2-ethyl-butylamine (1.98 g, 73%). MS (DCI) m / z 271 (M + H) ^<+> .

Example 164B
1- (2-Phenylethyl) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione Substituting the product of 164A for the product of Example 3A The title compound was prepared according to the procedure of Example 3B (0.53 g, 99%). MS (DCI) m / z 269 (M + H) ^<+> .

Example 164C
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (2-phenylethyl) -1,8-naphthyridine-2 (1H) - instead of the product of one example 1B using the product of example 164B, the title compound was prepared according to the procedure of example 1D (0.132g, 59%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 165
1-butyl-4-chloro-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one Example 15B The title compound was prepared according to the procedure of Example 161, substituting the product of Example 1D for the product of

Example 166
4-Amino-1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one Example 165 A solution of the product (0.10 g, 0.24 mmol) and ammonia (2 M methanol solution 2 mL, 4.0 mmol) was stirred in a sealed tube at 100 ° C. for 2 hours and allowed to cool to room temperature. The resulting solid was collected by filtration and washed with methanol (2 mL) to give the title compound as a brown solid (0.019 g, 20%).

Example 167
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- (methylamino) -1,8-naphthyridin-2 (1H) -one The title compound was obtained as a brown solid (0.023 g, 23%) according to the procedure of Example 166 using methylamine (2M methanol solution) instead of ammonia (2M methanol solution).

Example 168
1-butyl-4- (dimethylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one The title compound was obtained as a brown solid (0.015 g, 15%) according to the procedure of Example 166 using dimethylamine (2M methanol solution) instead of ammonia (2M methanol solution).

Example 169
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydrazino-1,8-naphthyridin-2 (1H) -one ammonia (2M The title compound was obtained as a brown solid (0.026 g, 26%) according to the procedure of Example 166 using hydrazine instead of methanol solution).

Example 170
4-Azido-1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridin-2 (1H) -one Example 165 Of dimethylformamide (2.5 mL) of the product of (0.1 g, 0.24 mmol) and sodium azide (0.037 g, 0.571 mmol) at 80 ° C. for 1.5 hours, allowed to cool to room temperature. And concentrated under reduced pressure. The crude residue was purified by C8 HPLC column eluting with 20% to 80% acetonitrile / water (containing 1% trifluoroacetic acid) to give the title compound (0.025 g, 26% after column purification). .

Example 171
1-butyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(2-hydroxyethyl) amino] -1,8-naphthyridine-2 The title compound was prepared according to the procedure of Example 166 using ethanolamine (0.25 g, 4.0 mmol) and dehydrated methanol (2 mL) instead of (1H) -one ammonia (2M methanol solution) (0.02 g 19%).

Example 172
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-propoxyquinolin-2 (1H) -one
Example 172A
The title compound is prepared from ethyl 2-nitrobenzoate according to the procedure of ethyl 2- (hydroxyamino) benzoate (Entwistle and Gilkerson, Tetrahedron, 34, 1978, 213-215).

Example 172B
Ethyl 2- (propoxyamino) benzoate The title compound according to the procedure of Example 1B, substituting the product of Example 172A for the product of Example 1A and substituting n-propyl bromide for n-butyl bromide Is manufactured.

Example 172C
2-[(3-Ethoxy-3-oxopropanoyl) (propoxy) amino] ethyl benzoate The title compound was prepared according to the procedure of Example 157B substituting the product of Example 172B for the product of Example 157A. Manufactured.

Example 172D
Ethyl 4-hydroxy-2-oxo-1-propoxy-1,2-dihydroquinoline-3-carboxylate Follow the procedure of Example 157C, substituting the product of Example 172C for the product of Example 157B. A compound is produced.

Example 172E
N- [2- (Aminosulfonyl) phenyl] -4-hydroxy-2-oxo-1-propoxy-1,2-dihydroquinoline-3-carboxamide The product of Example 172D was substituted for the product of Example 84B. The title compound is prepared according to the procedure of Example 84C using 2-aminosulfonamide instead of the product of Example 84A.

Example 172F
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-propoxyquinolin-2 (1H) -one in place of the product of Example 84C The title compound is prepared according to the procedure of Example 84D using the product of Example 172E. The sodium salt of the title compound is prepared according to the procedure of Example 1D.

Example 173
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-3- (hydroxymethyl) -7,7a-dihydrothieno [2, 3-b] Pyridin-6 (3aH) -one
Example 173A
2-amino-4- (hydroxymethyl) thiophene-3-carboxylate methyl cyanoacetate (1.18mL, 13.28mmol) and methanol (25mL of sodium sulfide decahydrate (3.20g, 13.28mmol) ) The solution was treated with 1-acetoxy-3-chloroacetone (2.0 g, 13.28 mmol) at 0 ° C. The cooling bath was removed and triethylamine (1.86 mL, 13.28 mmol) was added dropwise. The solution was stirred at room temperature for 20 hours, diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound (1.25 g, 51%).

Example 173B
2-Amino-4-({[tert-butyl (dimethyl) silyl] oxy} methyl) thiophene-3-carboxylate Product of Example 173A (1.25 g, 6.70 mmol) and N, N-diisopropylethylamine A solution of (0.71 mL, 7.35 mmol) in methylene chloride was treated at 0 ° C. with t-butyldimethylsilyl trifluoromethanesulfonate (0.85 mL, 6.70 mmol). After stirring at 0 ° C. for 1 hour, the solution was poured into water, extracted with methylene chloride, and dehydrated with sodium sulfate. The solvent was removed under reduced pressure to give the title compound (0.87 g, 78%).

Example 173C
2- (Benzylamino) -4-({[tert-butyl (dimethyl) silyl] oxy} methyl) thiophene-3-carboxylate The product of Example 173B (0.36 g, 1.20 mmol) and potassium carbonate ( A solution of 0.185 g, 1.30 mmol) in acetonitrile (5 mL) was treated with benzyl bromide (0.16 mL, 1.25 mmol) at 45 ° C. for 24 hours. The solution was poured into water and extracted with ethyl acetate (twice). The combined organic layers were concentrated and purified by flash chromatography eluting with methylene chloride to give the title compound (0.17 g, 36%).

Example 173D
1-Benzyl-5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2H-thieno [2,3-d] [1,3] oxazine-2,4 (1H) -dione Example 3A The title compound was prepared according to the procedure of Example 3B using the product of Example 173C in place of the product of (0.015 g, 83%). _{MS (DCI / NH 3) m} / z404 (M + H) +.

Example 173E
7-Benzyl-5- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-3- (hydroxymethyl) -7,7A-dihydrothieno [2, 3-b] pyridin-6 (3AH) -one The title compound was prepared according to the procedure of Example 1D using the product of Example 173D in place of the product of Example 1B (0.013 g, 8%). .

Example 174
1-Benzyl-3- (6-chloro-1,1-dioxide-4H-thieno [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine -2 (1H) -ON
Example 174A
The title compound is prepared according to the procedure of the 3-amino-5-chlorothiophene-2-sulfonamide literature (Hansen, J. and coworkers, J. of Medicinal Chemistry 2002, 45, 4171-4187).

Example 174B
N- [2- (Aminosulfonyl) -5-chlorothien-3-yl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide Example 84A Follow the procedure of Example 84C using the product of Example 174A instead of the product and 3-amino-5-chlorothiophene-2-sulfonamide instead of 2-amino-5-bromobenzenesulfonamide. The title compound is produced.

Example 174C
1-Benzyl-3- (6-chloro-1,1-dioxide-4H-thieno [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine -(1H) -one The title compound is prepared according to the procedure of Example 84D, substituting the product of Example 174B for the product of Example 84C.

Example 175
1-Benzyl-3- (6-chloro-1,1-dioxide-4H-thieno [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxyquinoline-2 (1H) -ON
Example 175A
N- [2- (Aminosulfonyl) -5-chlorothien-3-yl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide instead of the product of Example 84A The title compound is prepared according to the procedure of Example 84C using the product of Example 174A, substituting the product of Example 99A for the product of Example 84B. Example 175B

1-Benzyl-3- (6-chloro-1,1-dioxide-4H-thieno [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxyquinoline-2 (1H) - using the product of example 175A instead of the product of one example 84C, the title compound is prepared according to the procedure of example 84D.

Example 176
3- [5- (Aminomethyl) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1-benzyl-4-hydroxy-1,8-naphthyridine-2 ( 1H) -one A mixture of the product of Example 97 (91.6 mg, 0.2002 mmol) and Raney-Nickel (0.94 g) in tetrahydrofuran (92 mL) and triethylamine (4.5 mL) was added at about 0.41 MPa (60 psi). ) Hydrogenated at 50 ° C. for 2 days at H ₂ pressure, and additional Raney-nickel (0.94 g) was added after 24 hours. The reaction was cooled to room temperature, filtered and concentrated on a rotary evaporator to give a greenish-yellow solid. The residue was washed on a Waters Symmetry C8 column (40 mm × 100 mm, particle size using a gradient of 10% to 100% acetonitrile / 0.1% aqueous TFA in 12 minutes (15 minutes elution time) at a flow rate of 70 mL / min. Purification by preparative HPLC at 7 μm) gave the title compound as a white solid (11 mg, 12%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 177
8-Benzyl-3-chloro-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -5-hydroxypyrido [2,3-c] pyridazine-7 (8H) -ON
Example 177A
A solution of 3- (benzylamino) -6-chloropyridazine-4-carboxylic acid 2,5-dichloro-pyrididine-3-carboxylate (0.40 g, 2.07 mmol) in toluene (8 mL) was stirred at 90 ° C. for 8 hours. Was reacted with triethylamine (0.72 mL, 5.20 mmol) and benzylamine (0.23 mL, 2.07 mmol). The solution was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (0.257 g, 47%). _{MS (DCI / NH 3) m} / z264 (M + H +) +.

Example 177B
8-Benzyl-3-chloro-5H-pyridazino [3,4-d] [1,3] oxazine-5,7 (8H) -dione Substituting the product of Example 177A for the product of Example 108B The title compound is prepared according to the procedure of Example 108C.

Example 177C
8-Benzyl-3-chloro-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -5-hydroxypyrido [2,3-c] pyridazine-7 (8H) -one The title compound is prepared according to the procedure of Example 1D, substituting the product of Example 177B for the product of Example 1B.

Example 178
8-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -5-hydroxy-3- (methylthio) pyrido [2,3-c] pyridazine- 7 (8H) -On The product of Example 177 is reacted with a toluene solution of methanethiol at elevated temperature. Concentrate the reaction to give the title compound.

Example 179
8-Benzyl-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -5-hydroxypyrido [2,3-c] pyridazine-7 (8H)- The title compound is prepared by the procedure of Example 109 substituting the product of Example 178 for the product of On Example 108D.

Example 180
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,6-naphthyridin-2- (1H) -one
Example 180A
From 3-carbomethoxy-4-chloropyridine and benzylamine according to the procedure of methyl 4- (benzylamino) nicotinate (Winn, et. Al., J. Med. Chem., 36, 1993, 2676-2688) The title compound is produced.

Example 180B
1-Benzyl-2H-pyrido [4,3-d] [1,3] oxazine-2,4 (1H) -dione Example 1 substituting the product of Example 180A for the product of Example 3A The title compound is prepared according to the procedure of 3B.

Example 180C
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,6-naphthyridin-2 (1H) -one Example 1B The title compound is prepared according to the procedure of Example 1D, substituting the product of Example 180B for the product of

Example 181
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,7-naphthyridin-2 (1H) -one
Example 181A
2H-pyrido [3,4-d] [1,3] oxazine-2,4 (1H) -dione The title compound is prepared from 3-aminoisonicotinic acid according to the procedure of Example 110A.

Example 181B
1-Benzyl-2H-pyrido [3,4-d] [1,3] oxazine-2,4 (1H) -dione, respectively, using the product of Example 181A in place of the product of Example 1A, DMA The title compound is prepared according to the procedure of Example 1B using DMF instead of and benzyl bromide instead of n-butyl bromide.

Example 181C
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,7-naphthyridin-2 (1H) -one Example 1B The title compound is prepared according to the procedure of Example 1D using the product of Example 181C in place of the product of

Example 182
1- (Benzylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2- (1H) -one of Example 162 A slurry of the product (0.133 g, 0.3 mmol) and 10% palladium / carbon (0.02 g, catalytic amount) in THF (25 mL) was hydrogenated under 1 atmosphere of hydrogen for 4 hours, filtered through celite, The filtrate was concentrated. The residue was slurried in 1 mL DMSO / 5 mL MeOH for 15 min and the solid was collected by filtration and dried in vacuo to give the title compound (0.08 g, 60%). MS (ESI-) m / z445 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 183A
The title compound was prepared from 4-methoxyaniline using the procedure described in the 2-amino-5-methoxybenzenesulfonamide literature (Journal of the Chemical Society, Perkin 1, 1979, 1043).

Example 183B
(7-Methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) ethyl acetate The product of Example 183A (0.534 g, 2.64 mmol) and triethylamine (0. Ethylmalonyl chloride (0.39 mL, 3.04 mmol) was added dropwise to a solution of 44 mL, 3.17 mmol) in anhydrous methylene chloride (8 mL) at 0 ° C. under nitrogen. The resulting mixture was stirred at 25 ° C. for 6 hours. The reaction mixture was diluted with 1N HCl (30 mL) and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the resulting brown solid was recrystallized from methylene chloride / methanol to give a pink solid (420 mg). The solid was treated with a solution of anhydrous sodium carbonate (700 mg, 6.65 mmol) in dehydrated ethanol (15 mL) and heated to reflux for 7 hours. The solid was filtered off and the filtrate was concentrated to give the title compound as a white solid (420 mg, total yield of 2 steps, 50%).

Example 183C
4-hydroxy-3- (7-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (3-methylbutyl) -1,8-naphthyridine-2 (1H) -one A solution of the product of Example 183B (0.5 g, 1.6 mmol) and the product of Example 12A (0.375 g, 1.6 mmol) in dehydrated THF (16 mL) at 0 ° C. under nitrogen. Sodium hydride (95%, 0.162 g, 6.4 mmol) was added. The reaction was heated to reflux for 4 hours, cooled to 0 ° C., and glacial acetic acid (3 mL) was added dropwise. The resulting mixture was heated to reflux for 2 hours, cooled to 25 ° C., and diluted with ice water (150 mL). The resulting precipitate was collected by filtration, washed with water and recrystallized from dioxane / water to give the title compound (566 mg, 80%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 184
4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (3-methylbutyl) -1,8-naphthyridine-2 (1H) -one A solution of the product of Example 183C (0.027 g, 0.061 mmol) in methylene chloride (0.6 mL) was added boron tribromide (1.0 M, 0.37 mL, 18 h at 25 ° C.). 0.37 mmol) in methylene chloride solution. The reaction was quenched with methanol and stirred at 25 ° C. for 30 minutes. The reaction was concentrated under reduced pressure to give the title compound as a solid (20.4 mg, 78%). The disodium salt of the title compound was prepared according to the procedure of Example 1D using 2 equivalents of sodium hydroxide.

Example 185
({3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl} oxy) acetonitrile A solution of the product of Example 184 (0.050 g, 0.12 mmol) in N, N-dimethylformamide (1 mL) was added at 25 ° C. over 30 hours over a period of 30 hours. Reacted with bromoacetonitrile (14 μL, 0.2 mmol), potassium carbonate (0.029 g, 0.22 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water (50 mL) and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with hexane and methylene chloride to give the title compound as a pale yellow solid (16.8 mg, 30%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 186
3- (1,1-Dioxide-7-propoxy-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -1,8-naphthyridine-2 (1H) -one A solution of the product of Example 184 (0.030 g, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added to 1-bromopropane (0.025 mL, .0. 28 mmol), potassium carbonate (60 mg, 0.42 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from methylene chloride: hexane to give the title compound (14 mg, 43%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 187
4-hydroxy-3- [7- (methoxymethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- (3-methylbutyl) -1,8- Naphthyridin-2 (1H) -one A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added bromo (methoxy) methane (0.021 mL, 0.28 mmol), potassium carbonate (38 mg, 0.28 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with 3: 1 hexane / ethyl acetate to give the title compound.

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 188
4-Hydroxy-1- (3-methylbutyl) -3- {7-[(2-methylprop-2-enyl) oxy] -1,1-dioxide-4H-1,2,4-benzothiadiazine-3 -Il} -1,8-naphthyridin-2 (1H) -one A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added at 25 ° C. over 24 hours. Reaction with bromo-2-methylprop-1-ene (8 μL, 0.077 mmol), potassium carbonate (60 mg, 0.42 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from methylene chloride: hexane to give the title compound (17.4 mg, 50%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 189
({3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl} oxy) tert-butyl acetate A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was stirred at 25 ° C. over 24 hours. Reaction was with tert-butyl acetate (0.04 mL, 0.28 mmol), potassium carbonate (0.04 g, 0.28 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with 3: 1 hexane / ethyl acetate to give the title compound (20 mg, 53%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 190
2-({3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl} oxy) acetamide A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added at 25 ° C. over 48 hours. Reacted with bromoacetamide (16 mg, 0.12 mmol), potassium carbonate (24 mg, 0.17 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with methylene chloride: hexane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 191
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (3-methylbutyl) -1,8- Naphthyridin-2 (1H) -one A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added (bromomethyl) benzene (0.0138 mL, 0 mL) at 25 ° C. for 96 hours. .11 mmol), cesium carbonate (50 mg, 0.15 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate to give the title compound (13 mg, 36%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 192
3- [1,1-Dioxide-7- (2-pyrrolidin-1-ylethoxy) -4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (3-methylbutyl) -1,8-naphthyridin-2 (1H) -one A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was stirred at 25 ° C. for 72 hours with 1- (2- Reaction with chloroethyl) pyrrolidine hydrochloride (19 mg, 0.11 mmol), potassium carbonate (96 mg, 0.69 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with 5% methanol / methylene chloride to give the title compound. The potassium salt of the title compound was prepared according to the procedure of Example 1D using potassium hydroxide instead of sodium hydroxide.

Example 193
3- [1,1-Dioxide-7- (2-oxo-2-phenylethoxy) -4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (3-methylbutyl ) -1,8-naphthyridin-2 (1H) -one A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added 2-bromo- over 96 hours at 25 ° C. Reaction with 1-phenylethanone (30 mg, 0.15 mmol), potassium carbonate (60 mg, 0.42 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with 0.2% methanol / methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 194
3- [7- (Allyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (3-methylbutyl) -1,8-naphthyridine -(1H) -one A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added 3-iodoprop-1-ene (0.007 mL) at 25 ° C. for 96 hours. 0.077 mmol), potassium carbonate 60 mg, 0.42 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with hexane to give the title compound.

Example 195
4-Hydroxy-3- (7-isobutoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (3-methylbutyl) -1,8-naphthyridine-2 (1H) -one A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added to 1-bromo-2-methylpropane (0.034 mL, 0.3 mmol), potassium carbonate (60 mg, 0.42 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from hexane: methylene chloride to give the title compound (10.5 mg, 31%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 196
4-({3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl} oxy) butanenitrile A solution of the product of Example 184 (30 mg, 0.07 mmol) in N, N-dimethylformamide (1 mL) was added over 4 hours at 25 ° C. over 96 hours. Reaction with bromobutanenitrile (0.0154 mL, 0.15 mmol), potassium carbonate (60 mg, 0.42 mmol) and tetrabutylammonium iodide (catalytic amount). The reaction mixture was diluted with water and acidified to pH 5 with concentrated acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from hexane: methylene chloride to give the title compound (21.8 mg, 62%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 197
({3- [1- (3-Methylbutyl) -4-oxide-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl] oxy) acetate A solution of the product of Example 189 (15 mg, 0.028 mmol) in a mixture of trifluoroacetic acid (0.8 mL) and methylene chloride (0.2 mL) Stir at 25 ° C. for 2 hours. The solvent was removed under reduced pressure to give a yellow solid that was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The aqueous layer was acidified with 1N HCl to pH 2 and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (8 mg, 62%). The disodium salt was prepared according to the procedure of Example 1D using 2 equivalents of sodium hydroxide.

Example 198
3- [7- (2-aminoethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (3-methylbutyl) -1, 8-Naphthyridin-2 (1H) -one A solution of the product of Example 185 (21.8 mg, 62%) in anhydrous tetrahydrofuran (0.5 mL) was treated with LiBH ₄ (10 mg, 0.46 mmol) and treated at room temperature for 16 Stir for hours, dilute with water (30 mL) and extract with ethyl acetate (2 x 30 mL). The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The slurry was filtered and the solvent removed under reduced pressure to give the title compound as a yellow solid (10.1 mg, 97%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 199
2-({3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl} oxy) -N-methylacetamide Example 197 (4.7 mg, 0.0097 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 1.4 mg, 0.01 mmol), a solution of methylamine in tetrahydrofuran (2.0 M, 10 μL, 0.02 mmol) and 1-hydroxybenzotriazole (1.4 mg, 0.01 mmol) in N, N-dimethylformamide (0. The mixture in 2 mL) was stirred at 25 ° C. for 5 hours. The reaction mixture is diluted with ethyl acetate (40 mL), washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate. The dehydrating agent was removed by filtration and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (4 mg, 83%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 200
Acetic acid 3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2,4 A mixture of benzothiadiazin-7-yl Example 184 (30 mg, 0.07 mmol), triethylamine (12 μL, 0.084 mmol) and acetic anhydride (8 μL, 0.084 mmol) in dehydrated methylene chloride (1 mL) Stir at 16 ° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and water, acidified to pH 5 with acetic acid and partitioned. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with saturated sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to give the title compound as a white solid (29.5 mg, 89%).

Example 201
3- [1,1-Dioxide-7- (pyridin-2-yloxy) -4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (3-methylbutyl) -1 , 8-naphthyridin-2 (1H) -one The product of Example 184 (10 mg, 0.023 mmol) was treated with 2-bromo in dimethyl sulfoxide (0.1 mL) at 110 ° C. in a microwave reactor for 2 hours. Reaction with pyridine (2.4 μL, 0.025 mmol), cesium carbonate (15 mg, 0.046 mmol) and metallic copper (40 mg). The mixture was cooled to 25 ° C., poured into water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to give a tan solid. The solid was chromatographed on silica gel eluting first with methylene chloride and then 1% methanol / methylene chloride to give the title compound as a light brown solid (5 mg, 42%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 202
3- [1,1-Dioxide-7- (pyrimidin-2-yloxy) -1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (3-methylbutyl) -1,8 -Naphthyridin- 2 (1H) -one The product of Example 184 (10 mg, 0.023 mmol) was treated with 2-bromo in dimethyl sulfoxide (0.1 mL) in a microwave reactor at 110 ° C. for 1 hour. Reacted with pyrimidine (4.5 mg, 0.028 mmol), cesium carbonate (15 mg, 0.046 mmol) and tetrabutylammonium iodide (1 mg). The mixture was cooled to 25 ° C., poured into water (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to give a tan solid. The solid was chromatographed on silica gel eluting first with methylene chloride and then 2% methanol / methylene chloride to give the title compound as a white solid (6 mg, 51%). The sodium salt of the title compound was prepared according to the procedure described in Example 1D.

Example 203
2-({3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl} oxy) -N, N-dimethylacetamide The title according to the procedure of Example 185, substituting 2-chloro-N, N -dimethylacetamide for 2 -bromoacetonitrile. The compound was prepared. The compound was purified by trituration with methanol. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 204
4-Hydroxy-1- (3-methylbutyl) -3- (7-nitro-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H) -On while stirring the product of Example 12B (0.229 g, 0.56 mmol) at 0 ° C. in concentrated sulfuric acid (1.5 mL) at 0 ° C. for 30 minutes, ammonium nitrate (0.058 g, 0.72 mmol). The reaction mixture was poured into crushed ice and the pH was adjusted to 9 with aqueous sodium hydroxide. The resulting solid was isolated by filtration to give the title compound (0.21 g, 81%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 205 RZ
3- (7-Amino-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -1,8-naphthyridine-2 (1H) -one Methanol: tetrahydrofuran of the product of Example 204 (0.198 g, 0.43 mmol), iron powder (0.121 g, 2.16 mmol) and NH ₄ Cl (0.031 g, 0.58 mmol): The mixture in water (3: 3: 1, 7 mL) was stirred at reflux for 9 hours. The reaction mixture was cooled to 25 ° C. and the iron was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (0.121 g, 66%).

Example 206
({3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl} amino) acetonitrile To a solution of the product from Example 205 (10 mg, 0.023 mmol) in N, N-dimethylformamide (0.2 mL) was added bromoacetonitrile (2.5 μL, 0.035 mmol) and potassium carbonate (5 mg, 0.035 mmol) were added. The mixture was stirred while heating at 100 ° C. for 1 hour in a 100 ° C. microwave reactor. After cooling to 25 ° C., the orange-red solution was diluted with water and the pH of the aqueous layer was adjusted to pH 5 with acetic acid. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers are washed with water and brine, dried over magnesium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel eluting with 1% methanol / methylene chloride to give the title compound. Obtained as a yellow solid (6.0 mg, 55%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 207
7-hydroxy-6- (7-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- (3-methylbutyl) thieno [3,2-b] Pyridine-5 (4H) -one The procedure of Example 1D using the product of Example 125A in place of the product of Example 1B and using the product of Example 183B in place of the product of Example 1C. The title compound was prepared according to The sodium salt was prepared according to the procedure of Example 1D.

Example 208
4-Benzyl-7-hydroxy-6- (7-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -thieno [3,2-b] pyridine-5 (4H) -On The title compound according to the procedure of Example 1D, substituting the product of Example 110B for the product of Example 1B and substituting the product of Example 183B for the product of Example 1C. Manufactured. The sodium salt was prepared according to the procedure of Example 1D.

Example 209A
The title compound was prepared from 3-methoxy-6-methyl-aniline using the procedure described in the 2-amino-6-methoxy-3-methylbenzenesulfonamide literature (JCS Perkin 1, 1979, 1043).

Example 209B
N- [2- (Aminosulfonyl) -3-methoxy-6-methylphenyl] -1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide Example 84A The title compound was prepared according to the procedure of Example 84C using the product of Example 209A in place of the product of to give the title compound (0.22 g, 100%).

Example 209C
1-Benzyl-3- (8-methoxy-5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -one The title compound was prepared according to the procedure of Example 84D, substituting the product of Example 209B for the product of Example 84C. The solution was acidified with 6N aqueous HCl (10 mL), filtered, and the solid was washed with methanol (10 mL) to give the title compound as a white solid (0.12 g, 56% yield). MS (ESI-) m / z 477 (M-H) ^<+> . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 210
1-Benzyl-3- (8-hydroxy-5-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H) -one A mixture of the product of Example 209C (20 mg, 0.042 mmol) and boron tribromide (1.0 M in methylene chloride) (840 μL, 0.84 mmol) in dichloroethane (5 mL) at 70 ° C. Stir for 16 hours. The reaction mixture was cooled to 25 ° C., quenched with water (10 mL) and extracted with ethyl acetate (20 mL). The resulting organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a white solid (0.019 g, 98% yield). MS (ESI-) m / z 463 (M-H) ^<+> . The disodium salt of the title compound was prepared according to the procedure of Example 1D using 2 equivalents of sodium hydroxide.

Example 211
{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -5-methyl-1,1-dioxide-4H-1,2, 4-Benzothiadiazin-8-yl] oxy} acetonitrile The product of Example 210 (23 mg, 0.050 mmol), bromoacetonitrile (14 μL, 0.2 mmol) and potassium carbonate (15 mg, 0.11 mmol) N, The mixture in N-dimethylformamide (1 mL) was stirred at 25 ° C. for 3 days. The reaction mixture was concentrated under reduced pressure and the resulting oil was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid (0.003 g, 12% yield). MS (ESI-) m / z500 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 212A
The title compound was prepared from 2-methoxyaniline using the procedure described in the 2-amino-3-methoxybenzenesulfonamide literature (Journal of Chemical Society, Perkin 1, 1979, 1043).

Example 212B
(5-Methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) ethyl acetate Performed using the product of Example 212A instead of 2-aminobenzenesulfonamide The title compound was prepared according to the procedure of Example 1C. . MS (DCI) m / z 299 (M + H) ^<+> . Example 212C

1-Benzyl-4-hydroxy-3- (5-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- The title compound is prepared according to the procedure described in Example 1D using the product of Example 15A in place of the product of Example 1B and the product of Example 212B in place of the product of Example 1C. (187 mg, 41%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 213
1-Benzyl-4-hydroxy-3- (5-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure described in Example 184 using the product of Example 212C instead of the product of On Example 183C. (ESI−) m / z 447 (M−H) ⁻ . The disodium salt of the title compound was prepared according to the procedure of Example 1D using 2 equivalents of sodium hydroxide.

Example 214A
{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzothi [Asiadin-5-yl] oxy} acetonitrile The title compound was prepared according to the procedure described in Example 185, substituting the product of Example 213 for the product of Example 184.

Example 214B
3- [5- (2-Aminoethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1-benzyl-4-hydroxy-1,8-naphthyridine- 2 (1H) -one The title compound was prepared according to the procedure described in Example 198 using the product of Example 214A in place of the product of Example 185. (ESI−) m / z 490 (M−H) ⁻ . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 215
2-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4- Benzothiadiazin-5-yl] oxy} acetamide The title compound was prepared according to the procedure described in Example 190, substituting the product of Example 213 for the product of Example 184. (ESI−) m / z 504 (M−H) ⁻ . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 216
1-benzyl-4-hydroxy-3- {5-[(4-nitrobenzyl) oxy] -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl} -1,8 -Naphthyridin-2 (1H) -one The procedure described in Example 185, substituting the product of Example 213 for the product of Example 184 and using para-nitrobenzyl bromide for 2-bromoacetonitrile. The title compound was prepared according to (ESI−) m / z 582 (M−H) ⁻ . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 217A
N- [2- (aminosulfonyl) phenyl] -1-benzyl-6-chloro-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide To the product of Example 84B Instead of ethyl 1-benzyl-6-chloro-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate instead of the product of Example 84A 2-amino The title compound was prepared according to the procedure of Example 84C using benzenesulfonamide.

Example 217B
1-Benzyl-6-chloro-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D, substituting the product of Example 217A for the product of On Example 84C. The sodium salt of the title compound was prepared according to the procedure described in Example 1D.

Example 218A
N- [2- (aminosulfonyl) phenyl] -1-benzyl-4-hydroxy-2-oxo-6-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxamide To the product of Example 84B Instead of 1-benzyl-6-phenyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate instead of the product of Example 84A, 2-amino The title compound was prepared according to the procedure of Example 84C using benzenesulfonamide.

Example 218B
1-Benzyl-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-6-phenyl-1,8-naphthyridine-2 (1H)- The title compound was prepared according to the procedure of Example 84D, substituting the product of Example 218A for the product of On Example 84C. MS (ESI-) m / z507 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure described in Example 1D.

Example 219A
The title compound was prepared according to the procedure described in the 2-amino-4-methoxybenzenesulfonamide literature (Topliss et al, J. Med. Chem. 6, 1963, 122).

Example 219B
(6-Methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) ethyl acetate Performed using the product of Example 219A instead of 2-aminobenzenesulfonamide The title compound was prepared according to the procedure of Example 1C. MS (DCI) m / z 299 (M + H) ^<+> .

Example 219C
1-Benzyl-4-hydroxy-3- (6-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- The title compound is prepared according to the procedure described in Example 1D using the product of Example 15A instead of the product of Example 1B and the product of Example 219B instead of the product of Example 1C. did. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 220A
The title compound was prepared according to the procedure described in the N- [3-amino-4- (aminosulfonyl) phenyl] acetamide literature (Topliss et al, J. Med. Chem. 6, 1963, 122).

Example 220B
[6- (acetylamino) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] ethyl acetate In place of 2-aminobenzenesulfonamide, the product of Example 220A was used. The title compound was prepared according to the procedure described in Example 1C. MS (DCI) m / z 326 (M + H) ^<+> .

Example 220C
N- [3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-6-yl] acetamide Example 1D using the product of Example 15A in place of the product of Example 1B and the product of Example 220B in place of the product of Example 1C The title compound was prepared according to the described procedure. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 221
1-Benzyl-4-hydroxy-3- (6-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- A mixture of the product of On Example 219C (20 mg, 0.043 mmol) and boron tribromide (1.0 M in methylene chloride, 20 eq) in 1,2 dichloroethane (5 mL) was stirred at reflux for 28 hours. The reaction mixture was cooled to 25 ° C., diluted with tetrahydrofuran and 1N aqueous HCl and refluxed for 2 hours. The resulting solid was collected by filtration and dried to give the title compound (11.3 mg). The disodium salt of the title compound was prepared according to the procedure of Example 1D using 2 equivalents of sodium hydroxide.

Example 222A
The title compound 2-amino-6-methylbenzenesulfonamide was prepared according to the procedure described in the literature (Topliss et al, J. Med. Chem. 6, 1963, 122).

Example 222B
Example 1C substituting the product of Example 222A for (8-methyl-1,1-dioxide-4H-12,4-benzothiadiazin-3-yl) ethyl acetate 2-aminobenzenesulfonamide The title compound was prepared according to the procedure of

Example 222C
1-Benzyl-4-hydroxy-3- (8-methyl-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1,8-naphthyridine-2 (1H)- The title compound is prepared according to the procedure described in Example 1D using the product of Example 15A in place of the product of On Example 1B and the product of Example 222B in place of the product of Example 1C. (35.8 mg, 10%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 223
4-hydroxy-3- (5-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (3-methylbutyl) -1,8-naphthyridine-2 (1H) -On The title compound according to the procedure of Example 1D, substituting the product of Example 12A for the product of Example 1B and substituting the product of Example 212B for the product of Example 1C. Manufactured. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 224
7-Hydroxy-6- (5-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4- (3-methylbutyl) thieno [3,2-b] Pyridine-5 (4H) -one The procedure of Example 1D using the product of Example 125A in place of the product of Example 1B and using the product of Example 212B in place of the product of Example 1C. The title compound was prepared according to The sodium salt of the title compound was prepared according to the procedure described in Example 1D.

Example 225
4-Benzyl-7-hydroxy-6- (5-methoxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) thieno [3,2-b] pyridine-5 ( 4H) -one The title compound is obtained according to the procedure of Example 1D, substituting the product of Example 110B for the product of Example 1B and substituting the product of Example 212B for the product of Example 1C. Manufactured. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 226A
A solution of methyl 2- [2-benzylidenehydrazino] benzoate 2- (N′-benzylidene-hydrazino) -benzoic acid (5.0 g, 20.81 mmol) in 1: 1 tetrahydrofuran and methanol (50 mL) at 0 ° C. Reaction with hexane solution of trimethylsilyldiazomethane (2.0 M, 12 mL, 25.0 mmol) for 1 hour, then stirred at 25 ° C. for 48 hours. The solvent was removed under reduced pressure to give the title compound as a solid (6.00 g, 100%).

Example 226B
Methyl 2- [2-benzylidene-1- (3-ethoxy-3-oxopropanoyl) hydrazino] benzoate A solution of the product of Example 226A (5.29 g, 20.81 mmol) in toluene (80 mL) was refluxed. For 4 hours with ethyl chloromalonate (2.68 mL, 25.0 mmol). The reaction mixture was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with diethyl ether and hexane (3: 1) to give the title compound (5.17 g, 70%).

Example 226C
Ethyl 4-hydroxy-2-oxo-1-{[phenylmethylene] amino} -1,2-dihydroquinoline-3-carboxylate The product of Example 226B (5.17 g, 14.59 mmol) in ethanol (100 mL). The solution was reacted with sodium (21 wt% in ethanol, 5.50 mL, 14.60 mmol) at 25 ° C and heated at 50 ° C for 1 hour. After cooling to 25 ° C., the reaction mixture was poured into water, acidified to pH 4 with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound (4.51 g, 96%).

767087 Example 226D PKD
1-amino-3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Product of Example 226C (4 .51 g, 14.00 mmol) was reacted with 2-aminobenzenesulfonamide (2.41 g, 14.00 mmol) in toluene (65 mL) at reflux for 6 hours. After cooling to 25 ° C., the solid (5.52 g) was collected by filtration and further reacted with 10% aqueous potassium hydroxide (100 mL) at 130 ° C. for 8 hours. After cooling to 25 ° C., the reaction mixture was poured into ice and acidified to pH 2 with 1M hydrochloric acid. The resulting solid was isolated by filtration and dried to give the title compound (3.50 g, 71%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 227A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1-propylbutylidene) amino] quinoline-2 (1H)- The product of On Example 226D (0.080 g, 0.22 mmol) was added in 4-heptanone (0 mL) in N, N-dimethylacetamide (1 mL) in a microwave reactor at 135 ° C. for 45 minutes in a sealed tube. .63 mL, 4.49 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound as a solid (0.032 g, 32%). MS (ESI-) m / z 453 (MH) ^- .

Example 227B
1- (1-propyl-butylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 227A (0.032 g, 0.07 mmol) in tetrahydrofuran (2 mL) and methanol (0.010 mL, 0.14 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran (0.055 mL). , 0.11 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was suspended in tetrahydrofuran (2 mL), adsorbed on about 0.5 g of silica gel, and the solvent was distilled off. The crude product and silica slurry in methylene chloride was loaded onto an Alltech Sep-pack and eluted with methylene chloride. Fractions containing product were combined and concentrated under reduced pressure to give the title compound (0.013 g, 40%). MS (ESI-) m / z 453 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 228A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[2-methylpropylidene] amino} quinoline-2 (1H)- The product of On Example 226D (0.178 g, 0.50 mmol) was added to 2-methylpropanal (3 mL) in N, N-dimethylacetamide (3 mL) in a sealed tube at 135 ° C. for 45 min. 0.9 mL, 10.0 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 228B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one Production of Example 228A Product (0.132 g, 0.32 mmol) in tetrahydrofuran (6 mL) and methanol (0.026 mL, 0.64 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran (0.24 mL, 0.48 mmol). ). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (12 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with 1: 1 ethyl acetate: hexane (10 mL) and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 229A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(1-ethylpropylidene) amino] -4-hydroxyquinoline-2 (1H)- On The product of Example 226D (0.178 g, 0.5 mmol) was added in pentane-3-one (4 mL) in N, N-dimethylacetamide (4 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. 0.53 mL, 5.0 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 229B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(1-ethylpropyl) amino] -4-hydroxyquinolin 2 (1H) -one A solution of the product of Example 229A (0.122 g, 0.287 mmol) in tetrahydrofuran (8 mL) and methanol (0.023 mL, 0.57 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran (0.215 mL). , 0.43 mmol). The reaction was stirred at 25 ° C. for 2 hours, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 98: 2 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 230A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [ pentylideneamino ] quinolin-2 (1H) -one of Example 226D The product (0.05 g, 0.14 mmol) was pentanal (0.015 mL, 1.4 mmol) in N, N-dimethylacetamide (2 mL) in a microwave reactor for 45 minutes at 135 ° C. in a sealed tube. And reacted. The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 230B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (pentylamino) quinolin-2 (1H) -one Production of Example 203A Product (0.034 g, 0.08 mmol) in tetrahydrofuran (2 mL) and methanol (0.0064 mL, 0.16 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran (0.06 mL, 0.12 mmol). ). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 98: 2 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 231A
1- (cyclohexylideneamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Example 226D Product (0.155 g, 0.60 mmol) was reacted with cyclohexanone (20 molar equivalents) in N, N-dimethylacetamide (2 mL) in a microwave reactor in a sealed tube at 135 ° C. for 60 minutes. It was. The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 231B
1- (cyclohexylamino) -3- (1,1-dioxide-4H-1,2.4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Production of Example 231A Product (0.087 g, 0.2 mmol) in tetrahydrofuran (4 mL) and methanol (0.016 mL, 0.4 mmol) at 0 ° C., 2.0 M lithium borohydride in tetrahydrofuran (0.15 mL, 0.3 mmol) ). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH ˜2-4, diluted with water (5 mL), and the resulting precipitate was collected by filtration and dried to give the title compound. . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 232A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(2-methyl-1,3-thiazol-4-yl) Methylene] amino} quinolin-2 (1H) -one The product of Example 226D (0.119 g, 0.33 mmol) was added to N, N-dimethyl in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. Reacted with 2-methyl-1,3-thiazole-4-carbaldehyde (5 molar equivalents) in acetamide (3 mL). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 232B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(2-methyl-1,3-thiazol-4-yl) Methyl] amino} quinolin-2 (1H) -one A solution of the product of Example 232A (0.097 g, 0.208 mmol) in tetrahydrofuran (5 mL) and methanol (0.016 mL, 0.40 mmol) at 0 ° C. Treated with dropwise addition of 0.0M lithium borohydride in tetrahydrofuran (0.15 mL, 0.3 mmol). The reaction was stirred at 25 ° C. for 3 hours, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on a C-18 reverse phase column eluting with water: acetonitrile 90:10 to 0: 100 to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 233A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1-methylethylidene) amino] quinolin-2 (1H) -one The product of Example 226D (0.080 g, 0.22 mmol) was added in acetone (0. 0 mL) in N, N-dimethylacetamide (1.0 mL) in a microwave reactor in a sealed tube at 125 ° C. for 25 minutes. 34 mL, 4.50 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 233B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (isopropylamino) quinolin-2 (1H) -one Production of Example 233A Product (0.044 g, 0.11 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran (0.085 mL, 0 mL). .17 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 234A
1- (Cyclobutylideneamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Example 226D Of the product (0.080 g, 0.22 mmol) in cyclobutanone (0.50 mL, 7) in N, N-dimethylacetamide (0.50 mL) in a microwave reactor at 125 ° C. for 40 minutes in a sealed tube. .10 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 234B
1- (Cyclobutylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one of Example 234A A solution of the product (0.032 g, 0.078 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0 ° C. was added 2.0 M lithium borohydride in tetrahydrofuran (0.025 mL, 0.0550 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 235A
1- (Cyclopentylideneamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Example 226D Product (0.079 g, 0.22 mmol) in cyclopentanone (0.195 mL) in N, N-dimethylacetamide (1.50 mL) in a microwave reactor at 130 ° C. for 30 minutes in a sealed tube. , 2.22 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 235B
1- (Cyclopentylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Production of Example 235A Product (0.030 g, 0.071 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0 ° C., 2.0 M lithium borohydride in tetrahydrofuran (0.060 mL, 0 mL). .12 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH ˜2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 236A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[3-methylcyclopentylidene] amino} quinoline-2 (1H) - the product of example 226D (0.080 g, 0.22 mmol) and, in a microwave reactor over at 135 ° C. 40 min in a sealed tube in N, N- dimethylacetamide (1.0 mL) 3- Reacted with methylcyclopentanone (0.50 mL, 5.09 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 236B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[3-methylcyclopentyl] amino} quinolin-2 (1H) -one A solution of the product of Example 236A (0.068 g, 0.16 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.100 mL, 0.20 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 237A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (tetrahydro-4H-pyran-4-ylideneamino) quinoline-2 (1H) On product of Example 226D (0.080 g, 0.22 mmol) was tetrahydro-in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 130 ° C. for 35 minutes in a sealed tube. Reaction with 4H-pyran-4-one (0.215 mL, 2.33 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 237B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (tetrahydro-2H-pyran-4-ylamino) quinoline-2 (1H) On solution of the product of Example 237A (0.082 g, 0.19 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0 ° C., 2.0 M lithium borohydride in tetrahydrofuran Treated dropwise with solution (0.140 mL, 0.28 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 238A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[1-ethylbutylidene] amino} -4-hydroxyquinoline-2 (1H)- The product of On Example 226D (0.085 g, 0.24 mmol) was hexane-3 in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 140 ° C. for 60 minutes in a sealed tube. Reaction with -one (0.55 mL, 4.48 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 238B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[1-ethylbutyl] amino} -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 238A (0.049 g, 0.11 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran (0 .152 mL, 0.30 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH ˜2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 239A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(3R) -3-methylcyclohexylidene] amino} quinoline- 2 (1H) -one The product of Example 226D (0.080 g, 0.22 mmol) was added to N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 130 ° C. for 35 minutes in a sealed tube. In (3R) -3-methylcyclohexanone 0.275 mL, 2.25 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 239B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(3R) -3-methylcyclohexyl] amino} quinoline-2 ( 1H) -On A solution of the product of Example 239A (0.045 g, 0.10 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0 ° C., 2.0 M lithium borohydride. Was treated dropwise with a tetrahydrofuran solution (0.075 mL, 0.15 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH ˜2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 240A
The title compound was prepared according to the procedure described in Example 162A substituting cycloheptanone for 2- (2-cycloheptylidenehydrazino) benzoic acid benzaldehyde.

Example 240B
1- (Cycloheptylideneamino) -2H-3,1-benzoxazine-2,4 (1H) -dione Example 162B uses the product of Example 240A instead of the product of Example 162A. The title compound was prepared according to the described procedure.

Example 240C
1- (Cycloheptylideneamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Examples The title compound was prepared according to the procedure described in Example 1D, substituting the product of Example 240B for the product of 1B.

Example 240D
1- (Cycloheptylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one of Example 240C A solution of the product (0.099 g, 0.22 mmol) in tetrahydrofuran (4.0 mL) (0.099 g, 0.22 mmol) in tetrahydrofuran (4.0 mL) and methanol (0.020 mL, 0.49 mmol) at 0 ° C. , 2.0M lithium borohydride in tetrahydrofuran (0.16 mL, 0.32 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH ˜2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 241A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[3-ethylcyclopentylidene] amino} -4-hydroxyquinoline-2 (1H) - the product of example 226D (0.080 g, 0.22 mmol) and, in a microwave reactor over 35 minutes at 135 ° C. in a sealed tube in N, N- dimethylacetamide (1.0 mL) 3- Reacted with ethyl cyclopentanone (0.380 mL, 3.30 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 241B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[3-ethylcyclopentyl] amino} -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 241A (0.031 g, 0.068 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.25 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.055 mL, 0.11 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 242A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-isopropylbutylidene] amino} quinoline-2 (1H)- The product of ON Example 226D (0.080 g, 0.22 mmol) was added 2-methyl in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. Reacted with hexane-3-one (0.620 mL, 4.48 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 242B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-isopropylbutyl] amino} quinolin-2 (1H) -one A solution of the product of Example 242A (0.049 g, 0.11 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.25 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.085 mL, 0.17 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using to give methylene chloride, the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 243A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-phenylethylidene] amino} quinolin-2 (1H) -one The product of Example 226D (0.080 g, 0.22 mmol) was added in 1-phenylethane in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 135 ° C. for 40 minutes in a sealed tube. Reacted with non (0.49 mL, 4.20 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 243B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-phenylethyl] amino} quinolin-2 (1H) -one A solution of the product of Example 243A (0.093 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.152 mL, 0.30 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 244A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-thien-3-ylethylidene] amino} quinoline-2 ( 1H) -On product of Example 226D (0.080 g, 0.22 mmol) in N, N-dimethylacetamide (0.50 mL) in a microwave reactor at 135 ° C. for 45 min in a sealed tube. Reacted with 1-thien-3-ylethanone (0.14 g, 1.11 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 244B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1-thien-3-ylethyl] amino} quinoline-2 (1H ) -On a solution of the product of Example 244A (0.070 g, 0.15 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0 ° C. with 2.0 M lithium borohydride. Treated dropwise with tetrahydrofuran solution (0.090 mL, 0.18 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 245A
1-{[3,5-Dimethylcyclohexylideneamino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline-2 (1H ) -On the product of Example 226D (0.080 g, 0.22 mmol) was added in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 135 ° C. for 40 minutes in a sealed tube. , 5-dimethylcyclohexanone (0.57 g, 4.52 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 245B
1-{[3,5-dimethylcyclohexyl] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline-2 (1H) On solution of the product of Example 245A (0.064 g, 0.14 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.25 mmol) at 0 ° C., 2.0 M lithium borohydride in tetrahydrofuran Treated dropwise with solution (0.100 mL, 0.20 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 246A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[4-isopropylcyclohexylidene] amino} quinoline-2 (1H) On product of Example 226D (0.080 g, 0.22 mmol) in 4-, N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 135 ° C. for 45 min in a sealed tube Reacted with isopropylcyclohexanone (0.63 mL, 4.11 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 246B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(4-isopropylcyclohexyl) amino] quinolin-2 (1H) -one A solution of the product of Example 246A (0.095 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.150 mL, 0.30 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 247A
1- [3,4-Dihydronaphthalene-2 (1H) -ylideneamino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline- 2 (1H) -one The product of Example 226D (0.080 g, 0.22 mmol) was added to N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 135 ° C. for 45 minutes in a sealed tube. In a reaction with 3,4-dihydronaphthalen-2 (1H) -one (0.60 mL, 4.54 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 247B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- [1,2,3,4-tetrahydronaphthalen-2-ylamino] quinoline -2 (1H) -one A solution of the product of Example 247A (0.070 g, 0.14 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.25 mmol) at 0 ° C. and 2.0 M hydrogen. The solution was treated dropwise with a lithium solution of boron borohydride (0.110 mL, 0.22 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 248A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[3- (trifluoromethyl) cyclohexylidene] amino} quinoline- 2 (1H) -one The product of Example 226D (0.080 g, 0.22 mmol) was added to N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 135 ° C. for 40 minutes in a sealed tube. In the reaction with 3- (trifluoromethyl) cyclohexanone (0.75 mL, 4.54 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with diethyl ether and filtered to give the title compound.

Example 248B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[3- (trifluoromethyl) cyclohexyl] amino} quinoline-2 ( 1H) -On A solution of the product of Example 248A (0.103 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0 ° C., 2.0 M lithium borohydride. Was treated dropwise with a tetrahydrofuran solution (0.15 mL, 0.30 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 249A
1- [Butylidenamino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one of Example 226D The product (0.060 g, 0.168 mmol) was added in butyraldehyde (0.135 mL, 1 mL) in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. .50 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 249B
1- (Butylamino) -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one Production of Example 249A Product (0.040 g, 0.097 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.194 mmol) at 0 ° C., 2.0 M lithium borohydride in tetrahydrofuran (0.074 mL, 0 .148 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and washed with water (5. 0 mL twice) and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 250A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[3-methylbutylidene] amino} quinoline-2 (1H)- The product of On Example 226D (0.060 g, 0.168 mmol) was 3-methylated in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reacted with butanal (0.161 mL, 1.50 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 250B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(3-methylbutyl) amino] quinolin-2 (1H) -one A solution of the product of Example 250A (0.041 g, 0.097 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.194 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran (0 074 mL, 0.148 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 251A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[3-furylmethylene] amino} -4-hydroxyquinolin-2 (1H) -one The product of Example 226D (0.070 g, 0.196 mmol) was added to 3-furaldehyde in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. (0.147 mL, 1.78 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 251B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(3-furylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 251A (0.028 g, 0.064 mmol) in tetrahydrofuran (1.3 mL) and methanol (0.005 mL, 0.128 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( (0.050 mL, 0.100 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 252A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[2-furylmethylene] amino} -4-hydroxyquinolin-2 (1H) -one The product of Example 226D (0.070 g, 0.196 mmol) was treated with 2-furaldehyde in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. (0.147 mL, 1.78 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 252B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(2-furylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 252A (0.058 g, 0.134 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.010 mL, 0.268 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.105 mL, 0.210 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 253A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[thien-2-ylmethylene] amino} quinoline-2 (1H)- The product of On Example 226D (0.070 g, 0.196 mmol) was thiophene-2 in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reaction with carbaldehyde (0.166 mL, 1.78 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 253B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(thien-2-ylmethyl) amino] quinoline-2 (1H)- A solution of the product of On Example 253A (0.025 g, 0.055 mmol) in tetrahydrofuran (1.2 mL) and methanol (0.005 mL, 0.110 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. Treated with dropwise (0.044 mL, 0.088 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 254A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[1,3-thiazol-2-ylmethylene] amino} quinoline-2 (1H) -On The product of Example 226D (0.060 g, 0.168 mmol) in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. And reacted with 1,3-thiazole-2-carbaldehyde (0.132 mL, 1.5 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 254B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(1,3-thiazol-2-ylmethyl) amino] quinoline-2 (1H) -one A solution of the product of Example 254A (0.030 g, 0.066 mmol) in tetrahydrofuran (1.3 mL) and methanol (0.005 mL, 0.132 mmol) at 0 ° C. and 2.0 M borohydride. Treated dropwise with a solution of lithium in tetrahydrofuran (0.050 mL, 0.100 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 255A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[(2-ethyl-3-methylbutylidene] amino} -4-hydroxyquinoline- 2 (1H) -one The product of Example 226D (0.070 g, 0.196 mmol) was added to N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reacted with 2-ethyl-3-methylbutanal (0.110 mL, 0.733 mmol) in. The reaction mixture was cooled to 25 ° C. and concentrated The resulting residue was triturated with ethyl acetate. And filtered to give the title compound.

Example 255B
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-{[2-ethyl-3-methylbutyl] amino} -4-hydroxyquinoline-2 (1H ) -On a solution of the product of Example 255A (0.031 g, 0.069 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.006 mL, 0.138 mmol) at 0 ° C. with 2.0 M lithium borohydride. Treat with dropwise addition of tetrahydrofuran solution (0.054 mL, 0.108 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel eluting with 30% ethyl acetate / hexanes to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 256A
3- (1,1-dioxide-4H-1,2,3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[ (4-Methylphenyl) methylene] amino} quinolin-2 (1H) -one The product of Example 226D (0.070 g, 0.196 mmol) was placed in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reacted with 4-methylbenzaldehyde (0.210 mL, 1.78 mmol) in N, N-dimethylacetamide (1.2 mL) at rt The reaction mixture was cooled to 25 ° C. and concentrated. Was triturated with ethyl acetate and filtered to give the title compound.

Example 256B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(4-methylbenzyl) amino] quinolin-2 (1H) -one A solution of the product of Example 256A (0.065 g, 0.142 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.012 mL, 0.284 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.111 mL, 0.222 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 257A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(3-methylphenyl) methylene] amino} quinoline-2 (1H ) -On the product of Example 226D (0.070 g, 0.196 mmol) was added in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reaction with methylbenzaldehyde (0.210 mL, 1.78 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 257B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(3-methylbenzyl) amino] quinolin-2 (1H) -one A solution of the product of Example 257A (0.038 g, 0.083 mmol) in tetrahydrofuran (1.7 mL) and methanol (0.007 mL, 0.166 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.065 mL, 0.130 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 258A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(2-methylphenyl) methylene] amino} quinoline-2 (1H ) -On the product of Example 226D (0.070 g, 0.196 mmol) was added in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reaction with methylbenzaldehyde (0.206 mL, 1.78 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 258B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(2-methylbenzyl) amino] quinolin-2 (1H) -one A solution of the product of Example 258A (0.026 g, 0.057 mmol) in tetrahydrofuran (1.2 mL) and methanol (0.005 mL, 0.114 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.045 mL, 0.090 mmol). The reaction is stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (5.0 mL), and the resulting precipitate is collected by filtration, washed with water and dried. It was. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 259A
3-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(3-methylthien-2-yl) methyl] amino} quinoline-2 (1H)- The product of On Example 226D (0.060 g, 0.168 mmol) was 3-methylated in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 135 ° C. for 45 minutes in a sealed tube. Reacted with thiophene-2-carbaldehyde (0.180 mL, 1.50 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 259B
3- (1,1-dioxide-4H-1,2,3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[ (3-Methylthien-2-yl) methyl] amino} quinolin-2 (1H) -one The product of Example 259A (0.020 g, 0.043 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.004 mL, 0.086 mmol) solution was treated dropwise with 2.0M lithium borohydride in tetrahydrofuran (0.033 mL, 0.065 mmol) at 0 ° C. The reaction was stirred for 1 hour at 25 ° C. and pH with 1M hydrochloric acid. Acidified to about 2-4, diluted with water (5.0 mL) and the resulting precipitate was collected by filtration and dried, the crude product was triturated with methylene chloride / diethyl ether, Filtered and was prepared sodium salt of the title compound according to the procedure of the title compound was obtained. Example 1D.

Example 260A
3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[(4-methoxyphenyl) methylene] amino} quinoline-2 (1H ) -On the product of Example 226D (0.070 g, 0.196 mmol) was added in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reaction with -methoxybenzaldehyde (0.217 mL, 1.78 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 260B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(4-methoxybenzyl) amino] quinolin-2 (1H) -one A solution of the product of Example 260A (0.045 g, 0.095 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.19 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.074 mL, 0.148 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methanol / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 261A
1-{[(5-chlorothien-2-yl) methylene] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline- 2 (1H) -one The product of Example 226D (0.060 g, 0.168 mmol) was added to N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. In a reaction with 5-chlorothiophene-2-carbaldehyde (0.160 mL, 1.50 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 261B
1-{[(5-chlorothien-2-yl) methyl] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline- 2 (1H) -one A solution of the product of Example 261A (0.048 g, 0.099 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.198 mmol) at 0 ° C. with 2.0 M hydrogenation. The solution was treated dropwise with a solution of lithium boron in tetrahydrofuran (0.074 mL, 0.149 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 262A
1-{[(2-Chloro-1,3-thiazol-5-yl) methylene] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-Hydroxyquinolin-2 (1H) -one The product of Example 226D (0.070 g, 0.196 mmol) was N, N-dimethyl in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reacted with 2-chloro-1,3-thiazole-5-carbaldehyde (0.157 mL, 1.06 mmol) in acetamide (1.2 mL). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 262B
1-{[(2-Chloro-1,3-thiazol-5-yl) methyl] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) 4-Hydroxyquinolin-2 (1H) -one A solution of the product of Example 262A (0.040 g, 0.082 mmol) in tetrahydrofuran (1.7 mL) and methanol (0.007 mL, 0.164 mmol) at 0 ° C. , 2.0M lithium borohydride in tetrahydrofuran (0.064 mL, 0.128 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 263A
1-{[(3-Bromophenyl) methylene] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline-2 (1H ) -On the product of Example 226D (0.059 g, 0.165 mmol) was added in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. -Reaction with bromobenzaldehyde (0.175 mL, 1.5 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 263B
1-[(3-Bromobenzyl) amino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 263A (0.048 g, 0.091 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.182 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.130 mL, 0.260 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 264A
1-{[(4-Bromophenyl) methylene] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline-2 (1H ) -On the product of Example 226D (0.060 g, 0.168 mmol) in 4 in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reaction with bromobenzaldehyde (0.278 mL, 1.50 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 264B
1-[(4-Bromobenzyl) amino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 264A (0.049 g, 0.094 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.188 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.134 mL, 0.268 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 265A
1-{(2-bromophenyl) methylene] amino} -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinoline-2 (1H) On product of Example 226D (0.060 g, 0.168 mmol) was added in N, N-dimethylacetamide (1.0 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reacted with bromobenzaldehyde (0.175 mL, 1.50 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 265B
1-[(2-Bromobenzyl) amino] -3- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 265A (0.068 g, 0.129 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.011 mL, 0.258 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran ( 0.184 mL, 0.368 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 266A
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-{[pyridin-3-ylmethylene] amino} quinoline-2 (1H)- The product of On Example 226D (0.070 g, 0.196 mmol) was added to nicotinaldehyde (1.2 mL) in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. 0.168 mL, 1.78 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 266B
3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-[(pyridin-3-ylmethyl) amino] quinoline-2 (1H)- A solution of the product of On Example 266A (0.062 g, 0.14 mmol) in tetrahydrofuran (2.5 mL) and methanol (0.012 mL, 0.280 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. Treated dropwise with (0.105 mL, 0.210 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methanol / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 267A
3-({[3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxoquinolin-1 (2H) -yl] imino} Methyl) benzonitrile The product of Example 226D (0.070 g, 0.196 mmol) was added in N, N-dimethylacetamide (1.2 mL) in a microwave reactor at 110 ° C. for 35 minutes in a sealed tube. Reacted with 3-formylbenzonitrile (0.080 mL, 0.610 mmol). The reaction mixture was cooled to 25 ° C. and concentrated. The resulting residue was triturated with ethyl acetate and filtered to give the title compound.

Example 267B
3-({[3- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-2-oxoquinolin-1 (2H) -yl] amino} Methyl) benzonitrile A solution of the product of Example 267A (0.055 g, 0.117 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.234 mmol) was added at 0 ° C. to 2.0 M borohydride. Treated dropwise with a solution of lithium in tetrahydrofuran (0.088 mL, 0.176 mmol). The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methylene chloride / diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 268A
3-[(2E) -2-Benzylidenehydrazino] thiophene-2-carboxylate methyl 3-hydrazinothiophene-2-carboxylate (Maybridge industrial grade, 2.0 g, 0.11 mol) ethanol The (250 mL) solution was reacted at 25 ° C. with a solution of benzaldehyde (12.32 g, 0.11 mol) in ethanol (100 mL). The mixture was stirred at 25 ° C. for 1.5 hours and concentrated to give 30 g of a white solid. HPLC / MS shows a single peak with a retention time of 2.35 minutes and an M + 1 peak at 261.

Example 268B
Methyl 3- [2-benzylidene-1- (3-ethoxy-3-oxopropanoyl) hydrazino] thiophene-2-carboxylate The product of Example 185A (26.4 g, 0.101 mol) was added to toluene (400 mL). The mixture was reacted with ethyl chloromalonate (18.3 g, 0.121 mol) in the mixture and stirred at reflux for 4 hours to release HCl gas from the condenser. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with 3: 1 hexane / ethyl acetate to give the title compound (37.1 g, 98%).

Example 268C
Ethyl 7-hydroxy-5-oxo-4-{[phenylmethylene] amino} -4,5-dihydrothieno [3,2-b] pyridine-6-carboxylate The product of Example 268B (37.8 g,. 101 mol) in ethanol (0.5 L) was reacted with an ethanol solution of sodium ethoxide (21 wt%, 32.8 g, 0.104 mol) under nitrogen at room temperature. The mixture was gradually warmed to 50 ° C., stirred at 40-50 ° C. for 1 hour, cooled to 25 ° C., partitioned between ethyl acetate and water and acidified to pH 4 with 1M hydrochloric acid. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (12.0 g, 35%).

Example 268D
4-Amino-6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one Of Example 268C (2.29 g, 6.69 mmol) was reacted with a solution of 2-aminobenzenesulfonamide (1.15 g, 6.69 mmol) in toluene (60 mL) and stirred at reflux for 5 hours. The reaction was cooled to 25 ° C. and the resulting precipitate was collected by filtration and dried (1.95 g, 62%). The obtained solid (1.95 g, 4.2 mmol) was reacted with 10% aqueous KOH solution (60 mL) under reflux for 24 hours, cooled to 25 ° C., and acidified to pH 2 with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed repeatedly with water and dried to give the title compound (1.5 g, 98%). (Sodium salt produced?)

Example 269A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[2-methylpropylidene] amino} thieno [3,2-b ] The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide (3 mL) in a microwave reactor at 135 ° C. for 40 minutes in a sealed tube. ) With 2-methyl-propionaldehyde (0.20 g, 2.77 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with a 25% ethyl acetate / hexane mixture and filtered to give the title compound as a solid (0.073 g, 65%). MS (APCI +) m / z 417 (M + H) ^<+> .

Example 269B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (isobutylamino) thieno [3,2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.073 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.20 mL, 0.40 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was suspended in tetrahydrofuran (10 mL), adsorbed on about 5 g of silica gel, and the solvent was distilled off. The product was eluted with methanol / chloroform. Fractions containing product were combined and evaporated under reduced pressure to give the title compound (0.032 g, 42%). MS (ESI-) m / z 417 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 270A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(3S) -3-methylcyclopentylidene] amino} thieno [ 3,2-b] Pyridin-5 (4H) -one The product of Example 268D (0.065 g, 0.18 mmol) was added to the N, N in a microwave reactor at 135 ° C. for 90 minutes in a sealed tube. Reaction with (3S) -3-methylcyclopentanone (0.54 g, 5.6 mmol) in dimethylacetamide (2 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate / hexane (2: 1) and filtered to give the title compound.

Example 270B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(3S) -3-methylcyclopenta] amino} thieno [3 , 2-b] pyridin-5 (4H) -one in a solution of the product of Example 269A (0.060 g, 0.14 mmol) in tetrahydrofuran (4 mL) and methanol (0.012 mL, 0.3 mmol) at 0 ° C. A 2.0 M solution of lithium borohydride in tetrahydrofuran (0.12 mL, 0.24 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 2 hours, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to methylene chloride / methanol (99: 1). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 271A
4-{[1-cyclopropylethylidene] amino} -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b ] Pyridin-5 (4H) -one The product of Example 268D (0.065 g, 0.18 mmol) was added in N, N-dimethylacetamide (2 mL) in a microwave reactor at 135 ° C. for 120 minutes in a sealed tube. ) With 1-cyclopropylethanone (0.54 g, 6.4 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate / hexane (2: 1) and filtered to give the title compound.

Example 271B
4-{[1-Cyclopropylethyl] amino} -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b ] Pyridin-5 (4H) -one A solution of the product of Example 269A (0.058 g, 0.14 mmol) in tetrahydrofuran (4 mL) and methanol (0.012 mL, 0.3 mmol) at 0 ° C. and 2.0 M hydrogen. A solution of lithium borohydride in tetrahydrofuran (0.12 mL, 0.24 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 2 hours, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using methylene chloride to methylene chloride / methanol (99: 1) to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 272A
4-[(Butylideneamino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H) -On The product of Example 268D (0.10 g, 0.27 mmol) was butyl in N, N-dimethylacetamide (3 mL) in a microwave reactor at 130 ° C. for 40 minutes in a sealed tube. Reaction with aldehyde (0.5 g, 6.9 mmol) The reaction was cooled to 25 ° C. and concentrated under reduced pressure The resulting residue was triturated with diethyl ether, filtered and the title compound (0.075 g, 65%) was obtained.

Example 272B
4- (Butylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.075 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.029 mL, 0.5 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 273A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-{[2-ethylbutylidene] amino} -7-hydroxythieno [3,2-b ] The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide (3 mL) in a microwave reactor at 130 ° C. for 40 minutes in a sealed tube. ) With 2-ethylbutanal (0.5 g, 5.2 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.082 g, 68%).

Example 273B
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(2-ethylbutyl) amino] -7-hydroxythieno [3,2-b] pyridine -5 (4H) -one A solution of the product of Example 269A (0.82 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C., 2.0 M borohydride. A solution of lithium in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 274A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- [pentylideneamino] thieno [3,2-b] pyridine-5 ( 4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was converted to pentanal (3 mL) in N, N-dimethylacetamide (3 mL) in a microwave reactor at 130 ° C. for 40 min. 0.5 g, 5.0 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.081 g, 70%).

Example 274B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (pentylamino) thieno [3,2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.081 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 275A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[3-methylbutylidene] amino} thieno [3,2-b ] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was added to N, N-dimethylacetamide (3 mL in a microwave reactor at 130 ° C. for 40 minutes in a sealed tube. ) With 3-methylbutanal (0.5 g, 5.8 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.083 g, 71%).

Example 275B
6- (1,1-dioxide-4H1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methylbutyl) amino] thieno [3,2-b] pyridine-5 (4H) -On a solution of the product of Example 269A (0.083 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. with 2.0 M lithium borohydride. Tetrahydrofuran solution (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 276A
4-{[3,3-Dimethylbutylidene] amino} -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2 -B] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide in a microwave reactor at 130 ° C. for 40 minutes in a sealed tube. (3 mL) was reacted with 3,3-dimethylbutanal (0.5 g, 5.0 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.072 g, 77%).

Example 276B
4-[(3,3-Dimethylbutyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2- b] Pyridin-5 (4H) -one To a solution of the product of Example 269A (0.072 g, 0.21 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C., 2.0 M A solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 277A
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(3-methylphenyl) methylene] amino} thieno [3,2 -B] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide in a microwave reactor at 130 ° C. for 40 minutes in a sealed tube. Reacted with 3-methylbenzaldehyde (0.5 g, 4.2 mmol) in (3 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.092, 73%).

Example 277B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methylbenzyl) amino] thieno [3,2-b] Pyridine-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.090 g, 0.2 mmol) in tetrahydrofuran (4 mL) and methanol (0.015 mL; 0.4 mmol). A solution of lithium boron in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 278A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(2-methylphenyl) methylene] amino} thieno [3,2 -B] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. Reacted with 2-methylbenzaldehyde (0.5 g, 4.2 mmol) in (3 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.072 g, 57%).

Example 278B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(2-methylbenzyl) amino] thieno [3,2-b] Pyridine-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.072 g, 0.15 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol). A solution of lithium boron in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 279A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(4-methylphenyl) methylene] amino} thieno [3,2 -B] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. Reacted with 4-methylbenzaldehyde (0.5 g, 4.2 mmol) in (3 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.10 g, 81%).

Example 279B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(4-methylbenzyl) amino] thieno [3,2-b] Pyridin-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.10 g, 0.22 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol). A solution of lithium boron in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 280A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[3-methylbut-2-enelidene] amino} thieno [3,2 -B] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide in a microwave reactor at 130 ° C. for 40 minutes in a sealed tube. Reaction with 3-methylbut-2-enal (0.5 g, 5.9 mmol) in (3 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g, 80%).

Example 280B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methylbut-2-enyl) amino] thieno [3,2 -B ] pyridin-5 (4H) -one in a solution of the product of Example 269A (0.093 g, 0.22 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. A tetrahydrofuran solution (0.150 mL, 0.3 mmol) of 0M lithium borohydride was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 281A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- [propylideneamino] thieno [3,2-b] pyridine-5 ( 4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was propionaldehyde in N, N-dimethylacetamide (3 mL) in a microwave reactor at 120 ° C. for 90 minutes in a sealed tube. (0.5 g, 8.6 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.073 g, 67%).

Example 281B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- (propylamino) thieno [3,2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.073 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 282A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[pyridin-4-ylmethylene] amino} thieno [3,2-b ] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was added to N, N-dimethylacetamide (3 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. ) With isonicotialdehyde (0.5 g, 4.7 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g, 76%).

Example 282B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(pyridin-4-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one A solution of the product of Example 269A (0.093 g, 0.21 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. and 2.0 M hydrogen. A solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 283A
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[pyridin-3-ylmethylene] amino} thieno [3,2-b ] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was added to N, N-dimethylacetamide (3 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. ) With nicotinaldehyde (0.5 g, 4.7 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.102 g, 84%).

Example 283B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(pyridin-3-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one A solution of the product of Example 269A (0.102 g, 0.23 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. and 2.0 M hydrogen. A solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 284A
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[pyridin-2-ylmethylene] amino} thieno [3,2-b ] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was added to N, N-dimethylacetamide (3 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. ) With 2-pyridinecarboxaldehyde (0.5 g, 4.7 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.071 g, 58%).

Example 284B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(pyridin-2-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one A solution of the product of Example 269A (0.071 g, 0.16 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. and 2.0 M hydrogen. A solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 5% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 285A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(3-methoxyphenyl) methylene] amino} thieno [3,2 -B] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. Reacted with 3-methoxybenzaldehyde (0.5 g, 3.7 mmol) in (3 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g, 72%).

Example 285B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(3-methoxybenzyl) amino] thieno [3,2-b] Pyridin-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.093 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol). A solution of lithium boron in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 286A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-{[3-furylmethylene] amino} -7-hydroxythieno [3,2-b] Pyridin-5 (4H) -one The product of Example 268D (0.10 g, 0.27 mmol) was added to N, N-dimethylacetamide (3 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. Reacted with 3-furaldehyde (0.5 g, 5.2 mmol) in The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.103 g, 87%).

Example 286B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(3-furylmethyl) amino] -7-hydroxythieno [3,2-b] Pyridine-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.103 g, 0.23 mmol) in tetrahydrofuran (4 mL) and methanol (0.030 mL, 0.8 mmol). A solution of lithium boron in tetrahydrofuran (0.200 mL, 0.4 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 287A
3-({[6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-5-oxothieno [3,2-b] pyridine-4 ( 5H) -yl] imino} methyl) benzonitrile The product of Example 268D (0.100 g, 0.27 mmol) was N, N-dimethylacetamide in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. (3 mL) was reacted with 3-formylbenzonitrile (0.362 g, 2.75 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.088 g, 69%).

Example 287B
3-({[6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-5-oxothieno [3,2-b] pyridine-4 ( 5H) -yl] amino} methyl) benzonitrile To a solution of the product of Example 269A (0.088 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. A tetrahydrofuran solution (0.150 mL, 0.3 mmol) of 0M lithium borohydride was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 288A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[thien-3-ylmethylene] amino} thieno [3,2-b ] The product of Example 268D (0.10 g, 0.27 mmol) was N, N-dimethylacetamide (3 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. ) With thiophene-3-carbaldehyde (0.5 g, 4.5 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.077 g, 63%).

Example 288B
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(thien-3-ylmethyl) amino] thieno [3,2-b ] Pyridin-5 (4H) -one A solution of the product of Example 269A (0.077 g, 0.17 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. and 2.0 M hydrogen. A solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH˜2-4, diluted with water (25 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 2% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 289A
4- (Cyclobutylideneamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H) -On The product of Example 268D (0.10 g, 0.27 mmol) was added to cyclobutanone in N, N-dimethylacetamide (2 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. (1.0 g, 14.3 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.086 g, 77%).

Example 289B
4- (Cyclobutylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 ( 4H) -On a solution of the product of Example 269A (0.077 g, 0.21 mmol) in tetrahydrofuran (4 mL) and methanol (0.030 mL, 0.8 mmol) at 0 ° C. and 2.0 M lithium borohydride in tetrahydrofuran. The solution (0.200 mL, 0.4 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 290A
6- (1,1-Dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[phenylmethylene] amino} thieno [3,2-b] pyridine- The product of 5 (4H) -one Example 268D (0.115 g, 0.30 mmol) was added in N, N-dimethylacetamide (2 mL) in a microwave reactor at 135 ° C. for 50 minutes in a sealed tube. Reacted with benzaldehyde (0.32 g, 3.0 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with 0.1 M HCl (20 mL) and filtered to give the title compound.

Example 290B
4- (Benzylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.116 g, 0.257 mmol) in tetrahydrofuran (5 mL) and methanol (0.021 mL, 0.514 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.19 mL, 0.386 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 2 hours, acidified with 1M hydrochloric acid to pH ˜2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried to give the title compound. . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 291A
4-{[cyclohexylmethylene] amino} -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine- The product of 5 (4H) -one Example 268D (0.115 g, 0.30 mmol) was placed in a sealed tube in a microwave reactor in N, N-dimethylacetamide (3 mL) at 135 ° C. for 60 minutes. Reacted with cyclohexanecarbaldehyde (0.336 g, 3.0 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with 0.1 M HCl (20 mL) and filtered to give the title compound.

Example 291B
4-[(Cyclohexylmethyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine- 5 (4H) -one 2.0 M lithium borohydride at 0 ° C. in a solution of the product of Example 269A (0.12 g, 0.26 mmol) in tetrahydrofuran (5 mL) and methanol (0.021 mL, 0.52 mmol) In tetrahydrofuran (0.195 mL, 0.39 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 97: 3 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 292A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[1,3-thiazol-5-ylmethylene] amino} thieno [3 , 2-b] pyridin-5 (4H) -one The product of Example 268D (0.115 g, 0.30 mmol) was added to the N, N— in a microwave reactor at 140 ° C. for 80 minutes in a sealed tube. Reacted with 1,3-thiazole-5-carbaldehyde (0.35 g, 3.0 mmol) in dimethylacetamide (3 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with 0.1 M HCl (20 mL) and filtered to give the title compound.

Example 292B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-[(1,3-thiazol-5-ylmethyl) amino] thieno [3 , 2-b] pyridin-5 (4H) -one in a solution of the product of Example 269A (0.137 g, 0.30 mmol) in tetrahydrofuran (7 mL) and methanol (0.025 mL, 0.6 mmol) at 0 ° C. A 2.0 M solution of lithium borohydride in tetrahydrofuran (0.225 mL, 0.45 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 2 hours, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 95: 5 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 293A
4-{[(3-Bromophenyl) methylene] amino} -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2 -B] Pyridin-5 (4H) -one The product of Example 268D (0.115 g, 0.30 mmol) was N, N-dimethylacetamide in a microwave reactor at 135 ° C. for 30 minutes in a sealed tube. Reacted with 3-bromobenzaldehyde (0.555 g, 3.0 mmol) in (2 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate (3 mL) and filtered to give the title compound.

Example 293B
4-[(3-Bromobenzyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] Pyridin-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.13 g, 0.245 mmol) in tetrahydrofuran (4 mL) and methanol (0.015 mL, 0.36 mmol). A solution of lithium boron in tetrahydrofuran (0.15 mL, 0.30 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 2 hours, acidified with 1M hydrochloric acid to pH ˜2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried to give the title compound. . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 294A
4- (Cyclohexylideneamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H) -On The product of Example 268D (0.054 g, 0.15 mmol) was cyclohexanone in N, N-dimethylacetamide (1 mL) in a microwave reactor at 135 ° C. for 45 min in a sealed tube. (0.44 g, 4.5 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 294B
4- (Cyclohexylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.051 g, 0.115 mmol) in tetrahydrofuran (5 mL) and methanol (0.01 mL, 0.23 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.090 mL, 0.175 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 97: 3 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 295A
4- (Cyclopentylideneamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H) -On The product of Example 268D (0.054 g, 0.15 mmol) was cyclohexane in N, N-dimethylacetamide (1 mL) in a microwave reactor at 135 ° C. for 60 minutes in a sealed tube. Reacted with pentanone (0.95 g, 11.3 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 295B
4- (Cyclopentylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.040 g, 0.09 mmol) in tetrahydrofuran (3 mL) and methanol (0.008 mL, 0.19 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.07 mL, 0.14 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 98: 2 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 296A
4- (Cycloheptylideneamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine- 5 (4H) -one The product of Example 268D (0.054 g, 0.15 mmol) was added in N, N-dimethylacetamide (1 mL) in a microwave reactor at 135 ° C. for 45 minutes in a sealed tube. Reacted with cycloheptanone (0.84 g, 7.5 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 296B
4- (Cycloheptylamino) -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-pyridine-5 (4H) - the product of example 269A (0.06 g, 0.13 mmol) in tetrahydrofuran (4 mL) and methanol (0.011 mL, 0.26 mmol) in solution in 0 ° C., 2.0 M lithium borohydride in tetrahydrofuran ( 0.10 mL, 0.2 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 98: 2 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 297A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4- [3-methylcyclohexylidene] amino} thieno [3,2-b ] The product of Example 268D (0.054 g, 0.15 mmol) was N, N-dimethylacetamide (1 mL) in a microwave reactor at 135 ° C. for 45 min in a sealed tube. ) With 3-methylcyclohexanone (1.26 g, 11.25 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 297B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[3-methylcyclohexyl] amino} thieno [3,2-b] Pyridine-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.060 g, 0.13 mmol) in tetrahydrofuran (4 mL) and methanol (0.011 mL, 0.26 mmol). A solution of lithium boron in tetrahydrofuran (0.1 mL, 0.20 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 98: 2 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 298A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(3R) -3-methylcyclohexylidene] amino} thieno [ 3,2-b] Pyridin-5 (4H) -one The product of Example 268D (0.073 g, 0.2 mmol) was added to N, N in a microwave reactor at 135 ° C. for 45 minutes in a sealed tube. Reaction with (3R) -3-methylcyclohexanone (1.12 g, 10.0 mmol) in dimethylacetamide (2 mL). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 298B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[(3R) -3-methylcyclohexyl] amino} thieno [3, 2-b] Pyridin-5 (4H) -one A solution of the product of Example 269A (0.06 g, 0.13 mmol) in tetrahydrofuran (6 mL) and methanol (0.011 mL, 0.26 mmol) at 0 ° C. A tetrahydrofuran solution (0.1 mL, 0.2 mmol) of 0.0 M lithium borohydride was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 98: 2 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 299A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(1-ethylpropylidene) amino] -7-hydroxythieno [3,2-b ] The product of Example 268D (0.073 g, 0.2 mmol) was N, N-dimethylacetamide (2 mL) in a microwave reactor at 135 ° C. for 40 minutes in a sealed tube. ) With pentane-3-one (0.86 g, 10.0 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 299B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-[(1-ethylpropyl) amino] -7-hydroxythieno [3,2-b] Pyridin-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.08 g, 0.18 mmol) in tetrahydrofuran (7 mL) and methanol (0.015 mL, 0.36 mmol). A solution of lithium boron in tetrahydrofuran (0.135 mL, 0.27 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 98: 2 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 300A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[1-phenylethylidene] amino} thieno [3,2-b] Pyridin-5 (4H) -one The product of Example 268D (0.073 g, 0.2 mmol) was N, N-dimethylacetamide (2 mL) in a microwave reactor at 135 ° C. for 75 minutes in a sealed tube. Reacted with 1-phenylethanone (1.2 g, 10.0 mmol) in The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 300B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[1-phenylethyl] amino} thieno [3,2-b] Pyridin-5 (4H) -one 2.0 M hydrogenation at 0 ° C. to a solution of the product of Example 269A (0.046 g, 0.10 mmol) in tetrahydrofuran (5 mL) and methanol (0.005 mL, 0.12 mmol). A solution of lithium boron in tetrahydrofuran (0.06 mL, 0.12 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 3 hours, acidified with 1M hydrochloric acid to a pH of about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 99: 1 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 301A
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[1-methylbutylidene] amino} thieno [3,2-b ] Pyridin-5 (4H) -one The product of Example 268D (0.073 g, 0.2 mmol) was charged with N, N-dimethylacetamide (2 mL) in a sealed tube at 135 ° C. for 60 minutes in a microwave reactor. ) With pentan-2-one (0.9 g, 10.4 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.

Example 301B
6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy-4-{[1-methylbutyl] amino} thieno [3,2-b] pyridine -5 (4H) -one A solution of the product of Example 269A (0.070 g, 0.16 mmol) in tetrahydrofuran (mL) and methanol (0.013 mL, 0.32 mmol) at 0 ° C., 2.0 M borohydride. A solution of lithium in tetrahydrofuran (0.12 mL, 0.24 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel using 99: 1 methylene chloride / methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 303A
4-{[Cyclopropylmethylene] amino} -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxythieno [3,2-b] pyridine -5 (4H) -one The product of Example 268D (0.15 g, 0.41 mmol) in N, N-dimethylacetamide (3 mL) in a microwave reactor at 120 ° C. for 90 minutes in a sealed tube. And reacted with cyclopropanecarbaldehyde (1.0 g, 14 mmol). The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.104 g, 60%).

Example 303B
4-[(Cyclopropylmethyl) amino] -6- (1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -7-hydroxy 2-b] pyridine-5 (4H ) -On a solution of the product of Example 269A (0.104 g, 0.25 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0 ° C. in 2.0 M lithium borohydride in tetrahydrofuran. (0.200 mL, 0.4 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified with 1M hydrochloric acid to pH about 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol / chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 304A
4- (Benzyloxy) -2-fluoro-1-nitrobenzene 3-fluoro-4--4-nitro-phenol (10 g, 0.064 mol) was benzylated in N, N-dimethylformamide (100 mL) at 25 ° C. for 18 hours. Reacted with bromide (8.3 mL, 0.070 mol), cesium carbonate (22.7 g, 0.07 mol), and tetrabutylammonium iodide (0.05 g). The reaction mixture was poured into distilled water (500 mL) and stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound as a light yellow solid (15 g).

Example 304B
4- (Benzyloxy) -2- (benzylthio) -1-nitrobenzene A slurry of the product of Example 304A (15 g, 0.061 mol) in ethanol (100 mL) was added to sodium carbonate (6.41 g, 0.061 mol) and Treated with a solution of benzyl mercaptan (7.5 mL, 0.058 mol) in water (50 mL). The reaction mixture was refluxed for 5 hours, cooled to 25 ° C. and poured into distilled water (800 mL). The resulting slurry was stirred at 25 ° C. for 1 hour and filtered. The resulting yellow solid was washed with and dried in water at 50 ° C. in a vacuum dryer to give the title compound (20.53 g).

Example 304C
5- (Benzyloxy) -2-nitrobenzenesulfonamide A slurry of the product of Example 304B (5 g, 0.014 mol) in glacial acetic acid (50 mL) and water (5.5 mL) at 0 ° C. with chlorine gas for 10 minutes. Blow and stir for an additional 30-45 minutes. The reaction mixture was poured into ice water (200 g), stirred for 30 minutes and extracted with methylene chloride (2 × 100 mL). The combined methylene chloride extracts were cooled in an ice bath to about 5 ° C. and concentrated aqueous ammonium hydroxide (40 mL) was added slowly, resulting in foaming and foaming as ammonia was added. After 30 minutes, effervescence ceased, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (100 mL). The combined organic extracts were washed with 1N phosphoric acid (50 mL), brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to give the title compound as a white solid (3.85 g). .

Example 304D
2-Amino-5- (benzyloxy) benzenesulfonamide The product of Example 304C (3.85 g, 0.0125 mol) was dissolved in methanol (100 mL) and water (50 mL) with iron powder (4.3 g, 0 0.077 mol, 6.15 eq) and ammonium chloride (4.4 g, 0.082 mol) and stirred at reflux for 1 hour. The hot reaction mixture was filtered through fluted filter paper and washed with hot methanol. The filtrate was concentrated under reduced pressure to give a white semi-solid. It was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound as an off-white solid (2.5 g).

Example 304E
1-amino-N- [2- (aminosulfonyl) -4- (benzyloxy) phenyl] -4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide The product of Example 304D (4. 0 g, 14.37 mmol) and the product of Example 226C (2.42 g, 7.20 mmol) in toluene (50 mL) were reacted at 118 ° C. for 4 hours. Filter the mixture while still warm and dry the solid to give the title compound (3.13 g, 90%).

Example 304F
1-amino-3- [7- (benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxyquinolin-2 (1H) -one The product of Example 304E (3.13 g, 6.51 mmol) was suspended in 10% potassium hydroxide solution (50 mL) and heated at 125 ° C. for 24 hours and then at 140 ° C. for 24 hours. The mixture was poured into ice and 1M hydrochloric acid, filtered and dried to give the title compound (2.03 g, 67%).

Example 304G
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- (cyclobutylideneamino) -4-hydroxyquinoline-2 ( 1H) -On A solution of the product of Example 304F (0.285 g, 0.62 mmol) in N, N-dimethylacetamide (1.5 mL) in a microwave reactor in a sealed tube at 130 ° C. for 45 min. 0.85 mL, 10.9 mmol). The reaction was cooled to 25 ° C., concentrated under a nitrogen stream heated to a manifold heated to 165 ° C., and the resulting residue was triturated with diethyl ether to give the title compound (0. 178 g, 56%).

Example 304H
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl- (cyclobutylamino) -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 304G (0.178 g, 0.35 mmol) in tetrahydrofuran (3 mL) was treated at 0 ° C. with methanol (0.025 mL, 0.70 mmol), then 2.0 M lithium borohydride in Tetrahydrofuran solution (0.260 mL, 0.52 mmol) was added dropwise, stirred at 25 ° C. for 1 hour, and diluted with 1N HCl. The resulting precipitate was filtered and dried. The solid was dissolved in tetrahydrofuran and evaporated on silica gel by evaporating the solvent until dry. The resulting silica was loaded onto a 2 g Alltech Seppac and eluted with methylene chloride to give the title compound (0.059 g, 33%).

Example 304I
1- (cyclobutylamino) -4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) quinolin-2 (1H) -one A solution of the product of Example 304H (0.059 g, 0.11 mmol) in tetrahydrofuran (4 mL) was reacted with platinum oxide (50 mg) at 25 ° C. for 20 hours under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (0.048 g, 100%). MS (ESI-) m / z425 ( M-H) -.

Example 304J
2-({3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl} oxy) acetamide A solution of the product of Example 304I (0.048 g, 0.11 mmol) in N, N-dimethylformamide (2 mL) was added to cesium carbonate (0.15 g, 0.45 mmol). , Bromoacetamide (0.026 mL, 0.18 mmol) and a catalytic amount of tetrabutylammonium iodide at 25 ° C. for 3 hours. The reaction solution was concentrated under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting residue was triturated with water, filtered and dried. The resulting solid was triturated with moderately hot ethyl acetate, filtered and dried to give the title compound (0.020 g, 37%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 305A
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- (cyclopentylideneamino) -4-hydroxyquinoline-2 ( 1H) -one A solution of the product of Example 304F (0.284 g, 0.61 mmol) and cyclopentanone (0.80 mL, 9.04 mmol) in N, N-dimethylacetamide (2 mL) was placed in a microwave reactor. And allowed to react at 130 ° C. for 40 minutes in a sealed tube. The reaction solution was concentrated under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.210 g, 65%).

Example 305B
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- (cyclopentylamino) -4-hydroxyquinoline-2 (1H) On solution of the product of Example 305A (0.21 g, 0.40 mmol) in tetrahydrofuran (3 mL) and methanol (0.030 mL) at 0 ° C., lithium borohydride (2.0 M solution in tetrahydrofuran, 0.30 mL). , 0.60 mmol). The reaction was stirred at 25 ° C. for 1 hour, then diluted with 1M aqueous hydrochloric acid and filtered. The product was purified by dissolving in tetrahydrofuran, absorbing onto silica gel, loading onto a 2 g Alltec Seppac and eluting with methylene chloride. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.124 g, 59%).

Example 305C
1- (cyclopentylamino) -4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) quinolin-2 (1H) -one A solution of the product of Example 305B (0.122 g, 0.23 mmol) in tetrahydrofuran (15 mL) was added to a catalytic amount of palladium hydroxide oxide / carbon, a catalytic amount of 5% palladium / carbon and ammonium formate (0.080 g, 1. 27 mmol) and 60 ° C. for 2 hours. The warm reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give the title compound (0.10 g, 100%).

Example 305D
2-({3- [1- (Cyclopentylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) acetamide The product of Example 305C (0.10 g, 0.23 mmol) was added to cesium carbonate (0.30 g, 0.92 mmol), 2-bromoacetamide ( 0.050 g, 0.37 mmol) and a catalytic amount of tetrabutylammonium iodide in N, N-dimethylformamide (5 mL). The reaction solution was concentrated to a half volume under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.095 g, 85%). MS (ESI-) m / z 496 (M-H) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 306A
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- (cyclohexylideneamino) -4-hydroxyquinoline-2 ( The title compound was prepared according to the procedure described in Example 304G, substituting cyclohexanone for 1H) -one cyclobutanone.

Example 306B
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- (cyclohexylamino) -4-hydroxyquinoline-2 (1H) - using one example 304G product of example 306A instead of the product the title compound was prepared according to the procedure described in example 304H (0.11g, 78%).

Example 306C
1- (cyclohexylamino) -4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) quinolin-2 (1H) -one The title compound was prepared according to the procedure of Example 305C using the product of Example 306B instead of the product of Example 305B (39 mg, 42%).

Example 306D
2-({3- [1- (cyclohexylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yloxy) acetamide Following the procedure described in Example 304J, a solution of the product of Example 306C (13 mg, 0.028 mmol) in N, N-dimethylformamide (5 mL) was added to cesium carbonate (0.0137 g, 0.114 mol) and 2-bromoacetamide (0.008 g, 0.058 mmol) to give the title compound. The sodium salt was prepared according to the procedure of Example 1D (7 mg, 48%).

Example 307
4-[(2-Chloro-1,3-thiazol-5-yl) methyl] -7-hydroxy-6- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazine -3-yl) thieno [3,2-b] pyridin-5 (4H) -one
Example 307A
[7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] ethyl acetate 2-amino-benzenesulfonamide instead of the product of Example 304D The title compound was prepared according to the procedure of Example 1C.

Example 307B
(7-Hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) ethyl acetate The product of Example 307A (1.42 g, 3.79 mmol) in tetrahydrofuran (60 mL) The solution was reacted with 10% palladium / carbon (0.2 g) at 25 ° C. under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give an oil. The residue was purified on silica gel eluting with ethyl acetate to give the title compound as a white solid (0.8 g).

Example 307C
{1,1-dioxide-7-[(triisopropylsilyl) oxy] -4H-1,2,4-benzothiadiazin-3-yl} ethyl acetate The product of Example 307B (0.1 g,. 352 mmol) was reacted with 2,6-lutidine (0.045 mL, 0.387 mmol) and triisopropyl trifluoromethanesulfonate (0.1 mL, 0.387 mmol) in methylene chloride (10 mL) at 5 ° C. for 3 hours. . The reaction solution was diluted with methylene chloride and extracted with a 1N aqueous phosphoric acid solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow solid (0.13 g, 84%).

Example 307D
4-[(2-Chloro-1,3-thiazol-5-yl) methyl] -6- {1,1-dioxide-7-[(triisopropylsilyl) oxy] -4H-1,2,4-benzo Thiadiazin-3-yl} -7-hydroxythieno [3,2-b] pyridin-5 (4H) -one The product of Example 140C was used instead of the product of Example 1B. The title compound was prepared according to the procedure of Example 1D using the product of Example 307C instead of product (0.29 g, 66%).

Example 307E
4-[(2-Chloro-1,3-thiazol-5-yl) methyl] -7-hydroxy-6- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazine -3-yl) thieno [3,2-b] pyridin-5 (4H) -one A solution of the product of Example 307D (0.235 g, 0.36 mmol) in tetrahydrofuran (10 mL) was added at 25 ° C. over 2 h. Reaction with tetrahydrofuran solution of tetrabutylammonium fluoride (1M, 0.43 mL). The reaction mixture was diluted with water (50 mL), adjusted to pH 2 with 1M HCl and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (0.15 g, 84%). MS (ESI-) m / z 493 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 308
2-[(3- {4-[(2-Chloro-1,3-thiazol-5-yl) methyl] -7-hydroxy-5-oxo-4,5-dihydrothieno [3,2-b] pyridine- 6-yl} -1,1-dioxide-4H-1,2,4-benzothiadiazin-7-yl) oxy] acetamide N, N of the product of Example 307E (0.065 g, 0.13 mmol) -A solution of dimethylformamide (5 mL) was reacted with cesium carbonate (0.171 g, 0.53 mmol) and 2-bromoacetamide (0.036 g, 0.26 mmol) at 25 ° C for 24 hours. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration to give the title compound (0.036 g, 50%). MS (ESI-) m / z550 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 309A
According to the procedure described in the 1-benzyl-4-hydroxy-1H-quinolin-2-one literature (DR Buckle, BC Cantello, H. Smith, BA Spicer, Journal of Medicinal Chemistry, 18, 726-732 (1975)) The title compound was prepared.

Example 309B
To a suspension of 1-benzyl-3- (bis-methylsulfanyl-methylene) -1H-quinoline-2,4-dione sodium hydride (0.75 g, 16 mmol) in N, N-dimethylformamide (20 mL) at 0 ° C. A solution of the product of Example 309A (2 g, 7.97 mmol) in N, N-dimethylformamide (30 mL) was added over 30 minutes. When the obtained red-orange red mixture was heated to 25 ° C. and stirred for 30 minutes, it gradually became a violet color. The reaction was heated at 50 ° C. for 2 hours and cooled to 25 ° C. over 30 minutes. Carbon disulfide (1.13 mL, 16 mmol) was added to the mixture. The mixture was heated at 50 ° C. for 2 hours (red-brown) and cooled to 25 ° C. Methyl iodide (1.2 mL, 16 mmol) was added and the reaction was stirred at 25 ° C. for 30 minutes. The reaction was quenched with phosphate buffer (10 mL, pH = 7), and the reaction was concentrated under reduced pressure. The residue is triturated with pH 7 phosphate buffer and ethyl acetate / hexane (1: 1) and the resulting orange solid is collected by filtration, washed with hexane, dried under reduced pressure and dried to give the title compound. (1.76 g, 62%) was obtained.

Example 309C
According to the procedure described in methyl 4- (benzylthio) -5- nitrothiophene -3-carboxylate (Stanetty, P. et. Al., Journal of Heterocyclic Chemistry, 36, 761-765 (1999)) Manufactured.

Example 309D
[4- (Benzylthio) -5-nitrothien-3-yl] methanol To a solution of the product of Example 309C (5 g, 16.2 mmol) in methylene chloride (150 mL) at −40 ° C. at diisobutylaluminum hydride (1M methylene chloride). Solution, 36 mL, 2.2 eq.) Was allowed to react dropwise. The reaction was stirred for 15 minutes after the addition was complete, quenched with 10% aqueous sodium potassium tartrate, and stirred at 25 ° C. for 1 hour. The organic layer was separated, filtered through Celite (registered trademark; diatomaceous earth), and the filtrate was concentrated under reduced pressure. The resulting oil was purified by flash chromatography on silica gel using a Biotage-40s column eluting with 2:98 methanol / methylene chloride to give the title compound as an oil (4 .32 g, 95%).

Example 309E
3- (Benzylthio) -4-[(methoxymethoxy) methyl] -2- nitrothiophene A solution of the product of Example 309D (3.9 g, 13.9 mmol) in methylene chloride (8 mL) was added diisopropylethylamine (7.42 mL, 3 equivalents) and methoxymethyl chloride (2.38 mL, 2.25 equivalents) at 25 ° C. for 16 hours. The reaction was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a Biotage-40m column eluting with methylene chloride to give the title compound as a yellowish oil (4. 32g, 94%).

Example 309F
4-[(Methoxymethoxy) methyl] -2- nitrothiophene -3-sulfonamide A solution of the product of Example 309E (4 g, 12.3 mmol) in methylene chloride (70 mL) and 1N aqueous hydrochloric acid (35 mL) at 0 ° C. The mixture was reacted with chlorine gas blown slowly over 0.5 hours, and further stirred for 1 hour. The reaction mixture was purged with nitrogen gas to remove excess chlorine, and solid sodium sulfite (11 g) was slowly added to the mixture as it was stirred for 5 minutes. Methylene chloride (15 mL) and water (15 mL) were added and the organic layer was separated and eluted with 40 g of a 50:50 mixture of MgSO ₄ / Na ₂ SO ₄ . The filtrate was concentrated under reduced pressure. Ammonia gas was bubbled into a methylene chloride (100 mL) solution of the concentrate (4.7 g) at −40 ° C. over 10 minutes. The reaction mixture was stirred for an additional 15 minutes and purged with nitrogen gas to drive off excess ammonia and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel using a Biotage-40s column eluting with 5:95 methanol / methylene chloride to give the title compound as an oil (2.3 g, 66%).

Example 309G
2-Amino-4-[(methoxymethoxy) methyl] thiophene-3-sulfonamide The product of Example 309F (1.8 g, 6.4 mmol) was added in acetic acid (70 mL) at 50 ° C. for 7.5 hours. Reacted with iron powder (1.43 g, 4 eq) and then concentrated under reduced pressure. A slurry of the residue in 5% methanol / methylene chloride (60 mL) and water (6 mL) was filtered through silica gel (20 g) and further washed with 5% methanol / methylene chloride (300 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a Biotage-12s column eluting with 2.5: 97.5 methanol: methylene chloride to give the title compound. (1 g, 62%).

Example 309H
1-benzyl-4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} Quinoline-2 (1H) -one The product of Example 309G (35 mg, 0.14 mmol) and the product of Example 309B (50 mg, 0.14 mmol) were reacted in toluene (3 mL) at 100 ° C. for 3 hours. I let you. The resulting precipitate was collected by filtration and washed with toluene and diethyl ether to give the title compound (52 mg, 73.3%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 310
1-benzyl-4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} quinoline-2 (1H) -On A suspension of the product of Example 309H (46 mg, 0.09 mmol) in 6N aqueous hydrochloric acid (2.5 mL) and tetrahydrofuran (5 mL) was heated at 70 ° C. for 4 hours, cooled to 25 ° C. And left at room temperature for 18 hours. The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound (39 mg, 92.8%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 311A
The title compound was prepared according to the procedure described in N- (tert-butyl) -5-chlorothiophene-2-sulfonamide literature (Unterhalt, B, Moghaddam, S. Pharmazie, 1994, 49, 115-117).

Example 311B
3-Azido-N- (tert-butyl) -5-chlorothiophene-2-sulfonamide Example 311A (1.01 g, 3.99 mmol) in tetrahydrofuran (32 mL) at −78 ° C., sec-BuLi (1 4M hexane solution, 2.1 equivalents) was added dropwise. The reaction was warmed to −20 ° C., stirred for 30 minutes, treated with a solution of tosyl azide (1.1 eq) in tetrahydrofuran (7 mL) at −20 ° C., and stirred at 25 ° C. for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 30% methylene chloride / hexane to 100% methylene chloride to give an approximately 2: 1 mixture of starting material / title compound.

Example 311C
3-Amino-5-chloro-N-isopropylthiophene-2-sulfonamide To a solution of the product of Example 311B (0.739 g) in toluene (20 mL) and hexadecyltributylphosphonium bromide (0.128 g, 0.25 mmol) At 0 ° C., a solution of sodium borohydride (0.109 g, 2.9 mmol) in water (0.80 mL) was added dropwise. The reaction was stirred at 25 ° C. for 18 hours and at 5 ° C. for 72 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 1: 1 hexane / methylene chloride to 100% methylene chloride to give the title compound (0.252 g, 23%).

Example 311D
3-Amino-5-chloro-N-isopropylthiophene-2-sulfonamide trifluoroacetate salt A solution of the product of Example 311C (0.0998 g) in trifluoroacetic acid (3.9 mL) was stirred at 25 ° C. for 18 hours. did. The reaction was concentrated under reduced pressure and azeotroped with ethyl acetate three times to give the title compound as the trifluoroacetate salt (0.160 g).

Example 311E
1-Benzyl-3- (6-chloro-1,1-dioxide-4H-thieno [3,2-e] [1,2,4] thiadiazin-3-yl) -4-hydroxyquinoline-2 (1H) - instead of the product of one example 309G using the product of example 311D, in the presence of diisopropylethylamine (3 eq) the title compound was prepared according to the procedure of example 309 h. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 312A
5-Bromo-4-nitro-1H-imidazole 4-bromo-1H-imidazole (2.0 g, 13.6 mmol) was added to a solution of concentrated nitric acid (0.947 mL, 14.96 mmol) in concentrated sulfuric acid (20 mL) at 110 ° C. For 1 hour. The reaction solution was cooled to 25 ° C. and poured into 200 mL of ice water. The resulting white precipitate was collected by filtration to give the title compound (2.3 g, 87%).

Example 312B
1-Benzyl-5-bromo-4-nitro-1H-imidazole A solution of the product of Example 312A (2.3 g, 11.98 mmol) in dehydrated N, N-dimethylformamide (40 mL) at 25 ° C. and sodium bicarbonate. (2.0 g, 24 mmol) and benzyl bromide (1.58 mL, 13.17 mmol) was added dropwise. The reaction was stirred at 25 ° C. for a further 12 hours. The reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on a C18 column eluting with a gradient of acetonitrile / water (containing 0.1% trifluoroacetic acid) (5:95 to 100) to give the title compound ( 1.63 g, 48%).

Example 312C
1-Benzyl-4-nitro-1H-imidazole-5-ammonium thiolate A solution of the product of Example 312B in 5N ammonium hydroxide (16 mL) and dioxane (10 mL) was bubbled with hydrogen sulfide gas at 35 ° C. for 15 minutes. . The reaction flask was sealed and stirring was continued for 1 hour. The reaction was purged with nitrogen gas for 10 minutes and concentrated under reduced pressure to give the title compound.

Example 312D
1-Benzyl-4-nitro-1H-imidazole-5-sulfonyl chloride A solution of the product of Example 312C in 1N HCl (20 mL) and dioxane (10 mL) was bubbled with chlorine gas at 30 ° C. for 15 minutes. The reaction flask was sealed and the reaction mixture was stirred for 1 hour. Chlorine addition was repeated as above and the reaction mixture was stirred for an additional hour. The reaction was cooled with an ice bath. Cold water was added to the reaction and the resulting precipitate was collected by filtration to give the title compound (1.51 g, 87% over 2 steps).

Example 312E
1-Benzyl-4-nitro-1H-imidazole-5-sulfonamide Ammonia gas was bubbled into a dioxane (25 mL) solution of the product of Example 312D (1.5 g, 4.97 mmol) at 25 ° C. for 10 minutes. The reaction flask was sealed and the reaction mixture was stirred for an additional 30 minutes. This above process was repeated. The reaction mixture was concentrated under reduced pressure and the residue was washed several times with cold water to give the title compound (1.27 g, 90%).

Example 312F
4-Amino-1-benzyl-1H-imidazole-5-sulfonamide A solution of the product of Example 312E (434 mg, 1.54 mmol) in acetic acid (4.3 mL) and dioxane (4.3 mL) was added at 50 ° C. Reacted with iron powder (343 mg, 6.15 mmol) over time. The reaction mixture was cooled to 25 ° C., filtered through a Celite (registered trademark; diatomaceous earth) layer, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with methylene chloride (twice) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using a gradient of methanol / methylene chloride (0% to 5%) to give the title compound (180 mg, 46%).

Example 312G
1-Benzyl-3- (7-benzyl-1,1-dioxide-4,7-dihydroimidazo [4,5-e] [1,2,4] thiadiazin-3-yl) -4-hydroxyquinoline-2 (1H) -On The product of Example 312F (152 mg, 0.602 mmol) was reacted with the product of Example 309B (214 mg, 0.602 mmol) in toluene (8 mL) at 100 ° C. for 3 hours. . The reaction was allowed to cool to 25 ° C. and diluted with hexane. The resulting precipitate was collected by filtration. The residue was chromatographed on silica gel eluting with a gradient of 0% to 2% methanol / methylene chloride to give the title compound (155 mg, 50%).

Example 313
1-Benzyl-3- (1,1-dioxide-4,7-dihydroimidazo [4,5-e] [1,2,4] thiadiazin-3-yl) -4-hydroxyquinoline-2 (1H)- Dehydrated dimethyl sulfoxide (2.5 mL) of the product of On Example 312 (19.35 mg, 0.0378 mmol) was added to a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 0.265 mL, 0.265 mmol) at 25 ° C. for 12 hours. ). The reaction was quenched by adding saturated aqueous ammonium chloride and extracted with methylene chloride. The aqueous layer was basified with sodium bicarbonate solution and extracted twice with methylene chloride. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a reverse phase C18 column eluting with 5% to 100% acetonitrile / water (containing 0.1% trifluoroacetic acid) to give the title compound (17 mg, 81%).

Example 314
N ² - {3- [4- hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl} glycinamide To a solution of the product of Example 206 (10.8 mg, 0.023 mmol) in concentrated sulfuric acid (0.6 mL), water (0.1 mL) was added slowly. The resulting yellow solution was stirred at 25 ° C. for 18 hours. The reaction mixture was poured into ice and the pH was adjusted to pH 9 with 50% NaOH and aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (9.1 mg, 83%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 315A
1-butyl-4-hydroxy-1,8-naphthyridin-2 (1H) -one A slurry of the product of Example 89A (3.24 g, 11.16 mmol) in 2N sodium hydroxide (100 mL) was heated to reflux for 3 hours. The solution was cooled to 10 ° C., and concentrated hydrochloric acid was added dropwise to obtain a constant pH of 3. The resulting white solid was collected by filtration, washed with water and dried to give the title compound (2.47 g, quantitative).

Example 315B
3- [Bis (methylthio) methylene] -1-butyl-1,8-naphthyridine-2,4 (1H, 3H) -dione Performed using the product of Example 315A instead of the product of Example 309A The title compound was prepared according to the procedure of Example 309B.

Example 315C
1-butyl-4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} -1,8 -naphthyridin-2 (1H) -one The product of Example 309G (110 mg, 0.43 mmol) and the product of Example 315B (140.6 mg, 0.43 mmol) were dissolved in toluene (5 mL). And reacted at 100 ° C. for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using a Biotage-12m column eluting with 1:99 methanol: methylene chloride to give the title compound as a white solid ( 114 mg, 54.6%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 316
1-butyl-4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1, 8-Naphthyridin-2 (1H) -one The product of Example 315C (92 mg, 0.19 mmol) was reacted with 6N aqueous hydrochloric acid (4 mL) and tetrahydrofuran (8 mL) at 70 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran and treated with methanol (5 mL). The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound as a white solid (65 mg, 77.8%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 317A
Methyl 4- (aminosulfonyl) -5- nitrothiophene -3-carboxylate A solution of the product of Example 309A (2 g, 6.5 mmol) in methylene chloride (38 mL) and 1.5N aqueous hydrochloric acid (21 mL) at 0 ° C. Then, chlorine gas was blown in over 30 minutes. The reaction flask was sealed and stirred for an additional hour. Nitrogen gas was blown into the reaction solution to drive out chlorine, and then solid sodium sulfite (5.12 g) was added and stirred for 5 minutes. Methylene chloride (10 mL) and water (10 mL) were added to the reaction. The organic layer was separated and eluted through 20 g of a 1: 1 mixture of magnesium sulfate and sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was triturated with hexanes to give the sulfonyl chloride as a white solid (1.8 g, 97%). A solution of crude sulfonyl chloride (1.5 g) in methylene chloride (15 mL) was bubbled with ammonia gas at −40 ° C. over 5 minutes. The reaction flask was sealed and stirred for an additional 15 minutes. Nitrogen gas was bubbled through the reaction mixture to drive off the ammonia. The reaction solution was concentrated under reduced pressure while maintaining the temperature at 0 ° C. The residue was chromatographed on silica gel using a Biotage-40s column eluting with 5:95 methanol: methylene chloride to give an oil. The oil was triturated with 5% methanol: methylene chloride (20 mL) and hexane (20 mL) to give the title compound as a yellow solid (0.75 g, 54%).

Methyl 5-amino-4- (aminosulfonyl) thiophene-3-carboxylate The product of Example 317A (0.75 g, 2.86 mmol) was iron in acetic acid (30 mL) at 50 ° C. for 7.5 hours. Reacted with flour (0.64 g, 4 equivalents). The reaction is concentrated under reduced pressure and the residue is slurried with 5% methanol: methylene chloride (20 mL) and water (2 mL) and filtered through a short silica gel column (20 g) which is added to 5% methanol: methylene chloride (200 mL). ). The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using a Biotage-12s column eluting with 1: 1 ethyl acetate / hexane to give the title compound as a yellow solid (0. 0. 527g, 78%).

Example 317C
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxylic acid Methyl 1,1-dioxide The product of Example 317B (180 mg, 0.76 mmol) and the product of Example 309B (270 mg, 0.76 mmol) were reacted in toluene (15 mL) at 100 ° C. for 3 hours. It was. The reaction was cooled to 25 ° C. and the resulting precipitate was collected by filtration and washed with toluene and diethyl ether to give the title compound (302 mg, 80%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 318
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxylic acid 1,1- Dioxide The product of Example 317C (90 mg, 0.09 mmol) was dissolved in 1N aqueous sodium hydroxide (0.8 mL, 4.4 eq) in ethanol (2 mL) at 70 ° C. for 1.5 h. And reacted. The reaction solution was filtered, and the filtrate was acidified with 1N aqueous hydrochloric acid solution (0.8 mL). The resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound (80 mg, 91.5%).

  The disodium salt of the title compound was prepared according to the procedure of Example 1D using 2 equivalents of sodium hydroxide instead of 1 equivalent of sodium hydroxide.

Example 319
3-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1,1- product dioxide example 317C (25 mg, 0.05 mmol) was suspended in ammonium hydroxide (1 mL) and heated 16 hours at 40 ° C.. The reaction mixture was cooled to 25 ° C., concentrated under reduced pressure to remove excess ammonia, and a solution of 1N HCl (0.8 mL), MeOH (1 mL) and water (3 mL) was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound (19 mg, 78.4%).

  The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 320A
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1-{[cyclopropylmethylene] amino} -4-hydroxyquinoline- 2 (1H) -one A solution of the product of Example 304F (0.800 g, 1.73 mmol) and cyclopropanecarboxaldehyde (1.60 mL, 20.76 mmol) in N, N-dimethylacetamide (2 mL) was microwaved. The reaction was allowed to proceed for 60 minutes at 120 ° C. in a sealed tube in the reactor. The reaction solution was concentrated under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.750 g, 84%).

Example 320B
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1-[(cyclopropylmethyl) amino] -4-hydroxyquinoline- 2 (1H) -one A solution of the product of Example 320A (0.75 g, 1.46 mmol) in tetrahydrofuran (8 mL) and methanol (0.100 mL) at 0 ° C., lithium borohydride (2.0 M tetrahydrofuran solution, (1.0 mL, 2.0 mmol). The reaction was stirred at 25 ° C. for 1 hour, diluted with 1M aqueous hydrochloric acid and filtered. The product was purified by trituration with methyl sulfoxide, filtered and dried to give the title compound (0.296 g, 40%).

Example 320C
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) quinoline-2 (1H ) -On a solution of the product of Example 320B (0.296 g, 0.57 mmol) in tetrahydrofuran (15 mL) at 60 ° C. over 2 hours over a catalytic amount of palladium hydroxide / carbon, catalytic amount of 5% palladium / carbon and Reacted with ammonium formate (0.180 g, 2.85 mmol). The warm reaction mixture was filtered through Celite (registered trademark; diatomaceous earth), the filtrate was diluted with diethyl ether, the precipitate was filtered and dried to give the title compound (0.127 g, 53%).

Example 320D
2-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl) oxy] acetamide The product of Example 320C (0.125 g, 0.29 mmol) was carbonated in N, N-dimethylformamide (3 mL) at 25 ° C. for 2 hours. Reacted with cesium (0.38 g, 1.17 mmol), 2-bromoacetamide (0.060 g, 0.43 mmol) and a catalytic amount of tetrabutylammonium iodide. The reaction solution was concentrated to a half volume under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.134 g, 95%). MS (ESI-) m / z482 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 321A
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1-{[2-methylpropylidene] amino} Quinoline-2 (1H) -one A solution of the product of Example 304F (0.150 g, 0.32 mmol) and isobutyraldehyde (0.44 mL, 4.84 mmol) in N, N-dimethylacetamide (1.5 mL) was added. The reaction was carried out at 125 ° C. for 40 minutes in a sealed tube in a microwave reactor. The reaction solution was concentrated under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.140 g, 84%).

Example 321B
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (isobutylamino) quinoline-2 (1H) On solution of the product of Example 321A (0.140 g, 0.27 mmol) in tetrahydrofuran (3 mL) and methanol (0.020 mL) at 0 ° C., lithium borohydride (2.0 M tetrahydrofuran solution, 0.20 mL, 0.40 mmol). The reaction was stirred at 25 ° C. for 1 hour, diluted with 1M aqueous hydrochloric acid and filtered. The product was purified by dissolving in tetrahydrofuran, absorbing onto silica gel, loading onto a silica gel column and eluting with methylene chloride. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.081 g, 58%).

Example 321C
4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (isobutylamino) quinolin-2 (1H) -one The product of Example 321B (0.081 g, 0.16 mmol) in tetrahydrofuran (10 mL) was charged with catalytic amounts of palladium hydroxide / carbon, catalytic amounts of 5% palladium / carbon and ammonium formate (0. 040 g, 0.64 mmol). The warm reaction mixture was filtered through Celite® (diatomaceous earth) and the filtrate was evaporated under reduced pressure to give the title compound (0.048 g, 72%).

Example 321D
2-({3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) acetamide The product of Example 321C (0.048 g, 0.11 mmol) was added in N, N-dimethylformamide (3 mL) at 25 ° C. for 2 hours at 0 ° C. 11 g, 0.34 mmol), 2-bromoacetamide (0.023 g, 0.17 mmol) and a catalytic amount of tetrabutylammonium iodide. The reaction solution was concentrated to a half volume under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.042 g, 77%). MS (ESI-) m / z484 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 322A
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- [butylideneamino] -4-hydroxyquinoline-2 (1H ) -On a solution of the product of Example 304F (0.150 g, 0.32 mmol) and butyraldehyde (0.29 mL, 3.24 mmol) in N, N-dimethylacetamide (1.5 mL) was placed in a microwave reactor. And allowed to react at 120 ° C. for 25 minutes in a sealed tube. The reaction solution was concentrated under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.134 g, 80%).

Example 322B
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1- (butylamino) -4-hydroxyquinoline-2 (1H) On solution of the product of Example 322A (0.134 g, 0.26 mmol) in tetrahydrofuran (3 mL) and methanol (0.020 mL) at 0 ° C., lithium borohydride (2.0 M tetrahydrofuran solution, 0.195 mL, 0.39 mmol). The reaction was stirred at 25 ° C. for 1 hour, diluted with 1M aqueous hydrochloric acid and filtered. The product was dissolved in tetrahydrofuran, absorbed onto silica gel, purified on a silica gel column and eluted with methylene chloride. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.045 g, 33%).

Example 322C
1- (Butylamino) -4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) quinolin-2 (1H) -one A solution of the product of Example 322B (0.045 g, 0.087 mmol) in tetrahydrofuran (8 mL) was charged with catalytic amounts of palladium hydroxide / carbon, catalytic amounts of 5% palladium / carbon and ammonium formate (0 0.03 g, 0.48 mmol). The warm reaction mixture was filtered through Celite (registered trademark; diatomaceous earth) and the filtrate was evaporated under reduced pressure to give the title compound (0.038 g, 100%).

Example 322D
2-({3- [1- (Butylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiazin-7-yl} oxy) acetamide The product of Example 322C (0.038 g, 0.089 mmol) was added in N, N-dimethylformamide (3 mL) at 25 ° C. for 2 hours at 0 ° C. 087 g, 0.27 mmol), 2-bromoacetamide (0.018 g, 0.13 mmol) and a catalytic amount of tetrabutylammonium iodide. The reaction solution was concentrated to a half volume under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.041 g, 95%). MS (ESI-) m / z484 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 323A
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1-{[(1E) -3-methylbuty Reden] amino} quinolin-2 (1H) -one The product of Example 304F (0.220 g, 0.48 mmol) and isovaleraldehyde (0.77 mL, 7.18 mmol) in N, N-dimethylacetamide (1. 5 mL) solution was reacted for 35 minutes at 130 ° C. in a sealed tube in a microwave reactor. The reaction solution was concentrated under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.181 g, 72%).

Example 323B
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1-[(3-methylbutyl) amino] quinoline- 2 (1H) -one A solution of the product of Example 323A (0.061 g, 0.11 mmol) in tetrahydrofuran (3 mL) and methanol (0.010 mL) at 0 ° C., lithium borohydride (2.0 M tetrahydrofuran solution, 0.09 mL, 0.18 mmol). The reaction was stirred at 25 ° C. for 1 hour, diluted with 1M aqueous hydrochloric acid and filtered. The product was purified by dissolving in tetrahydrofuran, absorbing onto silica gel, loading onto a 2 g Alltec Seppac and eluting with methylene chloride. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.037 g, 62%).

Example 323C
4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(3-methylbutyl) amino] quinoline-2 (1H ) -On a solution of the product of Example 323B (0.037 g, 0.07 mmol) in tetrahydrofuran (8 mL) at 60 ° C. over 30 minutes with catalytic amounts of palladium hydroxide / carbon, catalytic amounts of 5% palladium / carbon and Reacted with ammonium formate (0.018 g, 0.29 mmol). The warm reaction mixture was filtered through Celite® (diatomaceous earth) and the filtrate was evaporated under reduced pressure to give the title compound (0.025 g, 80%).

Example 323D
2-[(3- {4-hydroxy-1-[(3-methylbutyl) amino] -2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl) oxy] acetamide The product of Example 323C (0.025 g, 0.057 mmol) was carbonated in N, N-dimethylformamide (3 mL) at 25 ° C. for 2 hours. Reacted with cesium (0.055 g, 0.17 mmol), 2-bromoacetamide (0.012 g, 0.087 mmol) and a catalytic amount of tetrabutylammonium iodide. The reaction solution was concentrated to a half volume under a nitrogen stream heated through a manifold heated to 165 ° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.020 g, 72%). MS (ESI-) m / z 498 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 324A
4-amino-N- [2- (aminosulfonyl) -4- (benzyloxy) phenyl] -7-hydroxy-5-oxo-4,5-dihydrothieno [3,2-b] pyridine-6-carboxamide and N -[2- (aminosulfonyl) -4- (benzyloxy) phenyl] -7-hydroxy-5-oxo-4-{[(1E) -phenylmethylene] amino} -4,5-dihydrothieno [3,2- b] Pyridine-6-carboxamide A solution of the product of Example 304D (1.55 g, 5.57 mmol) and the product of Example 268C (1.27 g, 3.71 mmol) in toluene (100 mL) Reacted for hours. The cooled slurry was filtered, washed with 25 mL toluene and dried to give the title compound.

Example 324B
4-Amino-6- [7- (benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -7-hydroxythieno [3,2-b] pyridine -5 (4H) -one The product of Example 324A (1.95 g, 3.7 mmol) was reacted with 10% aqueous potassium hydroxide (100 mL) at reflux for 24 hours, cooled to 25 ° C., Acidified to pH 2 with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed repeatedly with water and dried to give the title compound (2.05 g, 100%). MS (ESI-) m / z 467 (MH) ^- .

Example 324C
6- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4- (cyclohexylideneamino) -7-hydroxythieno [3 2-b] pyridin-5 (4H) -one A solution of the product of Example 324B (0.20 g, 0.42 mmol) and cyclohexanone (2.0 g, 20 mmol) in N, N-dimethylacetamide (4 mL) The reaction was carried out at 130 ° C. for 60 minutes in a sealed tube in a wave reactor. The solvent was removed under reduced pressure and the resulting residue was triturated with diethyl ether (8 mL), filtered and dried to give the title compound (0.167 g, 73%).

Example 324D
6- [7-Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4- (cyclohexylamino) -7-hydroxythieno [3,2-b ] Pyridine-5 (4H) -one A solution of the product of Example 324C (0.167 g, 30 mmol) in tetrahydrofuran (6 mL) and methanol (0.030 mL, 0.8 mmol) at 0 ° C. with lithium borohydride (2 Reaction with 0.0 M tetrahydrofuran solution, 0.250 mL, 0.50 mmol). The reaction was stirred at 25 ° C. for 1.5 hours, acidified to pH 2 with 1M aqueous hydrochloric acid and diluted with water (25 mL). The resulting precipitate was collected by filtration and dried to a constant weight to give the title compound (0.114 g, 69%). MS (APCI +) m / z 551 (M + H) ^<+> .

Example 324E
4- (Cyclohexylamino) -7-hydroxy-6- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) thieno [3,2-b] pyridine -5 (4H) -one A solution of the product of Example 324D (0.114 g, 0.21 mmol) in dehydrated acetonitrile (11 mL) at 25 ° C. with iodotrimethylsilane (0.29 mL, 2.1 mmol) at 50 ° C. The reaction was performed for 4 hours. The reaction was cooled to 25 ° C. and diluted with water (50 mL). The resulting precipitate was collected by filtration and dried in vacuo to give the title compound (0.083 g, 87% yield).

Example 324F
2-({3- [4- (cyclohexylamino) -7-hydroxy-5-oxo-4,5-dihydrothieno [3,2-b] pyridin-6-yl] -1,1-dioxide-4H-1 , 2,4-Benzothiadiazin-7-yl} oxy) acetamide The product of Example 324E (0.209 g, 0.45 mmol) was added in N, N-dimethylformamide (8 mL) at 25 ° C. for 18 hours. Reacted with cesium carbonate (0.589 g, 1.81 mmol), 2-bromoacetamide (0.125 g, 0.91 mmol) and a catalytic amount of tetrabutylammonium iodide over time. The reaction was diluted with 50 mL of water and acidified to pH 2 with 1M hydrochloric acid. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel eluting with 5% methanol / chloroform to give the title compound (0.050 g, 21% yield). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 325
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- (2-hydroxyethyl) -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg, 1. 48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) were stirred at room temperature for 15 min. To the mixture was added ethanolamine (2.8 μL, 1.1 eq) followed by N-methylmorpholine (8 μL, 1.72 eq) and the solution was stirred for 16 h. Add 1N hydrochloric acid solution (4 mL),
The resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (18.7 mg, 85.8%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

79523 Example 326
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -2-hydroxy-1- (aminocarbonyl) ethyl] -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3- A solution of ethylcarbodiimide hydrochloride (11.76 mg, 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 min. did. To the mixture was added L-serinamide hydrochloride (6.5 mg, 1.1 eq) and then N-methylmorpholine (12.6 μL, 2.72 eq) and the solution was stirred for 16 hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (17.1 mg, 73%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 327
N- (2-amino-2-oxoethyl) -3- (1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [ 1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg , 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) were stirred at room temperature for 15 min. To the mixture was added glycinamide hydrochloride (5.1 mg, 1.1 eq) and then N-methylmorpholine (14 μL, 3 eq) and the solution was stirred for 3 h. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (17 mg, 76%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 328
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -2-hydroxy-1-methylethyl] -4H-thieno [2, 3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride A solution of the salt (11.76 mg, 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 min. To the mixture was added (S)-(+)-2-amino-1-pronol (3.6 μL, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was 16 Stir for hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (18.4 mg, 82%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 329
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N, N-bis (2-hydroxyethyl) -4H-thieno [2,3-e] [ 1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg , 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) were stirred at room temperature for 15 min. To the mixture was added diethanolamine (4.43 μL, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was stirred for 16 h. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (6.85 mg, 29%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 330
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxy-1- (hydroxymethyl) ethyl] -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride A solution of (11.76 mg, 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 min. To the mixture was added serinol (4.21 mg, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was stirred for 16 h. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (18.2 mg, 79%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 331
1-benzyl-4-hydroxy- (7-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} -1,1-dioxide-4H-thieno [2,3-e] [1,2, 4] Thiadiazin-3-yl) quinolin-2 (1H) -one The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg) , 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) were stirred at room temperature for 15 min. To the mixture was added (R)-(+)-3-pyrrolidinol (3.84 μL, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was stirred for 16 hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (19.8 mg, 87%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 332
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- (3-hydroxypropyl) -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg, 1. 48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) were stirred at room temperature for 15 min. To the mixture was added 2- (methylamino) -ethanol (2.8 μL, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was stirred for 16 hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (19.2 mg, 86%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 333
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(2S) -2,3-dihydroxypropyl] -4H-thieno [2,3- e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( A solution of 11.76 mg, 1.48 equivalents) and 1-hydroxybenzotriazole (8.66 mg, 1.54 equivalents) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 minutes. To the mixture was added (S)-(−)-3-amino-1,2-propanediol (4.21 mg, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq), The solution was stirred for 16 hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (18.4 mg, 80%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 334
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -1- (hydroxymethyl) propyl] -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride A solution of (11.76 mg, 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 min. To the mixture was added (S)-(+)-2-amino-1-butanol (4.36 μL, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was added to 16 Stir for hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (16.5 mg, 72%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 335
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3- A solution of ethylcarbodiimide hydrochloride (11.76 mg, 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 min. did. To the mixture was added (S)-(+)-2-amino-3-methyl-1-butanol (5.15 μL, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq). The solution was stirred for 16 hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (18.8 mg, 80%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 336
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxybutyl] -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg, 1. 48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) were stirred at room temperature for 15 min. To the mixture was added 1-amino-2-butanol (4.43 μL, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was stirred for 16 hours. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (19.97 mg, 87%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 337
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -4H-thieno [2 , 3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide A solution of hydrochloride (11.76 mg, 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 minutes. To the mixture was added octopamine hydrochloride (8.6 mg, 1.1 eq) and then N-methylmorpholine (12.6 μL, 2.72 eq) and the solution was stirred for 16 h. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (13.58 mg, 53%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 338
1-Benzyl-3- [1,1-dioxide-7- (piperazin-1-ylcarbonyl) -4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -4- Hydroxyquinolin-2 (1H) -one The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg, 1.48 eq) and A solution of 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) was stirred at room temperature for 15 minutes. To the mixture was added piperazine (4 mg, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was stirred for 16 h. Water (5 mL) was added and the resulting precipitate was collected by filtration and washed with water, methanol and diethyl ether to give the title compound as a white solid (18.3 mg, 80.16%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 339
N- [5- (aminocarbonyl) pyridin-2-yl] -3- (1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide The product of Example 318 (20 mg, 0.042 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.76 mg, 1.48 eq) and 1-hydroxybenzotriazole (8.66 mg, 1.54 eq) in N, N-dimethylformamide (0.4 mL) were stirred at room temperature for 15 min. To the mixture was added 6-aminonicotinamide (6.33 mg, 1.1 eq) and then N-methylmorpholine (8 μL, 1.72 eq) and the solution was heated at 70 ° C. for 16 h. 1N hydrochloric acid solution (4 mL) was added and the resulting precipitate was collected by filtration and washed with water and diethyl ether. The solid was dissolved in 5% methanol / methylene chloride containing 2 drops of triethylamine and purified by flash chromatography on silica gel using a Biotage-12s column eluting with 10:90 methanol / methylene chloride to give the title compound as white Obtained as a solid (5.4 mg, 21.6%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 340A
Ethyl 2- (isopentylamino) nicotinate 2-ethyl chloronicotinate (3.71 g, 20 mmol), isoamylamine (3.03 mL, 26 mmol) and triethylamine (3.62 mL, 26 mmol) in a sealed tube at 140 ° C. For 8 hours, cooled to 25 ° C., diluted with ethyl acetate, and the mixture was washed with water. The organic layer was extracted with 1N aqueous hydrochloric acid. The acidic aqueous layer was adjusted to pH 8.0 with saturated sodium bicarbonate solution and extracted with ethyl acetate (twice). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (3.58 g, 76%).

Example 340B
2- ( Isopentylamino ) nicotinic acid A mixture of Example 340A (1.73 g, 7.31 mmol), 1N aqueous sodium hydroxide (14.6 mL) and methanol (7 mL) was stirred for 18 hours and diluted with water. The aqueous mixture was washed with ethyl acetate and then methylene chloride and adjusted to pH 7.5 with 1N aqueous hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water and air dried to give the title compound (424.4 mg, 28%).

Example 340C
4-hydroxy-1- (3-methylbutyl) -1,8 -naphthyridin-2 (1H) -one A mixture of Example 340B (1 g, 4.81 mmol), acetic anhydride (10 mL) and glacial acetic acid (10 mL) was prepared. Heated at ° C for 2 hours. The mixture was cooled to 25 ° C. and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with a step gradient from 0% to 100% hexane / ethyl acetate to give the title compound (100 mg, 9%).

Example 340D
3- [Bis (methylthio) methylene] -1-butyl-1,8-naphthyridine-2,4 (1H, 3H) -dione The product of Example 340C (0.2 g, 0.86 mmol) in dimethylformamide (7 mL ) The solution was treated with sodium hydride (76 mg, 60% in mineral oil, 2.2 eq), stirred at 25 ° C. for 30 min, treated with carbon disulfide (0.14 g, 2.2 eq), 50 ° C. For 6 hours, cooled to 25 ° C., and treated with methyl iodide (0.27 g, 2.2 eq). The mixture was stirred at 25 ° C. for 18 hours and concentrated. The residue was triturated with water and the resulting solid was filtered and dried in vacuo to give the title compound (0.23 g, crude yield 80%).

Example 340E
4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} -1- ( 3- Methylbutyl) -1,8 -naphthyridin-2 (1H) -one The product of Example 309G (37.5 mg, 0.15 mmol) and the product of Example 340D (50 mg, 0.15 mmol) were dissolved in toluene ( (5 mL) at 100 ° C. for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using a Biotage-12m column eluting with 2:98 methanol: methylene chloride to give the title compound as a yellow solid. (36 mg, 49%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 341
4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1- (3-methylbutyl ) -1,8 -naphthyridin-2 (1H) -one The product of Example 340C (23 mg, 0.05 mmol) was reacted with 6N aqueous hydrochloric acid (1 mL) in tetrahydrofuran (2 mL) at 70 ° C. for 3 hours. I let you. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran and treated with methanol (5 mL). The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound as a white solid (13 mg, 62%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 342
[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] A thiadiazin-7-yl] methylcarbamate suspension of the product of Example 310 (40 mg, 0.086 mmol) in N, N-dimethylformamide (2 mL) and acetonitrile (0.6 mL) at −20 ° C. And treated with chlorosulfonyl isocyanate (16.4 μL, 2.2 eq). The mixture was stirred at −20 ° C. for 0.5 h, 0 ° C. for 2 h, 6N hydrochloric acid (2 mL) was added and the mixture was heated at 70 ° C. for 2.5 h. The mixture was cooled, water (10 mL) was added and the resulting precipitate was collected by filtration and washed with water and diethyl ether. The solid was dissolved in 5% methanol / methylene chloride containing a few drops of triethylamine and purified by flash chromatography on silica gel using a Biotage-12s column eluting with 6:94 methanol / methylene chloride to give the title compound as white Obtained as a solid (23 mg, 52.6%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 343
[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] A thiadiazin-7-yl] methylaminocarbonylcarbamate suspension of the product of Example 310 (40 mg, 0.086 mmol) in N, N-dimethylformamide (2 mL) and acetonitrile (0.6 mL) at -20 Treated with chlorosulfonyl isocyanate (16.4 [mu] L, 2.2 eq) at [deg.] C. The mixture was stirred at −20 ° C. for 0.5 h and 0 ° C. for 2 h, 6N hydrochloric acid (2 mL) was added and the mixture was heated at 70 ° C. for 2.5 h. The mixture was cooled, water (10 mL) was added and the resulting precipitate was collected by filtration and washed with water and diethyl ether. The solid is purified by flash chromatography on silica gel using a Biotage-12s column dissolved in 5% methanol / methylene chloride containing a few drops of triethylamine and eluting with 6:94 methanol / methylene chloride to give the title compound. Obtained (6 mg, 12.7%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 344
3- [7- (Azidomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-benzyl-4-hydroxyquinoline-2 ( 1H) -one To a solution of the product of Example 310 (156.4 mg, 0.33 mmol) in methylene chloride (3 mL) was added 1,8-diazabicyclo [5.4.0] undec-7-ene (0.37 mL, 2.47 mmol) and diphenylphosphoryl azide (0.54 mL, 2.50 mmol) were added at room temperature. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with ethanol, and aqueous hydrogen chloride solution (1N, 2 mL) was slowly added, resulting in precipitation. The solid was filtered and washed with a solution of ethanol / water (2: 1) to give the title compound as a light brown solid (124.47 mg, 76%).

Example 345
3- [7- (Aminomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-benzyl-4-hydroxyquinoline-2 (1H) -one To a solution of the product of Example 344 (136.2 mg, 0.28 mmol) in pyridine (1.68 mL) and concentrated ammonium hydroxide (1.12 mL), triphenylphosphine (145 mg, 0.55 mmol). Was added at room temperature. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with toluene and the solid was filtered to give the title compound as a light brown solid (100.78 mg, 78%).

Example 346
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} methanesulfonamide To a solution of the product of Example 345 (15 mg, 0.032 mmol) in tetrahydrofuran (0.4 mL) was added triethylamine (0.018 mL, 0.129 mmol) and then Was added 1,8-diazabicyclo [5.4.0] undec-7-ene (0.018 mL, 0.129 mmol). The mixture was cooled to 0 ° C. and methanesulfonyl chloride was added (0.003 mL, 0.032 mmol). The mixture was stirred at 0 ° C. for 2.5 hours, warmed to 23 ° C. and stirred for 2.5 hours. Additional 1,8-diazabicyclo [5.4.0] undec-7-ene (0.010 mL, 0.064 mmol) and methanesulfonyl chloride (0.003 mL, 0.032 mmol) were added and the mixture was stirred at 23 ° C. for 15 Stir for hours. A few drops of N, N-dimethylformamide were added to increase the solubility. Additional methanesulfonyl chloride (0.003 mL, 0.032 mmol) was added and the reaction mixture was stirred at 23 ° C. for 3 hours. A few drops of N, N-dimethylformamide and methanesulfonyl chloride (0.003 mL, 0.032 mmol) were added and the reaction mixture was stirred at 23 ° C. for 1 hour. Additional methanesulfonyl chloride (0.006 mL, 0.064 mmol) was added and the reaction mixture was stirred at 23 ° C. for 72 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with diethyl ether and 1N hydrochloric acid was added until no additional precipitation was observed. The precipitate was washed with water and then with diethyl ether. The solid was dissolved in 1% triethylamine / methylene chloride and purified by preparative thin layer chromatography using 5% (5% triethylamine / methanol) / methylene chloride as a developing solution. The silica gel was washed with 10% (5% triethylamine / methanol) / methylene chloride to give the triethylamine salt of the title compound (4.7 mg, 23%).

Example 347
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} nicotinamide To a solution of the product of Example 345 (0.015 g, 0.032 mmol) in tetrahydrofuran (0.4 mL), triethylamine (0.022 mL, 0.160 mmol), And 1,8-diazabicyclo [5.4.0] undec-7-ene (0.020 mL, 0.129 mmol) were added. The mixture was cooled to 0 ° C. and nicotinoyl chloride hydrochloride (0.007 g, 0.035 mmol) was added. The mixture was stirred for 2.5 hours, warmed to 23 ° C. and stirred for 2.5 hours. Additional 1,8 diazabicyclo [5.4.0] undec-7-ene (0.010 mL, 0.068 mmol) and nicotinoyl chloride hydrochloride (0.006 g, 0.032 mmol) were added and the mixture was at 23 ° C. Stir for 15 hours. Additional nicotinoyl chloride hydrochloride (0.006 g, 0.032 mmol) was added and stirred at 23 ° C. for 6 hours. A few drops of N, N-dimethylformamide were added to increase the solubility. Additional nicotinoyl chloride hydrochloride (0.006 g, 0.032 mmol) was added and stirred at 23 ° C. for 72 hours. Hydrochloric acid (4M dioxane solution) (0.095 mL, 0.370 mmol) was added and the reaction mixture was concentrated under reduced pressure. The resulting solid was washed with diethyl ether and water. The solid was dissolved in 1% triethylamine / methylene chloride and purified by preparative thin layer chromatography eluting with 5% (5% triethylamine / methanol) / methylene chloride. The silica gel was washed with 10% (5% triethylamine / methanol) / methylene chloride to give the triethylamine salt of the title compound (0.0068 g, 31%).

Example 348
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} morpholine-4-carboxamide To a solution of the product of Example 345 (0.015 g, 0.032 mmol) in tetrahydrofuran (0.4 mL) was added triethylamine (0.009 mL, .0. 064 mmol) was added. The mixture was cooled to 0 ° C. and 4-morpholine carbonyl chloride (0.004 mL, 0.035 mmol) was added. The reaction mixture was warmed to 23 ° C. and stirred for 15 hours. 1N hydrochloric acid (0.065 mL, 0.064 mmol) was added and the mixture was concentrated under reduced pressure. The product was washed with diethyl ether and water to give the title compound (7.5 mg, 40%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 349
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} -2-hydroxyacetamide To a solution of the product of Example 345 (0.0226 g, 0.048 mmol) in N, N-dimethylformamide (0.5 mL) was added triethylamine (0 .020 mL, 0.145 mmol), 4- (dimethylamino) pyridine (0.018 g, 0.145 mmol), glycolic acid (0.011 g, 0.145 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride (0.028 g, 0.145 mmol) was added. The mixture was stirred at 23 ° C. for 15 hours, heated to 60 ° C. and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with methylene chloride, cooled to 0 ° C., and hydrochloric acid (4M dioxane solution) was added (0.037 mL, 0.145 mmol). The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile / [0.1% trifluoroacetic acid / water] to 95% acetonitrile / [0.1% trifluoroacetic acid / water]. To give the title compound (10.8 mg, 42%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 350A
1-amino-4-hydroxyquinolin-2 (1H) -one A solution of 25% by weight aqueous potassium hydroxide (200 mL) and 1,4-dioxane (50 mL) was heated to 90-100 ° C. while heating to Example 226C. Product (6.72 g, 20.0 mmol) was added in small portions. The reaction mixture was heated to reflux for 90 minutes to cause distillation, and additional water and dioxane (30 mL each) were added to the reaction vessel to bring the initial volume. The mixture was distilled at reflux for an additional 90 minutes, cooled, washed with 200 mL of 1: 1 diethyl ether / ethyl acetate, acidified to pH 2 with concentrated hydrochloric acid, the resulting solid was collected by filtration, washed with water, Drying to constant weight gave the title compound as a tan solid (3.22 g, 91% yield).

Example 350B
2- (4-Hydroxy-2-oxoquinolin-1 (2H) -yl) -1H-isoindole-1,3 (2H) -dione The product of Example 350A (0.54 g, 3 mmol), phthalic anhydride A mixture of (1.36 g, 2.2 eq) and diisopropylethylamine (1.97 g, 5 eq) in dioxane (20 mL) was heated at 100 ° C. for 2 h, cooled to 25 ° C. and concentrated. The residue was triturated with water and ether. The resulting solid was filtered and dried in vacuo to give the title compound (0.6 g, crude yield 64%). It was used directly in the next step.

Example 350C
3- [Bis (methylthio) methylene] -1- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) quinolin-2,4 (1H, 3H) -dione of Example 350B A solution of the product (0.6 g, 1.96 mmol) in acetic acid: pyridine (5: 1, 15 mL) was added to tris (methylthio) methyl methylsulfate (Reference (Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)) (1.6 g, 3 eq) and heated at 100 ° C. for 2 hours. The reaction mixture was treated with ice and the precipitated solid was filtered and dried in vacuo to give 0.53 g (66%) of the title compound.

Example 350D
2- [4-Hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl}- 2- Oxoquinolin -1 (2H) -yl] -1H-isoindole- 1,3 (2H) -dione The product of Example 309G (32.6 mg, 0.13 mmol) and the product of Example 350C (53 mg , 0.13 mmol) was reacted in toluene (3 mL) at 100 ° C. for 3 hours. The resulting precipitate was collected by filtration and washed with methanol and diethyl ether to give the title compound (45 mg, 61.5%).

Example 350E
1-amino-4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} Quinoline-2 (1H) -one The product of Example 350D (185 mg, 0.326 mmol), methylhydrazine (43.47 μL, 2.5 eq) and triethylamine (0.126 mL, 3 eq) in 1,4-dioxane. The (10 mL) solution was heated at 102 ° C. for 3 hours. The reaction was concentrated under reduced pressure and treated with a solution of methanol (75 mL) and 1N hydrochloric acid (100 mL). The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound as a white solid (94 mg, 66%).

Example 350F
1-{[cyclopropylmethylene] amino} -4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-3-yl] quinolin-2 (1H) -one The product of Example 350D (94 mg, 0.22 mmol) was sealed in a microwave reactor in N, N-dimethylacetamide (1 mL). And reacted with cyclopropanecarbaldehyde (0.162 mL, 2.2 mmol) at 120 ° C. for 90 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to give the title compound (78.9 mg, 75%).

Example 350G
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-3-yl] quinolin-2 (1H) -one in a solution of the product of Example 350F (78.9 mg, 0.16 mmol) in tetrahydrofuran (4 mL) and methanol (0.013 mL, 0.32 mmol) at 0 ° C. Then, a 2.0 M lithium borohydride tetrahydrofuran solution (0.131 mL, 0.24 mmol) was added dropwise. The reaction was stirred at 25 ° C. for 1 hour, acidified to about pH 2-4 with 1N hydrochloric acid, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol / methylene chloride to give the title compound (41.6 mg, 52.5%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 351
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazine- 3-yl] quinolin-2 (1H) -one The product of Example 350G (35 mg, 0.07 mmol) was treated at 0 ° C. with 4N hydrogen chloride in 1,4-dioxane (1 mL). The reaction was stirred at 0 ° C. for 2 hours and at 25 ° C. for 3 hours, basified with 10% sodium bicarbonate (3 mL) and extracted with 2% methanol / methylene chloride. The solvent was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 7% methanol / methylene chloride to give the title compound as a white solid (20 mg, 62.7%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 352A
3-{[2- (Aminosulfonyl) -4- (benzyloxy) phenyl] amino} -3-oxopropanoate The product of Example 304D (508.3 mg, 1.826 mmol) and triethylamine (0.47 mL, 3. Suspension of 3.394 mmol) in dehydrated methylene chloride (10 mL) was cooled to 0 ° C. under a nitrogen atmosphere. Ethylmalonyl chloride (0.43 mL, 3.023 mmol) was added dropwise and the resulting golden solution was stirred at 0 ° C. for 15 minutes and then at room temperature for 5 hours. The reaction was diluted with methylene chloride (50 mL) and washed with water (20 mL). The aqueous wash was extracted with methylene chloride (25 mL) and the combined organic layers were washed with 1N aqueous hydrochloric acid (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The yellow oil was purified by column chromatography on silica gel eluting with a gradient of 12% to 15% ethyl acetate / methylene chloride to give the title compound as a white solid (340 mg, 47%).

Example 352B
[7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] ethyl acetate The product of Example 352A (292 mg, 0.744 mmol) and sodium carbonate ( A solution of 394 mg, 3.722 mmol) in dehydrated ethanol (12 mL) was heated to reflux for 6.5 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 3% methanol / methylene chloride to give the title compound as a white solid (237 mg, 85%).

Example 352C
(7-Hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) ethyl acetate A solution of the product of Example 352B (277 mg, 0.7398 mmol) in ethanol (20 mL) was added. Hydrogenated with 1% hydrogen pressure (balloon) with 10% palladium / carbon (28 mg, 10 wt%) for 1.25 hours. The reaction solution was filtered through a PTFE membrane filter (0.45 μm), and the catalyst was thoroughly washed with ethanol (50 mL). The filtrate was concentrated under reduced pressure and the resulting oil was triturated with methylene chloride / hexane (1: 1 volume ratio) to give the title compound as a crystalline white solid (194 mg, 92%).

Example 352D
(7-Hydroxy-8-nitro-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) ethyl acetate Example 352C product (100 mg, 0.352 mmol) glacial acetic acid The (3 mL) suspension was treated with glacial acetic acid solution of concentrated nitric acid (1.43 M, 0.305 mL, 0.436 mmol) at room temperature and stirred at that temperature for 19 hours. Additional 1.43 M nitric acid / acetic acid (0.020 mL, 0.029 mmol) was added and stirred for 1.5 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 8% methanol / methylene chloride to give the title compound as a light yellow solid (47 mg, 41%).

Example 352E
(8-amino-7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) ethyl acetate Example 352D product (61 mg, 0.1852 mmol) in methanol ( 5 mL) solution was hydrogenated with 10% palladium / carbon (9 mg, 15 wt%) for 45 min at 1 atmosphere of hydrogen pressure (balloon). The reaction solution was filtered through a PTFE membrane filter (0.45 μm), and the catalyst was thoroughly washed with warm methanol (50 mL). The filtrate was concentrated under reduced pressure to give the title compound as a beige solid (55 mg, 99%).

Example 352F
(8-methyl-1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl) ethyl acetate Product of Example 352E (56.3 mg, 0.188 mmol) in dehydrated N, N-dimethylformamide (2 mL) was added trimethyl orthoacetate (0.098 mL, 0.752 mmol) and p-toluenesulfone under nitrogen atmosphere for 3 hours at room temperature. Treated with acid monohydrate (1 mg). The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 4% methanol / methylene chloride to give the title compound as a white crystalline solid (48 mg, 79%).

Example 352G
4-Hydroxy-1- (3-methylbutyl) -3- (8-methyl-1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadia Gin-3-yl) -1,8-naphthyridin-2 (1H) -one The product of Example 12A (16.7 mg, 0.0714 mmol) and the product of Example 352F (23.1 mg, 0.0714 mmol) Sodium hydride (60%, 11.4 mg, 0.286 mmol) was added to a dehydrated tetrahydrofuran (2 mL) solution at 0 ° C. under a nitrogen atmosphere. The reaction was heated to reflux for 3 hours, cooled to 0 ° C., and treated with glacial acetic acid (0.165 mL). The resulting yellow solution was heated to reflux for 2 hours, cooled to 0 ° C., diluted with water (5 mL) and acidified to pH 3 with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a yellow solid (20 mg, 60%).

  A suspension of the product of Example 352G (14.6 mg, 0.0312 mmol) in dehydrated tetrahydrofuran (3 mL) and distilled water (1 mL) is treated with 0.998 N aqueous sodium hydroxide (0.0313 mL, 0.0312 mmol). And the yellow solution was mixed for 15 minutes. The solvent was removed under reduced pressure and the residue was dried to give Example 352G sodium salt (15 mg, 98%).

Example 353A
1-[(Cyclopropylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one To a suspension of the product of Example 350A (1.033 g, 5.86 mmol) in methanol (58 mL), acetic acid (0 .29 mL) and cyclopropylcarboxaldehyde (482 μL, 6.45 mmol) were added followed by sodium cyanoborohydride (744.6 mg, 11.85 mmol) at room temperature. The suspension was stirred at room temperature overnight and quenched with half-saturated brine (100 mL) and sodium bicarbonate (425 mg, 5.06 mmol). The mixture was extracted with ethyl acetate (300 mL) and the organic layer was separated and washed with half-saturated brine (2 × 50 mL). The combined aqueous layer was extracted with methylene chloride (2 x 100 mL). The combined organic solution was dried over magnesium sulfate, filtered and concentrated. The residue was used without further purification.

Example 353B
3- [Bis (methylthio) methylene] -1-[(cyclopropylmethyl) amino] quinoline-2,4 (1H, 3H) -dione The product of Example 353A (984.4 mg, 4.28 mmol) in 1, To a suspension of 4-dioxane (40 mL), pyridine (2.8 mL, 34.6 mmol) and methyl tris (methylthio) sulfate (Reference (Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)) (2.26 g, 8.55 mmol) was added at room temperature. The suspension was placed in an oil bath preheated to 55 ° C. and stirred for 15 minutes. To the solution was added additional tris (methylthio) methyl methylsulfate (2.26 g, 8.55 mmol) and the mixture was stirred at 55 ° C. for 15 minutes and cooled to room temperature. Concentrate the mixture under reduced pressure and dilute the residue with methylene chloride and load onto a silica gel column eluting with methylene chloride, 2% ethyl acetate / methyl chloride, then 5% ethyl acetate / methylene chloride to give the title compound. Obtained (852.1 mg, 60%).

Example 353C
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-3-yl} quinolin-2 (1H) -one The product of Example 353B (500.3, 1.5 mmol) and the product of Example 309G (377.62 mg, 1.5 mmol) in dioxane (15 mL) ) The solution was stirred at reflux for 1.5 hours and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 0-10% ethyl acetate / methylene chloride to give the title compound (384.7 mg, 25%).

Example 353D
3- [7- (azidomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-[(cyclopropylmethyl) amino]- 4-Hydroxyquinolin-2 (1H) -one To the product of Example 353C (384.7 mg, 0.78 mmol) was added hydrogen chloride in dioxane (4N, 7.8 mL) at 0 ° C. The solution was warmed to room temperature, stirred for 5.5 hours, and concentrated under reduced pressure. The solid was suspended in methylene chloride (7.8 mL) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.6 mL, 4.01 mmol) and diphenylphosphoryl azide were suspended in the suspension. (0.85 mL, 3.94 mmol) was added at room temperature and stirred overnight. The solution was concentrated under reduced pressure. The residue was purified by chromatography eluting with 1% triethylamine / methylene chloride to give the triethylamine salt of the title compound (357 mg, 79%).

Example 353E
3- [7- (Aminomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-[(cyclopropylmethyl) amino] 4-Hydroxyquinolin-2 (1H) -one To a solution of the product of Example 353D (357 mg, 0.62 mmol) in pyridine (4.6 mL) and concentrated ammonium hydroxide (3 mL) was added triphenylphosphine (397 mg, 1 .51 mmol) was added at room temperature. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with 30% hexane / toluene and the solid was filtered to give the title compound (250 mg, 90%).

Example 353F
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] methanesulfonamide Triethylamine salt of the product of Example 353E (85.26 mg, 0.16 mmol) of N, N-dimethylformamide (1. 6 mL) suspension was added triethylamine (48 μL, 0.34 mmol) followed by methanesulfonyl chloride (13.3 μL, 0.17 mmol) at room temperature. The solution was stirred at room temperature for 20 minutes and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 20% to 95% acetonitrile / [0.1% trifluoroacetic acid / water] to give the title compound (39.86 mg, 49%).

Example 354
3- (8-amino-7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (isobutylamino) quinoline-2 (1H ) -On A solution of the product of Example 321C (0.26 g, 0.61 mmol) in concentrated sulfuric acid (4 mL) was treated at 0 ° C. with ammonium nitrate (55 mg, 0.69 mmol). After stirring at room temperature for 30 minutes, the solution was poured into ice water and the precipitate was filtered, dried and triturated with ethyl acetate to give the nitrated intermediate (0.23 g, 79%). A solution of the solid (0.23 g, 0.48 mmol) in methanol: tetrahydrofuran: water (3: 3: 1) (2.3 mL) was added iron powder (0.12 g, 2.15 mmol) and 60 ° C. over 1 hour. Treated with ammonium chloride (0.031 g, 0.58 mmol). The resulting warm solution was filtered through diatomaceous earth and washed with tetrahydrofuran. The filtrate was concentrated and the resulting solid was triturated with 1: 1 methylene chloride: ethyl acetate to give the title compound (0.088 g, 42%).

Example 355
3- (1,1-Dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl) -4-hydroxy-1- (isobutylamino ) Quinolin-2 (1H) -one A solution of Example 354 (0.036 g, 0.081 mmol) in dimethylformamide (2 mL) was added trimethylorthoformate (1 mL) and catalytic amount of para-toluenesulfonic acid at room temperature for 20 hours. Was processed. The solvent was removed under a warm stream of nitrogen and the residue was triturated with 1: 1 ethyl acetate: tetrahydrofuran, filtered and dried to give the title compound (8 mg, 22%).

Example 356
2-({8-amino-3- [4-hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl} oxy) acetamide A solution of the product of Example 321C (0.49 g, 1.15 mmol) in concentrated sulfuric acid (6 mL) at 0 ° C. with ammonium nitrate (100 mg, 1.25 mmol). Processed. After stirring at room temperature for 1 hour, the solution was poured into ice water and the precipitate was filtered, dried and triturated with ethyl acetate to give the nitrated intermediate (0.27 g, 49%). A solution of the nitrated intermediate (75 mg, 0.16 mmol) in N, N-dimethylformamide (3 mL) was added 2-bromoacetamide (33 mg, 0 mL) in the presence of catalytic amount of tetrabutylammonium iodide at room temperature for 24 hours. .24 mmol) and cesium carbonate (206 mg, 0.63 mmol). The solvent was removed under a warm stream of nitrogen and the residue was triturated with water, filtered and dried to give the alkylated product (76 mg, 90%). A solution of the material in a methanol: tetrahydrofuran: water (2.3 mL) 3: 3: 1 mixture with iron powder (36 mg, 0.64 mmol) and ammonium chloride (9 mg, 0.17 mmol) at 60 ° C. for 2 hours. Processed. The solution was filtered through diatomaceous earth and washed with tetrahydrofuran. The filtrate was concentrated and purified by flash column eluting with 1% methanol / methylene chloride to give the title compound (16 mg, 22%). The sodium salt was prepared by the procedure of Example 1D.

Example 357
3- [8- (Chloromethyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] -4- Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one A solution of Example 354 (0.030 g, 0.067 mmol) in dimethylformamide (3 mL) was added 2-chloro-1,1 over 4 hours at 60 ° C. , 1-trimethoxyethane (0.50 mL) and a catalytic amount of para-toluenesulfonic acid. The solvent was removed under a warm stream of nitrogen and the resulting residue was triturated with water, filtered, triturated with methanol and filtered to give the title compound (22 mg, 51%). The sodium salt was prepared by the procedure of Example 1D.

Example 358A
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- [propylideneamino] quinoline-2 (1H ) -On solution of the product of Example 304F (0.1 g, 0.22 mmol) in N, N-dimethylacetamide (1 mL) in a sealed tube in a microwave reactor at 100 ° C. for 60 minutes. Reacted with acetal (0.34 mL, 2.2 mmol). The reaction was cooled to 25 ° C., concentrated under a stream of nitrogen heated through a manifold heated to 165 ° C., and the resulting residue was triturated with diethyl ether to give the title compound (0 0.045 g, 42%).

Example 358B
3- [7- (Benzyloxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -4-hydroxy-1- (propylamino) quinoline-2 (1H) - the product of example 358A (0.045 g, 0.09 mmol) in tetrahydrofuran (2 mL) solution at 0 ° C., methanol (0.005 mL, 0.35 mmol) treated with, then 2.0M borohydride A solution of lithium in tetrahydrofuran (0.07 mL, 0.13 mmol) was added dropwise, stirred at 25 ° C. for 1 hour, and diluted with 1N hydrochloric acid. The resulting precipitate was filtered and dried. The solid was dissolved in tetrahydrofuran, and the solvent was distilled off to dryness to be absorbed by silica gel. The resulting silica was loaded onto a 2 g Alltech Seppac and eluted with methylene chloride to give the title compound (0.020 g, 44%). MS (ESI-) m / z503 ( M-H) -.

Example 358C
4-hydroxy-3- (7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (propylamino) quinolin-2 (1H) -one A solution of the product of Example 358B (0.020 g, 0.04 mmol) in tetrahydrofuran (5 mL) was treated with ammonium formate (13 mg, 0.19 mmol), palladium hydroxide (2 mg) and 10% Pd / C (1 mg). . The resulting mixture was refluxed for 1 hour. The catalyst was removed by filtration, and the filtrate was evaporated to give a white solid. The solid residue was partitioned between ethyl acetate (100 mL) and water (5 mL). The layers were separated and the organic solvent was removed under reduced pressure to give the title compound (0.016 g, 100%). MS (ESI-) m / z 413 (MH) ^- .

Example 358D
2-({3- [4-Hydroxy-2-oxo-1- (propylamino) -1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) acetamide A solution of the product of Example 358C (0.016 g, 0.04 mmol) in N, N-dimethylformamide (2 mL) was added cesium carbonate (0.015 g) at 25 ° C. over 3 hours. , 0.045 mmol), bromoacetamide (0.006 g, 0.18 mmol) and a catalytic amount of tetrabutylammonium iodide. The reaction was concentrated under a stream of nitrogen heated up through a manifold heated to 165 ° C. and the resulting residue was triturated with water, filtered and dried. The resulting solid was triturated in hot ethyl acetate, filtered and dried to give the title compound (0.008 g, 37%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 359
3- {3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H- [1,3] oxazolo [5 4-h] [1,2,4] benzothiadiazin-8-yl} propanoic acid The product of Example 354 (15 mg, 0.033 mmol) and maleic anhydride (100 mg, 1.0 mmol) in pyridine (2 mL) ) The solution was heated in a microwave reactor at 160 ° C. for 1 hour. The crude mixture was cooled to 25 ° C. and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous trifluoroacetic acid. To give the title compound (5.3 mg, 30%). The disodium salt was prepared by the procedure of Example 1D using 2 equivalents of sodium hydroxide.

Example 360
3- (8-{[(2-Aminoethyl) amino] methyl} -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazine -3-yl) -4-hydroxy-1- (isobutylamino) quinolin-2 (1H) -one product from Example 357 (20 mg, 0.039 mmol) and tert-butyl-N- (2-aminoethyl) ) A solution of carbamate (7.7 mg, 0.046 mmol) in N, N-dimethylformamide (3 mL) was treated with cesium carbonate (39 mg, 0.117 mmol) at 50 ° C. for 2 hours. The solvent was removed with a warm stream of nitrogen and the resulting residue was triturated with water, filtered and dried. The solid was suspended in 1,4-dioxane (2 mL), treated with 4 M hydrochloric acid in 1,4-dioxane (2 mL), and stirred at room temperature for 20 hours. The solution was concentrated to half volume, filtered and dried to give the dihydrochloride salt of the title compound (5.8 mg, 24%).

Example 361
2-({3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) propanamide To a solution of the product of Example 321C (20 mg, 0.0467 mmol) in N, N-dimethylformamide (2 mL) was added 2-bromopropionamide (10.6 mg, 0.070 mmol). ), Tetra-n-butylammonium iodide (1.7 mg, 0.0047 mmol) and cesium carbonate (61 mg, 0.187 mmol). The mixture was stirred at 25 ° C. for 72 hours. To the solution was added 1N aqueous hydrochloric acid (10 mL), and the mixture was extracted with ethyl acetate (10 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (18.4 mg, 79%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 362
2-({3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} oxy) butanamide To a solution of the product of Example 321C (20 mg, 0.0467 mmol) in N, N-dimethylformamide (2 mL) was added 2-chlorobutyramide (8.5 mg, 0.070 mmol). , Tetra-n-butylammonium iodide (1.7 mg, 0.0047 mmol) and cesium carbonate (61 mg, 0.187 mmol) were added. The mixture was stirred at 25 ° C. for 18 hours and heated at 80 ° C. for 3 hours. After cooling to 25 ° C., 1N aqueous hydrochloric acid (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL). The resulting organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (24 mg, 100%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 363
{3- [4-Hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H- [1,3] oxazolo [5,4- h] [1,2,4] benzothiadiazin-8-yl} methyl acetate A solution of the product of Example 354 (67.5 mg, 0.015 mmol) in N, N-dimethylformamide (2 mL) was added to p- Treated with toluenesulfonic acid monohydrate (1 mg) and monoorthomalonic acid tetramethyl ester (272 mg, 1.52 mmol). The mixture was heated at 50 ° C. in an oil bath under a nitrogen atmosphere and the resulting yellow solution was stirred for 3 hours. At that time, additional orthoester was added (272 mg, 1.52 mmol) and heating was continued for another 5 hours. The reaction was cooled to room temperature and the solution was concentrated under reduced pressure on a rotary evaporator. The residue was further dried with a vacuum pump, dissolved in methylene chloride (100 mL), washed with water (2 × 50 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 1% methanol / methylene chloride. The resulting less pure material was rechromatographed on silica gel eluting with a gradient of 5% to 7% acetonitrile / methylene chloride to give the title compound (36 mg, 45%).

  A suspension of the product of Example 363 (6.0 mg, 0.0114 mmol) in dehydrated tetrahydrofuran (3 mL) and distilled water (1 mL) was treated with 0.998N aqueous sodium hydroxide solution (0.0114 mL, 0.0114 mmol). The resulting yellow solution was mixed for 15 minutes. The solvent was removed under reduced pressure and the residue was dried with a vacuum pump to give the sodium salt of Example 363 (6.1 mg, 98%).

Example 364
4-hydroxy-3- (8-{[3-hydroxypyrrolidin-1-yl] methyl} -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4 Benzothiadiazin-3-yl) -1- (isobutylamino) quinolin-2 (1H) -one The product from Example 357 (80 mg, 0.160 mmol) and 3-hydroxypyrrolidine (20 mg, 0.240 mmol) ) In acetonitrile (4 mL) was treated with diisopropylethylamine (0.115 mL, 0.640 mmol) at room temperature for 24 hours. The solvent was removed under a warm stream of nitrogen and the residue was fractionated on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous trifluoroacetic acid. Purification by preparative HPLC gave the title compound (16.2 mg, 18%). The sodium salt was prepared by the procedure of Example 1D.

Example 365
3- [1,1-Dioxide-8- (pyridinium-1-ylmethyl) -4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] -1- (isobutylamino) -2-oxo-1,2-dihydroquinoline-4- olate A solution of the product of Example 357 (16.5 mg, 0.033 mmol) in pyridine (2 mL) at 45 ° C. for 20 hours. Heated. Excess pyridine was removed under a warm nitrogen stream and the residue was collected on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous trifluoroacetic acid. Was purified by preparative HPLC to give the title compound (6 mg, 34%).

Example 366
3- [1,1-Dioxide-8- (pyrrolidin-1-ylmethyl) -4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] 4-Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one A solution of the product from Example 357 (80 mg, 0.160 mmol) and pyrrolidine (17 mg, 0.240 mmol) in acetonitrile (4 mL) was added. Treated with diisopropylethylamine (0.115 mL, 0.640 mmol) at room temperature for 24 hours. Solvent was removed under a warm stream of nitrogen and the residue was fractionated on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous trifluoroacetic acid. Purification by HPLC gave the title compound (12.4 mg, 15%). The sodium salt was prepared by the procedure of Example 1D.

Example 367
Methanesulfonic acid 8-amino-3- [4-hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4 -A solution of the product of benzothiadiazin-7-yl Example 354 (44 mg, 0.099 mmol) and methanesulfonyl chloride (0.010 mL, 0.011 mmol) in tetrahydrofuran (4 mL) at room temperature over 2 hours with diisopropylethylamine. (0.075 mL, 0.040 mmol). The solution was poured into water. The resulting precipitate was filtered, dried and purified by flash column eluting with 1% methanol / methylene chloride to give the title compound (14.2 mg, 28%). The sodium salt was prepared by the procedure of Example 1D.

Example 368
3- [8- (3-Aminophenyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl]- 4-Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one Polyphosphoric acid (1 mL) of the product of Example 354 (38 mg, 0.086 mmol) and 3-aminobenzoic acid (13 mg, 0.094 mmol) The medium mixture was heated at 190 ° C. for 1 hour. The solution was cooled to 25 ° C. and triturated with water and 10% sodium carbonate solution. The solid was filtered, dried and purified by flash column eluting with 2% methanol / methylene chloride to give the title compound (15 mg, 38%). The sodium salt was prepared by the procedure of Example 1D.

Example 369
3- [8- (Aminomethyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl] -4- Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one A solution of the product of Example 357 (32 mg, 0.063 mmol) in tetrahydrofuran (2 mL) was added 20% ammonia in methanol (1 mL) at room temperature for 16 h. ) And ammonium hydroxide (1 mL) and 1M sodium hydroxide solution (0.063 mL, 0.063 mmol). The mixture was dried by blowing warm nitrogen and the resulting residue was partitioned between water and ethyl acetate. The organic layer was concentrated and purified by flash chromatography eluting with a gradient of 100% methylene chloride to 2% methanol / methylene chloride to give the title compound (4 mg, 13%).

Example 370
4-hydroxy-3- [8- (hydroxymethyl) -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl ] -1- (isobutylamino) quinolin-2 (1H) -one A solution of the product of Example 357 (32 mg, 0.063 mmol) in tetrahydrofuran (2 mL) was added 20% ammonia in methanol (1 mL) at room temperature for 16 h. ) And ammonium hydroxide (1 mL) and 1M sodium hydroxide solution (0.063 mL, 0.063 mmol). The mixture was dried by blowing warm nitrogen and the resulting residue was partitioned between water and ethyl acetate. The aqueous layer was adjusted to pH 1 with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (5 mg, 16%).

Example 371
3- {8-[(Butylamino) methyl] -1,1-dioxide-4H- [1,3] oxazolo [5,4-h] [1,2,4] benzothiadiazin-3-yl} -4-Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one A solution of the product of Example 357 (15.5 mg, 0.031 mmol) in pyridine (2 mL) was stirred at room temperature over 4 hours with n-butylamine. (0.030 mL, 0.31 mmol). Solvent was removed under a warm stream of nitrogen and the residue was fractionated on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous trifluoroacetic acid. Purification by HPLC gave the title compound (1.2 mg, 7.2%).

Example 372 RZ
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} acetamide To a solution of the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.5 mL), acetic anhydride (0.057 g, 0.0053 mL, 0 0.056 mmol) was added. The reaction mixture was heated in a microwave reactor at 100 ° C. for 30 minutes. The reaction was poured into 30 mL of water. The solid was collected by filtration to give the title compound (15.8 mg, 72%).

Example 373
2,2,2-trifluoro-N- {3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1, 1-dioxide-4H-1,2,4-benzothiadiazin-7-yl} acetamide To a slurry of the product of Example 205 (0.043 g, 0.1 mmol) in chloroform (5 mL) was added trifluoroacetic anhydride. (0.074 g, 0.35 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.048 g, 92% yield). MS (EST) m / z522 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 374
2,2,2-trifluoro-N- {3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -8- A solution of nitro-1,1-dioxide-4H-1,2,4-benzothiadiazin-7-yl} acetamide trifluoroacetic acid (2.5 mL) and trifluoroacetic anhydride (2.5 mL) at 0 ° C. The product of Example 205 (0.5 g, 1.17 mmol) was added in small portions. The resulting red solution was stirred at 0 ° C. for 30 minutes, cooled to −20 ° C., and potassium nitrate (0.13 g, 1.3 mmol) was added in small portions. The mixture was stirred at −20 ° C. for 1 hour, poured into ice and the resulting tan solid was collected by filtration, washed with water and dried to give the title compound as a constant weight (0.628 g, yield). 94%). MS (ESI-) m / z 567 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 375
3- [1,1-Dioxide-8- (trifluoromethyl) -4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl] -4-hydroxy -1- (3- Methylbutyl) -1,8 -naphthyridin-2 (1H) -one Acetic acid of the product of Example 374 (0.043 g, 0.075 mmol) and iron powder (0.025 g, 0.45 mmol) The mixture in (2 mL) was heated at 80 ° C. for 1 h, cooled, diluted with 20 mL of ethyl acetate and filtered through a Celite® layer. The ethyl acetate filtrate was washed with water, brine, dried over sodium sulfate, filtered and concentrated to give the title compound as an orange-red solid (0.035 g, 90% yield). MS (ESI-) m / z 519 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 376
3- (7-Amino-8-nitro-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -1,8 -Naphthyridin- 2 (1H) -one The product of Example 374 (0.500 g, 0.88 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in methanol (20 mL), tetrahydrofuran (8 mL) and water (8 mL) ) The mixture was heated at 60 ° C. for 4 h, cooled and concentrated. The resulting residue was dissolved in ethyl acetate and treated with 1M hydrochloric acid to a pH of about 1, washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a brown solid ( 0.4 g, yield 96%). MS (ESI-) m / z 471 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 377
3- (7,8-Diamino-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1- (3-methylbutyl) -1,8-naphthyridine -2 (1H) -one Product of Example 376 (2.1 g, 4.45 mmol), iron powder (1.24 g, 22.25 mmol) and ammonium chloride (0.29 g, 5.3 mmol) in methanol (50 mL) ), Tetrahydrofuran (50 mL) and water (20 mL) were heated at 75 ° C. for 6 h, cooled and filtered through a Celite® layer. The filtrate was treated with 1M hydrochloric acid to a pH of about 2, and the solution was concentrated under reduced pressure. The resulting residue was stirred in 100 mL of water for 30 minutes and filtered to recover the solid, which was triturated with 50 mL of diethyl ether, filtered and dried to give the title compound (1.72 g, Yield 87%). MS (ESI-) m / z441 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 378
4-hydroxy-3- (8-hydroxy-1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl) -1- ( 3-Methylbutyl) -1,8-naphthyridin-2 (1H) -one N, N-dimethylacetamide of the product of Example 377 (0.022 g, 0.05 mmol) and urea (0.012 g, 0.2 mmol) (0.5 mL) The mixture was heated in a sealed tube by microwave at 180 ° C. for 60 minutes. The mixture was cooled, partitioned between ethyl acetate and water and adjusted to pH 3 with 1M hydrochloric acid. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with methylene chloride and then 96: 4 methylene chloride / methanol to give the title compound (0.022 g, 90% yield). MS (ESI-) m / z 467 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 379
4-Hydroxy-1- (3-methylbutyl) -3- (8-methyl-1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazine- 3-yl) -1,8-naphthyridin-2 (1H) -one A mixture of the product of Example 377 (0.022 g, 0.05 mmol) and acetic acid (1 mL) in a sealed tube at 160 ° C. for 30 min. Heated with wave, cooled and filtered to collect solids. It was washed repeatedly with diethyl ether and dried to give the title compound as a tan solid (0.006 g, 26% yield). MS (ESI-) m / z465 ( M-H) -. The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 380
3- [1,1-Dioxide-8- (pentafluoroethyl) -4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl] -4-hydroxy -1- (3-Methylbutyl) -1,8-naphthyridin-2 (1H) -one Seal the mixture of the product of Example 377 (0.022 g, 0.05 mmol) and pentafluoropropionic acid (0.5 mL). Heat in a tube at 130 ° C. for 30 minutes with microwave, cool and concentrate under reduced pressure. The crude material was chromatographed on silica eluting first with methylene chloride and then with 99: 1 methylene chloride / methanol to give the title compound (0.011 g, 38% yield). MS (ESI-) m / z 569 (MH) ^- . The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 381
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- (7-hydroxy-8-nitro-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) quinoline A solution of the product of Example 320C (47 mg, 0.11 mmol) in concentrated sulfuric acid (2 mL) at 0 ° C. was treated with ammonium nitrate (10 mg, 0.13 mmol). After stirring at room temperature for 25 minutes, the solution was poured into ice water, the precipitate was filtered, dried and purified by flash chromatography eluting with 2% methanol / methylene chloride to give the title compound (10 mg, 19 %).

Example 382
3- (7- {2-[(3S) -3-Aminopyrrolidin-1-yl] -2-oxoethoxy} -1,1-dioxide-4H-1,2,4-benzothiadiazine-3- Yl) -1-[(cyclopropylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one product of Example 384, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride And pyrrolidin-3 (S) -yl-carbamic acid tert-butyl ester is added to a mixture of 1-hydroxybenzotriazole in N, N-dimethylformamide. The mixture is stirred for 1 day. The solution is poured into ethyl acetate, washed with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is triturated with methanol / water and filtered. The solid is added to hydrochloric acid (1M dioxane solution, 2 mL), stirred overnight, filtered and washed with ethyl acetate / hexane (1: 1) to give the title compound.

Example 383
2-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl) oxy] -N-ethylacetamide The product of Example 384 (24 mg, 0.05 mmol), 1- [3- (dimethylamino) propyl] -3 ethylcarbodiimide hydrochloride ( Ethylamine (100 μL, 2M tetrahydrofuran solution, 0.2 mmol) was added to a solution of 16 mg, 0.08 mmol) and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in N, N-dimethylformamide (2 mL). The mixture was stirred for 1 day. The solution was poured into ethyl acetate (40 mL), washed with saturated aqueous sodium bicarbonate, water, brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with methanol / water and filtered to give the title compound (6 mg, 24%).

Example 384A
[(3- {1-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4- Benzthiadiazin -7-yl) oxy] tert-butyl acetate A solution of the product of Example 320C (400 mg, 0.94 mmol) in N, N-dimethylformamide (10 mL) was added to tert-butyl bromoacetate (0.555 mL, 3.76 mmol), potassium carbonate (1.225 g, 3.76 mmol) and tetrabutylammonium iodide (catalytic amount) were reacted at 25 ° C. overnight. The reaction mixture was diluted with water and adjusted to pH 7 with glacial acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with a gradient of 3: 1 hexane: ethyl acetate to 1: 1 hexane: ethyl acetate to give the title compound (195 mg, 38%).

Example 384B
[(3- {1-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4- Benzothiadiazin-7-yl) oxy] acetic acid A mixture of the product of Example 384A (195 mg, 0.36 mmol) in trifluoroacetic acid (5 mL) and methylene chloride (5 mL) was stirred at 25 ° C. for 3 hours. The solvent was removed under reduced pressure. The residue was triturated with hexane / ethyl acetate (1: 1) and filtered to give the title compound (114 mg, 65%).

Example 385
3- {7- [2- (3-Aminopyrrolidin-1-yl) -2-oxoethoxy] -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl} -1 -[(Cyclopropylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one The product of Example 384B (24 mg, 0.05 mmol), 1- [3- (dimethylamino) propyl] -3-ethyl To a solution of carbodiimide hydrochloride (16 mg, 0.08 mmol) and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in N, N-dimethylformamide (2 mL) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester (19 mg). 0.1 mmol) was added. The mixture was stirred for 1 day. The solution was poured into ethyl acetate (40 mL), washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated with methanol / water and filtered. The solid was treated with hydrochloric acid (1M dioxane solution, 2 mL), stirred overnight, filtered and washed with ethyl acetate / hexane (1: 1) to give the title compound (15 mg, 51%).

793695 Example 386DL2
3- (8-Amino-7-hydroxy-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(cyclopropylmethyl) amino] -4-hydroxyquinoline -2 (1H) -one Product of Example 381 (10 mg, 0.021 mmol), iron powder (5.9 mg, 0.105 mmol) and ammonium chloride (1.3 mg, 0.024 mmol) in methanol: tetrahydrofuran: water The mixture in (2: 2: 1, 2 mL) was heated at 60 ° C. for 1 hour. The solution was filtered through Celite® and washed with tetrahydrofuran. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered, washed with water and dried to give the title compound (5 mg, 53%).

Example 387A
2-[(3- {1-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -8-nitro-1,1-dioxide-4H- 1,2,4-Benzothiadiazin-7-yl) oxy] acetamide A solution of the product of Example 381 (20 mg, 0.042 mmol) in N, N-dimethylformamide (2 mL) was added 2-bromoacetamide (11. 6 mg, 0.084 mmol), potassium carbonate (54.7 mg, 0.168 mmol) and tetrabutylammonium iodide (catalytic amount) were treated at 25 ° C. and stirred at 25 ° C. for 18 hours. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and washed with water to give the title compound (12 mg, 54%). The product of Example 387A (12 mg, 0.023 mmol), iron powder (6.0 mg, 0.107 mmol) and ammonium chloride (1.4 mg, 0.026 mmol) in methanol: tetrahydrofuran: water (2: 2: 1, The mixture was heated at 60 ° C. for 1 hour. The solution was filtered through Celite® and washed with tetrahydrofuran. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered, washed with water and dried to give the title compound (7 mg, 62%).

Example 388A
[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -8-nitro-1,1-dioxide-4H-1, 2,4-benzothiadiazin-7-yl) oxy] acetonitrile A solution of the product of Example 381 (20 mg, 0.042 mmol) in N, N-dimethylformamide (2 mL) was added at 2- Reacted with bromoacetonitrile (6 μL, 0.086 mmol), potassium carbonate (54.7 mg, 0.168 mmol) and tetrabutylammonium iodide (catalytic amount). The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and washed with water to give the title compound (13 mg, 60%).

Example 388B
[(8-amino-3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1, 2,4-benzothiadiazin-7-yl) oxy] acetonitrile The product of Example 388A (13 mg, 0.025 mmol), iron powder (6.0 mg, 0.107 mmol) and ammonium chloride (1.5 mg, 0 .028 mmol) in methanol: tetrahydrofuran: water (2: 2: 1, 2 mL) was heated at 60 ° C. for 1 h. The solution was filtered through Celite® and washed with tetrahydrofuran. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered, washed with water and dried to give the title compound (5 mg, 41%).

Example 389
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- [7- (2-hydroxyethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] Quinoline-2 (1H) -one To a solution of the product of Example 384 (10 mg, 0.021 mmol) in tetrahydrofuran (10 mL) was added borane (0.8 mL, 1 M tetrahydrofuran solution, 0.8 mmol). The mixture was refluxed for 4 hours. It was poured into ice water (20 mL) and acidified to pH 2 with 1N hydrochloric acid. The solid was filtered and washed with water to give the title compound (5 mg, 51%).

Example 390A
3- {7-[(1-Benzyl-1H-imidazol-2-yl) methoxy] -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl} -1-[( Cyclopropylmethyl) amino] -4-hydroxyquinolin-2 (1H) -one A solution of the product of Example 320C (20 mg, 0.047 mmol) in N, N-dimethylformamide (1 mL) was added to 1-benzyl-2- ( Chloromethyl) -1H-imidazole hydrochloride (23 mg, 0.095 mmol), potassium carbonate (0.061 g, 0.187 mmol) and tetrabutylammonium iodide (catalytic amount) at 120 ° C. for 2 hours in a microwave reactor And heated. The solution was cooled to 25 ° C. and concentrated. The residue was triturated with ethyl acetate, filtered and washed with water to give the title compound (21 mg, 75%).

Example 390B
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- [7- (1H-imidazol-2-ylmethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazine-3 -Il ] quinolin-2 (1H) -one To a solution of the product of Example 390A (16 mg, 0.027 mmol) in N, N-dimethylformamide (1 mL) was added 1,4-cyclodiene (25.5 μL, 0.27 mmol). ) And palladium black (16 mg) were added. The mixture was heated at 70 ° C. for 1 day. The mixture was filtered through Celite® and washed with N, N-dimethylformamide. The solution was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with methylene chloride: methanol (98: 2) to give the title compound (6 mg, 44%).

Example 391A
To a solution of 1,3-thiazol-2-ylmethanolthiazole- 2-carbaldehyde (113 mg, 1 mmol) in methanol (10 mL) was added sodium borohydride (41 mg, 1.2 mmol) in small portions at 0 ° C. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, acidified to pH 3 with 1M hydrochloric acid and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (69 mg, 60%).

Example 391B
2- (Chloromethyl) -1,3-thiazole The product of Example 391A (66 mg, 0.57 mmol) was added to thionyl chloride (0.2 mL, 2.7 mmol) in methylene chloride while maintaining the temperature at 25 ° C. (9 mL) was added dropwise to the solution. The mixture was refluxed for 2 hours. The solvent was distilled off to give the title compound (quantitative yield).

Example 391C
1-[(Cyclopropylmethyl) amino] -3- [1,1-dioxide-7- (1,3-thiazol-2-ylmethoxy) -4H-1,2,4-benzothiadiazin-3-yl ] 4-Hydroxyquinolin-2 (1H) -one A solution of the product of Example 320C (15 mg, 0.035 mmol) in N, N-dimethylformamide (1 mL) was prepared as Example 391B (19 mg, 0.142 mmol), carbonic acid. Heated at 120 ° C. for 2 hours with potassium (68 g, 0.209 mmol) and tetrabutylammonium iodide (catalytic amount). The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate / hexane (1: 1), filtered and washed with water to give the title compound (17 mg, 92%).

Example 392A
[(3- {1-[(Cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4- Benzothiadiazin-7-yl) oxy] acetonitrile A solution of the product of Example 320C (0.050 g, 0.117 mmol) in N, N-dimethylformamide (2 mL) was added 2-bromoacetonitrile at 25 ° C. for 1 day. (16 μL, 0.230 mmol), potassium carbonate (0.15 g, 0.46 mmol) and tetrabutylammonium iodide (catalytic amount). The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate / hexane (1: 1), filtered and washed with water to give the title compound (52 mg, 95%).

Example 392B
2-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2, Methyl 4-benzothiadiazin-7-yl) oxy] ethanimidate A solution of the product of Example 392A (50 mg, 0.11 mmol) in methanol (10 mL) was bubbled with hydrogen chloride gas at 0 ° C. until saturation. The reaction was stirred at room temperature for 3 hours. The solution was evaporated under reduced pressure to give the title compound (quantitative yield).

Example 392C
1-[(Cyclopropylmethyl) amino] -3- [7- (4,5-dihydro-1H-imidazol-2-ylmethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazine -3-yl] -4-hydroxyquinolin-2 (1H) -one To a solution of the product of Example 392B (53 mg, 0.11 mmol) in methanol (10 mL) in ethane-1,2-diamine (0.2 mL, 3 mmol). ) And refluxed overnight. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluting with 4: 1 methylene chloride / methanol to 3: 2 methylene chloride / methanol to give the title compound (11 mg, 20% ).

Example 393A
2- (Bromomethyl) -1,3-thiazole-4-carbonitrile To a solution of 2-methyl-1-thiazole-4-carbonitrile (248 mg, 2 mmol) in benzene (20 mL) was added N-bromosuccinimide (1.78 g). 10 mmol) and dibenzoyl peroxide (20 mg, 0.08 mmol) were added. The mixture was refluxed for 2 days. The solution was evaporated under reduced pressure. The residue was partitioned between methylene chloride and water. The organic layer was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 1: 1 methylene chloride: hexane to give the title compound (190 mg, 47%).

Example 393B
2-{[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl) oxy] methyl} -1,3-thiazole-4-carbonitrile N, N-dimethylformamide (2 mL) of the product of Example 320C (20 mg, 0.047 mmol). The solution was reacted with Example 393A (20 mg, 0.099 mmol), potassium carbonate (0.070 g, 0.215 mmol) and tetrabutylammonium iodide (catalytic amount) at room temperature overnight. The solution was concentrated under reduced pressure and the residue was triturated with ethyl acetate / hexane (1: 1), filtered and washed with water to give the title compound (23 mg, 89%).

Example 394
3- [7- (2-Aminoethoxy) -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl] -1-[(cyclopropylmethyl) amino] -4-hydroxy Quinolin-2 (1H) -one A solution of the product of Example 392A (39 mg, 0.084 mmol) in dehydrated tetrahydrofuran (2 mL) was treated with LiBH ₄ (1 mL, 2M tetrahydrofuran solution, 0.2 mmol) and 30 minutes at room temperature. Stir, add 18 μL of water and stir overnight. The solution was diluted with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The slurry was filtered and the solvent was removed under reduced pressure to give the title compound (38 mg, 97%).

Example 395
N- {2-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1 , 2,4-Benzothiadiazin-7-yl) oxy] ethyl} methanesulfonamide To a solution of the product of Example 394 (15 mg, 0.032 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (12 μL,. 156 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was purified by chromatography on silica gel eluting with 199: 1 methylene chloride: methanol to give the title compound (5 mg, 29%).

Example 396
3- [9- (Butylamino) -1,1-dioxide-4H, 8H- [1,4] oxazino [2,3-h] [1,2,4] benzothiadiazin-3-yl]- 4-Hydroxy-1- (isobutylamino) quinolin-2 (1H) -one A solution of the product of Example 357 (15.5 mg, 0.031 mmol) in pyridine (2 mL) was added n-butylamine (2 mL) at room temperature over 4 hours. 0.030 mL, 0.31 mmol). Solvent was removed under a warm stream of nitrogen and the residue was fractionated on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile / 0.1% aqueous trifluoroacetic acid. Purification by HPLC gave the title compound (3.3 mg, 20%).

Example 397
3- {7-[(5-Bromopyridin-2-yl) oxy] -1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl} -4-hydroxy-1- ( The product of Example 321C (40.0 mg, 0.09 mmol), cesium carbonate (112 mg, 0.8 mg) with heating at 110 ° C. in an isobutylamino) quinolin-2 (1H) -one microwave reactor for 20 minutes. 34 mmol) and 2,5-dibromopyridine (40.0 mg, 0.17 mmol) in dimethyl sulfoxide (1.2 mL) was stirred. After cooling to 25 ° C., the purple mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a stepwise gradient of methylene chloride / hexane (0% to 100%). The title compound was obtained as an off-white solid (34.0 mg, 63%).

Example 398
4-hydroxy-1- (isobutylamino) -3- {7-[(3-nitropyridin-2-yl) oxy] -1,1-dioxide-4H-1,2,4-benzothiadiazine-3 -Il } quinolin-2 (1H) -one The product of Example 321C (10.0 mg, 0.02 mmol), cesium carbonate (27.7 mg, 0.09 mmol) and 2-bromo-3-nitropyridine (8. A mixture of 4 mg, 0.04 mmol) in dimethyl sulfoxide (0.3 mL) was stirred with heating at 110 ° C. for 20 minutes in a microwave reactor. After cooling to 25 ° C., the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel eluting with a step gradient from 0% to 100% methylene chloride / hexane to give the title The compound was obtained as a yellow solid (8.6 mg, 68%).

Example 399
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] methanesulfonamide Methanesulfonyl chloride (0.0064 g, 0.0043 mL) in a solution of the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL). , 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100 ° C. for 38 minutes. The reaction was diluted with ethyl acetate (40 mL) and washed with 1N hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid. It was purified by chromatography on silica gel eluting with 99: 1 methylene chloride: methanol to give the title compound (8.3 mg, 35%).

Example 400
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} benzenesulfonamide To a solution of the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added benzenesulfonyl chloride (0.0099 g,. 0072 mL, 0.056 mmol) was added. The reaction mixture was heated in a microwave reactor at 100 ° C. for 35 minutes. The reaction was cooled to 25 ° C., diluted with ethyl acetate (40 mL) and washed with 1N hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99: 1 methylene chloride: methanol to give the title compound (18.6 mg, 69%).

Example 401
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} thiophene-2-sulfonamide To a solution of the product of Example 205 (21.5 mg, 0.05 mmol) in pyridine (1 mL) was added 2-thiophenesulfonyl chloride (44 mg, 0 .24 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with hexane: ethyl acetate (1: 1). The crude product was chromatographed on silica gel eluting with 199: 1 methylene chloride: methanol to give the title compound (10 mg, 35%).

Example 402
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} -1-methyl-1H-imidazole-4-sulfonamide To a solution of the product of Example 205 (21.5 mg, 0.05 mmol) in pyridine (1 mL) was added 1- Methylimidazolesulfonyl chloride (44 mg, 0.24 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate to give the title compound (21 mg, 73%).

Example 403
4,5-dichloro-N- {3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide -4H-1,2,4-benzothiadiazin-7-yl} thiophene-2-sulfonamide To a solution of the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 2 , 3-Dichlorothiophene-5-sulfonyl chloride (0.015 g, 0.056 mmol) was added. The reaction mixture was heated in a microwave reactor at 100 ° C. for 15 minutes. The reaction was diluted with ethyl acetate (40 mL) and washed with 1N hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99: 1 methylene chloride: methanol to give the title compound (14.8 mg, 50%).

Example 404
2,2,2-trifluoro-N- {3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1, 1-dioxide-4H-1,2,4-benzothiadiazin-7-yl} ethanesulfonamide To a solution of the product of Example 205 (21.5 mg, 0.05 mmol) in pyridine (1 mL), 2,2 , 2-trifluoroethanesulfonyl chloride (28 μL, 0.25 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was chromatographed on silica gel eluting with 1: 1 ethyl acetate / hexane to give the title compound (5 mg, 17%).

Example 405
[({3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} amino) sulfonyl] methyl acetate To a solution of the product of Example 205 (21.5 mg, 0.05 mmol) in methylene chloride (1 mL) was added chlorosulfonyl-acetic acid methyl ester (35 mg). , 0.2 mmol) and triethylamine (30 μL, 0.22 mmol) were added. The resulting mixture was stirred at room temperature for 3 days. After completion of the reaction, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with 199: 1 methylene chloride: methanol. The product was dissolved in methylene chloride, 2 drops of acetic acid was added, stirred at room temperature for 10 minutes and washed with water. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give the title compound (2 mg, 7%).

Example 406
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} ethanesulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added ethanesulfonyl chloride (19 μL, 0.2 mmol). It was. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was chromatographed on silica gel eluting with 199: 1 methylene chloride: methanol to give the title compound (3 mg, 11%).

Example 407
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} propane-2-sulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added isopropylsulfonyl chloride (22 μL, 0.2 mmol). ) Was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was chromatographed on silica gel eluting with 199: 1 methylene chloride: methanol to give the title compound (2 mg, 7%).

Example 408
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl} -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} -1-phenylmethanesulfonamide A solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added α-toluenesulfonyl chloride (38 mg, 0.2 mmol), heated in a microwave reactor at 120 ° C. for 120 minutes, cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with hexane: ethyl acetate (1: 1). The crude product was chromatographed on silica gel eluting with methylene chloride: methanol (399: 1) to give the title compound (7 mg, 24%).

Example 409A
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -2-nitrobenzenesulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol ) in pyridine (1 mL) was added 2-nitrobenzenesulfonyl chloride (44 mg, 0.2 mmol). added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction solution was concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with hexane: ethyl acetate (1: 1). The crude product was chromatographed on silica gel eluting with methylene chloride: methanol (399: 1) to give the title compound (8 mg, 26%).

Example 409B
2-Amino-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] benzenesulfonamide Example 409A product (8 mg, 0.013 mmol), iron powder (5.0 mg, 0.089 mmol) and NH ₄ Cl (1 mg, 0.019 mmol). ) In methanol: tetrahydrofuran: water (2: 2: 1, 10 mL) was heated at 60 ° C. for 2 h. The solution was filtered through Celite® and washed with THF. The solution was concentrated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated to give the title compound (7 mg, 92%).

Example 410
3- [8- (Chloromethyl) -1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl] -4-hydroxy- 1- (3-Methylbutyl) -1,8-naphthyridin-2 (1H) -one A mixture of the product of Example 377 (0.022 g, 0.05 mmol) and chloroacetic acid (0.06 g, 0.63 mmol). In a sealed tube, heated in a microwave reactor at 120 ° C. for 30 minutes, cooled to 25 ° C., and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with methylene chloride and then 98: 2 methylene chloride: methanol to give the title compound (0.010 g, 40% yield).

Example 411
{3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4,7-dihydroimidazo [ 4,5-h] [1,2,4] benzothiadiazin-8-yl} acetonitrile The product of Example 377 (0.044 g, 0.1 mmol) and cyanoacetic acid (0.085 g, 1.0 mmol) The medium mixture was heated in a sealed tube in a microwave reactor at 120 ° C. for 30 minutes, cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue. It was chromatographed on silica gel eluting first with methylene chloride and then with 98: 2 methylene chloride / methanol to give the title compound (0.007 g, 14% yield).

Example 412
{3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4,7-dihydroimidazo [ 4,5-h] [1,2,4] benzothiadiazin-8-yl} methyl acetate Product of Example 377 (0.088 g, 0.2 mmol), 3,3,3-trimethoxy-propionic acid A mixture of methyl ester (0.360 g, 2.0 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate was heated in a sealed tube at 60 ° C. for 30 minutes in a sealed tube, cooled to 25 C. Partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting first with methylene chloride and then with 97: 3 methylene chloride / methanol to give the title compound (0.051 g, 49% yield).

Example 413
3- (9,9-dioxide-6H- [1,2,5] thiadiazolo [3,4-h] [1,2,4] benzothiadiazin-7-yl) -4-hydroxy-1- ( 3- Methylbutyl) -1,8 -naphthyridin-2 (1H) -one A mixture of the product of Example 377 (0.044 g, 0.1 mmol) and sulfamide (0.048 g, 0.5 mmol) was placed in a sealed tube. The mixture was heated in a microwave reactor at 190 ° C. for 4 minutes, cooled to 25 ° C., and concentrated. The crude product was eluted from [0.1% trifluoroacetic acid / water] / methanol (90/10) to [0.1% trifluoroacetic acid / water] / methanol (5/95). To give the title compound (0.005 g, 11% yield).

Example 414A
tert-Butyl 4-amino-3- (aminosulfonyl) phenylcarbamate 2,5-diaminosulfonamide [prepared according to the procedure of literature (J. Amer. Chem. Soc., 1943, 65, 738)] (0.168 g, A mixture of 0.896 mmol) and di-tert-butyl dicarbonate (0.196 g, 0.896 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 3: 2 hexane / ethyl acetate to give the title compound (0.202 g, 78% yield).

Example 414B
tert-Butyl 3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4 -Benzothiadiazin- 7- ylcarbamate The product of Example 414A (78.1 mg, 0.272 mmol) and the product of Example 353B (91.0 mg, 0.272 mmol) in dehydrated dioxane (2.7 mL). The mixture was heated to reflux for 3 hours. The reaction mixture was cooled to 25 ° C. and concentrated under reduced pressure to give an oily solid. The solid was triturated with methanol to give the title compound (72.5 mg, 51%).

  Example 414B (3.9 mg, 0.0074 mmol) was reacted with 1N sodium hydroxide solution (0.0074 mL, 0.0074 mmol) in water 0.5 mL and tetrahydrofuran 0.5 mL at room temperature for 1.2 hours. The sodium salt of the compound was prepared. The reaction mixture was evaporated under a nitrogen stream to obtain a sodium salt (4.1 mg, yield 100%).

Example 415
3- (7-amino-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1-[(cyclopropylmethyl) amino] -4-hydroxyquinoline-2 (1H ) -On A solution of the product of Example 414B (10.1 mg, 0.0192 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) was stirred at room temperature for 15 minutes. The solvent was distilled off under a stream of nitrogen to give the title compound (10.4 mg, quantitative yield).

Example 416
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} -4- (methylsulfonyl) benzenesulfonamide To a solution of the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 4-methyl Sulfonylbenzenesulfonyl chloride (0.014 g, 0.056 mmol) was added. The reaction mixture was heated in a microwave reactor at 100 ° C. for 30 minutes. The reaction was cooled to 25 ° C., diluted with ethyl acetate (40 mL) and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99: 1 methylene chloride: methanol to give the title compound (15 mg, 50%).

Example 417
3-[({3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1 , 2,4-Benzothiadiazin-7-yl} amino) sulfonyl] methyl thiophene-2-carboxylate To a solution of the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL), 2- (Methoxylcarbonyl) thiophene-3-sulfonyl chloride (0.014 g, 0.056 mmol) was added. The reaction mixture was heated in a microwave reactor at 100 ° C. for 30 minutes. The reaction was cooled to 25 ° C., diluted with ethyl acetate (40 mL) and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99: 1 methylene chloride / methanol to give the title compound (15 mg, 50%).

Example 418
3- (8-amino-1,1-dioxide-4,7-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl) -4-hydroxy-1- ( 3-methylbutyl) -1,8-naphthyridin-2 (1H) -one The product of Example 377 (24 mg, 0.055 mmol) was suspended in water (0.1 mL), cooled in an ice bath and cooled to 0 ° C. It was. To the slurry was added cyanogen bromide in acetonitrile (0.1 mL, 0.067 mmol) and the mixture was stirred at room temperature for 42 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (23.5 mg, 92%). The compound was converted to the sodium salt according to the method described in Example 1D.

Example 419
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} propane-1-sulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 1-propanesulfonyl chloride (22.5 mL). 0.2 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was chromatographed on reverse phase HPLC eluting with 0.1% aqueous trifluoroacetic acid / methanol (90/10) to 0.1% aqueous trifluoroacetic acid / methanol (5/95). To give the title compound (3 mg, 11%).

Example 420
2-chloro-N- {3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H -1,2,4-Benzothiadiazin-7-yl} benzenesulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2-chlorobenzenesulfonyl chloride (27 mL, 0.2 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was purified by chromatography on silica gel eluting with 199: 1 methylene chloride: methanol to give the title compound (14 mg, 46%).

Example 421
1-chloro-N- {3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H -1,2,4-Benzothiadiazin-7-yl} methanesulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added chloromethylsulfonyl chloride (18 mL, 0 mL). .2 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was eluted from [0.1% trifluoroacetic acid / water] / methanol (90/10) to [0.1% trifluoroacetic acid / water] / methanol (5/95). Purification by chromatography on gave the title compound (6 mg, 22%).

Example 422
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} butane-1-sulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 1-butanesulfonyl chloride (26 mL, 0 .2 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was chromatographed on silica gel eluting with 199: 1 methylene chloride: methanol to give the title compound (8 mg, 29%).

Example 423
2,6-dichloro-N- {3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide -4H-1,2,4-benzothiadiazin-7-yl} benzenesulfonamide To a solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2,6-dichlorobenzene. Sulfonyl chloride (49, 0.2 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 ° C. for 120 minutes. The reaction was cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered and washed with 1: 1 hexane: ethyl acetate. The crude product was chromatographed on silica gel eluting with 399: 1 methylene chloride: methanol to give the title compound (5 mg, 16%).

Example 424
2-chloro-6-({3- [4-hydroxy-1- (isobutylamino) -2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl] oxy) methyl isonicotinate The product of Example 321C (40.0 mg, 0.138 mmol), potassium carbonate (19.1 mg, 0.138 mmol), copper (II) oxide A mixture of (18.4 mg, 0.23 mmol) and methyl 2,6-dichloroisonicotinate (28.4 mg, 0.138 mmol) in pyridine (0.2 mL) was heated in a microwave reactor at 125 ° C. And stirred for 100 minutes. After cooling to 25 ° C., the mixture was loaded directly onto silica gel and eluted with a step gradient from 0% to 5% methanol / methylene chloride. Fractions containing the desired product were combined and concentrated. The title compound was isolated by recrystallization of the residue using ethyl acetate / hexane (4.3 mg, 68%).

Example 425A
4- (Benzyloxy) -1- (3-methylbutyl) pyridin-2 (1H) -one 4-benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1-bromo-3- A solution of methylbutane (0.715 mL, 5.96 mmol) in N, N-dimethylformamide (20 mL) was added to 1,8-diazabicyclo [5.4.0] undec-7-ene (1.86 mL) at 65 ° C. for 5 days. , 12.43 mmol). The mixture was cooled to 25 ° C. and partitioned between water and methylene chloride. The organic layer was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 1% methanol / methylene chloride to give the title compound (0.57 g, 42%).

Example 425B
4-Hydroxy-1- (3-methylbutyl) pyridin-2 (1H) -one A solution of the product of Example 425A (0.55 g, 2.03 mmol) in tetrahydrofuran (10 mL) was added ammonium formate at 60 ° C. over 3 hours. (0.37 g, 5.87 mmol) and a catalytic amount of 20% palladium hydroxide / carbon. The solution was filtered through diatomaceous earth and the filtrate was concentrated to give the title compound (0.21 g, 57%).

Example 425C
3- [Bis (methylthio) methylene] -1- (3-methylbutyl) pyridine-2,4 (1H, 3H) -dione The product of Example 425B (0.038 g, 0.21 mmol) of 1,4-dioxane (3 mL) solution was added to pyridine (0.135 mL, 1.68 mmol) and tris (methylthio) methyl methyl sulfate (Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)) (0.11 g, 0.42 mmol). Additional tris (methylthio) methylsulfate (0.11 g, 0.42 mmol) was added and the solution was heated at 85 ° C. for 1 hour. The reaction mixture was cooled to 25 ° C. and the solvent was removed under a warm stream of nitrogen. The residue was chromatographed on a 1 gram Alltech Seppack cartridge eluting with 100% methylene chloride and then 30% ethyl acetate / methylene chloride to give the title compound (19 mg, 33%). .

Example 425D
2-amino-5-[(methylsulfonyl) amino] benzenesulfonamide 2,5-diamino-benzenesulfonamide (0.288 g, 0.0015 ml, 1 equiv), a mixture of methylene chloride (5 mL) and pyridine (5 mL) Was stirred at 0 ° C. Methanesulfonyl chloride (119 μL, 0.0015 mol, 1 equivalent) was added dropwise over 3 minutes. The reaction mixture was warmed to 25 ° C. and stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel using a step gradient from 0% to 4% methanol / methylene chloride to give the title compound (68% yield).

Example 425E
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydropyridin-3-yl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} methanesulfonamide A solution of the product of Example 425C (0.019 g, 0.067 mmol) and the product of Example 425D (0.018 g, 0.067 mmol) in 1,4-dioxane was added at 100 ° C. For 1 hour. Solvent was removed under a warm stream of nitrogen and the residue was fractionated on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile / 0.1% aqueous trifluoroacetic acid. Purification by HPLC gave the title compound (0.007 g, 23%).

Example 426A
The title compound was prepared by the method of 1-benzyl-4-hydroxypyridin-2- (1H) -one literature (Eschenhof, et. Al., Tetrahedron, v 48, 30, p 6225-6230, 1992).

Example 426B
1-benzyl-3- [bis (methylthio)]-3- [bis (methylthio) methylene] pyridine-2,4 (1H, 3H) -dione of the product of Example 426A (0.124 g, 0.62 mmol) The 1,4-dioxane (6 mL) solution was added to pyridine (0.400 mL, 4.96 mmol) and tris (methylthio) methyl methylsulfate (Reference (Synthesis, 22-25, 1988; M. Barbero) at 40 ° C. for 15 minutes. S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)) (0.32 g, 1.24 mmol). Additional methyl tris (methylthio) sulfate (0.32 g, 1.24 mmol) was added and the solution was heated at 90 ° C. for 1 hour. The solvent was removed under a warm stream of nitrogen and the residue was purified using a 1 gram Alltech Seppac cartridge eluting with 100% methylene chloride and then 30% ethyl acetate / methylene chloride to give the title compound. (79 mg, 42%) was obtained.

Example 426C
N- [3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7- Yl] methanesulfonamide A 1,4-dioxane solution of the product of Example 426B (0.028 g, 0.092 mmol) and the product of Example 425D (0.025 g, 0.092 mmol) is heated at 100 ° C. for 40 minutes. did. The solvent was removed under a warm stream of nitrogen and the residue was triturated with water and ethyl acetate. The precipitate in the organic layer was filtered and dried to give the title compound (0.006 g, 12%).

Example 427
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] ethanesulfonamide A solution of the product of Example 353E (16.1 mg, 0.036 mmol) in N, N-dimethylformamide (0.4 mL). To was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0 ° C. and ethanesulfonyl chloride (0.0036 mL, 0.038 mmol) was added. The mixture was warmed to 23 ° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile / [0.1% trifluoroacetic acid / water] to 95% acetonitrile / [0.1% trifluoroacetic acid / water]. To give the title compound (7.7 mg, 40%). To a solution of the title compound (7.7 mg, 0.014 mmol) in water (0.4 mL), 1N sodium hydroxide (0.029 mL, 0.0029 mmol) is added and stirred for 30 minutes to produce the sodium salt of the title compound. did. The reaction mixture was concentrated under reduced pressure.

Example 428
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] propane-1-sulfonamide The product of Example 353E (16.7 mg, 0.037 mmol) of N, N-dimethylformamide (0. To the 4 mL) solution was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0 ° C. and 1-propanesulfonyl chloride (0.005 mL, 0.041 mmol) was added. The mixture was warmed to 23 ° C. and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile / [0.1% trifluoroacetic acid / water] to 95% acetonitrile / [0.1% trifluoroacetic acid / water]. To give the title compound (9.9 mg, 48%).

Example 429
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno and 2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] propane-2-sulfonamide The product of Example 353E (16.2 mg, 0.036 mmol) of N, N-dimethylformamide (0. To the 4 mL) solution, triethylamine (0.011 mL, 0.079 mmol) was added. The mixture was cooled to 0 ° C. and isopropylsulfonyl chloride (0.0043 mL, 0.038 mmol) was added. The mixture was warmed to 23 ° C. and stirred for 3 hours. Additional isopropylsulfonyl chloride (0.006 mL, 0.055 mmol) was added and the reaction mixture was stirred at 23 ° C. for 15 hours. The reaction mixture was stirred at 50 ° C. for 2 hours. Additional triethylamine (0.040 mL, 0.287 mmol) and isopropylsulfonyl chloride (0.010 mL, 0.091 mmol) were added and the reaction mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to 25 ° C. and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile / [0.1% trifluoroacetic acid / water] to 95% acetonitrile / [0.1% trifluoroacetic acid / water]. To give the title compound (6.7 mg, 33%). The sodium salt of the title compound was prepared according to the procedure of Example 1D.

Example 430
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] benzenesulfonamide A solution of the product of Example 353E (16.9 mg, 0.038 mmol) in N, N-dimethylformamide (0.4 mL). To was added triethylamine (0.012 mL, 0.083 mmol) and benzenesulfonyl chloride (0.006 mL, 0.042 mmol). The reaction mixture was stirred at 23 ° C. for 0.75 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile / [0.1% trifluoroacetic acid / water] to 95% acetonitrile / [0.1% trifluoroacetic acid / water]. To give the title compound (10.7 mg, 48%).

Example 431
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] -1-phenylmethanesulfonamide The product of Example 353E (16.5 mg, 0.037 mmol) of N, N-dimethylformamide (0 .4 mL) solution was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0 ° C. and α-toluenesulfonyl chloride (0,008 g, 0.041 mmol) was added. The reaction mixture was warmed to 23 ° C. and stirred for 0.5 hour. The reaction mixture was heated to 50 ° C. and stirred for 1.75 hours. Additional triethylamine (0.010 mL, 0.074 mmol) and α-toluenesulfonyl chloride (0.007 g, 0.037 mmol) were added and the reaction mixture was stirred at 23 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile / [0.1% trifluoroacetic acid / water] to 95% acetonitrile / [0.1% trifluoroacetic acid / water]. To give the title compound (7.7 mg, 35%).

Example 432A
1- (Cyclobutylamino) -4-hydroxyquinolin-2 (1H) -one The product of Example 350A (0.516 g, 2.9 mmol) and cyclobutanone (1.05 g, 15.0 mmol) in acetic acid (0. To a solution of 90 g, 15.0 mmol) and methanol (20 mL), sodium cyanoborohydride (0.94 g, 15.0 mmol) was added dropwise, stirred for 48 hours, and concentrated. The residue was treated with 0.5M aqueous sodium bicarbonate, acidified to pH 2 with 1M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was chromatographed on silica gel eluting with 3: 2 hexane / ethyl acetate to give the title compound (0.400 g, 60%).

Example 432B
3- [Bis (methylthio) methylene] -1- (cyclobutylamino) quinoline-2,4 (1H, 3H) -dione The product of Example 432A (0.115 g, 0.5 mmol) and methyl tris (methylthio) ) Methyl (produced using the procedure of literature (Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)) (0.27 g, 1 0.0 mmol) in pyridine (0.316 g, 4.0 mmol) and dioxane (5.0 mL) was heated at 60 ° C. for 30 min. Additional methyl tris (methylthio) sulfate was added (0.27 g, 1.0 mmol) and heating was continued for 30 minutes. The mixture was cooled to 25 ° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude material was chromatographed on silica gel eluting with 95/5 methylene chloride / ethyl acetate to give the title compound (0.146 g, 87% yield).

Example 432C
N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] -1,1-dioxide-4H-1,2,4-benzothi Asiadin-7-yl} methanesulfonamide The product of Example 425D (0.195 g, 0.585 mmol, 1.5 eq) and the product of Example 432B (0.100 g, 0.390 mmol, 1.5 eq) ) In dehydrated dioxane (10 mL) was heated at 120 ° C. for 1 h. After cooling to 25 ° C., the reaction mixture was treated with methanol (20 mL) and diethyl ether (20 mL) and the precipitated product was collected by vacuum filtration to give the title compound (25 mg, 12% yield). .

Example 433
N- (3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-1,2,4 -Benzothiadiazin- 7-yl) methanesulfonamide The product of Example 353B (0.090 g, 0.269 mmol, 1 eq) and the product of Example 425D (0.071 g, 0.269 mmol, 1 eq) Of dehydrated dioxane (5 mL) was heated at 120 ° C. for 1 h. After the reaction mixture was cooled to 25 ° C., methanol (20 mL) and diethyl ether (20 mL) were added and the precipitated product was collected by vacuum filtration to give the title compound (21 mg, 15.5% yield). ).

Example 434
4-hydroxy-3- [8- (hydroxyl) -1,1-dioxide-4,9-dihydroimidazo [4,5-h] [1,2,4] benzothiadiazin-3-yl] -1 -(3- Methylbutyl) -1,8 -naphthyridin-2 (1H) -one The product of Example 377 (14 mg, 0.033 mmol) was added 4N HCl (0.5 mL) and glycolic acid (4 mg, 0.052 mmol). And the resulting mixture was heated to reflux for 24 hours. The mixture was concentrated under reduced pressure to give a white pasty solid. The solid was purified by chromatography on silica gel eluting with 95: 5 methylene chloride: methanol to give the title compound (10 mg, 63%). The title compound was converted to the sodium salt according to the method described in Example 1D.

Example 435A
2-chloroethyl ({3- [4-hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1 , 2,4-Benzothiadiazin-7-yl} amino) sulfonyl carbamate chlorosulfonyl isocyanate (33 mg, 0.23 mmol) in methylene chloride (8 mL) was cooled to 0 ° C. and 2-chloroethanol (18. 8 mg, 0.23 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 90 minutes, then a solution of Example 205 product (100 mg, 0.23 mmol) and triethylamine (71 mg, 0.70 mmol) in methylene chloride (2 mL) was added. The mixture was stirred at 25 ° C. for 24 hours and partitioned between methylene chloride (25 mL) and 1N aqueous hydrochloric acid (20 mL). The resulting organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (96 mg, 67%).

Example 435B
N- {3- [4-Hydroxy-1- (3-methylbutyl) -2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl} -2-oxo-1,3-oxazolidine-3-sulfonamide To a solution of the product of Example 435A (90 mg, 0.147 mmol) in methylene chloride (10 mL) was added triethylamine. (1 mL) was added. The mixture was stirred at 25 ° C. for 6 hours. The reaction was treated with 1N aqueous hydrochloric acid (10 mL) and extracted with methylene chloride (20 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless solid (70 mg, 82%).

Example 435C
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -N ′-(2-phenylethyl) sulfamide The product of Example 435B (28 mg, 0.05 mmol) and phenethylamine (6 mg, 0.05 mmol) in acetonitrile (10 mL) and triethylamine (0 The mixture was heated to reflux for 18 hours. The reaction mixture was cooled to 25 ° C., diluted with ethyl acetate and extracted with 10 mL of 1N HCl, then 10 mL of brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The product was isolated by preparative thin layer chromatography on silica gel eluting with 25% ethyl acetate / methylene chloride to give 2 mg (10% yield) of the title compound.

Example 436
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylate 2,2-dioxide chlorosulfonyl isocyanate (24.5 μL, 0.281 mmol) in methylene chloride (2 mL) to benzyl alcohol (29 μL, 0.281 mmol) Was added dropwise at 25 ° C., stirred at 25 ° C. for 30 minutes, treated with a solution of the product of Example 205 (100 mg, 0.234 mmol) and triethylamine (130 μL, 0.936 mmol) in methylene chloride (3 mL) at 25 ° C. For 2 hours. The reaction mixture was treated with methylene chloride (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (122 mg, 81%).

Example 437
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] sulfamide A solution of the product of Example 436 (40 mg, 0.0625 mmol) in methanol (5 mL) was treated with 10% palladium / carbon (20 mg) and 5 hours at 25 ° C. under hydrogen atmosphere. Stir. The resulting solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (25 mg, 78%).

Example 438
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-propyldiazathian-1-carboxylate 2,2-dioxide triphenylphosphine (1.5 equivalents) in methylene chloride at 25 ° C. with diethyl azodicarboxylate ( 1.5 equivalents) is added dropwise. The solution is stirred for 10 minutes and then a methylene chloride solution containing the product of Example 436 (1 eq) and n-propanol (1.1 eq) is added dropwise. The resulting solution is stirred at 25 ° C. for 20 hours, then methylene chloride and 1N aqueous hydrochloric acid are added. The resulting organic layer is separated, dried over magnesium sulfate and filtered to give the title compound.

Example 439
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -N-propylsulfamide A methanol solution of the product of Example 438 is treated with 10% palladium / carbon and stirred at 25 ° C. for 5 hours under hydrogen atmosphere. The resulting solution is filtered and the filtrate is concentrated under reduced pressure to give the title compound.

Example 440
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylate methyl 2,2-dioxide chlorosulfonyl isocyanate (4.9 μL, 0.0562 mmol) in methylene chloride (2 mL) with stirring at 25 ° C. with methanol ( 2.3 μL, 0.0562 mmol) was added dropwise. After 30 minutes, a solution of the product of Example 205 (20 mg, 0.0468 mmol) and triethylamine (26 μL, 0.187 mmol) in methylene chloride (2 mL) was added and stirred at 25 ° C. for 24 hours. The reaction mixture was diluted with methylene chloride (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a triethylamine salt (12 mg, 39%).

Example 441
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-methyldiazathian-1-carboxylate 2,2-dioxide 1: 1 product of tetrahydrofuran (0.032 g, 0.05 mmol ) in tetrahydrofuran / methanol (2 mL) ) Trimethylsilyldiazomethane (2.0 M hexane solution, 50 μL, 0.1 mmol) was added dropwise to the solution at −10 ° C., stirred at 25 ° C. for 16 hours, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3% methanol / methylene chloride to give the title compound (5 mg, 15% yield).

Example 442
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -N′-methylsulfamide A solution of the product of Example 441 (14 mg, 0.0214 mmol) in methanol (3 mL) was stirred under a hydrogen atmosphere at 25 ° C. for 2 hours. And reacted with 10% palladium / carbon (10 mg). The solution was filtered and concentrated under reduced pressure to give the title compound (8 mg, 73%).

Example 443
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] diazathian-1-carboxylate 2-aminoethyl-2,2- dioxidechlorosulfonyl isocyanate (7.3 μL, 0.0843 mmol) in methylene chloride (2 mL) at 25 ° C. Butyl N- (2-hydroxyethyl) carbamate (13.6 mg, 0.0843 mmol) was added. After 30 minutes, the solution was treated with a solution of the product of Example 205 (30 mg, 0.0703 mmol) and triethylamine (39 μL, 0.281 mmol) in methylene chloride (2 mL) and stirred for 24 hours. The reaction mixture was diluted with methylene chloride (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was collected on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 min run time) at a flow rate of 40 mL / min. ) To give 8 mg of solid. The solid was treated with a solution of trifluoroacetic acid (1.6 mL) and methylene chloride (0.4 mL) at 25 ° C. for 3 hours. The solvent was removed under reduced pressure to give the title compound as the trifluoroacetate salt (12 mg, 24%).

Example 444
N-cyclopentyl-N ′-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl] sulfamide To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added 1-aminocyclopentane (0.0085 g, 0.0099 mL). 0.1 mmol) was added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a C8 column (25 mm × 100 mm, particle size 7 μm) gave the title compound (11 mg, 38%).

Example 445
N-cyclobutyl-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] sulfamide To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added 1-aminocyclobutane (0.0071 g, 0.0085 mL, 0 0.1 mmol) was added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a C8 column (25 mm × 100 mm, particle size 7 μm) gave the title compound (8 mg, 28%).

A-825309.1
Example 446A
4-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2. 4-benzothiadiazin-7-yl] amino} sulfonyl) amino] -1-piperidinecarboxylate tert-butyl To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added N. -1-Boc-4-aminopiperidine (0.020 g, 0.1 mmol) was added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a C8 column (25 mm × 100 mm, particle size 7 μm) gave the title compound (12 mg, 35%).

Example 446B
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -N ′-(4-piperidinyl) sulfamide The product of Example 446A (0.012 g, 0.017 mmol) was dissolved in 1,4-dioxane solution of hydrogen chloride (4N, 3 mL). It was. The mixture was stirred at 25 ° C. for 18 hours. The solvent was removed under reduced pressure to give the title compound as its hydrochloride salt (10 mg, 92%).

A-825311.0 Example 447 DL2
N- (2-hydroxyethyl) -N '-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide -4H-1,2,4-benzothiadiazin-7-yl] sulfamide To a solution of the product of Example 435B (0.006 g, 0.0104 mmol) in tetrahydrofuran (2 mL), water (0.1 mL) and sodium Ethanol solution in ethanol (20 wt%, 1 mL) was added. The mixture was stirred at 25 ° C. for 24 hours. The reaction solution was concentrated under a stream of warm nitrogen gas, and the residue was treated with 1N hydrochloric acid (2 mL) for 10 minutes with stirring. The resulting solid was filtered and dried to give the title compound (4 mg, 70%).

Example 448
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl] amino} sulfonyl) amino] propanamide To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added glycinamide hydrochloride (0.0125 g , 0.1 mmol) and potassium carbonate (0.4 mmol). The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a C8 column (25 mm × 100 mm, particle size 7 μm) gave the title compound (3 mg, 10%).

A-832731.0 Example 449
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1- azetidinesulfonamide To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added azetidine hydrochloride (0.0095 g, 0.1 mmol). And potassium carbonate (0.4 mmol) were added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a C8 column (25 mm × 100 mm, particle size 7 μm) gave the title compound (2 mg, 7%).

A-832735.0 Example 450 DL2
3-hydroxy-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] -1-azetidinesulfonamide To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added 3-hydroxyazetidine hydrochloride ( 0.011 g, 0.1 mmol) and potassium carbonate (0.4 mmol) were added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a C8 column (25 mm × 100 mm, particle size 7 μm) gave the title compound (3 mg, 13%).

Example 451A
tert-Butyl 1-({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl] amino} sulfonyl) -3-pyrrolidinylcarbamate To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added N-Boc. -3-Aminopyrrolidine (0.0186 g, 0.1 mmol) was added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry C8 using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a column (25 mm × 100 mm, particle size 7 μm) gave the title compound (23 mg, 68%).

Example 451B
3-Amino-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] -1-pyrrolidinesulfonamide The product of Example 446A (0.012 g, 0.017 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4N, 3 mL). It was. The mixture was stirred at 25 ° C. for about 18 hours. The solvent was removed under reduced pressure to give the title compound as its hydrochloride salt (16 mg, 88%).

Example 452A
Piperidine (12.6 g, 150 mmol) was added dropwise to a solution of 1-piperidinesulfonyl chloride sulfuryl chloride (1N methylene chloride solution, 75 mL, 75 mmol) at −20 ° C., stirred at 0 ° C. for 2 hours, and methylene chloride and water ( (50 mL). The organic layer was washed with 1N aqueous HCl, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was distilled under reduced pressure (1 mmHg) at 105 ° C. to give the title compound (5 g).

Example 452B
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-piperidinesulfonamide The product of Example 205 (2 mg, 0.1 mL), the product of Example 451A (17 mg, 0.1 mmol) and triethylamine (0.1 mL) The mixture in methylene (2 mL) was stirred at 25 ° C. for 18 hours, diluted with methylene chloride (25 mL) and washed with 1N HCl and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was added to a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile / 10 mM aqueous ammonium acetate over 8 minutes (10 minutes run time) at a flow rate of 40 mL / min. ) To give the title compound (10 mg).

A-805330.0 Example 453 DLM
N-benzyl-N ′-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1, 2,4-Benzothiadiazin-7-yl] sulfamide The product of Example 435B (28 mg, 0.05 mmol), benzylamine (6 mg, 0.05 mmol) and triethylamine (0.5 mL) in acetonitrile (2 mL). The mixture was stirred at 70 ° C. for 18 hours. The reaction mixture was cooled to about 25 ° C. and partitioned between ethyl acetate and 1N HCl (10 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was collected on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 min run time) at a flow rate of 40 mL / min. ) To give the title compound (12 mg).

Example 454
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2, 4-benzothiadiazin-7-yl] amino} sulfonyl) amino] ethyl benzoate 3-amino-benzoic acid ethyl ester (0.165 g, 1.0 mmol) in methylene chloride (6 mL) at about 0 ° C., Chlorosulfonic acid (0.128 g, 1.1 mmol) was added dropwise. The reaction mixture was stirred at 25 ° C. for 1 hour, phosphorus pentachloride (0.229 g, 1.1 mmol) was added and the reaction mixture was heated to reflux for 3.5 hours. The reaction mixture was cooled to about 25 ° C. and the solvent was distilled off under reduced pressure. A solution of the residue in methylene chloride (10 mL) was treated with the product of Example 205 (0.214 g, 0.5 mmol) followed by triethylamine (0.152 g, 1.5 mmol). The reaction mixture was stirred at 25 ° C. for 3 hours and poured into 25 mL of 1N aqueous hydrochloric acid. The reaction mixture was extracted with methylene chloride (3 x 25 mL). The combined organic layers were dehydrated over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 0-2% methanol / methylene chloride to give the title compound (0.166 g, 48% yield).

A-824028.0 Example 455
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl] amino} sulfonyl) amino] benzoic acid A solution of the product of Example 454 (25.5 mg, 0.389 mmol) in 1N aqueous sodium hydroxide (1 mL) and methanol (1 mL) was added. Stir at 25 ° C. for 17 hours and concentrate under a warm stream of nitrogen. The residue was treated with 2 mL of 1N aqueous hydrochloric acid. The resulting solid was isolated by vacuum filtration, washed with 10 mL of water and dried to give the title compound (21.4 mg, 88% yield).

Example 456
3-[({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2, 4-Benzothiadiazin-7-yl] amino} sulfonyl) amino] benzamide A solution of the product of Example 454 (7.6 mg, 0.012 mmol) in ammonium hydroxide (1 mL) was stirred at 25 ° C. for 17 hours. The solvent was distilled off under a warm nitrogen stream to give the title compound (7.4 mg).

Example 457A
4- (Benzyloxy) -1-isopentyl-2 (1H) -pyridinone 4-Benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1,8-diazabicyclo [5.4.0] ] A solution of undec-7-ene (1.86 mL, 12.43 mmol) and 1-bromo-3-methylbutane (0.715 mL, 5.96 mmol) in N, N-dimethylacetamide (20 mL) was heated at 65 ° C. for 5 days. did. The solution was cooled to about 25 ° C., partitioned between 10% aqueous ammonium chloride and methylene chloride, and the organic layer was separated under reduced pressure and concentrated. The residue was chromatographed on silica gel eluting with 1% methanol / methylene chloride to give the title compound (0.569 g, 42%).

Example 457B
4-Hydroxy-1-isopentyl-2 (1H) -pyridinone A solution of the product of Example 457A (0.452 g, 1.67 mmol) in tetrahydrofuran (20 mL) was added ammonium formate (0.30 g) at 60 ° C. over 2 h. , 5.01 mmol) and a catalytic amount of 20% palladium hydroxide / carbon. The reaction was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give the title compound (0.30 g, 100%).

Example 457C
3- [Bis (methylsulfanyl) methylene] -1-isopentyl-2,4 (1H, 3H) -pyridinedione The product of Example 457B (2.24 g, 12.37 mmol) in pyridine (8.0 mL, 98. 96 mmol) and dioxane (50 mL) at 90 ° C. with an excess of tris (methylthio) methyl methylsulfate (Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A Manufactured by using the procedure of Gatti, V. Regondi), stirred at 90 ° C. for 1.5 hours and cooled to about 25 ° C. The reaction solution was taken from the obtained solid by a gradient method, and the solvent was removed under reduced pressure. The residue was dissolved in hexane, loaded onto a silica gel layer (300 mL) and eluted with hexane, then methylene chloride, then 25% ethyl acetate / methylene chloride to give the title compound (2.42 g, 75%).

Example 457D
3- (7-Amino-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -4-hydroxy-1-isopentyl-2 (1H) -pyridinone Formation of Example 457C The product (2.08 g, 7.29 mmol) was treated with a solution of the product of Example 414A (2.00 g, 6.96 mmol) in dioxane (20 mL) at 115 ° C. for 30 minutes and cooled to 25 ° C. And concentrated under reduced pressure. A 4M hydrochloric acid / dioxane (20 mL) solution of the residue was stirred at 25 ° C. for 18 hours and concentrated under reduced pressure. The residue was triturated with methylene chloride and filtered to give the title compound. The filtrate containing the protected intermediate was concentrated and purified by chromatography on silica gel eluting with 1% methanol / methylene chloride. The protected product was again exposed to the above deprotection conditions to give the title compound as its hydrochloride salt (2.02 g, 96%).

Example 457E
3- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7- Yl] diazathian-1-carboxylic acid benzyl 2,2-dioxide chlorosulfonyl isocyanate (61.8 mg, 0.436 mmol) and benzyl alcohol (47.0 mg, 0.436 mmol) in methylene chloride (7.5 mL) at 25 ° C. And then added a solution of the product of Example 457D (150 mg, 0.363 mmol) and triethylamine (183.7 mg, 1.82 mmol) in methylene chloride (14 mL) and stirred at 25 ° C. for 20 hours, Partitioned between methylene chloride (25 mL) and 1N aqueous hydrochloric acid (25 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (200 mg, 93%).

Example 458
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7- Yl] sulfamide A solution of the product of Example 457E (40 mg, 0.068 mmol) in methanol (5 mL) was stirred with 10% palladium / carbon (22 mg) at 25 ° C. for 4 hours under a hydrogen atmosphere. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound (28 mg, 99%).

Example 459A
tert-butyl 2-[({[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1 , 2,4-Benzothiadiazin-7-yl] amino} sulfonyl) amino] ethylcarbamate To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added tert-butyl N- (2-Aminoethyl) carbamate (0.016 g, 0.016 mL, 0.1 mmol) was added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry C8 using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a column (25 mm × 100 mm, particle size 7 μm) gave the title compound (6.3 mg, 20%).

Example 459B
N- (2-aminoethyl) -N '-[3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide -4H-1,2,4-benzothiadiazin-7-yl] sulfamide in the hydrogen chloride / 1,4-dioxane solution (4N, 3 mL) of the product of Example 459A (0.0053 g, 0.0082 mmol). The solution was stirred at 25 ° C. and stirred for 18 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt (4 mg, 89%).

Example 460
1-({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4 -Benzothiadiazin -7-yl] amino} sulfonyl) -3-piperidinecarboxylate To a solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL), ethyl nipecotate (0. 016 g, 0.016 mL, 0.1 mmol) was added. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry C8 using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a column (25 mm × 100 mm, particle size 7 μm) gave the title compound (20.3 mg, 63%).

Example 461A
(2S) -1- (Chlorosulfonyl) -2-pyrrolidinecarboxylic acid methyl L-proline methyl ester hydrochloride (0.33 g, 0.002 mol) in toluene (5 mL), methylene chloride (2 mL) and triethylamine (0.6 mL) , 0.004 mol) was added dropwise over 3 minutes to a cooled toluene solution of sulfuryl chloride (0.32 mL, 0.0039 mol) (−20 ° C.). The mixture was stirred at −20 ° C. for an additional 45 minutes. The reaction was filtered and the solvent removed under reduced pressure to give the title compound (0.40 g).

Example 461B
(2S) -1-({[3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1 , 2,4-Benzothiadiazin-7-yl] amino} sulfonyl) -2-pyrrolidinecarboxylate A solution of the product of Example 205 (0.030 g, 0.0703 mmol) in acetonitrile (2 mL) was prepared as Example 461A. Of the product (0.018 g, 0.077 mmol) and triethylamine (0.011 mL, 0.077 mmol), stirred at 60 ° C. for 20 hours, and cooled to about 25 ° C. The solvent is distilled off under reduced pressure and the residue is a Waters Symmetry C8 column using a gradient from 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 min (10 min run time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on (25 mm × 100 mm, particle size 7 μm) gave the title compound (7 mg, 16%).

Example 462
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl] -1-pyrrolidinesulfonamide A solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added to pyrrolidine (0.0076 g, 0.009 mL, 0.1 mmol). Was processed. The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry C8 using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a column (25 mm × 100 mm, particle size 7 μm) gave the title compound (2.6 mg, 9%).

Example 463
3-hydroxy-N- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide-4H-1,2 , 4-Benzothiadiazin-7-yl] -1-piperidinesulfonamide A solution of the product of Example 435B (0.029 g, 0.05 mmol) in acetonitrile (2 mL) was added to 3-hydroxypiperidine hydrochloride (0.0079 g). , 0.1 mmol) and triethylamine (0.00796 mL, 0.057 mmol). The reaction mixture was heated in a microwave reactor at 80 ° C. for 2 hours and cooled to about 25 ° C. Waters symmetry C8 using a gradient of 10% to 100% acetonitrile / 10 mM ammonium acetate in water over a period of 8 minutes (10 minutes running time) at a flow rate of 40 mL / min. Purification by reverse phase preparative HPLC on a column (25 mm × 100 mm, particle size 7 μm) gave the title compound (4.8 mg, 18%).

Example 464A
tert-Butyl 3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7- ylcarbamate A mixture of the product of Example 432B (1.25 g, 3.74 mmol) and the product of Example 414A (1.06 g, 3.7 mmol) in dehydrated dioxane (50 mL) was heated to reflux for 3 hours. And cooled to 25 ° C. and concentrated under reduced pressure. The residue was triturated in hot 3: 1 hexane / ethyl acetate (30 mL), cooled and the solid was collected by filtration and dried to give the title compound (1.5 g, 76% yield).

Example 464B
Implementation of 3- (7-amino-1,1-dioxide-4H-1,2,4-benzothiadiazin-3-yl) -1- (cyclobutylamino) -4-hydroxy-2 (1H) -quinolinone To a slurry of the product of Example 464A (1.5 g, 2.85 mmol) in methylene chloride (10 mL) was added dropwise 6 mL of trifluoroacetic acid at 0 ° C., stirred at 25 ° C. for 2 hours, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 10% aqueous sodium bicarbonate (3 x 50 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. (1.1 g, 91% yield).

Example 464C
N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} ethanesulfonamide Ethanesulfonyl chloride (0.026 mg, 0.2 mmol) was added dropwise to a solution of the product of Example 464B (0.0425 g, 0.1 mmol) in pyridine (300 μL) at 25 ° C. For 1 hour and concentrated under reduced pressure. The residue was collected on a Waters Symmetry C8 column (25 mm × 100 mm, granule) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous TFA over 8 minutes at a flow rate of 40 mL / min (10 min run time). Purification by reverse phase preparative HPLC with a diameter of 7 μm) afforded the title compound (0.020 g, 39% yield).

Example 465
3- {3- [1- (Cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} diazathian-1-carboxylate benzyl 2,2-dioxide chlorosulfonyl isocyanate (0.051 g, 0.36 mmol) in methylene chloride (2 mL) to benzyl alcohol (0.039 g, 0.36 mmol) Was added dropwise at 0 ° C., stirred at 25 ° C. for 30 minutes and treated with a solution of the product of Example 464B (0.127 g, 0.03 mmol) and triethylamine (0.12 g, 1.2 mmol) in methylene chloride (4 mL). did. The reaction mixture was stirred at 25 ° C. for 2 hours and partitioned between methylene chloride (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3% methanol / methylene chloride to give the title compound (0.127 g, 66% yield).

Example 466A
3- {3- [1- (Cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Din -7-yl} -1-methyldiazathian-1-carboxylate 2,2-dioxide A 1: 1 tetrahydrofuran / methanol (2 mL) solution of the product of Example 465 (0.045 g, 0.07 mmol). At −10 ° C., trimethylsilyldiazomethane (2.0 M hexane solution, 70 μL, 0.14 mmol) was added dropwise, stirred at 25 ° C. for 16 hours, and concentrated under reduced pressure to give the title compound (0.045 g, Yield 98%).

Example 466B
N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} -N-methylsulfamide A solution of the product of Example 466A (0.045 g, 0.069 mmol) in tetrahydrofuran (8 mL) and methanol (2 mL) was added with 10% palladium / carbon (20 mg). Treated and stirred at 25 ° C. under hydrogen atmosphere for 24 hours. The resulting solution was filtered through Celite (registered trademark; diatomaceous earth), and the filtrate was concentrated under reduced pressure. The residue was collected on a Waters Symmetry C8 column (25 mm × 100 mm, granule) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous TFA over 8 minutes at a flow rate of 40 mL / min (10 min run time). Purification by reverse phase preparative HPLC with a diameter of 7 μm) afforded the title compound (0.006 g, 17% yield).

Example 467
N- {3- [1- (cyclobutylamino) -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} sulfamide A solution of the product of Example 465 (0.790 g, 1.2 mmol) in tetrahydrofuran (80 mL) and methanol (20 mL) was treated with 10% palladium / carbon (200 mg) under a hydrogen atmosphere. And stirred at 25 ° C. for 24 hours. The reaction solution was filtered through Celite (registered trademark; diatomaceous earth), and the filtrate was concentrated under reduced pressure to obtain the title compound (0.500 g, yield 83%).

Example 468A
4- (Benzyloxy) -1- (cyclobutylmethyl) -2 (1H) -pyridinone 4-Benzyloxy-1H-pyridin-2-one (0.60 g, 2.98 mmol) of N, N-dimethylacetamide ( 10 mL) solution was treated with sodium hydride (0.086 g, 3.58 mmol) at 0 ° C. for 03 min, bromomethylcyclobutane (0.40 mL, 3.58 mmol) was added and the mixture was stirred at 25 ° C. for 48 h. . The solution was partitioned between 10% aqueous ammonium chloride and methylene chloride, the organic layer was separated and concentrated under reduced pressure, and the residue was chromatographed on silica gel eluting with 1% methanol / methylene chloride. To give the title compound (0.426 g, 53%).

Example 468B
1- (Cyclobutylmethyl) -4-hydroxy-2 (1H) -pyridinone A solution of the product of Example 468A (0.426 g, 1.58 mmol) in tetrahydrofuran (20 mL) was added ammonium formate at 70 ° C. over 2 hours. (0.38 g, 6.03 mmol) and a catalytic amount of 20% palladium hydroxide / carbon. The reaction mixture was cooled to about 25 ° C., filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (0.244 g, 86%).

Example 468C
3- [Bis (methylsulfanyl) methylene] -1- (cyclobutylmethyl) -2,4 (1H, 3H) -pyridinedione The product of Example 468B (0.244 g, 1.36 mmol) and pyridine (0. A solution of 88 mL, 10.89 mmol) in dioxane (6 mL) was added to an excess of tris (methylthio) methyl methylsulfate (Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi)) and stirred at 90 ° C. for 1.5 hours and cooled to about 25 ° C. The reaction solution was removed from the resulting solid by a gradient method and the solvent was removed under a warm stream of nitrogen. The residue was dissolved in hexane and loaded onto a 2 g Alltech Seppac and eluted with hexane, then methylene chloride, then 25% ethyl acetate / methylene chloride to give the title compound (0.192 g, 50%).

Example 468D
N- {3- [1- (cyclobutylmethyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl] -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl} methanesulfonamide A solution of the product of Example 468C (0.050 g, 0.176 mmol) in dioxane (5 mL) was treated with the product of Example 425D (0.030 g, 0.113 mmol). The mixture was stirred at 110 ° C. for 1 hour and cooled to 25 ° C. The solid precipitate was collected by filtration and dried to give the title compound (0.018 g, 35%).

Example 469
N- {3- [5-Bromo-1- (cyclomethyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl] -1,1-dioxide-4H-1,2,4-benzo Thiadiazin-7-yl} methanesulfonamide A solution of the product of Example 468D (0.030 g, 0.066 mmol) in tetrahydrofuran (2 mL) was added 1,3-dibromo-5,5 over 18 hours at 25 ° C. -Treated with dimethyl-hydantoin (0.015 g, 0.052 mmol). Concentrate the reaction under a warm stream of nitrogen and use a gradient of 10% to 100% acetonitrile: 0.1% aqueous TFA over 10 minutes at a flow rate of 40 mL / min (10 min run time). Purification by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm × 100 mm, particle size 7 μm) gave the title compound (0.008 g, 23%).

Example 470A
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadiazine-7- Yl] methanesulfonamide A solution of the product of Example 457C (0.195 g, 0.68 mmol) in dioxane (10 mL) was added with the product of Example 425D (0.17 g, 0.64 mmol) at 115 ° C. over 1 hour. Reacted. After cooling to about 25 ° C., the solid precipitate was collected by filtration and dried to give the title compound (0.258 g, 89%).

Example 470B
N- [3- (5-Bromo-4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl] methanesulfonamide A solution of the product of Example 470A (0.258 g, 0.57 mmol) in tetrahydrofuran (10 mL) was added 1,3-dibromo-5,5-dimethyl at 25 ° C. over 18 hours. Treated with hydantoin (0.24 g, 0.84 mmol). The solvent was removed under a warm stream of nitrogen and the residue was chromatographed on silica gel eluting with methylene chloride to give the title compound (0.13 g, 43%).

Example 470C
N- [3- (4-Hydroxy-1-isopentyl-2-oxo-5-vinyl-1,2-dihydro-3-pyridinyl) -1,1-dioxide-4H-1,2,4-benzothiadia Gin-7-yl] methanesulfonamide A solution of the product of Example 470B (0.027 g, 0.051 mmol) and tributyl (vinyl) tin (0.015 mL, 0.051 mmol) in tetrahydrofuran and a catalytic amount of dichlorobis (triphenyl). Phosphine) palladium (II) was reacted at 75 ° C. for 20 hours. The solution was cooled to about 25 ° C. and concentrated. The residue was collected on a Waters Symmetry C8 column (25 mm × 100 mm, granule) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous TFA over 8 minutes at a flow rate of 40 mL / min (10 min run time). Purification by reverse phase preparative HPLC with a diameter of 7 μm) afforded the title compound (0.005 g, 21%).

Example 471
N- (2-furylmethyl) -3- [3- (4-hydroxy-1-isopentyl-2-oxo-1,2-dihydro [1,8] naphthyridin-3-yl) -1,1-dioxide- 4H-1,2,4-benzothiadiazin-7-yl] diazathian-1-carboxamide 2,2-dioxide chlorosulfonyl isocyanate (4.9 μL, 0.0562 mmol) in methylene chloride (2 mL) was added to furfurylamine. (5 μL, 0.0562 mmol) was added dropwise at 25 ° C. and stirred at 25 ° C. for 30 minutes, the product of Example 205 (20 mg, 0.0468 mmol) and triethylamine (26 μL, 0.187 mmol) in methylene chloride (2 mL). The solution was treated and stirred at 25 ° C. for 24 hours. The reaction mixture was partitioned between methylene chloride (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (15%). MS m / z 630 (M + H) ^<+> .

The following other compounds of the invention can be prepared by one skilled in the art using known synthetic methods or by the synthetic methods described in the synthetic schemes and examples included herein. Additional compounds included in the table below contain one nucleus from Table 1, one R ¹ substituent from Table 2 (X ₁ represents a core ring structure), one or two Y from Table 4. ^{The three} substituents can be described by taking Y ₁ and / or Y ₂ substituents from Table 3 as needed.

  It will be appreciated by those skilled in the art that the present invention is not limited to the illustrative examples described above, and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof. It will be obvious. Accordingly, the above embodiments are to be considered in all respects as illustrative and not restrictive, and should refer to the appended claims rather than the foregoing embodiments, All changes that come within the meaning and range of equivalency of the claims are to be embraced by the invention.

Claims (7)

A compound of the following formula (Vb) or a pharmaceutically acceptable salt or stereoisomer of the compound:

[Where:
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkenyl , cycloalkylalkyl , formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylsulfonylalkyl, Heterocyclic ring, heterocyclic alkenyl, heterocyclic alkyl, Droxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl _-, is selected from _{R f R} g C = N- and _R k group consisting O-; ^{R 1} is alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy , Aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(alkyl) (NR _c R _e ), -SR _c , -S (O) R _{c, -S (O) 2 R} c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) _NR c R the group consisting of _e It is substituted with 0, 1, 2 or 3 substituents et selected;
R ⁴ is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R _a R _b N—, N ₃ — and R _e S—; R ⁴ is halo, nitro, cyano, —OH Substituted with 0, 1 or 2 substituents selected from the group consisting of:, —NH ₂ , and —COOH;
R ⁵ is R _a SO ₂ N (R _f ) —, R _a SO ₂ N (R _f ) alkyl-, R _a R _b NSO ₂ N (R _f ) —, and R _a R _b NSO ₂ N (R _f ) selected from the group consisting of alkyl-;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) _{, -C (O) R a,} -C (O) is selected from oR _a and -C (O) _NR a group consisting of _{R b;} each ^{R 6} is independently, a alkyl, alkenyl, alkynyl, oxo, halo , Haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and — NC (O) _{R a} Tona It is substituted with 0, 1, 2 or 3 substituents selected from the group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} c R d N -alkyl -, R _c R _d NC (O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R _c OC (O) alkyl _{-, R} c R _d Alkyl _{C (O) -, R c} R d NC (O) -, R c R d NC (O) O -alkyl _- is selected from the group consisting of _{-, R c R d NC (} O) N (R e) alkyl R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl); _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) 2 RC, -OR c, -N (R c) (R d) Substituted with 0, 1 or 2 substituents selected from the group consisting of: -C (O) R _c , -C (O) OR _c and -C (O) NR _c R _d ;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; ring is independently A alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) (OR _c), - _{(alkyl) (NR c R d),} - alkyl _SO 2 _NR c _{R d,} - alkyl _{C (O) NR c R d} , -SR c, -S (O) R c, -S (O _{) 2 R c, -OR c,} -N (R c) (R d), - C (O) R c, -C (O) oR c and -C (O) _NR c _{R d} Tona It is substituted with 0, 1, 2 or 3 substituents selected from the group;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl , heteroarylalkyl, selected from the group consisting of heterocyclic and heterocyclic alkyl; independently each R _c and R _d, a alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, Heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyal Le, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _f ), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h), - Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of C (O) R _f , —C (O) OR _f and —C (O) NR _f R _h ;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Selected from the group consisting of heteroarylalkyl; each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle , Heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl ), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N (H _{) C (O) NH 2,} -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of (O) N (H) (alkyl) and —C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), -NH _2, -N (H) (alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O - alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl), Alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) alkyl, - _{C (O) NH 2, -C} (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0, 1, 2, which is selected from the group consisting of _{(alkyl) 2} Or is substituted with 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4. ] The compound, salt or stereoisomer according to claim 1, wherein R ⁴ is hydroxy. R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkenyl, cycloalkylalkyl, formyl Alkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic alkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl _{-, R f R g C =} N- and _R k a compound according to claim 2 which is selected from the group consisting of O-, salts or stereoisomers. Pharmaceutically acceptable salt or stereoisomer of reduction compounds of formula (VIb) or the compound.

[Where:
R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylsulfanylalkyl, arylsulfonylalkyl , Carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkenyl , cycloalkylalkyl , formylalkyl, haloalkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylsulfonylalkyl, Heterocyclic ring, heterocyclic alkenyl, heterocyclic alkyl, Droxyalkyl, nitroalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl-, R _a R _b NC (O) O alkyl-, R _a R _b NC (O) NR _c alkyl _{-, R f R} g C = is selected from N- and _R k group consisting O-; ^{R 1} is a alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, halo alkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R e),} - SR c, -S (O) _{R c, -S (O) 2} R c, -OR c, -N (R c) (R e), - C (O) R c, -C (O) oR c and -C (O) NR _c the group consisting of R _e It is substituted with 0, 1, 2 or 3 substituents et selected;
R ⁴ is alkoxy, arylalkoxy, aryloxy, halo, _{hydroxy, R a R b N-, N} 3 -, is selected from the group consisting of _R e S-; ^{R 4} is C b, nitro, cyano, - OH, it is substituted with 0, 1 or 2 substituents selected from the group consisting of -NH _2, and -COOH;
R ⁵ is R _a SO ₂ N (R _f ) —, R _a SO ₂ N (R _f ) alkyl-, R _a R _b NSO ₂ N (R _f ) — and R _a R _b NSO ₂ N (R _f ) Selected from the group consisting of alkyl-;
R ⁶ is independently in each case alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl,-(alkyl) ( OR _k ),-(alkyl) (NR _a R _b ), -SR _a , -S (O) R _a , -S (O) ₂ R _a , -OR _k , -N (R _a ) (R _b ) , —C (O) R _a , —C (O) OR _a and —C (O) NR _a R _b ; each R ⁶ is independently alkyl, alkenyl, alkynyl, oxo, halo, Haloalkyl, cyano, nitro, —OR _a , —NR _a R _b , —SR _a , —SOR _a , —SO ₂ R _a , —C (O) OR _a , —C (O) NR _a R _b and —NC (O) _{R a} Tona It is substituted with 0, 1, 2 or 3 substituents selected from the group;
R _a and R _b are each independently hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl , formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocycloalkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, _{nitroalkyl, R c R d N-, R} c R d N -alkyl -, R _c R _d NC (O) alkyl _{-, R c SO 2 -,} R c SO 2 alkyl _{-, R c C (O)} -, R c C (O) alkyl _{-, R c OC (O)} -, R _c OC (O) alkyl _{-, R} c R _d Alkyl _{C (O) -, R c} R d NC (O) - is selected from the group consisting of _{-, R c R d NC (} O) O -alkyl - and _{R c R d NC (O)} N (R e) alkyl R _a and R _b are alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl); _(OR c), - _{(alkyl) (NR c R d),} - SR c, -S (O) R c, -S (O) 2 RC, -OR c, -N (R c) (R d) Substituted with 0, 1 or 2 substituents selected from the group consisting of: -C (O) R _c , -C (O) OR _c and -C (O) NR _c R _d ;
Alternatively, R _a and R _b together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _c ),-(Alkyl) (NR _c R _d ), -alkyl SO ₂ NR _c R _d , -alkyl C (O) NR _c R _d , -SR _c , -S (O) R _c , -S (O) _{2 R c, -OR c, -N} (R c) (R d), - C (O) R c, -C (O) oR c and -C (O) _NR c _{R d} Tona It is substituted with 0, 1, 2 or 3 substituents selected from the group;
R _c and _{R d} is independently at each occurrence, _{hydrogen, -NR f R h, -OR f} , -CO (R f), - SR f, -SOR f, -SO 2 R f, -C (O) _{NR f R h, -SO 2 NR} f R h, -C (O) OR f, alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl Each of R _c and R _d is independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heterozygote, heteroarylalkyl, heterocycle and heterocyclealkyl; Aryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyal Le, - (alkyl) _(OR f), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N ( _{R f) (R h),} - C (O) R f, -C (O) OR f, -C (O) NR f R h, -C (O) N (H) NR f R h, -N (R _e ) C (O) OR _f , -N (R _e ) SO ₂ NR _f R _h , -N (R _e ) C (O) NR _f R _h , -alkyl N (R _e ) C (O) 0, 1, 2, or 3 substitutions selected from the group consisting of OR _f , -alkyl N (R _e ) SO ₂ NR _f R _h and -alkyl N (R _e ) C (O) NR _f R _h Substituted with a group;
Alternatively, R _c and R _d together with the nitrogen atom to which they are attached form a 3-6 membered ring selected from the group consisting of heteroaryl and heterocycle; The rings are independently alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl,-(alkyl) (OR _f ), - _{(alkyl) (NR f R h),} - SR f, -S (O) R f, -S (O) 2 R f, -OR f, -N (R f) (R h), - Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of C (O) R _f , —C (O) OR _f and —C (O) NR _f R _h ;
R _e is selected from the group consisting of hydrogen, alkenyl, alkyl and cycloalkyl;
R _f , R _g and R _h are each independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl and Selected from the group consisting of heteroarylalkyl; each R _f , R _g and R _h is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle , Heteroaryl, heteroarylalkyl, —OH, —O (alkyl), —NH ₂ , —N (H) (alkyl), —N (alkyl) ₂ , —S (alkyl), —S (O) (alkyl ), - SO ₂ alkyl, - alkyl -OH, - alkyl -O- alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl N _{(alkyl) 2,} - alkyl S (alkyl), - alkyl S (O) (alkyl), - alkyl SO ₂ alkyl, -N (H _{) C (O) NH 2,} -C (O) OH, -C (O) O ( alkyl), - C (O) _{alkyl, -C (O) NH 2,} -C (O) NH 2, -C Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of (O) N (H) (alkyl) and —C (O) N (alkyl) ₂ ;
Alternatively, R _f and R _g together with the carbon atom to which they are attached form a 3-7 membered ring selected from the group consisting of cycloalkyl, cycloalkenyl and heterocycle;
Alternatively, R _f and R _h together with the nitrogen atom to which they are attached form a 3-7 membered ring selected from the group consisting of heterocycle and heteroaryl; Each aryl is independently alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O (alkyl), -NH _2, -N (H) (alkyl), - N _(alkyl) 2, -S (alkyl), - S (alkyl), - S (O) (alkyl), - alkyl -OH, - alkyl -O - alkyl, - alkyl NH _2, - alkyl N (H) (alkyl), - alkyl S (alkyl), - alkyl S (O) (alkyl), Alkyl SO ₂ alkyl, - alkyl N _{(alkyl) 2, -N (H) C} (O) NH 2, -C (O) OH, -C (O) O ( alkyl), - C (O) alkyl, - _{C (O) NH 2, -C} (O) NH 2, -C (O) N (H) ( alkyl) and -C (O) N 0, 1, 2, which is selected from the group consisting of _{(alkyl) 2} Or is substituted with 3 substituents;
R _k is hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl , Nitroalkyl, R _a R _b N alkyl-, R _a O alkyl-, R _a R _b NC (O)-, R _a R _b NC (O) alkyl, R _a S-, R _a S (O)- R _a SO ₂ —, R _a S alkyl—, R _a (O) S alkyl—, R _a SO ₂ alkyl—, R _a OC (O) —, R _a OC (O) alkyl—, R _a C ( _{O) -, R a C (} O) alkyl - is selected from the group consisting of; each _{R k} is independently alkyl, alkenyl, alkynyl, oxo, halo, Ano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, - (alkyl) _(OR c), - _{(alkyl) (NR c R d),} - SR _{c, -S (O) R c} , -S (O) 2 R c, -OR c, -N (R c) (R d), - C (O) R c, -C (O) oR c , and Substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —C (O) NR _c R _d ;
m is 0, 1, 2, 3 or 4. ] The compound, salt or stereoisomer according to claim 4 , wherein R ⁴ is hydroxy. R ¹ is hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkenyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkenyl, cycloalkylalkyl, formyl Alkyl, haloalkyl, heteroarylalkenyl, heteroarylalkyl, heterocyclic, heterocyclic alkenyl, heterocyclic alkyl, hydroxyalkyl, R _a R _b N-, R _a R _b N alkyl-, R _a R _b NC (O) alkyl - _a compound according to claim 5 which is selected from R _f R g C = N- and _R k group consisting O-. 1 -benzyl-4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl} Quinolin-2 (1H) -one;
1-benzyl-4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] quinoline-2 (1H) -on;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxylic acid 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1 , 1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroxyquinolin-3-yl) -N- (2-hydroxyethyl) -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroxyquinolin-3-yl) -N-[(1S) -2-hydroxy-1 (aminocarbonyl) ethyl] -4H-thieno [ 2,3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
N- (2-amino-2-oxoethyl) -3- (1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3-e] [ 1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -2-hydroxy-1-methylethyl] -4H-thieno [2, 3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N, N-bis (2-hydroxyethyl) -4H-thieno [2,3-e] [ 1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxy-1- (hydroxymethyl) ethyl] -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
1-benzyl-4-hydroxy-3- (7-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-3-yl) quinolin-2 (1H) -one;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- (3-hydroxypropyl) -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroxyquinolin-3-yl) -N-[(2S) -2,3-dihydroxypropyl] -4H-thieno [2,3- e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -1- (hydroxymethyl) propyl] -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -4H-thieno [2,3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxybutyl] -4H-thieno [2,3-e] [1,2 , 4] thiadiazine-7-carboxamide 1,1-dioxide;
3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -4H-thieno [2 , 3-e] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
1-Benzyl-3- [1,1-dioxide-7- (piperazin-1-ylcarbonyl) -4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -4- Hydroxyquinolin-2 (1H) -one;
N- [5- (aminocarbonyl) pyridin-2-yl] -3- (1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -4H-thieno [2,3 -E] [1,2,4] thiadiazine-7-carboxamide 1,1-dioxide;
[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-7-yl] methyl carbamate;
[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-7-yl] methylaminocarbonyl carbamate;
3- [7- (Azidomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-benzyl-4-hydroxyquinoline-2 ( 1H) -on;
3- [7- (Aminomethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-3-yl] -1-benzyl-4-hydroxyquinoline-2 (1H) -on;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} methanesulfonamide;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} nicotinamide;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} morpholine-4-carboxamide;
N-{[3- (1-Benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -1,1-dioxide-4H-thieno [2,3-e] [1, 2,4] thiadiazin-7-yl] methyl} -2-hydroxyacetamide;
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- {7-[(methoxymethoxy) methyl] -1,1-dioxide-4H-thieno [2,3-e] [1,2,4 ] Thiadiazin-3-yl} quinolin-2 (1H) -one;
1-[(Cyclopropylmethyl) amino] -4-hydroxy-3- [7- (hydroxymethyl) -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazine- 3-yl] quinolin-2 (1H) -one;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] methanesulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] ethanesulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] propane-1-sulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] propane-2-sulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] benzenesulfonamide;
N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2, 3-e] [1,2,4] thiadiazin-7-yl) methyl] -1-phenylmethanesulfonamide; and N-[(3- {1-[(cyclopropylmethyl) amino] -4-hydroxy- 2-oxo-1,2-dihydroquinolin-3-yl} -1,1-dioxide-4H-thieno [2,3-e] [1,2,4] thiadiazin-7-yl) methyl] -methanesulfone The compound, salt or stereoisomer according to claim 1 selected from the group consisting of amides.