JP7654426B2 - Method for producing imidazopyridinone compounds - Google Patents

Description

The present invention relates to a method for producing an imidazopyridinone compound that is useful as a pharmaceutical. More specifically, the present invention relates to a method for producing an imidazopyridinone compound or a pharmacologically acceptable salt thereof that has an inhibitory effect on prolyl hydroxylase and is useful as a therapeutic agent for inflammatory bowel diseases such as ulcerative colitis.

Inflammatory bowel disease (IBD) is a chronic disease in which an immune hyperresponse causes inflammation and ulcers in the intestinal mucosa, and includes, for example, ulcerative colitis and Crohn's disease.
Ulcerative colitis is a disease of the large intestine that causes diffuse nonspecific inflammation of unknown cause. The mucous membrane of the large intestine is invaded, and erosions or ulcers may form in the mucous membrane. Ulcerative colitis can be divided into an "active stage" in which bloody stools, erosions, ulcers, etc. are observed, and a "remission stage" in which the symptoms of the active stage disappear. Since relapses and remissions often occur repeatedly during the course of the disease, long-term treatment is required.
5-aminosalicylic acid preparations (5-ASA) are used as the standard drug for the treatment of ulcerative colitis. However, the efficacy of 5-ASA is about 50-65%, and only about 30-45% of patients achieve remission with 5-ASA administration. When 5-ASA is ineffective, steroids are used. In addition to these drugs, immunosuppressants and anti-TNFα antibodies may be used to treat ulcerative colitis. However, all of these drugs have issues such as side effects and the need for careful administration, and there is a need for a treatment for ulcerative colitis with a new mechanism of action.

In the pathology of IBD, it is known that hypoxia-inducible factor 1α (HIF-1α) induces the expression of genes related to the barrier function of the gastrointestinal epithelium. HIF-1α is one of the subtypes of hypoxia-inducible factor α (HIF-α). HIF-α is stabilized in a hypoxic environment (hypoxia) and activates the transcription of various genes in response to hypoxia. On the other hand, in an oxygen-rich environment (normoxia), the proline residues of HIF-α are hydroxylated by prolyl hydroxylases (PHDs), and the HIF-α is degraded by the proteasome.

PHDs are known to have three subtypes: PHD1, PHD2, and PHD3. AKB-4924 is known as a PHD2 inhibitor, and it has been reported that AKB-4924 stabilizes HIF-1α in colonic tissue (Non-Patent Document 1). Furthermore, AKB-4924 has been shown to have an ameliorating effect in a trinitrobenzene sulfonic acid (TNBS)-induced colitis model.
On the other hand, PHDs inhibitors such as Roxadustat and Daprodustat have hematopoietic effects and have been developed as therapeutic agents for anemia (Non-Patent Document 2). Therefore, when using PHDs inhibitors as therapeutic agents for IBD, it is important to distinguish them from systemic effects such as hematopoietic effects.

As PHDs inhibitors, for example, spiro compounds are described in Patent Documents 1 and 5, and Non-Patent Documents 3 and 4. In addition, compounds containing imidazopyridinone are described or exemplified in Patent Documents 2 to 4. However, the imidazopyridinone compounds of the present invention are neither described nor suggested in the above documents.

US Patent Application Publication No. 2011/0152304 International Publication No. 2009/029609 International Publication No. 2003/037890 International Publication No. 2017/066014 US Patent Application Publication No. 2010/0137297

Ellen Marks et al., Inflamm. Bowel. Dis., 2015, Vol. 21, No. 2, pp. 267-275 Mun Chiang Chan et al., Molecular Aspects of Medicine, 2016, Vol. 47-48, pp. 54-75 Guanghui Deng et al., Bioorganic & Medicinal Chemistry, 2013, Vol. 21, pp. 6349-6358 Petr Vachal et al., Journal of Medicinal Chemistry, 2012, Vol. 55, pp. 2945-2959

The objective of the present invention is to provide a method for producing an imidazopyridinone compound that has a PHD2 inhibitory effect and is useful for treating inflammatory bowel disease.

〔式中、
環Wは、C_6-10アリール、5若しくは6員環ヘテロアリール、9若しくは10員環ヘテロアリール、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
環Zは、以下の(a)～(c)からなる群から選択される基：

及び

（式中、
R^a、R^b及びR^cは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり；
R^dは、水素原子、又はC_1-6アルキルである）；
R¹は、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり（mが2又は3である場合、2以上のR¹は互いに異なっていてもよい）；
R²は、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ヒドロキシ、－CO₂R⁴、又は－CONR⁵R^5’であり（nが2又は3である場合、2以上のR²は互いに異なっていてもよい）；
R⁴は、水素原子、又はC_1-6アルキルであり；
R⁵及びR^5’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
R³は、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、ヒドロキシ、シアノ、ニトロ、－NR⁶R^6’、－CO₂R⁷、－CONR⁸R^8’、又は以下の基Aであり（uが2又は3である場合、2以上のR³は互いに異なっていてもよい）；
R⁶及びR^6’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R⁷は、水素原子、又はC_1-6アルキルであり；
R⁸及びR^8’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基Aは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群Bから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群Bから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群Bは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、シアノ、－NR⁹R^9’、－NR⁹SO₂R¹⁰、－CO₂R¹⁰、及び－CONR¹¹R^11’からなる群であり；
R⁹及びR^9’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R¹⁰は、水素原子、又はC_1-6アルキルであり；
R¹¹及びR^11’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
m、n及びuは、それぞれ独立して、1から3の整数であり；
p及びqは、それぞれ独立して、1又は2であり；
rは、0から6の整数である〕で表される化合物又はその薬理学的に許容される塩の製造方法であって、
式（II）：

〔式中、m、n、p及びqは、前記定義の通りであり；
R^1Rは、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、保護基で保護されていてもよいヒドロキシ、又は保護基で保護されていてもよいカルボキシであり（mが2又は3である場合、2以上のR^1Rは互いに異なっていてもよい）；
R^2Rは、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、－CO₂R^4R、又は－CONR^5RR^5R’であり（nが2又は3である場合、2以上のR^2Rは互いに異なっていてもよい）；
R^4Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^5R及びR^5R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
R^Xは、水素原子、又は式（III）：

（式中、環W、u及びrは、前記定義の通りであり；
R^3Rは、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、保護基で保護されていてもよいヒドロキシ、シアノ、ニトロ、－NR^6RR^6R’、－CO₂R^7R、－CONR^8RR^8R’、又は以下の基AAであり（uが2又は3である場合、2以上のR^3Rは互いに異なっていてもよい）；
R^6R及びR^6R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^7Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^8R及びR^8R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基AAは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群BBから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群BBから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群BBは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、シアノ、－NR^9RR^9R’、－NR^9RSO₂R^10R、－CO₂R^10R、及び－CONR^11RR^11R’からなる群であり；
R^9R及びR^9R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^10Rは、保護基、水素原子、又はC_1-6アルキルであり；及び
R^11R及びR^11R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルである）〕で表される化合物又はその塩と、
式（IV）：

〔式中、環ZZは、以下の(a)～(c)からなる群から選択される基：

及び

（式中、
R^A、R^B及びR^Cは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、保護基で保護されていてもよいヒドロキシ、又は保護基で保護されていてもよいカルボキシであり；
R^Dは、保護基、水素原子、又はC_1-6アルキルである）〕で表される化合物又はその塩を用いて、
式（V）：

〔式中、環ZZ、R^1R、R^2R、R^X、m、n、p及びqは、前記定義の通りである〕で表される化合物又はその塩を得る工程を包含することを特徴とする、製造方法。
〔２〕前記〔１〕に記載の製造方法であって、
式（IIA）：

〔式中、R^1R、R^2R、R^3R、環W、m、n、p、q、r及びuは、前記〔１〕と同じ意味である〕
で表される化合物又はその塩と、
前記式（IV）で表される化合物又はその塩を用いて、
式（VA）：

〔式中、環W、環ZZ、R^1R、R^2R、R^3R、m、n、p、q、r及びuは、前記〔１〕と同じ意味である〕で表される化合物又はその塩を得る工程を包含することを特徴とする、製造方法。
〔３〕前記〔１〕に記載の製造方法であって、
式（IIB）：

〔式中、R^1R、R^2R、m、n、p及びqは、前記〔１〕と同じ意味である〕
で表される化合物又はその塩と、
前記式（IV）で表される化合物又はその塩を用いて、
式（VB）：

〔式中、環ZZ、R^1R、R^2R、m、n、p及びqは、前記〔１〕と同じ意味である〕で表される化合物又はその塩を得る工程を包含することを特徴とする、製造方法。
〔４〕式（I）：

〔式中、
環Wは、C_6-10アリール、5若しくは6員環ヘテロアリール、9若しくは10員環ヘテロアリール、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
環Zは、以下の(a)～(c)からなる群から選択される基：

及び

（式中、
R^a、R^b及びR^cは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり；
R^dは、水素原子、又はC_1-6アルキルである）；
R¹は、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり（mが2又は3である場合、2以上のR¹は互いに異なっていてもよい）；
R²は、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ヒドロキシ、－CO₂R⁴、又は－CONR⁵R^5’であり（nが2又は3である場合、2以上のR²は互いに異なっていてもよい）；
R⁴は、水素原子、又はC_1-6アルキルであり；
R⁵及びR^5’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
R³は、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、ヒドロキシ、シアノ、ニトロ、－NR⁶R^6’、－CO₂R⁷、－CONR⁸R^8’、又は以下の基Aであり（uが2又は3である場合、2以上のR³は互いに異なっていてもよい）；
R⁶及びR^6’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R⁷は、水素原子、又はC_1-6アルキルであり；
R⁸及びR^8’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基Aは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群Bから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群Bから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群Bは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、シアノ、－NR⁹R^9’、－NR⁹SO₂R¹⁰、－CO₂R¹⁰、及び－CONR¹¹R^11’からなる群であり；
R⁹及びR^9’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R¹⁰は、水素原子、又はC_1-6アルキルであり；
R¹¹及びR^11’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
m、n及びuは、それぞれ独立して、1から3の整数であり；
p及びqは、それぞれ独立して、1又は2であり；及び
rは、0から6の整数である〕で表される化合物又はその薬理学的に許容される塩の製造方法であって、
式（IIC）：

〔式中、
環Wは、C_6-10アリール、5若しくは6員環ヘテロアリール、9若しくは10員環ヘテロアリール、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
R^1Rは、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、保護基で保護されていてもよいヒドロキシ、又は保護基で保護されていてもよいカルボキシであり（mが2又は3である場合、2以上のR^1Rは互いに異なっていてもよい）；
R^2Rは、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、－CO₂R^4R、又は－CONR^5RR^5R’であり（nが2又は3である場合、2以上のR^2Rは互いに異なっていてもよい）；
R^4Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^5R及びR^5R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
R^3RAは、ハロゲン原子、又は基AAであり；
R^3RB及びR^3RCは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、保護基で保護されていてもよいヒドロキシ、シアノ、ニトロ、－NR^6RR^6R’、－CO₂R^7R、－CONR^8RR^8R’、又は以下の基AAであり；
R^6R及びR^6R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^7Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^8R及びR^8R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基AAは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群BBから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群BBから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群BBは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、シアノ、－NR^9RR^9R’、－NR^9RSO₂R^10R、－CO₂R^10R、及び－CONR^11RR^11R’からなる群であり；
R^9R及びR^9R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^10Rは、保護基、水素原子、又はC_1-6アルキルであり；及び
R^11R及びR^11R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
m及びnは、それぞれ独立して、1から3の整数であり；
p及びqは、それぞれ独立して、1又は2であり；及び
rは、0から6の整数である〕
で表される化合物又はその塩を経由することを特徴とする、製造方法。
〔５〕式（I）：

〔式中、
環Wは、C_6-10アリール、5若しくは6員環ヘテロアリール、9若しくは10員環ヘテロアリール、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
環Zは、以下の(a)～(c)からなる群から選択される基：

及び

（式中、
R^a、R^b及びR^cは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり；
R^dは、水素原子、又はC_1-6アルキルである）；
R¹は、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり（mが2又は3である場合、2以上のR¹は互いに異なっていてもよい）；
R²は、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ヒドロキシ、－CO₂R⁴、又は－CONR⁵R^5’であり（nが2又は3である場合、2以上のR²は互いに異なっていてもよい）；
R⁴は、水素原子、又はC_1-6アルキルであり；
R⁵及びR^5’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
R³は、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、ヒドロキシ、シアノ、ニトロ、－NR⁶R^6’、－CO₂R⁷、－CONR⁸R^8’、又は以下の基Aであり（uが2又は3である場合、2以上のR³は互いに異なっていてもよい）；
R⁶及びR^6’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R⁷は、水素原子、又はC_1-6アルキルであり；
R⁸及びR^8’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基Aは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群Bから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群Bから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群Bは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、シアノ、－NR⁹R^9’、－NR⁹SO₂R¹⁰、－CO₂R¹⁰、及び－CONR¹¹R^11’からなる群であり；
R⁹及びR^9’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R¹⁰は、水素原子、又はC_1-6アルキルであり；
R¹¹及びR^11’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
m、n及びuは、それぞれ独立して、1から3の整数であり；
p及びqは、それぞれ独立して、1又は2であり；及び
rは、0から6の整数である〕で表される化合物又はその薬理学的に許容される塩の製造方法であって、
式（VC）：

〔式中、
環Wは、C_6-10アリール、5若しくは6員環ヘテロアリール、9若しくは10員環ヘテロアリール、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
環ZZは、以下の(a)～(c)からなる群から選択される基：

及び

（式中、
R^A、R^B及びR^Cは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、保護基で保護されていてもよいヒドロキシ、又は保護基で保護されていてもよいカルボキシであり；
R^Dは、保護基、水素原子、又はC_1-6アルキルである）であり；
R^1Rは、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、保護基で保護されていてもよいヒドロキシ、又は保護基で保護されていてもよいカルボキシであり（mが2又は3である場合、2以上のR^1Rは互いに異なっていてもよい）；
R^2Rは、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、－CO₂R^4R、又は－CONR^5RR^5R’であり（nが2又は3である場合、2以上のR^2Rは互いに異なっていてもよい）；
R^4Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^5R及びR^5R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
R^3RAは、ハロゲン原子、又は基AAであり；
R^3RB及びR^3RCは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、保護基で保護されていてもよいヒドロキシ、シアノ、ニトロ、－NR^6RR^6R’、－CO₂R^7R、－CONR^8RR^8R’、又は以下の基AAであり；
R^6R及びR^6R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^7Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^8R及びR^8R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基AAは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群BBから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群BBから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群BBは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、シアノ、－NR^9RR^9R’、－NR^9RSO₂R^10R、－CO₂R^10R、及び－CONR^11RR^11R’からなる群であり；
R^9R及びR^9R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^10Rは、保護基、水素原子、又はC_1-6アルキルであり；及び
R^11R及びR^11R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
m及びnは、それぞれ独立して、1から3の整数であり；
p及びqは、それぞれ独立して、1又は2であり；及び
rは、0から6の整数である〕
で表される化合物又はその塩を経由することを特徴とする、製造方法。
〔６〕前記〔１〕から〔５〕の何れかに記載の製造方法であって、
環Zが、以下の(a)～(j)：

及び

からなる群から選択される基であり；及び
環ZZが、以下の(aa)～(jj)からなる群から選択される基：

及び

（式中、PGは水素原子、又は保護基である）
からなる群から選択される基である、製造方法。
〔７〕環Wが、フェニル、又は5若しくは6員環ヘテロアリールである、前記〔１〕から〔６〕の何れかに記載の製造方法。
〔８〕rが0である、前記〔１〕から〔７〕の何れかに記載の製造方法。
〔９〕pが2であって、かつqが1である、前記〔１〕から〔８〕の何れかに記載の製造方法。
〔１０〕R¹及びR^1Rが、水素原子、又はハロゲン原子である、前記〔１〕から〔９〕の何れかに記載の製造方法。
〔１１〕前記〔１〕から〔１０〕の何れかに記載の製造方法であって、
R²が、水素原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、カルボキシ、又は－CONR⁵R^5’であり；
R⁵及びR^5’は、それぞれ独立して、水素原子、カルボキシC_1-6アルキル、又は3～8員環ヘテロシクロアルキルであり；
R^2Rが、水素原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、保護基で保護されていてもよいカルボキシ、又は－CONR^5RR^5R’であり；及び
R^5R及びR^5R’は、それぞれ独立して、保護基、水素原子、保護基で保護されていてもよいカルボキシC_1-6アルキル、又は3～8員環ヘテロシクロアルキルである、製造方法。
〔１２〕前記〔１〕から〔１１〕の何れかに記載の製造方法であって、
R³が、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_1-6アルキルスルファニル、C_1-6アルキルスルホニル、ヒドロキシ、シアノ、－CO₂R⁷、－CONR⁸R^8’、又は基Aであり；
R⁸及びR^8’が、それぞれ独立して、水素原子、又はカルボキシC_1-6アルキルであり；
基Aが、非置換若しくは置換基群Bから選択される1から3個の基で置換されたフェニル、又は非置換5若しくは6員環ヘテロアリールであり；
置換基群Bは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、シアノ、又はカルボキシであり；
R^3Rが、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_1-6アルキルスルファニル、C_1-6アルキルスルホニル、保護基で保護されていてもよいヒドロキシ、シアノ、－CO₂R^7R、－CONR^8RR^8R’、又は基AAであり；
R⁷、R^7R及びuが、前記〔１〕と同じ意味であり；
R^8R及びR^8R’が、それぞれ独立して、保護基、水素原子、又は保護基で保護されていてもよいカルボキシC_1-6アルキルであり；
基AAが、非置換若しくは置換基群BBから選択される1から3個の基で置換されたフェニル、又は非置換5若しくは6員環ヘテロアリールであり；及び
置換基群BBは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、シアノ、又は保護基で保護されていてもよいカルボキシである、製造方法。
〔１３〕前記〔１〕から〔１２〕の何れかに記載の製造方法であって、
環Zが、以下の(a)～(e)：

及び

からなる群から選択される基であり；及び
環ZZが、以下の(aa)～(ee)：

及び

（式中、PGは水素原子、又は保護基である）
からなる群から選択される基である、製造方法。
〔１４〕前記〔１〕から〔１１〕の何れかに記載の製造方法であって、
uが、2又は3であり；
1つのR³が、基Aであり；
それ以外のR³が、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_1-6アルキルスルファニル、C_1-6アルキルスルホニル、ヒドロキシ、シアノ、ニトロ、－NR⁶R^6’、－CO₂R⁷、又は－CONR⁸R^8’であり；
1つのR^3Rが、基AAであり；
それ以外のR^3Rが、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_1-6アルキルスルファニル、C_1-6アルキルスルホニル、保護基で保護されていてもよいヒドロキシ、シアノ、ニトロ、－NR^6RR^6R’、－CO₂R^7R、又は－CONR^8RR^8R’であり；
基A、R⁶、R^6’、R⁷、R⁸、R^8’、基AA、R^6R、R^6R’、R^7R、R^8R及びR^8R’が前記〔１〕と同じ意味である、製造方法。
〔１５〕式（IA）：

〔式中、
Xは、CR³、又はNであり；
R¹は、水素原子、又はハロゲン原子であり（mが2又は3である場合、2以上のR¹は互いに異なっていてもよい）；
R²は、水素原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、カルボキシ、又は－CONR⁵R^5’であり（nが2又は3である場合、2以上のR²は互いに異なっていてもよい）；
R⁵及びR^5’は、それぞれ独立して、水素原子、カルボキシC_1-6アルキル、又は3～8員環ヘテロシクロアルキルであり；
R³は、水素原子、C_1-6アルキル、又はヒドロキシであり（uが2である場合、2つのR³は互いに異なっていてもよい）；
基Aは、非置換若しくは置換基群Bから選択される1から3個の基で置換されたフェニル、又は非置換5若しくは6員環ヘテロアリールであり；
置換基群Bは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、シアノ、又はカルボキシであり；
環Zは、以下の(a)～(e)：

及び

からなる群から選択される基であり；
m及びnは、それぞれ独立して、1から3の整数であり；
uは、1又は2である〕で表される化合物又はその薬理学的に許容される塩の製造方法であって、
式（IID）：

〔式中、m及びnは、前記〔１〕と同じ意味であり；
R^1Rは、水素原子、又はハロゲン原子であり（mが2又は3である場合、2以上のR^1Rは互いに異なっていてもよい）；
R^2Rは、水素原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、保護基で保護されていてもよいカルボキシ、又は－CONR^5RR^5R’であり（nが2又は3である場合、2以上のR^2Rは互いに異なっていてもよい）；
R^5R及びR^5R’は、それぞれ独立して、保護基、水素原子、保護基で保護されていてもよいカルボキシC_1-6アルキル、又は3～8員環ヘテロシクロアルキルであり；及び
R^Yは、水素原子、式（IIIA）：

又は、式（IIIB）：

（式中、uは、1又は2であり；
X^Rは、CR^3R、又はNであり；
R^3Rは、水素原子、C_1-6アルキル、保護基で保護されていてもよいヒドロキシであり（uが2である場合、2つのR^3Rは互いに異なっていてもよい）；
Lは、ハロゲン原子であり；
基AAは、非置換又は置換基群BBから選択される1から3個の基で置換されたフェニル、又は非置換5又は6員環ヘテロアリールであり；及び
置換基群BBは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、シアノ、又は保護基で保護されていてもよいカルボキシである）〕で表される化合物又はその塩と、
式（IV）：

〔式中、環ZZは、以下の(aa)～(ee)からなる群から選択される基：

及び

（式中、PGは水素原子、又は保護基である）〕
で表される化合物又はその塩を用いて、
式(VD）：

〔式中、環ZZ、R^1R、R^2R、R^Y、m及びnは、〔１５〕内の前記と同じ意味である〕で表される化合物又はその塩を得る工程を包含することを特徴とする、製造方法。
〔１６〕式（IIC）：

〔式中、
R^3RAは、ハロゲン原子、又は基AAであり；
R^3RB及びR^3RCは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、保護基で保護されていてもよいヒドロキシ、シアノ、ニトロ、－NR^6RR^6R’、－CO₂R^7R、－CONR^8RR^8R’、又は以下の基AAであり；
R^6R及びR^6R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^7Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^8R及びR^8R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基AAは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群BBから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群BBから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群BBは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、シアノ、－NR^9RR^9R’、－NR^9RSO₂R^10R、－CO₂R^10R、及び－CONR^11RR^11R’からなる群であり；
R^9R及びR^9R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^10Rは、保護基、水素原子、又はC_1-6アルキルであり；及び
R^11R及びR^11R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
環W、R^1R、R^2R、m、n、p、q及びrは、前記〔１〕と同じ意味である〕で表される化合物又はその塩。
〔１７〕式（VC）：

〔式中、
R^3RAは、ハロゲン原子、又は基AAであり；
R^3RB及びR^3RCは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、保護基で保護されていてもよいヒドロキシ、シアノ、ニトロ、－NR^6RR^6R’、－CO₂R^7R、－CONR^8RR^8R’、又は以下の基AAであり；
R^6R及びR^6R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^7Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^8R及びR^8R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基AAは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群BBから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群BBから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群BBから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群BBから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群BBは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、保護基で保護されていてもよいヒドロキシ、シアノ、－NR^9RR^9R’、－NR^9RSO₂R^10R、－CO₂R^10R、及び－CONR^11RR^11R’からなる群であり；
R^9R及びR^9R’は、それぞれ独立して、保護基、水素原子、又はC_1-6アルキルであり；
R^10Rは、保護基、水素原子、又はC_1-6アルキルであり；
R^11R及びR^11R’は、それぞれ独立して、保護基、水素原子、C_1-6アルキル、保護基で保護されていてもよいカルボキシC_1-6アルキル、保護基で保護されていてもよいヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；及び
環W、環ZZ、R^1R、R^2R、m、n、p、q及びrは、前記〔１〕と同じ意味である〕で表される化合物又はその塩。 The present invention relates to a method for producing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof. That is, the present invention relates to the following [1] to [17], etc.
[1] A compound represented by formula (I):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or a C _1-6 alkyl;
R ¹ is a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
R ² is a hydrogen atom, a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' (when n is 2 or 3, two or more R ² may be different from each other);
^R4 is a hydrogen atom or _C1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or the following group A (when u is 2 or 3, two or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or a C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
The group A is a group selected from the group consisting of the following (a) to (h):
(a) a C _6-10 aryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(e) a 5- or 6-membered heteroaryl C _1-6 alkyl group unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and
(h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9′ are each independently a hydrogen atom or a C _1-6 alkyl;
R ¹⁰ is a hydrogen atom or C _1-6 alkyl;
R ¹¹ and R ^11' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
m, n, and u are each independently an integer from 1 to 3;
p and q are each independently 1 or 2;
and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof,
Formula (II):

wherein m, n, p and q are as defined above;
R ^1R is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a cyano, a hydroxyl group which may be protected by a protecting group, or a carboxyl group which may be protected by a protecting group (when m is 2 or 3, two or more R ^1R may be different from each other);
^R2R is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, hydroxy which may be protected by a protecting ^group , _-CO2R4R , or ^{-CONR5R5R '} (when n is 2 or 3, two or more ^R2R may be different from each other);
R ^4R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
R ^X is a hydrogen atom or a group represented by formula (III):

(Wherein, rings W, u and r are as defined above;
^R3R _is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, C1-6 alkoxy, _haloC1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkylsulfanyl, _C1-6 alkylsulfinyl, _C1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, ^{-NR6R3R6R '} , _-CO2R7R ^{, -CONR8R3R8R '} , or the following group AA (when u is 2 or 3, two or more ^R3R may be different from each other);
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl; and
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, a C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl,
Formula (IV):

[In the formula, ring ZZ is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^A , R ^B and R ^C are each independently a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, a hydroxyl which may be protected by a protecting group, or a carboxyl which may be protected by a protecting group;
R ^D is a protecting group, a hydrogen atom, or a C _1-6 alkyl group, or a salt thereof,
Formula (V):

A production method comprising the step of obtaining a compound represented by the formula: wherein ring ZZ, R ^1R , R ^2R , R ^x , m, n, p and q are as defined above, or a salt thereof.
[2] The manufacturing method according to [1] above,
Formula (IIA):

(In the formula, ^R1R , ^R2R , ^R3R , ring W, m, n, p, q, r and u have the same meanings as defined in [1] above.)
or a salt thereof;
Using the compound represented by formula (IV) or a salt thereof,
Formula (VA):

[In the formula, ring W, ring ZZ, ^R1R , ^R2R , ^R3R , m, n, p, q, r and u have the same meanings as defined in the above [1]] or a salt thereof,
[3] The manufacturing method according to [1],
Formula (IIB):

(In the formula, ^R1R , ^R2R , m, n, p and q are the same as defined in [1] above.)
or a salt thereof;
Using the compound represented by formula (IV) or a salt thereof,
Formula (VB):

[In the formula, ring ZZ, ^R1R , ^R2R , m, n, p and q are as defined in the above [1]] or a salt thereof,
[4] Formula (I):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or a C _1-6 alkyl;
R ¹ is a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
R ² is a hydrogen atom, a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' (when n is 2 or 3, two or more R ² may be different from each other);
^R4 is a hydrogen atom or _C1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or the following group A (when u is 2 or 3, two or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or a C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
The group A is a group selected from the group consisting of the following (a) to (h):
(a) a C _6-10 aryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(e) a 5- or 6-membered heteroaryl C _1-6 alkyl group unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and
(h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9′ are each independently a hydrogen atom or a C _1-6 alkyl;
R ¹⁰ is a hydrogen atom or C _1-6 alkyl;
R ¹¹ and R ^11' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
m, n, and u are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof,
Formula (IIC):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ^1R is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a cyano, a hydroxyl group which may be protected by a protecting group, or a carboxyl group which may be protected by a protecting group (when m is 2 or 3, two or more R ^1R may be different from each other);
^R2R is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, hydroxy which may be protected by a protecting ^group , _-CO2R4R , or ^{-CONR5R5R '} (when n is 2 or 3, two or more ^R2R may be different from each other);
R ^4R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
R ^3RA is a halogen atom or a group AA;
R ^3RB and R ^3RC are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, -NR ^6R R ^6R' , -CO ₂ R ^7R , -CONR ^8R R ^8R' , or the following group AA;
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl; and
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
m and n are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
r is an integer from 0 to 6.
or a salt thereof.
[5] Formula (I):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or a C _1-6 alkyl;
R ¹ is a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
R ² is a hydrogen atom, a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' (when n is 2 or 3, two or more R ² may be different from each other);
^R4 is a hydrogen atom or _C1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or the following group A (when u is 2 or 3, two or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or a C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
The group A is a group selected from the group consisting of the following (a) to (h):
(a) a C _6-10 aryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(e) a 5- or 6-membered heteroaryl C _1-6 alkyl group unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and
(h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9′ are each independently a hydrogen atom or a C _1-6 alkyl;
R ¹⁰ is a hydrogen atom or C _1-6 alkyl;
R ¹¹ and R ^11' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
m, n, and u are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof,
Formula (VC):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring ZZ is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^A , R ^B and R ^C are each independently a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, a hydroxyl which may be protected by a protecting group, or a carboxyl which may be protected by a protecting group;
R ^D is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^1R is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a cyano, a hydroxyl group which may be protected by a protecting group, or a carboxyl group which may be protected by a protecting group (when m is 2 or 3, two or more R ^1R may be different from each other);
^R2R is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, hydroxy which may be protected by a protecting ^group , _-CO2R4R , or ^{-CONR5R5R '} (when n is 2 or 3, two or more ^R2R may be different from each other);
R ^4R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
R ^3RA is a halogen atom or a group AA;
R ^3RB and R ^3RC are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, -NR ^6R R ^6R' , -CO ₂ R ^7R , -CONR ^8R R ^8R' , or the following group AA;
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl; and
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
m and n are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
r is an integer from 0 to 6.
or a salt thereof.
[6] The manufacturing method according to any one of [1] to [5],
Ring Z is any one of the following (a) to (j):

and

and ring ZZ is a group selected from the group consisting of (aa) to (jj):

and

(wherein PG is a hydrogen atom or a protecting group).
The method for producing the compound according to claim 1, wherein the compound is a group selected from the group consisting of
[7] The method according to any one of [1] to [6] above, wherein ring W is phenyl, or a 5- or 6-membered heteroaryl.
[8] The method for producing a compound according to any one of [1] to [7] above, wherein r is 0.
[9] The method for producing any one of [1] to [8] above, wherein p is 2 and q is 1.
[10] The method according to any one of [1] to [9] above, wherein ^R1 and ^R1R are hydrogen atoms or halogen atoms.
[11] The manufacturing method according to any one of [1] to [10],
R ² is a hydrogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, carboxy, or -CONR ⁵ R ^5' ;
R ⁵ and R ^5' are each independently a hydrogen atom, a carboxyC _1-6 alkyl, or a 3- to 8-membered heterocycloalkyl;
R ^2R is a hydrogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, carboxy which may be protected by a protecting group, or -CONR ^5R R ^5R' ; and
The production method, wherein R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, a carboxyC _1-6 alkyl which may be protected by a protecting group, or a 3- to 8-membered heterocycloalkyl.
[12] The manufacturing method according to any one of [1] to [11],
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, cyano, —CO ₂ R ⁷ , —CONR ⁸ R ^8′ , or a group A;
R ⁸ and R ^8' are each independently a hydrogen atom or carboxyC _1-6 alkyl;
Group A is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, or unsubstituted 5- or 6-membered heteroaryl;
Substituent group B is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, or carboxy;
^R3R is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, C1-6 _{alkoxy, haloC1-6 alkoxy} , _C2-6 alkenyl, _C1-6 alkylsulfanyl, _C1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, _-CO2R7R ^{, -CONR8RR8R '} , or a group AA;
R ⁷ , R ^7R and u are the same as defined in [1] above;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, or a carboxyC _1-6 alkyl optionally protected by a protecting group;
A production method in which the group AA is unsubstituted or phenyl substituted with 1 to 3 groups selected from the substituent group BB, or unsubstituted 5- or 6-membered heteroaryl; and the substituent group BB is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, or carboxy which may be protected by a protecting group.
[13] The manufacturing method according to any one of [1] to [12],
Ring Z is any one of the following (a) to (e):

and

and ring ZZ is a group selected from the group consisting of (aa) to (ee) below:

and

(wherein PG is a hydrogen atom or a protecting group).
The method for producing the compound according to claim 1, wherein the compound is a group selected from the group consisting of
[14] The manufacturing method according to any one of [1] to [11],
u is 2 or 3;
one ^R3 is a group A;
The remaining ^R3s are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , or -CONR ⁸ R ^8' ;
one ^R3R is a group AA;
The remaining ^R3R are each independently a hydrogen atom, a halogen atom, C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, _haloC1-6 alkoxy, _C2-6 alkenyl, _C1-6 alkylsulfanyl, _C1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, ^-NR6R R6R ^' , ^-CO2R7R , or ^{-CONR8R R8R} _{' ;}
The group A, ^R6 , R6 ^' , ^R7 , ^R8 , ^R8' , group AA, ^R6R , R6R ^' , ^R7R , ^R8R and R8R ^' have the same meanings as defined in the above [1].
[15] Formula (IA):

[Wherein,
X is ^CR3 or N;
R ¹ is a hydrogen atom or a halogen atom (when m is 2 or 3, two or more R ¹ may be different from each other);
R ² is a hydrogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, carboxy, or -CONR ⁵ R ^5' (when n is 2 or 3, two or more R ² may be different from each other);
R ⁵ and R ^5' are each independently a hydrogen atom, a carboxyC _1-6 alkyl, or a 3- to 8-membered heterocycloalkyl;
^R3 is a hydrogen atom, a _C1-6 alkyl, or a hydroxyl (when u is 2, the two ^R3 may be different from each other);
Group A is phenyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, or unsubstituted 5- or 6-membered heteroaryl;
Substituent group B is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, or carboxy;
Ring Z is any one of (a) to (e) below:

and

is a group selected from the group consisting of:
m and n are each independently an integer from 1 to 3;
and u is 1 or 2; or a pharmacologically acceptable salt thereof,
Formula (IID):

[In the formula, m and n are the same as defined in [1] above;
R ^1R is a hydrogen atom or a halogen atom (when m is 2 or 3, two or more R ^1R may be different from each other);
R ^2R is a hydrogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, carboxy which may be protected by a protecting group, or -CONR ^5R R ^5R' (when n is 2 or 3, two or more R ^2R may be different from each other);
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, a carboxyC _1-6 alkyl group which may be protected by a protecting group, or a 3- to 8-membered heterocycloalkyl group; and
R ^Y is a hydrogen atom, a group represented by formula (IIIA):

Or, the formula (IIIB):

(Wherein, u is 1 or 2;
^XR is ^CR3R or N;
R ^3R is a hydrogen atom, a C _1-6 alkyl, or a hydroxyl group which may be protected by a protecting group (when u is 2, the two R ^3R may be different from each other);
L is a halogen atom;
group AA is unsubstituted or phenyl substituted with 1 to 3 groups selected from the substituent group BB, or unsubstituted 5- or 6-membered heteroaryl; and the substituent group BB is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, or carboxy which may be protected by a protecting group) or a salt thereof;
Formula (IV):

[In the formula, ring ZZ is a group selected from the group consisting of the following (aa) to (ee):

and

(wherein PG is a hydrogen atom or a protecting group).
or a salt thereof,
Formula (VD):

[In the formula, ring ZZ, R ^1R , R ^2R , R ^Y , m and n are as defined above in [15]] or a salt thereof.
[16] Formula (IIC):

[Wherein,
R ^3RA is a halogen atom or a group AA;
R ^3RB and R ^3RC are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, -NR ^6R R ^6R' , -CO ₂ R ^7R , -CONR ^8R R ^8R' , or the following group AA;
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl; and
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
Ring W, ^R1R , ^R2R , m, n, p, q and r are as defined in the above [1], or a salt thereof.
[17] Formula (VC):

[Wherein,
R ^3RA is a halogen atom or a group AA;
R ^3RB and R ^3RC are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, -NR ^6R R ^6R' , -CO ₂ R ^7R , -CONR ^8R R ^8R' , or the following group AA;
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl which may be protected by a protecting group, hydroxy C _1-6 alkyl which may be protected by a protecting group, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; and ring W, ring ZZ, R ^1R , R ^2R , m, n, p, q and r are as defined in the above [1], or a salt thereof.

The present invention is useful as it provides a novel method for producing an imidazopyridinone compound represented by formula (I) or a pharmacologically acceptable salt thereof, which has excellent PHD2 inhibitory activity. Therefore, the imidazopyridinone compound or a pharmacologically acceptable salt thereof produced by the production method of the present invention is useful as a therapeutic agent for inflammatory bowel disease.

The following describes an embodiment of the present invention in more detail.

In this invention, each term has the following meaning unless otherwise specified.

The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. As ^{R 1} , R ² and R ³ , a fluorine atom is preferred.
"C _1-6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like.
"C _2-6 alkenyl" means a straight or branched alkenyl group having 2 to 6 carbon atoms. Examples include vinyl, allyl, 1-propenyl, isopropenyl, and the like.
"C _2-6 alkynyl" means a straight or branched alkynyl group having 2 to 6 carbon atoms. Examples include ethynyl and 2-propynyl.
"C _1-6 alkoxy" means a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

"Carboxy C _1-6 alkyl" means a C _1-6 alkyl substituted with one carboxy. For example, carboxymethyl and the like are included.
"Hydroxy _C1-6 alkyl" means a _C1-6 alkyl substituted with one hydroxyl group, for example, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, etc.
"Halo C _1-6 alkyl" means a C _1-6 alkyl substituted with 1 to 3 of the same or different halogen atoms, such as monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, etc.
"Halo C _1-6 alkoxy" means C _1-6 alkoxy substituted with 1 to 3 of the same or different halogen atoms, for example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, etc.

"C _1-6 alkylsulfanyl" means a group represented by (C _1-6 alkyl)-S-.
"C _1-6 alkylsulfinyl" means a group represented by (C _1-6 alkyl)-S(=O)-.
"C _1-6 alkylsulfonyl" refers to a group represented by (C _1-6 alkyl)-SO ₂ -. Examples include methylsulfonyl, ethylsulfonyl, and the like.

"C _6-10 aryl" means phenyl or naphthyl. As the group A and the group AA, phenyl is preferable.
"5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. Ring W is preferably thienyl, pyridyl, and the like, more preferably pyridyl. Group A and group AA are preferably pyridyl, and the like.
"9- or 10-membered heteroaryl" refers to a bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms in the ring. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, pryl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, pteridinyl, chromenyl, isochromenyl and the like. As ring W, quinolyl and the like are preferable.
"C _3-8 cycloalkyl" refers to a saturated hydrocarbon group having 3 to 8 ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
"3- to 8-membered heterocycloalkyl" refers to a 3- to 8-membered heterocycloalkyl group containing one or two heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in the ring. Examples include aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, etc. As ^R5 and R5 ^' , tetrahydropyranyl, etc. are preferable.

" _C6-10 aryl _C1-6 alkyl" means a _C1-6 alkyl substituted with one _C6-10 aryl, for example benzyl.
"C _6-10 aryloxy" refers to a group represented by (C _6-10 aryl)-O-. For example, phenoxy is mentioned.
"5- or 6-membered heteroaryl C _1-6 alkyl" means a C _1-6 alkyl substituted with one 5- or 6-membered heteroaryl.
The term "5- or 6-membered heteroaryloxy" refers to a group represented by (5- or 6-membered heteroaryl)-O-.
When substituted with two or three groups selected from the substituent group B, each group may be the same or different.
When substituted with two or three groups selected from the substituent group BB, each group may be the same or different.

"May be protected by a protecting group" means that hydroxy, amino, amide, and carboxy may be protected by a group that is commonly used as a protecting group, and any group may be used as long as it functions as a protecting group. Examples of the protecting group include the protecting groups described in "Greene's Protective Groups in Organic Synthesis", 4th Edition, edited by Theodra W. Greene & Peter G. M. Wuts, Wiley-Interscience, 2006, or "Greene's Protective Groups in Organic Synthesis", 5th Edition, edited by Peter G. M. Wuts, Wiley-Interscience, 2014.

The following abbreviations used in the text, figures and tables have the following meanings:
CDI: Carbonyldiimidazole
CPME: Cyclopentyl methyl ether
DEAD: Diethyl azodicarboxylate
DIPEA: N,N-diisopropylethylamine
DMA: N,N-dimethylacetamide
DMAP: 4-dimethylaminopyridine
DMF: N,N-dimethylformamide
DMSO: Dimethyl sulfoxide
DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EDC.HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HOBt: 1-hydroxybenzotriazole
_HOBt.H2O : 1-hydroxybenzotriazole monohydrate
LAH: Lithium aluminum hydride
LDA: Lithium diisopropylamide
NaBH(OAc) ₃ : Sodium triacetoxyborohydride
NMP: 1-methyl-2-pyrrolidinone
Pd(amphos)Cl ₂ : Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
THF: Tetrahydrofuran
TsCl: p-toluenesulfonyl chloride
T3P®: Propylphosphonic anhydride (cyclic trimer)
9-BBN: 9-Borabicyclo[3.3.1]nonane amino silica gel: Aminopropylated silica gel
ODS column chromatography: Octadecylsilylated silica gel column chromatography
Process
Scheme
Ref.No.: Reference number
Ex.No.: Example number
Structure: Structural formula
Physical data: Physical properties
_IC50 : 50% inhibitory concentration (numbers with "*" in the table indicate the inhibition rate at a compound concentration of 100 μM)
FITC: Fluorescein isothiocyanate
^1H -NMR: Hydrogen nuclear magnetic resonance spectrum
DMSO-d6: Dimethylsulfoxide-d6
_CDCl3 : Chloroform-d1
MS: Mass spectrometry
ESI_APCI: Electrospray ionization - Atmospheric pressure chemical ionization multi-ionization method

An embodiment of the compound represented by formula (I) is, for example, a compound represented by the following formula: In the formula, R3 ^' has the same meaning as ^R3 in [1] above (provided that R3 ^' is not group A). The other symbols have the same meaning as in [1] above.

An embodiment of the compound represented by formula (IIA) is, for example, a compound represented by the following formula: In the formula, R ^3R' has the same meaning as R ^3R in the above [1] (provided that R ^3R' is not a group AA). The other symbols have the same meaning as in the above [1].

式中の記号は、上記〔1〕と同じ意味である。

One embodiment of the compound represented by formula (I) is a compound in which the group represented by the following formula is a group selected from the group consisting of (a) to (d) below.

The symbols in the formula have the same meanings as in [1] above.

式中の記号は、上記〔1〕と同じ意味である。

One embodiment of the compounds represented by formulas (II), (IIA), (IIB) and (IIC) includes compounds in which the group represented by the following formula is a group selected from the group consisting of the following (a) to (d):

The symbols in the formula have the same meanings as in [1] above.

式中の記号は、上記〔1〕と同じ意味である。

One embodiment of the compounds represented by formulae (V), (VA), (VB) and (VC) includes compounds in which the group represented by the following formula is a group selected from the group consisting of the following (a) to (d):

The symbols in the formula have the same meanings as in [1] above.

及び

又はその薬理学的に許容される塩が挙げられる。 In one embodiment of the compound of formula (I), a compound selected from the group consisting of:

and

or a pharmacologically acceptable salt thereof.

又はその薬理学的に許容される塩が挙げられる。 In one embodiment of the compound of formula (I), there is provided the compound:

or a pharmacologically acceptable salt thereof.

As one embodiment of the compound represented by formula (I), the compound described in the above [1] is preferably a group selected from the group consisting of the following [A] to [I] or a combination thereof.
[A] Ring W is phenyl, naphthyl, thienyl, pyridyl, quinolyl, or cyclohexyl.
[B] R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, methyl, cyano, hydroxy or carboxy.
[C]R ^d is a hydrogen atom or methyl.
[D] R ¹ is a hydrogen atom, a halogen atom, or methyl.
[E] ^R2 is a hydrogen atom, methyl, trifluoromethyl, methoxy, _-CO2H , or ^{-CONR5R5 '} ;
^R5 and R5 ^' are each independently a hydrogen atom, carboxymethyl, or tetrahydropyranyl.
[F] R ³ is a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, vinyl, methylthio, ethylsulfonyl, hydroxy, cyano, nitro, dimethylamino, -CO ₂ R ⁷ , -CONR ⁸ R ^8' or a group A (when u is 2, the two R ³ may be different from each other);
The group A is a group selected from the group consisting of (a) to (f) below:
(a) unsubstituted or substituted phenyl with 1 to 2 groups selected from the substituent group B;
(b) pyridyl,
(c) benzyl,
(d) phenyloxy,
(e) cyclopropyl, and
(f) morpholino;
Substituent group B is the group consisting of a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, cyano, -NHSO ₂ R ¹⁰ and -CO ₂ R ^10' ;
R ¹⁰ and R ^10' are each independently a hydrogen atom or methyl;
^R7 is a hydrogen atom or methyl;
R ⁸ and R ^8' are each independently a hydrogen atom or carboxymethyl.
[G] m, n, and u are each independently 1 or 2.
[H] p and q each independently represent 1 or 2.
[I] r is 0 or 1.

As one embodiment of the compounds represented by formulae (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), which are the compounds described in the above items [1] to [5] and [15] to [17], are preferably a group selected from the group consisting of the following items [A] to [I] or a combination thereof.
[A] Ring W is phenyl, naphthyl, thienyl, pyridyl, quinolyl, or cyclohexyl.
[B] R ^A , R ^B and R ^C each independently represent a hydrogen atom, a halogen atom, methyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group.
[C]R ^D is a hydrogen atom or methyl.
[D] R ^1R is a hydrogen atom, a halogen atom, or methyl.
[E] ^R2R is a hydrogen atom, methyl, trifluoromethyl, methoxy, carboxy which may be protected by a protecting group, or ^{-CONR5R5R5R '} ;
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, carboxymethyl which may be protected by a protecting group, or tetrahydropyranyl.
[F] ^R3R is a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, vinyl, methylthio, ethylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, ^{dimethylamino} , _-CO2R7R , ^{-CONR8R R8R'} , or a group AA (when u is 2, the two ^R3R may be different from each other);
The group AA is a group selected from the group consisting of the following (a) to (f):
(a) phenyl which is unsubstituted or substituted with 1 to 2 groups selected from the substituent group BB;
(b) pyridyl,
(c) benzyl,
(d) phenyloxy,
(e) cyclopropyl, and
(f) morpholino;
Substituent group BB is the group consisting of a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy which may be protected by a protecting group, cyano, -NHSO ₂ R ^10R and -CO ₂ R ^10R' ;
R ^10R and R ^10R' are each independently a protecting group, a hydrogen atom, or methyl;
R ^7R is a hydrogen atom or methyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, or a carboxymethyl which may be protected by a protecting group.
[G] m, n, and u are each independently 1 or 2.
[H] p and q each independently represent 1 or 2.
[I] r is 0 or 1.

In the compounds represented by formulas (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), when one or more asymmetric carbon atoms are present, the present invention also includes compounds in which each asymmetric carbon atom is in the R configuration, the S configuration and any combination thereof. In addition, their racemic compounds, racemic mixtures, single enantiomers and diastereomeric mixtures are also included within the scope of the present invention.

When cis-trans isomers exist in the compounds represented by formulas (I), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), the present invention includes all of the cis-trans isomers.

When tautomers exist in the compounds represented by formulas (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), the present invention includes all of the tautomers.

In the present invention, the determination of stereochemistry can also be performed by methods well known in the art.

The compound represented by formula (I) can be converted into its pharmacologically acceptable salt according to a conventional method, if necessary. Such salts include acid addition salts and salts with bases.

The compounds represented by formulas (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD) can be converted into salts thereof, if necessary, in a conventional manner. Examples of such salts include acid addition salts and salts with bases.

Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

Examples of salts with bases include salts with inorganic bases such as lithium, sodium, potassium, calcium, and magnesium, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

When the compounds represented by formula (I) and (IA) or pharmacologically acceptable salts thereof exist, for example, as crystals, the present invention includes any crystalline form. For example, pharmacologically acceptable salts also include solvates with medicamentously acceptable solvents such as water or ethanol, cocrystals with a suitable coformer, etc.

When the compounds represented by formulas (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD) or salts thereof exist, for example, as crystals, any crystalline form is included. For example, the salts also include solvates with pharma- ceutical acceptable solvents such as water or ethanol, cocrystals with an appropriate coformer, etc.

In the compounds represented by formulae (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), a part ^of each atom may be replaced with the corresponding isotope. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include isotopes of hydrogen atoms, carbon ^atoms , chlorine atoms, fluorine atoms, iodine atoms, ^nitrogen atoms, oxygen atoms, ^phosphorus atoms and sulfur atoms represented by ^2H , ^3H , ^11C , ^13C , ^14C , ^36Cl , ^18F , ^123I , ^125I , 13N, 15N, ^15O , 17O, 18O, ^32P and ^35S , respectively. In one embodiment, a compound represented by formula (I) in which some hydrogen atoms are replaced with ^2H (D: deuterium atom) is exemplified.

In the compounds represented by formulae (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), compounds in which some atoms are replaced with isotopes can be produced by the same method as the production method described below using a commercially available building block containing an isotope. For example, a compound in which some hydrogen atoms in a compound represented by formula (I) are replaced with deuterium atoms can also be produced by the above method and a method described in the literature (see, for example, Journal of Organic Synthesis, Vol. 65, No. 12, pp. 1179-1190, 2007). In addition, for example, a compound in which some carbon atoms in a compound represented by formula (I) are replaced with ¹³ C can also be produced by the above method and a method described in the literature (see, for example, RADIOISOTOPES, Vol. 56, No. 11, pp. 35-44, 2007).

The compound represented by formula (I) can be prepared, for example, by the methods shown in Schemes 1 to 5 or methods similar thereto, or by methods described in the literature or methods similar thereto.

In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.
In the reaction of each step, the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days unless otherwise specified.
In the reactions of each step, the reaction temperature varies depending on the starting materials and solvents used, but is usually from −78° C. to the reflux temperature, unless otherwise specified.
In the reaction of each step, the pressure varies depending on the starting materials, the solvent, the reaction temperature, etc. used, but is usually 1 atm to 20 atm unless otherwise specified.
In the reactions of each step, a microwave reaction apparatus such as Biotage Initiator can also be used. When a microwave reaction apparatus is used, the reaction can be carried out under the following conditions, which vary depending on the raw materials, solvent, and model used: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

In the reactions of each step, unless otherwise specified, these reactions are carried out without solvent or using a suitable solvent. Examples of suitable solvents include solvents that are inert to the reaction. Specific examples of the solvent include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents.
Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.;
Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, 2-methyloxolane, CPME, etc.;
Aromatic hydrocarbons: chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.;
Saturated hydrocarbons: cyclohexane, n-hexane, etc.;
Amides: DMF, DMA, NMP, etc.;
Halogenated hydrocarbons: dichloromethane, 1,2-dichloroethane, carbon tetrachloride, etc.;
Nitriles: acetonitrile, etc.;
Sulfoxides: dimethyl sulfoxide, etc.;
Aromatic organic bases: pyridine, etc.;
Acid anhydrides: acetic anhydride, etc.;
Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.;
Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.;
Ketones: acetone, methyl ethyl ketone, etc.;
water.
The above solvents may be used in combination of two or more kinds in an appropriate ratio.

When a base is used in the reaction of each step, the reaction is carried out using a base suitable for each reaction. Specific examples of the base include the bases described in the Reference Examples or Examples corresponding to each step, or the following bases.
Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.;
Organic bases: triethylamine, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, piperidine, etc.;
Metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.;
Alkali metal hydrides: sodium hydride, etc.;
Metal amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.;
Organomagnesiums: methylmagnesium bromide, isopropylmagnesium chloride, allylmagnesium bromide, phenylmagnesium bromide, etc.;
Organolithium compounds: n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

When an acid or an acid catalyst is used in the reaction of each step, the reaction is carried out using an acid or an acid catalyst suitable for each reaction. Specific examples of the acid or acid catalyst include the acids or acid catalysts described in the Reference Examples or Examples corresponding to each step, or the following acids or acid catalysts.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.;
Lewis acids: boron trifluoride-diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

In the case where a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for each reaction. Specific examples of the condensing agent include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents.
Carbodiimides: EDC·HCl, N,N'-dicyclohexylcarbodiimide, etc.;
Carbodiimidazoles: CDI etc.;
Uronium and phosphonium salts: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.;
Triazines: DMTMM etc.;
Others: T3P, etc.

When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for each reaction. Specific examples of the reducing agent include those described in the Reference Examples or Examples corresponding to each step, or the following reducing agents.
Metal hydrides: LAH, lithium borohydride, sodium borohydride, NaBH(OAc) ₃ , sodium cyanoborohydride, diisobutylaluminum hydride, etc.;
Boranes: borane-tetrahydrofuran complex, 9-BBN, picoline borane, etc.

In each step, if a protecting group is required depending on the type of functional group, it is also possible to carry out a suitable combination of introduction and removal operations according to a conventional method. For the types of protecting groups, protection, and deprotection, the methods described in, for example, "Greene's Protective Groups in Organic Synthesis," edited by Theodora W. Greene & Peter G. M. Wuts, fourth edition, Wiley-Interscience, 2006, can be mentioned.

When removing protecting groups in each step, these reactions can be carried out using hydrolysis reactions, etc.

When a hydrolysis reaction is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of acids and bases include those mentioned above.

When catalytic reduction reactions are carried out in each step, these reactions can be carried out under a hydrogen atmosphere in the presence of a catalyst. Examples of catalysts include palladium carbon powder, platinum carbon powder, Raney nickel, etc.

When a reduction reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent include those mentioned above.

When an amidation reaction is carried out in each step, the reaction can be carried out in the presence of a condensing agent and a base, or in the presence of a condensing agent. Examples of the condensing agent and base include those mentioned above. When a carbodiimide is used as the condensing agent, an additive such as HOBt or DMAP may be added to the reaction as necessary. The amidation reaction can also be carried out using an acyl halide or an acid anhydride.

In each step, when a reductive amination reaction is carried out, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent include those mentioned above. As the reducing agent, preferably, NaBH(OAc) ₃ and the like are included.

When an aromatic nucleophilic substitution reaction is carried out in each step, the reaction can be carried out in the presence of a base. Examples of the base include those mentioned above.

When an intramolecular carbonylation reaction is carried out in each step, the reaction can be carried out in the presence of a condensing agent. Examples of the condensing agent include those mentioned above.

When the Ullmann condensation reaction is carried out in each step, the reaction can be carried out in the presence of a copper catalyst, a ligand, and a base. The copper catalyst can be copper iodide or the like. The ligand can be N,N'-dimethylethylenediamine or the like. The base can be the examples mentioned above.

When a Chan-Lam-Evans coupling reaction is carried out in each step, the reaction can be carried out in the presence of a copper catalyst and a base. The copper catalyst can be copper(II) acetate or the like. The base can be any of the examples mentioned above.

When the Mitsunobu reaction is carried out in each step, these reactions can be carried out in the presence of an azodicarboxylate and a phosphine. Examples of the azodicarboxylate include DEAD. Examples of the phosphine include triphenylphosphine.

When the Suzuki-Miyaura cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst and a base. The palladium catalyst can be Pd(amphos)Cl ₂ or the like. The base can be any of the above-mentioned examples.

In each step, unless otherwise specified, the symbols in the formula have the same meaning as in the above [1]. Y is a bromine atom, an iodine atom, a boronic acid, or a hydroxyl. Y' is a fluorine atom or a chlorine atom. Y'' is a boronic acid or a boronic acid ester. X is ^CR3 or N.

The compound represented by formula (I) can be produced, for example, according to the methods of steps 1-1 to 1-3 described in Scheme 1.

Step 1-1
Compound (1-3) can also be produced by Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction of compound (1-1) and compound (1-2).
When Y is bromine or iodine, r is 0, and W is aryl or heteroaryl, the Ullmann condensation reaction is preferred. When Y is boronic acid, r is 0, and W is aryl or heteroaryl, the Chan-Lam-Evans coupling reaction is preferred. When Y is hydroxy, r is 0, and W is cycloalkyl or heterocycloalkyl, the Mitsunobu reaction is preferred. When Y is hydroxy and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Step 1-2
Compound (1-4) can also be prepared by removing the protecting group of compound (1-3).

Step 1-3
Compound (I) can also be produced by subjecting compound (1-4) to a reductive amination reaction with compound (1-5). If necessary, the protecting group may be removed.

Compound (1-1) can be produced, for example, according to the methods of steps 2-1 to 2-3 described in Scheme 2.

Step 2-1
Compound (2-3) can also be produced by subjecting compound (2-1) and compound (2-2) to an aromatic nucleophilic substitution reaction.

Step 2-2
The compound (2-4) can also be produced by catalytic reduction of the compound (2-3).

Step 2-3
The compound (1-1) can also be produced by an intramolecular carbonylation reaction of the compound (2-4).

Compound (IA) can be produced, for example, according to the methods of steps 3-1 to 3-4 described in Scheme 3.

Step 3-1
Compound (3-2) can also be produced by subjecting compound (1-1) and compound (3-1) to Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction.
When Y is a bromine atom or an iodine atom and r is 0, the Ullmann condensation reaction is preferred. When Y is a boronic acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. When Y is a hydroxyl and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Step 3-2
Compound (3-4) can also be produced by subjecting compound (3-2) and compound (3-3) to Suzuki-Miyaura cross-coupling reaction.

Step 3-3
Compound (3-5) can also be prepared by removing the protecting group of compound (3-4).

Step 3-4
Compound (IA) can also be produced by subjecting compound (3-5) to a reductive amination reaction with compound (1-5). If necessary, the protecting group may be removed.

Compound (I) can be produced, for example, according to the methods of steps 4-1 to 4-3 described in Scheme 4.

Step 4-1
Compound (4-1) can also be prepared by removing the protecting group of compound (1-1).

Step 4-2
Compound (4-2) can also be produced by subjecting compound (4-1) to a reductive amination reaction with compound (1-5).

Step 4-3
Compound (I) can also be produced by Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction of compound (4-2) and compound (1-2). If necessary, protective groups may be removed.
When Y is bromine or iodine, r is 0, and W is aryl or heteroaryl, the Ullmann condensation reaction is preferred. When Y is boronic acid, r is 0, and W is aryl or heteroaryl, the Chan-Lam-Evans coupling reaction is preferred. When Y is hydroxy, r is 0, and W is cycloalkyl or heterocycloalkyl, the Mitsunobu reaction is preferred. When Y is hydroxy and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Compound (IA) can be produced, for example, according to the methods of steps 5-1 and 5-2 described in Scheme 5.

Step 5-1
Compound (5-1) can also be produced by Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction of compound (4-2) and compound (3-1).
When Y is a bromine atom or an iodine atom and r is 0, the Ullmann condensation reaction is preferred. When Y is a boronic acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. When Y is a hydroxyl and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Step 5-2
Compound (IA) can also be produced by subjecting compound (5-1) to Suzuki-Miyaura cross-coupling reaction with compound (3-3). If necessary, protective groups may be removed.

The scheme shown above is an example of a method for producing a compound represented by formula (I) or a production intermediate thereof. The above scheme can be modified in various ways that can be easily understood by a person skilled in the art.

The compound represented by formula (I) and its production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.
Examples of silica gel column chromatography and amino silica gel column chromatography include flash chromatography using SNAP Ultra and SNAP Isolute NH2 (Biotage), and Hi-Flash columns (Yamazen).
Examples of ODS column chromatography include separation using a preparative purification LC system (Gilson, flow rate: 30 mL/min, detection: UV at 225 nm) and a column: CAPCELL PAK C18 UG80 (5 μm 20x50 mm).

The compound represented by formula (I) or a pharmacologically acceptable salt thereof has excellent PHD2 inhibitory activity and can be used as a therapeutic agent for IBD (see Nature Reviews Drug Discovery, 2014, 13, p.852-869). In the present invention, IBD includes, for example, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious enteritis, radiation enteritis, drug-induced enteritis, ischemic enteritis, mesenteric venous sclerosis (venous sclerosing colitis), obstructive colitis, and enteritis associated with collagen disease. Preferably, the compound of the present invention can be used as a therapeutic agent for ulcerative colitis or Crohn's disease (see Inflamm. Bowel. Dis., 2015, 21 (2), p.267-275).

In the present invention, "treatment" includes the meaning of "prevention." For example, the treatment of ulcerative colitis includes the meanings of "prevention of relapse" and "maintenance of remission."

The therapeutic effect of the compound represented by formula (I) or its pharmacologically acceptable salt on colitis can be confirmed by the method described in Test Example 2 or a method well known in the art. For example, the method described in Biol. Pharm. Bull., 2004, 27 (10), p. 1599-1603, etc., or a method similar thereto can be mentioned.

In one embodiment, in order to limit off-target effects due to stabilization of HIF-α, the compound represented by formula (I) or a pharmacologically acceptable salt thereof is a PHD2 inhibitor that acts specifically on colon tissue. "Acting specifically on colon tissue" means, for example, that the compound is concentrated at a higher level in colon tissue compared to blood, and exerts a therapeutic effect in the colon without any systemic effect (e.g., hematopoietic effect) (see Test Examples 2 and 3).

Pharmaceutical compositions containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient are used in various dosage forms depending on the method of use. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, and enemas.

Pharmaceutical compositions containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient are prepared using the compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting or dissolving with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, etc., by methods known in pharmaceutical science according to the dosage form.

When a pharmaceutical composition containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient is used for treatment, the dosage of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the age, sex, weight, disease, and degree of treatment of the patient. The daily dosage may be administered once, twice, three times, or four times. Preferably, the pharmaceutical composition of the present invention is administered orally.
In the case of oral administration, the dosage for an adult can be set, for example, in the range of 0.1 to 1000 mg/day. In one embodiment, the oral dosage can be set in the range of 1 to 500 mg/day, preferably in the range of 10 to 200 mg/day.
In the case of parenteral administration, the dosage for an adult can be set, for example, in the range of 0.1 to 1000 mg/day. In one embodiment, the parenteral dosage can be set in the range of 0.5 to 200 mg/day, preferably in the range of 1 to 20 mg/day.

In one embodiment, the pharmaceutical composition containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient can be used in combination with other drugs other than PHDs inhibitors. Examples of other drugs that can be used in combination in the treatment of inflammatory bowel disease include 5-ASA, steroids, immunosuppressants, anti-TNFα antibodies, Janus kinase inhibitors, and _α4β7 integrin antibodies _.

When the compound represented by formula (I) or a pharmacologically acceptable salt thereof is used in combination with another drug, these active ingredients can be administered in the form of a preparation containing these active ingredients together, or in the form of a preparation in which each of these active ingredients is formulated separately. When formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or a pharmacologically acceptable salt thereof may be appropriately reduced depending on the dosage of the other drug used in combination.

The compound represented by formula (I) may be appropriately converted into a prodrug before use. For example, a prodrug of the compound represented by formula (I) can be produced by introducing a group constituting the prodrug using a prodrug-forming reagent such as a corresponding halide, followed by purification. Examples of groups constituting the prodrug include those described in "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, p. 163-198.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

The names of the compounds described in the following examples were created using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.

Reference Example A-1
(S)-3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate tert-butyl Under ice cooling, 2-fluoro-3-nitropyridine (10.00 g), (S)-3-aminopyrrolidine-1-carboxylate tert-butyl (13.10 g) and potassium carbonate (11.67 g) were added to NMP (100 mL). The reaction mixture was stirred at 150° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added and mixed. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (21.70 g).

Reference Example A-2
(R)-tert-Butyl 3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate
A mixture of 2-fluoro-3-nitropyridine (2.00 g), (R)-3-aminopyrrolidine-1-tert-butyl carboxylate (2.62 g), potassium carbonate (2.33 g) and NMP (15 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite®, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 70/30) to obtain the title compound (3.61 g).

Reference Example A-3
4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate tert-Butyl
A mixture of 2-fluoro-3-nitropyridine (1.00 g), tert-butyl 4-aminopiperidine-1-carboxylate (1.41 g), potassium carbonate (1.94 g) and DMF (10 mL) was stirred at 120° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.25 g).

Reference Example A-4
tert-Butyl 3-((3-nitropyridin-2-yl)amino)azetidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example A-3, except that tert-butyl 3-aminoazetidine-1-carboxylate was used instead of tert-butyl 4-aminopiperidine-1-carboxylate.

Reference Example A-5
(3R,4R)-tert-butyl 3-fluoro-4-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate
A mixture of 2-fluoro-3-nitropyridine (0.69 g), (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate tert-butyl (1.00 g), potassium carbonate (1.35 g) and DMF (10 mL) was stirred at 80°C for 1 hour under microwave irradiation. Ethyl acetate and water were added to the reaction mixture and mixed. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (1.40 g).

Reference Example A-6
(S)-tert-Butyl 3-((3-nitro-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate
A mixture of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.00 g), (S)-3-aminopyrrolidine-1-carboxylate tert-butyl (0.82 g), potassium carbonate (1.22 g) and DMF (10 mL) was stirred at 80°C for 1 hour under microwave irradiation. Ethyl acetate and water were added to the reaction mixture and mixed. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (1.66 g).

Reference Example A-7
4-Methyl-4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate tert-Butyl
The title compound was obtained in the same manner as in Reference Example A-5, except that tert-butyl 4-amino-4-methylpiperidine-1-carboxylate was used instead of tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate.

Reference Example A-8
(S)-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-5-nitropicolinic acid methyl ester
A mixture of methyl 6-chloro-5-nitropicolinate (1.00 g), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (0.86 g), potassium carbonate (1.27 g) and DMF (10 mL) was stirred at 120° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.47 g).

Reference Example A-9
(S)-tert-Butyl 3-((5-methyl-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example A-6, except that 2-chloro-5-methyl-3-nitropyridine was used instead of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine.

Reference Example A-10
(S)-tert-Butyl 3-((5-methoxy-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example A-6, except that 2-chloro-5-methoxy-3-nitropyridine was used instead of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine.

Reference Example B-1
(S)-3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylate tert-butyl Reference Example A-1 (21.70 g) and ethanol (300 mL) were added with palladium 10%-carbon (2.17 g, wet) under an argon atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (19.74 g).

Reference Example B-2
(R)-tert-butyl 3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylate embedded image The title compound was obtained in the same manner as in Reference Example B-1, using Reference Example A-2 instead of Reference Example A-1.

Reference Example B-3
4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate tert-butyl Reference Example A-3 (2.25 g), ethanol (20 mL) and THF (10 mL) were added with palladium 10%-carbon (0.22 g, wet) under an argon atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.06 g).

Reference Example B-4
tert-Butyl 3-((3-aminopyridin-2-yl)amino)azetidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1, using Reference Example A-4 instead of Reference Example A-1.

Reference Example B-5
(3R,4R)-3-((3-aminopyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate tert-butyl Example 13 Using Reference Example A-5 instead of Reference Example A-1, the title compound was obtained in the same manner as in Reference Example B-1.

Reference Example B-6
(S)-tert-butyl 3-((3-amino-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate Using Reference Example A-6 instead of Reference Example A-1, the title compound was obtained in the same manner as in Reference Example B-1.

Reference Example B-7
tert-Butyl 4-((3-aminopyridin-2-yl)amino)-4-methylpiperidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1 using Reference Example A-7 instead of Reference Example A-1.

Reference Example B-8
(S)-methyl 5-amino-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)picolinate Using Reference Example A-8 instead of Reference Example A-1, the title compound was obtained in the same manner as in Reference Example B-1.

Reference Example B-9
(S)-tert-butyl 3-((3-amino-5-methylpyridin-2-yl)amino)pyrrolidine-1-carboxylate Using Reference Example A-9 instead of Reference Example A-1, the title compound was obtained in the same manner as in Reference Example B-1.

Reference Example B-10
(S)-tert-butyl 3-((3-amino-5-methoxypyridin-2-yl)amino)pyrrolidine-1-carboxylate Using Reference Example A-10 instead of Reference Example A-1, the title compound was obtained in the same manner as in Reference Example B-1.

Reference Example C-1
(S)-3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl To a mixture of Reference Example B-1 (19.59 g) and THF (200 mL), CDI (22.82 g) was added under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydroxide solution (5 mol/L, 30 mL) was added to the reaction mixture and stirred for 10 minutes. Hydrochloric acid (2 mol/L, 75 mL) was added to the reaction mixture, stirred, and concentrated under reduced pressure. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 50/50 to 0/100) to obtain the title compound (17.61 g). MS (ESI_APCI, m/z): 303 (MH) ^-

Reference Example C-2
(R)-3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl To a mixture of Reference Example B-2 (3.68 g) and THF (20 mL), CDI (4.28 g) was added. The reaction mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydroxide solution (5 mol/L, 4 mL) was added to the reaction mixture and stirred for 5 minutes. Hydrochloric acid (2 mol/L, 10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 50/50 to 0/100) to obtain the title compound (4.00 g). MS (ESI_APCI, m/z): 303 (MH) ^-

Reference Example C-3
4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate tert-butyl. To a mixture of Reference Example B-3 (2.06 g) and THF (30 mL), CDI (2.29 g) was added. The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (1.96 g). MS (ESI_APCI, m/z): 317 (MH) ^-

Reference Example C-4
3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-carboxylate tert-butyl. Using Reference Example B-4 instead of Reference Example B-1, the title compound was obtained in the same manner as in Reference Example C-1. MS (ESI_APCI, m/z): 289 (MH) ^-

Reference Example C-5
(3R,4R)-3-fluoro-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example B-5 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m/z): 321 (MH) ^-

Reference Example C-6
(S)-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example B-6 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m/z): 371 (MH) ^-

Reference Example C-7
4-Methyl-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate tert-butyl. Using Reference Example B-7 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m/z): 331 (MH) ^-

Reference Example C-8
(S)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl. Using Reference Example B-8 instead of Reference Example B-3, the title compound was obtained in the same manner as in Reference Example C-3. MS (ESI_APCI, m/z): 361 (MH) ^-

Reference Example C-9
(S)-3-(6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example B-9 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m/z): 317 (MH) ^-

Reference Example C-10
(S)-3-(6-methoxy-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example B-10 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m/z): 333 (MH) ^-

Reference Example D-1
(S)-3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example C-1 (168 mg), (4-chloro-2-methylphenyl)boronic acid (282 mg), copper(II) acetate (201 mg), triethylamine (0.383 mL) and dichloromethane (3 mL) were stirred at room temperature for 3 hours. Water and hydrochloric acid (1 mol/L) were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (114 mg).

Reference Example D-2
(S)-3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example C-1 (500 mg), 1-chloro-4-iodobenzene (431 mg), N,N'-dimethylethylenediamine (0.212 mL), copper(I) iodide (375 mg), potassium carbonate (681 mg) and acetonitrile (10 mL) were stirred at 90°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol/L), and the mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (583 mg).

Reference Example D-3
(R)-3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example C-2 instead of Reference Example C-1, the title compound was obtained in the same manner as in Reference Example D-1.

Reference Example D-4
(S)-3-(1-(4-chloro-2-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example C-1 (100 mg), 5-chloro-2-iodophenol (125 mg), N,N'-dimethylethylenediamine (0.042 mL), copper iodide (I) (75 mg), potassium carbonate (136 mg) and acetonitrile (3 mL) were stirred at 100 ° C. for 2 hours under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L), and the mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 35 / 65) to obtain the title compound (61 mg).

Reference Example D-5
(S)-3-(1-(4-chloro-3-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example C-1 (100 mg), 2-chloro-5-iodophenol (100 mg), N,N'-dimethylethylenediamine (0.042 mL), copper iodide (I) (75 mg), potassium carbonate (136 mg) and acetonitrile (3 mL) were stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 35 / 65) to obtain the title compound (135 mg).

Reference Example D-6
(S)-3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example C-1 (100 mg), 2-chloro-5-iodopyridine (94 mg), N,N'-dimethylethylenediamine (0.042 mL), copper iodide (I) (75 mg), potassium carbonate (136 mg) and acetonitrile (3 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol/L). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 35/65) to obtain the title compound (117 mg).

Reference Example D-7
(R)-3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example C-2 (500 mg), 2-chloro-5-iodopyridine (433 mg), N,N'-dimethylethylenediamine (0.212 mL), copper(I) iodide (375 mg), potassium carbonate (681 mg) and acetonitrile (10 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 45/55) to obtain the title compound (420 mg).

Reference Example E-1
(S)-3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example C-1 (113 mg), 4-iodo-1,1'-biphenyl (125 mg), N,N'-dimethylethylenediamine (0.048 mL), copper(I) iodide (85 mg), potassium carbonate (154 mg) and acetonitrile (4 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol/L). The mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (138 mg).

Reference Example E-2
(R)-3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example C-2 instead of Reference Example C-1, the title compound was obtained in the same manner as in Reference Example E-1.

Reference Example E-3
(S)-tert-Butyl 3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-1, except that iodobenzene was used instead of 4-iodo-1,1'-biphenyl.

Reference Example E-4
4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate tert-butyl Ethyl Compound The title compound was obtained in the same manner as in Reference Example E-1 using Reference Example C-3 instead of Reference Example C-1.

Reference Example E-5
3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-carboxylate tert-butyl Reference Example C-4 (100 mg), 4-iodo-1,1'-biphenyl (96 mg), N,N'-dimethylethylenediamine (0.044 mL), copper(I) iodide (79 mg), potassium carbonate (143 mg) and acetonitrile (3 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (105 mg).

Reference Example E-6
(S)-3-(1-(4-(methoxycarbonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example C-1 (200 mg), methyl 4-iodobenzoate (172 mg), N,N'-dimethylethylenediamine (0.085 mL), copper(I) iodide (150 mg), potassium carbonate (272 mg) and acetonitrile (1 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 45/55) to obtain the title compound (271 mg).

Reference Example E-7
(S)-3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example C-1 (100 mg), 1-iodo-4-methoxybenzene (85 mg), N,N'-dimethylethylenediamine (0.042 mL), copper(I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (1 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol/L). After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (119 mg).

Reference Example E-8
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester Reference Example C-8 (100 mg), 4-iodo-1,1'-biphenyl (93 mg), N,N'-dimethylethylenediamine (0.036 mL), copper(I) iodide (63 mg), potassium carbonate (114 mg) and acetonitrile (1 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 45/55) to obtain the title compound (120 mg).

Reference Example E-9
4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpiperidine-1-carboxylate tert-butyl Reference Example C-7 (50 mg), 4-iodo-1,1'-biphenyl (51 mg), N,N'-dimethylethylenediamine (0.019 mL), copper iodide (I) (34 mg), potassium carbonate (50 mg) and acetonitrile (3 mL) were stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80/20 to 40/60) to obtain the title compound (70 mg).

Reference Example E-10
(S)-3-(6-methoxy-1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example C-10 (136 mg), 4'-bromo-[1,1'-biphenyl]-4-methyl carboxylate (131 mg), N,N'-dimethylethylenediamine (0.053 mL), copper iodide (I) (94 mg), potassium carbonate (136 mg) and acetonitrile (1 mL) were stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 25/75) to obtain the title compound (128 mg).

Reference Example E-11
(3R,4R)-3-fluoro-4-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example C-5 instead of Reference Example C-10, the title compound was obtained in the same manner as in Reference Example E-10.

Reference Example E-12
(S)-3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example C-6 instead of Reference Example C-10, the title compound was obtained in the same manner as in Reference Example E-10.

Reference Example E-13
(S)-3-(1-(3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example D-1 (114 mg), phenylboronic acid (39 mg), Pd(amphos)Cl ₂ (19 mg), sodium carbonate (68 mg), DMF (1 mL) and water (0.1 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (87 mg).

Reference Example E-14
(S)-3-(1-(2'-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example D-2 (100 mg), o-tolylboronic acid (39 mg), Pd(amphos)Cl ₂ (17 mg), sodium carbonate (61 mg), DMF (1 mL) and water (0.1 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (105 mg).

Reference Example E-15
(R)-3-(1-(3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example D-3 instead of Reference Example D-1, the title compound was obtained in the same manner as in Reference Example E-13.

Reference Example E-16
(S)-tert-Butyl 3-(1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-14, except that (4-fluorophenyl)boronic acid was used instead of o-tolylboronic acid.

Reference Example E-17
(S)-tert-Butyl 3-(1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-14, except that (4-methoxyphenyl)boronic acid was used instead of o-tolylboronic acid.

Reference Example E-18
(S)-tert-Butyl 3-(2-oxo-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-14, except that (2-(trifluoromethyl)phenyl)boronic acid was used instead of o-tolylboronic acid.

Reference Example E-19
(S)-tert-Butyl 3-(1-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-14, except that (4-cyanophenyl)boronic acid was used instead of o-tolylboronic acid.

Reference Example E-20
(S)-tert-Butyl 3-(2-oxo-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-14, except that (4-(trifluoromethoxy)phenyl)boronic acid was used instead of o-tolylboronic acid.

Reference Example E-21
(S)-tert-Butyl 3-(1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-1, except that 4'-iodo-[1,1'-biphenyl]-4-ol was used instead of 4-iodo-1,1'-biphenyl.

Reference Example E-22
(S)-tert-Butyl 3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-14, except that 4-pyridylboronic acid was used instead of o-tolylboronic acid.

Reference Example E-23
(S)-3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-2 (200 mg), (4-(methoxycarbonyl)phenyl)boronic acid (104 mg), Pd(amphos)Cl ₂ (34 mg), sodium carbonate (123 mg), DMF (2 mL) and water (0.2 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. The mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (212 mg).

Reference Example E-24
(R)-3-(1-(4'-(methoxycarbonyl)-3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example D-3 instead of Reference Example D-2, the title compound was obtained in the same manner as in Reference Example E-23.

Reference Example E-25
(S)-3-(1-(3-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-4 (61 mg), (4-(methoxycarbonyl)phenyl)boronic acid (31 mg), Pd(amphos)Cl ₂ (10 mg), sodium carbonate (36 mg), DMF (1 mL) and water (0.1 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20-35/65) to obtain the title compound (55 mg).

Reference Example E-26
(S)-3-(1-(2-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-5 (135 mg), (4-(methoxycarbonyl)phenyl)boronic acid (113 mg), Pd(amphos)Cl ₂ (22 mg), sodium carbonate (80 mg), NMP (3 mL) and water (0.3 mL) were stirred at 150°C for 5 hours under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 30/70) to obtain the title compound (122 mg).

Reference Example E-27
(S)-3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-6 (117 mg), (4-(methoxycarbonyl)phenyl)boronic acid (61 mg), Pd(amphos)Cl ₂ (20 mg), sodium carbonate (72 mg), DMF (3 mL) and water (0.3 mL) were stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80/20 to 30/70) to obtain the title compound (95 mg).

Reference Example E-28
(S)-3-(1-(4'-hydroxy-3'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-2 (121 mg), 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (98 mg), Pd(amphos)Cl ₂ (21 mg), sodium carbonate (75 mg), DMF (1 mL) and water (0.1 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 30/70) to obtain the title compound (71 mg).

Reference Example E-29
(S)-3-(1-(2'-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-2 (200 mg), 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (147 mg), Pd(amphos)Cl ₂ (34 mg), sodium carbonate (123 mg), DMF (1 mL) and water (0.1 mL) were stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20-35/65) to give the title compound (165 mg).

Reference Example E-30
(S)-3-(1-(6-(4-(methoxycarbonyl)-2-methylphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-6 (353 mg), (4-(methoxycarbonyl)-2-methylphenyl)boronic acid (198 mg), Pd(amphos)Cl ₂ (60 mg), sodium carbonate (216 mg), DMF (10 mL) and water (1 mL) were stirred at 120° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20-35/65) to obtain the title compound (406 mg).

Reference Example K-19
(S)-3-(1-(4-chloro-3-(methoxymethoxy)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. To a mixture of Reference Example D-5 (1.29 g) and THF (15 mL), DIPEA (1.55 mL) and chloromethyl methyl ether (0.34 mL) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (1.33 g).

Reference Example E-31
(S)-3-(1-(3'-cyano-4'-hydroxy-2-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example K-19 (500 mg), 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (387 mg), Pd(amphos)Cl ₂ (75 mg), sodium carbonate (268 mg), DMF (10 mL) and water (1 mL) were stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 40/60) to give the title compound (332 mg).

Reference Example E-32
(S)-3-(1-(6-(3-cyano-4-hydroxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl ester. The title compound was obtained in the same manner as in Reference Example E-31 using Reference Example D-6 instead of Reference Example K-19.

Reference Example K-20
(S)-3-(1-(4-chloro-2-(methoxymethoxy)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example D-4 instead of Reference Example D-5, the title compound was obtained in the same manner as in Reference Example K-19.

Reference Example E-33
(S)-3-(1-(3'-cyano-4'-hydroxy-3-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl ester. The title compound was obtained in the same manner as in Reference Example E-31, using Reference Example K-20 instead of Reference Example K-19.

Reference Example K-2
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid Reference Example E-8 (251 mg), methanol (0.5 mL), THF (0.5 mL) and water (1 mL) were mixed to add lithium hydroxide monohydrate (103 mg). The reaction mixture was stirred at room temperature for 3 hours. Hydrochloric acid (2 mol/L, 1.2 mL) was added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (227 mg).

Reference Example E-34
(S)-tert-butyl 3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate. To a mixture of Reference Example K-2 (100 mg) and DMF (1 mL), EDC.HCl (77 mg), HOBt.H ₂ O (61 mg), triethylamine (0.139 mL) and 4-aminotetrahydropyran (24 mg) were added. The reaction mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (19 mg).

Reference Example E-35
(S)-tert-Butyl 3-(1-([1,1'-biphenyl]-4-yl)-5-((2-methoxy-2-oxoethyl)carbamoyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example E-34, except that glycine methyl ester hydrochloride was used instead of 4-aminotetrahydropyran.

Reference Example E-36
(R)-3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl Reference Example D-7 (420 mg), (4-(methoxycarbonyl)phenyl)boronic acid (236 mg), Pd(amphos)Cl ₂ (72 mg), sodium carbonate (257 mg), DMF (10 mL) and water (1 mL) were stirred at 120° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 40/60) to obtain the title compound (377 mg).

Reference Example E-37
(S)-3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example C-1 (200 mg), 2-bromonaphthalene (136 mg), N,N'-dimethylethylenediamine (0.085 mL), copper(I) iodide (150 mg), potassium carbonate (218 mg) and acetonitrile (3 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (250 mg).

Reference Example E-38
(S)-3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Reference Example C-1 (200 mg), 3-bromo-1,1'-biphenyl (153 mg), N,N'-dimethylethylenediamine (0.085 mL), copper(I) iodide (150 mg), potassium carbonate (218 mg) and acetonitrile (3 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (345 mg).

Reference Example E-39
(S)-3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl. Using Reference Example C-9 instead of Reference Example C-10, the title compound was obtained in the same manner as in Reference Example E-10.

Reference Example F-1
(S)-1-([1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride A mixture of Reference Example E-1 (138 mg) and hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (110 mg). MS (ESI_APCI, m/z): 357 (M+H) ⁺

Reference Example F-2
(R)-1-([1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-2 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 357 (M+H) ⁺

Reference Example F-3
(S)-1-Phenyl-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride A mixture of Reference Example E-3 (360 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 2 mL) and methanol (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (400 mg). MS (ESI_APCI, m/z): 281 (M+H) ⁺

Reference Example F-4
1-([1,1'-biphenyl]-4-yl)-3-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-4 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3. MS (ESI_APCI, m/z): 371 (M+H) ⁺

Reference Example F-5
1-([1,1'-biphenyl]-4-yl)-3-(azetidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-5 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3. MS (ESI_APCI, m/z): 343 (M+H) ⁺

Reference Example F-6
(S)-4-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoic acid methyl ester hydrochloride Using Reference Example E-6 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 339 (M+H) ⁺

Reference Example F-7
(S)-1-(4-methoxyphenyl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-7 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example F-8
(S)-1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester hydrochloride Using Reference Example E-8 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example F-9
1-([1,1'-biphenyl]-4-yl)-3-(4-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride The title compound was obtained in the same manner as in Reference Example F-3 using Reference Example E-9 instead of Reference Example E-3.

Reference Example F-10
(S)-4'-(6-methoxy-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride Using Reference Example E-10 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example F-11
4'-(3-((3R,4R)-4-fluoropyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride. Using Reference Example E-11 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example F-12
(S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride Using Reference Example E-12 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example F-13
(S)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-13 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 371 (M+H) ⁺

Reference Example F-14
(S)-1-(2'-methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-14 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 371 (M+H) ⁺

Reference Example F-15
(R)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-15 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 371 (M+H) ⁺

Reference Example F-16
(S)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-16 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 375 (M+H) ⁺

Reference Example F-17
(S)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-17 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 387 (M+H) ⁺

Reference Example F-18
(S)-3-(pyrrolidin-3-yl)-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-18 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 425 (M+H) ⁺

Reference Example F-19
(S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carbonitrile hydrochloride Using Reference Example E-19 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 382 (M+H) ⁺

Reference Example F-20
(S)-3-(pyrrolidin-3-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-20 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 441 (M+H) ⁺

Reference Example F-21
(S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-21 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 373 (M+H) ⁺

Reference Example F-22
(S)-1-(4-(pyridin-4-yl)phenyl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-22 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 358 (M+H) ⁺

Reference Example F-23
(S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl hydrochloride Reference Example E-23 (212 mg) and hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (205 mg). MS (ESI_APCI, m/z): 415 (M+H) ⁺

Reference Example F-24
(R)-3'-methyl-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl hydrochloride Using Reference Example E-24 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m/z): 429 (M+H) ⁺

Reference Example F-25
(S)-3'-hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl hydrochloride Reference Example E-25 (55 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) and methanol (1 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (59 mg).

Reference Example F-26
(S)-2'-hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl hydrochloride Reference Example E-26 (122 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) and methanol (1 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (147 mg).

Reference Example F-27
(S)-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester hydrochloride Reference Example E-27 (95 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) and methanol (1 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (126 mg).

Reference Example F-28
(S)-4-Hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylate methyl hydrochloride Reference Example E-28 (71 mg) and hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (67 mg).

Reference Example F-29
(S)-2-Hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl hydrochloride Reference Example E-29 (165 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) and methanol (1 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (147 mg).

Reference Example F-30
(S)-3-Methyl-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester hydrochloride Reference Example E-30 (406 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 3 mL) and methanol (2 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (308 mg).

Reference Example F-31
(S)-2',4-Dihydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carbonitrile hydrochloride Reference Example E-31 (332 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 3 mL) and methanol (2 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (384 mg).

Reference Example F-32
(S)-2-Hydroxy-5-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzonitrile hydrochloride Reference Example E-32 (472 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 2 mL) and methanol (2 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (349 mg).

Reference Example F-33
(S)-3',4-Dihydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carbonitrile hydrochloride Reference Example E-33 (77 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) and methanol (1 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (73 mg).

Reference Example F-34
(S)-1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxamide hydrochloride Reference Example E-34 (19 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) and methanol (1 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (18 mg).

Reference Example F-35
Methyl (S)-(1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonyl)glycinate hydrochloride Reference Example E-35 (91 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 1 mL) and methanol (1 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (79 mg).

Reference Example F-36
(R)-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester hydrochloride Reference Example E-36 (377 mg), hydrogen chloride-1,4-dioxane solution (4 mol/L, 2 mL) and methanol (1 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (418 mg).

Reference Example F-37
(S)-1-(naphthalen-2-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-37 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example F-38
(S)-1-([1,1'-biphenyl]-3-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-38 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example F-39
(S)-4'-(6-methyl-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride Using Reference Example E-39 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3.

Reference Example G-1
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester. To a mixture of Reference Example F-1 (30 mg), 2-formyl isonicotinic acid methyl ester (25 mg) and dichloromethane (1 mL), NaBH(OAc) ₃ (65 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 45/55) to obtain the title compound (26 mg). MS (ESI_APCI, m/z): 506 (M+H) ⁺

Reference Example G-2
(S)-6-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)nicotinic acid methyl ester
The title compound was obtained by the same method as in Reference Example G-1, except that 6-formyl methyl nicotinate was used instead of 2-formyl methyl isonicotinate. MS (ESI_APCI, m/z): 506 (M+H) ⁺

Reference Example G-3
(S)-2-((3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester. Using Reference Example F-7 instead of Reference Example F-1, the title compound was obtained in the same manner as in Reference Example G-1. MS (ESI_APCI, m/z): 460 (M+H) ⁺

Reference Example G-4
(S)-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester. Using Reference Example F-3 instead of Reference Example F-1, the title compound was obtained in the same manner as in Reference Example G-1. MS (ESI_APCI, m/z): 430 (M+H) ⁺

Reference Example J-1
1-Methyl-1H-imidazole-5-carboxylate tert-Butyl
A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (5.00 g), tert-butanol (37.7 mL), pyridine (16.0 mL) and TsCl (15.11 g) was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (6.24 g).

Reference Example J-2
2-Formyl-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Reference Example J-1 (5.82 g), DMF (7.43 mL) and THF (60 mL) were slowly dripped with LDA (1.0 mol/L, THF/n-hexane solution, 48 mL) at -70°C or lower in a dry ice/acetone bath. The reaction mixture was stirred for 10 minutes under ice cooling. Again, LDA (1.0 mol/L, THF/n-hexane solution, 16 mL) and DMF (1 mL) were slowly dripped into the reaction mixture at -70°C or lower in a dry ice/acetone bath. The reaction mixture was further stirred for 10 minutes under ice cooling. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and stirred for 5 minutes, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (6.72 g).

Reference Example G-6
2-((4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpiperidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Reference Example F-9 (67 mg), THF (1 mL) and triethylamine (0.112 mL) were mixed and added with Reference Example J-2 (41 mg) and NaBH(OAc) ₃ (68 mg). The reaction mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (73 mg). MS (ESI_APCI, m/z): 579 (M+H) ⁺

Reference Example G-7
(S)-2-((3-(6-methoxy-1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Using Reference Example F-10 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m/z): 639 (M+H) ⁺

Reference Example G-8
2-(((3R,4R)-3-fluoro-4-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Using Reference Example F-11 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m/z): 627 (M+H) ⁺

Reference Example G-9
(S)-2-((3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Using Reference Example F-12 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m/z): 677 (M+H) ⁺

Reference Example G-14
(S)-2-((3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester. Using Reference Example F-23 instead of Reference Example F-1, the title compound was obtained in the same manner as in Reference Example G-1. MS (ESI_APCI, m/z): 564 (M+H) ⁺

Reference Example G-16
(S)-2-((3-(1-(2-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester Reference Example F-26 (200 mg), 2-formyl isonicotinic acid methyl ester (141 mg) and dichloromethane (2 mL) were added to a mixture of NaBH(OAc) ₃ (363 mg). The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/80/20) to obtain the title compound (207 mg). MS (ESI_APCI, m/z): 580 (M+H) ⁺

Reference Example G-17
(S)-2-((3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester Using Reference Example F-27 instead of Reference Example F-26, the title compound was obtained in the same manner as in Reference Example G-16. MS (ESI_APCI, m/z): 565 (M+H) ⁺

Reference Example G-18
(S)-2-((3-(1-(3-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. To a mixture of Reference Example F-25 (502 mg), Reference Example J-2 (339 mg) and dichloromethane (3 mL), NaBH(OAc) ₃ (912 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (450 mg). MS (ESI_APCI, m/z): 625 (M+H) ⁺

Reference Example G-19
(S)-2-((3-(1-(6-(4-(methoxycarbonyl)-2-methylphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. To a mixture of Reference Example F-30 (308 mg), Reference Example J-2 (221 mg) and dichloromethane (3 mL), NaBH(OAc) ₃ (561 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (3 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (558 mg). MS (ESI_APCI, m/z): 624 (M+H) ⁺

Reference Example G-20
(S)-2-((3-(1-(3'-cyano-2,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester. To a mixture of Reference Example F-31 (150 mg), 2-formyl methyl isonicotinate (110 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (283 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/50/50) to obtain the title compound (188 mg). MS (ESI_APCI, m/z): 563 (M+H) ⁺

Reference Example G-21
(S)-2-((3-(1-(6-(3-cyano-4-hydroxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester Reference Example F-32 (200 mg), 2-formyl isonicotinic acid methyl ester (152 mg) and dichloromethane (2 mL) were mixed and added with NaBH(OAc) ₃ (390 mg). The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/50/50) to obtain the title compound (495 mg). MS (ESI_APCI, m/z): 548 (M+H) ⁺

Reference Example G-22
(S)-2-((3-(1-(3'-cyano-3,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester. To a mixture of Reference Example F-33 (63 mg), 2-formyl methyl isonicotinate (46 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (119 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/50/50) to obtain the title compound (77 mg). MS (ESI_APCI, m/z): 563 (M+H) ⁺

Reference Example G-23
(S)-1-Methyl-2-((3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate tert-butyl. Using Reference Example F-37 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m/z): 525 (M+H) ⁺

Reference Example G-24
(S)-2-((3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Using Reference Example F-38 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m/z): 551 (M+H) ⁺

Reference Example H-1
(S)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Reference Example C-1 (3.00 g), hydrogen chloride-1,4-dioxane solution (4 mol/L, 10 mL) and methanol (4 mL) were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (2.80 g).

Reference Example I-1
(S)-1-methyl-2-((3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate tert-butyl. A mixture of Reference Example H-1 (2.68 g), Reference Example J-2 (3.05 g), THF (30 mL) and triethylamine (4.67 mL) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (3.55 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Methanol was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate and water were added to the residue. The mixture was stirred and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 95/5/0-0/100/0-0/90/10) to obtain the title compound (3.52 g).

Reference Example G-25
(S)-2-((3-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl Reference Example I-1 (100 mg), 4-bromo-N,N-dimethylaniline (55 mg), N,N'-dimethylethylenediamine (0.032 mL), copper iodide (I) (57 mg), potassium carbonate (83 mg) and acetonitrile (3 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (77 mg). MS (ESI_APCI, m/z): 518 (M+H) ⁺

Reference Example G-26
(S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(4-phenoxyphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-iodo-4-phenoxybenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 567 (M+H) ⁺

Reference Example G-27
(S)-tert-butyl 2-((3-(1-(4-benzylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-benzyl-4-iodobenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 565 (M+H) ⁺

Reference Example G-28
(S)-1-Methyl-2-((3-(2-oxo-1-(p-tolyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate tert-butyl ester
The title compound was obtained by the same method as in Reference Example G-25, except that 1-iodo-4-methylbenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 489 (M+H) ⁺

Reference Example G-29
(S)-tert-butyl 2-((3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-chloro-4-iodobenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 509 (M+H) ⁺

Reference Example G-30
(S)-tert-Butyl 1-methyl-2-((3-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 4-iodothioanisole was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 521 (M+H) ⁺

Reference Example G-31
(S)-tert-Butyl 2-((3-(1-(4-(ethylsulfonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-(ethylsulfonyl)benzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 567 (M+H) ⁺

Reference Example G-32
(S)-tert-butyl 1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained in the same manner as in Reference Example G-25, except that 1-bromo-4-(trifluoromethoxy)benzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 559 (M+H) ⁺

Reference Example G-33
(S)-tert-butyl 1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-(trifluoromethyl)benzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 543 (M+H) ⁺

Reference Example G-34
(S)-tert-butyl 2-((3-(1-(4-cyanophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained in the same manner as in Reference Example G-25, except that 4-bromobenzonitrile was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 500 (M+H) ⁺

Reference Example G-35
(S)-tert-Butyl 1-methyl-2-((3-(1-(4-nitrophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-nitrobenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 520 (M+H) ⁺

Reference Example G-36
(S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(quinolin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 3-bromoquinoline was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 526 (M+H) ⁺

Reference Example G-37
(S)-tert-Butyl 1-methyl-2-((3-(1-(4-morpholinophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained in the same manner as in Reference Example G-25, except that 4-(4-iodophenyl)morpholine was used instead of 4-bromo-N,N-dimethylaniline.

Reference Example G-38
(S)-1-methyl-2-((3-(2-oxo-1-(4-phenylcyclohexyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate tert-butyl. Reference Example I-1 (100 mg), 4-phenylcyclohexan-1-ol (44 mg), triphenylphosphine (99 mg) and THF (3 mL) were added slowly to a mixture of DEAD (40% toluene solution, 0.171 mL) under ice-cooling and stirring. The reaction mixture was stirred at the same temperature for 10 minutes and further stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (59 mg). MS (ESI_APCI, m/z): 557 (M+H) ⁺

Reference Example G-39
(S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(4-vinylphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-vinylbenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 501 (M+H) ⁺

Reference Example G-40
(S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(thiophen-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 3-bromothiophene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 481 (M+H) ⁺

Reference Example G-41
(S)-tert-Butyl 2-((3-(1-benzyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-38, except that benzyl alcohol was used instead of 4-phenylcyclohexan-1-ol. MS (ESI_APCI, m/z): 489 (M+H) ⁺

Reference Example G-42
(S)-tert-Butyl 2-((3-(1-(4-cyclopropylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-cyclopropylbenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 515 (M+H) ⁺

Reference Example G-43
(S)-tert-Butyl 2-((3-(1-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained by the same method as in Reference Example G-25, except that 4-bromophenol was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m/z): 491 (M+H) ⁺

Reference Example G-44
(S)-1-methyl-2-((3-(1-(4'-(methylsulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate tert-butyl Reference Example G-29 (50 mg), 4-(methylsulfonylamino)phenylboronic acid (25 mg), Pd(amphos)Cl ₂ (6.8 mg), sodium carbonate (25 mg), DMF (1 mL) and water (0.1 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (37 mg). MS (ESI_APCI, m/z): 644 (M+H) ⁺

Reference Example G-45
(S)-2-((3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. To a mixture of Reference Example F-39 (72 mg) and THF (3 mL), triethylamine (0.065 mL) and Reference Example J-2 (36 mg) were added. The reaction mixture was stirred at room temperature for 5 minutes. NaBH(OAc) ₃ (98 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. Methanol was added to the reaction mixture, and the mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 30/70) to obtain the title compound (65 mg). MS (ESI_APCI, m/z): 623 (M+H) ⁺

Reference Example G-46
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Reference Example F-34 (18 mg), triethylamine (0.024 mL) and THF (1.0 mL) were mixed and added with Reference Example J-2 (8.7 mg) and NaBH(OAc) ₃ (15 mg). The reaction mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (20 mg). MS (ESI_APCI, m/z): 678 (M+H) ⁺

Reference Example G-47
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-5-((2-methoxy-2-oxoethyl)carbamoyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Reference Example F-35 (79 mg), triethylamine (0.11 mL) and THF (1.0 mL) were mixed and added with Reference Example J-2 (40 mg) and NaBH(OAc) ₃ (67 mg). The reaction mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (92 mg).

Reference Example K-1
Methyl (S)-(4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoyl)glycinate Example 21 (50 mg), glycine methyl ester hydrochloride (15 mg), EDC.HCl (31 mg), HOBt.H ₂ O (22 mg), triethylamine (0.119 mL) and DMF (1 mL) were stirred at room temperature overnight. Water, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to obtain the title compound (7 mg). MS (ESI_APCI, m/z): 501 (M+H) ⁺

Reference Example K-3
Methyl (5-bromopyridine-2-carbonyl)glycinate
A mixture of 5-bromopicolinic acid (300 mg), glycine methyl ester hydrochloride (224 mg), EDC.HCl (427 mg), HOBt.H ₂ O (341 mg), triethylamine (1.03 mL) and THF (3 mL) was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture and stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 50/50) to obtain the title compound (247 mg).

Reference Example K-4
(S)-2-((3-(1-(6-((2-methoxy-2-oxoethyl)carbamoyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl. Reference Example I-1 (100 mg), Reference Example K-3 (75 mg), N,N'-dimethylethylenediamine (0.032 mL), copper iodide (I) (57 mg), potassium carbonate (83 mg) and acetonitrile (1 mL) were stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 0/100) to give the title compound (25 mg). MS (ESI_APCI, m/z): 591 (M+H) ⁺

The chemical structures of some reference examples are shown in the table below.

Example G-5
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl. To a mixture of Reference Example F-8 (105 mg), 1-methyl-1H-imidazole-2-carbaldehyde (51 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (197 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (128 mg). MS (ESI_APCI, m/z): 509 (M+H) ⁺

Example G-10
(S)-3'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl. Using Reference Example F-25 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m/z): 525 (M+H) ⁺

Example G-11
(S)-2'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl. Using Reference Example F-26 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m/z): 525 (M+H) ⁺

Example G-12
(S)-4-(5-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester. The title compound was obtained in the same manner as in Example G-5 using Reference Example F-27 instead of Reference Example F-8. MS (ESI_APCI, m/z): 510 (M+H) ⁺

Example G-13
(S)-4-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylate methyl. Using Reference Example F-28 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m/z): 525 (M+H) ⁺

Example G-15
(S)-2-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl. Using Reference Example F-29 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m/z): 525 (M+H) ⁺

Example G-48
(S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl. To a mixture of Reference Example F-23 (100 mg), 3-methyl-2-pyridinecarboxaldehyde (54 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (282 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (80 mg). MS (ESI_APCI, m/z): 520 (M+H) ⁺

Example K-5
(S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. To a mixture of Reference Example F-21 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (139 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (415 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (286 mg). MS (ESI_APCI, m/z): 545 (M+H) ⁺

Example K-6
(S)-2-((3-(1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carbonitrile Example K-5 (286 mg), tetrakis(triphenylphosphine)palladium(0) (61 mg), zinc cyanide (123 mg) and NMP (3 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (185 mg). MS (ESI_APCI, m/z): 492 (M+H) ⁺

Example K-7
(S)-4'-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl. To a mixture of Reference Example F-23 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (168 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (376 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (218 mg). MS (ESI_APCI, m/z): 587 (M+H) ⁺

Example K-8
(S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate Methyl Example K-7 (218 mg), tetrakis(triphenylphosphine)palladium(0) (43 mg), zinc cyanide (87 mg) and NMP (3 mL) were stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80/20 to 0/100) to obtain the title compound (319 mg). MS (ESI_APCI, m/z): 534 (M+H) ⁺

Example K-9
(S)-4'-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-carboxylate methyl. To a mixture of Reference Example F-26 (200 mg), 5-bromo-1-methyl-1H-imidazol-2-carbaldehyde (162 mg) and dichloromethane (3 mL), NaBH(OAc) ₃ (363 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (3 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/80/20) to give the title compound (297 mg). MS (ESI_APCI, m/z): 603 (M+H) ⁺

Example K-10
(S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-carboxylate methyl Example K-9 (297 mg), tetrakis(triphenylphosphine)palladium(0) (57 mg), zinc cyanide (116 mg) and NMP (3 mL) were stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water. The mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/80/20) to give the title compound (178 mg). MS (ESI_APCI, m/z): 550 (M+H) ⁺

Example K-11
(S)-4-(5-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester Reference Example F-27 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (167 mg) and dichloromethane (2 mL) were mixed and NaBH(OAc) ₃ (375 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (214 mg). MS (ESI_APCI, m/z): 588 (M+H) ⁺

Example K-12
(S)-4-(5-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester Example K-11 (214 mg), tetrakis(triphenylphosphine)palladium(0) (42 mg), zinc cyanide (86 mg) and NMP (3 mL) were stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80/20 to 0/100) to obtain the title compound (244 mg). MS (ESI_APCI, m/z): 535 (M+H) ⁺

Example K-13
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-1 instead of Reference Example F-27, the title compound was obtained in the same manner as in Example K-11. MS (ESI_APCI, m/z): 529 (M+H) ⁺

Example K-14
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carbonitrile The title compound was obtained in the same manner as in Example K-12, using Example K-13 instead of Example K-11. MS (ESI_APCI, m/z): 476 (M+H) ⁺

Example K-15
(S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-3 instead of Reference Example F-27, the title compound was obtained in the same manner as in Example K-11. MS (ESI_APCI, m/z): 453 (M+H) ⁺

Example K-16
(S)-1-Methyl-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carbonitrile Example K-15 (103 mg), tetrakis(triphenylphosphine)palladium(0) (26 mg), zinc cyanide (53 mg) and DMF (1 mL) were stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80/20 to 0/100) to obtain the title compound (75 mg). MS (ESI_APCI, m/z): 400 (M+H) ⁺

Example K-17
(R)-4-(5-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester. The title compound was obtained in the same manner as in Example K-11 using Reference Example F-36 instead of Reference Example F-27. MS (ESI_APCI, m/z): 588 (M+H) ⁺

Example K-18
(R)-4-(5-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester. The title compound was obtained in the same manner as in Example K-16, using Example K-17 instead of Example K-15. MS (ESI_APCI, m/z): 535 (M+H) ⁺

Example 1
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. To a mixture of Reference Example F-1 (20 mg), 3-methyl-2-pyridinecarboxaldehyde (8.0 mg) and dichloromethane (1 mL), NaBH(OAc) ₃ (65 mg) was added. The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (16 mg).

Example 2
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-1 (20 mg), 1-methyl-1H-imidazole-2-carbaldehyde (7.2 mg) and dichloromethane (1 mL), NaBH(OAc) ₃ (65 mg) was added. The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 0/100) and then ODS column chromatography (eluent: water/acetonitrile = 80/20 to 30/70) to obtain the title compound (11 mg).

Example 3
(R)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. To a mixture of Reference Example F-2 (20 mg), 1-methyl-1H-imidazole-2-carbaldehyde (11 mg) and dichloromethane (1 mL), NaBH(OAc) ₃ (65 mg) was added. The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water/acetonitrile = 80/20 to 30/70) to obtain the title compound (10 mg).

Example 4
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
The title compound was obtained in the same manner as in Example 2, except that 2-pyridinecarboxaldehyde was used instead of 1-methyl-1H-imidazole-2-carbaldehyde.

Example 5
(S)-3-(1-((1H-imidazol-4-yl)methyl)pyrrolidin-3-yl)-1-([1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
The title compound was obtained in the same manner as in Example 1, except that 1H-imidazole-4-carbaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 6
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-4-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride. To a mixture of Reference Example F-1 (30 mg), 1-methyl-1H-imidazole-4-carbaldehyde (17 mg) and dichloromethane (1 mL), NaBH(OAc) ₃ (81 mg) was added and stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10). Hydrogen chloride (1 mol/L, ethanol solution, 0.2 mL) was added to the obtained product and stirred. The mixture was concentrated under reduced pressure to give the title compound (37 mg).

Example 7
(S)-3-(1-((1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-([1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
The title compound was obtained in the same manner as in Example 1, except that 1H-imidazole-2-carbaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 8
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((3-hydroxypyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
The title compound was obtained in the same manner as in Example 1, except that 3-hydroxypyridine-2-carboxaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 9
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((5-hydroxypyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
The title compound was obtained in the same manner as in Example 1, except that 5-hydroxypyridine-2-carboxaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 10
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((4-hydroxypyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. To a mixture of Reference Example F-1 (30 mg), 4-hydroxypyridine-2-carboxaldehyde (19 mg) and dichloromethane (1 mL), NaBH(OAc) ₃ (65 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water/acetonitrile = 80/20 to 30/70) to obtain the title compound (14 mg).

Example 11
(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride. To a mixture of Reference Example F-3 (100 mg), 1-methyl-1H-imidazole-2-carbaldehyde (70 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (268 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) and then ODS column chromatography (elution solvent: water/acetonitrile = 80/20 to 30/70). Hydrogen chloride (4 mol/L, ethyl acetate solution, 2 mL) was added to the obtained product and stirred. The mixture was concentrated under reduced pressure to give the title compound (59 mg).

Example 12
1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Reference Example F-4 (237 mg), 1-methyl-1H-imidazole-2-carbaldehyde (128 mg) and dichloromethane (3 mL) were mixed and NaBH(OAc) ₃ (495 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. Water was added to the reaction mixture and stirred, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 20/80) and then ODS column chromatography (eluent: water/acetonitrile = 80/20 to 30/70) to obtain the title compound (144 mg).

Example 13
1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)azetidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. To a mixture of Reference Example F-5 (105 mg), 1-methyl-1H-imidazole-2-carbaldehyde (61 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (354 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water/acetonitrile = 80/20 to 30/70). Hydrogen chloride (4 mol/L, ethyl acetate solution) and methanol were added to the resulting product and stirred. The mixture was concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography (eluent: water/acetonitrile=80/20-30/70) to obtain the title compound (2.8 mg).

Example 14
(S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-21 instead of Reference Example F-2, the title compound was obtained in the same manner as in Example 3.

Example 15
(S)-4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoic acid methyl ester The title compound was obtained in the same manner as in Example 1 using Reference Example F-6 instead of Reference Example F-1.

Example 16
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Aqueous sodium hydroxide solution (5 mol/L, 1 mL) was added to a mixture of Reference Example G-1 (26 mg), methanol (0.5 mL) and THF (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with hydrochloric acid (2 mol/L). The mixture was purified by ODS column chromatography (elution solvent: water/acetonitrile = 90/10 to 30/70) to obtain the title compound (9.5 mg).

Example 17
(S)-6-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)nicotinic acid Using Reference Example G-2 instead of Reference Example G-1, the title compound was obtained in the same manner as in Example 16.

Example 18
(S)-2-((3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Using Reference Example G-3 instead of Reference Example G-1, the title compound was obtained in the same manner as in Example 16.

Example 19
(S)-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Using Reference Example G-4 instead of Reference Example G-1, the title compound was obtained in the same manner as in Example 16.

Example 20
(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid To a mixture of Example G-5 (118 mg), methanol (0.5 mL) and THF (0.5 mL), an aqueous sodium hydroxide solution (5 mol/L, 1 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with hydrochloric acid (2 mol/L) and stirred for 20 minutes. The precipitate was collected by filtration, and the obtained solid was dried to obtain the title compound (44 mg).

Example 21
(S)-4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoic acid hydrochloride To a mixture of Example 15 (257 mg), methanol (1 mL), and THF (1 mL), aqueous sodium hydroxide solution (5 mol/L, 2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding hydrochloric acid (2 mol/L, 5 mL). The mixture was concentrated under reduced pressure. Dichloromethane and anhydrous magnesium sulfate were added to the resulting residue. The mixture was stirred for 10 minutes. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Dichloromethane and hydrogen chloride (4 mol/L, ethyl acetate solution, 1 mL) were added to the resulting residue, and the mixture was stirred. The mixture was concentrated under reduced pressure to give the title compound (120 mg).

Example 22
(S)-1-Methyl-2-((3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Hydrogen chloride (4 mol/L, ethyl acetate solution, 2 mL) was added to a mixture of Reference Example G-23 (154 mg), ethyl acetate (1 mL) and methanol (0.5 mL). The reaction mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%)/acetonitrile = 90/10-30/70) to obtain the title compound (107 mg).

Example 23
2-((4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpiperidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Reference Example G-6 (73 mg), dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) were heated under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%)/acetonitrile = 90/10-30/70) to give the title compound (39 mg).

Example 24
(S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-6-methoxy-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-7 (145 mg), water (0.5 mL) and concentrated sulfuric acid (0.024 mL) was stirred at 90°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and then methanol (0.5 mL) and lithium hydroxide monohydrate (95 mg) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%)/acetonitrile = 90/10 to 30/70) to obtain the title compound (85 mg).

Example 25
2-(((3R,4R)-3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-fluoropyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-8 instead of Reference Example G-7, the title compound was obtained in the same manner as in Example 24.

Example 26
(S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-9 instead of Reference Example G-7, the title compound was obtained in the same manner as in Example 24.

Example 27
(S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Reference Example G-45 (65 mg), methanol (0.2 mL), water (1 mL) and concentrated sulfuric acid (0.04 mL) were stirred at 110 ° C. for 1 hour under microwave irradiation. Lithium hydroxide monohydrate (100 mg) was added to the reaction mixture and stirred at 50 ° C. for 1 hour. The reaction mixture was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%) / acetonitrile = 90/10 to 30/70) to obtain the title compound (27 mg).

Example 28
(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-13 instead of Reference Example F-2, the title compound was obtained in the same manner as in Example 3.

Example 29
(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(2'-methyl-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-14 instead of Reference Example F-2, the title compound was obtained in the same manner as in Example 3.

Example 30
(R)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-15 instead of Reference Example F-2, the title compound was obtained in the same manner as in Example 3.

Example 31
(S)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-16 instead of Reference Example F-1, the title compound was obtained in the same manner as in Example 1.

Example 32
(S)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-17 instead of Reference Example F-1, the title compound was obtained in the same manner as in Example 1.

Example 33
(S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-18 instead of Reference Example F-1, the title compound was obtained in the same manner as in Example 1.

Example 34
(S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carbonitrile Using Reference Example F-19 instead of Reference Example F-1, the title compound was obtained in the same manner as in Example 1.

Example 35
(S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-20 instead of Reference Example F-1, the title compound was obtained in the same manner as in Example 1.

Example 36
(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride. Reference Example F-22 (43 mg), 1-methyl-1H-imidazole-2-carbaldehyde (22 mg) and dichloromethane (1 mL) were mixed and NaBH(OAc) ₃ (127 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water/acetonitrile = 80/20 to 30/70). Hydrogen chloride (4 mol/L, ethyl acetate solution) and methanol were added to the resulting product and stirred. The mixture was concentrated under reduced pressure to give the title compound (25 mg).

Example 37
(S)-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl. The title compound was obtained in the same manner as in Example 3 using Reference Example F-23 instead of Reference Example F-2.

Example 38
(R)-3'-methyl-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl. The title compound was obtained in the same manner as in Example 3 using Reference Example F-24 instead of Reference Example F-2.

Example 39
(S)-3'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid A mixture of Example G-10 (20 mg), methanol (0.5 mL), THF (0.5 mL) and aqueous sodium hydroxide solution (5 mol/L, 1 mL) was stirred at room temperature overnight. Hydrochloric acid (2 mol/L, 2.5 mL) was added to the reaction mixture and stirred. The mixture was concentrated under reduced pressure. Methanol was added to the obtained residue and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography (elution solvent: water/acetonitrile = 90/10 to 30/70) to obtain the title compound (6.3 mg).

Example 40
(S)-2'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid Using Example G-11 instead of Example G-10, the title compound was obtained in the same manner as in Example 39.

Example 41
(S)-4-(5-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid The title compound was obtained in the same manner as in Example 39 using Example G-12 instead of Example G-10.

Example 42
(S)-4-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylic acid Using Example G-13 instead of Reference Example G-1, the title compound was obtained in the same manner as in Example 16.

Example 43
(S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Using Reference Example G-14 instead of Reference Example G-1, the title compound was obtained in the same manner as in Example 16.

Example 44
(S)-2-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid Using Example G-15 instead of Reference Example G-1, the title compound was obtained in the same manner as in Example 16.

Example 45
(S)-2-((3-(1-(4'-carboxy-2-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Aqueous sodium hydroxide solution (5 mol/L, 1 mL) was added to a mixture of Reference Example G-16 (207 mg), methanol (0.5 mL) and THF (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with hydrochloric acid. The mixture was purified by ODS column chromatography (elution solvent: water/acetonitrile = 98/2-30/70) to obtain the title compound (109 mg).

Example 46
(S)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Aqueous sodium hydroxide solution (5 mol/L, 1 mL) was added to a mixture of Reference Example G-17 (455 mg), methanol (0.5 mL) and THF (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding hydrochloric acid (2 mol/L), and the precipitate was collected by filtration. The obtained solid was purified by ODS column chromatography (elution solvent: water/acetonitrile = 98/2-30/70) to obtain the title compound (280 mg).

Example 47
(S)-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid To a mixture of Example 37 (48 mg), methanol (0.5 mL) and THF (0.5 mL), an aqueous sodium hydroxide solution (5 mol/L, 1 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. Hydrochloric acid (2 mol/L, 2.5 mL) was added to the reaction mixture and mixed. The mixture was concentrated under reduced pressure. Methanol was added to the obtained residue and mixed. Insoluble matter was removed through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography (elution solvent: water/acetonitrile = 90/10 to 30/70) to obtain the title compound (17 mg).

Example 48
(R)-3'-methyl-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid The title compound was obtained in the same manner as in Example 47, except that Example 38 was used instead of Example 37.

Example 49
(S)-2-((3-(1-(4'-carboxy-3-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-18 (450 mg) and concentrated hydrochloric acid (2 mL) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was left to stand at room temperature, and the precipitate was collected by filtration. The obtained solid was washed with cold water and dried. A portion of the obtained product (26 mg out of 222 mg) was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%)/acetonitrile = 98/2 to 30/70) to obtain the title compound (15 mg).

Example 50
(S)-2-((3-(1-(6-(4-carboxy-2-methylphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-19 (413 mg) and concentrated hydrochloric acid (2 mL) was stirred at 110 ° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding aqueous sodium hydroxide solution (5 mol / L), and insoluble matter was removed by filtration. The filtrate was purified by ODS column chromatography (elution solvent: aqueous formic acid solution (0.1%) / acetonitrile = 90 / 10-70 / 30-10 / 90) to obtain the title compound (224 mg).

Example 51
(S)-2-((3-(1-(3'-carboxy-2,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid A mixture of Reference Example G-20 (188 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110°C for 1 hour under microwave irradiation. Concentrated sulfuric acid (0.2 mL) was added to the reaction mixture under stirring and ice cooling. The reaction mixture was heated under reflux for 4 days. The reaction mixture was allowed to cool to room temperature, and then neutralized by adding an aqueous sodium hydroxide solution (5 mol/L). The precipitate was collected by filtration. The obtained solid was purified by ODS column chromatography (elution solvent: water/acetonitrile = 98/2 to 30/70) to obtain the title compound (16 mg).

Example 52
(S)-2-((3-(1-(6-(3-carboxy-4-hydroxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Using Reference Example G-21 instead of Reference Example G-20, the title compound was obtained in the same manner as in Example 51.

Example 53
(S)-2-((3-(1-(3'-carboxy-3,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid A mixture of Reference Example G-22 (77 mg), water (0.5 mL) and concentrated sulfuric acid (0.5 mL) was heated under reflux for 7 hours. The reaction mixture was allowed to cool to room temperature, and then an aqueous sodium hydroxide solution (5 mol/L, 4 mL) was added under ice cooling. The mixture was stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (elution solvent: water/acetonitrile = 98/2-30/70) to obtain the title compound (3 mg).

Example 54
(S)-2-((3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-24 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 55
(S)-2-((3-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-25 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 56
(S)-1-Methyl-2-((3-(2-oxo-1-(4-phenoxyphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-26 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 57
(S)-2-((3-(1-(4-benzylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-27 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 58
(S)-1-Methyl-2-((3-(2-oxo-1-(p-tolyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-28 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 59
(S)-2-((3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-29 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 60
(S)-1-methyl-2-((3-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-30 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 61
(S)-2-((3-(1-(4-(ethylsulfonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-31 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 62
(S)-1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-32 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 63
(S)-1-Methyl-2-((3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-33 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 64
(S)-2-((3-(1-(4-cyanophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-34 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 65
(S)-1-Methyl-2-((3-(1-(4-nitrophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-35 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 66
(S)-1-Methyl-2-((3-(2-oxo-1-(quinolin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-36 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 67
(S)-1-Methyl-2-((3-(1-(4-morpholinophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-37 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 68
(S)-1-Methyl-2-((3-(2-oxo-1-(4-phenylcyclohexyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-38 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 69
(S)-1-methyl-2-((3-(2-oxo-1-(4-vinylphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-39 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 70
(S)-1-Methyl-2-((3-(2-oxo-1-(thiophen-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-40 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 71
(S)-2-((3-(1-benzyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-41 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 72
(S)-2-((3-(1-(4-cyclopropylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-42 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 73
(S)-2-((3-(1-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-43 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 74
(S)-1-methyl-2-((3-(1-(4'-(methylsulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Using Reference Example G-44 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 75
(S)-(4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoyl)glycine Aqueous sodium hydroxide solution (5 mol/L, 1 mL) was added to a mixture of Reference Example K-1 (7.7 mg), methanol (0.5 mL) and THF (0.5 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was purified by ODS column chromatography (elution solvent: water/acetonitrile = 90/10 to 30/70) to obtain the title compound (2.5 mg).

Example 76
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example G-46 instead of Reference Example G-6, the title compound was obtained in the same manner as in Example 23.

Example 77
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-5-((carboxymethyl)carbamoyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Reference Example G-47 (92 mg), methanol (0.5 mL), water (0.5 mL) and concentrated sulfuric acid (0.022 mL) were heated under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, and then lithium hydroxide monohydrate (70 mg) was added and stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%)/acetonitrile = 98/2-30/70) to obtain the title compound (33 mg).

Example 78
(S)-2-((3-(1-(6-((carboxymethyl)carbamoyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Using Reference Example K-4 instead of Reference Example G-47, the title compound was obtained in the same manner as in Example 77.

Example 79
(S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. To a mixture of Reference Example F-22 (285 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (250 mg) and dichloromethane (2 mL), NaBH(OAc) ₃ (561 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (363 mg).

Example 80
(S)-1-Methyl-2-((3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carbonitrile A mixture of Example 79 (351 mg), tetrakis(triphenylphosphine)palladium(0) (77 mg), zinc cyanide (155 mg) and NMP (3 mL) was stirred at 120° C. for 90 minutes under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by aminosilica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to obtain the title compound (68 mg).

Example 81
(S)-1-Methyl-2-((3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid A mixture of Example 80 (190 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. An aqueous sodium hydroxide solution (5 mol/L) was added to the reaction mixture under ice cooling until a precipitate was formed. The precipitate was collected by filtration. The obtained solid was purified by ODS column chromatography (elution solvent: water/acetonitrile=98/2-30/70) to obtain the title compound (25 mg).

Example 82
(S)-2-((3-(1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Example K-6 (150 mg) and concentrated hydrochloric acid (2 mL) were stirred at 110 ° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and then purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2-30 / 70) to obtain the title compound (83 mg).

Example 83
(S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Example K-8 (199 mg) and concentrated hydrochloric acid (1 mL) were stirred at 110 ° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and then purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2-30 / 70) to obtain the title compound (101 mg).

Example 84
(S)-2-((3-(1-(4'-carboxy-2-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-10 (178 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110 ° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized with an aqueous sodium hydroxide solution (5 mol / L) and then purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2-30 / 70). A part of the obtained product (16 mg out of 107 mg) was purified by ODS column chromatography (elution solvent: aqueous formic acid solution (0.1%) / acetonitrile = 98 / 2-30 / 70) to obtain the title compound (8 mg).

Example 85
(S)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-12 (195 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110 ° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and insoluble matter was removed through Celite. The filtrate was purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2-30 / 70) to obtain the title compound (60 mg).

Example 86
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-14 (58 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding aqueous sodium hydroxide solution (5 mol/L) and then concentrated under reduced pressure. DMSO was added to the resulting residue, and the insoluble matter was removed through Celite. The filtrate was purified by ODS column chromatography (elution solvent: water/acetonitrile = 90/10 to 30/70) to obtain the title compound (2.2 mg).

Example 87
(S)-1-Methyl-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid A mixture of Example K-16 (75 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110 ° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and then purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2-30 / 70) to obtain the title compound (48 mg).

Example 88
(R)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-18 (207 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol/L). The precipitate was collected by filtration, and the obtained solid was dried to obtain the title compound (40 mg).

Example 89
(S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. To a mixture of Reference Example F-21 (35 mg), 3-methyl-2-pyridinecarboxaldehyde (18 mg) and dichloromethane (1 mL), NaBH(OAc) ₃ (94 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to obtain the title compound (32 mg).

Example 90
(S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-22 instead of Reference Example F-21, the title compound was obtained in the same manner as in Example 89.

Example 91
(S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid Example G-48 (72 mg), methanol (1 mL) and THF (1 mL) were mixed and an aqueous sodium hydroxide solution (5 mol/L, 2 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. Hydrochloric acid (2 mol/L, 5 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes under ice cooling. The precipitate was collected by filtration, and the obtained solid was dried to obtain the title compound (37 mg).

The chemical structures, physical properties, and PHD2 inhibitory activity (see Test Example 1) of the examples are shown in the table below.

Test Example 1 PHD2 Inhibition Test (1) Expression and Preparation of Human PHD2 _184-418
Human PHD2 _184-418 , which contains amino acid residues 184 to 418 of the protein represented by GenBank accession ID: CAC42509, was expressed and prepared by the following method.
An N-terminal histidine tag was incorporated into the expression construct for human PHD2 _184-418 , which was then introduced into the pET-30a(+) vector and the sequence was confirmed. This vector was introduced into the BL21(DE3) strain, which was then cultured at 37°C in LB medium containing antibiotics. After culture, a cell lysis solution was added to the cells, which were then disrupted and suspended by ultrasonication. The disrupted suspension was centrifuged, and the supernatant was purified using a Ni column to obtain human PHD2 _184-418 .
(2) Test method Human HIF-1α _556-574 (FITC-labeled HIF-1α _556-574 ), which contains amino acid residues 556 to 574 (partial peptide) of human HIF-1α, was used as a substrate. Using FITC-labeled HIF-1α _{556-574 ,} the competitive inhibition between 2-oxoglutarate and the test compound (PHD inhibitor) was evaluated by the change in fluorescence polarization of FITC-labeled HIF-1α _556-574 as follows.
The enzyme (human PHD2 _184-418 ) and substrate were diluted in assay buffer (pH 7.4) containing 10 mM HEPES, 150 mM NaCl, 10 μM MnCl ₂ · 4H ₂ O, 2 μM 2-oxoglutarate, and 0.05% Tween-20. Test compounds were diluted in DMSO. The test compound, human PHD2 _184-418 , was pre-added to a 384-well plate (Corning, black, opaque bottom), and the reaction was started by adding FITC-labeled HIF-1α _556-574 . After incubation at 37 °C for 60 minutes, fluorescence polarization (excitation wavelength 470 nm, emission wavelength 530 nm) was measured using a PHERAstar FSX (BMG Labtech). Fluorescence polarization of each well was measured, and the human PHD2 binding inhibitory activity of the test compound was calculated based on the value of the group without the addition of the test substance.
(3) Results As shown in the above table, the compounds of the present invention inhibited the binding of PHD2 to HIF-1α. Therefore, it was revealed that the compounds of the present invention are useful as PHD2 inhibitors.

Test Example 2 Therapeutic effect in a colitis model (1) TNBS-induced colitis model rats
It is known that administration of TNBS into the rat large intestine induces local inflammation in the large intestine, disrupts the intestinal barrier function, and increases mesenteric permeability. Therefore, the inhibitory effect of oral administration of test compounds on mesenteric permeability was evaluated as an index of drug efficacy.
(2) Test method
Eight-week-old SLC:SD male rats (Japan SLC) were used. Under pentobarbital anesthesia, 300 μL of 28 mg/mL TNBS prepared with 50% ethanol was administered to the site 8 cm from the anus in the large intestine to induce inflammation. 300 μL of 50% ethanol was administered to the solvent treatment group. The rats were fasted for 48 hours before administration of TNBS. From the next day, the test compound (3 mg/kg) prepared in 0.05% methylcellulose solution was orally administered once a day for a total of three days. Three days after administration, 50 mg/kg FITC was orally administered 4 hours after administration of the test compound, and blood was collected from the jugular vein under isoflurane anesthesia 4 hours later. The serum was centrifuged, and the concentration of FITC that had permeated into the circulating blood through the mesentery was measured by detecting the fluorescence intensity with a PHERAstar FSX (BMG Labtech). The mesenteric permeability inhibition rate of the test compound was calculated based on the value of the group without test substance added being 0 and the value of the TNBS untreated group being 100.
(3) Results The mesenteric permeability inhibition rate (%, mean value) of each test compound is shown below.
The intestinal membrane permeability of FITC, which was enhanced by administration of TNBS, was suppressed by administration of the compound of the present invention, demonstrating that the compound of the present invention is useful as a therapeutic agent for inflammatory bowel disease.

表中の記号は、以下の意味である。
Cmax：試験化合物の経口投与における最高血漿中濃度（ng/mL）
AUC：血漿中試験化合物濃度‐時間曲線下面積（ng*min/mL）
Plasma：8時間後の血漿中試験化合物の濃度（ng/mL）
Colon：8時間後の大腸組織における試験化合物の濃度（ng/g）
C / P：上記ColonとPlasmaの比
NC：Not Calculated（算出限界以下） Test Example 3 Compound concentration in colonic tissue (1) PK study in rats
Test compounds (3mg/kg/5mL) prepared with 0.05% methylcellulose were orally administered to non-fasted rats (SD, 8 weeks old, male, Japan SLC). Blood was collected from the jugular vein 0.25, 0.5, 1, 2, 4, 6 and 8 hours after administration, and the rat was opened under isoflurane anesthesia to remove the large intestine. Approximately 5cm of the distal large intestine was collected and cut open, and the removed large intestine was washed with saline on a dish. After washing, the large intestine was minced with small scissors, and approximately 150mg of it was transferred to a tube. 100μL of saline was added to the tube, and the mixture was homogenized with a Shake Master (1000rpm x 30 minutes). 4 volumes of saline were added to the final volume to prepare the sample. The test compound concentrations in the colon tissue and plasma were measured by quantitative analysis using liquid chromatography mass spectrometry (LC/MS).
(2) Compound Concentration in Colon Tissue and Plasma As shown in the table below, it was revealed that the compound of the present invention has a higher concentration in colon tissue than in plasma. Therefore, the preferred compound of the present invention is a PHD2 inhibitor that acts specifically on colon tissue.

The symbols in the table have the following meanings.
Cmax: Maximum plasma concentration of the test compound after oral administration (ng/mL)
AUC: Area under the plasma test compound concentration-time curve (ng*min/mL)
Plasma: Plasma concentration of test compound after 8 hours (ng/mL)
Colon: Concentration of the test compound in colon tissue after 8 hours (ng/g)
C/P: Ratio of colon to plasma
NC: Not Calculated (below calculation limit)

The manufacturing method of the present invention is useful as a method for manufacturing a compound represented by formula (I) or a pharmacologically acceptable salt thereof.

Claims (5)

Formula (I):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or a C _1-6 alkyl;
R ¹ is a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
R ² is a hydrogen atom, a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' (when n is 2 or 3, two or more R ² may be different from each other);
^R4 is a hydrogen atom or _C1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or the following group A (when u is 2 or 3, two or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or a C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
The group A is a group selected from the group consisting of the following (a) to (h):
(a) a C _6-10 aryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(e) a 5- or 6-membered heteroaryl C _1-6 alkyl group unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and
(h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9′ are each independently a hydrogen atom or a C _1-6 alkyl;
R ¹⁰ is a hydrogen atom or C _1-6 alkyl;
R ¹¹ and R ^11' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
m, n, and u are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof,
Formula (II):

wherein m, n, p and q are as defined above;
R ^1R is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a cyano, a hydroxyl group which may be protected by a protecting group, or a carboxyl group which may be protected by a protecting group (when m is 2 or 3, two or more R ^1R may be different from each other);
^R2R is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, hydroxy which may be protected by a protecting ^group , _-CO2R4R , or ^{-CONR5R5R '} (when n is 2 or 3, two or more ^R2R may be different from each other);
R ^4R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
R ^X is a hydrogen atom or a group represented by formula (III):

(Wherein, rings W, u and r are as defined above;
^R3R _is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, C1-6 alkoxy, _haloC1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkylsulfanyl, _C1-6 alkylsulfinyl, _C1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, ^{-NR6R3R6R '} , _-CO2R7R ^{, -CONR8R3R8R '} , or the following group AA (when u is 2 or 3, two or more ^R3R may be different from each other);
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl; and
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, a C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl,
Formula (IV):

[Wherein,
Ring ZZ is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^A , R ^B and R ^C are each independently a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, a hydroxyl which may be protected by a protecting group, or a carboxyl which may be protected by a protecting group;
R ^D is a protecting group, a hydrogen atom, or a C _1-6 alkyl group, or a salt thereof,
Formula (V):

A production method comprising the step of obtaining a compound represented by the formula: wherein ring ZZ, R ^1R , R ^2R , R ^x , m, n, p and q are as defined above, or a salt thereof. The method according to claim 1,
Formula (IIA):

(In the formula, ^R1R , ^R2R , ^R3R , ring W, m, n, p, q, r, and u have the same meanings as in claim 1.)
or a salt thereof;
Using the compound represented by formula (IV) or a salt thereof,
Formula (VA):

wherein ring W, ring ZZ, ^R1R , ^R2R , ^R3R , m, n, p, q, r and u have the same meanings as defined in claim 1, or a salt thereof. The method according to claim 1,
Formula (IIB):

(wherein R ^1R , R ^2R , m, n, p and q have the same meanings as in claim 1 ).
or a salt thereof;
Using the compound represented by formula (IV) or a salt thereof,
Formula (VB):

(wherein ring ZZ, R ^1R , R ^2R , m, n, p and q have the same meanings as in claim 1 ).
or a salt thereof. Formula (I):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or a C _1-6 alkyl;
R ¹ is a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
R ² is a hydrogen atom, a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' (when n is 2 or 3, two or more R ² may be different from each other);
^R4 is a hydrogen atom or _C1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or the following group A (when u is 2 or 3, two or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or a C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
The group A is a group selected from the group consisting of the following (a) to (h):
(a) a C _6-10 aryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(e) a 5- or 6-membered heteroaryl C _1-6 alkyl group unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and
(h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9′ are each independently a hydrogen atom or a C _1-6 alkyl;
R ¹⁰ is a hydrogen atom or C _1-6 alkyl;
R ¹¹ and R ^11' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
m, n, and u are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof,
Formula (IIC):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ^1R is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a cyano, a hydroxyl group which may be protected by a protecting group, or a carboxyl group which may be protected by a protecting group (when m is 2 or 3, two or more R ^1R may be different from each other);
^R2R is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, hydroxy which may be protected by a protecting ^group , _-CO2R4R , or ^{-CONR5R5R '} (when n is 2 or 3, two or more ^R2R may be different from each other);
R ^4R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
R ^3RA is a halogen atom or a group AA;
R ^3RB and R ^3RC are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, -NR ^6R R ^6R' , -CO ₂ R ^7R , -CONR ^8R R ^8R' , or the following group AA;
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl; and
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
m and n are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
r is an integer from 0 to 6.
or a salt thereof. Formula (I):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or a C _1-6 alkyl;
R ¹ is a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
R ² is a hydrogen atom, a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' (when n is 2 or 3, two or more R ² may be different from each other);
^R4 is a hydrogen atom or _C1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or the following group A (when u is 2 or 3, two or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or a C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
The group A is a group selected from the group consisting of the following (a) to (h):
(a) a C _6-10 aryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(e) a 5- or 6-membered heteroaryl C _1-6 alkyl group unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and
(h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9′ are each independently a hydrogen atom or a C _1-6 alkyl;
R ¹⁰ is a hydrogen atom or C _1-6 alkyl;
R ¹¹ and R ^11' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
m, n, and u are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof,
Formula (VC):

[Wherein,
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl;
Ring ZZ is a group selected from the group consisting of the following (a) to (c):

and

(Wherein,
R ^A , R ^B and R ^C are each independently a hydrogen atom, a halogen atom, a C _1-6 alkyl, cyano, a hydroxyl which may be protected by a protecting group, or a carboxyl which may be protected by a protecting group;
R ^D is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^1R is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a cyano, a hydroxyl group which may be protected by a protecting group, or a carboxyl group which may be protected by a protecting group (when m is 2 or 3, two or more R ^1R may be different from each other);
^R2R is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, hydroxy which may be protected by a protecting ^group , _-CO2R4R , or ^{-CONR5R5R '} (when n is 2 or 3, two or more ^R2R may be different from each other);
R ^4R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^5R and R ^5R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
R ^3RA is a halogen atom or a group AA;
R ^3RB and R ^3RC are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy which may be protected by a protecting group, cyano, nitro, -NR ^6R R ^6R' , -CO ₂ R ^7R , -CONR ^8R R ^8R' , or the following group AA;
R ^6R and R ^6R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^7R is a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^8R and R ^8R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
The group AA is a group selected from the group consisting of the following (a) to (h):
(a) C _6-10 aryl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(c) C _6-10 arylC _1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
(g) C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB;
Substituent group BB is a group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR ^9R R ^9R' , -NR ^9R SO ₂ R ^10R , -CO ₂ R ^10R , and -CONR ^11R R ^11R' ;
R ^9R and R ^9R' are each independently a protecting group, a hydrogen atom, or a C _1-6 alkyl;
R ^10R is a protecting group, a hydrogen atom, or a C _1-6 alkyl; and
R ^11R and R ^11R' are each independently a protecting group, a hydrogen atom, C _1-6 alkyl, a carboxy C _1-6 alkyl which may be protected by a protecting group, a hydroxy C _1-6 alkyl which may be protected by a protecting group, a halo C _1-6 alkyl, a C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
m and n are each independently an integer from 1 to 3;
p and q are each independently 1 or 2; and
r is an integer from 0 to 6.
or a salt thereof.