JP5620417B2 - Pharmaceuticals containing aminopyrazole derivatives - Google Patents

Description

  The present invention relates to a medicament containing an aminopyrazole derivative and use thereof.

  Currently, many of the molecular target drugs for cancer are inhibitors that inhibit receptor tyrosine kinases such as erlotinib and lapatinib. Many of them exhibit high efficacy against cancers that exhibit target gene mutation, gene over-amplification, and overexpression. However, these molecular targeted drugs cannot exhibit a drug effect against cancers in which genes other than their target genes have been changed, and an effective therapeutic method for such cancers has not yet been established. In other words, inhibitors against new genes that have changed in cancer are expected to make a significant contribution to the treatment of cancer patients that have not been effective so far.

  Fibroblast growth factor receptor (FGFR) is a kinase belonging to the receptor tyrosine kinase family, and FGFR1, FGFR2, FGFR3, and FGFR4 constitute the FGFR family. The ligand is fibroblast growth factor (FGF), and 22 structurally similar proteins make up the family. It is known that FGFR is activated by overexpression, gene over-amplification, mutation, and translocation, respectively, and is one of the causes of cancer. The FGFR signal flows to the MAPK pathway and the PI3K / AKT pathway, In cancer, it is known to be involved in cell proliferation, angiogenesis, cell migration, invasion, metastasis, and the like. (Non-Patent Document 1)

  FGFR1 is a gene over-amplified in breast cancer and non-small cell lung cancer (Non-patent Documents 2 and 3), a gene mutation in glioblastoma (Non-patent Document 4), and fusion protein formation by gene translocation in acute myeloid leukemia (Non-patent Document 5), overexpression is also known in pancreatic cancer, bladder cancer, prostate cancer, and esophageal cancer. Furthermore, it is also known that FGFR1 is expressed in new blood vessels and greatly contributes to angiogenesis (Non-patent Document 6). In addition, FGFR2 has gene over-amplification in gastric cancer and breast cancer (Non-patent Documents 7 and 8), and gene mutation in non-patent body cancer (Non-patent Document 9), prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, brain tumor, colon cancer Overexpression is known. FGFR3 is known to be overexpressed in multiple myeloma gene translocation (Non-Patent Document 10), bladder cancer gene mutation (Non-Patent Document 11), ovarian cancer, non-small cell lung cancer, and hepatocellular carcinoma. Yes. Finally, FGFR4 is known to be mutated in lung cancer, ovarian cancer, prostate cancer, and overexpressed in thyroid cancer, ovarian cancer, and the like.

  Thus, all the FGFR family kinases have been strongly suggested to be associated with cancer, and inhibiting these FGFR family kinases in cancer tissues is considered to be a promising therapeutic method for the above-mentioned cancer types.

Cytokine & Growth Factor Reviews 16 (2005) 139-149 Breast Cancer Research 2007, 9: R23 Cancer Res 2005; 65 (13): 5561-70 PNAS (2005), 102 (40), 14344-14349. Acta Haematol 2002; 107: 101-107 Nature Medicine 3, 887-89, 1997 J Pathol. 2003 Nov; 201 (3): 439-50 Anal Cell Pathol. 2001; 22 (4): 229-34 Cancer Res 2008; 68 (17): 6902-7 Blood. 2003; 101: 4569-4575 Nat Genet. 1999 Sep; 23 (1): 18-20.

  It is to provide a novel pharmaceutical effective for cancer containing a fibroblast growth factor receptor (FGFR) family kinase selective inhibitor compound.

（式中、Ｒ_１〜Ｒ_４は、それぞれ独立に以下の基を示す；
Ｒ_１は、水素、ヒドロキシ、ハロゲン、シアノ、ニトロ、Ｃ_１−４ハロアルキル、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−７シクロアルキル、Ｃ_６−１０アリールＣ_１−４アルキル、−ＯＲ_５、−ＮＲ_６Ｒ_７、−（ＣＲ_８Ｒ_９）_ｎＺ_１、−Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、−ＳＲ_１４、−ＳＯＲ_１５、−ＳＯ_２Ｒ_１６、−ＮＲ_１７ＳＯ_２Ｒ_１８、ＣＯＯＨ、Ｐ群から独立して選択される１または複数の基で置換されていてもよいＣ_６−１０アリール、Ｑ群から独立して選択される１または複数の基で置換されていてもよい５〜１０員ヘテロアリールもしくは３〜１０員ヘテロシクリル、−ＣＯＲ_１９、−ＣＯＯＲ_２０、−ＯＣ（Ｏ）Ｒ_２１、−ＮＲ_２２Ｃ（Ｏ）Ｒ_２３、−ＮＲ_２４Ｃ（Ｓ）Ｒ_２５、−Ｃ（Ｓ）ＮＲ_２６Ｒ_２７、−ＳＯ_２ＮＲ_２８Ｒ_２９、−ＯＳＯ_２Ｒ_３０、−ＳＯ_３Ｒ_３１または−Ｓｉ（Ｒ_３２）_３を示し；
Ｒ_２は、水素、ヒドロキシ、ハロゲン、シアノ、ニトロ、Ｃ_１−４ハロアルキル、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−７シクロアルキル、Ｃ_６−１０アリールＣ_１−４アルキル、−ＯＲ_５、−ＮＲ_６Ｒ_７、−（ＣＲ_８Ｒ_９）_ｎＺ_１、−Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、−ＳＲ_１４、−ＳＯＲ_１５、−ＳＯ_２Ｒ_１６、−ＮＲ_１７ＳＯ_２Ｒ_１８、ＣＯＯＨ、Ｐ群から独立して選択される１または複数の基で置換されていてもよいＣ_６−１０アリール、Ｑ群から独立して選択される１または複数の基で置換されていてもよい５〜１０員ヘテロアリールもしくは３〜１０員ヘテロシクリル、−ＣＯＲ_１９、−ＣＯＯＲ_２０、−ＯＣ（Ｏ）Ｒ_２１、−ＮＲ_２２Ｃ（Ｏ）Ｒ_２３、−ＮＲ_２４Ｃ（Ｓ）Ｒ_２５、−Ｃ（Ｓ）ＮＲ_２６Ｒ_２７、−ＳＯ_２ＮＲ_２８Ｒ_２９、−ＯＳＯ_２Ｒ_３０、−ＳＯ_３Ｒ_３１または−Ｓｉ（Ｒ_３２）_３を示し；
またはＲ_１およびＲ_２は、それらが結合している原子と一緒になって、３〜１０員ヘテロシクリルまたは５〜１０員ヘテロアリールを形成し、ここで該ヘテロシクリルまたは該ヘテロアリールは、ハロゲンで置換されていてもよく；
Ｒ_３は水素、Ｃ_１−５アルキル、Ｃ_６−１０アリールＣ_１−６アルキルまたはＣ_１−４ハロアルキルを示し；
Ｒ_４は、水素、ハロゲン、Ｃ_１−３アルキル、Ｃ_１−４ハロアルキル、ヒドロキシ、シアノ、ニトロ、Ｃ_１−４アルコキシ、−（ＣＨ_２）_ｎＺ_１、−ＮＲ_６Ｒ_７、−ＯＲ_５、−Ｃ（Ｏ）ＮＲ_１２Ｒ_１３、−ＳＲ_１４、−ＳＯＲ_１５、−ＳＯ_２Ｒ_１６、ＮＲ_１７ＳＯ_２Ｒ_１８、ＣＯＯＨ、−ＣＯＲ_１９、−ＣＯＯＲ_２０、−ＯＣ（Ｏ）Ｒ_２１、−ＮＲ_２２Ｃ（Ｏ）Ｒ_２３、−ＮＲ_２４Ｃ（Ｓ）Ｒ_２５、−Ｃ（Ｓ）ＮＲ_２６Ｒ_２７、−ＳＯ_２ＮＲ_２８Ｒ_２９、−ＯＳＯ_２Ｒ_３０−ＳＯ_３Ｒ_３１または−Ｓｉ（Ｒ_３２）_３を示し；
Ａは、５〜１０員ヘテロアリール環またはＣ_６−１０アリール環であり；
Ｒ_５はＣ_１−５アルキル、Ｃ_３−７シクロアルキル、Ｃ_３−７シクロアルキルＣ_１−３アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｃ_１−３アルコキシＣ_２−４アルキル、Ｃ_１−３アルコキシＣ_２−４アルコキシＣ_２−４アルキル、Ｃ_２−４アミノアルキル、Ｃ_１−４アルキルアミノＣ_２−４アルキル、ジ（Ｃ_１−４アルキル）アミノＣ_２−４アルキル、Ｃ_６−１０アリール、Ｃ_６−１０アリールＣ_１−３アルキル、Ｑ群から独立して選択される１または複数の基で置換されていてもよい３〜１０員ヘテロシクリルＣ_１−３アルキル、３〜１０員ヘテロシクリル、５〜１０員ヘテロアリール、５〜１０員ヘテロアリールＣ_１−３アルキル、Ｃ_２−６モノヒドロキシアルキル、Ｃ_２−６ジヒドロキシアルキルまたはＣ_２−６トリヒドロキシアルキルを示し；
Ｒ_６およびＲ_７は、同一でも異なってもよく、それぞれ、水素、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｃ_１−３アルコキシＣ_２−４アルキル、Ｃ_６−１０アリールＣ_１−３アルキル、３〜１０員ヘテロシクリルＣ_１−３アルキル、５〜１０員ヘテロアリールＣ_１−３アルキル、Ｃ_２−６モノヒドロキシアルキル、Ｃ_２−６ジヒドロキシアルキル、Ｃ_２−６トリヒドロキシアルキル、３〜１０員ヘテロシクリル、Ｃ_２−４アミノアルキル、Ｃ_１−４アルキルアミノＣ_２−４アルキル、ジ（Ｃ_１−４アルキル）アミノＣ_２−４アルキルまたはシアノ（Ｃ_１−３アルキル）を示すか、またはＲ_６およびＲ_７は、それらが結合している窒素原子と一緒になって３〜１０員ヘテロシクリルまたは５〜１０員ヘテロアリールを形成し；
ｎは１〜３を示し；
Ｒ_８およびＲ_９は、同一でも異なってもよく、それぞれ水素、Ｃ_１−４アルキルまたはハロゲンを示すか、またはＲ_８およびＲ_９は、それらが結合している炭素原子と一緒になって脂環式環を形成してもよく；
Ｚ_１は、水素、ＮＲ_１０Ｒ_１１、-ＯＨ、またはＱ群から選択される１または複数の基で置換されていてもよい３〜１０員ヘテロシクリルもしくは５〜１０員ヘテロアリールを示し；
Ｒ_１０およびＲ_１１は、同一でも異なってもよく、それぞれＣ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｃ_１−３アルコキシＣ_２−４アルキル、シアノ（Ｃ_１−３アルキル）またはＣ_１−３アルキルスルホニルＣ_２−４アルキルを示すか、またはＲ_１０およびＲ_１１は、それらが結合している窒素原子と一緒になって３〜１０員ヘテロシクリルまたは５〜１０員ヘテロアリールを形成してもよく；
Ｒ_１２およびＲ_１３は同一でも異なってもよく、それぞれ水素、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｃ_１−３アルコキシＣ_２−４アルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリール、３〜１０員ヘテロシクリル、Ｃ_６−１０アリールＣ_１−４アルキル、３〜１０員ヘテロシクリルＣ_１−３アルキル、５〜１０員ヘテロアリールＣ_１−３アルキル、シアノ（Ｃ_１−３アルキル）、Ｃ_１−３アルキルスルホニルＣ_２−４アルキル、３〜１０員脂環式環、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示すか、またはＲ_１２およびＲ_１３は、それらが結合している窒素原子と一緒になって、Ｑ群から独立して選択される１または複数の基で置換されていてもよい３〜１０員ヘテロシクリルもしくは５〜１０員ヘテロアリールを形成してもよく；
Ｒ_１４は、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｐ群から独立して選択される１または複数の基で置換されていてもよいＣ_６−１０アリール、またはＱ群から独立して選択される１または複数の基で置換されていてもよい５〜１０員ヘテロアリールもしくは３〜１０員ヘテロシクリルを示し；
Ｒ_１５は、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｐ群から独立して選択される１または複数の基で置換されていてもよいＣ_６−１０アリール、またはＱ群から独立して選択される１または複数の基で置換されていてもよい５〜１０員ヘテロアリールもしくは３〜１０員ヘテロシクリルを示し；
Ｒ_１６は、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｐ群から独立して選択される１または複数の基で置換されていてもよいＣ_６−１０アリール、またはＱ群から独立して選択される１または複数の基で置換されていてもよい５〜１０員ヘテロアリールもしくは３〜１０員ヘテロシクリルを示し；
Ｒ_１７は、水素またはＣ_１−４アルキルを示し；
Ｒ_１８は、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｐ群から独立して選択される１または複数の基で置換されていてもよいＣ_６−１０アリール、またはＱ群から独立して選択される基で置換されていてもよい５〜１０員ヘテロアリールもしくは３〜１０員ヘテロシクリルを示し；
Ｒ_１９は、水素、Ｃ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_１−４ハロアルキル、Ｃ_６−１０アリール、またはＱ群から独立して選択される１または複数の基で置換されていてもよい５〜１０員ヘテロアリールもしくは３〜１０員ヘテロシクリルを示し；
Ｒ_２０は、Ｃ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_１−４ハロアルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示し；
Ｒ_２１は、Ｃ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_１−４ハロアルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示し；
Ｒ_２２は、水素、Ｃ_１−４アルキルまたはＣ_１−４ハロアルキルを示し；
Ｒ_２３は、水素、Ｃ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_１−４ハロアルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示し；
Ｒ_２４は、水素、Ｃ_１−４アルキルまたはＣ_１−４ハロアルキルを示し；
Ｒ_２５は、Ｃ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_１−４ハロアルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示し；
Ｒ_２６およびＲ_２７は、同一でも異なってもよく、それぞれ水素、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｃ_１−３アルコキシＣ_２−４アルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリール、３〜１０員ヘテロシクリル、Ｃ_６−１０アリールＣ_１−４アルキル、３〜１０員ヘテロシクリルＣ_１−３アルキル、５〜１０員ヘテロアリールＣ_１−３アルキル、シアノ（Ｃ_１−３アルキル）、Ｃ_１−３アルキルスルホニルＣ_２−４アルキル、３〜１０員脂環式環、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示すか、またはＲ_２６およびＲ_２７は、それらが結合している窒素原子と一緒になって３〜１０員ヘテロシクリルまたは５〜１０員ヘテロアリールを形成してもよく；
Ｒ_２８およびＲ_２９は、同一でも異なってもよく、それぞれ水素、Ｃ_１−４アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−４ハロアルキル、Ｃ_１−３アルコキシＣ_２−４アルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリール、３〜１０員ヘテロシクリル、Ｃ_６−１０アリールＣ_１−４アルキル、３〜１０員ヘテロシクリルＣ_１−３アルキル、５〜１０員ヘテロアリールＣ_１−３アルキル、シアノ（Ｃ_１−３アルキル）、Ｃ_１−３アルキルスルホニルＣ_２−４アルキル、３〜１０員脂環式環、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示すか、またはＲ_２８およびＲ_２９は、それらが結合している窒素原子と一緒になって３〜１０員ヘテロシクリルまたは５〜１０員ヘテロアリールを形成してもよく；
Ｒ_３０は、Ｃ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_１−４ハロアルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示し；
Ｒ_３１は、Ｃ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_１−４ハロアルキル、Ｃ_６−１０アリール、５〜１０員ヘテロアリールまたは３〜１０員ヘテロシクリルを示し；
Ｒ_３２は、Ｃ_１−４アルキルまたはＣ_６−１０アリールを示し；
<Ｐ群>
ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４ハロアルキル、−ＯＨ、Ｃ_１−３アルコキシ、Ｃ_１−３ハロアルコキシ、３〜１０員ヘテロシクリルアミノ、−ＳＯ_２Ｒ_１６、−ＣＮ、−ＮＯ_２、および３〜１０員ヘテロシクリル。
<Ｑ群>
ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４ハロアルキル、−ＯＨ、Ｃ_１−３アルコキシ、Ｃ_１−６モノヒドロキシアルキル、Ｃ_１−６ジヒドロキシアルキルまたはＣ_１−６トリヒドロキシアルキル、３〜１０員ヘテロシクリルアミノ、−ＳＯ_２Ｒ_１６、−ＣＮ、−ＮＯ_２、Ｃ_３−７シクロアルキル、−ＣＯＲ_１９、およびＣ_１−４アルキルで置換されていてもよい３〜１０員ヘテロシクリル。
〔２〕前記Ａがベンゼン、インドール、アザインドール、ベンゾフラン、ベンゾチオフェン、ベンゾチアゾール、キノリンまたはピロールである、〔１〕記載の化合物、またはその薬学的に許容される塩を有効成分として含有する医薬。
〔３〕前記Ｒ_３が、水素、Ｃ_１−４アルキル、アリールＣ_１−４アルキルまたはＣ_１−３ペルフルオロアルキルを示す、〔１〕または〔２〕に記載の化合物、またはその薬学的に許容される塩を有効成分として含有する医薬。
〔４〕前記Ｒ_４が、水素、ハロゲン、Ｃ_１−３アルキル、Ｃ_１−３ペルフルオロアルキル、シアノ、メタンスルホニル、ヒドロキシル、アルコキシまたはアミノを示す、〔１〕〜〔３〕のいずれか一項記載の化合物、またはその薬学的に許容される塩を有効成分として含有する医薬。
〔５〕以下の群から選択される、〔１〕に記載の化合物、またはその薬学的に許容される塩を有効成分として含有する医薬：
（１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ピロリジン−１−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−ヒドロキシ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−ピロロ［３，２−ｃ］ピリジン−２−イル）−メタノン；
（５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ピペラジン−１−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−モルホリン−４−イル−エトキシ）−１Ｈ−インドール−２−イル］−メタノン；
（７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（テトラヒドロ−ピラン−４−イルオキシ）−１Ｈ−インドール−２−イル］−メタノン；
（８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−クロロ−１Ｈ−インドール−２−イル）−メタノン；
（９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ブロモ−１Ｈ−インドール−２−イル）−メタノン；
（１０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−ヨード−１Ｈ−インドール−２−イル）−メタノン；
（１１） ２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−５−カルボニトリル；
（１２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ブロモ−５−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（１３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−エチニル−１Ｈ−インドール−２−イル）−メタノン；
（１４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−フルオロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（１５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−フルオロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（１６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−フルオロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（１７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−クロロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（１８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−クロロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（１９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−クロロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（２０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−トリフルオロメチル−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（２１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−トリフルオロメチル−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（２２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−トリフルオロメチル−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（２３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−ブロモ−１Ｈ−インドール−２−イル）−メタノン；
（２４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−フルオロ−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−メチル−１Ｈ−インドール−２−イル）−メタノン；
（２６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（４，４−ジフルオロ−ピペリジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３，３−ジフルオロ−ピペリジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２８） ２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−５−カルボン酸（２，２，２−トリフルオロ−エチル）−アミド；
（２９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−トリフルオロメチル−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（３０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（６−トリフルオロメチル−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（３１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−クロロ−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（３２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−メチル−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（３３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−クロロ−４−フルオロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（３４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−トリフルオロメチル−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（３５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−トリフルオロメチル−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（３６） ［５−アミノ−１−（６−フルオロ−２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（３７） ２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−６−カルボン酸；
（３８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ヒドロキシメチル−１Ｈ−インドール−２−イル）−メタノン；
（３９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−｛６−［２−（４−メチル−ピペラジン−１−イル）−エトキシ］−１Ｈ−インドール−２−イル｝−メタノン；
（４０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−メチル−オキセタン−３−イルメトキシ）−１Ｈ−インドール−２−イル］−メタノン；
（４１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−フルオロ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（４２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−｛［ビス−（２−メトキシ−エチル）−アミノ］−メチル｝−１Ｈ−インドール−２−イル）−メタノン；
（４３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−｛６−［（メチル−プロパ−２−イニル−アミノ）−メチル］−１Ｈ−インドール−２−イル｝−メタノン；
（４４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３，３−ジフルオロ−ピロリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（４５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２，５−ジメチル−ピロリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（４６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３，３−ジフルオロ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（４７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（（Ｓ）−３−メチル−モルホリン−４−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（４８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ブロモ−１Ｈ−インドール−２−イル）−メタノン；
（４９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ヨード−１Ｈ−インドール−２−イル）−メタノン；
（５０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−ピロロ［３，２−ｂ］ピリジン−２−イル）−メタノン；
（５１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ブロモ−６−トリフルオロメチル−１Ｈ−インドール−２−イル）−メタノン；
（５２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ヨード−１Ｈ−インドール−２−イル）−メタノン；
（５３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−メチル−１Ｈ−インドール−２−イル）−メタノン；
（５４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−イソプロピル−１Ｈ−インドール−２−イル）−メタノン；
（５５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（２−フルオロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（５６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ベンジル−１Ｈ−インドール−２−イル）−メタノン；
（５７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（２−トリフルオロメチル−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（５８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３−フルオロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（５９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３−トリフルオロメチル−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（６０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−エチニル−１Ｈ−インドール−２−イル）−メタノン；
（６１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５Ｈ−［１，３］ジオキソロ［４，５−ｆ］インドール−６−イル）−メタノン；
（６２） ［５−アミノ−１−（７−フルオロ−２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（６３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（４−トリフルオロメチル−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（６４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ブトキシ−１Ｈ−インドール−２−イル）−メタノン；
（６５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（１−メチル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（６６） Ｎ−｛２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−６−イル｝−メタンスルホンアミド；
（６７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（６−モルホリン−４−イル−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（６８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ブチル−１Ｈ−インドール−２−イル）−メタノン；
（６９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（１−メチル−１Ｈ−ピラゾール−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（７０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−メトキシ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（７１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−メトキシ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（７２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−シクロプロピル−１Ｈ−インドール−２−イル）−メタノン；
（７３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−メトキシ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（７４） ５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−フェニル−１Ｈ−インドール−２−イル）−メタノン；
（７５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−メタンスルホニル−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（７６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−イソプロピル−１Ｈ−インドール−２−イル）−メタノン；
（７７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ピリジン−２−イル−１Ｈ−インドール−２−イル）−メタノン；
（７８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−シクロプロピル−１Ｈ−インドール−２−イル）−メタノン；
（７９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ピリダジン−３−イル−１Ｈ−インドール−２−イル）−メタノン；
（８０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−イソプロポキシ−１Ｈ−インドール−２−イル）−メタノン；
（８１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（２−メトキシ−エトキシ）−１Ｈ−インドール−２−イル］−メタノン；
（８２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−シクロプロピルメトキシ−１Ｈ−インドール−２−イル）−メタノン；
（８３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（２，２−ジフルオロ−５Ｈ−［１，３］ジオキソロ［４，５−ｆ］インドール−６−イル）−メタノン；
（８４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−クロロ−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（８５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−フルオロ−ピリジン−２−イル）−１Ｈ−インドール−２−イル］−メタノン；
（８６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（６−モルホリン−４−イル−ピリダジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（８７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−クロロ−６−シクロプロピルメトキシ−１Ｈ−インドール−２−イル）−メタノン；
（８８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２，４−ジフルオロ−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（８９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ピリダジン−４−イル−１Ｈ−インドール−２−イル）−メタノン；
（９０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（３−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（９１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（１−イソプロピル−ピペリジン−４−イル）−６−トリフルオロメチル−１Ｈ−インドール−２−イル］−メタノン；
（９２） ２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−６−カルボニトリル；
（９３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（１，２，３，６−テトラヒドロ−ピリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（９４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ピペリジン−４−イル−１Ｈ−インドール−２−イル）−メタノン；
（９５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（（Ｒ）−３−フルオロ−ピロリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（９６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−フルオロ−５−ピペリジン−４−イル−１Ｈ−インドール−２−イル）−メタノン；
（９７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−フルオロ−５−（１−メチル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（９８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（１−イソプロピル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（９９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−フルオロ−５−（１−イソプロピル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１００） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ピリジン−３−イル−１Ｈ−インドール−２−イル）−メタノン；
（１０１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（６−モルホリン−４−イル−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１０２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ピリジン−３−イル−１Ｈ−インドール−２−イル）−メタノン；
（１０３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（６−ピペラジン−１−イル−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１０４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（６−ヒドロキシ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１０５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−フルオロ−５−（４−メチル−ピペラジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１０６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−フルオロ−５−ピロリジン−１−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（１０７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（１−メチル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１０８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−モルホリン−４−イル−フェニル）−１Ｈ−インドール−２−イル］−メタノン；
（１０９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３，４，５，６−テトラヒドロ−２Ｈ−［１，２’］ビピリジン−５’−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１１０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（６−ピペラジン−１−イル−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１１１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（６−メトキシ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１１２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（（Ｓ）−３−メチル−モルホリン−４−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１１３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（（Ｒ）−３−フルオロ−ピロリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１１４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（２，５−ジメチル−ピロリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１１５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３−フルオロ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１１６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３，３−ジフルオロ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１１７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−｛６−［２−（４−メチル−ピペラジン−１−イル）−ピリジン−４−イル］−１Ｈ−インドール−２−イル｝−メタノン；
（１１８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ピリジン−４−イル−１Ｈ−インドール−２−イル）−メタノン；
（１１９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（４−フルオロ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１２０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（４，４−ジフルオロ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１２１） ［５−アミノ−１−（２−ジフルオロメチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（１−メチル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１２２） ［５−アミノ−１−（２−ジフルオロメチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（１２３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３，３−ジフルオロ−ピロリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１２４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（１−シクロペンチル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１２５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（１−シクロヘキシル−ピペリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（１２６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−ブロモ−１Ｈ−ピロール−２−イル）−メタノン；
（１２７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−ピロール−２−イル）−メタノン；
（１２８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−フェニル−１Ｈ−ピロール−２−イル）−メタノン；
（１２９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（３−クロロ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（１３０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（４−フルオロ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（１３１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（３−フルオロ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（１３２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（１３３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（２−モルホリン−４−イル−エチルアミノ）−１Ｈ−インドール−２−イル］−メタノン；
（１３４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（４−メチル−ピペラジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（１３５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−モルホリン−４−イル−エチルアミノ）−１Ｈ−インドール−２−イル］−メタノン；
（１３６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（ピペラジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（１３７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（２−メトキシ−エチルアミノ）−１Ｈ−インドール−２−イル］−メタノン；
（１３８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（２−ヒドロキシ−１−ヒドロキシメチル−エチルアミノ）−１Ｈ−インドール−２−イル］−メタノン；
（１３９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（２−ピリジン−４−イル−エチルアミノ）−１Ｈ−インドール−２−イル］−メタノン；
（１４０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−メトキシ−エチルアミノ）−１Ｈ−インドール−２−イル］−メタノン；
（１４１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−モルホリン−４−イル−１Ｈ−インドール−２−イル）−メタノン；
（１４２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−モルホリン−４−イル−１Ｈ−インドール−２−イル）−メタノン；
（１４３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（１４４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（１４５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（モルホリン−４−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（１４６） ［５−アミノ−１−（２−イソプロピル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（１４７） ［５−アミノ−１−（２−プロピル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（１４８） ［５−アミノ−１−（１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（１４９） ［５−アミノ−１−（２−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（１５０） ［５−アミノ−１−（２−エチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（１５１） ［５−アミノ−１−（２−ベンジル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン；
（１５２） １−（４−｛２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−５−イルメチル｝−ピペラジン−１−イル）−エタノン；
（１５３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（４−メタンスルホニル−ピペラジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１５４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ピペラジン−１−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（１５５） １−（４−｛２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−６−イルメチル｝−ピペラジン−１−イル）−エタノン；
（１５６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−メチル−ピペラジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１５７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（４−メチル−ピペラジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１５８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ピロリジン−１−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（１５９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（１６０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（１６１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（１６２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−２−イル）−メタノン；
（１６３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−フルオロ−６−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン；
（１６４） ２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−５−カルボン酸；
（１６５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−メトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１６６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，６−ジメトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１６７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−メトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１６８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−メトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１６９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，６−ジメチル−１Ｈ−インドール−２−イル）−メタノン；
（１７０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−tert−ブチル−１Ｈ−インドール−２−イル）−メタノン；
（１７１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−イソプロピル−１Ｈ−インドール−２−イル）−メタノン；
（１７２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ベンジルオキシ−１Ｈ−インドール−２−イル）−メタノン；
（１７３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−ベンジルオキシ−１Ｈ−インドール−２−イル）−メタノン；
（１７４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５，６−ジメトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１７５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−tert−ブチル−１Ｈ−インドール−２−イル）−メタノン；
（１７６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−フルオロ−４−トリフルオロメチル−１Ｈ−インドール−２−イル）−メタノン；
（１７７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−フェノキシ−１Ｈ−インドール−２−イル）−メタノン；
（１７８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−メチルスルファニル−１Ｈ−インドール−２−イル）−メタノン；
（１７９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−tert−ブチル−１Ｈ−インドール−２−イル）−メタノン；
（１８０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−メチル−１Ｈ−インドール−２−イル）−メタノン；
（１８１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−エチル−１Ｈ−インドール−２−イル）−メタノン；
（１８２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−フルオロ−６−トリフルオロメチル−１Ｈ−インドール−２−イル）−メタノン；
（１８３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−フルオロ−５−メトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１８４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−クロロ−５−メトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１８５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−クロロ−６−メトキシ−１Ｈ−インドール−２−イル）−メタノン；
（１８６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−イソプロポキシ−１Ｈ−インドール−２−イル）−メタノン；
（１８７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ベンジルオキシ−１Ｈ−インドール−２−イル）−メタノン；
（１８８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−イソプロポキシ−１Ｈ−インドール−２−イル）−メタノン；
（１８９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（２，３−ジヒドロ−６Ｈ−［１，４］ジオキシノ［２，３−ｆ］インドール−７−イル）−メタノン；
（１９０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，６−ジ−tert−ブチル−１Ｈ−インドール−２−イル）−メタノン；
（１９１） ２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−４−カルボニトリル；
（１９２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−イミダゾール−１−イル−１Ｈ−インドール−２−イル）−メタノン；
（１９３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−トリフルオロメチルスルファニル−１Ｈ−インドール−２−イル）−メタノン；
（１９４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−メチルスルファニル−１Ｈ−インドール−２−イル）−メタノン；
（１９５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−メタンスルホニル−１Ｈ−インドール−２−イル）−メタノン；
（１９６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４，４−ジフルオロ−ピペリジン−１−イルメチル）１Ｈ−インドール−２−イル］−メタノン；
（１９７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−フルオロ−ピペリジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン；
（１９８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（オキセタン−３−イルオキシ）−１Ｈ−インドール−２−イル］−メタノン；
（１９９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ヒドロキシ−１Ｈ−インドール−２−イル）−メタノン；
（２００） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−メタンスルホニル−１Ｈ−インドール−２−イル）−メタノン；
（２０１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，５−ジブロモ−１Ｈ−ピロール−２−イル）−メタノン；
（２０２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，５−ジフェニル−１Ｈ−ピロール−２−イル）−メタノン；
（２０３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，５−ジ−ピリジン−３−イル−１Ｈ−ピロール−２−イル）−メタノン；
（２０４） ［５−アミノ−１−（２−メチル−３Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−クロロ−１Ｈ−インドール−２−イル）−メタノン；
（２０５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−クロロ−１Ｈ−インドール−２−イル）−メタノン；
（２０６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−３−イル）−メタノン；
（２０７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−６−イル）−メタノン；
（２０８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ブロモ−６−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（２０９） ［５−アミノ−１−（２−エチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ブロモ−６−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（２１０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−トリフルオロメチル−１Ｈ−インドール−２−イル）−メタノン；
（２１１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−トリフルオロメトキシ−１Ｈ−インドール−２−イル）−メタノンｖ
（２１２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，６−ジクロロ−１Ｈ−インドール−２−イル）−メタノン；
（２１３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ブロモ−４−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（２１４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−トリフルオロメトキシ−１Ｈ−インドール−２−イル）−メタノン；
（２１５） ［５−アミノ−１−（２−エチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−トリフルオロメトキシ−１Ｈ−インドール−２−イル）−メタノン；
（２１６） ［５−アミノ−１−（２−エチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−トリフルオロメチル−１Ｈ−インドール−２−イル）−メタノン；
（２１７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５，６−ジクロロ−１Ｈ−インドール−２−イル）−メタノン；
（２１８） ［５−アミノ−１−（２−エチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ブロモ−５−フルオロ−１Ｈ−インドール−２−イル）−メタノン；
（２１９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，５−ジクロロ−１Ｈ−インドール−２−イル）−メタノン；
（２２０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４，６−ジフルオロ−１Ｈ−インドール−２−イル）−メタノン；
（２２１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−クロロ−ピリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２２２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（６−メチル−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２２３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−フルオロ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２２４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−トリフルオロメチル−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２２５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−クロロ−２−メトキシ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２２６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（５−クロロ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２２７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−チオフェン−３−イル−１Ｈ−インドール−２−イル）−メタノン；
（２２８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−クロロ−ピリジン−３−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２２９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−チオフェン−２−イル−１Ｈ−インドール−２−イル）−メタノン；
（２３０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（３−フルオロ−ピリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２３１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（２−トリフルオロメチル−ピリジン−４−イル）−１Ｈ−インドール−２−イル］−メタノン；
（２３２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３，３−ジフルオロ−ピロリジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２３３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（２，６−ジメチル−モルホリン−４−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２３４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（［１，４’］ビピペリジニル−１’−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２３５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−｛５−［４−（２，２，２−トリフルオロ−エチル）−ピペラジン−１−カルボニル］−１Ｈ−インドール−２−イル｝−メタノン；
（２３６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−｛５−［４−（２−ヒドロキシ−エチル）−ピペラジン−１−カルボニル］−１Ｈ−インドール−２−イル｝−メタノン；
（２３７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（３，３，４，４−テトラフルオロ−ピロリジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２３８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（（Ｒ）−３−フルオロ−ピロリジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２３９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（（Ｓ）−３−フルオロ−ピロリジン−１−カルボニル）−１Ｈ−インドール−２−イル］−メタノン；
（２４０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（４−メトキシ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（２４１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（３−メトキシ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（２４２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４，５−ビス−（３−フルオロ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（２４３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４，５−ビス−（４−メトキシ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（２４４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（２，４−ジフルオロ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（２４５） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（４−トリフルオロメトキシ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（２４６） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４，５−ビス−（３−メトキシ−フェニル）−１Ｈ−ピロール−２−イル］−メタノン；
（２４７） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−ベンゾフラン−２−イル−メタノン；
（２４８） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−ベンゾ［ｂ］チオフェン−２−イル−メタノン；
（２４９） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−ベンゾチアゾール−２−イル−メタノン；
（２５０） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（４−フルオロ−フェニル）−メタノン；
（２５１） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（３−クロロ−フェニル）−メタノン；
（２５２） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−キノリン−３−イル−メタノン；
（２５３） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−キノリン−７−イル−メタノン；および
（２５４） ［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−キノリン−６−イル−メタノン。
〔６〕ＦＧＦＲ活性阻害剤である、〔１〕〜〔５〕のいずれか一項に記載の医薬。
〔７〕癌の予防又は治療剤である、〔１〕〜〔５〕のいずれか一項に記載の医薬。
〔８〕前記癌が、乳癌、急性骨髄性白血病、膵臓癌、膀胱癌、前立腺癌、食道癌、血管新生、胃癌、子宮体癌、卵巣癌、脳腫瘍、大腸癌、多発性骨髄腫、肝細胞癌、肺癌および甲状腺癌からなる群から選ばれる少なくとも１種である、〔７〕に記載の医薬。 Specifically, the present invention includes the following.
[1] A medicament comprising as an active ingredient a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

(Wherein R _{1 to} R ₄ each independently represent the following group;
R ₁ is hydrogen, hydroxy, halogen, cyano, nitro, C _1-4 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl C _{1-4 alkyl, -OR 5, -NR 6 R 7} , - (CR 8 R 9) n Z 1, -C (O) NR 12 R 13, -SR 14, -SOR 15, -SO 2 R 16 , —NR ₁₇ SO ₂ R ₁₈ , COOH, C _6-10 aryl optionally substituted with one or more groups independently selected from group P, one or more independently selected from group Q of is 5 to 10 membered may be heteroaryl or 3-10 membered heterocyclyl optionally substituted with a _{group, -COR 19, -COOR 20, -OC} (O) R 21, -NR 22 C (O) R 23, -NR _{2 4 represents} C (S) R ₂₅ , —C (S) NR ₂₆ R ₂₇ , —SO ₂ NR ₂₈ R ₂₉ , —OSO ₂ R ₃₀ , —SO ₃ R ₃₁ or —Si (R ₃₂ ) ₃ ;
R ₂ is hydrogen, hydroxy, halogen, cyano, nitro, C _1-4 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl C _{1-4 alkyl, -OR 5, -NR 6 R 7} , - (CR 8 R 9) n Z 1, -C (O) NR 12 R 13, -SR 14, -SOR 15, -SO 2 R 16 , —NR ₁₇ SO ₂ R ₁₈ , COOH, C _6-10 aryl optionally substituted with one or more groups independently selected from group P, one or more independently selected from group Q of is 5 to 10 membered may be heteroaryl or 3-10 membered heterocyclyl optionally substituted with a _{group, -COR 19, -COOR 20, -OC} (O) R 21, -NR 22 C (O) R 23, -NR _{2 4 represents} C (S) R ₂₅ , —C (S) NR ₂₆ R ₂₇ , —SO ₂ NR ₂₈ R ₂₉ , —OSO ₂ R ₃₀ , —SO ₃ R ₃₁ or —Si (R ₃₂ ) ₃ ;
Or R ₁ and R ₂ together with the atoms to which they are attached form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl or the heteroaryl is substituted with a halogen May be;
R ₃ represents hydrogen, C _1-5 alkyl, C _6-10 aryl C _1-6 alkyl or C _1-4 haloalkyl;
R ₄ is hydrogen, halogen, C _1-3 alkyl, C _1-4 haloalkyl, hydroxy, cyano, nitro, C _1-4 alkoxy, — (CH ₂ ) _n Z ₁ , —NR ₆ R ₇ , —OR _5. , —C (O) NR ₁₂ R ₁₃ , —SR ₁₄ , —SOR ₁₅ , —SO ₂ R ₁₆ , NR ₁₇ SO ₂ R ₁₈ , COOH, —COR ₁₉ , —COOR ₂₀ , —OC (O) R ₂₁ , _{-NR 22 C (O) R 23} , -NR 24 C (S) R 25, -C (S) NR 26 R 27, -SO 2 NR 28 R 29, -OSO 2 R 30 -SO 3 R 31 or - Si (R ₃₂ ) ₃ is shown;
A is a 5-10 membered heteroaryl ring or a C _6-10 aryl ring;
R ₅ is C _1-5 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 Alkoxy _C2-4 alkyl, _C1-3 alkoxy _C2-4 alkoxy _C2-4 alkyl, _C2-4 aminoalkyl, _C1-4 alkylamino _C2-4 alkyl, di ( _C1-4 alkyl) Amino C _2-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q C _1-3 alkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C _1-3 alkyl, C _2-6 monohydroxyalkyl, C _2-6 dihi Represents droxyalkyl or C _2-6 trihydroxyalkyl;
R ₆ and R ₇ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxy C _{2- 4} alkyl, C _6-10 aryl C _1-3 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _1-3 alkyl, C _2-6 monohydroxyalkyl, C _2-6 dihydroxy Alkyl, C _2-6 trihydroxyalkyl, 3-10 membered heterocyclyl, C _2-4 aminoalkyl, C _1-4 alkylamino C _2-4 alkyl, di (C _1-4 alkyl) amino C _2-4 alkyl or cyano _{(C 1-3} alkyl) or shown or _{R 6} and _{R 7,} are 3-10 membered Heteroshiku together with the nitrogen atom to which they are attached Forming a Le or 5-10 membered heteroaryl;
n represents 1 to 3;
R ₈ and R ₉ may be the same or different and each represents hydrogen, C _1-4 alkyl or halogen, or R ₈ and R ₉ together with the carbon atom to which they are attached May form a cyclic ring;
Z ₁ represents hydrogen, NR ₁₀ R ₁₁ , —OH, or 3 to 10 membered heterocyclyl or 5 to 10 membered heteroaryl optionally substituted with one or more groups selected from group Q;
R ₁₀ and R ₁₁ may be the same or different and are each C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxy C _2-4 alkyl, Represents cyano (C _1-3 alkyl) or C _1-3 alkylsulfonyl C _2-4 alkyl, or R ₁₀ and R ₁₁ together with the nitrogen atom to which they are attached are 3-10 membered heterocyclyl Or may form a 5-10 membered heteroaryl;
R ₁₂ and R ₁₃ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxy C _2-4 alkyl , C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 arylC _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _{1 -3} alkyl, cyano ( _C1-3 alkyl), _C1-3 alkylsulfonyl _C2-4 alkyl, 3-10 membered alicyclic ring, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, or R ₁₂ and R _13, together with the nitrogen atom to which they are attached, optionally substituted with one or more groups independently selected from Q group May form a have 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
R ₁₄ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q;
R ₁₅ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q;
R ₁₆ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q;
R ₁₇ represents hydrogen or C _1-4 alkyl;
R ₁₈ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with a group independently selected from group Q;
R ₁₉ is substituted with one or more groups independently selected from hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, or Q group. Optionally represents 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₀ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₁ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₂ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;
R ₂₃ represents hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₄ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;
R ₂₅ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₆ and R ₂₇ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxy C _2-4. Alkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 arylC _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C Does it represent _1-3 alkyl, cyano (C _1-3 alkyl), C _1-3 alkylsulfonyl C _2-4 alkyl, 3-10 membered alicyclic ring, 5-10 membered heteroaryl or 3-10 membered heterocyclyl? , or _{R 26} and _{R 27,} form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl together with the nitrogen atom to which they are attached At best;
R ₂₈ and R ₂₉ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxy C _2-4 Alkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 arylC _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C Does it represent _1-3 alkyl, cyano (C _1-3 alkyl), C _1-3 alkylsulfonyl C _2-4 alkyl, 3-10 membered alicyclic ring, 5-10 membered heteroaryl or 3-10 membered heterocyclyl? , or _{R 28} and _{R 29,} form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl together with the nitrogen atom to which they are attached At best;
R ₃₀ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₃₁ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₃₂ represents C _1-4 alkyl or C _6-10 aryl;
<P group>
_{Halogen, C 1-4 alkyl, C 1-4} haloalkyl, _{-OH, C 1-3 alkoxy, C 1-3} haloalkoxy, 3-10 membered _{heterocyclylamino, -SO 2 R 16, -CN,} -NO 2, And 3-10 membered heterocyclyl.
<Q group>
_{Halogen, C 1-4 alkyl, C 1-4} haloalkyl, _{-OH, C 1-3 alkoxy, C 1-6 mono-hydroxyalkyl, C 1-6} dihydroxyalkyl or _{C 1-6} trihydroxy alkyl, 3-10 membered Heterocyclylamino, —SO ₂ R ₁₆ , —CN, —NO ₂ , C _3-7 cycloalkyl, —COR ₁₉ , and 3 to 10 membered heterocyclyl optionally substituted with C _1-4 alkyl.
[2] A pharmaceutical comprising the compound according to [1], wherein A is benzene, indole, azaindole, benzofuran, benzothiophene, benzothiazole, quinoline or pyrrole, or a pharmaceutically acceptable salt thereof as an active ingredient .
[3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R ₃ represents hydrogen, C _1-4 alkyl, aryl C _1-4 alkyl or C _1-3 perfluoroalkyl. The pharmaceutical which contains the salt made as an active ingredient.
[4] Any one of [1] to [3], wherein R ₄ represents hydrogen, halogen, C _1-3 alkyl, C _1-3 perfluoroalkyl, cyano, methanesulfonyl, hydroxyl, alkoxy, or amino. A medicament comprising the described compound or a pharmaceutically acceptable salt thereof as an active ingredient.
[5] A drug containing the compound according to [1] or a pharmaceutically acceptable salt thereof selected from the following group as an active ingredient:
(1) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(2) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyrrolidin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(3) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-hydroxy-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(4) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrolo [3,2-c] pyridin-2-yl ) -Methanone;
(5) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-piperazin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(6) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-morpholin-4-yl-ethoxy) -1H -Indol-2-yl] -methanone;
(7) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (tetrahydro-pyran-4-yloxy) -1H-indole -2-yl] -methanone;
(8) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-chloro-1H-indol-2-yl) -methanone;
(9) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-1H-indol-2-yl) -methanone;
(10) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-iodo-1H-indol-2-yl) -methanone;
(11) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-5-carbonitrile;
(12) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-5-fluoro-1H-indol-2-yl) ) -Methanone;
(13) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-ethynyl-1H-indol-2-yl) -methanone;
(14) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(15) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(16) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(17) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-chloro-phenyl) -1H-indole-2 -Yl] -methanone;
(18) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-phenyl) -1H-indole-2 -Yl] -methanone;
(19) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-chloro-phenyl) -1H-indole-2 -Yl] -methanone;
(20) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(21) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(22) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(23) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-bromo-1H-indol-2-yl) -methanone;
(24) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(25) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methyl-1H-indol-2-yl) -methanone;
(26) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4,4-difluoro-piperidine-1-carbonyl) -1H-indol-2-yl] -methanone;
(27) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-piperidine-1-carbonyl) -1H-indol-2-yl] -methanone;
(28) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-5-carboxylic acid (2,2,2 -Trifluoro-ethyl) -amide;
(29) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(30) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(31) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-chloro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(32) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-methyl-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(33) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-4-fluoro-phenyl) -1H -Indol-2-yl] -methanone;
(34) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(35) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(36) [5-Amino-1- (6-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(37) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-6-carboxylic acid;
(38) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-hydroxymethyl-1H-indol-2-yl) -methanone ;
(39) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{6- [2- (4-methyl-piperazin-1-yl) ) -Ethoxy] -1H-indol-2-yl} -methanone;
(40) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-methyl-oxetan-3-ylmethoxy) -1H -Indol-2-yl] -methanone;
(41) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(42) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-{[bis- (2-methoxy-ethyl) -amino ] -Methyl} -1H-indol-2-yl) -methanone;
(43) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{6-[(methyl-prop-2-ynyl-amino)- Methyl] -1H-indol-2-yl} -methanone;
(44) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3,3-difluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(45) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2,5-dimethyl-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(46) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3,3-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(47) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-((S) -3-methyl-morpholine-4- Ylmethyl) -1H-indol-2-yl] -methanone;
(48) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-1H-indol-2-yl) -methanone;
(49) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-iodo-1H-indol-2-yl) -methanone;
(50) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrolo [3,2-b] pyridin-2-yl ) -Methanone;
(51) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-6-trifluoromethyl-1H-indole-2) -Yl) -methanone;
(52) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-iodo-1H-indol-2-yl) -methanone;
(53) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-methyl-1H-indol-2-yl) -methanone;
(54) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-isopropyl-1H-indol-2-yl) -methanone;
(55) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(56) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-benzyl-1H-indol-2-yl) -methanone;
(57) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(58) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(59) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(60) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-ethynyl-1H-indol-2-yl) -methanone;
(61) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5H- [1,3] dioxolo [4,5-f] Indol-6-yl) -methanone;
(62) [5-Amino-1- (7-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(63) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(64) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-butoxy-1H-indol-2-yl) -methanone;
(65) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-methyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(66) N- {2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indol-6-yl} -methanesulfone An amide;
(67) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-morpholin-4-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(68) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-butyl-1H-indol-2-yl) -methanone;
(69) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (1-methyl-1H-pyrazol-4-yl) -1H-indol-2-yl] -methanone;
(70) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-methoxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(71) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-methoxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(72) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-cyclopropyl-1H-indol-2-yl) -methanone ;
(73) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-methoxy-phenyl) -1H-indole-2 -Yl] -methanone;
(74) 5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-phenyl-1H-indol-2-yl) -methanone;
(75) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-methanesulfonyl-pyridin-3-yl)- 1H-indol-2-yl] -methanone;
(76) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-isopropyl-1H-indol-2-yl) -methanone;
(77) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridin-2-yl-1H-indol-2-yl) ) -Methanone;
(78) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-cyclopropyl-1H-indol-2-yl) -methanone ;
(79) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridazin-3-yl-1H-indol-2-yl) ) -Methanone;
(80) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-isopropoxy-1H-indol-2-yl) -methanone ;
(81) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2-methoxy-ethoxy) -1H-indole-2 -Yl] -methanone;
(82) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-cyclopropylmethoxy-1H-indol-2-yl)- Methanone;
(83) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(2,2-difluoro-5H- [1,3] dioxolo [ 4,5-f] indol-6-yl) -methanone;
(84) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(85) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-fluoro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(86) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-morpholin-4-yl-pyridazine-3- Yl) -1H-indol-2-yl] -methanone;
(87) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-chloro-6-cyclopropylmethoxy-1H-indole-2) -Yl) -methanone;
(88) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2,4-difluoro-phenyl) -1H-indole -2-yl] -methanone;
(89) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridazin-4-yl-1H-indol-2-yl) ) -Methanone;
(90) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(3-fluoro-1H-indol-2-yl) -methanone;
(91) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-isopropyl-piperidin-4-yl) -6 -Trifluoromethyl-1H-indol-2-yl] -methanone;
(92) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-6-carbonitrile;
(93) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1,2,3,6-tetrahydro-pyridine) 4-yl) -1H-indol-2-yl] -methanone;
(94) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-piperidin-4-yl-1H-indol-2-yl) ) -Methanone;
(95) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((R) -3-fluoro-pyrrolidine-1- Ylmethyl) -1H-indol-2-yl] -methanone;
(96) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-5-piperidin-4-yl-1H-indole -2-yl) -methanone;
(97) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-fluoro-5- (1-methyl-piperidine-4-yl) Yl) -1H-indol-2-yl] -methanone;
(98) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-isopropyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(99) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-fluoro-5- (1-isopropyl-piperidine-4-yl) Yl) -1H-indol-2-yl] -methanone;
(100) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridin-3-yl-1H-indol-2-yl) ) -Methanone;
(101) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-morpholin-4-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(102) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-pyridin-3-yl-1H-indol-2-yl) ) -Methanone;
(103) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-piperazin-1-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(104) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-hydroxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(105) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-fluoro-5- (4-methyl-piperazine-1- Ylmethyl) -1H-indol-2-yl] -methanone;
(106) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-5-pyrrolidin-1-ylmethyl-1H-indole -2-yl) -methanone;
(107) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (1-methyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(108) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-morpholin-4-yl-phenyl) -1H -Indol-2-yl] -methanone;
(109) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3,4,5,6-tetrahydro-2H- [1,2 ′] bipyridin-5′-yl) -1H-indol-2-yl] -methanone;
(110) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-piperazin-1-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(111) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-methoxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(112) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((S) -3-methyl-morpholine-4- Ylmethyl) -1H-indol-2-yl] -methanone;
(113) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-((R) -3-fluoro-pyrrolidine-1- Ylmethyl) -1H-indol-2-yl] -methanone;
(114) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2,5-dimethyl-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(115) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(116) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(117) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{6- [2- (4-methyl-piperazin-1-yl) ) -Pyridin-4-yl] -1H-indol-2-yl} -methanone;
(118) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridin-4-yl-1H-indol-2-yl) ) -Methanone;
(119) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(120) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4,4-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(121) [5-Amino-1- (2-difluoromethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-methyl-piperidin-4-yl)- 1H-indol-2-yl] -methanone;
(122) [5-Amino-1- (2-difluoromethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(123) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(124) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-cyclopentyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(125) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-cyclohexyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(126) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-bromo-1H-pyrrol-2-yl) -methanone;
(127) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrol-2-yl) -methanone;
(128) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-phenyl-1H-pyrrol-2-yl) -methanone;
(129) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (3-chloro-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(130) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (4-fluoro-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(131) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (3-fluoro-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(132) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl) ) -Methanone;
(133) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-morpholin-4-yl-ethylamino)- 1H-indol-2-yl] -methanone;
(134) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-methyl-piperazine-1-carbonyl) -1H -Indol-2-yl] -methanone;
(135) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-morpholin-4-yl-ethylamino)- 1H-indol-2-yl] -methanone;
(136) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (piperazine-1-carbonyl) -1H-indole-2 -Yl] -methanone;
(137) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-methoxy-ethylamino) -1H-indole- 2-yl] -methanone;
(138) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-hydroxy-1-hydroxymethyl-ethylamino) -1H-indol-2-yl] -methanone;
(139) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-pyridin-4-yl-ethylamino)- 1H-indol-2-yl] -methanone;
(140) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-methoxy-ethylamino) -1H-indole- 2-yl] -methanone;
(141) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-morpholin-4-yl-1H-indol-2-yl) ) -Methanone;
(142) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-morpholin-4-yl-1H-indol-2-yl) ) -Methanone;
(143) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-morpholin-4-ylmethyl-1H-indol-2-yl ) -Methanone;
(144) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-morpholin-4-ylmethyl-1H-indol-2-yl ) -Methanone;
(145) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (morpholine-4-carbonyl) -1H-indole-2 -Yl] -methanone;
(146) [5-Amino-1- (2-isopropyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(147) [5-amino-1- (2-propyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(148) [5-Amino-1- (1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(149) [5-Amino-1- (2-trifluoromethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(150) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(151) [5-Amino-1- (2-benzyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(152) 1- (4- {2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indol-5-ylmethyl} -Piperazin-1-yl) -ethanone;
(153) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-methanesulfonyl-piperazin-1-ylmethyl)- 1H-indol-2-yl] -methanone;
(154) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-piperazin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(155) 1- (4- {2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indol-6-ylmethyl} -Piperazin-1-yl) -ethanone;
(156) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-methyl-piperazin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(157) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-methyl-piperazin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(158) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-pyrrolidin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(159) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-fluoro-1H-indol-2-yl) -methanone;
(160) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-1H-indol-2-yl) -methanone;
(161) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-1H-indol-2-yl) -methanone;
(162) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrolo [2,3-b] pyridin-2-yl ) -Methanone;
(163) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-6-morpholin-4-ylmethyl-1H-indole -2-yl) -methanone;
(164) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-5-carboxylic acid;
(165) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methoxy-1H-indol-2-yl) -methanone;
(166) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-dimethoxy-1H-indol-2-yl)- Methanone;
(167) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-methoxy-1H-indol-2-yl) -methanone;
(168) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methoxy-1H-indol-2-yl) -methanone;
(169) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-dimethyl-1H-indol-2-yl)- Methanone;
(170) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-tert-butyl-1H-indol-2-yl)- Methanone;
(171) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-isopropyl-1H-indol-2-yl) -methanone;
(172) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-benzyloxy-1H-indol-2-yl) -methanone ;
(173) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-benzyloxy-1H-indol-2-yl) -methanone ;
(174) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5,6-dimethoxy-1H-indol-2-yl)- Methanone;
(175) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-tert-butyl-1H-indol-2-yl)- Methanone;
(176) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-4-trifluoromethyl-1H-indole-2) -Yl) -methanone;
(177) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-phenoxy-1H-indol-2-yl) -methanone;
(178) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methylsulfanyl-1H-indol-2-yl) -methanone ;
(179) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-tert-butyl-1H-indol-2-yl)- Methanone;
(180) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methyl-1H-indol-2-yl) -methanone;
(181) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-ethyl-1H-indol-2-yl) -methanone;
(182) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-6-trifluoromethyl-1H-indole-2) -Yl) -methanone;
(183) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-5-methoxy-1H-indol-2-yl) ) -Methanone;
(184) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-chloro-5-methoxy-1H-indol-2-yl) ) -Methanone;
(185) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-chloro-6-methoxy-1H-indol-2-yl) ) -Methanone;
(186) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-isopropoxy-1H-indol-2-yl) -methanone ;
(187) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-benzyloxy-1H-indol-2-yl) -methanone ;
(188) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-isopropoxy-1H-indol-2-yl) -methanone ;
(189) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(2,3-dihydro-6H- [1,4] dioxino [ 2,3-f] indol-7-yl) -methanone;
(190) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-di-tert-butyl-1H-indole-2 -Yl) -methanone;
(191) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-4-carbonitrile;
(192) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-imidazol-1-yl-1H-indol-2-yl) ) -Methanone;
(193) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethylsulfanyl-1H-indol-2-yl) -Methanone;
(194) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methylsulfanyl-1H-indol-2-yl) -methanone ;
(195) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methanesulfonyl-1H-indol-2-yl) -methanone ;
(196) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4,4-difluoro-piperidin-1-ylmethyl) 1H-indol-2-yl] -methanone;
(197) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(198) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (oxetane-3-yloxy) -1H-indole-2 -Yl] -methanone;
(199) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl) -methanone;
(200) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methanesulfonyl-1H-indol-2-yl) -methanone ;
(201) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-dibromo-1H-pyrrol-2-yl)- Methanone;
(202) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-diphenyl-1H-pyrrol-2-yl)- Methanone;
(203) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-di-pyridin-3-yl-1H-pyrrole -2-yl) -methanone;
(204) [5-Amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-chloro-1H-indol-2-yl) -methanone;
(205) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-chloro-1H-indol-2-yl) -methanone;
(206) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-3-yl) -methanone;
(207) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-6-yl) -methanone;
(208) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-6-fluoro-1H-indol-2-yl) ) -Methanone;
(209) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-6-fluoro-1H-indol-2-yl) ) -Methanone;
(210) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethyl-1H-indol-2-yl)- Methanone;
(211) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethoxy-1H-indol-2-yl)- Methanon v
(212) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-dichloro-1H-indol-2-yl)- Methanone;
(213) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-4-fluoro-1H-indol-2-yl) ) -Methanone;
(214) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-trifluoromethoxy-1H-indol-2-yl)- Methanone;
(215) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethoxy-1H-indol-2-yl)- Methanone;
(216) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethyl-1H-indol-2-yl)- Methanone;
(217) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5,6-dichloro-1H-indol-2-yl)- Methanone;
(218) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-5-fluoro-1H-indol-2-yl) ) -Methanone;
(219) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-dichloro-1H-indol-2-yl)- Methanone;
(220) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-difluoro-1H-indol-2-yl)- Methanone;
(221) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-pyridin-4-yl) -1H -Indol-2-yl] -methanone;
(222) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-methyl-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(223) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-fluoro-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(224) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-trifluoromethyl-pyridin-3-yl) -1H-indol-2-yl] -methanone;
(225) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-chloro-2-methoxy-pyridine-3- Yl) -1H-indol-2-yl] -methanone;
(226) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-chloro-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(227) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-thiophen-3-yl-1H-indol-2-yl) ) -Methanone;
(228) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-chloro-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(229) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-thiophen-2-yl-1H-indol-2-yl) ) -Methanone;
(230) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-pyridin-4-yl) -1H -Indol-2-yl] -methanone;
(231) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-trifluoromethyl-pyridin-4-yl) -1H-indol-2-yl] -methanone;
(232) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-pyrrolidin-1-carbonyl) -1H-indol-2-yl] -methanone;
(233) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2,6-dimethyl-morpholine-4-carbonyl) -1H-indol-2-yl] -methanone;
(234) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-([1,4 ′] bipiperidinyl-1′-carbonyl ) -1H-indol-2-yl] -methanone;
(235) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{5- [4- (2,2,2-trifluoro- Ethyl) -piperazine-1-carbonyl] -1H-indol-2-yl} -methanone;
(236) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{5- [4- (2-hydroxy-ethyl) -piperazine- 1-carbonyl] -1H-indol-2-yl} -methanone;
(237) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3,4,4-tetrafluoro-pyrrolidine -1-carbonyl) -1H-indol-2-yl] -methanone;
(238) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((R) -3-fluoro-pyrrolidine-1- Carbonyl) -1H-indol-2-yl] -methanone;
(239) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((S) -3-fluoro-pyrrolidine-1- Carbonyl) -1H-indol-2-yl] -methanone;
(240) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (4-methoxy-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(241) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (3-methoxy-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(242) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4,5-bis- (3-fluoro-phenyl) -1H -Pyrrol-2-yl] -methanone;
(243) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4,5-bis- (4-methoxy-phenyl) -1H -Pyrrol-2-yl] -methanone;
(244) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2,4-difluoro-phenyl) -1H-pyrrole -2-yl] -methanone;
(245) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (4-trifluoromethoxy-phenyl) -1H-pyrrole -2-yl] -methanone;
(246) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4,5-bis- (3-methoxy-phenyl) -1H -Pyrrol-2-yl] -methanone;
(247) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -benzofuran-2-yl-methanone;
(248) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -benzo [b] thiophen-2-yl-methanone;
(249) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -benzothiazol-2-yl-methanone;
(250) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-fluoro-phenyl) -methanone;
(251) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(3-chloro-phenyl) -methanone;
(252) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -quinolin-3-yl-methanone;
(253) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -quinolin-7-yl-methanone; and (254) [5-amino -1- (2-Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -quinolin-6-yl-methanone.
[6] The medicament according to any one of [1] to [5], which is an FGFR activity inhibitor.
[7] The medicament according to any one of [1] to [5], which is a preventive or therapeutic agent for cancer.
[8] The cancer is breast cancer, acute myeloid leukemia, pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, angiogenesis, gastric cancer, endometrial cancer, ovarian cancer, brain tumor, colon cancer, multiple myeloma, hepatocyte The medicine according to [7], which is at least one selected from the group consisting of cancer, lung cancer and thyroid cancer.

  The compound of the present invention or a pharmacologically acceptable salt thereof has an excellent selective FGFR family kinase inhibitory action, and also exhibits efficacy against a new gene that is altered in cancer (not a target gene). Can prevent and / or treat cancer that has been previously ineffective.

  The present invention relates to aminopyrazole derivatives and uses thereof. The present inventors synthesized for the first time a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and the compound or a salt thereof has an FGFR family kinase inhibitory activity, The pharmacologically acceptable salt was found to be a new drug effective against cancer.

“Alkyl” in the present specification is a monovalent group derived by removing an arbitrary hydrogen atom from an aliphatic hydrocarbon, does not contain a heteroatom or an unsaturated carbon-carbon bond in the skeleton, It has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl groups include linear and branched structures. As the alkyl group, preferably an alkyl group having 1 to 6 carbon atoms (C _1-6 , hereinafter, “C pq” means _{p to q} carbon atoms), C _{1 A -5} alkyl group, a _C1-4 alkyl group, a _C1-3 alkyl group, etc. are mentioned.

  Specific examples of the alkyl include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2 , 3-dimethylpropyl group, 3,3-dimethylbutyl group, hexyl group and the like.

As used herein, “alkenyl” is a monovalent hydrocarbon group having at least one double bond (two adjacent SP2 carbon atoms), and includes straight-chain or branched-chain ones. Depending on the arrangement of the double bonds and substituents (if any), the geometry of the double bonds can take the enthagegen (E) or tsuzanmen (Z), or cis or trans configurations. Preferred examples of the alkenyl group include a C _2-6 alkenyl group.

  Specific examples of alkenyl include, for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group (including cis and trans), 3-butenyl group, and pentenyl group. Hexenyl group and the like.

As used herein, “alkynyl” is a monovalent hydrocarbon group having at least one triple bond (two adjacent SP carbon atoms), and includes straight-chain or branched-chain ones. Preferably a _C2-6 alkynyl group is mentioned.

  Specific examples of alkynyl include ethynyl group, 1-propynyl group, propargyl group, 3-butynyl group, pentynyl group, hexynyl group and the like.

  Alkenyl or alkynyl can have one or more double bonds or triple bonds, respectively.

“Cycloalkyl” in the present specification means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, and includes a monocyclic ring, a bicyclic ring, and a spiro ring. Preferred examples of the cycloalkyl include a C _3-7 cycloalkyl group. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

“Cycloalkylalkyl” in the present specification means a group in which any hydrogen atom in the above-mentioned definition “alkyl” is substituted with the above-mentioned “cycloalkyl”. Preferred examples of the cycloalkylalkyl include C _3-7 cycloalkylC _1-3 alkyl, and specific examples include a cyclopropylmethyl group and a cyclopropylethyl group.

  As used herein, “heteroatom” means a nitrogen atom (N), an oxygen atom (O), or a sulfur atom (S).

  In the present specification, “halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, “haloalkyl” is the same or different, preferably 1-9, more preferably 1-5, a group in which the “halogen atom” is bonded to the “alkyl”.
Specifically, for example, chloromethyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, difluoromethyl group, perfluoroalkyl group (for example, trifluoromethyl group, —CF ₂ CF ₃ etc.), 2, 2, Examples include 2-trifluoroethyl group.

In the present specification, “alkoxy” means an oxy group to which the above-defined “alkyl” is bonded, and preferably includes a C _1-4 alkoxy group, a C _1-3 alkoxy group, and the like. Specific examples of alkoxy include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, tert-butoxy group and the like.
The “haloalkoxy” in the present specification is the same or different, preferably 1-9, more preferably 1-5, a group in which the “halogen atom” is bonded to the “alkoxy”.
Specific examples include a chloromethoxy group, a trichloromethoxy group, a trifluoromethoxy group, and the like.

“Aryl” in the present specification means a monovalent aromatic hydrocarbon ring, preferably C _6-10 aryl and the like. Specific examples of the aryl include a phenyl group and a naphthyl group (for example, a 1-naphthyl group and a 2-naphthyl group).

  The “alicyclic ring” in the present specification means a monovalent non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond in the ring or may be a polycyclic group having two or more rings. Carbon atoms constituting the ring may be oxidized to form carbonyl. The number of atoms constituting the alicyclic ring is preferably 3 to 10 (3 to 10-membered alicyclic ring). Examples of the alicyclic ring include a cycloalkyl ring, a cycloalkenyl ring, and a cycloalkynyl ring.

  “Heteroaryl” in the present specification means an aromatic monovalent heterocyclic group containing preferably 1 to 5 heteroatoms in the atoms constituting the ring. Heteroaryl may be partially saturated and may be monocyclic or fused (eg, bicyclic heteroaryl fused with a benzene ring or monoheteroaryl ring). The number of atoms constituting the ring is preferably 5 to 10 (5 to 10 membered heteroaryl).

  Specific examples of the heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, Pyridyl group, pyrimidyl group, pyridazinyl group, pyrazinyl group, triazinyl group, benzofuranyl group, benzothienyl group, benzothiadiazolyl group, benzothiazolyl group, benzoxazolyl group, benzooxadiazolyl group, benzimidazolyl group, indolyl group, isoindolyl Group, azaindolyl group, indazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, benzodioxolyl group, indolizinyl group, imidazopyridy Such as a group, and the like.

  As used herein, “heterocyclyl” means a non-aromatic monovalent heterocyclic group containing preferably 1 to 5 heteroatoms in the atoms constituting the ring. The heterocyclyl may have a double or triple bond in the ring, the carbon atom may be oxidized to form a carbonyl, and may be a single ring or a condensed ring. The number of atoms constituting the ring is preferably 3 to 10 (3 to 10 membered heterocyclyl).

  Specific examples of heterocyclyl include oxetanyl group, dihydrofuryl group, tetrahydrofuryl group, dihydropyranyl group, tetrahydropyranyl group, tetrahydropyridyl group, morpholinyl group, thiomorpholinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, Pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, oxazolidinyl group, isoxazolidinyl group, thiazolidinyl group, isothiazolidinyl group, thiadiazolidinyl group, azetidinyl group, oxazolidone group, benzodioxanyl group, benzoxazolyl Group, dioxolanyl group, dioxanyl group and the like.

In the present specification, “arylalkyl” means a group in which any hydrogen atom in the above-mentioned definition “alkyl” is substituted with the above-mentioned definition “aryl”. Preferred examples of the arylalkyl include C _6-10 aryl C _1-4 alkyl and C _6-10 aryl C _1-3 alkyl. Specific examples include a benzyl group, a phenethyl group, and a naphthylmethyl group.

As used herein, “heteroarylalkyl” means a group in which any hydrogen atom in the above-mentioned definition “alkyl” is substituted with the above-mentioned definition “heteroaryl”. The heteroarylalkyl is preferably a 5- to 10-membered heteroaryl C _1-3 alkyl, and specifically includes, for example, pyrrolylmethyl group, imidazolylmethyl group, thienylmethyl group, pyridylmethyl group, pyrimidylmethyl group, quinolylmethyl, and the like. Group, pyridylethyl group and the like.

“Heterocyclylalkyl” in the present specification means a group in which any hydrogen atom in the above-mentioned definition “alkyl” is substituted with the above-mentioned definition “heterocyclyl”. Preferred examples of the heterocyclylalkyl include 3 to 10-membered heterocyclyl _C1-3 alkyl. Specific examples thereof include morpholinylmethyl group, morpholinylethyl group, thiomorpholinylmethyl group, pyrrolidinyl. Examples include a methyl group, piperidinylmethyl group, piperazinylmethyl group, piperazinylethyl group, oxetanylmethyl group and the like.

“Monohydroxyalkyl” in the present specification means a group in which any one hydrogen atom in the above-mentioned definition “alkyl” is substituted with one hydroxyl group. As monohydroxyalkyl, preferably, C _1-6 monohydroxyalkyl, C _2-6 monohydroxyalkyl and the like can be mentioned, and specifically, for example, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group Etc. are included in this.

In the present specification, “dihydroxyalkyl” means a group in which any two hydrogen atoms in the above-mentioned definition “alkyl” are substituted with two hydroxyl groups. Preferred examples of dihydroxyalkyl include C _1-6 dihydroxyalkyl, C _2-6 dihydroxyalkyl, and the like. Specifically, for example, 1,2-dihydroxyethyl group, 1,2-dihydroxypropyl group, 1,3 This includes dihydroxypropyl groups and the like.

“Trihydroxyalkyl” in the present specification means a group in which any three hydrogen atoms in the above-mentioned definition “alkyl” are substituted with three hydroxyl groups. Preferred examples of trihydroxyalkyl include C _1-6 trihydroxyalkyl and C _2-6 trihydroxyalkyl.

In the present specification, “alkoxyalkyl” means a group in which any hydrogen atom in the above-defined “alkyl” is substituted with “alkoxy” as defined above. The alkoxyalkyl preferably includes C _1-3 alkoxy C _1-4 alkyl, C _1-3 alkoxy C _2-4 alkyl and the like, and specifically includes, for example, methoxyethyl and the like.

The term “alkoxyalkoxyalkyl” in the present specification means a group in which any hydrogen atom in the terminal alkyl in the above-mentioned definition “alkoxyalkyl” is substituted with “alkoxy” as defined above. As alkoxyalkoxyalkyl, _{preferably, C 1-3} alkoxy _{C 1-4} alkoxy _{C 1-4 alkyl,} such as _{C 1-3} alkoxy _{C 2-4} alkoxy _{C 2-4} alkyl.

In the present specification, “aminoalkyl” means a group in which any hydrogen atom in the above-mentioned definition “alkyl” is substituted with an amino group. Preferred examples of the aminoalkyl group include C _1-4 aminoalkyl and C _2-4 aminoalkyl.

In the present specification, “alkylamino” means an amino group in which one “alkyl” as defined above is bonded. Alkylamino is preferably C _1-4 alkylamino.

In the present specification, “dialkylamino” means an amino group in which two “alkyl” defined above are bonded, and the alkyl may be the same or different. Preferred examples of the dialkylamino include di (C _1-4 alkyl) amino.

As used herein, “alkylaminoalkyl” means a group in which any hydrogen atom in “alkyl” as defined above is substituted with “alkylamino” as defined above. As alkylamino alkyl, _{preferably, C 1-4} alkylamino _{C 1-4 alkyl,} such as _{C 1-4} alkylamino _{C 2-4} alkyl.

As used herein, “dialkylaminoalkyl” means a group in which any hydrogen atom in “alkyl” as defined above is substituted with “dialkylamino” as defined above. Preferred examples of the dialkylaminoalkyl include di (C _1-4 alkyl) amino C _1-4 alkyl, di (C _1-4 alkyl) amino C _2-4 alkyl, and the like.

  “Heterocyclylamino” in the present specification means an amino group in which one “heterocyclyl” defined above is bonded. Preferred examples of the heterocyclylamino include 3- to 10-membered heterocyclylamino.

The “cyanoalkyl” in the present specification means a group in which any hydrogen atom in the above-defined “alkyl” is substituted with a cyano group. As cyanoalkyl, Preferably, cyano ( _C1-3 alkyl) etc. are mentioned.

As used herein, “alkylsulfonyl” means a sulfonyl group to which the above-defined “alkyl” is bound (ie, alkyl-SO ₂ —). Preferred examples of the alkylsulfonyl include C _1-3 alkylsulfonyl, and specifically include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl and the like.

As used herein, “alkylsulfonylalkyl” means a group in which any hydrogen atom in the above-defined “alkyl” is substituted with “alkylsulfonyl” as defined above. As alkylsulfonyl alkyl, _{preferably, C 1-3} alkylsulfonyl _{C 1-4 alkyl,} such as _{C 1-3} alkylsulfonyl _{C 2-4} alkyl.

  The compound according to the present invention is included in the present invention even in a free form or a pharmacologically acceptable salt. Examples of such “salts” include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, and the like.

  Preferable examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and preferable examples of organic acid salts include, for example, acetate, succinate and fumarate. Acid salts, maleates, tartrate, citrate, lactate, malate, stearate, benzoate, methanesulfonate, p-toluenesulfonate, and the like. A particularly preferred salt in the present invention is malate.

  Preferable examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Preferred examples of organic base salts Examples thereof include diethylamine salt, diethanolamine salt, meglumine salt, N, N-dibenzylethylenediamine salt and the like.

  Preferable examples of the acidic amino acid salt include aspartate and glutamate, and preferable examples of the basic amino acid salt include arginine salt, lysine salt and ornithine salt.

When the compound of the present invention is allowed to stand in the air, it may absorb moisture and adsorb water or become a hydrate. Such a hydrate is also included in the salt of the present invention.
Furthermore, the compound according to the present invention may absorb a certain other solvent and become a solvate, and such a solvate is also included in the salt of the present invention.

  All isomers (geometric isomers, optical isomers, stereoisomers, tautomers, etc.) and isomer mixtures occurring in the structure of the compound according to the present invention are included in the present invention.

  The compounds according to the present invention may have crystalline polymorphs, all of which are included in the present invention.

  The compounds according to the present invention include their prodrugs. A prodrug is a derivative of a compound of the present invention that has a group that can be chemically or metabolically decomposed and is restored to the original compound after administration to a living body and exhibits its original medicinal properties. No complexes and salts.

The compounds according to the present invention include those in which one or more atoms in the molecule are replaced by isotopes. In the present invention, the isotope means atoms having the same atomic number (number of protons) but different mass numbers (sum of the number of protons and neutrons). Examples of atoms to be substituted for isotopes contained in the compound of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, and the like. The body includes ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and the like. In particular, radioactive isotopes such as ³ H and ¹⁴ C that decay by emitting radioactivity are useful in pharmaceutical tissue or compound tissue distribution tests. Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity. The isotope substitute of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.

  The compounds represented by the formula (I) of the present invention are preferably as follows.

R ₁ is preferably hydrogen, hydroxy, halogen, cyano, nitro, C _1-4 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl C _1-4 alkyl, —OR ₅ , —NR ₆ R ₇ , — (CR ₈ R ₉ ) _n Z ₁ , —C (O) NR ₁₂ R ₁₃ , —SR ₁₄ , —SOR ₁₅ , — SO ₂ R ₁₆ , —NR ₁₇ SO ₂ R ₁₈ , COOH, C _6-10 aryl optionally substituted with one or more groups independently selected from the P group, independently selected from the Q group 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups, —COR ₁₉ , —COOR ₂₀ , —OC (O) R ₂₁ , —NR ₂₂ C (O) R _23, in _{-NR 24 C (S) R 25} , -C (S) NR 26 R 27, -SO 2 NR 28 R 29, -OSO 2 R 30, -SO 3 R 31 or -Si _{(R 32) 3} is there.

R ₁ is more preferably hydrogen, hydroxy, halogen, cyano, C _1-4 haloalkyl, C _1-6 alkyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl C _{1- 4 alkyl, -OR 5, -NR 6 R 7} , - (CR 8 R 9) n Z 1, -C (O) NR 12 R 13, -SR 14, -SO 2 R 16, -NR 17 SO 2 R ₁₈ , COOH, C _6-10 aryl optionally substituted with one or more groups independently selected from group P, or substituted with one or more groups independently selected from group Q It may be 5 to 10 membered heteroaryl or 3 to 10 membered heterocyclyl. The 5- to 10-membered heteroaryl here is specifically preferably an imidazolyl group, thienyl group, pyridyl group, pyridazinyl group or pyrazolyl group, and the 3- to 10-membered heterocyclyl is specifically morpholinyl group or tetrahydropyridyl group. A piperidinyl group is particularly preferred.

R ₂ is preferably hydrogen, hydroxy, halogen, cyano, nitro, C _1-4 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl C _1-4 alkyl, —OR ₅ , —NR ₆ R ₇ , — (CR ₈ R ₉ ) _n Z ₁ , —C (O) NR ₁₂ R ₁₃ , —SR ₁₄ , —SOR ₁₅ , — SO ₂ R ₁₆ , —NR ₁₇ SO ₂ R ₁₈ , COOH, C _6-10 aryl optionally substituted with one or more groups independently selected from the P group, independently selected from the Q group 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups, —COR ₁₉ , —COOR ₂₀ , —OC (O) R ₂₁ , —NR ₂₂ C (O) R _23, in _{-NR 24 C (S) R 25} , -C (S) NR 26 R 27, -SO 2 NR 28 R 29, -OSO 2 R 30, -SO 3 R 31 or -Si _{(R 32) 3} is there.

More preferably, R ₂ may be substituted with one or more groups independently selected from hydrogen, halogen, C _1-4 haloalkyl, C _1-6 alkyl, —OR ₅ , P group. C _6-10 aryl is a 5-10 membered heteroaryl optionally substituted with one or more groups independently selected from group Q. Specifically, the 5- to 10-membered heteroaryl here is particularly preferably a pyridyl group.

Said R ₁ and said R ₂ are preferably taken together with the atoms to which they are attached to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl. Here, the heterocyclyl or the heteroaryl may have a halogen atom as a substituent. As the 3- to 10-membered heterocyclyl formed together with the bonded atoms, specifically, a dioxolanyl group and a dioxanyl group are particularly preferable.

The R ₃ is preferably hydrogen, C _1-5 alkyl, C _6-10 aryl C _1-6 alkyl or C _1-4 haloalkyl, more preferably hydrogen, C _1-4 alkyl, C _{6-6. It is 10} aryl C _1-4 alkyl or C _1-3 perfluoroalkyl, particularly preferably C ₁ alkyl.

The R ₄ is preferably hydrogen, halogen, C _1-3 alkyl, C _1-4 haloalkyl, hydroxy, cyano, nitro, C _1-4 alkoxy, — (CH ₂ ) _n Z ₁ , —NR ₆ R _7. , —OR ₅ , —C (O) NR ₁₂ R ₁₃ , —SR ₁₄ , —SOR ₁₅ , —SO ₂ R ₁₆ , NR ₁₇ SO ₂ R ₁₈ , COOH, —COR ₁₉ , —COOR ₂₀ , —OC (O _{) R 21, -NR 22 C (} O) R 23, -NR 24 C (S) R 25, -C (S) NR 26 R 27, -SO 2 NR 28 R 29, -OSO 2 R 30 -SO 3 R ₃₁ or —Si (R ₃₂ ) ₃ .

R ₄ is more preferably hydrogen, halogen, C _1-3 alkyl, C _1-3 perfluoroalkyl, cyano, methanesulfonyl, hydroxyl, alkoxy, or amino, and particularly preferably hydrogen or halogen.

で表される基（本明細書において単に「Ａ」ということがある。）である。Ａ環として、好ましくは、５〜１０員ヘテロアリール環またはＣ_６−１０アリール環であり、より好ましくは、ベンゼン、インドール、アザインドール、ベンゾフラン、ベンゾチオフェン、ベンゾチアゾール、キノリンまたはピロールであり、特に好ましくはインドールまたはピロールである。 Said A ring has the following formula:

(In this specification, it may be simply referred to as “A”). The A ring is preferably a 5- to 10-membered heteroaryl ring or a C _6-10 aryl ring, more preferably benzene, indole, azaindole, benzofuran, benzothiophene, benzothiazole, quinoline or pyrrole, especially Indole or pyrrole is preferred.

R ₅ is preferably C _1-5 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl. C _1-3 alkoxy C _1-4 alkyl, C _1-3 alkoxy C _1-4 alkoxy C _1-4 alkyl, C _1-4 aminoalkyl, C _1-4 alkylamino C _1-4 alkyl, di (C _1-4 alkyl) amino C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, optionally substituted with one or more groups independently selected from group Q 3-10 membered heterocyclyl _{C 1-3} alkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl _{C 1-3 alkyl, C 1-6} monohydroxyalkyl al _Le, a _{C 1-6} dihydroxyalkyl or _{C 1-6} trihydroxy alkyl.

R ₅ is more preferably C _1-5 alkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _1-4 haloalkyl, C _1-3 alkoxy C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q, C _1-3 alkyl, 3-10 membered heterocyclyl. . As the 3- to 10-membered heterocyclylalkyl, specifically, piperazinylethyl group, oxetanylmethyl group, and morpholinylethyl group are particularly preferable, and as the 3- to 10-membered heterocyclyl, specifically, oxetanyl group, tetrahydro A pyranyl group is particularly preferred.

R ₆ and R ₇ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _{1-, respectively. 3} alkoxy C _2-4 alkyl, C _6-10 aryl C _1-3 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _1-3 alkyl, C _1-6 monohydroxyalkyl, C _1-6 dihydroxyalkyl, C _1-6 trihydroxyalkyl, 3-10 membered heterocyclyl, C _1-4 aminoalkyl, C _1-4 alkylamino C _1-4 alkyl, di (C _1-4 alkyl) amino C _{It is 1-4} alkyl or cyano (C _1-3 alkyl).

More preferably, R ₆ and R ₇ are each independently hydrogen, C _1-3 alkoxyC _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _{1. -3} alkyl, or C _1-6 dihydroxyalkyl. Specifically, the morpholinylethyl group is particularly preferable as the 3- to 10-membered heterocyclylalkyl here, and the pyridylethyl group is particularly preferable as the 5- to 10-membered heteroarylalkyl here.

Alternatively, R ₆ and R ₇ are preferably taken together with the nitrogen atom to which they are attached to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl.

  N represents an integer of 1 to 3, and preferably n is 1.

R ₈ and R ₉ may be the same or different and are each hydrogen, C _1-4 alkyl or halogen, and more preferably hydrogen.

Alternatively, R ₈ and R ₉ can preferably be combined with the carbon atom to which they are attached to form an alicyclic ring.

Said Z ₁ is preferably hydrogen, NR ₁₀ R ₁₁ , —OH, or 3 to 10 membered heterocyclyl or 5 to 10 member optionally substituted with one or more groups independently selected from group Q It is heteroaryl, more preferably NR ₁₀ R ₁₁ or —OH, or 3- to 10-membered heterocyclyl optionally substituted with one or more groups independently selected from Group Q. As the 3- to 10-membered heterocyclyl here, specifically, a pyrrolidinyl group, a piperazinyl group, a piperidinyl group, and a morpholinyl group are particularly preferable.

The R ₁₀ and the R ₁₁ may be the same or different, and each is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxyC. _1-4 alkyl, cyano (C _1-3 alkyl) or C _1-3 alkylsulfonyl C _1-4 alkyl, more preferably C _1-4 alkyl, C _2-6 alkynyl, or C _1-3 alkoxy. C _2-4 alkyl.

Alternatively, R ₁₀ and R ₁₁ are preferably taken together with the nitrogen atom to which they are attached to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl.

R ₁₂ and R ₁₃ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3. Alkoxy C _1-4 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 aryl C _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5- 10-membered heteroaryl C _1-3 alkyl, cyano (C _1-3 alkyl), C _1-3 alkylsulfonyl C _1-4 alkyl, or 3-10 membered alicyclic ring, more preferably hydrogen, C _1-4 alkyl, C _1-4 haloalkyl.

Alternatively, R ₁₂ and R ₁₃ are preferably substituted with one or more groups independently selected from group Q together with the nitrogen atom to which they are bonded. A 10-membered heterocyclyl or a 5-10 membered heteroaryl can be formed. Particularly preferred is a 3- to 10-membered heterocyclylalkyl, specifically a piperazinyl group, a morpholinyl group, a pyrrolidinyl group or a piperidinyl group.

Said R ₁₄ is preferably substituted with one or more groups independently selected from C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, group P. C _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q, more preferably C _1-4 alkyl and C _1-4 haloalkyl.

Said R ₁₅ is preferably substituted with one or more groups independently selected from C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, group P. Or an optionally substituted C _6-10 aryl, or a 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q.

Said R ₁₆ is preferably substituted with one or more groups independently selected from C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, group P. C _6-10 aryl, which may be substituted, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl optionally substituted with one or more groups independently selected from group Q, more preferably C _1-4 alkyl.

R ₁₇ is preferably hydrogen or C _1-4 alkyl, and more preferably hydrogen.

R ₁₈ is preferably substituted with one or more groups independently selected from C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, group P. C _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q, more preferably C _1-4 alkyl.

Said R ₁₉ is preferably one or more groups independently selected from hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, or group Q 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl optionally substituted with hydrogen, more preferably hydrogen or one or more groups independently selected from group Q 5-10 membered heteroaryl or 3-10 membered heterocyclyl. Specifically, the 3- to 10-membered heterocyclyl mentioned here is more preferably a piperazinyl group, a morpholinyl group, a pyrrolidinyl group, or a piperidinyl group.

Said R ₂₀ is preferably C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

Said R ₂₁ is preferably C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

Said R ₂₂ is preferably hydrogen, C _1-4 alkyl or C _1-4 haloalkyl.

R ₂₃ is preferably hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

Said R ₂₄ is preferably hydrogen, C _1-4 alkyl or C _1-4 haloalkyl.

Said R ₂₅ is preferably C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

R ₂₆ and R ₂₇ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3. Alkoxy C _1-4 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 aryl C _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5- 10-membered heteroaryl C _1-3 alkyl, cyano (C _1-3 alkyl), C _1-3 alkylsulfonyl C _1-4 alkyl, or 3-10 membered alicyclic ring.

Alternatively, R ₂₆ and R ₂₇ are preferably taken together with the nitrogen atom to which they are attached to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl.

R ₂₈ and R ₂₉ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3. Alkoxy C _1-4 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 aryl C _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5- 10-membered heteroaryl C _1-3 alkyl, cyano (C _1-3 alkyl), C _1-3 alkylsulfonyl C _1-4 alkyl, or 3-10 membered alicyclic ring.

Alternatively, R ₂₈ and R ₂₉ are preferably taken together with the nitrogen atom to which they are attached to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl.

Said R ₃₀ is preferably C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

Said R ₃₁ is preferably C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

R ₃₂ is preferably C _1-4 alkyl or C _6-10 aryl.

As the substituent contained in the P group, preferably, halogen, C _1-4 alkyl, C _1-4 haloalkyl, —OH, C _1-3 alkoxy, C _1-3 haloalkoxy, 3 to 10-membered heterocyclylamino, —SO ₂ R, —CN, —NO ₂ , or 3 to 10 membered heterocyclyl, and more preferably halogen, C _1-4 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, or 3 to 10 Heterocyclyl. Specifically, the 3- to 10-membered heterocyclyl referred to here is particularly preferably a morpholinyl group.

As the substituent contained in the Q group, preferably, halogen, C _1-4 alkyl, C _1-4 haloalkyl, —OH, C _1-3 alkoxy, C _1-6 monohydroxyalkyl, C _1-6 dihydroxyalkyl Or substituted with C _1-6 trihydroxyalkyl, 3-10 membered heterocyclylamino, —SO ₂ R, —CN, —NO ₂ , C _3-7 cycloalkyl, —COR ₁₉ , or C _1-4 alkyl. 3-10 membered heterocyclyl, more preferably halogen, C _1-4 alkyl, C _1-4 haloalkyl, —OH, C _1-3 alkoxy, C _1-6 monohydroxyalkyl, —SO ₂ R _16. , _{C 3-7} cycloalkyl, -COR ₁₉ or _{C 1-4} 3 to 10-membered heterocyclyl der which may be substituted by alkyl, . Specifically, the 3- to 10-membered heterocyclyl here is more preferably a piperazinyl group, a piperidinyl group, or a morpholinyl group.

Specific examples of the compound according to the present invention include the following compounds.
(1) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(2) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyrrolidin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(3) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-hydroxy-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(4) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrolo [3,2-c] pyridin-2-yl ) -Methanone;
(5) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-piperazin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(6) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-morpholin-4-yl-ethoxy) -1H -Indol-2-yl] -methanone;
(7) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (tetrahydro-pyran-4-yloxy) -1H-indole -2-yl] -methanone;
(8) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-chloro-1H-indol-2-yl) -methanone;
(9) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-1H-indol-2-yl) -methanone;
(10) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-iodo-1H-indol-2-yl) -methanone;
(11) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-5-carbonitrile;
(12) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-5-fluoro-1H-indol-2-yl) ) -Methanone;
(13) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-ethynyl-1H-indol-2-yl) -methanone;
(14) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(15) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(16) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(17) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-chloro-phenyl) -1H-indole-2 -Yl] -methanone;
(18) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-phenyl) -1H-indole-2 -Yl] -methanone;
(19) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-chloro-phenyl) -1H-indole-2 -Yl] -methanone;
(20) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(21) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(22) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(23) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-bromo-1H-indol-2-yl) -methanone;
(24) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(25) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methyl-1H-indol-2-yl) -methanone;
(26) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4,4-difluoro-piperidine-1-carbonyl) -1H-indol-2-yl] -methanone;
(27) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-piperidine-1-carbonyl) -1H-indol-2-yl] -methanone;
(28) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-5-carboxylic acid (2,2,2 -Trifluoro-ethyl) -amide;
(29) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(30) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(31) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-chloro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(32) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-methyl-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(33) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-4-fluoro-phenyl) -1H -Indol-2-yl] -methanone;
(34) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(35) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl] -methanone;
(36) [5-Amino-1- (6-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(37) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-6-carboxylic acid;
(38) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-hydroxymethyl-1H-indol-2-yl) -methanone ;
(39) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{6- [2- (4-methyl-piperazin-1-yl) ) -Ethoxy] -1H-indol-2-yl} -methanone;
(40) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-methyl-oxetan-3-ylmethoxy) -1H -Indol-2-yl] -methanone;
(41) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(42) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-{[bis- (2-methoxy-ethyl) -amino ] -Methyl} -1H-indol-2-yl) -methanone;
(43) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{6-[(methyl-prop-2-ynyl-amino)- Methyl] -1H-indol-2-yl} -methanone;
(44) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3,3-difluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(45) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2,5-dimethyl-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(46) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3,3-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(47) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-((S) -3-methyl-morpholine-4- Ylmethyl) -1H-indol-2-yl] -methanone;
(48) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-1H-indol-2-yl) -methanone;
(49) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-iodo-1H-indol-2-yl) -methanone;
(50) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrolo [3,2-b] pyridin-2-yl ) -Methanone;
(51) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-6-trifluoromethyl-1H-indole-2) -Yl) -methanone;
(52) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-iodo-1H-indol-2-yl) -methanone;
(53) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-methyl-1H-indol-2-yl) -methanone;
(54) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-isopropyl-1H-indol-2-yl) -methanone;
(55) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(56) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-benzyl-1H-indol-2-yl) -methanone;
(57) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(58) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3-fluoro-phenyl) -1H-indole-2 -Yl] -methanone;
(59) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(60) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-ethynyl-1H-indol-2-yl) -methanone;
(61) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5H- [1,3] dioxolo [4,5-f] Indol-6-yl) -methanone;
(62) [5-Amino-1- (7-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(63) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-trifluoromethyl-phenyl) -1H-indole -2-yl] -methanone;
(64) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-butoxy-1H-indol-2-yl) -methanone;
(65) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-methyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(66) N- {2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indol-6-yl} -methanesulfone An amide;
(67) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-morpholin-4-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(68) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-butyl-1H-indol-2-yl) -methanone;
(69) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (1-methyl-1H-pyrazol-4-yl) -1H-indol-2-yl] -methanone;
(70) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-methoxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(71) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-methoxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(72) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-cyclopropyl-1H-indol-2-yl) -methanone ;
(73) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-methoxy-phenyl) -1H-indole-2 -Yl] -methanone;
(74) 5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-phenyl-1H-indol-2-yl) -methanone;
(75) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-methanesulfonyl-pyridin-3-yl)- 1H-indol-2-yl] -methanone;
(76) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-isopropyl-1H-indol-2-yl) -methanone;
(77) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridin-2-yl-1H-indol-2-yl) ) -Methanone;
(78) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-cyclopropyl-1H-indol-2-yl) -methanone ;
(79) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridazin-3-yl-1H-indol-2-yl) ) -Methanone;
(80) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-isopropoxy-1H-indol-2-yl) -methanone ;
(81) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2-methoxy-ethoxy) -1H-indole-2 -Yl] -methanone;
(82) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-cyclopropylmethoxy-1H-indol-2-yl)- Methanone;
(83) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(2,2-difluoro-5H- [1,3] dioxolo [ 4,5-f] indol-6-yl) -methanone;
(84) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(85) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-fluoro-pyridin-2-yl) -1H -Indol-2-yl] -methanone;
(86) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-morpholin-4-yl-pyridazine-3- Yl) -1H-indol-2-yl] -methanone;
(87) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-chloro-6-cyclopropylmethoxy-1H-indole-2) -Yl) -methanone;
(88) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2,4-difluoro-phenyl) -1H-indole -2-yl] -methanone;
(89) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridazin-4-yl-1H-indol-2-yl) ) -Methanone;
(90) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(3-fluoro-1H-indol-2-yl) -methanone;
(91) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-isopropyl-piperidin-4-yl) -6 -Trifluoromethyl-1H-indol-2-yl] -methanone;
(92) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-6-carbonitrile;
(93) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1,2,3,6-tetrahydro-pyridine) 4-yl) -1H-indol-2-yl] -methanone;
(94) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-piperidin-4-yl-1H-indol-2-yl) ) -Methanone;
(95) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((R) -3-fluoro-pyrrolidine-1- Ylmethyl) -1H-indol-2-yl] -methanone;
(96) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-5-piperidin-4-yl-1H-indole -2-yl) -methanone;
(97) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-fluoro-5- (1-methyl-piperidine-4-yl) Yl) -1H-indol-2-yl] -methanone;
(98) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-isopropyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(99) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-fluoro-5- (1-isopropyl-piperidine-4-yl) Yl) -1H-indol-2-yl] -methanone;
(100) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridin-3-yl-1H-indol-2-yl) ) -Methanone;
(101) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-morpholin-4-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(102) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-pyridin-3-yl-1H-indol-2-yl) ) -Methanone;
(103) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-piperazin-1-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(104) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-hydroxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(105) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-fluoro-5- (4-methyl-piperazine-1- Ylmethyl) -1H-indol-2-yl] -methanone;
(106) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-5-pyrrolidin-1-ylmethyl-1H-indole -2-yl) -methanone;
(107) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (1-methyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(108) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-morpholin-4-yl-phenyl) -1H -Indol-2-yl] -methanone;
(109) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3,4,5,6-tetrahydro-2H- [1,2 ′] bipyridin-5′-yl) -1H-indol-2-yl] -methanone;
(110) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-piperazin-1-yl-pyridin-3- Yl) -1H-indol-2-yl] -methanone;
(111) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-methoxy-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(112) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((S) -3-methyl-morpholine-4- Ylmethyl) -1H-indol-2-yl] -methanone;
(113) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-((R) -3-fluoro-pyrrolidine-1- Ylmethyl) -1H-indol-2-yl] -methanone;
(114) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2,5-dimethyl-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(115) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(116) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(117) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{6- [2- (4-methyl-piperazin-1-yl) ) -Pyridin-4-yl] -1H-indol-2-yl} -methanone;
(118) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-pyridin-4-yl-1H-indol-2-yl) ) -Methanone;
(119) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(120) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4,4-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(121) [5-Amino-1- (2-difluoromethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-methyl-piperidin-4-yl)- 1H-indol-2-yl] -methanone;
(122) [5-Amino-1- (2-difluoromethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(123) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl] -methanone;
(124) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-cyclopentyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(125) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (1-cyclohexyl-piperidin-4-yl) -1H -Indol-2-yl] -methanone;
(126) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-bromo-1H-pyrrol-2-yl) -methanone;
(127) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrol-2-yl) -methanone;
(128) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-phenyl-1H-pyrrol-2-yl) -methanone;
(129) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (3-chloro-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(130) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (4-fluoro-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(131) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (3-fluoro-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(132) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl) ) -Methanone;
(133) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-morpholin-4-yl-ethylamino)- 1H-indol-2-yl] -methanone;
(134) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-methyl-piperazine-1-carbonyl) -1H -Indol-2-yl] -methanone;
(135) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-morpholin-4-yl-ethylamino)- 1H-indol-2-yl] -methanone;
(136) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (piperazine-1-carbonyl) -1H-indole-2 -Yl] -methanone;
(137) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-methoxy-ethylamino) -1H-indole- 2-yl] -methanone;
(138) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-hydroxy-1-hydroxymethyl-ethylamino) -1H-indol-2-yl] -methanone;
(139) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-pyridin-4-yl-ethylamino)- 1H-indol-2-yl] -methanone;
(140) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-methoxy-ethylamino) -1H-indole- 2-yl] -methanone;
(141) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-morpholin-4-yl-1H-indol-2-yl) ) -Methanone;
(142) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-morpholin-4-yl-1H-indol-2-yl) ) -Methanone;
(143) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-morpholin-4-ylmethyl-1H-indol-2-yl ) -Methanone;
(144) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-morpholin-4-ylmethyl-1H-indol-2-yl ) -Methanone;
(145) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (morpholine-4-carbonyl) -1H-indole-2 -Yl] -methanone;
(146) [5-Amino-1- (2-isopropyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(147) [5-amino-1- (2-propyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(148) [5-Amino-1- (1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(149) [5-Amino-1- (2-trifluoromethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(150) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(151) [5-Amino-1- (2-benzyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone;
(152) 1- (4- {2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indol-5-ylmethyl} -Piperazin-1-yl) -ethanone;
(153) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-methanesulfonyl-piperazin-1-ylmethyl)- 1H-indol-2-yl] -methanone;
(154) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-piperazin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(155) 1- (4- {2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indol-6-ylmethyl} -Piperazin-1-yl) -ethanone;
(156) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-methyl-piperazin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(157) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (4-methyl-piperazin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(158) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-pyrrolidin-1-ylmethyl-1H-indol-2-yl) ) -Methanone;
(159) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-fluoro-1H-indol-2-yl) -methanone;
(160) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-1H-indol-2-yl) -methanone;
(161) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-1H-indol-2-yl) -methanone;
(162) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-pyrrolo [2,3-b] pyridin-2-yl ) -Methanone;
(163) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-6-morpholin-4-ylmethyl-1H-indole -2-yl) -methanone;
(164) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-5-carboxylic acid;
(165) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methoxy-1H-indol-2-yl) -methanone;
(166) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-dimethoxy-1H-indol-2-yl)- Methanone;
(167) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-methoxy-1H-indol-2-yl) -methanone;
(168) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methoxy-1H-indol-2-yl) -methanone;
(169) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-dimethyl-1H-indol-2-yl)- Methanone;
(170) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-tert-butyl-1H-indol-2-yl)- Methanone;
(171) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-isopropyl-1H-indol-2-yl) -methanone;
(172) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-benzyloxy-1H-indol-2-yl) -methanone ;
(173) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-benzyloxy-1H-indol-2-yl) -methanone ;
(174) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5,6-dimethoxy-1H-indol-2-yl)- Methanone;
(175) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-tert-butyl-1H-indol-2-yl)- Methanone;
(176) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-4-trifluoromethyl-1H-indole-2) -Yl) -methanone;
(177) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-phenoxy-1H-indol-2-yl) -methanone;
(178) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methylsulfanyl-1H-indol-2-yl) -methanone ;
(179) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-tert-butyl-1H-indol-2-yl)- Methanone;
(180) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methyl-1H-indol-2-yl) -methanone;
(181) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-ethyl-1H-indol-2-yl) -methanone;
(182) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-fluoro-6-trifluoromethyl-1H-indole-2) -Yl) -methanone;
(183) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-fluoro-5-methoxy-1H-indol-2-yl) ) -Methanone;
(184) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-chloro-5-methoxy-1H-indol-2-yl) ) -Methanone;
(185) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-chloro-6-methoxy-1H-indol-2-yl) ) -Methanone;
(186) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-isopropoxy-1H-indol-2-yl) -methanone ;
(187) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-benzyloxy-1H-indol-2-yl) -methanone ;
(188) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-isopropoxy-1H-indol-2-yl) -methanone ;
(189) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(2,3-dihydro-6H- [1,4] dioxino [ 2,3-f] indol-7-yl) -methanone;
(190) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-di-tert-butyl-1H-indole-2 -Yl) -methanone;
(191) 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-4-carbonitrile;
(192) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-imidazol-1-yl-1H-indol-2-yl) ) -Methanone;
(193) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethylsulfanyl-1H-indol-2-yl) -Methanone;
(194) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methylsulfanyl-1H-indol-2-yl) -methanone ;
(195) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-methanesulfonyl-1H-indol-2-yl) -methanone ;
(196) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4,4-difluoro-piperidin-1-ylmethyl) 1H-indol-2-yl] -methanone;
(197) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-fluoro-piperidin-1-ylmethyl) -1H -Indol-2-yl] -methanone;
(198) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (oxetane-3-yloxy) -1H-indole-2 -Yl] -methanone;
(199) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl) -methanone;
(200) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methanesulfonyl-1H-indol-2-yl) -methanone ;
(201) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-dibromo-1H-pyrrol-2-yl)- Methanone;
(202) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-diphenyl-1H-pyrrol-2-yl)- Methanone;
(203) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-di-pyridin-3-yl-1H-pyrrole -2-yl) -methanone;
(204) [5-Amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-chloro-1H-indol-2-yl) -methanone;
(205) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-chloro-1H-indol-2-yl) -methanone;
(206) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-3-yl) -methanone;
(207) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-6-yl) -methanone;
(208) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-6-fluoro-1H-indol-2-yl) ) -Methanone;
(209) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-bromo-6-fluoro-1H-indol-2-yl) ) -Methanone;
(210) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethyl-1H-indol-2-yl)- Methanone;
(211) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethoxy-1H-indol-2-yl)- Methanon v
(212) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-dichloro-1H-indol-2-yl)- Methanone;
(213) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-4-fluoro-1H-indol-2-yl) ) -Methanone;
(214) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-trifluoromethoxy-1H-indol-2-yl)- Methanone;
(215) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethoxy-1H-indol-2-yl)- Methanone;
(216) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-trifluoromethyl-1H-indol-2-yl)- Methanone;
(217) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5,6-dichloro-1H-indol-2-yl)- Methanone;
(218) [5-Amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-bromo-5-fluoro-1H-indol-2-yl) ) -Methanone;
(219) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-dichloro-1H-indol-2-yl)- Methanone;
(220) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,6-difluoro-1H-indol-2-yl)- Methanone;
(221) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-chloro-pyridin-4-yl) -1H -Indol-2-yl] -methanone;
(222) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (6-methyl-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(223) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-fluoro-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(224) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-trifluoromethyl-pyridin-3-yl) -1H-indol-2-yl] -methanone;
(225) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-chloro-2-methoxy-pyridine-3- Yl) -1H-indol-2-yl] -methanone;
(226) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (5-chloro-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(227) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-thiophen-3-yl-1H-indol-2-yl) ) -Methanone;
(228) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-chloro-pyridin-3-yl) -1H -Indol-2-yl] -methanone;
(229) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-thiophen-2-yl-1H-indol-2-yl) ) -Methanone;
(230) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (3-fluoro-pyridin-4-yl) -1H -Indol-2-yl] -methanone;
(231) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (2-trifluoromethyl-pyridin-4-yl) -1H-indol-2-yl] -methanone;
(232) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3-difluoro-pyrrolidin-1-carbonyl) -1H-indol-2-yl] -methanone;
(233) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (2,6-dimethyl-morpholine-4-carbonyl) -1H-indol-2-yl] -methanone;
(234) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-([1,4 ′] bipiperidinyl-1′-carbonyl ) -1H-indol-2-yl] -methanone;
(235) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{5- [4- (2,2,2-trifluoro- Ethyl) -piperazine-1-carbonyl] -1H-indol-2-yl} -methanone;
(236) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-{5- [4- (2-hydroxy-ethyl) -piperazine- 1-carbonyl] -1H-indol-2-yl} -methanone;
(237) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (3,3,4,4-tetrafluoro-pyrrolidine -1-carbonyl) -1H-indol-2-yl] -methanone;
(238) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((R) -3-fluoro-pyrrolidine-1- Carbonyl) -1H-indol-2-yl] -methanone;
(239) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-((S) -3-fluoro-pyrrolidine-1- Carbonyl) -1H-indol-2-yl] -methanone;
(240) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (4-methoxy-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(241) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (3-methoxy-phenyl) -1H-pyrrole-2 -Yl] -methanone;
(242) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4,5-bis- (3-fluoro-phenyl) -1H -Pyrrol-2-yl] -methanone;
(243) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4,5-bis- (4-methoxy-phenyl) -1H -Pyrrol-2-yl] -methanone;
(244) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2,4-difluoro-phenyl) -1H-pyrrole -2-yl] -methanone;
(245) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (4-trifluoromethoxy-phenyl) -1H-pyrrole -2-yl] -methanone;
(246) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4,5-bis- (3-methoxy-phenyl) -1H -Pyrrol-2-yl] -methanone;
(247) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -benzofuran-2-yl-methanone;
(248) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -benzo [b] thiophen-2-yl-methanone;
(249) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -benzothiazol-2-yl-methanone;
(250) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4-fluoro-phenyl) -methanone;
(251) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(3-chloro-phenyl) -methanone;
(252) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -quinolin-3-yl-methanone;
(253) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -quinolin-7-yl-methanone; and (254) [5-amino -1- (2-Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -quinolin-6-yl-methanone.

  Such a compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is useful as a compound having an inhibitory action on a fibroblast growth factor receptor (FGFR) family kinase, (For example, breast cancer, acute myeloid leukemia, pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, angiogenesis, stomach cancer, endometrial cancer, ovarian cancer, brain tumor (including glioblastoma), colon cancer, multiple bone marrow For the prevention and / or treatment of tumors, hepatocellular carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer) and thyroid cancer).

  The compound according to the present invention or a salt thereof is converted into a tablet, powder, fine granule, granule, coated tablet, capsule, syrup, troche, inhalant, suppository, injection, ointment by a conventional method. , Ointments, eye drops, nasal drops, ear drops, poultices, lotions and the like. Excipients, binders, lubricants, colorants, flavoring agents, and if necessary stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, Antioxidants and the like can be used. In general, ingredients that are used as raw materials for pharmaceutical preparations are blended to prepare a preparation by a conventional method.

  For example, in order to produce an oral preparation, the compound according to the present invention or a pharmacologically acceptable salt and excipient thereof, and optionally a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent. After adding the agent, etc., it is made into powders, fine granules, granules, tablets, coated tablets, capsules, etc. by conventional methods.

  Examples of these components include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; cetostearyl alcohol and behenyl alcohol Higher alcohols; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers Water-soluble such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methylcellulose Molecules; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate Body and purified water.

  Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like.

  Examples of the binder include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol, polyoxyethylene block polymer, meglumine, and the like. It is done.

  Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium and the like.

  Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like.

  As coloring agents, those permitted to be added to pharmaceuticals are used, and as flavoring agents, cocoa powder, mint brain, fragrance powder, mint oil, dragon brain, cinnamon powder, and the like are used.

  Of course, these tablets and granules may be appropriately coated with sugar coating or other necessary. Further, when producing a liquid preparation such as a syrup or an injectable preparation, a compound according to the present invention or a pharmacologically acceptable salt thereof, a pH adjuster, a solubilizer, an isotonic agent, etc. are necessary. Add a solubilizing agent, stabilizer, etc. accordingly, and formulate it by a conventional method. For example, injectable formulations contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such a pharmaceutical composition comprises further additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, antioxidants, buffers, absorption enhancers or solubilizers. May be included. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use. A solution that may contain these adjuvants and the like may be stored in a container and then prepared as a solid preparation by lyophilization or the like. Moreover, the single dose may be stored in one container, and the multiple doses may be stored in one container.

  The method for producing the external preparation is not limited and can be produced by a conventional method. That is, as a base material used for formulation, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics, and the like can be used. Specific examples of base materials to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, Examples include raw materials such as water-soluble polymers, clay minerals, and purified water. If necessary, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, etc. may be added. However, the base material of the external preparation according to the present invention is not limited thereto.

  Moreover, components having differentiation-inducing action, blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, and the like can be blended as necessary. In addition, the addition amount of the said base raw material is an amount used as the density | concentration normally set in manufacture of an external preparation.

  When the compound according to the present invention or a salt thereof or a hydrate thereof is administered, the form is not particularly limited, and it may be administered orally or parenterally by a commonly used method. For example, tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions, etc. It can be formulated and administered as an agent.

  The dosage of the medicament according to the present invention can be appropriately selected according to the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, and the like.

  The dose varies significantly depending on the patient's disease type, symptom severity, patient age, sex difference, sensitivity to drugs, etc., but is usually about 0.03-1000 mg per day as an adult, preferably 0.1- 500 mg, more preferably 0.1-100 mg, is administered in 1 to several divided doses per day. In the case of an injection, it is usually about 1 μg / kg-3000 μg / kg, preferably about 3 μg / kg-1000 μg / kg.

  In addition, the pharmaceutical composition of the present invention includes one or more drugs selected from other chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents or molecular target drugs (hereinafter sometimes abbreviated as concomitant drugs) and You may use it in combination. These active ingredients may be low molecular weight compounds, may be high molecular weight proteins, polypeptides, antibodies, or vaccines. Two or more active ingredients may be mixed and used at an appropriate ratio.

  For example, examples of the “chemotherapeutic agent” include alkylating agents, platinum preparations, antimetabolites, topoisomerase inhibitors, anticancer antibiotics, plant-derived anticancer agents and the like. Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, altretamine, ambmustine, dibrospdium hydrochloride, fotemustine, predonimustine, pumitepa, ribomustine, temosofredomestre , Trophosphamide, Dinostatin styramer, Carbocon, Adzelesin, Systemustin, Vizeresi And the like. Examples of the “platinum preparation” include carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin and the like. Examples of the “antimetabolite” include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine okphosphat, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, garocitabine, emiteful, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritroxime, idoxyuridine, mitoxifridin , And ambamustine. Topoisomerase I inhibitors (eg, irinotecan, topotecan, etc.), topoisomerase II inhibitors (eg, sobuzoxane, etc.), and “anticancer antibiotics” include, for example, anthracycline anticancer agents (doxorubicin hydrochloride, daunorubicin hydrochloride, hydrochloric acid hydrochloride) Actinubicin, pirarubicin hydrochloride, epirubicin hydrochloride, etc.), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, neocartinostatin, mythramycin, sarcomycin, carcinophilin, mitotane, Zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like can be mentioned. Examples of “plant-derived anticancer agents” include vinca alkaloid anticancer drugs (vinblastine sulfate, vincristine sulfate, vindesine sulfate, etc.), taxane anticancer drugs (paclitaxel, docetaxel, etc.), etoposide, etoposide phosphate, teniposide, vinorelbine, etc. Is mentioned.

  Examples of the “hormone therapeutic agent” include adrenocortical hormone drugs (eg, dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), and prednisolone is particularly preferable.

  Examples of the “immunotherapeutic agent (BRM)” include, for example, picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, lymphotoxin, BCG vaccine, corynebacterium parvum , Levamisole, polysaccharide K, procodazole and the like.

  The “molecular target drug” includes “a drug that inhibits the action of a cell growth factor and its receptor” and the like, and any “cell growth factor” may be used as long as it promotes cell growth. In general, a peptide having a molecular weight of 20,000 or less includes a factor that exerts an action at a low concentration by binding to a receptor. Specifically, (1) EGF (epidermal growth factor) or substantially (Eg, EGF, haregulin (HER2 ligand), etc.), (2) insulin or a substance having substantially the same activity [eg, insulin, IGF (insulin-like growth factor) -1 , IGF-2, etc.], (3) FGF (fibroblast growth factor) or a substance having substantially the same activity [eg, acidic FGF, basic FGF, KGF (keratinocyte growth fact] or), FGF-10, etc.], (4) VEGF (vascular endothelial growth factor), (5) Other cell growth factors [eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2) ), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factorβ), HGF (hepatocyte growth factor), ALK (anaplastic lymphoma kinase) and the like.

The “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, and specifically includes an EGF receptor, a haregulin receptor (HER2). Insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, HGF receptor (c-met), VEGF receptor, SCF receptor (c-kit) and the like. Examples of the “drug that inhibits the action of cell growth factor” include Herceptin (HER2 antibody), GLEEVEC (c-kit, abl inhibitor), Iressa (EGF receptor inhibitor) and the like.
Also included are drugs that inhibit the action of multiple cell growth factors with a single drug, and drugs that block intracellular information emitted by cell growth factors. In addition to the above drugs, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin / cobalt complex, mercury hematoporphyrin / sodium, differentiation inducer (eg, retinoid, vitamin D), angiogenesis inhibitor, α-blocker (Eg, tamsulosin hydrochloride, etc.) can also be used.
Among the above-mentioned combination drugs, platinum complexes (eg, carboplatin, cisplatin, oxaliplatin, etc.), antimetabolites (eg, gemcitabine, pemetrexed, etc.), topoisomerase I inhibitors (eg, irinotecan, topotecan, etc.), plant-derived Anticancer drugs (taxane drugs (eg, paclitaxel, docetaxel), vinorelbine), anticancer antibiotics (eg, mitomycin C), etc., hormone therapy drugs (eg, prednisolone), immunotherapy drugs (eg, picibanil, krestin, etc.) ), Molecular target drugs (eg, anti-VEGF antibodies such as bevacizumab, EGFR inhibitors such as erlotinib, and VEGFR inhibitors such as sunitinib) are preferred. Furthermore, cisplatin, gemcitabine, paclitaxel, bevacizumab and the like are preferable. It can also be used in combination with a combination therapy of these drugs. Examples include cisplatin and vinblastine and mitomycin C, cisplatin and vinorelbine, cisplatin and paclitaxel, cisplatin and gemcitabine, carboplatin and paclitaxel, pemetrexed and cisplatin, bevacizumab and cisplatin and pemetrexed.

  The administration timing of the solid preparation and the concomitant drug of the present invention is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, you may administer the solid formulation and concomitant drug of this invention to an administration subject as a single formulation containing these. For example, there are multi-drug combination therapy in which a plurality of drugs are combined and infused over 3 to 6 months, and a method of taking an oral preparation for about 2 years.

  In addition, preoperative adjuvant therapy such as “chemotherapy” may be performed before surgery to suppress cancer cells that have already spread and prevent recurrence due to metastasis or to reduce the scope of surgery.

  Furthermore, local treatment such as surgery or radiation is not enough, and postoperative adjuvant therapy such as "chemotherapy" may be performed to suppress the growth of remaining cancer cells and prevent recurrence due to metastasis. is there.

  Furthermore, the anticancer agent used in combination acts on normal cells as well as cancer cells, which appears as a side effect. Typical side effects include nausea, vomiting, loss of appetite, stomatitis, diarrhea or constipation due to disorders of the digestive mucosa, taste abnormalities, decreased white blood cells / red blood cells / platelets due to bone marrow disorders, loss of immunity, etc Further, side effect reducing drugs for suppressing these can be used in combination. Examples thereof include an antiemetic agent that effectively suppresses nausea (eg, granisetron hydrochloride), a drug that accelerates recovery from bone marrow injury (eg, erythropoietin, G-CSF, GM-CSF) and the like.

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the solid preparation of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the solid preparation.

  In the production of the compounds according to the present invention, the raw material compounds and various reagents may form salts, hydrates or solvates, all of which vary depending on the starting materials, the solvent used, etc., and inhibit the reaction. It is not particularly limited as long as it is not.

  It goes without saying that the solvent to be used is not particularly limited as long as it varies depending on starting materials, reagents and the like, and can dissolve the starting material to some extent without inhibiting the reaction.

  Various isomers (eg geometric isomers, optical isomers based on asymmetric carbon, rotational isomers, stereoisomers, tautomers, etc.) can be obtained by conventional separation means such as recrystallization, diastereomeric salt methods. In addition, it can be purified and isolated by using an enzyme resolution method and various types of chromatography (for example, thin layer chromatography, column chromatography, high performance liquid chromatography, gas chromatography, etc.).

  When the compound concerning this invention is obtained as a free body, it can convert into the state of the salt which the said compound may form, or those hydrates according to a conventional method. Moreover, when the compound concerning this invention is obtained as the salt or hydrate of the said compound, it can convert into the free body of the said compound according to a conventional method.

  Isolation and purification of the compound according to the present invention can be carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.

  All prior art documents cited herein are hereby incorporated by reference.

The general production methods and examples of the compounds of the present invention are shown below.
The compounds of the present invention can be synthesized by various methods, some of which are illustrated in the following schemes. The scheme is exemplary and the invention is not limited to only the explicit chemical reactions and conditions. In the following schemes, some substituents may be excluded for clarity, but these are not intended to limit the disclosure of the scheme. The representative compounds of the present invention can be synthesized using appropriate intermediates, known compounds, and reagents.

Preparation of Compounds of Formula (I) Scheme A describes a method for preparing compounds of formula (I).
Here, in the following schemes and general production methods, definitions of R _{1 and the} like are as shown in each scheme and general production method, and R _{33 to} R ₃₇ are defined as follows:
R ₃₃ represents an alkyl group.
R ₃₄ and R ₃₅ represent an alkyl group, or a plurality of R ₃₄ or a plurality of R ₃₅ together form a ring.
R ₃₆ represents an alkyl group, or a plurality of R ₃₆ together form a ring.
R ₃₇ represents an alkyl group or an aryl group.

Scheme A
The compound of the formula (I) in which R ₁ , R ₂ , R ₃ and R ₄ have the same meaning as the compound represented by the general formula (I) can be prepared by the method described below.

  The 2-ketoacetonitrile of formula (2) is obtained by reaction of the carboxylic acid ester of formula (1) with the acetonitrile anion generated by the basic action of acetonitrile.

Compounds of formula (1) are commercially available or can be prepared by methods well known in the art. For example, indole-2-carboxylic acid ethyl ester, benzofuran-2-carboxylic acid ethyl ester, benzothiophene-2-carboxylic acid methyl ester, pyrrole-2-carboxylic acid methyl ester, quinoline-6-carboxylic acid methyl ester Formula (1) aryl / heteroaryl carboxylic acid esters are commercially available. Others can be prepared by heating the corresponding carboxylic acid in alcohol (R ₃₃ OH) in the presence of an acid (such as sulfuric acid). Alternatively, a methyl ester of formula (1) in which R ₃₃ is a methyl group can be prepared by reaction with trimethylsilyldiazomethane or diazomethane in a solvent (eg, dichloromethane, methanol, etc.).

  Compounds of formula (2) can be prepared by methods well known in the art. It can be prepared by treating acetonitrile with a base (eg, lithium diisopropylamide, n-butyllithium, etc.) followed by reaction of the resulting acetonitrile anion with an aryl / heteroaryl carboxylic acid ester.

  Compounds of formula (3) can be prepared by methods well known in the art. By reacting 2-ketoacetonitrile of the formula (2) and N, N-dimethylformamide dimethylacetal in a solvent (for example, toluene, tetrahydrofuran, etc.), the 2-keto-3-dimethylamino-acrylonitrile of the formula (3) is reacted. Can be prepared.

  Compounds of formula (4) can be prepared by methods well known in the art. By reacting 2-ketoacetonitrile of the formula (2) and trialkylorthoformate in a solvent (for example, acetonitrile, chloroform, acetic anhydride, etc.) under heating, the 2-keto-3-form of the formula (4) is reacted. Alkoxy-acrylonitrile can be prepared.

  Compounds of formula (I) can be prepared by methods well known in the art. 2-keto-3-dimethylamino-acrylonitrile of formula (3) and benzimidazol-5-yl-hydrazine of formula (5) in the presence or absence of a base (eg triethylamine, pyridine, etc.) By reacting in (e.g. ethanol, N, N-dimethylacetamide, etc.) or 2-keto-3-alkoxy-acrylonitrile of formula (4) and benzimidazol-5-yl-hydrazine of formula (5) Or a hydrazine-protected compound of the formula (5) (for example, N-benzhydrylidene-N ′-(2-methyl-1H-benzoimidazol-5-yl) -hydrazine, N ′-(2-methyl-1H -Benzimidazol-5-yl) -hydrazinecarboxylic acid tert-butyl ester, N-tert-butoxycarbonyl-N '-(2-me 1H-benzimidazol-5-yl) -hydrazinecarboxylic acid tert-butyl ester, etc.) in the presence or absence of a base (eg, triethylamine, pyridine, etc.) in a solvent (eg, ethanol, N, N— The 5-amino-ketopyrazole of formula (I) can be prepared by reacting in dimethylacetamide and the like).

  In some cases, the synthesis of a compound having an NH group such as indole or pyrrole in the A ring uses an ester of the formula (1) in which the NH group is protected, and the formula (3) or the formula (4) and the formula ( After forming the aminopyrazole ring by the reaction of 5), deprotection is performed to obtain the formula (I) in which the A ring has an NH group.

  As the indole protecting group, an arylsulfonyl group (for example, a benzenesulfonyl group, a toluenesulfonyl group, etc.) and the like can be used.

  Formula (1) in which A ring is an indole ring protected with an arylsulfonyl group is obtained by converting Formula (I) in which A ring is an unprotected indole in the presence of a base (for example, sodium hydride, diisopropylethylamine, etc.) It can be obtained by reacting arylsulfonyl chloride (eg, benzyl halide, p-methoxybenzyl halide, etc.) in a solvent (eg, tetrahydrofuran, dimethylformamide, etc.).

  As the protecting group for pyrrole, a benzyl group (for example, benzyl group, p-methoxybenzyl group, etc.) and the like can be used. Formula (1) in which A is a pyrrole ring protected with a benzyl group is obtained by reacting Formula (I) in which A is an unprotected pyrrole in a solvent (eg, tetrahydrofuran, dimethylformamide, etc.) with a benzyl halide (eg, Benzyl chloride, benzyl bromide, 4-methoxybenzyl bromide and the like) can be obtained.

When the compounds of formula (1) with _{R 1,} or _{R 2} of interest is not commercially available and has a _{R 1,} or _{R 2} is an object with the following methods from (a) (y), formula ( After synthesizing the ester of 1), formula (I) can be synthesized in the same manner as in Scheme A. Or, convertible substituents R _1, or a compound of formula (I) with R ₂ after synthesizing, by converting the substituent R ₁ of _interest, or R _2, may be synthesized.

Transformation of substituents R ₁ and R ₂ can be prepared by either method (a) or (y) described below.

Method (a)
The compound of formula (I), wherein R ₁ is ether (—OR ₅ ), is obtained by Mitsunobu reaction of a compound of formula (6), wherein R ₁ is a hydroxyl group, with an alcohol (R ₅ OH) or a base is present The compound can be prepared by an etherification reaction between the compound of the formula (6) in which R ₁ is a hydroxyl group and R ₅ X having a leaving group X such as a halogen or an alkylsulfonyloxy group.

Alternatively, the ester of formula (1) in which R ₁ is ether (—OR ₅ ) is the Mitsunobu of the ester of formula (7) and alcohol (R ₅ OH), wherein R ₁ has a hydroxyl group. It can be prepared by an etherification reaction between the ester of formula (7) and R ₅ X having a leaving group X such as halogen or an alkylsulfonyloxy group in the presence of a reaction or a base.

R ₁ is an ether (-OR _5), with an ester of formula (1), in a manner similar to Scheme A, _{R 1} is an ether (-OR _5), formula (I) Compounds can be prepared.

Mitsunobu reaction generally involves a compound having a hydroxyl group and an alcohol (R ₅ OH), an azo compound (eg, diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.), phosphine (eg, triphenylphosphine, tri-n-butyl). Phosphine etc.) in the presence of a solvent (eg tetrahydrofuran, dioxane etc.).

The etherification reaction generally involves reacting a compound having a hydroxyl group with R ₅ X having a leaving group X such as a halogen or alkylsulfonyloxy group in the presence of a base (eg, sodium hydride, potassium carbonate, etc.) , Dimethylformamide, tetrahydrofuran, etc.).

Method (b)
The compound of the formula (I) in which R ₁ is an amino group (NR ₆ R ₇ ) is obtained from a compound of the formula (8) having a halogen from a base (for example, cesium carbonate, tert-butyloxy sodium, phosphoric acid) Potassium), a ligand (eg, N, N-dimethylglycine, 1,10-phenanthroline, tri-tert-butylphosphine, etc.) in the presence of a copper catalyst (eg, copper iodide) or a palladium catalyst (eg, acetic acid). It can be adjusted by reacting with amine (NR ₆ R ₇ ) at room temperature or under heating in a solvent (for example, dimethyl sulfoxide, dimethylformamide, toluene, dioxane, etc.) using palladium.

Method (c)
The compound of formula (I), wherein R ₁ is an aminomethyl group (— (CR ₈ R ₉ ) _n Z ₁ , R ₈ = R ₉ = H), is a compound of formula (9) having an aldehyde group It can be obtained by reductive amination with an amine (NHR ₈ R ₉ ). Alternatively, by reductive amination of the ester of formula (10) having an aldehyde group and an amine (NHR ₈ R ₉ ), R ₁ is converted to an aminomethyl group (— (CR ₈ R ₉ ) _n Z ₁ , R The ester body of the formula (1) in which ₈ = R ₉ = H) can be obtained. R ₁ is an aminomethyl group (— (CR ₈ R ₉ ) _n Z ₁ , R ₈ = R ₉ = H). A compound of formula (I) in which ₁ is an aminomethyl group (— (CR ₈ R ₉ ) _n Z ₁ , R ₈ = R ₉ = H) can be obtained.

The reductive amination reaction generally involves aldehyde and amine (NHR ₈ R ₉ ) in a solvent (eg, dichloromethane, 1,2-dichloroethane, methanol, etc.), optionally in the presence of an acid (eg, acetic acid, etc.) From room temperature to room temperature using a reducing agent (eg, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc.).

Method (d)
A compound of formula (I) wherein R ₁ is an amide (CONR ₁₂ R ₁₃ ) is prepared by reacting a carboxylic acid of formula (11) with an amine (NHR ₁₂ R ₁₃ ) in the presence of a condensing agent. Can do.

In general, the synthesis of amides involves converting a carboxylic acid to an acyl halide or activated ester with a halogenating agent (eg, thionyl chloride, oxalyl chloride, etc.) or an activator (eg, ethyl chloroformate, etc.). , By reacting an amine (NHR ₁₂ R ₁₃ ) in a solvent (eg, tetrahydrofuran, dimethylformamide, dichloromethane, etc.).

Alternatively, an active ester is synthesized after a carboxylic acid is synthesized with a condensing agent (eg, dicyclohexylcarbodiimide, etc.) in the presence of a base (eg, triethylamine) in a solvent (eg, tetrahydrofuran, dimethylformamide, dichloromethane, etc.), and then an amine. It is performed by treating with (NHR ₁₂ R ₁₃ ).

Method (e)
A compound of formula (I) wherein R ₁ is sulfide (—SR ₁₄ ) is a compound of formula (8) having a halogen and a thiol with a base (eg, cesium carbonate, lithium hexamethyldisilazide, potassium phosphate Etc.), and in the presence of a catalyst (eg, copper iodide, palladium acetate, etc.), in a solvent (eg, dimethyl sulfoxide, 1,2-dimethoxyethane, etc.), the reaction can be performed by heating.

The ester of formula (1), wherein R ₁ is sulfide (—SR ₁₄ ), the ester of formula (12) having a halogen and a thiol, a base (eg, cesium carbonate, lithium hexamethyldisilazide, potassium phosphate) Etc.), and in the presence of a catalyst (eg, copper iodide, palladium acetate, etc.), in a solvent (eg, dimethyl sulfoxide, 1,2-dimethoxyethane, etc.), the reaction can be performed by heating.

Alternatively, the ester of formula (12) is reacted with a base (eg, n-butyllithium, etc.) in a solvent (eg, diethyl ether, tetrahydrofuran, etc.) at a low temperature (−80 ° C. to 0 ° C.), and then an alkyl sulfide. Alternatively, it can be prepared by reacting a dialkyl disulfide. R ₁ is a sulfide _{(-SR 14),} with an ester of formula (1), in Scheme A the same way, _{R 1} is a sulfide _{(-SR 14),} the compound of formula (I) Can be prepared.

Method (f)
The compound of formula (I), wherein R ₁ is sulfoxide (—SO ₂ R ₁₅ ), has the sulfide group (—SR ₁₅ ), the compound of formula (13) in a solvent (eg, dichloromethane, methanol, water, etc.) ), An oxidizing agent (for example, m-chloroperbenzoic acid, oxone, hydrogen peroxide, etc.).

Method (g)
A compound of formula (I), wherein R ₁ is sulfone (—SO ₂ R ₁₆ ), is a compound of formula (14) having sulfide (—SR ₁₆ ) in a solvent (eg, dichloromethane, methanol, water, etc.) It can be prepared by treatment with an oxidizing agent (for example, m-chloroperbenzoic acid, oxone, hydrogen peroxide, etc.).

An ester of formula (1) wherein R ₁ is a sulfone (—SO ₂ R ₁₆ ) is obtained by reacting a sulfide of formula (15) in a solvent (eg, dichloromethane, methanol, water, etc.) and an oxidizing agent (eg, m- (Chloroperbenzoic acid, oxone, hydrogen peroxide, etc.). R ₁ is a sulfonic _{(-SO 2 R 16),} where an ester of formula (1), in a manner similar to Scheme A, _{R 1} is a sulfone _{(-SO 2 R 16),} formula ( Compounds of I) can be prepared.

Method (h)
The compound of formula (I), wherein R ₁ is an alkylsulfonamide (—NR ₁₇ SO ₂ R ₁₈ ), is an alkyl or arylsulfone in the presence of a metal such as formula (8) and copper, wherein R ₁ is halogen. It can be prepared by reaction with an amide (HNR ₁₇ SO ₂ R ₁₈ ). Alternatively, it can be prepared by reacting the formula (16) having an amino group (—NHR ₁₇ ) with an alkyl or arylsulfonyl halide or the like.

Or, R ₁ is an alkylsulfonamide (—NR ₁₇ SO ₂ R ₁₈ ), and the ester of the formula (1) has a halogen, an ester of the formula (12) and a metal such as copper, It can be prepared by reaction with an arylsulfonamide (HNR ₁₇ SO ₂ R ₁₈ ). Alternatively, it can be prepared by reacting an ester of formula (17) having an amino group (—NHR ₁₇ ) with an alkyl or arylsulfonyl halide or the like. R ₁ is an alkyl sulfonamide _{(-NR 17 SO 2 R 18)} , where an ester of formula (1), in Scheme A the same way, _{R 1} is an alkyl sulfonamide _(-NR 17 SO A compound of formula (I) can be prepared which is ₂ R ₁₈ ).

  In general, synthesis from a halogen compound consists of a halogen compound and an alkyl or aryl sulfonamide as a base (eg, cesium carbonate, potassium phosphate, etc.), a catalyst (eg, palladium acetate, copper iodide, etc.), and optionally a ligand (eg, , Tri-t-butylphosphine, N, N-dimethylglycine, etc.) in the presence of a solvent (for example, dioxane, toluene, dimethylformamide, etc.).

  In general, a synthesis from an amine compound can be prepared by reacting an amine compound and an alkyl or arylsulfonyl halide in the presence of a base (eg, triethylamine) in a solvent (eg, dichloromethane).

Method (i)
A compound of formula (I) wherein R ₁ is aryl or heteroaryl is a compound of formula (8) having a halogen and an aryl boronic acid, heteroaryl boronic acid, or aryl boronic acid ester, heteroaryl boronic acid ester It can be prepared by the Suzuki coupling reaction.

Alternatively, the ester of formula (1) in which R ₁ is aryl or heteroaryl is an ester of formula (12) and an arylboronic acid, heteroarylboronic acid, arylboronic acid ester, heterozygote having halogen It can be prepared by a Suzuki coupling reaction with an aryl boronic ester. R ₁ is aryl or heteroaryl, with an ester of formula (1), in a manner similar to Scheme A, R ₁ is an aryl or heteroaryl, to prepare a compound of formula (I) be able to.

  In general, the Suzuki coupling reaction involves reacting an aryl halide or heteroaryl halide with an aryl boronic acid, heteroaryl boronic acid, or aryl boronic acid ester, heteroaryl boronic acid ester with a base (eg, potassium phosphate, Cesium carbonate, etc.) and a catalyst (eg, palladium acetate, tetrakistriphenylphosphine, etc.) in the presence of a solvent (eg, dioxane, toluene, etc.).

Method (j)
A compound of formula (I) wherein R ₁ is a cyano group can be prepared by reaction of a compound of formula (8) having halogen (X) with a cyanide compound such as copper cyanide.
In general, a cyanation reaction is performed by using a halogen compound, an alkylsulfonyloxy compound, or an arylsulfonyloxy compound and a cyanating agent (for example, cuprous cyanide, potassium cyanide, etc.) as a solvent (for example, dimethylformamide, N-methyl). Pyrrolidone etc.) by heating.

Method (k)
The compound of formula (I), wherein R ₁ is an alkyl group, is obtained by Suzuki reaction of a compound of formula (8) having halogen and an alkyl boronic acid, alkyl boronic acid ester, or boron trifluoride alkyl complex. Can be prepared.

The ester of formula (1) in which R ₁ is an alkyl group is obtained by Suzuki reaction of an ester of formula (12) with an alkyl boronic acid, an alkyl boronic acid ester, or a boron trifluoride alkyl complex having a halogen. Can be prepared. R ₁ is an alkyl group, with an ester of formula (1), in a manner similar to Scheme A, R ₁ is an alkyl group, it is possible to prepare compounds of formula (I).

  In general, the Suzuki reaction is performed by using a halogen compound and a boron derivative (eg, alkyl boronic acid, alkyl boronic acid ester, boron trifluoride alkyl complex, etc.) and a base (eg, potassium carbonate, potassium phosphate, etc.) solvent (eg, xylene, A mixture of toluene, dimethylformamide, dioxane, tetrahydrofuran, etc.) is heated by adding a ligand (for example, triphenylphosphine) in the presence of a palladium catalyst (for example, palladium acetate) in some cases.

Method (l)
A compound of formula (I) wherein R ₁ is a perfluoroalkyl group can be prepared by reaction of a compound of formula (8) with a halogen and a perfluoroalkylating agent. Esters of formula (12) wherein R ₁ is a perfluoroalkyl group can be prepared by reaction of an ester of formula (11) with a perfluoroalkylating agent having a halogen. R ₁ is a perfluoroalkyl group, with an ester of formula (1), in a manner similar to Scheme A, wherein R ₁ is is a perfluoroalkyl group, to prepare a compound of formula (I) be able to.

  In general, perfluoroalkylation involves a halogen compound, copper (eg, copper, cuprous iodide, etc.) and a perfluoroalkylating agent (potassium perfluoroalkylcarboxylate, triethylsilylperfluoroalkyl, perfluoroalkyl iodide, etc.) in a solvent (eg, , Dimethyl sulfoxide, dimethylformamide, etc.).

Method (m)
Compounds of formula (I) wherein R ₁ is an alkynyl group can be prepared by the Sonogashira reaction of formula (8) with halogen.

Esters of formula (1) wherein R ₁ is an alkynyl group can be prepared by Sonogashira reaction of esters of formula (12) with halogen. R ₁ is an alkynyl group, with an ester of formula (1), in a manner similar to Scheme A, wherein R ₁ is is an alkynyl group, to prepare compounds of formula (I) it can.

  In general, the Sonogashira reaction includes an aryl halide or heteroaryl halide and an alkynylating agent (eg, trimethylsilylacetylene), a base (eg, triethylamine, potassium carbonate, etc.) and a copper catalyst (eg, cuprous iodide). ) And a palladium catalyst (for example, bis (triphenylphosphine) palladium dichloride) in a solvent (for example, tetrahydrofuran, toluene, etc.) under heating.

Method (n)
A compound of formula (I) wherein R ₁ is a carboxyl group can be prepared by a carbon monoxide introduction reaction to a compound of formula (8) having a halogen.

The ester of the formula (1) in which R ₁ is a carboxyl group can be prepared by a carbon monoxide introduction reaction to the ester of the formula (12) having a halogen. In the ester of the formula (1) in which R ₁ is a carboxyl group, after protecting the carboxyl group (for example, tert-butyl ester), R ₁ is a carboxyl group in the same manner as in Scheme A. Compounds of formula (I) can be prepared.

  In general, the carbon monoxide introduction reaction is performed by reacting an aryl halide or a heteroaryl halide with a base (eg, triethylamine, sodium carbonate, etc.), a palladium catalyst (eg, palladium acetate), a ligand (eg, triphenylphosphine). In the presence, the reaction is carried out in a solvent (eg, dimethyl sulfoxide, water, etc.) under a carbon monoxide atmosphere. Alternatively, an aryl halide or heteroaryl halide was allowed to react with a base (for example, n-butyllithium, etc.) in a solvent (for example, diethyl ether, tetrahydrofuran, etc.) at a low temperature (−80 to 0 degrees). Thereafter, carbon dioxide is allowed to act.

Method (o)
Formula (I), wherein R ₁ is a hydroxyl group, can be prepared by dealkylation reaction of a compound of formula (18) having a methoxy group or a benzyloxy group.

  In general, the methoxy group demethylation reaction is performed by adding a Lewis acid (for example, boron trifluoride, aluminum chloride, or the like) to a mixture of a methoxy compound and a solvent (for example, dichloromethane or the like) and reacting the mixture. Alternatively, the reaction is carried out by heating the methoxy compound in the presence of pyridine hydrochloride.

  In general, the debenzylation reaction of a benzyloxy group is performed by reacting in a solvent (eg, methanol) in the presence of a catalyst (eg, palladium carbon, palladium hydroxide, etc.) in a hydrogen atmosphere.

Method (p)
A compound of formula (I) wherein R ₁ is an aliphatic heterocycle is obtained by a Suzuki coupling reaction of formula (8) with an aliphatic heterocyclic boronic acid or an aliphatic heterocyclic boronic ester having a halogen. Can be prepared.

The ester of formula (1), wherein R ₁ is an aliphatic heterocycle, is a Suzuki coupling of an ester of formula (12) with an aliphatic heterocyclic boronic acid or an aliphatic heterocyclic boronic ester having a halogen It can be prepared by reaction. Using the ester of formula (1), wherein R ₁ obtained here is an aliphatic heterocycle, in the same manner as in Scheme A, R ₁ is an aliphatic heterocycle of formula (I) Compounds can be prepared.

  In general, the Suzuki coupling reaction of an aliphatic heterocycle is performed by reacting an aryl halide or a halogenated heteroaryl with an aliphatic heterocyclic boronic acid or an aliphatic heterocyclic boronic ester as a base (for example, potassium phosphate). It can be prepared by reacting under heating in a solvent (eg, dioxane, water, etc.) under a palladium catalyst (eg, tetrakistriphenylphosphine).

Method (q)
The compound of formula (I), wherein R ₁ is acyloxy (—OC (O) R ₂₁ ), is an acylation reaction between formula (6) and acyl halide or carboxylic anhydride, wherein R ₁ is a hydroxy group Can be prepared.

  In general, the acylation reaction of a hydroxyl group is carried out by reacting a hydroxy compound with acyl halide or carboxylic anhydride in the presence of a base (eg, triethylamine) in a solvent (eg, dichloromethane, pyridine, etc.).

Method (r)
A compound of formula (I), wherein R ₁ is a carboxamide (—NR ₂₂ C (O) R ₂₃ ), is prepared by an acylation reaction of a compound of formula (19) having an amino group (—NHR ₂₂ ). can do.

An ester of formula (1), wherein R ₁ is a carboxamide (—NR ₂₂ C (O) R ₂₃ ), is prepared by acylation reaction of an ester of formula (20) having an amino group (—NHR ₂₂ ). can do.

  In general, an acylation reaction of an amino group is performed by reacting an amine compound with acyl halide or carboxylic anhydride in a solvent (eg, dichloromethane, pyridine, etc.) in the presence of a base (eg, triethylamine). Alternatively, the reaction is performed by reacting an amine compound and a carboxylic acid in a solvent (eg, tetrahydrofuran, dichloromethane, etc.) in the presence of a base (eg, triethylamine) and a condensing agent (eg, dicyclohexylcarbodiimide).

Method (s)
Wherein R ₁ is an aldehyde (C (O) R ₁₉ , R ₁₉ = H), or a ketone (other than C (O) R ₁₉ , R ₁₉ = H), Formula (I) has a halogen, It can be prepared by introducing a carbonyl source of the compound of 8).

  In general, in the case of aldehyde synthesis, the introduction reaction of a carbonyl source is performed by converting a halogen compound into a catalyst (eg, palladium acetate, tetrakis (triphenylphosphine) palladium, etc.), a base (eg, , Sodium carbonate, triethylamine, etc.) and a reducing agent (eg, triethylsilane) in the presence of a solvent (eg, tetrahydrofuran, N, N-dimethylformamide, etc.). On the other hand, in the case of ketone synthesis, an aldehyde, an enol ether derivative, a hydrazone derivative, or the like is used as a carbonyl source instead of carbon monoxide.

  Alternatively, after halogen-metal exchange of a halogen compound with a base (for example, tert-butyl lithium), a carbonyl source (for example, N, N-dimethylformamide, N, N-dimethylalkylamide, carboxylic acid ester) Etc.) is performed.

Method (t)
The compound of formula (I), wherein R ₁ is thioamide (—NR ₂₄ C (S) R ₂₅ ), has the amide (—NR ₂₄ C (O) R ₂₅ ) and the compound of formula (21) and sulfur It can be prepared by treating with an agent (eg, Lawson's reagent). Alternatively, it can be prepared by reaction of a compound of formula (22) having an amino group (NHR ₂₄ ) with a thiocarboxylic acid ester.

  Generally, the reaction of thiocarbonylation is performed by reacting a carboamide compound and a sulfurizing agent (for example, Lawesson's reagent) in a solvent (for example, toluene) with heating.

The reaction of the compound of formula (22) having an amino group (NHR ₂₄ ) and the thiocarboxylic acid ester is prepared by reacting the amine compound and the thiocarboxylic acid ester with heating in a solvent (for example, methanol). be able to.

Method (u)
The compound of formula (I), wherein R ₁ is thioamide (—C (S) NR ₂₆ R ₂₇ ), has the amide (—C (O) NR ₂₆ R ₂₇ ), the compound of formula (23) and sulfur It can be prepared by treating with an agent (eg, Lawson's reagent). Or it can prepare by reaction of the compound of Formula (8) which has a halogen, and a thioisocyanate derivative.

Generally, the reaction of thiocarbonylation is performed by reacting a carboamide compound and a sulfurizing agent (for example, Lawesson's reagent) in a solvent (for example, toluene) with heating.
In the reaction with a thioisocyanate derivative, a halogen compound is generally treated with a solvent (for example, tetrahydrofuran, diethyl ether, etc.) and a base (for example, t-butyllithium, etc.) at a low temperature (for example, −80 to 0 degrees). Thereafter, it is carried out by acting a thioisocyanate derivative.

Method (v)
R ₁ is a sulfonamide (—SO ₂ NR ₂₈ R ₂₉ ), the compound of formula (I) has a sulfonic acid, the formula (24) is a halogenating agent (eg thionyl chloride, phosphorus oxychloride, etc.) Can be prepared by reacting with an amine (NHR ₂₈ R ₂₉ ) in the presence of a base (eg, triethylamine) in a solvent (eg, dichloromethane, pyridine, etc.).

Method (w)
R ₁ is a sulfonate ester (—OSO ₂ R ₃₀ ), a compound of formula (I) has a hydroxyl group, formula (6) is present in a base (eg triethylamine, pyridine, sodium hydride, etc.) It can be prepared by reacting with sulfonyl halide (R ₃₀ SO ₂ X) or sulfonic anhydride ((R ₃₀ SO ₂ ) O) in a solvent (for example, dichloromethane, dimethylformamide, etc.).

Method (x)
A compound of formula (I), wherein R ₁ is a sulfonate ester (—SO ₃ R ₃₁ ), is a compound of formula (25), wherein R ₁ is a sulfonyl halide, a base (eg, triethylamine, 4-dimethylamino It can be prepared by reacting an alcohol (R ₃₁ OH) in a solvent (eg, dichloromethane, diethyl ether, etc.) in the presence of pyridine.

Alternatively, Formula (24), wherein R ₁ is sulfonic acid, can be converted to a base (eg, triethylamine, 4-dimethylaminopyridine, sodium hydride, etc.) or a catalyst (eg, dichloromethane, diethyl ether, etc.) For example, it can be prepared by reacting alcohol (R ₃₁ OH) in the presence of cobalt chloride or the like. Alternatively, it can be prepared by reacting Formula (24), in which R ₁ is sulfonic acid, with a halogen compound (R ₃₁ X) in a solvent (eg, acetonitrile).

Method (y)
The compound of formula (I), wherein R ₁ is a trialkylsilyl group (—Si (R ₃₂ ) ₃ ), has a halogen, formula (8), a base (eg, tetrahydrofuran, etc.) in a solvent (eg, tetrahydrofuran, etc.) , N-butyllithium, etc.) can be prepared by treating at low temperature (-80 to 0 degrees) and treating a trialkyl halide (XSi (R ₃₂ ) ₃ ).

  Esters of formula (1) in which the A ring is an indole are commercially available or can be prepared by methods well known in the art. For example, it can be prepared by the methods (1) to (3) described below.

Method (1)
An indole of formula (27) having an alkoxycarbonyl group (C (O) OR ₃₃ ) is prepared by an alkoxycarbonylation reaction to an indole compound protected with an alkylsulfonyl group or an arylsulfonyl group, formula (26). can do.

  In general, an alkoxycarbonylation reaction is carried out by reacting an alkylsulfonyl group or an indole compound protected with an arylsulfonyl group, Formula (26), in a solvent (eg, tetrahydrofuran, etc.) with a base (eg, lithium diisopropylamide, etc.), Then, it can prepare by making it react with carbonyl sources (for example, ethyl chloroformate etc.).

Method (2)
The indole of the formula (29) having an alkoxycarbonyl group (C (O) OR ₃₃ ) is obtained by reacting a hydrazine derivative (28) and a pyruvate ester in a solvent (eg, methanol, ethanol, etc.) in an acidic (eg, hydrochloric acid, The hydrazone derivative is obtained by reaction under conditions such as acetic acid, and the hydrazone derivative obtained here is subjected to acidic (eg, hydrochloric acid, methanesulfonic acid, etc.) conditions in a solvent (eg, ethanol, dichloromethane, toluene, etc.). Then, it can be prepared by reacting.

Method (3)
An indole of formula (29) having an alkoxycarbonyl group (C (O) OR ₃₃ ) can be obtained using Hiroya, K. et al., J. Org. Chem., 69 using an o-ethynylaniline derivative, formula (30). , 1126, (2004) or in the presence of a catalyst (eg, copper acetate) in a solvent (eg, dichloroethane) as described in Hiroya, K. et al., Tetrahedron Letters, 43, 1277, (2002) It can be prepared by heating under.

  Esters of formula (1) in which the A ring is azaindole are commercially available or can be prepared by methods well known in the art. For example, it can be prepared by the methods (4) to (7) described below.

Method (4)
Azaindoles of formula (32) having an alkoxycarbonyl group (C (O) OR ₃₃ ) can be prepared using amino-halopyridines, formula (31) and pyruvates using Lachance, N. et al., Synthesis, 15, 2571. , (2005), after reacting in a solvent (eg, pyridine, etc.) to produce enamine, a palladium catalyst (eg, tetrakis (triphenylphosphine) palladium, etc.), a base (eg, dicyclohexylmethylamine). Etc.) can be prepared by heating in the presence.

Method (5)
An azaindole of formula (32) having an alkoxycarbonyl group (C (O) OR ₃₃ ) is methylnitropyridine, formula (33) as described in Romanelli, MN et al., Arkivoc, 286, (2004). And an oxalate ester in the presence of a base (sodium ethoxide, etc.) in a solvent (eg, ethanol, etc.) to synthesize an intermediate, formula (34), followed by catalytic reduction under a hydrogen atmosphere It can be prepared by reaction.

Method (6)
An azaindole of formula (32) having an alkoxycarbonyl group (C (O) OR ₃₃ ) can be obtained as described in Roy, PJ et al., Synthesis, 16, 2751, (2005). Pyridine acrylate ester, formula (35) can be prepared by thermally decomposing by heating in a solvent (for example, mesitylene etc.).

Method (7)
The azaindole of the formula (37) having an alkoxycarbonyl group (C (O) OR ₃₃ ) is converted into an azaindole compound protected with an alkylsulfonyl group or an arylsulfonyl group, by the alkoxycarbonylation reaction to the formula (36). Can be prepared.

  In general, the alkoxycarbonylation reaction to the 2-position of azaindole is carried out by subjecting an azaindole compound protected with an alkylsulfonyl group or arylsulfonyl group, formula (36), to a base (eg, lithium) in a solvent (eg, tetrahydrofuran). It can be prepared by reacting with diisopropylamide and the like and then reacting with a carbonyl source (for example, ethyl chloroformate and the like).

The ester of the formula (1) in which A is a pyrrole ring and either R ₁ or R ₂ or both are an aryl group or a heteroaryl group is a monobromopyrrole of the formula (38) or of the formula (39) It can be prepared by Suzuki coupling reaction with arylboronic acid, heteroarylboronic acid, or arylboronic acid ester, heteroarylboronic acid ester to dibromopyrrole.

  Benzimidazolyl-5-hydrazine of formula (5) is commercially available or can be prepared by methods well known in the art. For example, it can be prepared by method (8) to method (11) described below.

  The benzimidazolyl-5-hydrazine of formula (5) can be prepared by methods well known in the art.

Method (8)
4-nitro-1,2-phenylenediamine of formula (40) and carboxylic acid (R ₃ COOH), aldehyde (R ₃ CHO), orthocarboxylic acid triester (R ₃ C (OR) ₃ ) or acyl halide ( R ₃ COX) under acidic conditions (eg, hydrochloric acid, sulfuric acid, etc.) or in the presence of a Lewis acid (eg, boron trifluoride-diethyl ether complex, dichlorooxozirconium (IV), etc.), a solvent (eg, methanol, xylene) Etc.) to give 5-nitrobenzimidazole of the formula (41).

  The formula (41) obtained here was subjected to a catalytic reduction reaction in a solvent (eg, methanol, ethanol, etc.) in the presence of a catalyst (eg, palladium carbon, palladium hydroxide, etc.) in a hydrogen atmosphere to obtain a formula (42). Is obtained.

  Subsequently, 5-benzoimidazolyl-5-hydrazine of the formula (5) is obtained by diazotization under acidic (eg, hydrochloric acid) conditions, or by a reduction reaction (eg, tin (II) chloride) with tin (II) chloride or the like. Can be adjusted. Alternatively, 5-nitrobenzimidazole of formula (41) can also be prepared in nitration of benzimidazole of formula (43).

Examples of the functional group modification reaction include “Smith and March,“ March's Advanced Organic Chemistry ”(5th edition, John Wiley & Sons 2001)” or “Richard C. Larock, Comprehensive Organic Transformations (VCH Publishers, Inc. 1989)”. It can implement by the method as described in (1). As a raw material compound used in the production, commercially available compounds may be used, or they may be produced by a conventional method as necessary.
(Method 9)
Alternatively, 5-halobenzimidazole of formula (44) was introduced into the benzimidazole in the reaction system to obtain formula (46). The protecting group used here is preferably one that can be easily and selectively deprotected in a later step. Examples of the protecting group selection and desorption operation include the method described in “Greene and Wuts,“ Protective Groups in Organic Synthesis ”(3rd edition, John Wiley & Sons 1999)”. It may be used as appropriate. As an example, a dimethoxymethyl group, a trimethylsilyl group, a p-methoxybenzyl group, a tetrahydropyranyl group, a formyl group, a benzenesulfonyl group or the like can be introduced as a protective group under acidic conditions or basic conditions. The acid used for introducing the protecting group is preferably about 1% to about 1 equivalent, and the types of acids include inorganic acids such as hydrochloric acid, sulfonic acids such as sulfuric acid and toluenesulfonic acid, acetic acid, propionic acid and benzoic acid. A carboxylic acid such as pyridinium toluenesulfonic acid or a salt of strong acid such as trimethylsilyl chloride that generates hydrochloric acid in the system may be used. In addition to the Bronsted acid as described above, Lewis acids represented by metal halides such as zinc chloride, magnesium chloride, and lithium chloride are also effective for the protective group introduction reaction. When using a base for introducing a protecting group, it is better to use an excess of 1 equivalent to 3 equivalents in some cases. The base used here is a metal hydride such as sodium hydride or potassium hydride. Also suitable are metal carbonates such as potassium carbonate and cesium carbonate, and metal alcoholates such as potassium t-butoxide and sodium t-butoxide.
Subsequently, for the purpose of carrying out a halogen-metal exchange reaction, a base was added, leading to an intermediate in which the halogen group of formula (46) was replaced with a metal. The base used here is preferably alkyl lithium or alkyl magnesium halide. More preferred are lower alkyl magnesium halides typified by isopropyl magnesium chloride, isopropyl magnesium bromide, sec-butyl magnesium chloride, and cyclohexyl magnesium chloride. The solvent for the halogen-metal exchange reaction is preferably a solvent that allows the metal reagent to exist stably in the reaction system. For example, ether solvents such as diethyl ether, dimethoxyethane, and tetrahydrofuran are preferable. The reaction temperature is preferably such that the metal reagent can be stably present in the reaction system. Referring to the known halogen-metal exchange reaction, from −80 ° C. to around room temperature, preferably from −78 ° C. to 15 ° C. About the temperature is good. The base used here can be a commercially available solution or an alkyl halide prepared from metallic lithium or metallic magnesium. By treating the intermediate in which the halogen group of formula (46) is substituted with a metal with an azodicarboxylic acid derivative (for example, azodicarboxylic acid ditert.-butyl ester, azodicarboxylic acid diethyl ester, etc.), formula (47) is converted to can get. Thereafter, the protecting group of benzimidazole is deprotected to obtain a protected hydrazine of the formula (45). The protected hydrazine of the formula (45) can be purified and removed from the reaction solution as a free form or as an appropriate acid salt. As used herein, suitable acids are not limited to inorganic salts such as hydrochloric acid, hydrobromic acid, and sulfuric acid, but may be any acid that is excellent in crystallization and purification effects, such as methanesulfonic acid and toluenesulfonic acid. Carboxylic acids such as sulfonic acid, acetic acid, benzoic acid, malic acid, maleic acid and fumaric acid can be used. Finally, the benzimidazolyl hydrazine of formula (5) can be prepared by deprotecting the protecting group of hydrazine. The deprotection reaction can be carried out under acidic conditions known in the literature or basic conditions. Acids for performing the deprotection reaction include not only inorganic salts such as hydrochloric acid, hydrobromic acid and sulfuric acid, but also carboxylic acids such as trifluoroacetic acid and pentafluoropropionic acid, sulfonic acids such as methanesulfonic acid and toluenesulfonic acid, etc. A strong acid can be used, and the deprotection reaction can be performed by diluting with a suitable solvent as necessary. The solvent used here is preferably an amide-based solvent such as DMF, DMA, NMP, etc., and is treated at a temperature in the vicinity of the ice-cold temperature to the boiling point of the solvent, thereby leading to the target benzimidazolylhydrazine of formula (5). Is possible. Suitable bases for the deprotection reaction include hydroxides of alkyl metals such as sodium hydroxide and potassium hydroxide, and carbonates of alkyl metals such as sodium carbonate and potassium carbonate. It is possible to lead to the target benzimidazolyl hydrazine represented by the formula (5) by treatment at a temperature in the range of ice-cooled to the boiling point of the solvent in an alcohol typified by methanol or ethanol.
(Method 10)
Alternatively, 5-halobenzimidazole of the formula (44) is protected in the reaction system with a protecting group as described above to form the formula (46), and then a hydrazine derivative (for example, ditert.-butyloxy Carbonylhydrazine, etc.), base (eg, cesium carbonate, potassium carbonate, etc.), transition metal catalyst (eg, palladium acetate, copper iodide, copper bromide, etc.), ligand (eg, triphenylphosphine, N, N-dimethylglycine, In the presence of (N, N′-dimethylethylenediamine, etc.), the reaction is carried out in a solvent (for example, N, N-dimethylacetamide, etc.) under heating to obtain the formula (47). Then, the protective hydrazine of Formula (45) can be obtained by deprotecting the protecting group of benzimidazole. Finally, benzoimidazolylhydrazine of the formula (5) can be prepared by deprotecting the protecting group of hydrazine in the same manner as described above.
Method (11)
Alternatively, a boronic acid derivative of the formula (48) and a hydrazine derivative (for example, ditert.-butyloxycarbonylhydrazine, azodicarboxylic acid ditert.-butyl ester, etc.) are mixed with a base (for example, tetramethyl) under a nitrogen or air atmosphere. Ethylenediamine, etc.), in the presence of a copper catalyst (eg, copper iodide, copper fluoride, copper acetate, etc.), in a solvent (eg, methanol, tetrahydrofuran, 1,2-dimethoxyethane, etc.), from around room temperature to around the boiling point of the solvent. By stirring at temperature, the protected hydrazine of formula (45) can be obtained. Finally, benzoimidazolylhydrazine of formula (5) can be prepared by deprotecting the protecting group of hydrazine in the same manner as described above.
It should be noted that all prior art documents cited in the present specification are incorporated herein by reference.

The contents of the present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to the contents. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. ¹ H-NMR spectra are usually obtained with or without Me ₄ Si as an internal standard, EX270 (manufactured by JEOL), Mercury 300 (manufactured by varian), ECP-400 (manufactured by JEOL), or 400-MR ( (s = singlet, d = doublet, t = triplet, brs = broad singlet, m = multiple). Mass spectrometry was measured using a mass spectrometer LCQ Classic (manufactured by Thermo Electron), ZQ2000 (manufactured by Waters), and ZMD4000 (manufactured by Waters). As the microwave, Initiator ™ (manufactured by Biotage) was used.

Example 1
Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone

  [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl) -methanone (87 mg) 4M aqueous sodium hydroxide solution (1.67 mL) was added to an ethanol solution (17 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture is poured into water, and the resulting solid is collected by filtration, washed with water, and dried to give [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4. -Il]-(1H-indol-2-yl) -methanone (40 mg, 63%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.47 (1H, s), 11.70 (1H, s), 8.32 (1H, s), 7.70 (1H, d, J = 8) .0Hz), 7.66-7.55 (2H, m), 7.50-7.45 (2H, m), 7.31-7.23 (2H, m), 7.10-7.06. (1H, m), 7.01 (2H, brs), 2.53 (3H, s)
ESI (LC-MS positive mode) m / z 357 [(M + H) ⁺ ]

[５−アミノ−１−(２−メチル−３Ｈ−ベンゾイミダゾール−５−イル)−１Ｈ−ピラゾール―４−イル]−(１Ｈ−インドール−２−イル)−メタノン 水和物（１９０ｇ、０．５０７ ｍｏｌ）とＬ-リンゴ酸（６８ｇ、０．５０７ｍｏｌ）を秤量し、シメチルスホキシド（０．４１８Ｌ、２．２ｖ／ｗ）、アセトン（０．４１８Ｌ、２．２ｖ／ｗ）に溶解した後に桐山ロート（Ｎｏ４ろ紙）にてろ過を行い、１０Ｌジャケット付きセパラブルフラスコに投入後、５０度にて反応液を溶解した。 Example 1A
Synthesis of [5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone L-malate

[5-Amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone hydrate (190 g, 0. 507 mol) and L-malic acid (68 g, 0.507 mol) were weighed and dissolved in cymethyl sulfoxide (0.418 L, 2.2 v / w) and acetone (0.418 L, 2.2 v / w). After filtration with a Kiriyama funnel (No. 4 filter paper), the reaction solution was dissolved at 50 degrees after being put into a 10 L jacketed separable flask.

  L-malic acid (544.4 g, 4.06 mol) was weighed and dissolved in acetone (1.25 L, 6.6 v / w) and acetic acid (0.418 L, 2.2 v / w), and then Kiriyama funnel ( No. 4 filter paper) and put into a 10 L jacketed separable flask so that the internal temperature does not fall below 45 degrees, and the seed crystal (0.95 g, 0.5%) is suspended in acetone (7.5 mL). Thereafter, it was put into a separable flask with a 10 L jacket.

  After 7 hours, the suspension was cooled to 25 ° C., the crystals were filtered with a Kiriyama funnel, the crystals were washed twice with acetone (0.85 L, 5 v / w), and the resulting wet powder was covered with a 10 L jacket. It put into the attached separable flask. Acetone (2.85 L, 15 v / w) was added, and the suspension was stirred at 50 ° C. for 3 hours. After filtering the crystals with a Kiriyama funnel, the crystals were washed with acetone (0.85 L, 5 v / w). Washed twice. The wet powder was dried under reduced pressure at an external temperature of 40 ° C. for 3 hours to obtain [5-amino-1- (2-methyl-3H-benzoimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indole) -2-yl) -methanone L-malate (556.9 g, 73%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 11.69 (1H, s), 8.31 (1H, s), 8.25-7.00 (10H, m), 4.25-4.22 (1H, m), 3.33 (2H, brs), 2.69-2.32 (9H, m)
FAB positive mode m / z 157.1, 232.1, 289.2, 357.2 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン（１９４ｍｇ）をジメチルホルムアミド（１．９４ｍL）に溶解し、２M塩酸水溶液（３００μＬ）を２５度にて５回に分けて滴下した。反応液に２−プロパノール（４ｍL）を５分ごとに３分割で加えた。沈殿を濾取、２−プロパノール（１ｍL）で洗浄後、粉末を４０℃にて減圧乾燥し、乳白色粉末（１８８ｍｇ、８８％）を得た。 Example 1B
Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone hydrochloride

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone (194 mg) was converted to dimethylformamide (1 .94 mL), and 2M aqueous hydrochloric acid (300 μL) was added dropwise in 25 portions at 25 degrees. 2-Propanol (4 mL) was added to the reaction solution in 5 portions every 5 minutes. The precipitate was collected by filtration and washed with 2-propanol (1 mL), and then the powder was dried under reduced pressure at 40 ° C. to obtain a milky white powder (188 mg, 88%).

11.72 (1H, s), 8.39 (1H, s), 7.96 (1H, d, J = 2.1 Hz), 7.92 (1H, d, J = 8.7 Hz), 7. 71 (1H, t, J = 2.1 Hz), 7.68 (1H, t, J = 2.1 Hz), 7.51 (1H, s), 7.48 (1H, d, J = 2.1 Hz) ), 7.28 (1H, d, J = 7.6 Hz), 7.23 (3H, s), 7.09 (1H, t, J = 7.6 Hz), 2.82 (3H, s) ).
ESI (LC-MS positive mode) m / z 357 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン（４２ｇ）のジメチルホルムアミド溶液（４２０ｍＬ）に２Ｍメタンスルホン酸水溶液（６４．９ｍＬ）を加え、室温下２０分攪拌した。この反応液にメチル―ｔ−ブチルエーテル（１０５ｍＬ）を加え、種晶を３．０ｍｇ加え室温下撹拌した。結晶の析出を確認後、メチル―ｔ−ブチルエーテル（１０５ｍＬ）を１５分ごとに４回反応液に加えた。反応液を１．５時間室温下撹拌した後、得られた結晶を桐山ロートでろ取した。ろ取した固体を、メチル―ｔ−ブチルエーテル（２１０ｍＬ）で３回洗浄、乾燥し、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン―１−メタンスルホン酸塩−１水和物（４２．６８ｇ、８４％）を得た。 Example 1C
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone-1-methanesulfonate- Synthesis of monohydrate

A solution of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone (42 g) in dimethylformamide ( (420 mL) was added 2M aqueous methanesulfonic acid solution (64.9 mL), and the mixture was stirred at room temperature for 20 minutes. Methyl-t-butyl ether (105 mL) was added to the reaction solution, 3.0 mg of seed crystals were added, and the mixture was stirred at room temperature. After confirming the precipitation of crystals, methyl-t-butyl ether (105 mL) was added to the reaction solution four times every 15 minutes. The reaction solution was stirred at room temperature for 1.5 hours, and the obtained crystals were collected by filtration with a Kiriyama funnel. The solid collected by filtration was washed three times with methyl-t-butyl ether (210 mL), dried, and [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4- Yl]-(1H-indol-2-yl) -methanone-1-methanesulfonic acid monohydrate (42.68 g, 84%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 11.70 (1H, s), 8.39 (1H, s), 7.99 (1H, d, J = 1.6 Hz), 7.94 (1H , D, J = 8.8 Hz), 7.74-7.68 (2H, m), 7.51-7.46 (2H, m), 7.29-7.18 (3H, m), 7 .11-7.06 (1H, m), 2.84 (3H, s), 2.37 (3H, s)
ESI (LC-MS positive mode) m / z 357 [(M + H) ⁺ ]

In the same manner as in Example 1, the compounds of Examples 2 to 35 in Table 1 were synthesized.

［５−アミノ−１−（６−フルオロ−２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１−ベンゼンスルホニル−１Ｈ−インドール−２−イル）−メタノン（１１４ｍｇ、０．２２ｍｍｏｌ）をイソプロパノール（２．２ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（２．２ｍＬ）を加え、窒素雰囲気下、９０℃で２時間加熱撹拌した。反応混合物を室温に冷却した後、飽和リン酸二水素ナトリウム水溶液、水を加え、生成物を酢酸エチルで抽出した。有機層を分離し、飽和塩化ナトリウム水溶液で洗浄、硫酸マグネシウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（アミノシリカゲル、ジクロロメタン／メタノール＝１００／５）で精製し、黄色固体の［５−アミノ−１−（６−フルオロ−２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１Ｈ−インドール−２−イル）−メタノン（７５ｍｇ、８９．８％）を得た。 Example 36
Synthesis of [5-amino-1- (6-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone

[5-Amino-1- (6-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl)- Methanone (114 mg, 0.22 mmol) was dissolved in isopropanol (2.2 mL), 1M aqueous sodium hydroxide solution (2.2 mL) was added, and the mixture was stirred with heating at 90 ° C. for 2 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous sodium dihydrogen phosphate solution and water were added, and the product was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (amino silica gel, dichloromethane / methanol = 100/5) to give [5-amino-1- (6 -Fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone (75 mg, 89.8%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.60 (1.0 H, brs), 11.70 (1.0 H, brs), 8.31 (1.0 H, s), 7.69 (1 .0H, d, J = 7.6 Hz), 7.62 (1.0 H, d, J = 6.8 Hz), 7.55 (1.0 H, d, J = 10.7 Hz), 7.50− 7.45 (2.0 H, m), 7.25 (1.0 H, dd, J = 7.6, 7.6 Hz), 7.08 (1.0 H, dd, J = 7.6, 7. 6Hz), 7.02 (2.0H, brs), 2.53 (3.0H, s)
ESI (LC-MS positive mode) m / z 375 [(M + H) ⁺ ]

In the same manner as in Example 36, the compounds of Examples 37 to 63 in Table 2 were synthesized.

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−ブトキシ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（７０ｍｇ）、ジオキサン（３ｍＬ）、および５Ｍ水酸化ナトリウム水溶液（３００μＬ）の混合液を、還流下２時間撹拌した。反応混合物を氷浴で冷却し、５Ｍ塩酸水溶液で酸性とし、減圧下溶媒を留去した。減圧濃縮して得られた残渣に水を加え、固体をろ取、水で洗浄、乾燥し、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ブトキシ−１Ｈ−インドール−２−イル）−メタノン（３５ｍｇ、６５％）を得た。 Example 64
Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-butoxy-1H-indol-2-yl) -methanone

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-butoxy-1- (toluene-4-sulfonyl) -1H-indole- A mixture of 2-yl] -methanone (70 mg), dioxane (3 mL), and 5M aqueous sodium hydroxide (300 μL) was stirred under reflux for 2 hours. The reaction mixture was cooled in an ice bath, acidified with 5M aqueous hydrochloric acid solution, and the solvent was distilled off under reduced pressure. Water was added to the residue obtained by concentration under reduced pressure, and the solid was collected by filtration, washed with water, dried, and [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole. -4-yl]-(5-butoxy-1H-indol-2-yl) -methanone (35 mg, 65%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.45 (1H, s), 11.54 (1H, d, J = 1.8 Hz), 8.25 (1H, s), 7.65-7 .63 (1H, brm), 7.57-7.55 (1H, brm), 7.36 (1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 1.8 Hz) 7.30-7.28 (1H, brm), 7.12 (1H, d, J = 2.4 Hz), 7.01 (1H, brs), 6.95 (1H, brs), 6.90. (1H, dd, J = 8.8, 2.4 Hz), 3.98 (2H, t, J = 6.4 Hz), 2.53 (3H, s), 1.76-1.69 (2H, m), 1.51-1.44 (2H, m), 0.95 (3H, t, J = 7.3 Hz)
ESI (LC-MS positive mode) m / z 429 [(M + H) ⁺ ]

In the same manner as in Example 64, the compounds of Examples 65 to 89 and 204 to 239 in Table 3 were synthesized.

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［３−フルオロ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（２５．０ｍｇ、０．０４１ｍｍｏｌ）をメタンスルホン酸（０．２５ｍＬ）に溶解し、室温で１時間攪拌した。反応混合物を１Ｍ水酸化ナトリウム水溶液でｐＨ＝６に調整し、酢酸エチルで抽出し、抽出液を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去後、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝６０／１〜４０／１）で精製し、薄黄色固体の［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（３−フルオロ−１Ｈ−インドール−２−イル）−メタノン（８．７ｇ、５５％収率）を得た。 Example 90
Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(3-fluoro-1H-indol-2-yl) -methanone

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[3-fluoro-1- (toluene-4-sulfonyl) -1H-indole- 2-yl] -methanone (25.0 mg, 0.041 mmol) was dissolved in methanesulfonic acid (0.25 mL) and stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH = 6 with 1M aqueous sodium hydroxide solution, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 60/1 to 40/1) to give [5-amino-1 as a pale yellow solid. -(2-Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(3-fluoro-1H-indol-2-yl) -methanone (8.7 g, 55% yield) Got.

¹ H-NMR (DMSO-D ₆ ) δ: 12.48 (1H, s), 11.50 (1H, s), 8.03 (1H, d, J = 3.1 Hz), 7.69 (1H , D, J = 8.5 Hz), 7.62 (2H, s), 7.45 (1H, d, J = 8.5 Hz), 7.25-7.35 (2H, m), 7.15 (1H, t, J = 7.3 Hz), 7.05 (2H, s), 2.53 (3H, s)
ESI (LC-MS positive mode) m / z 375 [(M + H) ⁺ ]

In the same manner as in Example 90, the compounds of Examples 91 to 131 in Table 4 were synthesized.

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１−ベンゼンスルホニル−６−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン（１３２ｍｇ、０．２２ｍｍｏｌ）をテトラヒドロフラン（ＴＨＦ)（１．０ｍＬ）に溶解し、１Ｍフッ化テトラブチルアンモニウムのテトラヒドロフラン（ＴＨＦ)溶液（０．４６ｍＬ、０．４６ｍｍｏｌ）を加え、６５℃で２２時間加熱撹拌した。反応混合物を室温に冷却し、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１００／１０）で精製し、黄色固体の［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン（７４ｍｇ、７５％）を得た。 Example 132
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone Synthesis of

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1-benzenesulfonyl-6-morpholin-4-ylmethyl-1H-indole-2 -Il) -methanone (132 mg, 0.22 mmol) was dissolved in tetrahydrofuran (THF) (1.0 mL), and 1M tetrabutylammonium fluoride in tetrahydrofuran (THF) (0.46 mL, 0.46 mmol) was added. The mixture was heated and stirred at 65 ° C. for 22 hours. The reaction mixture was cooled to room temperature, concentrated and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 100/10) to give [5-amino-1- (2- Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone (74 mg, 75%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.48 (1.0 H, brs), 11.64 (1.0 H, brs), 8.30 (1.0 H, s), 7.64-7 .60 (3.0 H, m), 7.42-7.41 (2.0 H, m), 7.29 (1.0 H, dd, J = 8.5, 2.2 Hz), 7.06 ( 1.0H, dd, J = 8.3, 1.0 Hz), 6.99 (2.0 H, brs), 3.58 (4.0 H, t, J = 4.4 Hz), 3.55 (2 .0H, s), 2.53 (3.0H, s), 2.39-2.37 (4.0H, brm)
ESI (LC-MS positive mode) m / z 456 [(M + H) ⁺ ]

In the same manner as in Example 132, the compounds of Examples 133 to 143 in Table 5 were synthesized.

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１−ベンゼンスルホニル−５−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン（１１０ｍｇ）のメタノール溶液（２０ｍＬ）に炭酸セシウム（１．２９ｇ）を加え、室温で１６時間攪拌した。反応混合物に水（５ｍＬ）、アンモニア水（３ｍＬ）を加え、３時間攪拌した。反応混合物を減圧下濃縮し、得られた残渣に水を加え、酢酸エチルで抽出し、抽出液を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン＝０／１００から２０／１００）で精製し、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−モルホリン−４−イルメチル−１Ｈ−インドール−２−イル）−メタノン（３３ｍｇ）を得た。 Example 144
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone Synthesis of

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1-benzenesulfonyl-5-morpholin-4-ylmethyl-1H-indole-2 -Ils) -Methanone (110 mg) in methanol (20 mL) was added with cesium carbonate (1.29 g) and stirred at room temperature for 16 hours. Water (5 mL) and aqueous ammonia (3 mL) were added to the reaction mixture, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 20/100), and [5-amino-1- (2-methyl -1H-Benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone (33 mg) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.47 (1.0 H, s), 11.67 (1.0 H, s), 8.30 (1.0 H, s), 7.60 (3 0.0H, m), 7.44 (2.0 H, m), 7.30 (1.0 H, dd, J = 8.4, 2.1 Hz), 7.23 (1.0 H, dd, J = 8.4, 1.5 Hz), 7.01 (2.0 H, m), 3.58 (4.0 H, t, J = 4.4 Hz), 3.54 (2.0 H, s), 2. 55 (3.0H, s), 2.38 (4.0H, m)
ESI (LC-MS positive mode) m / z 456 [(M + H) ⁺ ]

In the same manner as in Example 144, the compounds of Examples 145 to 164 in Table 6 were synthesized.

粗２−（１−ベンゼンスルホニル−１Ｈ−インドール−２−カルボニル）−３−ジメチルアミノ−アクリロニトリル（１．１７ｇ）のエタノール溶液（１５ｍＬ）に、（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−ヒドラジン二塩酸塩（８３０ｍｇ）を加え、加熱還流下４時間攪拌した。反応混合物を室温に冷却した後、一晩室温で放置し、析出した固体をろ取、エタノールで洗浄し、黄色固体の［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（１−ベンゼンスルホニル−１Ｈ−インドール−２−イル）−メタノン（１．５ｇ、９１％、２工程収率）を得た。 Process 1
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl) -methanone (1001) Synthesis of

To an ethanol solution (15 mL) of crude 2- (1-benzenesulfonyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile (1.17 g) was added (2-methyl-1H-benzimidazol-5-yl. ) -Hydrazine dihydrochloride (830 mg) was added, and the mixture was stirred for 4 hours with heating under reflux. The reaction mixture was cooled to room temperature and then allowed to stand overnight at room temperature. The precipitated solid was collected by filtration, washed with ethanol, and converted into yellow solid [5-amino-1- (2-methyl-1H-benzimidazole-5 Yl) -1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl) -methanone (1.5 g, 91%, 2 step yield) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 8.15-8.13 (2H, m), 8.02 (1H, dd, J = 8.4, 0.8 Hz), 7.97 (1H, d, J = 2.0 Hz), 7.92 (1H, d, J = 8.8 Hz), 7.87 (1H, s), 7.76-7.62 (5H, m), 7.49- 7.45 (1H, m), 7.36-7.26 (4H, m), 2.82 (3H, m)
ESI (LC-MS positive mode) m / z 497 [(M + H) ⁺ ]

In the same manner as in Step 1, compound numbers 1002 to 1082 and 1511 to 1527 in Table 7 were synthesized.

Examples 165 to 195, 247 to 254
Using the compound in which the nitrogen atom of the indole ring was not protected, the compounds of Examples 165 to 195 and 247 to 254 in Table 8 were synthesized in the same manner as in Step 1.

３−（１−ベンゼンスルホニル−１Ｈ−インドール−２−イル）−３−オキソ−プロピオニトリル（１．０ｇ、３．０８ｍｍｏｌ）のテトラヒドロフラン（ＴＨＦ)溶液（８．５ｍＬ）に、室温で、Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール（６２０μＬ）を加え、１０分間攪拌した。反応混合物を減圧下濃縮し、黄色アモルファス状の粗２−（１−ベンゼンスルホニル−１Ｈ−インドール−２−カルボニル）−３−ジメチルアミノ−アクリロニトリルを得た。ここで得られた粗生成物は、精製することなく次の反応に用いた。 Process 2
Synthesis of 2- (1-benzenesulfonyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile (1083)

To a solution of 3- (1-benzenesulfonyl-1H-indol-2-yl) -3-oxo-propionitrile (1.0 g, 3.08 mmol) in tetrahydrofuran (THF) (8.5 mL) at room temperature, N , N-dimethylformamide dimethyl acetal (620 μL) was added and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude yellow amorphous 2- (1-benzenesulfonyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile. The crude product obtained here was used for the next reaction without purification.

ESI (LC-MS positive mode) m / z 380 [(M + H) ⁺ ]

In the same manner as in Step 2, compound numbers 1084 to 1184 and 1528 to 1549 in Table 9 were synthesized.

１−ベンゼンスルホニル−１Ｈ−インドール−２−カルボン酸エチルエステル（３３．４ｇ、０．１０１ｍｏｌ）のテトラヒドロフラン（ＴＨＦ)（１３５ｍＬ）溶液に、アセトニトリル（１０．６ｇ、０．２０２ｍｏｌ）を加え、−７８℃に冷却した。１Ｍリチウムビス（トリメチルシリル）アミドのテトラヒドロフラン（ＴＨＦ)溶液（２１３ｍＬ、０．２１３ｍｏｌ）を滴下し、３０分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液（８３ｍＬ）を加え、１０分間攪拌した後、水（５０ｍＬ）を加え、室温に昇温した。減圧下、溶媒を留去し、得られた残渣を酢酸エチルで抽出した。抽出液を、飽和塩化ナトリウム水溶液で洗浄、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた粗生成物をエタノールで洗浄し、３−（１−ベンゼンスルホニル−１Ｈ−インドール−２−イル）−３−オキソ−プロピオニトリル（４７．３ｇ、７０％）を得た。 Process 3
Synthesis of 3- (1-benzenesulfonyl-1H-indol-2-yl) -3-oxo-propionitrile (1185)

To a solution of 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (33.4 g, 0.101 mol) in tetrahydrofuran (THF) (135 mL) was added acetonitrile (10.6 g, 0.202 mol) and -78. Cooled to ° C. A solution of 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (THF) (213 mL, 0.213 mol) was added dropwise and stirred for 30 minutes. Saturated aqueous ammonium chloride solution (83 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes, water (50 mL) was added, and the mixture was warmed to room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure, and the resulting crude product was washed with ethanol to give 3- (1-benzenesulfonyl-1H-indol-2-yl) -3-oxo-propionitrile ( 47.3 g, 70%).

¹ H-NMR (CDCl ₃ ) δ: 8.12 (1.0 H, dq, J = 8.5, 0.8 Hz), 7.79-7.76 (2.0 H, m), 7.56- 7.48 (3.0 H, m), 7.42-7.38 (2.0 H, m), 7.32-7.28 (1.0 H, m), 7.20 (1.0 H, d) , J = 0.8 Hz), 4.16 (2.0 H, s)
ESI (LC-MS positive mode) m / z 325 [(M + H) ⁺ ]

In the same manner as in Step 3, compound numbers 1186 to 1284 and 1550 to 1571 in Table 10 were synthesized.

５０％水素化ナトリウム（１３．７ｇ、０．２８６ｍｏｌ）の脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)溶液（９０ｍＬ）を氷冷下、１Ｈ−インドール−２−カルボン酸エチルエステル（４５ｇ、０．２３８ｍｏｌ）の脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)溶液（７０ｍＬ）を滴下し、氷冷下１時間３０分間攪拌した後、室温に昇温し、１時間攪拌した。反応混合物を氷冷し、塩化ベンゼンスルホニル（５０．４ｇ）の脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)溶液を滴下し、１時間攪拌した。反応混合物に０．５規定塩酸水溶液を滴下後、水を加え、３０分間攪拌した。生成した固体を濾取し、水、および、ｎーヘキサンで洗浄した。得られた固体を、酢酸エチルに溶かし、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、減圧濃縮して粗１−ベンゼンスルホニル−１Ｈ−インドール−２−カルボン酸エチルエステルを得た。ここで得られた粗生成物を再結晶（酢酸エチル／ヘキサン）し、１−ベンゼンスルホニル−１Ｈ−インドール−２−カルボン酸エチルエステル（６８．９ｇ、７９％）を得た。 Process 4
Synthesis of 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (1285)

A solution of 50% sodium hydride (13.7 g, 0.286 mol) in dehydrated N, N-dimethylformamide (DMF) (90 mL) was cooled with ice and 1H-indole-2-carboxylic acid ethyl ester (45 g, 0.238 mol). ) Was added dropwise, and the mixture was stirred for 1 hour and 30 minutes under ice cooling, then warmed to room temperature and stirred for 1 hour. The reaction mixture was ice-cooled, and a dehydrated N, N-dimethylformamide (DMF) solution of benzenesulfonyl chloride (50.4 g) was added dropwise and stirred for 1 hour. A 0.5N aqueous hydrochloric acid solution was added dropwise to the reaction mixture, water was added, and the mixture was stirred for 30 min. The produced solid was collected by filtration and washed with water and n-hexane. The obtained solid was dissolved in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure to give crude 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester. The crude product obtained here was recrystallized (ethyl acetate / hexane) to obtain 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (68.9 g, 79%).

¹ H-NMR (CDCl ₃ ) δ: 8.12 (1H, d, J = 8.3 Hz), 8.04 (2H, d, J = 7.8 Hz), 7.60-7.52 (2H, m), 7.51-7.40 (3H, m), 7.31-7.21 (1H, m), 7.17 (1H, s), 4.40 (2H, q, J = 7. 0 Hz), 1.39 (3H, t, J = 7.0 Hz)
ESI (LC-MS positive mode) m / z 330 [(M + H) ⁺ ]

In the same manner as in Step 4, compound numbers 1286 to 1312 in Table 11 were synthesized.

ヨウ化銅（Ｉ）（１６ｍｇ、０．０８６ｍｍｏｌ）、Ｌ−プロリン（３７ｍｇ、０．３２ｍｍｏｌ）、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−ヨード−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（１０４ｍｇ）を脱水ジメチルスルホキシド（ＤＭＳＯ）に溶解し、１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン（４９μｌ）、２−メトキシエチルアミン（４３μｌ）を加え、窒素雰囲気下、８０℃で１８時間加熱撹拌した。反応混合物を室温に冷却した後、２５％アンモニア水を加え、酢酸エチルで抽出した。有機層を分離し、１Ｍ塩酸水溶液、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去後、減圧下溶媒を留去し、得られた残渣を少量のシリカゲルでクロマトグラフィー（ジクロロメタン／メタノール＝１００／５）をして粗生成物［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−（２−メトキシ−エチルアミノ）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノンを得た。ここで得られた粗生成物を精製することなく、次の反応に用いた。 Process 5
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-methoxy-ethylamino) -1- (toluene-4- Synthesis of (sulfonyl) -1H-indol-2-yl] -methanone (1313)

Copper (I) iodide (16 mg, 0.086 mmol), L-proline (37 mg, 0.32 mmol), [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole -4-yl]-[6-iodo-1- (toluene-4-sulfonyl) -1H-indol-2-yl] -methanone (104 mg) was dissolved in dehydrated dimethyl sulfoxide (DMSO) and 1,8-diazabicyclo [5.4.0] Undec-7-ene (49 μl) and 2-methoxyethylamine (43 μl) were added, and the mixture was heated and stirred at 80 ° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 25% aqueous ammonia was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 1M aqueous hydrochloric acid and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was chromatographed on a small amount of silica gel (dichloromethane / methanol = 100/5) to give the crude product [5-amino-1- (2 -Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4- (2-methoxy-ethylamino) -1- (toluene-4-sulfonyl) -1H-indole-2- Il] -methanone was obtained. The crude product obtained here was used for the next reaction without purification.

ESI (LC-MS positive mode) m / z 584 [(M + H) ⁺ ]

In the same manner as in Step 5, compound numbers 1314 to 1320 in Table 12 were synthesized.

２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（トルエン−４−スルホニル）−１Ｈ−インドール−５−カルボン酸（１１３ｍｇ）を、テトラヒドロフラン（ＴＨＦ)（１０ｍＬ）と水（５ｍＬ）に溶解し、モルホリン（５３．５μＬ）とＮ−（３−ジメチルアミノプロピル）−Ｎ’−エチルカルボジイミド塩酸塩（ＷＳＣ・ＨＣｌ）（４３ｍｇ）を加え、室温で２４時間攪拌した。反応混合物を減圧濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィー（メタノール：ジクロロメタン＝０/１００〜１７/１００）で精製し、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（モルホリン−４−カルボニル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（５９ｍｇ）を得た。 Step 6
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (morpholine-4-carbonyl) -1- (toluene-4-sulfonyl) ) -1H-Indol-2-yl] -methanone (1321)

2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-5-carvone Acid (113 mg) was dissolved in tetrahydrofuran (THF) (10 mL) and water (5 mL), morpholine (53.5 μL) and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (WSC · HCl). ) (43 mg) was added and stirred at room temperature for 24 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (methanol: dichloromethane = 0/100 to 17/100), and [5-amino-1- (2-methyl-1H-benzimidazole) was purified. -5-yl) -1H-pyrazol-4-yl]-[5- (morpholin-4-carbonyl) -1- (toluene-4-sulfonyl) -1H-indol-2-yl] -methanone (59 mg). Obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.49 (1.0 H, d, J = 9.3 Hz), 8.08 (3.0 H, m), 7.82-7.74 (2. 0H, m), 7.70-7.64 (1.0 H, m), 7.58 (1.0 H, d, J = 8.3 Hz), 7.53-7.42 (3.0 H, m ), 7.35-7.25 (2.0H, m), 7.13-6.89 (2.0H, m), 3.69-3.51 (4.0H, m), 3.40. -3.28 (4.0H, m), 2.54 (3.0H, s), 2.38 (3.0H, s)
ESI (LC-MS positive mode) m / z 624 [(M + H) ⁺ ]

In the same manner as in Step 6, compound numbers 1322 to 1326 and 1572 to 1579 in Table 13 were synthesized.

耐圧容器にて、酢酸パラジウム（１．０ｍｇ、０．００４４ｍｍｏｌ）、１，３−ビス（ジフェニルホスフィノ）プロパン（１．８ｍｇ、０．００４４ｍｍｏｌ）、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−ヨード−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（１００ｍｇ、０．１６ｍｍｏｌ）、炭酸ナトリウム（１８ｍｇ、０．１７ｍｍｏｌ）を脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)（０．２２ｍＬ）に溶解し、トリエチルシラン（５２μＬ、０３３ｍｍｏｌ）を加え、一酸化炭素置換を行った後、一酸化炭素加圧下（３ａｔｍ）、６０℃で２４時間加熱撹拌した。反応混合物を室温に冷却した後、常圧に戻し、酢酸エチルで希釈して炭酸ナトリウムを濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１００／５）で精製し、黄色固体の２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（トルエン−４−スルホニル）−１Ｈ−インドール−６−カルバルデヒド（８０ｍｇ、８５％）を得た。 Step 7
2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-6-carba Synthesis of Rudehydr (1327)

In a pressure vessel, palladium acetate (1.0 mg, 0.0044 mmol), 1,3-bis (diphenylphosphino) propane (1.8 mg, 0.0044 mmol), [5-amino-1- (2-methyl- 1H-Benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-iodo-1- (toluene-4-sulfonyl) -1H-indol-2-yl] -methanone (100 mg, 0.16 mmol) ), Sodium carbonate (18 mg, 0.17 mmol) was dissolved in dehydrated N, N-dimethylformamide (DMF) (0.22 mL), triethylsilane (52 μL, 033 mmol) was added, and carbon monoxide substitution was performed. The mixture was heated and stirred at 60 ° C. for 24 hours under carbon monoxide pressure (3 atm). The reaction mixture is cooled to room temperature, returned to normal pressure, diluted with ethyl acetate, filtered to remove sodium carbonate, concentrated and concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (dichloromethane / methanol = 100/5). And 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) as a yellow solid -1H-indole-6-carbaldehyde (80 mg, 85%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 10.14 (1.0 H, s), 9.81-9.40 (1.0 H, brm), 8.61 (1.0 H, d, J = 3. 9 Hz), 8.09 (2.0 H, d, J = 7.3 Hz), 7.86-7.72 (4.0 H, m), 7.52-7.30 (4.0 H, m), 7.02 (1.0H, s), 6.07 (1.0H, brs), 6.04 (1.0H, brs), 2.67 (3.0H, s), 2.40 (3. 0H, s)
ESI (LC-MS positive mode) m / z 539 [(M + H) ⁺ ]

工程７と同様にして、２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（トルエン−４−スルホニル）−１Ｈ−インドール−５−カルバルデヒドを合成した。 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-5-carba Synthesis of Rudehydr (1328)

In the same manner as in Step 7, 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl)- 1H-indole-5-carbaldehyde was synthesized.

ESI (LC-MS positive mode) m / z 539 [(M + H) ⁺ ]

２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（トルエン−４−スルホニル）−１Ｈ−インドール−６−カルバルデヒド（２９ｍｇ、０．０５４ｍｍｏｌ）、１−メチルピペラジン（７μｌ、０．０６６ｍｍｏｌ）、トリアセトキシホウ水素化ナトリウム（１７ｍｇ、０．０８３ｍｍｏｌ）を脱水ジクロロメタン（０．５ｍＬ）に溶解し、窒素雰囲気下、室温で１４時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を分離し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１００／１５）で精製し、黄色固体の［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（４−メチル−ピペラジン−１−イルメチル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（２９ｍｇ、８６％）を得た。 Process 8
Synthesis of 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-6-carbaldehyde (1329)

2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-6-carba Rudehydr (29 mg, 0.054 mmol), 1-methylpiperazine (7 μl, 0.066 mmol), sodium triacetoxyborohydride (17 mg, 0.083 mmol) were dissolved in dehydrated dichloromethane (0.5 mL), and under nitrogen atmosphere, Stir at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 100/15) to give [5-amino-1- (2-methyl- 1H-Benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (4-methyl-piperazin-1-ylmethyl) -1- (toluene-4-sulfonyl) -1H-indole-2- Yl] -methanone (29 mg, 86%).

ESI (LC-MS positive mode) m / z 623 [(M + H) ⁺ ]

In the same manner as in Step 8, compound numbers 1330 to 1358 in Table 14 were synthesized.

Examples 196, 197
In the same manner as in Step 8, Examples 196 and 197 in Table 15 were synthesized.

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ピペラジン−１−イルメチル−１Ｈ−インドール−２−イル）−メタノン（１０３ｍｇ）をジクロロメタン（２０ｍＬ）、メタノール（３ｍＬ）および飽和炭酸水素ナトリウム水溶液（２５ｍＬ）に溶解し、０度に冷却した。塩化アセチル（３２６ｕＬ）を３度に分けて加え、１．５時間攪拌した。反応混合液をジクロロメタンで抽出し、抽出液を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン＝０／１００〜１０／１００）で精製し、１−（４−｛２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−ベンゼンスルホニル−１ヒンドール−５−イルメチル｝−ピペラジン−１−イル）−エタノン（３２ｍｇ）を得た。 Step 9
1- (4- {2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1-benzenesulfonyl-1hindol-5-ylmethyl } -Piperazin-1-yl) -ethanone (1359)

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-piperazin-1-ylmethyl-1H-indol-2-yl) -methanone (103 mg) was dissolved in dichloromethane (20 mL), methanol (3 mL) and saturated aqueous sodium bicarbonate (25 mL) and cooled to 0 ° C. Acetyl chloride (326 uL) was added in three portions and stirred for 1.5 hours. The reaction mixture was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 10/100) to give 1- (4- {2- [5- Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1-benzenesulfonyl-1hindol-5-ylmethyl} -piperazin-1-yl) -ethanone ( 32 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.18-8.14 (2.0 H, m), 8.05 (1.0 H, d, J = 8.8 Hz), 7.78 (1.1 H, s), 7.60-7.56 (1.0 H, m), 7.50 (3.0 H, m), 7.40 (1.0 H, dd, J = 8.8, 1.5 Hz), 7.35 (1.0 H, m), 6.98 (1.0 H, s), 6.03 (2.0 H, m), 3.62 (2.0 H, t, J = 5.0 Hz), 3.58 (2.0 H, s), 3.45 (2.0 H, t, J = 5.0 Hz), 2.64 (3.0 H, s), 2.42 (4.0 H, m), 2.07 (3.0H, s)
ESI (LC-MS positive mode) m / z 637 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（５−ピペラジン−１−イルメチル−１Ｈ−インドール−２−イル）−メタノン（９４ｍｇ）をテトラヒドロフラン（ＴＨＦ)（５ｍＬ）と飽和炭酸水素ナトリウム水溶液（５ｍＬ）に溶解し、０度に冷却した。塩化メタンスルホニル（９４μＬ）を加え、０℃で１．５時間攪拌した。アンモニア水（５ｍＬ）を加え、０℃で２時間攪拌した。反応混合液を酢酸エチルで抽出し、抽出液を飽和塩化ナトリウムで洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン＝０／１００〜１５／１００）で精製し、５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［１−ベンゼンスルホニル−５−（４−メタンスルホニルピペラジン−１−イルメチル）−１Ｈ−インドール−２−イル］−メタノン（３９ｍｇ）を得た。 Step 10
5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[1-benzenesulfonyl-5- (4-methanesulfonylpiperazin-1-ylmethyl)- Synthesis of 1H-indol-2-yl] -methanone (1360)

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(5-piperazin-1-ylmethyl-1H-indol-2-yl) -methanone (94 mg) was dissolved in tetrahydrofuran (THF) (5 mL) and saturated aqueous sodium hydrogen carbonate (5 mL), and cooled to 0 ° C. Methanesulfonyl chloride (94 μL) was added and stirred at 0 ° C. for 1.5 hours. Aqueous ammonia (5 mL) was added, and the mixture was stirred at 0 ° C. for 2 hr. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 15/100) to give 5-amino-1- (2-methyl -1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[1-benzenesulfonyl-5- (4-methanesulfonylpiperazin-1-ylmethyl) -1H-indol-2-yl] -methanone (39 mg) was obtained.

¹ H-NMR (CD ₃ OD) δ: 8.09 (2.0 H, m), 7.98 (2.0 H, m), 7.84 (1.0 H, m), 7.75 (1. 0H, m), 7.65-7.57 (3.0 H, m), 7.53-7.40 (3.0 H, m), 7.12 (1.0 H, d, J = 3.9 Hz) ), 3.64 (2.0 H, m), 3.25-3.15 (4.0 H, m), 2.86 (3.0 H, s), 2.82 (3.0 H, s), 2.54 (4.0H, m)
ESI (LC-MS positive mode) m / z 673 [(M + H) ⁺ ]

５−ヒドロキシ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（１７５ｍｇ、０．４８ｍｍｏｌ）、トリフェニルホスフィン（１９７ｍｇ、０．７５ｍｍｏｌ）および２−プロパノール（０．２ｍＬ，４．０ｍｍｏｌ）の脱水テトラヒドロフラン（ＴＨＦ)溶液（２．５ｍＬ）に、アゾジカルボン酸ジイソプロピル（０．１５ｍＬ，０．７５ｍｍｏｌ）を加え、室温下、１時間攪拌した。反応混合物を減圧下濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィーで精製し、無色のガム状の５−イソプロポキシ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（１６６．７ｍｇ、８７％）を得た。 Step 11
Synthesis of 5-isopropoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1361)

5-hydroxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (175 mg, 0.48 mmol), triphenylphosphine (197 mg, 0.75 mmol) and 2-propanol (0.2 mL) , 4.0 mmol) in dehydrated tetrahydrofuran (THF) (2.5 mL) was added diisopropyl azodicarboxylate (0.15 mL, 0.75 mmol), and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography to give colorless gum-like 5-isopropoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid The ethyl ester (166.7 mg, 87%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 7.86 (1H, d, J = 9.1 Hz), 7.79 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.25 (1 H, s), 7.15 (1 H, d, J = 2.4 Hz), 7.04 (1 H, dd, J = 9.1, 2.4 Hz), 4.62-4.53 (1H, m), 4.34 (2H, q, J = 7.1 Hz), 2.34 (3H, s), 1.31 (3H, t, J = 7.1 Hz) ), 1.25 (6H, d, J = 6.1 Hz)
ESI (LC-MS positive mode) m / z 402 [(M + H) ⁺ ]

In the same manner as in Step 11, compound numbers 1362 to 1367 in Table 16 were synthesized.

５−ヒドロキシ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（１７３ｍｇ、０．４８ｍｍｏｌ）と炭酸カリウム（２７６ｍｇ、１．０ｍｍｏｌ）のアセトニトリル懸濁液（５．０ｍＬ）に、シクロプロピルメチル臭化物（０．０７２ｍＬ，０．７５ｍｍｏｌ）を加え、８０度で５時間攪拌した。反応混合物を室温に冷却した後、酢酸エチルおよび水を加え、酢酸エチルで抽出した。抽出液を水、および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィーで精製し、無色ガム状の５−シクロプロピルメトキシ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（１１２．５ｍｇ，５６％）を得た。 Step 12
Synthesis of 5-cyclopropylmethoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1368)

A suspension of 5-hydroxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (173 mg, 0.48 mmol) and potassium carbonate (276 mg, 1.0 mmol) in acetonitrile (5.0 mL) ) Was added cyclopropylmethyl bromide (0.072 mL, 0.75 mmol) and stirred at 80 degrees for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to give colorless gum-like 5-cyclopropylmethoxy-1- (toluene-4-sulfonyl) -1H-indole. 2-Carboxylic acid ethyl ester (112.5 mg, 56%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 7.87 (1H, d, J = 9.2 Hz), 7.76 (2H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.25 (1H, s), 7.11 (1H, d, J = 2.6 Hz), 7.07 (1H, dd, J = 9.2, 2.6 Hz), 4.33 (2H, q, J = 8.1 Hz), 3.80 (2H, d, J = 6.6 Hz), 2.33 (3H, s), 1.32 (3H, t, J = 8) .1Hz), 1.25-1.19 (1H, m), 0.58-0.52 (2H, m), 0.33-0.28 (2H, m)
ESI (LC-MS positive mode) m / z 414 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ヒドロキシ−１Ｈ−インドール−２−イル）−メタノン（２１ｍｇ、０．０５６ｍｍｏｌ）、トルエン−４−スルホン酸オキセタン−３−イルエステル（１９ｍｇ、０．０８４ｍｍｏｌ）、炭酸カリウム（１３ｍｇ、０．０９５ｍｍｏｌ）を脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)に溶解し、窒素雰囲気下、８０℃で６日間加熱撹拌した。反応混合物を室温まで冷却した後、水を加え、酢酸エチル／メタノール（１０／１）溶液で抽出した。有機層を分離、水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１００／３）で精製し、黄色固体の［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−（オキセタン−３−イルオキシ）−１Ｈ−インドール−２−イル］−メタノン（６．９ｍｇ、２９％）を得た。 Example 198
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (oxetane-3-yloxy) -1H-indol-2-yl] -Synthesis of methanone

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl) -methanone (21 mg, 0 0.056 mmol), toluene-4-sulfonic acid oxetane-3-yl ester (19 mg, 0.084 mmol), and potassium carbonate (13 mg, 0.095 mmol) were dissolved in dehydrated N, N-dimethylformamide (DMF) and a nitrogen atmosphere. Under stirring at 80 ° C. for 6 days. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with an ethyl acetate / methanol (10/1) solution. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (dichloromethane / methanol = 100/3) to give [5-amino-1- (2-methyl- 1H-Benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6- (oxetan-3-yloxy) -1H-indol-2-yl] -methanone (6.9 mg, 29%) was obtained. It was.

¹ H-NMR (DMSO-D ₆ ) δ: 12.48 (1.0 H, brs), 11.48 (1.0 H, brs), 8.28 (1.0 H, s), 7.62-7 .60 (3.0 H, m), 7.41 (1.0 H, brs), 7.28 (1.0 H, dd, J = 8.3, 2.0 Hz), 6.96 (1.0 H, brs), 6.94 (1.0 H, brs), 6.71 (1.0 H, dd, J = 8.5, 2.2 Hz), 6.67 (1.0 H, brs), 5.34- 5.29 (1.0 H, m), 4.94 (2.0 H, dd, J = 6.8, 6.8 Hz), 4.60 (2.0 H, dd, J = 6.8, 5. 1Hz), 2.53 (3.0H, s)
ESI (LC-MS positive mode) m / z 429 [(M + H) ⁺ ]

２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（トルエン−４−スルホニル）−１Ｈ−インドール−６−カルバルデヒド（６５０ｍｇ、１．０ｍｍｏｌ）、１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＩＩ）ジクロリド（４２ｍｇ、０．０５１ｍｍｏｌ）、ビス（ピナコラート）ジボロン（３１２ｍｇ、１．２３ｍｍｏｌ）、酢酸カリウム（３２３ｍｇ、３．３ｍｍｏｌ）を脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)（４．１ｍＬ）に溶解し、脱気した後、窒素雰囲気下、１００度で８時間加熱撹拌した。反応混合物を室温まで冷却した後、水を加え、析出した固体を濾取、水で洗浄後、乾燥し褐色固体（５３８ｍｇ）を得た。ここで得られた粗生成物を精製することなく、次反応に用いた。
ここで得られた褐色固体の粗生成物、４−メチルモルホリンＮ−オキシド（２５６ｍｇ、２．２ｍｍｏｌ）をテトラヒドロフラン（ＴＨＦ)（７．０ｍＬ）に溶解し、窒素雰囲気下、７０度で３時間半加熱撹拌した。反応混合物を室温まで冷却した後、水、酢酸エチルを加え、セライト（登録商標）により濾過し、濾液を有機層と水層に分離した。有機層を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（アミノシリカ、ジクロロメタン／メタノール＝１００／５〜１００／１０）で精製し、黄色アモルファスの［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−ヒドロキシ−１Ｈ−インドール−２−イル）−メタノン（１２３ｍｇ、二段階収率２３％）を得た。 Example 199
Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl) -methanone

2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-6-carba Rudehydr (650 mg, 1.0 mmol), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride (42 mg, 0.051 mmol), bis (pinacolato) diboron (312 mg, 1.23 mmol), potassium acetate ( (323 mg, 3.3 mmol) was dissolved in dehydrated N, N-dimethylformamide (DMF) (4.1 mL), degassed, and then heated and stirred at 100 ° C. for 8 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the precipitated solid was collected by filtration, washed with water, and dried to give a brown solid (538 mg). The crude product obtained here was used for the next reaction without purification.
The brown solid crude product obtained here, 4-methylmorpholine N-oxide (256 mg, 2.2 mmol), was dissolved in tetrahydrofuran (THF) (7.0 mL), and the mixture was maintained at 70 ° C. for 3.5 hours under nitrogen atmosphere. Stir with heating. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was filtered through Celite (registered trademark), and the filtrate was separated into an organic layer and an aqueous layer. The residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography (aminosilica, dichloromethane / methanol = 100/5 to 100/10) to give yellow amorphous [5-amino-1- (2-methyl -1H-Benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl) -methanone (123 mg, two-stage yield 23%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.51 (1.0 H, brs), 11.30 (1.0 H, brs), 9.40 (1.0 H, brs), 8.26 (1 .0H, s), 7.61-7.59 (2.0 H, m), 7.47 (1.0 H, d, J = 8.8 Hz), 7.34 (1.0 H, s), 7 .28 (1.0 H, d, J = 8.8 Hz), 6.91 (2.0 H, brs), 6.82 (1.0 H, s), 6.62 (1.0 H, d, J = 8.8 Hz), 2.53 (3.0 H, s)
ESI (LC-MS positive mode) m / z 373 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−３Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（１ｇ）、ヨウ化銅（Ｉ）（１６１ｍｇ）、ヨウ化ナトリウム（５０８ｍｇ）、trans−Ｎ，Ｎ’−ジメチルシクロヘキサン−１，２−ジアミン（２６７ｕＬ），および脱水ジオキサン（５ｍＬ）の混合液を、窒素雰囲気下、圧力容器中、１０５度から１１２度で２０時間撹拌した。反応混合物を２Ｍアンモニア水溶液にあけ、酢酸エチルで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン＝０／１００〜２０／１００）で精製し、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−ヨード−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（０．６７ｇ、６２％）を得た。 Step 13
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-iodo-1- (toluene-4-sulfonyl) -1H-indole- Synthesis of 2-yl] -methanone (1369)

[5-Amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-bromo-1- (toluene-4-sulfonyl) -1H-indole- 2-yl] -methanone (1 g), copper (I) iodide (161 mg), sodium iodide (508 mg), trans-N, N′-dimethylcyclohexane-1,2-diamine (267 uL), and dehydrated dioxane ( 5 mL) was stirred in a pressure vessel at 105 to 112 degrees for 20 hours under a nitrogen atmosphere. The reaction mixture was poured into 2M aqueous ammonia solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 20/100), and [5-amino-1- (2-methyl -1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-iodo-1- (toluene-4-sulfonyl) -1H-indol-2-yl] -methanone (0.67 g, 62%).

¹ H-NMR (DMSO-D ₆ ) δ: 12.44 (1.0 H, s), 8.30 (1.0 H, d, J = 0.6 Hz), 7.98 (2.0 H, d, J = 8.5 Hz), 7.75 (1.0 H, s), 7.66 (1.0 H, dd, J = 8.2, 1.4 Hz), 7.51 (1.0 H, d, J = 8.0 Hz), 7.46 (2.0 H, d, J = 8.5 Hz), 7.28 (1.0 H, d, J = 7.6 Hz), 7.23 (1.0 H, d, J = 0.4 Hz), 7.10-6.92 (2.0 H, m), 2.53 (3.0 H, s), 2.37 (3.0 H, s)
ESI (LC-MS positive mode) m / z 637 [(M + H) ⁺ ]

In the same manner as in Step 13, compound numbers 1370 and 1371 in Table 17 were synthesized.

２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（ベンゼンスルホニル）−５−ヨード−１Ｈ−インドール（１１７ｍｇ）、シアン化銅（Ｉ）（８４ｍｇ）および１−メチル−２−ピロリジノンの混合物を、マイクロウェーブ反応容器で反応させた（１９０度、２０分間）。反応混合物を、２Ｍアンモニア水（４０ｍＬ）、酢酸エチル（６０ｍＬ）、およびメタノール（７ｍＬ）の混合溶液に空け、５分間超音波をかけた。酢酸エチルで抽出し、抽出液を水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン＝０／１００〜２０／１００）で精製し、２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（ベンゼンスルホニル）−１Ｈ−インドール−５−カルボニトリル（８７ｍｇ、８９％）を得た。 Step 14
2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (benzenesulfonyl) -1H-indole-5-carbonitrile (1372) ) Synthesis

2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (benzenesulfonyl) -5-iodo-1H-indole (117 mg) , A mixture of copper (I) cyanide (84 mg) and 1-methyl-2-pyrrolidinone was reacted in a microwave reaction vessel (190 degrees, 20 minutes). The reaction mixture was emptied into a mixed solution of 2M aqueous ammonia (40 mL), ethyl acetate (60 mL), and methanol (7 mL), and sonicated for 5 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 20/100) to give 2- [5-amino-1- (2 -Methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (benzenesulfonyl) -1H-indole-5-carbonitrile (87 mg, 89%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.47 (1.0 H, d, J = 8.4 Hz), 8.27-8.21 (4.0 H, m), 7.86 (1. 0H, dd, J = 8.8, 1.8 Hz), 7.80-7.76 (2.0 H, m), 7.72-7.64 (3.0 H, m), 7.60-7 .55 (1.0 H, m), 7.35-7.25 (2.0 H, m), 7.12-7.02 (2.0 H, m), 2.54 (3.0 H, s)
ESI (LC-MS positive mode) m / z 522 [(M + H) ⁺ ]

In the same manner as in Step 14, compound numbers 1373 and 1374 in Table 18 were synthesized.

５−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（９４８．４ｍｇ、２．２４ｍｍｏｌ）、トリス(ジベンジリデンアセトン)二パラジウム(0)（０．１１２ｍｍｏｌ，１０３ｍｇ），４，５−ビス（ジフェニルホスフィノ）−９，９−ジメチルキサンテン（Xantphos）（０．２２５ｍｍｏｌ，１３０ｍｇ），ギ酸リチウム一水和物（５．６ｍｍｏｌ，３９４ｍｇ）、塩化リチウム（２８６ｍｇ、６．７５ｍｍｏｌ）、および脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)（５．９ｍＬ）の混合物を、脱気し、アルゴンで置換した後、Ｎ，Ｎ−ジイソプロピルエチルアミン（４．５ｍｍｏｌ，０．７８ｍＬ）および無水酢酸（４．５ｍｍｏｌ，０．４３ｍＬ）を加え、再度、脱気、アルゴン置換した。事前に８０度に加熱した反応装置に反応容器を設置し、２０時間攪拌した。反応混合物を室温に冷却した後、反応混合物を酢酸エチルと１Ｍ塩酸水溶液で薄め、セライトでろ過した。ここで得られたろ液を、１Ｍ塩酸水溶液、水、および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５／１から１／３、最終的には酢酸エチル／メタノール＝１５／１）で精製し、黄色のアモルファス状の１−（トルエン−４−スルホニル）−１Ｈ−インドール−２，５−ジカルボン酸２−エチルエステル（９３０ｍｇ）を得た。 Step 15
Synthesis of 1- (toluene-4-sulfonyl) -1H-indole-2,5-dicarboxylic acid 2-ethyl ester (1375)

5-Bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (948.4 mg, 2.24 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.112 mmol, 103 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.225 mmol, 130 mg), lithium formate monohydrate (5.6 mmol, 394 mg), lithium chloride (286 mg, 6.75 mmol), and a mixture of dehydrated N, N-dimethylformamide (DMF) (5.9 mL) was degassed and replaced with argon before N, N-diisopropylethylamine (4.5 mmol, 0.78 mL) And acetic anhydride (4.5 mmol, 0.43 mL) were added, degassed and purged with argon again. . A reaction vessel was placed in a reactor heated to 80 degrees in advance and stirred for 20 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with ethyl acetate and 1M aqueous hydrochloric acid and filtered through celite. The filtrate obtained here was washed with 1M aqueous hydrochloric acid, water, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1 to 1/3, finally ethyl acetate / methanol = 15/1). Purification gave yellow amorphous 1- (toluene-4-sulfonyl) -1H-indole-2,5-dicarboxylic acid 2-ethyl ester (930 mg).

¹ H-NMR (DMSO-D ₆ ) δ: 8.32 (1H, d, J = 1.5 Hz), 8.13 (1H, d, J = 8.8 Hz), 8.05 (1H, dd, J = 8.8, 1.5 Hz), 7.93 (2H, d, J = 8.2 Hz), 7.50 (1H, s), 7.46 (2H, d, J = 8.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 2.37 (3H, s), 1.34 (3H, t, J = 7.1 Hz)
ESI (LC-MS positive mode) m / z 388 [(M + H) ⁺ ]

工程１５と同様にして、２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１Ｈ−インドール−６−カルボン酸を合成した。 2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-6-carbon Synthesis of acid (1376)

In the same manner as in Step 15, 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1H-indole-6-carboxylic acid was synthesized. did.

ESI (LC-MS positive mode) m / z 555 [(M + H) ⁺ ]

１−（トルエン−４−スルホニル）−１Ｈ−インドール−２，５−ジカルボン酸２−エチルエステル（６９０ｍｇ，１．８５ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミドジ−tert−ブチルアセタール（３．０ｍＬ）に溶解し、８０度で２時間半攪拌した。さらに、Ｎ，Ｎ−ジメチルホルムアミドジ−tert−ブチルアセタール（２．０ｍＬ）を加え、８０度で３時間攪拌した。反応混合物を室温に冷却し、酢酸エチル（１５０ｍＬ）および水（７５ｍＬ）で希釈し、有機層を分離した。有機層を水、および飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２５／１から５／１）で精製し、１−（トルエン−４−スルホニル）−１Ｈ−インドール−２，５−ジカルボン酸５−tert−ブチルエステル２−エチルエステル（５５１ｍｇ，６９％）を得た。 Step 16
Synthesis of 1- (toluene-4-sulfonyl) -1H-indole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (1377)

1- (Toluene-4-sulfonyl) -1H-indole-2,5-dicarboxylic acid 2-ethyl ester (690 mg, 1.85 mmol) was added to N, N-dimethylformamide di-tert-butyl acetal (3.0 mL). Dissolved and stirred at 80 degrees for 2.5 hours. Further, N, N-dimethylformamide di-tert-butylacetal (2.0 mL) was added, and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL) and water (75 mL), and the organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 25/1 to 5/1) to give 1- (toluene-4-sulfonyl)- 1H-indole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (551 mg, 69%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 8.25 (1H, d, J = 1.4 Hz), 8.12 (1H, d, J = 8.8 Hz), 8.00 (1H, dd, J = 8.8, 1.4 Hz), 7.88 (2H, d, J = 8.0 Hz), 7.48 (1H, s), 7.43 (2H, d, J = 8.0 Hz), 4.37 (2H, q, J = 7.2 Hz), 2.37 (3H, s), 1.56 (9H, s), 1.34 (3H, t, J = 7.2 Hz)
ESI (LC-MS positive mode) m / z 444 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（１５０ｍｇ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（５４ｍｇ）、ヨウ化銅（Ｉ）（１０ｍｇ）、トリエチルアミン（０．７ｍＬ）、および脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)（０．７ｍＬ）を圧力容器に入れ、トリメチルシリルアセチレン（１５０ｍｇ）を加え、窒素下８０度から８５度で１５時間攪拌した。反応混合物を室温に冷却し、酢酸エチルで希釈後、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／ジクロロメタン＝０／１００％〜２０／１００）で精製し、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［１−（トルエン−４−スルホニル）−５−トリメチルシラニルエチニル−１Ｈ−インドール−２−イル］−メタノン（６５ｍｇ、４２％）を得た。 Step 17
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[1- (toluene-4-sulfonyl) -5-trimethylsilanylethynyl-1H -Indol-2-yl] -methanone (1378) synthesis

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5-bromo-1- (toluene-4-sulfonyl) -1H-indole- 2-yl] -methanone (150 mg), dichlorobis (triphenylphosphine) palladium (II) (54 mg), copper (I) iodide (10 mg), triethylamine (0.7 mL), and dehydrated N, N-dimethylformamide ( DMF) (0.7 mL) was placed in a pressure vessel, trimethylsilylacetylene (150 mg) was added, and the mixture was stirred at 80 to 85 degrees under nitrogen for 15 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol / dichloromethane = 0/100% to 20/100), and [5-amino-1- (2- Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[1- (toluene-4-sulfonyl) -5-trimethylsilanylethynyl-1H-indol-2-yl] -methanone ( 65 mg, 42%).

¹ H-NMR (DMSO-D ₆ ) δ: 12.48 (1H, d, J = 8.4 Hz), 8.04-7.95 (3H, m), 7.80 (1H, s), 7 .75 (1H, d, J = 3.7 Hz), 7.69-7.62 (1H, m), 7.62-7.54 (1H, m), 7.50 (1H, dd, J = 8.7, 1.7 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 7.9 Hz), 7.20 (1H, s), 7. 09-6.97 (2H, m), 2.54 (3H, s), 2.36 (3.0H, s), 0.23 (9.0H, s)
ESI (LC-MS positive mode) m / z 607 [(M + H) ⁺ ]

工程１７と同様にして、１−ベンゼンスルホニル−４−トリメチルシラニルエチニル−１Ｈ−インドール−２−カルボン酸エチルエステルを合成した。 Synthesis of 1-benzenesulfonyl-4-trimethylsilanylethynyl-1H-indole-2-carboxylic acid ethyl ester (1379)

In the same manner as in Step 17, 1-benzenesulfonyl-4-trimethylsilanylethynyl-1H-indole-2-carboxylic acid ethyl ester was synthesized.

ESI (LC-MS positive mode) m / z 426 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−ヨード−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（８０．３ｍｇ、０．１２６ｍｍｏｌ）、ヨウ化銅（Ｉ）（３７．５ｍｇ，０．１９７ｍｍｏｌ）、メタンスルホン酸アミド（３７．５ｍｇ，０．３９４ｍｍｏｌ）、ザルコシン（３６．２ｍｇ、０．４０６ｍｍｏｌ）、りん酸三カリウム（８６．０ｍｇ，９．４０５ｍｍｏｌ）を脱水１−メチル−２−ピロリジノン（０．３６ｍＬ）に溶解した。アルゴン雰囲気下、１４０度で３０分間加熱攪拌した。反応混合物を２０％塩化アンモニウム水溶液（２０ｍＬ）に滴下後、酢酸エチルで抽出した。有機層を２０％塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をアミノゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１５／１）で精製し、黄色アモルファス状のＮ−［２−［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−カルボニル］−１−（トルエン−４−スルホニル）−１Ｈ−インドール−６−イル］−メタンスルホンアミド（１７．９ｍｇ、２４％収率）を得た。 Step 18
N- [2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole- Synthesis of 6-yl] -methanesulfonamide (1380)

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-iodo-1- (toluene-4-sulfonyl) -1H-indole- 2-yl] -methanone (80.3 mg, 0.126 mmol), copper (I) iodide (37.5 mg, 0.197 mmol), methanesulfonic acid amide (37.5 mg, 0.394 mmol), sarcosine (36. 2 mg, 0.406 mmol) and tripotassium phosphate (86.0 mg, 9.405 mmol) were dissolved in dehydrated 1-methyl-2-pyrrolidinone (0.36 mL). The mixture was heated and stirred at 140 degrees for 30 minutes in an argon atmosphere. The reaction mixture was added dropwise to 20% aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate. The organic layer was washed with 20% aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by amino gel column chromatography (dichloromethane / methanol = 15/1) to give yellow amorphous N- [2- [5-amino- 1- (2-Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indol-6-yl] -methanesulfonamide (17 0.9 mg, 24% yield).

¹ H-NMR (DMSO-D ₆ ) δ: 12.47 (1H, s), 9.93 (1H, brs), 7.97 (1H, s), 7.94 (2H, d, J = 7) .9 Hz), 7.77 (1 H, s), 7.64-7.59 (3 H, m), 7.43 (2 H, d, J = 6.7 Hz), 7.29 (1 H, d, J = 7.9 Hz), 7.22-7.15 (2H, t, J = 5.2 Hz), 7.01 (2H, brs), 2.97 (3H, s), 2.53 (3H, s) ), 2.35 (3H, s)
ESI (LC-MS positive mode) m / z 604 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−メチルスルファニル−１Ｈ−インドール−２−イル）−メタノン（２３ｍｇ，０．０５７ｍｍｏｌ）をトリフルオロエタノール（５ｍＬ）に溶解し、オキソン（１０５ｍｇ，０．１７１ｍｍｏｌ）の水溶液（０．５ｍＬ）を加えて、窒素雰囲気下、室温で１．７５時間攪拌した。反応混合物を濾過し、濾液を濃縮後、得られた残渣をアミノゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝９９／１〜９２／８）で精製し［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−（６−メタンスルホニル−１Ｈ−インドール−２−イル）−メタノンを淡黄色固体（８ｍｇ、３２％）として得た。 Example 200
Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methanesulfonyl-1H-indol-2-yl) -methanone

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methylsulfanyl-1H-indol-2-yl) -methanone (23 mg, 0.057 mmol) was dissolved in trifluoroethanol (5 mL), an aqueous solution (0.5 mL) of oxone (105 mg, 0.171 mmol) was added, and the mixture was stirred at room temperature for 1.75 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by amino gel column chromatography (dichloromethane / methanol = 99/1 to 92/8) and purified by [5-amino-1- (2-methyl-1H). -Benzimidazol-5-yl) -1H-pyrazol-4-yl]-(6-methanesulfonyl-1H-indol-2-yl) -methanone was obtained as a pale yellow solid (8 mg, 32%).

¹ H-NMR (DMSO-D ₆ ) δ: 12.48 (1H, d, J = 4.9 Hz), 12.33 (1H, s), 8.35 (1H, d, J = 4.9 Hz) , 8.05 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.65-7.59 (4H, m), 7.31-7.27 (1H, m) 7.11 (2H, d, J = 21.4 Hz), 3.22 (3H, s), 2.54 (3H, s)
ESI (LC-MS positive mode) m / z 435 [(M + H) ⁺ ]

反応容器に６−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸メチルエステル（３００ｍｇ、０．７３ｍｍｏｌ）、酢酸パラジウム（１６．５ｍｇ、０．０７ｍｍｏｌ）、ビス（１，１−ジメチルエチル）フェニルホスフィン（０．０２８ｍＬ、０．１２ｍｍｏｌ）、シクロプロピルトリフルオロホウ酸カリウム（１６３ｍｇ、１．１ｍｍｏｌ）、炭酸セシウム（７１８ｍｇ、２．２ｍｍｏｌ）を量りとり、トルエン（５ｍＬ）、水（０．５ｍＬ）を加えた後に、１００度で１４時間攪拌した。室温に冷却後、混合物を酢酸エチルで希釈し、これを水で２回洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９７／３〜７／３）で精製し黄色固体（２０８ｍｇ、７７％）を得た。 Step 19
Synthesis of 6-cyclopropyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (1381)

In a reaction vessel, 6-bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (300 mg, 0.73 mmol), palladium acetate (16.5 mg, 0.07 mmol), bis (1 , 1-dimethylethyl) phenylphosphine (0.028 mL, 0.12 mmol), potassium cyclopropyltrifluoroborate (163 mg, 1.1 mmol), cesium carbonate (718 mg, 2.2 mmol), and toluene (5 mL) After adding water (0.5 mL), the mixture was stirred at 100 degrees for 14 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed twice with water and then dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 97 / 3-7 / 3) to give a yellow solid (208 mg, 77%). .

¹ H-NMR (DMSO-D ₆ ) δ: 7.82-7.80 (2H, m), 7.68 (1H, brs), 7.52 (1H, d, J = 8.2 Hz), 7 .42-7.39 (2H, m), 7.32 (1H, d, J = 0.8 Hz), 7.00 (1H, dd, J = 8.3, 1.5 Hz), 3.83 ( 3H, s), 2.33 (3H, s), 2.11-1.09 (1H, m), 1.03 (2H, ddd, J = 9.6, 5.2, 3.1 Hz), 0.73-0.70 (2H, m)
ESI (LC-MS positive mode) m / z 370 [(M + H) ⁺ ]

In the same manner as in Step 19, compound numbers 1382 to 1384 in Table 19 were synthesized.

Step 20
Synthesis of 5-imidazol-1-yl-1H-indole-2-carboxylic acid ethyl ester (1385)

[Hydrazone synthesis method]
Synthesis of 2-[(E) -4-imidazol-1-yl-phenylimino] -propionic acid ethyl ester 4-imidazol-1-yl-phenylamine (637 mg) was dissolved in 2M hydrochloric acid-MeOH (3 mL), Concentrated under reduced pressure. The residue was suspended in concentrated hydrochloric acid (1 mL), and an aqueous sodium nitrite solution (304 mg, 2.5 mL) was added dropwise at 0 ° C. over 30 minutes under ice cooling. The reaction mixture was slowly added dropwise to an aqueous solution prepared in advance from an aqueous hydrosulfite sodium solution (2.3 g, 13 mL) and a 5 M aqueous sodium hydroxide solution (400 μL) so that the internal temperature of the reaction mixture did not exceed 5 ° C. The mixture was further stirred at 25 ° C. for 1 hour. An ethanol solution (5 mL) of ethyl pyruvate (465 μL) was added dropwise to the reaction mixture, stirred at 50 ° C. for 30 minutes, and further stirred at 25 ° C. for 10 hours. A precipitate obtained by adjusting the pH to 11 with a 20% aqueous potassium phosphate solution (about 10 mL) was collected by filtration, dried, and 2-[(E) -4-imidazol-1-yl-phenylimino] -propionic acid. A pale yellow powder (1.1 g, 99%) of ethyl ester was obtained.

[Indole synthesis]
Synthesis of 5-imidazol-1-yl-1H-indole-2-carboxylic acid ethyl ester 2-[(E) -4-imidazol-1-yl-phenylimino] -propionic acid ethyl ester (842 mg) was added to Eaton's reagent ( 4 mL) and stirred at 100 ° C. for 1 hour. The reaction mixture was adjusted to pH 11 with 20% aqueous potassium phosphate solution (about 10 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL), the organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 5-imidazol-1-yl-1H-indole. A yellow amorphous crystal of -2-carboxylic acid ethyl ester (370 mg, 47%) was obtained.

ESI (LC-MS positive mode) m / z 256 [(M + H) ⁺ ]

In the same manner as in Step 20, compound numbers 1386 to 1394 in Table 20 were synthesized.

２−クロロ−５−ニトロ−フェノール（１．７ｇ，１０ｍｍｏｌ）、炭酸カリウム（２．７ｇ，２０ｍｍｏｌ）および脱水アセトニトリル（２０ｍＬ）の混合液に、シクロプロピルメチル臭化物（２．０ｍＬ，２０ｍｍｏｌ，２．０ｅｑ．）を加え、８０度で８時間攪拌した。反応混合物を室温に冷却した後、反応混合物をセライトろ過し、酢酸エチルで洗浄した。ろ液を減圧濃縮して得られた薄赤色固体の粗１−クロロ−２−シクロプロピルメトキシ−４−ニトロ−ベンゼンを得た。粗生成物は生成することなく、次の反応に用いた。 Step 21
Synthesis of 1-chloro-2-cyclopropylmethoxy-4-nitro-benzene (1395)

To a mixture of 2-chloro-5-nitro-phenol (1.7 g, 10 mmol), potassium carbonate (2.7 g, 20 mmol) and dehydrated acetonitrile (20 mL), cyclopropylmethyl bromide (2.0 mL, 20 mmol, 2. 0 eq.) Was added and stirred at 80 degrees for 8 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give a light red solid crude 1-chloro-2-cyclopropylmethoxy-4-nitro-benzene. The crude product was used in the next reaction without being produced.

¹ H-NMR (DMSO-D ₆ ) δ: 7.84 (1H, dd, J = 8.4, 2.5 Hz), 7.81 (1H, d, J = 2.5 Hz), 7.74 ( 1H, d, J = 8.4 Hz), 4.08 (2H, d, J = 7.1 Hz), 1.33-1.23 (1H, m), 0.63-0.59 (2H, m ), 0.41-0.37 (2H, m)

１−クロロ−２−シクロプロピルメトキシ−４−ニトロ−ベンゼン（２．３ｇ，１０ｍｍｏｌ）をエタノール（３０ｍＬ）および水（３０ｍＬ）に溶解し、そこに亜ジチオン酸ナトリウムを少しずつ加え、８０度で４時間半攪拌した。反応混合物を室温に冷却した後、５Ｍ塩酸水溶液（４０ｍＬ）を加え、室温で１時間攪拌した。その後、５Ｍ水酸化ナトリウム水溶液（４２ｍＬ）を加え、溶液をアルカリ性にし、酢酸エチルで抽出した。抽出液を水、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、薄黄色ガム状の４−クロロ−３−シクロプロピルメトキシ−フェニルアミン（１．４ｇ）を得た。 Step 22
Synthesis of 4-chloro-3-cyclopropylmethoxy-phenylamine (1396)

1-Chloro-2-cyclopropylmethoxy-4-nitro-benzene (2.3 g, 10 mmol) was dissolved in ethanol (30 mL) and water (30 mL), and sodium dithionite was added little by little at 80 ° C. Stir for 4 and a half hours. The reaction mixture was cooled to room temperature, 5M aqueous hydrochloric acid solution (40 mL) was added, and the mixture was stirred at room temperature for 1 hr. Thereafter, 5M aqueous sodium hydroxide solution (42 mL) was added to make the solution alkaline and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain light yellow gum-like 4-chloro-3-cyclopropylmethoxy-phenylamine (1.4 g). It was.

¹ H-NMR (DMSO-D ₆ ) δ: 6.95 (1H, d, J = 8.3 Hz), 6.28 (1H, d, J = 2.4 Hz), 6.11 (1H, dd, J = 8.3, 2.4 Hz), 5.19 (2H, s), 3.76 (2H, d, J = 7.1 Hz), 1.24-1.18 (1H, m), 0. 59-0.54 (2H, m), 0.35-0.30 (2H, m)
ESI (LC-MS positive mode) m / z 198,200 [(M + H) ⁺ ]

４−ブロモ−３−トリフルオロメチルアニリン（１．２ｇ，１．０ｍｍｏｌ）、硫酸銀（１．７２ｇ，５．５ｍｍｏｌ，１．１ｅｑ．）および脱水エタノール（３５ｍＬ）の混合液に、ヨウ素（１．４ｇ，５．５ｍｍｏｌ，１．１ｅｑ．）を少しずつ加え、室温で２時間半攪拌した。反応混合物をセライトろ過し、酢酸エチルで洗浄した。洗浄液を１０％チオ硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液、および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた固体の粗４−ブロモ−２−ヨード−５−トリフルオロメチル−フェニルアミンを得た。ここで得られた粗生成物は、精製することなく、次の反応に用いた。 Step 23
Synthesis of 4-bromo-2-iodo-5-trifluoromethyl-phenylamine (1397)

To a mixture of 4-bromo-3-trifluoromethylaniline (1.2 g, 1.0 mmol), silver sulfate (1.72 g, 5.5 mmol, 1.1 eq.) And dehydrated ethanol (35 mL), iodine (1 .4 g, 5.5 mmol, 1.1 eq.) Was added little by little, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The washing solution was washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure to obtain solid crude 4-bromo-2-iodo-5-trifluoromethyl-phenylamine. The crude product obtained here was used for the next reaction without purification.

¹ H-NMR (DMSO-D ₆ ) δ: 7.94 (1H, s), 7.15 (1H, s), 5.86 (2H, s)
ESI (LC-MS positive mode) m / z 366, 368 [(M + H) ⁺ ]

In the same manner as in Step 23, compound numbers 1398 to 1402 in Table 21 were synthesized.

４−ブロモ−２−ヨード−５−トリフルオロメチル−フェニルアミン（３６６ｍｇ，１．０ｍｍｏｌ）およびｐ−トルエンスルホニルクロリド（２８６ｍｇ，１．５ｍｍｏｌ，１．５ｅｑ．）を、脱水ピリジン（２．５ｍＬ）に溶解し、室温で１６時間攪拌した。反応混合物に１Ｍ水酸化ナトリウム水溶液を加え、５分間攪拌した。反応混合物を酢酸エチルで希釈後、有機層を分離し、１Ｍ塩酸水溶液、および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をテトラヒドロフラン（ＴＨＦ)（２．５ｍＬ）に溶解し、１Ｍフッ化テトラブチルアンモニウムのテトラヒドロフラン（ＴＨＦ)溶液を加え、室温で１７時間攪拌した。反応混合物を酢酸エチルで希釈し、有機層を分離し、水および飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィーで精製し、薄茶色固体のＮ−（４−ブロモ−２−ヨード−５−トリフルオロメチル−フェニル）−４−メチル−ベンゼンスルホンアミド（４９４ｍｇ，９５％３工程収率）を得た。 Step 24
Synthesis of N- (4-bromo-2-iodo-5-trifluoromethyl-phenyl) -4-methyl-benzenesulfonamide (1403)

4-Bromo-2-iodo-5-trifluoromethyl-phenylamine (366 mg, 1.0 mmol) and p-toluenesulfonyl chloride (286 mg, 1.5 mmol, 1.5 eq.) Were added to dehydrated pyridine (2.5 mL). And stirred at room temperature for 16 hours. 1M aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 5 minutes. After the reaction mixture was diluted with ethyl acetate, the organic layer was separated, washed with 1M aqueous hydrochloric acid solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, concentrated, and the residue obtained by concentration under reduced pressure was dissolved in tetrahydrofuran (THF) (2.5 mL). Stir. The reaction mixture was diluted with ethyl acetate, the organic layer was separated, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a light brown solid N- (4-bromo-2-iodo-5-trifluoromethyl-phenyl). -4-Methyl-benzenesulfonamide (494 mg, 95% 3 step yield) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 10.10 (1H, s), 8.34 (1H, s), 7.58 (2H, d, J = 8.2 Hz), 7.39 (2H , D, J = 8.2 Hz), 7.27 (1H, s), 2.38 (3H, s)
ESI (LC-MS positive mode) m / z 520,522 [(M + H) ⁺ ]

In the same manner as in Step 24, compound numbers 1404 to 1408 in Table 22 were synthesized.

Ｎ−（４−ブロモ−２−ヨード−５−トリフルオロメチル−フェニル）−４−メチル−ベンゼンスルホンアミド（２０８ｍｇ，０．４ｍｍｏｌ）、臭化亜鉛（２７０ｍｇ，１．２ｍｍｏｌ）の脱水テトラヒドロフラン（ＴＨＦ)溶液（３．２ｍＬ）に、Ｎ，Ｎ−ジイソプロピルエチルアミン（０．４２ｍＬ，２．４ｍｍｏｌ）、プロピオン酸エチル（０．１２ｍＬ，１．２ｍｍｏｌ）、およびテトラキス（トリフェニルホスフィン）パラジウム（４６ｍｇ，０．０４ｍｍｏｌ）を加えた後、脱気し、アルゴンで置換し、８０度で１３時間攪拌した。反応混合物を室温に冷却した後、反応混合物をセライトろ過し、酢酸エチルで洗浄した。洗浄液を飽和炭酸水素ナトリウム水溶液、および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、薄茶固体の５−ブロモ−１−（トルエン−４−スルホニル）−６−トリフルオロメチル−１Ｈ−インドール−２−カルボン酸エチルエステル（１９５ｍｇ，５０％）を得た。 Step 25
Synthesis of 5-bromo-1- (toluene-4-sulfonyl) -6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (1409)

N- (4-Bromo-2-iodo-5-trifluoromethyl-phenyl) -4-methyl-benzenesulfonamide (208 mg, 0.4 mmol), zinc bromide (270 mg, 1.2 mmol) in anhydrous tetrahydrofuran (THF) ) Solution (3.2 mL) was added N, N-diisopropylethylamine (0.42 mL, 2.4 mmol), ethyl propionate (0.12 mL, 1.2 mmol), and tetrakis (triphenylphosphine) palladium (46 mg, 0 .04 mmol) was added, then degassed, purged with argon, and stirred at 80 degrees for 13 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was filtered through celite and washed with ethyl acetate. The washing solution was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a light brown solid of 5-bromo-1- (toluene-4-sulfonyl) -6-trifluoromethyl-1H. -Indole-2-carboxylic acid ethyl ester (195 mg, 50%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 8.37 (1H, s), 8.29 (1H, s), 7.89 (2H, d, J = 8.2 Hz), 7.47 (2H , D, J = 8.2 Hz), 7.43 (1H, s), 4.36 (2H, q, J = 7.1 Hz), 2.38 (3H, s), 1.30 (3H, t , J = 7.1 Hz)
ESI (LC-MS positive mode) m / z 490, 492 [(M + H) ⁺ ]

In the same manner as in Step 25, compound numbers 1410 to 1414 in Table 23 were synthesized.

酢酸パラジウム（８．４ｍｇ、０．０３７ｍｍｏｌ）、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリ−ｉ−プロピル−１，１’−ビフェニル（Ｘ−ＰＨＯＳ）（３５．６ｍｇ、０．０７４ｍｍｏｌ）をtert−アミルアルコール（１０μｌ、０．０９３ｍｍｏｌ）、脱水エチレングリコールジメチルエーテル（０．２５ｍＬ）に溶解し、窒素雰囲気下、６０℃で５分間加熱撹拌し、触媒を調製した。別反応容器にて窒素雰囲気下、１−ブロモ−３，５−ジ−ｔ−ブチル−ベンゼン（５０１ｍｇ、１．９ｍｍｏｌ）、リチウムビス（トリメチルシリル）アミド（４７５ｍｇ、２．８ｍｍｏｌ）、ベンゾフェノンヒドラゾン（４０１ｍｇ、２．０ｍｍｏｌ）を脱水エチレングリコールジメチルエーテル（２．５ｍＬ）に溶解し、調製した触媒を含む溶液を加え、脱気した後、窒素雰囲気下、９０℃２時間加熱撹拌した。反応混合物を室温まで冷却した後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１００／５）で精製し、黄色アモルファス状のＮ−ベンズヒドリリデン−Ｎ’−（３，５−ジ−tert−ブチル−フェニル）−ヒドラジン（６９９ｍｇ、９７．７％）を得た。 Step 26
Synthesis of N-benzhydrylidene-N ′-(3,5-di-tert-butyl-phenyl) -hydrazine (1415)

Palladium acetate (8.4 mg, 0.037 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-tri-i-propyl-1,1′-biphenyl (X-PHOS) (35.6 mg, 0 0.074 mmol) was dissolved in tert-amyl alcohol (10 μl, 0.093 mmol) and dehydrated ethylene glycol dimethyl ether (0.25 mL), and the mixture was heated and stirred at 60 ° C. for 5 minutes in a nitrogen atmosphere to prepare a catalyst. In a nitrogen atmosphere in a separate reaction vessel, 1-bromo-3,5-di-t-butyl-benzene (501 mg, 1.9 mmol), lithium bis (trimethylsilyl) amide (475 mg, 2.8 mmol), benzophenone hydrazone (401 mg) , 2.0 mmol) was dissolved in dehydrated ethylene glycol dimethyl ether (2.5 mL), a solution containing the prepared catalyst was added, degassed, and then heated and stirred at 90 ° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100/5) to give yellow amorphous N-benzhydrylidene-N ′-( 3,5-Di-tert-butyl-phenyl) -hydrazine (699 mg, 97.7%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 8.72 (1.0 H, s), 7.63-7.53 (3.0 H, m), 7.42-7.25 (7.0 H, m), 7.11 (2.0H, s), 6.83 (1.0H, s), 1.26 (18.0H, s)
ESI (LC-MS positive mode) m / z 385 [(M + H) ⁺ ]

Ｎ−ベンズヒドリリデン−Ｎ’−（３，５−ジ−tert−ブチル−フェニル）−ヒドラジン（６１７ｍｇ、１．６ｍｍｏｌ）をエタノール（１２ｍＬ）に溶解し、ピルビン酸エチル（２１２μｌ、１．９ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物（９１４ｍｇ、４．８ｍｍｏｌ）を加え、窒素雰囲気下、マイクロウェーブにて１５０℃で１時間加熱撹拌した。反応混合物を室温まで冷却した後、飽和炭酸水素ナトリウム水溶液、水を加え、生成物を酢酸エチル中に抽出した。有機層を分離し、飽和塩化ナトリウム水溶液で洗浄し、硫酸マグネシウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１００／５）で精製し、褐色固体の４，６−ジ−ｔｅｒｔ−ブチル−１Ｈ−インドール−２−カルボン酸 エチル エステル（２６８ｍｇ、５６％）を得た。 Step 27
Synthesis of 4,6-di-tert-butyl-1H-indole-2-carboxylic acid ethyl ester (1416)

N-benzhydrylidene-N ′-(3,5-di-tert-butyl-phenyl) -hydrazine (617 mg, 1.6 mmol) was dissolved in ethanol (12 mL) and ethyl pyruvate (212 μl, 1.9 mmol) was dissolved. , P-toluenesulfonic acid monohydrate (914 mg, 4.8 mmol) was added, and the mixture was heated and stirred at 150 ° C. for 1 hour in a microwave under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added, and the product was extracted into ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100/5) to give 4,6-di-tert-butyl-1H as a brown solid. -Indole-2-carboxylic acid ethyl ester (268 mg, 56%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 11.76 (1.0 H, brs), 7.27 (1.0 H, s), 7.22-7.22 (1.0 H, brm), 7 .04-7.03 (1.0H, brm), 4.33 (2.0H, q, J = 7.2 Hz), 1.44 (9.0H, s), 1.36-1.32 ( 12.0H, m)
ESI (LC-MS positive mode) m / z 302 [(M + H) ⁺ ]

６−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸メチルエステル（２０２．０ｍｇ，０．４９５ｍｍｏｌ），ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（３５．６ｍｇ，０．０５１ｍｍｏｌ）、ビスピナコールジボラン（１８９．３ｍｇ，０．７４５ｍｍｏｌ），酢酸カリウム（１４７．３ｍｇ，１．５１ｍｍｏｌ）、ジオキサン（１．６ｍＬ）を混合し、減圧下、アルゴンで３回置換し、１２０度で３０分間マイクロウェーブを照射した。反応混合物にジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（３５．６ｍｇ，０．０５１ｍｍｏｌ）と２−ブロモ−５−フルオロピリジン（２０６．９ｍｇ，１．４８ｍｍｏｌ）を加え、脱気をした後、アルゴンで３回置換し、１００度で３時間加熱攪拌した。反応混合物を酢酸エチルで抽出し、抽出液を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をアミノゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝７／１００〜６３／１００）で精製し、６−（５−フルオロ−ピリジン−２−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸メチルエステルを薄黄色アモルファス（１５０．５ｍｇ、７２％収率）で得た。 Step 28
6- (5-Fluoro-pyridin-2-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (1417)

6-Bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (202.0 mg, 0.495 mmol), dichlorobis (triphenylphosphine) palladium (II) (35.6 mg, 0 .051 mmol), bispinacol diborane (189.3 mg, 0.745 mmol), potassium acetate (147.3 mg, 1.51 mmol), dioxane (1.6 mL), mixed with argon three times under reduced pressure, Microwave was irradiated for 30 minutes. Dichlorobis (triphenylphosphine) palladium (II) (35.6 mg, 0.051 mmol) and 2-bromo-5-fluoropyridine (206.9 mg, 1.48 mmol) were added to the reaction mixture, and after degassing, argon was added. For 3 hours, and heated and stirred at 100 degrees for 3 hours. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The residue obtained was purified by amino gel column chromatography (n-hexane / ethyl acetate = 7/100 to 63/100) to give 6- (5-fluoro- Pyridin-2-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester was obtained as a pale yellow amorphous (150.5 mg, 72% yield).

¹ H-NMR (CDCl ₃ ) δ: 8.70 (1H, s), 8.59 (1H, d, J = 2.7 Hz), 7.93 (3H, d, J = 8.2 Hz), 7 .83 (1H, dd, J = 8.8, 3.8 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.53 (1H, td, J = 8.4, 2.9 Hz) ), 7.29-7.25 (2H, m), 7.19 (1H, s), 3.95 (3H, s), 2.37 (3H, s)
ESI (LC-MS positive mode) m / z 425 [(M + H) ⁺ ]

In the same manner as in Step 28, compound numbers 1418 to 1427 in Table 24 were synthesized.

ジオキサン（０．６ｍＬ）、［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（６０ｍｇ、０．１０２ｍｍｏｌ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（１４ｍｇ、０．０２０ｍｍｏｌ）、２−メトキシ−５−ピリジンボロン酸（３９ｍｇ、０．２５５ｍｍｏｌ）および２Ｍ炭酸ナトリウム水溶液（０．２５５ｍＬ、０．５１ｍｍｏｌ）の混合物をマイクロウェーブリアクターを用いて１４０℃で６分間攪拌した。反応混合物をセライトにより濾過して、酢酸エチル続いてメタノールで洗浄し、濾液を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、得られた残渣をアミノゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝９９／１〜９２／８）で精製し、淡黄色固体の［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［５−（６−メトキシ−ピリジン−３−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（５４ｍｇ、８５％）を得た。 Step 29
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-methoxy-pyridin-3-yl) -1- (toluene) Synthesis of -4-sulfonyl) -1H-indol-2-yl] -methanone (1428)

Dioxane (0.6 mL), [5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl]-[5-bromo-1- (toluene-4- Sulfonyl) -1H-indol-2-yl] -methanone (60 mg, 0.102 mmol), dichlorobis (triphenylphosphine) palladium (II) (14 mg, 0.020 mmol), 2-methoxy-5-pyridineboronic acid (39 mg , 0.255 mmol) and 2M aqueous sodium carbonate (0.255 mL, 0.51 mmol) were stirred at 140 ° C. for 6 min using a microwave reactor. The reaction mixture was filtered through celite, washed with ethyl acetate followed by methanol, and the filtrate was dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated, and the resulting residue was purified by amino gel column chromatography (dichloromethane / methanol = 99/1 to 92/8) to give [5-amino-1- (2- Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[5- (6-methoxy-pyridin-3-yl) -1- (toluene-4-sulfonyl) -1H-indole- 2-yl] -methanone (54 mg, 85%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 12.50 (1H, s), 8.50 (1H, d, J = 2.4 Hz), 8.08-8.04 (4H, m), 7 .94 (1H, d, J = 1.8 Hz), 7.77 (1H, s), 7.74 (1H, dd, J = 9.1, 1.8 Hz), 7.63-7.61 ( 2H, m), 7.46-7.40 (2H, m), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.25 (1H, s), 7.06 ( 2H, s), 6.93 (1H, d, J = 8.5 Hz), 3.90 (3H, s), 2.54 (3H, s), 2.37 (3H, s)
ESI (LC-MS positive mode) m / z 618 [(M + H) ⁺ ]

In the same manner as in Step 29, compound numbers 1429 to 1462 and 1580 to 1590 in Table 25 were synthesized.

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−ヨード−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（１９４．９ｍｇ，０．３０６ｍｍｏｌ），［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）−ジクロロメタン付加体（１４．４ｍｇ，０．０１５ｍｍｏｌ）ビスピナコールジボラン（１００．９ｍｇ，０．３９７ｍｍｏｌ），酢酸カリウム（１３２．３ｍｇ，１．３５ｍｍｏｌ）、脱水ジメチルスルホキシド（ＤＭＳＯ）（１．５ｍＬ）の混合物を、脱気後、アルゴンで３回置換し、１１０度で６時間加熱攪拌した。反応混合物を酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１５／１）を通して得られた粗生成物に４−ブロモピリダジン（７８．０ｍｇ、０．４９１ｍｏｌ）ジクロロビス（トリフェニルホシン）パラジウム（ＩＩ）（１７．２ｍｇ，０．０２５ｍｍｏｌ）、２Ｍ−炭酸ナトリウム水溶液（０．３２５ｍｍｏｌ）とジオキサン（０．４ｍＬ）を混合した。脱気後、アルゴンで３回置換し、１５０度で５分間マイクロウェーブを照射した。反応混合物を酢酸エチルで抽出し、抽出液を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１％〜１２％）で精製し、薄黄色アモルファスの［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［６−ピリダジン−４−イル−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−イル］−メタノン（２０．０ｍｇ、１１％収率）を得た。 Step 30
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-pyridazin-4-yl-1- (toluene-4-sulfonyl)- Synthesis of 1H-indol-2-yl] -methanone (1463)

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-iodo-1- (toluene-4-sulfonyl) -1H-indole- 2-yl] -methanone (194.9 mg, 0.306 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (14.4 mg, 0.015 mmol) bispinacol A mixture of diborane (100.9 mg, 0.397 mmol), potassium acetate (132.3 mg, 1.35 mmol) and dehydrated dimethyl sulfoxide (DMSO) (1.5 mL) was degassed and replaced with argon three times. The mixture was heated and stirred for 6 hours. The reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was passed through silica gel column chromatography (dichloromethane / methanol = 15/1) to give the crude product 4-bromopyridazine (78.0 mg, 0. (491 mol) Dichlorobis (triphenylfosine) palladium (II) (17.2 mg, 0.025 mmol), 2M-sodium carbonate aqueous solution (0.325 mmol) and dioxane (0.4 mL) were mixed. After deaeration, the gas was replaced with argon three times and irradiated with microwaves at 150 degrees for 5 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 1% to 12%) to give pale yellow amorphous [5-amino-1- (2 -Methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[6-pyridazin-4-yl-1- (toluene-4-sulfonyl) -1H-indol-2-yl]- Methanone (20.0 mg, 11% yield) was obtained.

ESI (LC-MS positive mode) m / z 589 [(M + H) ⁺ ]

反応容器に水素化アルミニウムリチウム（１６７ｍｇ、４．４２ｍｍｏｌ）を量りとり、脱水テトラヒドロフラン（ＴＨＦ)（１５ｍＬ）を加え、０度に冷却した。得られた混合物に対して１−ベンゼンスルホニル−１Ｈ−インドール−６−カルボン酸メチルエステル（９３０ｍｇ、２．９５ｍｍｏｌ）の脱水テトラヒドロフラン（ＴＨＦ)（５ｍＬ）溶液を加え、さらに０度で３０分間攪拌した。混合物に飽和塩化アンモニウム水溶液（１ｍＬ）を加えた後、セライトろ過し、セライトをジクロロメタンで洗浄した。ろ液を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して、茶色油状物質の（１−ベンゼンスルホニル−１Ｈ−インドール−６−イル）−メタノール（８５９ｍｇ、１００％）を得た。 Step 31
Synthesis of (1-benzenesulfonyl-1H-indol-6-yl) -methanol (1464)

Lithium aluminum hydride (167 mg, 4.42 mmol) was weighed into a reaction vessel, dehydrated tetrahydrofuran (THF) (15 mL) was added, and the mixture was cooled to 0 ° C. A solution of 1-benzenesulfonyl-1H-indole-6-carboxylic acid methyl ester (930 mg, 2.95 mmol) in dehydrated tetrahydrofuran (THF) (5 mL) was added to the resulting mixture, and the mixture was further stirred at 0 ° C. for 30 minutes. . A saturated aqueous ammonium chloride solution (1 mL) was added to the mixture, and the mixture was filtered through celite, and the celite was washed with dichloromethane. The filtrate was dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure to give (1-benzenesulfonyl-1H-indol-6-yl) -methanol (859 mg, 100%) as a brown oily substance.

¹ H-NMR (DMSO-D ₆ ) δ: 7.96-7.92 (3H, m), 7.74 (1H, d, J = 3.7 Hz), 7.68-7.67 (1H, m), 7.60-7.55 (2H, m), 7.52 (1H, d, J = 8.0 Hz), 7.19-7.17 (1H, m), 6.80 (1H, dd, J = 3.7, 0.8 Hz), 5.30 (1H, t, J = 5.7 Hz), 4.59 (2H, d, J = 5.7 Hz)
ESI (LC-MS positive mode) m / z 288 [(M + H) ⁺ ]

反応容器に１−ベンゼンスルホニル−１Ｈ−インドール−６−イル）−メタノール（８５９ｍｇ、２．９９ｍｍｏｌ）、tert−ブチルジフェニルクロロシラン（２．３ｍＬ、８．９７ｍｍｏｌ）、イミダゾール（１．２ｇ、１７．９ｍｍｏｌ）を量りとり、ジメチルホルムアミド（３０ｍＬ）を加え、室温で２０時間攪拌した。反応混合物を酢酸エチル（６０ｍＬ）で希釈し、水で２回洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮して得られた粗生成物をそのまま次の反応に用いた。 Step 32
Synthesis of 1-benzenesulfonyl-6- (tert-butyl-diphenyl-silanyloxymethyl) -1H-indole (1465)

In a reaction vessel, 1-benzenesulfonyl-1H-indol-6-yl) -methanol (859 mg, 2.99 mmol), tert-butyldiphenylchlorosilane (2.3 mL, 8.97 mmol), imidazole (1.2 g, 17.9 mmol) ), Dimethylformamide (30 mL) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (60 mL), washed twice with water, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the crude product obtained by concentration was directly used in the next reaction.

ESI (LC-MS positive mode) m / z 526 [(M + H) ⁺ ]

１．０Ｍｎ−ブチルリチウムのヘキサン溶液（２．８ｍＬ、４．４９ｍｍｏｌ）を、０℃に冷却したＮ，Ｎ−ジイソプロピルアミン（０．６４ｍＬ、４．４９ｍｍｏｌ）の脱水テトラヒドロフラン（ＴＨＦ)（５ｍＬ）溶液に滴下し、リチウムジイソプロピルアミド（ＬＤＡ）のテトラヒドロフラン（ＴＨＦ)溶液を調製した。
粗１−ベンゼンスルホニル−６−（tert−ブチル−ジフェニル−シラニルオキシメチル）−１Ｈ−インドールの脱水テトラヒドロフラン（ＴＨＦ)（２０ｍＬ）溶液を、−７８℃に冷却し、調製したリチウムジイソプロピルアミド（ＬＤＡ）のテトラヒドロフラン（ＴＨＦ)溶液を加え、−７８℃で３０分間撹拌した。クロロぎ酸メチル（０．４３ｍＬ、５．９８ｍｍｏｌ）を加え、さらにー７８度で３０分間攪拌した。反応混合物に、飽和塩化アンモニウム水溶液を加え、室温に昇温し、酢酸エチルで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９８／２〜４／１）で精製し、茶色アモルファス状の１−ベンゼンスルホニル−６−（tert−ブチル−ジフェニル−シラニルオキシメチル）−１Ｈ−インドール−２−カルボン酸メチルエステルを（８８２ｍｇ、５１％）を得た。 Step 33
Synthesis of 1-benzenesulfonyl-6- (tert-butyl-diphenyl-silanyloxymethyl) -1H-indole-2-carboxylic acid methyl ester (1466)

A 1.0 Mn-butyllithium hexane solution (2.8 mL, 4.49 mmol) was cooled to 0 ° C. with a solution of N, N-diisopropylamine (0.64 mL, 4.49 mmol) in anhydrous tetrahydrofuran (THF) (5 mL). Was added dropwise to prepare a solution of lithium diisopropylamide (LDA) in tetrahydrofuran (THF).
A solution of crude 1-benzenesulfonyl-6- (tert-butyl-diphenyl-silanyloxymethyl) -1H-indole in dehydrated tetrahydrofuran (THF) (20 mL) was cooled to −78 ° C. and prepared lithium diisopropylamide (LDA). ) In tetrahydrofuran (THF) was added, and the mixture was stirred at −78 ° C. for 30 minutes. Methyl chloroformate (0.43 mL, 5.98 mmol) was added, and the mixture was further stirred at −78 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was warmed to room temperature, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 98/2 to 4/1) to give brown amorphous 1-benzenesulfonyl-6. -(Tert-Butyl-diphenyl-silanyloxymethyl) -1H-indole-2-carboxylic acid methyl ester was obtained (882 mg, 51%).

ESI (LC-MS positive mode) m / z 584 [(M + H) ⁺ ]

５−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（８４４ｍｇ，２．０ｍｍｏｌ）、４−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−３，６−ジヒドロ−２Ｈ−ピリジン−１−カルボン酸tert−ブチルエステル（７４２ｍｇ，２．４ｍｍｏｌ）、リン酸カリウム（８４８ｍｇ，４．０ｍｍｏｌ）、およびテトラキス（トリフェニルホスフィン）パラジウム（１１６ｍｇ，０．１ｍｍｏｌ）をフラスコに入れ、脱気し、窒素置換した。そこへ脱水ジオキサン（１６ｍＬ）、および水（４mＬ）を加え、８０℃で１５時間攪拌した。反応混合物を室温に冷却した後、セライトろ過し、酢酸エチルで洗浄した。ろ液を濃縮し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、無色アモルファス状の５−（１−tert−ブトキシカルボニル−１，２，３，６−テトラヒドロ−ピリジン−４−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（１．０ｇ，９７．２％）を得た。 Step 34
5- (1-tert-Butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1467) Synthesis of

5-Bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (844 mg, 2.0 mmol), 4- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (742 mg, 2.4 mmol), potassium phosphate (848 mg, 4.0 mmol), and tetrakis ( Triphenylphosphine) palladium (116 mg, 0.1 mmol) was placed in a flask, degassed and purged with nitrogen. Dehydrated dioxane (16 mL) and water (4 mL) were added thereto, and the mixture was stirred at 80 ° C. for 15 hours. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain colorless amorphous 5- (1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridine-4). -Yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1.0 g, 97.2%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 7.96 (1H, d, J = 9.1 Hz), 7.84 (2H, d, J = 8.2 Hz), 7.68 (1H, d, J = 1.8 Hz), 7.60 (1H, dd, J = 9.1, 1.8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.34 (1H, s), 6.17 (1H, s), 4.34 (2H, q, J = 7.0 Hz), 4.02-3.98 (2H, m), 3.57-3.51 (2H, m), 2.51-2.45 (1H, m), 2.34 (3H, s), 1.42 (9H, s), 1.32 (3H, t, J = 7.0 Hz)
ESI (LC-MS positive mode) m / z 525 [(M + H) ⁺ ]

In the same manner as in Step 34, compound numbers 1468 and 1469 in Table 26 were synthesized.

５−（１−tert−ブトキシカルボニル−１，２，３，６−テトラヒドロ−ピリジン−４−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（４９５ｍｇ，０．９ｍｍｏｌ）、５％パラジウム炭素（１００ｍｇ）、およびメタノール（２０ｍＬ）の混合液を、水素雰囲気下、１３時間攪拌した。反応混合物をセライトろ過し、酢酸エチルで洗浄した。ろ液を濃縮し、減圧濃縮で得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、無色アモルファス状の５−（１−tert−ブトキシカルボニル−ピペリジン−４−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（３１５．９ｍｇ，６４％）を得た。 Step 35
Synthesis of 5- (1-tert-butoxycarbonyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1470)

5- (1-tert-Butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (495 mg, 0.9 mmol), a mixture of 5% palladium on carbon (100 mg) and methanol (20 mL) was stirred under a hydrogen atmosphere for 13 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain colorless amorphous 5- (1-tert-butoxycarbonyl-piperidin-4-yl) -1- (toluene-4- Sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (315.9 mg, 64%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 7.92 (1H, d, J = 8.8 Hz), 7.87 (2H, d, J = 7.9 Hz), 7.53 (1H, d, J = 1.5 Hz), 7.42 (2H, d, J = 7.9 Hz), 7.39 (1H, dd, J = 8.8, 1.5 Hz), 7.30 (1H, s), 4.33 (2H, q, J = 7.0 Hz), 4.12-4.00 (2H, m), 2.85-2.70 (3H, m), 2.35 (3H, s), 1.78-1.70 (2H, m), 1.54-1.44 (2H, m), 1.41 (9H, s), 1.31 (3H, t, J = 7.0 Hz)
ESI (LC-MS positive mode) m / z 527 [(M + H) ⁺ ]

In the same manner as in Step 35, compound numbers 1471 and 1472 in Table 27 were synthesized.

５−（１−tert−ブトキシカルボニル−ピペリジン−４−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル（３６２ｍｇ、０．６８７ｍｍｏｌ）を酢酸エチル（４ｍＬ）および４Ｍ塩酸酢酸エチル溶液（８ｍＬ）の混合溶液に溶解し、窒素雰囲気下、室温で１．５時間攪拌した。反応混合物を減圧濃縮して無色アモルファス状の５−ピペリジン−４−イル−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル塩酸塩を（３３２ｍｇ）得た。 Step 36
Synthesis of 5-piperidin-4-yl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1473)

5- (1-tert-butoxycarbonyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (362 mg, 0.687 mmol) in ethyl acetate (4 mL) And a mixed solution of 4M hydrochloric acid ethyl acetate solution (8 mL) and stirred at room temperature for 1.5 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain colorless amorphous 5-piperidin-4-yl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester hydrochloride (332 mg).

¹ H-NMR (DMSO-D ₆ ) δ: 8.78 (1H, brs), 7.98 (1H, d, J = 8.5 Hz), 7.90 (2H, d, J = 8.5 Hz) 7.51 (1H, s), 7.44 (2H, d, J = 8.5 Hz), 7.38-7.36 (2H, m), 4.34 (2H, q, J = 7. 1 Hz), 3.02-2.90 (4H, m), 2.36 (3H, s), 1.95-1.78 (5H, m), 1.31 (3H, t, J = 7. 1Hz)
ESI (LC-MS positive mode) m / z 427 [(M + H) ⁺ ]

In the same manner as in Step 36, compound numbers 1474 and 1475 in Table 28 were synthesized.

ジクロロエタン（４ｍＬ）中の５−ピペリジン−４−イル−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステル塩酸塩（２５３ｍｇ、０．５９２ｍｍｏｌ）、トリエチルアミン（０．１７ｍＬ、１．１８ｍｍｏｌ）、アセトン（１．４４ｍＬ、１９．６ｍｍｏｌ）、酢酸（０．２８ｍＬ、４．８９ｍｍｏｌ）およびトリアセトキシホウ水素化ナトリウム（３１８ｍｇ、１．５０ｍｍｏｌ）の混合物を、室温で１４．５時間攪拌した。反応混合物を飽和炭酸水素ナトリウム水溶液でｐＨ９までアルカリ性とし、酢酸エチルで抽出した。抽出液を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、得られた残渣をアミノゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９２／８〜３５／６５）で精製し、無色ガム状の５−（１−イソプロピル−ピペリジン−４−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸エチルエステルを（１９１ｍｇ、６９％）得た。 Step 37
Synthesis of 5- (1-isopropyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1476)

5-piperidin-4-yl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester hydrochloride (253 mg, 0.592 mmol), triethylamine (0.17 mL, dichloroethane) (4 mL) 1.18 mmol), acetone (1.44 mL, 19.6 mmol), acetic acid (0.28 mL, 4.89 mmol) and sodium triacetoxyborohydride (318 mg, 1.50 mmol) was stirred at room temperature for 14.5 hours. Stir. The reaction mixture was made alkaline to pH 9 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated, and the resulting residue was purified by amino gel column chromatography (hexane / ethyl acetate = 92/8 to 35/65) to give colorless gum 5- (1-isopropyl-piperidine- 4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (191 mg, 69%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 7.91 (1H, d, J = 8.5 Hz), 7.87 (2H, d, J = 8.5 Hz), 7.52 (1H, d, J = 1.8 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.39 (1H, dd, J = 9.2, 1.8 Hz), 7.31 (1H, s), 4.34 (2H, q, J = 7.1 Hz), 2.87 (2H, d, J = 11.6 Hz), 2.74-2.67 (1H, m), 2.56-2.53 (1H, m), 2.35 (3H, s), 2.21 (2H, dd, J = 11.6, 5.8 Hz), 1.77-1.74 (2H, m), 1.63 -1.57 (2H, m), 1.31 (3H, t, J = 7.1 Hz), 0.98 (6H, d, J = 6.7 Hz)
ESI (LC-MS positive mode) m / z 469 [(M + H) ⁺ ]

In the same manner as in Step 37, compound numbers 1477 to 1480 in Table 29 were synthesized.

亜鉛試薬の調製：マグネシウム（２３４ｍｇ，９．６ｍｍｏｌ）の脱水テトラヒドロフラン（ＴＨＦ)懸濁溶液（０．５ｍＬ）に、４−クロロ−１−メチル−ピペリジン（８．５６ｍｍｏｌ，１．１ｍＬ）の脱水テトラヒドロフラン（ＴＨＦ)溶液（３．５ｍＬ）を８０度で加え、１時間攪拌した。反応混合物を室温に冷却した後、反応混合物を、臭化亜鉛（１．１ｇ，４．８ｍｍｏｌ）の脱水テトラヒドロフラン（ＴＨＦ)（２．０ｍＬ）と脱水１−メチル−２−ピロリジノン（０．６ｍＬ）の混合液に滴下し、３０分間攪拌した。
カップリング反応：６−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−インドール（３４０ｍｇ，０．９７ｍｍｏｌ）、トリス(ジベンジリデンアセトン)ジパラジウム(0)（２３ｍｇ，０．０２５ｍｍｏｌ）および（３−ジエトキシホスフィノチオイルスルファニル−１，４−ジオキサン−２−イル）スルファニル−ジエトキシ−スルファニリデン−ホスホラン（Ruphos）（４７ｍｇ，０．１ｍｍｏｌ）を、反応容器に入れ、脱気し、窒素で置換した。脱水テトラヒドロフラン（ＴＨＦ)（５．０ｍＬ）、および調製した亜鉛試薬の懸濁溶液を加え、７０度で１７時間攪拌した。反応混合物を室温に冷却し、飽和炭酸水素ナトリウム水溶液で、反応混合物をアルカリ性にし、析出した固体をセライトでろ去した。ろ液を酢酸エチルで抽出し、抽出液を水、および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ワックス様固体の６−（１−メチル−ピペリジン−４−イル）−１−（トルエン−４−スルホニル）−１Ｈ−インドール（２９３．７ｍｇ，８２％）を得た。 Step 38
Synthesis of 6- (1-methyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole (1481)

Preparation of zinc reagent: dehydrated tetrahydrofuran of 4-chloro-1-methyl-piperidine (8.56 mmol, 1.1 mL) in a dehydrated tetrahydrofuran (THF) suspension solution (0.5 mL) of magnesium (234 mg, 9.6 mmol) (THF) solution (3.5 mL) was added at 80 degrees and stirred for 1 hour. After cooling the reaction mixture to room temperature, the reaction mixture was diluted with zinc bromide (1.1 g, 4.8 mmol) in anhydrous tetrahydrofuran (THF) (2.0 mL) and anhydrous 1-methyl-2-pyrrolidinone (0.6 mL). The mixture was added dropwise and stirred for 30 minutes.
Coupling reaction: 6-bromo-1- (toluene-4-sulfonyl) -1H-indole (340 mg, 0.97 mmol), tris (dibenzylideneacetone) dipalladium (0) (23 mg, 0.025 mmol) and (3 -Diethoxyphosphinothioylsulfanyl-1,4-dioxan-2-yl) sulfanyl-diethoxy-sulfanilidene-phosphorane (47 mg, 0.1 mmol) was placed in a reaction vessel, degassed and replaced with nitrogen did. Dehydrated tetrahydrofuran (THF) (5.0 mL) and the prepared zinc reagent suspension were added and stirred at 70 degrees for 17 hours. The reaction mixture was cooled to room temperature, the reaction mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was filtered off through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a wax-like solid 6- (1-methyl-piperidin-4-yl) -1- (toluene-4 -Sulfonyl) -1H-indole (293.7 mg, 82%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 7.83 (2H, d, J = 8.2 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.71 (1H, d, J = 3.7 Hz), 7.48 (1H, d, J = 8.1 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.14 (1H, dd, J = 8.1) 1.5Hz), 6.76 (1H, d, J = 3.7 Hz), 2.89-2.87 (2H, m), 2.61-2.52 (1H, m), 2.31. (3H, s), 2.21 (3H, s), 1.99 (2H, td, J = 11.4, 5.7 Hz), 1.76-1.62 (4H, m)
ESI (LC-MS positive mode) m / z 369 [(M + H) ⁺ ]

In the same manner as in Step 38, compound numbers 1482 and 1483 in Table 30 were synthesized.

４−クロロ−１−（トルエン−４−スルホニル）−１Ｈ−インドールのテトラヒドロフラン（ＴＨＦ)溶液（６ｍＬ）に、ジイソプロピルアミン（３７０μｌ）の脱水テトラヒドロフラン（ＴＨＦ)（１．５ｍＬ）に−７８℃で１．０Ｍｎ−ブチルリチウムのヘキサン溶液を加えて調製したリチウムジイソプロピルアミド溶液を−７８℃で加え、１５分間攪拌した。反応混合物にクロロギ酸メチル（１６９μｌ）を加えた後、さらに−７８℃で１５分間攪拌後、−７８℃で１Ｍ塩酸水溶液（４ｍＬ）を加えた。反応混合物を室温に昇温し、酢酸エチル（１０ｍＬ）で抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、有機層を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）精製し、無色固体の４−クロロ−１−（トルエン−４−スルホニル）−１Ｈ−インドール−２−カルボン酸メチルエステル（５９１ｍｇ、８２％）を得た。 Step 40
Synthesis of 4-chloro-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (1484)

4-chloro-1- (toluene-4-sulfonyl) -1H-indole in tetrahydrofuran (THF) solution (6 mL), diisopropylamine (370 μl) in dehydrated tetrahydrofuran (THF) (1.5 mL) at −78 ° C. A lithium diisopropylamide solution prepared by adding a hexane solution of 0.0Mn-butyllithium was added at −78 ° C., and the mixture was stirred for 15 minutes. After adding methyl chloroformate (169 μl) to the reaction mixture, the mixture was further stirred at −78 ° C. for 15 minutes, and 1M hydrochloric acid aqueous solution (4 mL) was added at −78 ° C. The reaction mixture was warmed to room temperature and extracted with ethyl acetate (10 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give colorless solid 4-chloro-1- (toluene-4- Sulfonyl) -1H-indole-2-carboxylic acid methyl ester (591 mg, 82%) was obtained.

ESI (LC-MS positive mode) m / z 364, 366 [(M + H) ⁺ ]

In the same manner as in Step 39, compound numbers 1485 to 1490 in Table 31 were synthesized.

５−アミノ−２−メチル−１Ｈ−ベンゾイミダゾール塩酸塩（１６．５１ｇ）を濃塩酸（２００ｍＬ）の溶解し、０度に冷却した。この混合液に亜硝酸ナトリウム（７．５９ｇ）の水溶液（１５ｍＬ）を、０度で２０分間かけて滴下し、２０分間攪拌した。その後、塩化スズ（ＩＩ）二水和物（５５．７ｇ）の濃塩酸溶液（２０ｍＬ）を、０度で１時間かけて滴下し、滴下後３０分間攪拌した。析出した固体をろ取し、水で洗浄、乾燥し、粗（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−ヒドラジン二塩酸塩を得た。 Step 40
Synthesis of (2-methyl-1H-benzimidazol-5-yl) -hydrazine dihydrochloride (1491)

5-Amino-2-methyl-1H-benzimidazole hydrochloride (16.51 g) was dissolved in concentrated hydrochloric acid (200 mL) and cooled to 0 degrees. To this mixed solution, an aqueous solution (15 mL) of sodium nitrite (7.59 g) was added dropwise at 0 ° C. over 20 minutes and stirred for 20 minutes. Then, a concentrated hydrochloric acid solution (20 mL) of tin (II) chloride dihydrate (55.7 g) was added dropwise at 0 ° C. over 1 hour, followed by stirring for 30 minutes. The precipitated solid was collected by filtration, washed with water, and dried to obtain crude (2-methyl-1H-benzoimidazol-5-yl) -hydrazine dihydrochloride.

ESI (LC-MS positive mode) m / z 163 [(M + H) ⁺ ]

In the same manner as in Step 40, compound numbers 1492 to 1496 in Table 32 were synthesized.

酢酸パラジウム（１．２ｍｇ、０．００５２ｍｍｏｌ）、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリ−ｉ−プロピル−１，１’−ビフェニル（Ｘ−ＰＨＯＳ）（４．２ｍｇ、０．００８８ｍｍｏｌ）をtert−アミルアルコール（２．４μｌ、０．０２２ｍｍｏｌ）、Ｎ−メチルモルホリン（０．０５ｍＬ）に溶解し、窒素雰囲気下、６０℃５分間加熱撹拌し、触媒を調製した。
別反応容器で、窒素雰囲気下、７−フルオロ−２−メチル−３Ｈ−ベンゾイミダゾール−５−イルアミン（１００ｍｇ、０．４４ｍｍｏｌ）、リチウムビス（トリメチルシリル）アミド（１９０ｍｇ、１．１ｍｍｏｌ）、ベンゾフェノンヒドラゾン（９４．３ｍｇ、０．４８ｍｍｏｌ）をＮ−メチルモルホリン（０．５ｍＬ）に溶解し、調製した触媒を含む溶液を加え脱気した後、窒素雰囲気下、１００℃で２時間加熱撹拌した。反応混合物を室温に冷却した後、６Ｍ塩酸水溶液（０．５ｍＬ）を加え、有機層を分離し、減圧濃縮し、粗Ｎ−ベンズヒドリリデン−Ｎ’−（７−フルオロ−２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−ヒドラジンを得た。ここで得られた粗生成物は、精製することなく、次反応に用いた。
粗Ｎ−ベンズヒドリリデン−Ｎ’−（７−フルオロ−２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−ヒドラジン（３２５ｍｇ）、エタノール（０．７ｍＬ）の混合液に、濃塩酸（０．７ｍＬ）を加え、５９℃から６４℃で１時間半攪拌した。反応混合物を室温に冷却した後、析出した固体を濾取、乾燥し、７−フルオロ−２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−ヒドラジン二塩酸塩（９０ｍｇ、８０％）を得た。 Step 41
Synthesis of (7-fluoro-2-methyl-1H-benzimidazol-5-yl) -hydrazine dihydrochloride (1497)

Palladium acetate (1.2 mg, 0.0052 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-tri-i-propyl-1,1′-biphenyl (X-PHOS) (4.2 mg, 0 .0088 mmol) was dissolved in tert-amyl alcohol (2.4 μl, 0.022 mmol) and N-methylmorpholine (0.05 mL), and the mixture was heated and stirred at 60 ° C. for 5 minutes in a nitrogen atmosphere to prepare a catalyst.
In a separate reaction vessel, 7-fluoro-2-methyl-3H-benzimidazol-5-ylamine (100 mg, 0.44 mmol), lithium bis (trimethylsilyl) amide (190 mg, 1.1 mmol), benzophenone hydrazone ( 94.3 mg, 0.48 mmol) was dissolved in N-methylmorpholine (0.5 mL), a solution containing the prepared catalyst was added and deaerated, and then the mixture was heated and stirred at 100 ° C. for 2 hours in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 6M aqueous hydrochloric acid (0.5 mL) was added, the organic layer was separated, concentrated under reduced pressure, and crude N-benzhydrylidene-N ′-(7-fluoro-2-methyl-1H). -Benzimidazol-5-yl) -hydrazine was obtained. The crude product obtained here was used for the next reaction without purification.
To a mixture of crude N-benzhydrylidene-N ′-(7-fluoro-2-methyl-1H-benzimidazol-5-yl) -hydrazine (325 mg) and ethanol (0.7 mL), concentrated hydrochloric acid (0. 7 mL) was added, and the mixture was stirred at 59 to 64 ° C. for 1.5 hours. After cooling the reaction mixture to room temperature, the precipitated solid was collected by filtration and dried to obtain 7-fluoro-2-methyl-1H-benzimidazol-5-yl) -hydrazine dihydrochloride (90 mg, 80%). .

¹ H-NMR (DMSO-D ₆ ) δ: 7.11 (1.0 H, d, J = 1. 8 Hz), 6.99 (1.0 H, dd, J = 12.4, 1.8 Hz), 2.69 (3.1H, s)
ESI (LC-MS positive mode) m / z 181 [(M + H) ⁺ ]

In the same manner as in Step 41, 6-fluoro-2-methyl-1H-benzimidazol-5-yl) -hydrazine dihydrochloride (1498) was synthesized.

ESI (LC-MS positive mode) m / z 181 [(M + H) ⁺ ]

４−ブロモフェニレンジアミン（９３５ｍｇ，５．０ｍｍｏｌ）とジフルオロ酢酸（０．４７ｍＬ，７．５ｍｍｏｌ，１．５ｅｑ．）を５Ｍ塩酸水溶液（１０ｍＬ）に溶解し、１００℃で２４時間攪拌した。反応混合物を室温に冷却した後、５Ｍ水酸化ナトリウム水溶液（１０ｍＬ）を加え、アルカリ性にした後、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾去、濃縮後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、薄黄色固体の６−ブロモ−２−ジフルオロメチル−１Ｈ−ベンゾイミダゾール（１．０ｇ，８５．４％）を得た。 Step 42
Synthesis of 6-bromo-2-difluoromethyl-1H-benzimidazole (1499)

4-Bromophenylenediamine (935 mg, 5.0 mmol) and difluoroacetic acid (0.47 mL, 7.5 mmol, 1.5 eq.) Were dissolved in 5 M aqueous hydrochloric acid (10 mL), and the mixture was stirred at 100 ° C. for 24 hours. After the reaction mixture was cooled to room temperature, 5M aqueous sodium hydroxide solution (10 mL) was added to make it alkaline, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. The desiccant was filtered off, concentrated, and then the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain a light yellow solid of 6-bromo-2-difluoromethyl-1H-benzimidazole (1.0 g, 85. 4%).

¹ H-NMR (DMSO-D ₆ ) δ: 13.51 (1H, brs), 7.86 (1H, d, J = 1.8 Hz), 7.62 (1H, d, J = 8.5 Hz) , 7.44 (1H, dd, J = 8.5, 1.8 Hz), 7.41-7.14 (1H, m)
ESI (LC-MS positive mode) m / z 247,249 [(M + H) ⁺ ]

６−ブロモ−２−ジフルオロメチル−１Ｈ−ベンゾイミダゾール（１．０ｇ，４．２７ｍｍｏｌ）とＮ，Ｎ−ジイソプロピルエチルアミン（１．９ｍＬ，１０．６ｍｍｏｌ，２．５ｅｑ．）の脱水ジクロロメタン溶液（２２ｍＬ）に、（２−クロロメトキシ−エチル）−トリメチル−シラン（１．１ｍＬ，６．４ｍｍｏｌ，１．５ｅｑ．）を加え、室温で１８時間攪拌した。反応混合物を濃縮し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、黄色固体の６−ブロモ−２−ジフルオロメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール（１．３７ｇ，８５％）を得た。 Step 43
Synthesis of 6-bromo-2-difluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole (1500)

Dehydrated dichloromethane solution (22 mL) of 6-bromo-2-difluoromethyl-1H-benzimidazole (1.0 g, 4.27 mmol) and N, N-diisopropylethylamine (1.9 mL, 10.6 mmol, 2.5 eq.) (2-chloromethoxy-ethyl) -trimethyl-silane (1.1 mL, 6.4 mmol, 1.5 eq.) Was added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to give 6-bromo-2-difluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H- as a yellow solid. Benzimidazole (1.37 g, 85%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 8.07-8.02 (1H, m), 7.78-7.74 (1H, m), 7.60-7.28 (2H, m) , 5.76 (2H, s), 3.52 (2H, td, J = 8.4, 2.6 Hz), 0.83 (2H, td, J = 8.4, 2.6 Hz), −0 .10 (9H, s)
ESI (LC-MS positive mode) m / z 377, 379 [(M + H) ⁺ ]

６−ブロモ−２−ジフルオロメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール（７５４ｍｇ，２．０ｍｍｏｌ）、トリス(ジベンジリデンアセトン)ジパラジウム（０）（９２ｍｇ，０．１ｍｍｏｌ），２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリ−ｉ−プロピル−１，１’−ビフェニル（Ｘ−ＰＨＯＳ）（１４３ｍｇ，０．３ｍｍｏｌ）、炭酸セシウム（１．３ｇ，４．０ｍｍｏｌ）、およびカルバジン酸tertブチル（７９４ｍｇ，６．０ｍｍｏｌ）をフラスコに入れ、脱気、アルゴン置換した。脱水トルエン（８．０ｍＬ）を加え、１００℃で２０時間攪拌した。反応混合物を室温に冷却後、セライトろ過し、酢酸エチルで洗浄した。ろ液を濃縮し、減圧濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィーで精製し、薄黄色ガム状のtert−ブトキシカルボニル化されたヒドラジン（２２０ｍｇ，２６％）を得た。ここで得られたtert−ブトキシカルボニル化されたヒドラジンの酢酸エチル溶液（３．０ｍＬ）に、４Ｍ塩酸酢酸エチル溶液（６．０ｍＬ）を加え、室温で１時間半攪拌した。析出した固体をろ過、酢酸エチルで洗浄、乾燥し、黄色固体の粗［２−ジフルオロメチル−３−（２−トリメチルシラニル−エトキシメチル）−３Ｈ−ベンゾイミダゾール−５−イル］−ヒドラジン塩酸塩を得た。ここで得られた粗生成物は、精製することなく、次の反応に用いた。 Step 44
Synthesis of 2-difluoromethyl-3- (2-trimethylsilanyl-ethoxymethyl) -3H-benzimidazol-5-yl] -hydrazine hydrochloride (1501)

6-bromo-2-difluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole (754 mg, 2.0 mmol), tris (dibenzylideneacetone) dipalladium (0) (92 mg,. 1 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-tri-i-propyl-1,1′-biphenyl (X-PHOS) (143 mg, 0.3 mmol), cesium carbonate (1.3 g, 4.0 mmol) and tertbutyl carbazate (794 mg, 6.0 mmol) were placed in a flask, degassed and purged with argon. Dehydrated toluene (8.0 mL) was added and stirred at 100 ° C. for 20 hours. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain tert-butoxycarbonylated hydrazine (220 mg, 26%) as a pale yellow gum. To the obtained ethyl acetate solution (3.0 mL) of tert-butoxycarbonylated hydrazine was added 4M hydrochloric acid ethyl acetate solution (6.0 mL), and the mixture was stirred at room temperature for 1.5 hours. The precipitated solid was filtered, washed with ethyl acetate, dried, and crude [2-difluoromethyl-3- (2-trimethylsilanyl-ethoxymethyl) -3H-benzimidazol-5-yl] -hydrazine hydrochloride as a yellow solid Got. The crude product obtained here was used for the next reaction without purification.

ESI (LC-MS positive mode) m / z 329 [(M + H) ⁺ ]

工程Ａ
５−ヨード−２−メチル−１Ｈ−ベンゾイミダゾール（１０ｇ、３９ｍｍｏｌ）、トリメトキシ−メタン（２００ｍＬ）、クロロトリメチルシラン（０．０７５ｍＬ、０．５９ｍｍｏｌ）の混合溶液を窒素雰囲気下、１００℃で溶媒を留去させながら５時間加熱撹拌した（反応転換率９７％）。反応混合物を４０℃に冷却した後、カリウムtert−ブトキシドのテトラヒドロフラン溶液（０．８７ｍL、０．８７ｍｍｏｌ）を加え、減圧濃縮し、粗１−ジメトキシメチル−５−ヨード−２−メチル−１Ｈ−ベンゾイミダゾールを得た。 Synthesis of 1- (2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid di-tert-butyl mesylate

Process A
A mixed solution of 5-iodo-2-methyl-1H-benzimidazole (10 g, 39 mmol), trimethoxy-methane (200 mL) and chlorotrimethylsilane (0.075 mL, 0.59 mmol) was mixed with a solvent at 100 ° C. under a nitrogen atmosphere. The mixture was heated and stirred for 5 hours while distilling off (reaction conversion rate 97%). After the reaction mixture was cooled to 40 ° C., a solution of potassium tert-butoxide in tetrahydrofuran (0.87 mL, 0.87 mmol) was added, concentrated under reduced pressure, and crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzoate. Imidazole was obtained.

Process B
To a mixed solution of crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole in tetrahydrofuran (79 mL) was added 1.06 M cyclohexylmagnesium chloride in tetrahydrofuran (44 mL, 47 mmol), and −20 ° C. under a nitrogen atmosphere. For 2 hours. To the reaction mixture was added a toluene (40 mL) solution of di-tert-butyl azodicarboxylate (10.7 g, 46 mmol), and the mixture was stirred at −20 ° C. for 1 hour and at 0 ° C. for 1 hour in a nitrogen atmosphere (reaction conversion rate 96 %). To the reaction mixture was added 15% aqueous ammonium chloride solution (60 mL), and the mixture was extracted with isopropyl acetate-heptane (1-1, 50 mL) solution. The organic layer was washed with 2% aqueous sodium hydrogen carbonate solution (50 mL), and then 1-methyl -Pyrrolidin-2-one (15 mL) was added, concentrated under reduced pressure, and crude 1- (1- (dimethoxymethyl) -2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid was added. A solution of di-tert-butyl acid in 1-methyl-pyrrolidin-2-one (48 mL) was obtained.

  This crude 1- (1- (dimethoxymethyl) -2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylate di-tert-butyl 1-methyl-pyrrolidine-2- Isopropyl acetate (61 mL), water (0.2 mL), and mesylic acid (0.87 mL) were added to the on solution (16 mL), and the mixture was stirred at 40 ° C. for 2 hours. After cooling to 5 ° C., the precipitated solid was collected by filtration, dried, and 1- (2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylate di-tert-butyl mesyl. The acid salt (4.3 g, 73%) was obtained.

¹ H-NMR (CD ₃ OD) δ: 7.87 (1.0 H, m), 7.69-7.53 (2.0 H, m), 2.84 (3.0 H, s), 2. 70 (3.0H, s), 1.52-1.47 (18H, m)

  In Step A, crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole was prepared using magnesium chloride instead of chlorotrimethylsilane (reaction conversion rate 98%).

  In Step A, crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole was prepared using lithium chloride instead of chlorotrimethylsilane (reaction conversion rate 98%).

  In Step A, crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole was prepared using benzoic acid instead of chlorotrimethylsilane (reaction conversion rate 97%).

  In Step B, a crude 1- (1- (dimethoxymethyl) -2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine was obtained using a tetrahydrofuran solution of isopropylmagnesium chloride instead of a tetrahydrofuran solution of cyclohexylmagnesium chloride. Di-tert-butyl-1,2-dicarboxylate was prepared (reaction conversion 96%).

工程Ｂにおいて、 メシル酸、酢酸イソプロピルの代わりにテトラヒドロフラン、マレイン酸、ヘプタンを用いることで１−（２−メチル−１Ｈ−ベンゾ［ｄ］イミダゾール−５−イル）ヒドラジン−１，２−ジカルボン酸ジ−tert−ブチル マレイン酸塩テトラヒドロフラン和物を調製した（収率６２％）。 Synthesis of 1- (2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid di-tert-butyl maleate tetrahydrofuranate

In Step B, 1- (2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid diester was obtained by using tetrahydrofuran, maleic acid, and heptane instead of mesylic acid and isopropyl acetate. -Tert-Butyl maleate tetrahydrofuranate was prepared (yield 62%).

¹ H-NMR (CD ₃ OD) δ: 7.77 (1.0 H, m), 7.64-7.53 (2.0 H, m), 6.26 (2.0 H, s), 3. 74-3.71 (4.0H, m), 2.80 (3.0H, s), 1.90-1.85 (4.0H, m), 1.51-1.48 (18H, m) )

ヘキサンで洗浄した６０％油性水素化ナトリウム（３６２ｍｇ）を脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)（５ｍＬ）に懸濁させ、アルゴン気流下、０℃で１Ｈ−ピロール−２−カルボン酸エチルエステル（１．０５ｇ）のＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ)溶液（１５ｍＬ）を滴下した。反応混合物を２５℃で１時間攪拌後、０℃で４−メトキシベンジルクロリド（１．５ｍＬ）を加え、反応混合物をさらに２５℃で１０時間攪拌した。反応混合物に氷（約１０ｇ）を加え、酢酸エチル（２０ｍＬ）で抽出した。有機層を飽和塩化ナトリウム水溶液（６０ｍＬ）で洗浄後、有機層を濃縮し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、黄色油状物質（１．６４ｇ、８３％）を得た。 Step 45
Synthesis of 1- (4-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid ethyl ester (1502)

60% oily sodium hydride (362 mg) washed with hexane was suspended in dehydrated N, N-dimethylformamide (DMF) (5 mL), and 1H-pyrrole-2-carboxylic acid ethyl ester ( 1.05 g) of N, N-dimethylformamide (DMF) solution (15 mL) was added dropwise. After stirring the reaction mixture at 25 ° C. for 1 hour, 4-methoxybenzyl chloride (1.5 mL) was added at 0 ° C., and the reaction mixture was further stirred at 25 ° C. for 10 hours. Ice (about 10 g) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (60 mL), concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to give a yellow oil (1.64 g). 83%).

ESI (LC-MS positive mode) m / z 260 [(M + H) ⁺ ]

１Ｈ−ピロール−２−カルボン酸エチルエステル（１０ｇ）を四塩化炭素（５０ｍＬ）に溶解し、氷冷下、臭素の四塩化炭素溶液（５０ｍＬ）を３０分間かけて滴下した。反応混合物を２５度で１時間攪拌後、懸濁の反応混合物を氷冷下、１０％ナトリウムエトキシドエタノール溶液（１００ｍＬ）に２０分間かけて滴下した。溶媒を減圧濃縮後、残渣を酢酸エチル（４０ｍＬ）と水（２０ｍＬ）で希釈した。有機層を飽和塩化ナトリウム水溶液（１０ｍＬ）で洗浄後、有機層を濃縮し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、褐色固体（１０ｇ、９９％）を得た。 Step 46
Synthesis of 4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (1503)

1H-pyrrole-2-carboxylic acid ethyl ester (10 g) was dissolved in carbon tetrachloride (50 mL), and a carbon tetrachloride solution of bromine (50 mL) was added dropwise over 30 minutes under ice cooling. After stirring the reaction mixture at 25 ° C. for 1 hour, the suspended reaction mixture was added dropwise to a 10% sodium ethoxide ethanol solution (100 mL) over 20 minutes under ice cooling. The solvent was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (40 mL) and water (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL), concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to give a brown solid (10 g, 99% )

ESI (LC-MS positive mode) m / z 218, 220 [(M + H) ⁺ ]

１−（４−メトキシ−ベンジル）−１Ｈ−ピロール−２−カルボン酸エチルエステル（２ｇ）の脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)溶液（８ｍＬ）にＮ−ブロモスクシンイミド（２．７ｇ）の脱水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ)溶液（９ｍＬ）を、アルゴン気流下０℃で滴下した。反応混合物をさらに０℃で攪拌後、反応混合物に水（２０ｍＬ）を加え、酢酸エチル（３０ｍＬ）で抽出した。有機層を飽和塩化ナトリウム水溶液（７０ｍＬ）で洗浄後、有機層を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、淡褐色油状物質の４，５−ジブロモ−１−（４−メトキシ−ベンジル）−１Ｈ−ピロール−２−カルボン酸エチルエステル（２．９９ｇ、９２％）を得た。 Step 47
Synthesis of 4,5-dibromo-1- (4-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid ethyl ester (1504)

Dehydration of N-bromosuccinimide (2.7 g) into a dehydrated N, N-dimethylformamide (DMF) solution (8 mL) of 1- (4-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid ethyl ester (2 g) N, N-dimethylformamide (DMF) solution (9 mL) was added dropwise at 0 ° C. under an argon stream. The reaction mixture was further stirred at 0 ° C., water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (70 mL), the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4,5-dibromo as a light brown oily substance. -1- (4-Methoxy-benzyl) -1H-pyrrole-2-carboxylic acid ethyl ester (2.99 g, 92%) was obtained.

ESI (LC-MS positive mode) m / z 416, 418, 420 [(M + H) ⁺ ]

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−ブロモ−１−（トルエン−４−スルホニル）−１Ｈ−ピロール−２−イル］−メタノン（５７ｍｇ）、塩化パラジウムビストリフェニルホスフィン錯体（１０ｍｇ）、フェニルボロン酸（３７ｍｇ）に１Ｍ炭酸水素ナトリウム水溶液（１．５ｍＬ）とジオキサン（１．５ｍＬ）を加え、マイクロ波反応装置で１０分間１４０℃で反応させた。反応混合物を水（５ｍＬ）で希釈後、酢酸エチルで抽出した。合わせた有機層を減圧濃縮後、ＨＰＬＣで精製し、溶離液をＰＬＨＣＯ３カートリッジ（PolymerLabs社製）で脱塩後、減圧濃縮し黄色粉末の［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４−フェニル−１−（トルエン−４−スルホニル）−１Ｈ−ピロール−２−イル］−メタノン（１５ｍｇ、２６％）を得た。 Step 48
[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4-phenyl-1- (toluene-4-sulfonyl) -1H-pyrrole- Synthesis of 2-yl] -methanone (1505)

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4-bromo-1- (toluene-4-sulfonyl) -1H-pyrrole- 2-Mil] -methanone (57 mg), palladium chloride bistriphenylphosphine complex (10 mg) and phenylboronic acid (37 mg) were added with 1M aqueous sodium hydrogen carbonate solution (1.5 mL) and dioxane (1.5 mL), followed by microwave reaction. The reaction was carried out at 140 ° C. for 10 minutes in the apparatus. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and purified by HPLC. The eluent was desalted with a PLHCO3 cartridge (manufactured by PolymerLabs) and then concentrated under reduced pressure to give [5-amino-1- (2-methyl-1H-benzoic acid] as a yellow powder. Imidazol-5-yl) -1H-pyrazol-4-yl]-[4-phenyl-1- (toluene-4-sulfonyl) -1H-pyrrol-2-yl] -methanone (15 mg, 26%) was obtained. .

ESI (LC-MS positive mode) m / z 537 [(M + H) ⁺ ]

In the same manner as in Step 48, compound numbers 1506 to 1510 and 1591 to 1598 in Table 33 were synthesized.

［５−アミノ−１−（２−メチル−１Ｈ−ベンゾイミダゾール−５−イル）−１Ｈ−ピラゾール−４−イル］−［４，５−ジブロモ−１−（４−メトキシ−ベンジル）−１Ｈ−ピロール−２−イル］−メタノン（３１７ｍｇ）を酢酸エチル／硫酸（４／１、５ｍＬ）に溶解し、８０℃で４時間攪拌した。反応混合物を氷冷下、５Ｍ水酸化ナトリウム水溶液で塩基性（ｐＨ１１）とし、反応混合物を酢酸エチル／テトラヒドロフラン（ＴＨＦ)（１０ｍＬ）で抽出した。有機層を飽和塩化ナトリウム水溶液（５ｍＬ）で洗浄後、有機層を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）で精製し、褐色固体（１３５ｍｇ、５４％）を得た。 Example 201
Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(4,5-dibromo-1H-pyrrol-2-yl) -methanone

[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-[4,5-dibromo-1- (4-methoxy-benzyl) -1H- Pyrrole-2-yl] -methanone (317 mg) was dissolved in ethyl acetate / sulfuric acid (4/1, 5 mL) and stirred at 80 ° C. for 4 hours. The reaction mixture was made basic (pH 11) with 5M aqueous sodium hydroxide under ice-cooling, and the reaction mixture was extracted with ethyl acetate / tetrahydrofuran (THF) (10 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (5 mL), and the residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a brown solid (135 mg, 54%). .

¹ H-NMR (DMSO-D ₆ ) δ: 12.88 (1H, s), 12.46 (1H, s), 8.19 (1H, s), 7.63 (1H, d, J = 8) .7 Hz), 7.56-7.54 (1 H, m), 7.27-7.26 (3 H, m), 6.90 (1 H, t, J = 14.2 Hz), 2.53 (3 H , S)
ESI (LC-MS positive mode) m / z 463, 465, 467 [(M + H) ⁺ ]

Examples 202 and 203
In the same manner as in Example 201, the compounds of Examples 202, 203 and 240 in Table 34 were synthesized.

Pharmacological test method FGFR1 Enzyme Inhibitory Activity FGFR1 inhibitory activity was measured by the phosphorylation inhibitory activity of a biotinylated peptide (EGPWLEEEEEEYGWMDF) using a human FGFR1 enzyme (cat 08-133 manufactured by Carna Biosciences). Phosphorylated biotinylated peptide was detected by time-resolved fluorescence measurement using anti-phosphotyrosine antibody conjugated with europium cryptate and streptavidin conjugated with XL665, a derivative of allophycocyanin. A 50% inhibitory concentration (IC ₅₀ value) was calculated from the inhibition rate relative to the control group not containing.

2. Inhibitory activity of FGFR2 enzyme The FGFR2 inhibitory activity was measured by the phosphorylation inhibitory activity of biotinylated peptide (EGPWLEEEEEEAYWMDF) using human FGFR2 enzyme prepared in a baculovirus expression system. Phosphorylated biotinylated peptide was detected by time-resolved fluorescence measurement using anti-phosphotyrosine antibody conjugated with europium cryptate and streptavidin conjugated with XL665, a derivative of allophycocyanin. A 50% inhibitory concentration (IC ₅₀ value) was calculated from the inhibition rate relative to the control group not containing.

3. FGFR3 Enzyme Inhibitory Activity FGFR3 inhibitory activity was measured by the phosphorylation inhibitory activity of biotinylated peptide (EGPWLEEEEEEYGWMDF) using a human FGFR3 enzyme (cat 08-135 manufactured by Carna Biosciences). Phosphorylated biotinylated peptide was detected by time-resolved fluorescence measurement using anti-phosphotyrosine antibody conjugated with europium cryptate and streptavidin conjugated with XL665, a derivative of allophycocyanin. A 50% inhibitory concentration (IC ₅₀ value) was calculated from the inhibition rate relative to the control group not containing.

4). Measurement of SNU-16 cell growth inhibitory activity With respect to the test compounds described in the following table obtained in Examples, the cancer cell proliferation inhibitory activity by FGFR inhibitory activity was measured. The cancer cell proliferation inhibitory activity was measured using Cell Counting Kit-8 manufactured by Dojindo Laboratories.

A human gastric cancer cell line SNU-16 obtained from American Type Culture Collection (Virginia, USA) was inoculated 2000 pieces per well of a 96-well culture plate, and a FGFR inhibitor diluted 50-M with a top dose of 19 steps twice. After the addition, the cells were cultured for 4 days.
On the fourth day of the culture, a solution of Cell Counting Kit-8 was added, and the absorbance (measurement wavelength: 450 nm, reference wavelength: 615 nm) was measured according to the protocol attached to the kit to calculate a 50% growth inhibitory concentration (IC ₅₀ ).
The results are shown in Table 35.

Test results Compounds having FGFR1 inhibitory action (IC ₅₀ is 0.3 μM or less):
Examples 1-14, 16-18, 23-25, 27-32, 35-62, 64-87,
89-108, 110, 112-125, 130-161, 163-175,
177-191, 192-201

Compound having FGFR2 inhibitory action (IC ₅₀ is 0.3 μM or less):
Examples 1-14, 16-62, 64-108, 110, 112-126, 128-150, 152-161, 163-191, 192-201

Compound having FGFR3 inhibitory action (IC ₅₀ is 0.3 μM or less):
Examples 1-3, 5-9, 12-13, 25, 27-29, 32, 36, 38-50, 52-54, 56, 61, 64-67, 69-72, 74-81, 85- 87, 89, 91-100, 102-108, 110, 112-121, 123-125, 132-150, 152-161, 163-169, 174-176, 178, 180-187, 189-191, 192, 194-200

  The present invention provides a compound having an FGFR family kinase inhibitory action. In addition, according to the present invention, cancer (for example, breast cancer, acute myeloid leukemia, pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, angiogenesis, gastric cancer, endometrial cancer, ovarian cancer, brain tumor (including glioblastoma). For the prevention and / or treatment of colorectal cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer) and thyroid cancer).

Claims (7)

A medicament comprising as an active ingredient a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

(Wherein R _{1 to} R ₄ each independently represent the following group;
R ₁ is hydrogen, hydroxy, halogen, cyano, nitro, C _1-4 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl C _{1-4 alkyl, -OR 5, -NR 6 R 7} , - (CR 8 R 9) n Z 1, -C (O) NR 12 R 13, -SR 14, -SOR 15, -SO 2 R 16 _{, -NR 17 SO 2 R 18,} COOH, Q 1 or more optionally substituted by 5-10 membered heteroaryl or 3-10 membered heterocyclyl with groups independently selected from the group, -COR _19, - _{COOR 20, -OC (O) R} 21, -NR 22 C (O) R 23, -NR 24 C (S) R 25, -C (S) NR 26 R 27, -SO 2 NR 28 R 29, - OS ₂ R _30, shows a _-SO 3 _{R 31} or -Si _{(R 32) 3;}
R ₂ is hydrogen, hydroxy, halogen, cyano, nitro, C _1-4 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl C _{1-4 alkyl, -OR 5, -NR 6 R 7} , - (CR 8 R 9) n Z 1, -C (O) NR 12 R 13, -SR 14, -SOR 15, -SO 2 R 16 _{, -NR 17 SO 2 R 18,} COOH, Q 1 or more optionally substituted by 5-10 membered heteroaryl or 3-10 membered heterocyclyl with groups independently selected from the group, -COR _19, - _{COOR 20, -OC (O) R} 21, -NR 22 C (O) R 23, -NR 24 C (S) R 25, -C (S) NR 26 R 27, -SO 2 NR 28 R 29, - OS ₂ R _30, shows a _-SO 3 _{R 31} or -Si _{(R 32) 3;}
Or R ₁ and R ₂ together with the atoms to which they are attached form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl or the heteroaryl is substituted with a halogen May be;
R ₃ represents hydrogen, C _1-5 alkyl, C _6-10 aryl C _1-6 alkyl or C _1-4 haloalkyl;
R ₄ represents hydrogen, halogen, C _1-3 alkyl, C _1-3 perfluoroalkyl, cyano, methanesulfonyl, hydroxyl, alkoxy or amino ;
A is indole or pyrrole ;
R ₅ is C _1-5 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-3 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 Alkoxy C _1-4 alkyl, C _1-3 alkoxy C _1-4 alkoxy C _1-4 alkyl, C _1-4 aminoalkyl, C _1-4 alkylamino C _1-4 alkyl, di (C _1-4 alkyl) Amino C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q C _1-3 alkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C _1-3 alkyl, C _1-6 monohydroxyalkyl, C _1-6 dihi Represents droxyalkyl or C _1-6 trihydroxyalkyl;
R ₆ and R ₇ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxyC _{1- 4} alkyl, C _6-10 aryl C _1-3 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _1-3 alkyl, C _1-6 monohydroxyalkyl, C _1-6 dihydroxy Alkyl, C _1-6 trihydroxyalkyl, 3-10 membered heterocyclyl, C _1-4 aminoalkyl, C _1-4 alkylamino C _1-4 alkyl, di (C _1-4 alkyl) amino C _1-4 alkyl or cyano _{(C 1-3} alkyl) or shown or _{R 6} and _{R 7,} are 3-10 membered Heteroshiku together with the nitrogen atom to which they are attached Forming a Le or 5-10 membered heteroaryl;
n represents 1 to 3;
R ₈ and R ₉ may be the same or different and each represents hydrogen, C _1-4 alkyl or halogen, or R ₈ and R ₉ together with the carbon atom to which they are attached May form a cyclic ring;
Z ₁ represents hydrogen, NR ₁₀ R ₁₁ , —OH, or 3 to 10-membered heterocyclyl or 5 to 10-membered heteroaryl optionally substituted with one or more groups independently selected from group Q ;
R ₁₀ and R ₁₁ may be the same or different and are each C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxy C _1-4 alkyl, Represents cyano (C _1-3 alkyl) or C _1-3 alkylsulfonyl C _1-4 alkyl, or R ₁₀ and R ₁₁ together with the nitrogen atom to which they are attached are 3-10 membered heterocyclyl Or may form a 5-10 membered heteroaryl;
R ₁₂ and R ₁₃ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxy C _1-4 alkyl , C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 arylC _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _{1 -3} alkyl, cyano ( _C1-3 alkyl), _C1-3 alkylsulfonyl _C1-4 alkyl, 3-10 membered alicyclic ring, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, or R ₁₂ and R _13, together with the nitrogen atom to which they are attached, optionally substituted with one or more groups independently selected from Q group May form a have 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
R ₁₄ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q;
R ₁₅ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q;
R ₁₆ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q;
R ₁₇ represents hydrogen or C _1-4 alkyl;
R ₁₈ is C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C optionally substituted with one or more groups independently selected from the group P. _6-10 aryl, or 5-10 membered heteroaryl or 3-10 membered heterocyclyl optionally substituted with one or more groups independently selected from group Q;
R ₁₉ is substituted with one or more groups independently selected from hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, or Q group. Optionally represents 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₀ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₁ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₂ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;
R ₂₃ represents hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₄ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;
R ₂₅ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₂₆ and R ₂₇ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxyl C _1-4. Alkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 arylC _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _1-3 alkyl, cyano (C _1-3 alkyl), C _1-3 alkylsulfonyl C _1-4 alkyl, or 3-10 membered alicyclic ring, or R ₂₆ and R ₂₇ are attached May be taken together with the nitrogen atom to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
R ₂₈ and R ₂₉ may be the same or different and are each hydrogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-3 alkoxyl C _1-4. Alkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _6-10 arylC _1-4 alkyl, 3-10 membered heterocyclyl C _1-3 alkyl, 5-10 membered heteroaryl C _1-3 alkyl, cyano (C _1-3 alkyl), C _1-3 alkylsulfonyl C _1-4 alkyl, or 3-10 membered alicyclic ring, or R ₂₈ and R ₂₉ are attached May be taken together with the nitrogen atom to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
R ₃₀ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R ₃₁ represents C _1-4 alkyl, C _3-7 cycloalkyl, C _1-4 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;
R _{32 is} shows the _{C 1-4} alkyl or _{C 6-10} aryl;
<P group>
_{Halogen, C 1-4 alkyl, C 1-4} haloalkyl, _{-OH, C 1-3 alkoxy, C 1-3} haloalkoxy, 3-10 membered _{heterocyclylamino, -SO 2 R 16, -CN,} -NO 2, And 3-10 membered heterocyclyl.
<Q group>
_{Halogen, C 1-4 alkyl, C 1-4} haloalkyl, _{-OH, C 1-3 alkoxy, C 1-6 mono-hydroxyalkyl, C 1-6} dihydroxyalkyl or _{C 1-6} trihydroxy alkyl, 3-10 membered Heterocyclylamine, —SO ₂ R ₁₆ , —CN, —NO ₂ , C _3-7 cycloalkyl, —COR ₁₉ , and 3 to 10 membered heterocyclyl optionally substituted with C _1-4 alkyl ) . The compound according to claim 1 , wherein R ₃ represents hydrogen, C _1-4 alkyl, C _6-10 aryl C _1-4 alkyl, or C _1-3 perfluoroalkyl, or a pharmaceutically acceptable salt thereof. As an active ingredient. A pharmaceutical comprising the following compounds, or a pharmaceutically acceptable salt thereof as an active ingredient:
(1) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone ; or
[5-Amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl]-(1H-indol-2-yl) -methanone .   Pharmaceutically acceptable salts include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, malate, stearate, benzoate, methanesulfonate And the pharmaceutical according to any one of claims 1 to 3, selected from the group consisting of p-toluenesulfonate. The medicament according to any one of claims 1 to 4 , which is an FGFR activity inhibitor. The medicament according to any one of claims 1 to 4 , which is an agent for preventing or treating cancer. The cancer is breast cancer, acute myeloid leukemia, pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, angiogenesis, gastric cancer, endometrial cancer, ovarian cancer, brain tumor, colon cancer, multiple myeloma, hepatocellular carcinoma, lung cancer The medicament according to claim 6 , which is at least one selected from the group consisting of thyroid cancer and thyroid cancer.