JP2006117647A - Halogenopyrazolopyridine pyridazinone derivative, its addition salt and pde inhibitor having them as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new halogenopyrazolopyridine pyridazinone derivative useful as a medicine having phosphodiesterase inhibition behavior. <P>SOLUTION: The halogenopyrazolopyridine pyridazinone derivative is represented by general formula (1) (specific example: 6-(6-chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

本発明は、ホスホジエステラーゼ（PDE）阻害剤として有用なハロゲノピラゾロピリジンピリダジノン誘導体とその付加塩並びに水和物に関する。   The present invention relates to halogenopyrazolopyridine pyridazinone derivatives useful as phosphodiesterase (PDE) inhibitors, addition salts and hydrates thereof.

ホスホジエステラーゼ（ＰＤＥ）は生体内のセカンドメッセンジャーであるcycliｃ AMP(cＡＭＰ)、およびcyclic GMP(cGMP)を分解する酵素である。現在までに、PDEは1〜11までのタイプが見つかっており、タイプ毎にcAMPを特異的に分解するか、ｃGMPを特異的に分解するかあるいは両方を分解するかが決まっている。各PDEのタイプの組織分布には差がみられ、臓器の種類により、異なるタイプのPDEにより細胞反応がコントロールされていると考えられている。   Phosphodiesterase (PDE) is an enzyme that degrades cyclic AMP (cAMP) and cyclic GMP (cGMP), which are second messengers in vivo. To date, PDE types 1 to 11 have been found, and it is determined for each type whether cAMP is specifically decomposed, cGMP is specifically decomposed, or both are decomposed. There is a difference in the tissue distribution of each PDE type, and it is considered that the cellular response is controlled by different types of PDE depending on the type of organ.

PDE阻害剤の開発はこれまでに数多く行われており、例えばPDE3阻害剤は狭心症、心不全、高血圧症などの治療薬や血小板凝集抑制薬あるいは抗喘息薬として、またＰＤＥ４阻害剤は気管支喘息、慢性閉塞性肺疾患（COPD）、間質性肺炎、アレルギー性鼻炎、アトピー性皮膚炎、関節リウマチ、多発性硬化症、アルツハイマー、認知症、パーキンソン病などの治療薬として期待されている。ＰＤＥ５阻害剤は男性性機能障害治療薬としてすでに臨床において利用されている。さらに最近ではＰＤＥ１０Ａ modulatorとして、minocyclineをハンチントン病患者に試用して有効であったという報告があり（特許文献１）、ＰＤＥ１０阻害剤がハンチントン、アルツハイマー、認知症、パーキンソン病、精神***症などの各種精神障害治療薬として有効であることを示した公開特許公報も開示されてきている（特許文献２）。   Many PDE inhibitors have been developed so far. For example, PDE3 inhibitors are therapeutic agents for angina pectoris, heart failure, hypertension, etc., platelet aggregation inhibitors or anti-asthma drugs, and PDE4 inhibitors are bronchial asthma It is expected as a therapeutic agent for chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Alzheimer, dementia, Parkinson's disease, etc. PDE5 inhibitors are already used clinically as therapeutic agents for male sexual dysfunction. More recently, there was a report that minocycline was effective as a PDE10A modulator in patients with Huntington's disease (Patent Document 1), and PDE10 inhibitors are various types such as Huntington, Alzheimer, dementia, Parkinson's disease, and schizophrenia. An open patent publication showing effectiveness as a therapeutic agent for mental disorders has also been disclosed (Patent Document 2).

一方、ＰＤＥ阻害作用を有するピラゾロピリジンピリダジノン誘導体が（特許文献３、４）に開示されているが、本出願化合物の特徴でもあるピラゾロピリジン環の６位にハロゲン原子や炭素数１〜４の低級アルコキシ基を有する化合物類は含まれていない。また、ジヒドロピリダジノン基及びピリダジノン基がピラゾロピリジン環の３位に置換した化合物がすでにアデノシン拮抗剤として（特許文献５、６、７）に開示されている。しかし、これらの公開特許公報で請求された化合物は、ピラゾロピリジン環の２位置換基はベンゼン誘導体等のアリール基に限定されており、本発明化合物は含まれていない。さらにピラゾロピリジン環の２位にアルケニル基を有し、３位に置換基のないピリダジノン環が導入された化合物がアデノシン拮抗剤として（特許文献８）に開示されているが、ジヒドロピリダジノン環上やピリダジノン環上に置換基を有する本発明化合物は含まれていない。   On the other hand, a pyrazolopyridine pyridazinone derivative having a PDE inhibitory action is disclosed in (Patent Documents 3 and 4), but a halogen atom or a carbon number of 1 is located at the 6-position of the pyrazolopyridine ring, which is also a feature of the compound of the present application. Compounds having -4 lower alkoxy groups are not included. Further, compounds in which a dihydropyridazinone group and a pyridazinone group are substituted at the 3-position of the pyrazolopyridine ring have already been disclosed as adenosine antagonists (Patent Documents 5, 6, and 7). However, in the compounds claimed in these published patent publications, the 2-position substituent of the pyrazolopyridine ring is limited to an aryl group such as a benzene derivative, and does not include the compound of the present invention. Further, although a compound in which a pyridazinone ring having an alkenyl group at the 2-position of the pyrazolopyridine ring and having no substituent at the 3-position is introduced is disclosed as an adenosine antagonist (Patent Document 8), dihydropyridazinone This invention compound which has a substituent on a ring or a pyridazinone ring is not contained.

また、気管支拡張作用を有するピラゾロピリジン誘導体が（特許文献９）に開示されているが、これらで開示された化合物は本発明化合物と全く構造を異にするものである。
ＷＯ０１０２４７８１号パンフレット 特開平２００２−３６３１０３合公報 再公表WO９８／１４４４８号公報 特開平１０−１０９９８８号公報 特開平２−２４３６８９号公報 特開平４−２５３９７８号公報 ＷＯ０２０１８３８２号パンフレット ＷＯ０３００４４９４号パンフレット 特開平８−１２６７３号公報 Further, although pyrazolopyridine derivatives having bronchodilator action are disclosed in (Patent Document 9), the compounds disclosed therein are completely different in structure from the compound of the present invention.
WO01024781 pamphlet Japanese Patent Laid-Open No. 2002-363103 Republished WO98 / 14448 Japanese Patent Laid-Open No. 10-109988 Japanese Patent Laid-Open No. 2-243689 JP-A-4-253978 WO02018382 pamphlet WO03004494 pamphlet JP-A-8-12673

本発明は、優れたホスホジエステラーゼ阻害作用を有し、かつ副作用の少ないハロゲノピラゾロピリジンピリダジノン誘導体を提供することにある。   An object of the present invention is to provide a halogenopyrazolopyridine pyridazinone derivative having an excellent phosphodiesterase inhibitory action and less side effects.

本発明者らは、ホスホジエステラーゼ阻害活性を有し、かつ安全性の高い化合物を創製すべく鋭意研究を重ねた結果、これまでに知られているＰＤＥ阻害剤とは構造を異にした新規なハロゲノピラゾロピリジンピリダジノン誘導体がＰＤＥ阻害作用を有することを見出し、本発明を完成した。   As a result of intensive research to create a compound having phosphodiesterase inhibitory activity and high safety, the present inventors have found that a novel halogeno having a structure different from that of the previously known PDE inhibitors. The present invention was completed by finding that a pyrazolopyridine pyridazinone derivative has a PDE inhibitory action.

即ち、本発明は
１） 一般式（１） That is, the present invention is 1) General formula (1)

[式中、R₁はハロゲン原子又は炭素数１〜４の低級アルコキシ基を、
R₂は水素原子、ハロゲン原子、ヒドロキシ基又は炭素数１〜４の低級アルコキシ基を、
R₃は水素原子、ハロゲン原子、置換基を有しても良い炭素数１〜４の低級アルキル基、炭素数３〜８のシクロアルキル基、炭素数１〜４の低級アルケニル基、炭素数１〜４の低級アルコキシ基、炭素数１〜４の低級アルカノイル基、ヒドロキシ基又はカルボキシル基を、
R₄は炭素数１〜４の低級アルキル基を、
R₅は水素原子又はR₆-(CH₂)m-（式中、R₆は炭素数３〜８のシクロアルキル基、１〜２個の複素原子を含んでいても良い芳香族複素環又は飽和複素環を、mは１〜２の整数を示す）を、
- -は単結合又は二重結合を示す]
で表されることを特徴とするハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物、 [Wherein R ₁ represents a halogen atom or a lower alkoxy group having 1 to 4 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a hydroxy group or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ is a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a lower alkenyl group having 1 to 4 carbon atoms, or 1 carbon atom. -4 lower alkoxy group, 1 to 4 carbon lower alkanoyl group, hydroxy group or carboxyl group,
R ₄ represents a lower alkyl group having 1 to ₄ carbon atoms,
R ₅ is a hydrogen atom or R ₆ — (CH ₂ ) m — (wherein R ₆ is a cycloalkyl group having 3 to 8 carbon atoms, an aromatic heterocycle optionally containing 1 to 2 heteroatoms, or A saturated heterocyclic ring, m represents an integer of 1 to 2),
--Indicates a single bond or a double bond]
A halogenopyrazolopyridine pyridazinone derivative, an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof, characterized by:

２） 前記一般式（１）で表される化合物が、一般式（１ａ） 2) The compound represented by the general formula (1) is represented by the general formula (1a)

[式中、R₁、R₂、R₃及びR₄は前記定義に同じ]
で表されることを特徴とする１）に記載のハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物、 [Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
1) the halogenopyrazolopyridine pyridazinone derivative, its optical isomers and pharmacologically acceptable salts, and hydrates thereof,

３） 前記一般式（１ａ）においてR₁が塩素原子であることを特徴とする２）に記載のハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物、 3) The halogenopyrazolopyridine pyridazinone derivative, its optical isomer and pharmacologically acceptable salt thereof according to 2), wherein R ₁ is a chlorine atom in the general formula (1a) Hydrate,

４） 前記一般式（１ａ）においてR₁がフッ素原子であることを特徴とする２）に記載のハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物、 4) The halogenopyrazolopyridine pyridazinone derivative according to 2) above, wherein R ₁ is a fluorine atom in the general formula (1a), optical isomers and pharmacologically acceptable salts thereof, and Hydrate,

５） 前記一般式（１）で示される化合物が、
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（＋）−６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（−）−６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（＋）−６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（−）−６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
６−（６−クロロ−２−トリフルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン又は
６−（６−フルオロ−２−トリフルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノンである１）に記載のハロゲノピラゾロピリジンピリダジノン誘導体、及び薬理学的に許容しうる塩並びにその水和物、 5) The compound represented by the general formula (1) is
6- (6-chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(+)-6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(−)-6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
6- (2-ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(+)-6- (2-ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(−)-6- (2-ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
6- (6-Chloro-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone or 6- (6- The halogenopyrazolopyridine described in 1), which is fluoro-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone Pyridazinone derivatives, and pharmacologically acceptable salts and hydrates thereof,

（６） 一般式（１） (6) General formula (1)

[式中、R₁はハロゲン原子又は炭素数１〜４の低級アルコキシ基を、
R₂は水素原子、ハロゲン原子、ヒドロキシ基又は炭素数１〜４の低級アルコキシ基を、
R₃は水素原子、ハロゲン原子、置換基を有しても良い炭素数１〜４の低級アルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜４の低級アルケニル基、炭素数１〜４の低級アルコキシ基、炭素数１〜４の低級アルカノイル基、ヒドロキシ基又はカルボキシル基を、
R₄は炭素数１〜４の低級アルキル基を、
R₅は水素原子又はR₆-(CH₂)m-（式中、R₆は炭素数３〜８のシクロアルキル基、１〜２個の複素原子を含んでいても良い芳香族複素環又は飽和複素環を、mは１〜２の整数を示す）を、
- -は単結合又は二重結合を示す]
で表されることを特徴とするハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とするホスホジエステラーゼ（PDE）阻害剤、 [Wherein R ₁ represents a halogen atom or a lower alkoxy group having 1 to 4 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a hydroxy group or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ is a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms, or 1 carbon atom. -4 lower alkoxy group, 1 to 4 carbon lower alkanoyl group, hydroxy group or carboxyl group,
R ₄ represents a lower alkyl group having 1 to ₄ carbon atoms,
R ₅ is a hydrogen atom or R ₆ — (CH ₂ ) m — (wherein R ₆ is a cycloalkyl group having 3 to 8 carbon atoms, an aromatic heterocycle optionally containing 1 to 2 heteroatoms, or A saturated heterocyclic ring, m represents an integer of 1 to 2),
--Indicates a single bond or a double bond]
A phosphodiesterase (PDE) comprising at least one of halogenopyrazolopyridine pyridazinone derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof, characterized in that Inhibitors,

７） 前記一般式（１）で表される化合物が、一般式（１ａ） 7) The compound represented by the general formula (1) is represented by the general formula (1a)

[式中、R₁、R₂、R₃及びR₄は前記定義に同じ]
で表されることを特徴とする６）に記載のハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上
を有効成分とすることを特徴とする６）に記載のPDE阻害剤、 [Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
6) The halogenopyrazolopyridine pyridazinone derivative, its optical isomers and pharmacologically acceptable salts, and hydrates thereof as described in 6) above, 6) The PDE inhibitor according to 6),

８） 上記１〜７のいずれか１項に記載されたハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分として含有する医薬、
に関するものである。 8) At least one or more of the halogenopyrazolopyridine pyridazinone derivatives, optical isomers, pharmacologically acceptable salts and hydrates thereof described in any one of 1 to 7 above as active ingredients As a medicine,
It is about.

上述のように、本発明は、新規なハロゲノピラゾロピリジンピリダジノン誘導体とその付加塩が優れたPDE阻害作用を有することを見出したものである。このようなPDE阻害剤作用を有する化合物は、狭心症、心不全、高血圧症などの治療薬や血小板凝集抑制薬あるいは気管支喘息、慢性閉塞性肺疾患（COPD）、間質性肺炎、アレルギー性鼻炎、アトピー性皮膚炎、関節リウマチ、多発性硬化症、ハンチントン、アルツハイマー、認知症、パーキンソン病、精神***症などの各種精神障害等の予防または治療薬ならびに男性性機能障害治療薬として有用である。   As described above, the present invention has been found that a novel halogenopyrazolopyridine pyridazinone derivative and its addition salt have an excellent PDE inhibitory action. Such compounds with PDE inhibitor activity include therapeutic agents for angina pectoris, heart failure, hypertension, platelet aggregation inhibitors or bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis It is useful as a prophylactic or therapeutic agent for various psychiatric disorders such as atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Huntington, Alzheimer, dementia, Parkinson's disease, schizophrenia, etc., and a male sexual dysfunction therapeutic agent.

本発明における上記一般式（１）、一般式（１ａ）は新規化合物である。   The general formulas (1) and (1a) in the present invention are novel compounds.

本発明における一般式（１）で表される化合物の薬理学的に許容される塩には、塩酸塩、臭化水素酸塩、酢酸塩、トリフルオロ酢酸塩、メタンスルホン酸塩、クエン酸塩、酒石酸塩のような酸付加塩が挙げられる。   Examples of the pharmacologically acceptable salt of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, and citrate. And acid addition salts such as tartrate.

また、本発明の一般式（１）において、「ハロゲン原子」とはフッ素原子、塩素原子、臭素原子又はヨウ素原子を表し、「炭素数１〜４の低級アルコキシ基」、「炭素数１〜４の低級アルキル基」などの「低級アルキル基」とは、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル又はｔ−ブチルなどの直鎖もしくは分岐した炭素数１〜４の炭化水素が挙げられる。「置換基を有しても良い炭素数１〜４の低級アルキル基」とは、分岐あるいは直鎖上の炭素鎖上にハロゲン原子、ヒドロキシ基又は炭素数１〜４の低級アルコキシ基を有するものが挙げられる。「炭素数３〜８のシクロアルキル基」とは、例えばシクロプロピル、シクロブチル、シクロペンチル又はシクロヘキシルなどの炭素数３〜８の環状炭化水素が挙げられる。「炭素数２〜４の低級アルケニル基」とは、例えばビニル基、アリル基、１−プロペニル基、イソプロペニル基、１−ブテニル基、２−ブテニル基、２−メチルアリル基又は１−プロペニル基などの不飽和２重結合を有する炭素数２〜４の炭化水素が挙げられる。「炭素数１〜４の低級アルカノイル基」とは、ホルミル基、アセチル基、プロピオニル基、ブチリル基又はイソブチリル基などの直鎖もしくは分岐した炭素数１〜４の低級アルカノイル基が挙げられる。「１〜２個の複素原子を含んでいても良い芳香族複素環」とはピロール、フラン、チオフェン、ピラゾール、イソキサゾール、イソチアゾール、イミダゾール、オキサゾール、チアゾールなどの芳香族５員環単環化合物やピリジン、ピリダジン、ピリミジン、ピラジンなどの芳香族６員環単環化合物が挙げられる。「１〜２個の複素原子を含んでいても良い飽和複素環」とは、例えばピロリジン、ピペリジン、ピペラジン、モルホリンなどの５または６員環性の単環化合物が挙げられる。   In the general formula (1) of the present invention, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and represents a “lower alkoxy group having 1 to 4 carbon atoms” or “1 to 4 carbon atoms”. Examples of the “lower alkyl group” such as “lower alkyl group” include linear or branched hydrocarbons having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl. The “lower alkyl group having 1 to 4 carbon atoms which may have a substituent” means having a halogen atom, a hydroxy group or a lower alkoxy group having 1 to 4 carbon atoms on a branched or straight chain carbon chain. Is mentioned. Examples of the “C3-C8 cycloalkyl group” include C3-C8 cyclic hydrocarbons such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the “lower alkenyl group having 2 to 4 carbon atoms” include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 2-methylallyl group, and a 1-propenyl group. And a C2-C4 hydrocarbon having an unsaturated double bond. Examples of the “lower alkanoyl group having 1 to 4 carbon atoms” include linear or branched lower alkanoyl groups having 1 to 4 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group or isobutyryl group. “Aromatic heterocycle optionally containing 1 to 2 heteroatoms” means an aromatic 5-membered monocyclic compound such as pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, Aromatic 6-membered monocyclic compounds such as pyridine, pyridazine, pyrimidine, pyrazine and the like can be mentioned. Examples of the “saturated heterocyclic ring optionally containing 1 to 2 heteroatoms” include 5- or 6-membered monocyclic compounds such as pyrrolidine, piperidine, piperazine, morpholine and the like.

本発明よれば、上記一般式（１）で表される化合物のうち、R₅が水素原子で、- -が単結合である化合物、即ち一般式（１ａ） According to the present invention, among the compounds represented by the above general formula (1), a compound in which R ₅ is a hydrogen atom and--is a single bond, that is, the general formula (1a)

[式中、R₁、R₂、R₃及びR₄は前述の通り]
で表される化合物は、例えば以下に示す経路により製造することができる。 [Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above]
Can be produced by the following route, for example.

＜合成経路A＞ <Synthetic route A>

合成経路Aで一般式（３）   In the synthesis route A, the general formula (3)

[式中、R₁及びR₂は前述の通り]
で表される化合物は、一般式（２） [Wherein R ₁ and R ₂ are as described above]
The compound represented by general formula (2)

[式中、R₁及びR₂は前述の通り]
で表される化合物をO-メシチレンスルホニルヒドロキシアミン（MSH）と作用させることによって製造することができる（工程A-1）。 [Wherein R ₁ and R ₂ are as described above]
Can be produced by reacting with O-mesitylenesulfonylhydroxyamine (MSH) (step A-1).

反応は一般式（２）で表される化合物を塩化メチレンに溶解させ、０℃〜常温下にてMSHの塩化メチレン溶液を作用させることが好ましい。   In the reaction, the compound represented by the general formula (2) is preferably dissolved in methylene chloride, and a methylene chloride solution of MSH is allowed to act at 0 ° C. to room temperature.

合成経路Aで一般式（４）   In the synthesis route A, the general formula (4)

[式中、R₁、R₂、R₃及びR₄は前述の通り]
で表される化合物は、前記一般式（３）で表される化合物と一般式（６） [Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above]
The compound represented by the general formula (3) and the compound represented by the general formula (6)

[式中、R₃及びR₄は前述の通り]
で表される化合物を塩基存在下に作用させることによって製造することができる（工程A-2）。 [Wherein R ₃ and R ₄ are as described above]
In the presence of a base (step A-2).

反応は、メタノール、エタノール、１，４−ジオキサン、ジメチルスルホキシド（DMSO）、N,N-ジメチルホルムアミド（DMF）、テトラヒドロフラン（THF）、トルエン、ベンゼン、シクロヘキサン、シクロペンタン、塩化メチレン、クロロホルム，、アセトニトリルなどを反応溶媒として用い、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸カリウムなどの無機塩基存在下、あるいはトリエチルアミンなどの有機塩基の存在下、反応温度としては０℃、好適には常温下にて行うことができる。   Reaction is methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile In the presence of an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate or potassium carbonate, or in the presence of an organic base such as triethylamine, the reaction temperature is 0 ° C., preferably at room temperature. Can be done.

合成経路Aで一般式（５）   In the synthesis route A, the general formula (5)

[式中、R₆は炭素数１〜４の低級アルキル基及びベンジル基を示し、R₁、R₂、R₃及びR₄は前述の通り]
で表される化合物は、前記一般式（４）で表される化合物と一般式（７） [Wherein R ₆ represents a lower alkyl group having 1 to 4 carbon atoms and a benzyl group, and R ₁ , R ₂ , R ₃ and R ₄ are as described above]
The compound represented by the general formula (4) and the compound represented by the general formula (7)

[式中、Xは塩素原子、臭素原子及びヨウ素原子を示し、R₆は前述の通り]
で表される化合物を塩基の存在下に作用させることによって製造することができる（工程A-3）。 [Wherein X represents a chlorine atom, a bromine atom and an iodine atom, and R ₆ is as described above]
Can be produced by acting in the presence of a base (step A-3).

反応は水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシド、リチウムジイソプロピルアミド（LDA）、リチウム−２，２，６，６−テトラメチルピペリジド、リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミドを塩基として用い、反応溶媒としてはTHF、１，４−ジオキサン、１，２−ジメトキシエタンなどを用い、−７８℃〜常温下に行うことができる。   Reaction is sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, lithium diisopropylamide (LDA), lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium Bistrimethylsilylamide can be used as a base, and THF, 1,4-dioxane, 1,2-dimethoxyethane or the like can be used as a reaction solvent, and the reaction can be performed at −78 ° C. to room temperature.

合成経路Aで一般式（１ａ）で表される化合物は、前記一般式（５）で表される化合物を加水分解後にヒドラジンと作用させるか、直接ヒドラジンと作用させることによって製造することができる。   The compound represented by the general formula (1a) in the synthesis route A can be produced by reacting the compound represented by the general formula (5) with hydrazine after hydrolysis or directly with hydrazine.

反応は加水分解を経由する場合、エタノール、メタノール、THF、１，４−ジオキサンなどを溶媒として用い、塩基として水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液などを、０℃〜常温下に作用させ加水分解することが好ましい。得られた加水分解体はベンゼン、トルエン、酢酸、好ましくはエタノールを反応溶媒として用い、常温もしくは好ましくは加熱還流下にヒドラジンと反応させることができる。また直接一般式（５）で表される化合物をヒドラジンと反応させる場合には、酢酸溶媒中、常温〜加熱下に行うことが好ましい。   When the reaction goes through hydrolysis, ethanol, methanol, THF, 1,4-dioxane or the like is used as a solvent, and a sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution or the like is used as a base at 0 ° C. to room temperature. It is preferable to act and hydrolyze. The obtained hydrolyzate can be reacted with hydrazine at room temperature or preferably under heating and reflux using benzene, toluene, acetic acid, preferably ethanol as a reaction solvent. Further, when the compound represented by the general formula (5) is directly reacted with hydrazine, it is preferably carried out in an acetic acid solvent at room temperature to under heating.

＜合成経路B＞   <Synthetic route B>

合成経路Bで一般式（８）   In the synthesis route B, the general formula (8)

[式中、R₇は炭素数１〜４の低級アルキル基を示し、R₁、R₂、R₃及びR₄は前述の通り]
で表される化合物は、前記一般式（４）で表される化合物と一般式（１１） [Wherein R ₇ represents a lower alkyl group having 1 to 4 carbon atoms, and R ₁ , R ₂ , R ₃ and R ₄ are as described above]
The compound represented by general formula (4) and the compound represented by general formula (11)

[式中、R₇は前述の通り]
で表される化合物を塩基の存在下に作用させることによって製造することができる（工程B-1）。 [Wherein R ₇ is as described above]
Can be produced by acting in the presence of a base (step B-1).

反応は、ナトリウムアルコキシド、カリウムアルコキシド、水素化カリウムなどの無機塩基、好ましくは水素化ナトリウムの存在下、一般式（１１）の化合物を溶媒量用い、加熱還流下に行うことが好ましい。   The reaction is preferably carried out with heating under reflux using a compound of the general formula (11) in a solvent amount in the presence of an inorganic base such as sodium alkoxide, potassium alkoxide, potassium hydride, preferably sodium hydride.

合成経路Bで一般式（９）   In the synthesis route B, the general formula (9)

[式中、R₁、R₂、R₃、R₄、R₆及びR₇は前述の通り]
で表される化合物は、前記一般式（８）で表される化合物と一般式（７）で表される化合物を塩基の存在下に作用させることによって製造することができる（工程B-2）。 [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₆ and R ₇ are as described above]
The compound represented by general formula (8) and the compound represented by general formula (7) can be produced in the presence of a base (step B-2). .

反応は水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシド、リチウムジイソプロピルアミド（LDA）、リチウム−２，２，６，６−テトラメチルピペリジド、リチウムビストリメチルシリルアミド、ナトリウムビストリメトリシリルアミド、カリウムビストリメトリシリルアミドを塩基として用い、反応溶媒としてはTHF、１，４−ジオキサン、１，２−ジメトキシエタンなどを用い、−７８℃〜常温下に行うことができる。   The reaction is sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, lithium diisopropylamide (LDA), lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, sodium bistrimethysilylamide, Potassium bistrimethysilylamide is used as a base, and THF, 1,4-dioxane, 1,2-dimethoxyethane or the like is used as a reaction solvent, and the reaction can be performed at −78 ° C. to room temperature.

合成経路Bで一般式（１０）   In the synthesis route B, the general formula (10)

[式中、R₁、R₂、R₃及びR₄は前述の通り]
で表される化合物は上記一般式（９）で表される化合物を加水分解及び脱炭酸させることによって製造することができる（工程B-3）。 [Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above]
Can be produced by hydrolyzing and decarboxylating the compound represented by the general formula (9) (step B-3).

反応は、酸性条件の場合、塩酸または臭化水素酸中にて80〜100℃に加熱して反応を行うか、アルカリ性条件の場合、水酸化ナトリウム水溶液または水酸化カリウム水溶液を用い、メタノールやエタノールなどのアルコール系溶媒や、THF、DMF、DMSOなどの反応溶媒を用い、常温下に加水分解を行った後、酸性にすることによって脱炭酸させることができる。   The reaction is carried out by heating to 80 to 100 ° C. in hydrochloric acid or hydrobromic acid in the case of acidic conditions, or using an aqueous solution of sodium hydroxide or potassium hydroxide in the case of alkaline conditions, using methanol or ethanol. It can be decarboxylated by hydrolyzing at room temperature using an alcohol solvent such as THF, a reaction solvent such as THF, DMF, and DMSO and then acidifying.

合成経路Bで一般式（１ａ）で表される化合物は上記一般式（１０）で表される化合物をヒドラジンと作用させることによって製造することができる（工程B-４）。   In the synthesis route B, the compound represented by the general formula (1a) can be produced by reacting the compound represented by the general formula (10) with hydrazine (step B-4).

反応はヒドラジンとともにベンゼン、トルエン、酢酸、好ましくはエタノールを反応溶媒として用い、常温もしくは好ましくは加熱還流下に行うことができる。   The reaction can be carried out using benzene, toluene, acetic acid, preferably ethanol as a reaction solvent together with hydrazine at room temperature or preferably under heating and reflux.

合成経路Bで（１ａ）合成の中間体である一般式（１０）で表される化合物は、下記合成経路Cによっても製造することができる。   The compound represented by the general formula (10), which is an intermediate of the synthesis in (1a) in the synthesis route B, can also be produced by the following synthesis route C.

＜合成経路C＞ <Synthetic route C>

合成経路Cで一般式（１２）   In the synthesis route C, the general formula (12)

[式中、R₁、R₂、R₃、R₄及びXは前述の通り]
で表される化合物は、一般式（４）で表される化合物をハロゲン化することによって製造することができる（工程C-1）。 [Wherein R ₁ , R ₂ , R ₃ , R ₄ and X are as described above]
Can be produced by halogenating the compound represented by the general formula (4) (step C-1).

反応は、塩化スルフリル、臭素、ヨウ素または、N-クロロコハク酸イミド、N-ブロモコハク酸イミド、N-ヨウドコハク酸イミドを作用させるか、好ましくは塩化第二銅、臭化第二銅、ヨウ化第二銅を用い、THF、１，４−ジオキサン、塩化メチレン、クロロホルム、好ましくは酢酸エチルを溶媒として用い、加熱還流下に行うことができる。   In the reaction, sulfuryl chloride, bromine, iodine, or N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide is reacted, or preferably cupric chloride, cupric bromide, secondary iodide. The reaction can be performed under heating and reflux using copper, THF, 1,4-dioxane, methylene chloride, chloroform, preferably ethyl acetate as a solvent.

合成経路Cで一般式（１３）   In the synthesis route C, the general formula (13)

[式中、R₁、R₂、R₃、R₄及びR₆は前述の通り]
で表される化合物は上記一般式（１２）で表される化合物と一般式（１４） [Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₆ are as described above]
The compound represented by the general formula (12) and the general formula (14)

[式中、R₆は前述の通り]
で表される化合物を塩基の存在下に作用させることによって製造することができる（C-２）。 [Wherein R ₆ is as described above]
Can be produced by acting in the presence of a base (C-2).

反応はナトリウムアルコキシド、カリウムアルコキシド、LDA、リチウム−２，２，６，６−テトラメチルピペリジド、リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミド、水素化カリウムなどの無機塩基、好適には水素化ナトリウムを用い、反応溶媒としてTHF、DMF、１，４−ジオキサン、DMSOなどを用い、常温〜加熱還流下に行うことができる。   Reaction is sodium alkoxide, potassium alkoxide, LDA, lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, inorganic base such as potassium hydride, suitable In this step, sodium hydride is used, and THF, DMF, 1,4-dioxane, DMSO or the like is used as a reaction solvent.

合成経路Cで前述一般式（１０）で表される化合物は、上記一般式（１３）で表される化合物を加水分解することによって製造することができる（工程C-3）。   The compound represented by General Formula (10) in Synthesis Route C can be produced by hydrolyzing the compound represented by General Formula (13) (Step C-3).

反応は水酸化ナトリウム水溶液または水酸化カリウム水溶液を用い、メタノールやエタノールなどのアルコール系溶媒や、THF、DMF、DMSOなどの反応溶媒を用い、常温下に加水分解を行った後、酸性にすることによって脱炭酸させることができる。また、脱炭酸が不十分な場合は得られたジカルボン酸をメタノールやエタノールに溶解させ過熱還流することによって脱炭酸を完了させることができる。   For the reaction, use an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution, use an alcohol solvent such as methanol or ethanol, or a reaction solvent such as THF, DMF, DMSO, etc. Can be decarboxylated. When decarboxylation is insufficient, decarboxylation can be completed by dissolving the obtained dicarboxylic acid in methanol or ethanol and heating to reflux.

合成経路Aで一般式（４）で表される中間化合物、および合成経路Cで一般式（１２）で表される中間化合物は下記合成経路Dによっても製造することができる。   The intermediate compound represented by the general formula (4) in the synthetic route A and the intermediate compound represented by the general formula (12) in the synthetic route C can also be produced by the following synthetic route D.

＜合成経路D＞ <Synthetic route D>

合成経路Dで一般式（１５）   In the synthesis route D, the general formula (15)

[式中、R₁、R₂、R₃及びR₇は前述の通り]
で表される化合物は、前述一般式（３）で表される化合物と一般式（１８） [Wherein R ₁ , R ₂ , R ₃ and R ₇ are as described above]
The compound represented by general formula (3) is the same as the compound represented by general formula (3).

[式中、R₃及びR₇は前述の通り]
で表される化合物を塩基の存在下に作用させるか、または一般式（１９） [Wherein R ₃ and R ₇ are as described above]
Or a compound represented by the general formula (19):

[式中、R₃及びR₇は前述の通り]
で表される化合物を塩基の存在下に作用させることによって製造することができる（工程D-1）。 [Wherein R ₃ and R ₇ are as described above]
Can be produced by acting in the presence of a base (step D-1).

反応は、一般式（１８）との場合、メタノール、エタノール、１，４−ジオキサン、DMSO、DMF、THF、トルエン、ベンゼン、シクロヘキサン、シクロペンタン、塩化メチレン、クロロホルム、アセトニトリルなどを反応溶媒として用い、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸カリウムなどの無機塩基存在下、あるいはトリエチルアミンなどの有機塩の存在下に、反応温度としては０℃、好適には常温下にて行うことができる。   In the case of the general formula (18), the reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. as a reaction solvent. In the presence of an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate or potassium carbonate, or in the presence of an organic salt such as triethylamine, the reaction can be carried out at 0 ° C., preferably at room temperature.

また一般式（１９）との反応の場合は、一般にはエタノールを溶媒として用い、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸カリウムなどの無機塩基存在下、反応温度としては常温〜８０℃に加熱して行うことができる。また（１９）が水溶性の場合、水を溶媒として用いて同様に反応させることもできる。   In the case of the reaction with the general formula (19), ethanol is generally used as a solvent, and the reaction temperature is from room temperature to 80 ° C. in the presence of an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate. It can be performed by heating. Moreover, when (19) is water-soluble, it can be made to react similarly using water as a solvent.

合成経路Dで一般式（１６）   In the synthesis route D, the general formula (16)

[式中、R₁、R₂及びR₃は前述の通り]
で表される化合物は、上記一般式（１５）で表される化合物を脱炭酸させることによって製造することができる（工程D-2）。 [Wherein R ₁ , R ₂ and R ₃ are as described above]
Can be produced by decarboxylation of the compound represented by the general formula (15) (step D-2).

反応は、塩酸、臭化水素酸、または５０％硫酸中にて加熱還流し加水分解と同時に脱炭酸するか、水酸化ナトリウム水溶液、水酸化カリウム水溶液を用い、メタノールやエタノールなどのアルコール系溶媒や、THF、DMF、DMSOなどの反応溶媒を用い、常温下に加水分解を行いカルボン酸へと変換した後、塩酸または臭化水素酸中で加熱還流するか、エタノール中、触媒量の濃硫酸を加え加熱還流し脱炭酸することができる。   The reaction is heated to reflux in hydrochloric acid, hydrobromic acid, or 50% sulfuric acid and decarboxylated at the same time as hydrolysis, or using an aqueous solution of sodium hydroxide or aqueous potassium hydroxide, an alcoholic solvent such as methanol or ethanol, , Using a reaction solvent such as THF, DMF, DMSO, etc. to convert to carboxylic acid by hydrolysis at room temperature, then heating to reflux in hydrochloric acid or hydrobromic acid, or adding a catalytic amount of concentrated sulfuric acid in ethanol. In addition, it can be heated to reflux for decarboxylation.

合成経路Dで一般式（４）で表される化合物は、上記一般式（１６）で表される化合物を一般式（２０）   In the synthesis route D, the compound represented by the general formula (4) is the same as the compound represented by the general formula (16).

[式中、R₄及びXは前述の通り]
で表される化合物と作用させるか、または一般式（２１） [Wherein R ₄ and X are as described above]
Or a compound represented by the general formula (21)

[式中、R₄は前述の通り]
で表される化合物を酸触媒の存在下に作用させることによって製造することができる（工程D-３）。 [Wherein R ₄ is as described above]
Can be produced by acting in the presence of an acid catalyst (step D-3).

反応は、一般式（２０）との場合、塩化アルミニウム、塩化亜鉛などのルイス酸の存在下、反応溶媒としては塩化メチレン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、１，１，２，２−テロラクロロエタンなどを用い、反応温度は０〜５０℃にて行うことができる。またルイス酸非存在下、無溶媒にて５０〜１００℃に加熱して行うこともできる。   In the case of the general formula (20), the reaction is carried out in the presence of a Lewis acid such as aluminum chloride or zinc chloride, and as a reaction solvent, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2, The reaction temperature can be 0 to 50 ° C. using 2-terolachloroethane or the like. It can also be carried out by heating to 50 to 100 ° C. without solvent in the absence of Lewis acid.

また一般式（２１）との反応の場合、濃硫酸を酸触媒として無溶媒下に１００〜１２０℃にて加熱する方法が好ましい。   Moreover, in the case of reaction with General formula (21), the method of heating at 100-120 degreeC without a solvent using concentrated sulfuric acid as an acid catalyst is preferable.

合成経路Dで一般式（１７）   In the synthesis route D, the general formula (17)

[式中、R₁、R₂及びR₃は前述の通り]
で表される化合物は、一般式（１５）の化合物を加水分解した後、N,O-ジメチルヒドロキシアミンを縮合させることによって製造することができる（工程D-４）。 [Wherein R ₁ , R ₂ and R ₃ are as described above]
Can be produced by hydrolyzing the compound of the general formula (15) and then condensing N, O-dimethylhydroxyamine (step D-4).

反応は、水酸化ナトリウム水溶液、水酸化カリウム水溶液を用い、メタノールやエタノールなどのアルコール系溶媒や、THF、DMF、DMSOなどの反応溶媒を用い、常温下に加水分解を行いカルボン酸へと変換した後、N,O-ジメチルヒドロキシアミンとトリエチルアミン、ピリジンなどの有機塩基の存在下、ジシクロヘキシルカルボジイミド（DCC）、ジイソプロピルカルボジイミド（DIPC）、ジフェニルホスホリルアジド（DPPA）、ジエチルホスホリルシアニド（DEPC）、１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド（WSC）などの縮合剤を用い、場合によっては４−ジメチルアミノピリジン（DMAP）を触媒として加え、反応溶媒としてはTHF、塩化メチレン、DMSO、DMFなどを用い、反応温度としては０℃〜常温下にて行うことができる。   The reaction was converted to a carboxylic acid by hydrolysis at room temperature using an aqueous solution of sodium hydroxide or aqueous potassium hydroxide, an alcohol solvent such as methanol or ethanol, or a reaction solvent such as THF, DMF, or DMSO. Then, in the presence of organic bases such as N, O-dimethylhydroxyamine and triethylamine, pyridine, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), 1- Using a condensing agent such as ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), optionally adding 4-dimethylaminopyridine (DMAP) as a catalyst, THF, methylene chloride, DMSO, The reaction temperature can be 0 ° C. to room temperature using DMF or the like.

合成経路Dで一般式（４）で表される化合物は、上記一般式（１７）で表される化合物と一般式（２２）   The compound represented by the general formula (4) in the synthesis route D includes the compound represented by the general formula (17) and the general formula (22).

[式中、MはLi、MgCl、MgBr、MgIを示し、R₄は前述の通り]
で表される化合物を作用させることによって製造することができる（工程D-５）。 [Wherein, M represents Li, MgCl, MgBr, MgI, and R ₄ is as described above]
It can manufacture by making the compound represented by act (process D-5).

反応はTHF、１，４−ジオキサンを反応溶媒として用い、反応温度としては-78℃〜常温下に行うことができる。   The reaction can be carried out using THF and 1,4-dioxane as a reaction solvent at a reaction temperature of −78 ° C. to room temperature.

合成経路Dで一般式（１２）で表される化合物は、前記一般式（１６）で表される化合物と、一般式（２３）   The compound represented by the general formula (12) in the synthesis route D includes the compound represented by the general formula (16) and the general formula (23).

[式中、X及びR₄は前述の通り]
で表される化合物を作用させることによって製造することができる（工程D-6）。 [Wherein X and R ₄ are as described above]
It can manufacture by making the compound represented by act (step D-6).

反応は、塩化アルミニウム、塩化亜鉛などのルイス酸の存在下、反応溶媒としては塩化メチレン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、１，１，２，２−テロラクロロエタンなどを用い、反応温度は０〜５０℃にて行うことができる。またルイス酸非存在下、無溶媒にて50〜100℃に加熱して行うこともできる。   The reaction is carried out using methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-terolachloroethane, etc. as the reaction solvent in the presence of a Lewis acid such as aluminum chloride or zinc chloride. Temperature can be performed at 0-50 degreeC. It can also be carried out by heating to 50 to 100 ° C. without solvent in the absence of Lewis acid.

前述合成経路Bで一般式（８）で表される化合物は、下記合成経路Eによっても製造することができる。   The compound represented by the general formula (8) in the aforementioned synthesis route B can also be produced by the following synthesis route E.

＜合成経路E＞ <Synthetic route E>

合成経路Eで一般式（２４）   In the synthesis route E, the general formula (24)

[式中、R₁、R₂及びR₃は前述の通り]
で表される化合物は前記一般式（３）、（１６）及び（１７）から製造することができる。 [Wherein R ₁ , R ₂ and R ₃ are as described above]
Can be produced from the general formulas (3), (16) and (17).

一般式（３）からの場合、一般式（２６）   In the case of the general formula (3), the general formula (26)

[式中、R₃は前述の通り]
で表される化合物と反応させることによって製造することができる（工程E−１）。 [Wherein R ₃ is as described above]
It can manufacture by making it react with the compound represented by (process E-1).

反応は、メタノール、エタノール、１，４−ジオキサン、DMSO、DMF、THF、トルエン、ベンゼン、シクロヘキサン、シクロペンタン、塩化メチレン、クロロホルム、アセトニトリルなどを反応溶媒として用い、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸カリウムなどの無機塩基存在下、あるいはトリエチルアミンなどの有機塩基の存在下に、反応温度としては０℃、好適には常温下にて行うことができる。   For the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. are used as the reaction solvent. Sodium bicarbonate, sodium carbonate, bicarbonate The reaction can be carried out in the presence of an inorganic base such as potassium or potassium carbonate, or in the presence of an organic base such as triethylamine, at a reaction temperature of 0 ° C., preferably at room temperature.

また、一般式（１６）からの場合は、アセチルクロライド、アセチルブロマイドまたは無水酢酸と作用させることによって製造することができる（工程E-2）。   In the case of general formula (16), it can be produced by reacting with acetyl chloride, acetyl bromide or acetic anhydride (step E-2).

反応は、酸ハライドとの場合、塩化アルミニウム、塩化亜鉛などのルイス酸の存在下、反応溶媒としては塩化メチレン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、１，１，２，２−テロラクロロエタンなどを用い、反応温度は０〜５０℃にて行うことができる。またルイス酸非存在下、無溶媒にて50〜100℃に加熱して行うこともできる。   In the case of an acid halide, the reaction is carried out in the presence of a Lewis acid such as aluminum chloride or zinc chloride, and as a reaction solvent, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-telola. Using chloroethane or the like, the reaction temperature can be 0 to 50 ° C. It can also be carried out by heating to 50 to 100 ° C. without solvent in the absence of Lewis acid.

酸無水物との反応の場合、濃硫酸を酸触媒として無溶媒下に100〜120℃にて加熱する方法が好ましい。   In the case of a reaction with an acid anhydride, a method in which concentrated sulfuric acid is used as an acid catalyst and heated at 100 to 120 ° C. without solvent is preferred.

さらに一般式（１７）からの場合、メチルリチウム、メチルマグネシウムクロリド、メチルマグネシウムブロミドを作用させることによって製造することができる（工程E-3）。   Furthermore, in the case of general formula (17), it can be produced by reacting methyllithium, methylmagnesium chloride, and methylmagnesium bromide (step E-3).

反応はTHF、１，４−ジオキサンを反応溶媒として用い、反応温度としては-78℃〜常温下に行うことができる。   The reaction can be carried out using THF and 1,4-dioxane as a reaction solvent at a reaction temperature of −78 ° C. to room temperature.

合成経路Eで一般式（２５）   In the synthesis route E, the general formula (25)

[式中、R₁、R₂、R₃及びR₇は前述の通り]
で表される化合物は、上記一般式（２４）で表される化合物と前記一般式（１１）で表される化合物を塩基の存在下に作用させることによって製造することができる（工程E-4）。 [Wherein R ₁ , R ₂ , R ₃ and R ₇ are as described above]
The compound represented by general formula (24) and the compound represented by general formula (11) can be produced in the presence of a base (step E-4). ).

反応は、ナトリウムアルコキシド、カリウムアルコキシド、水素化カリウムなどの無機塩基、好ましくは水素化ナトリウムの存在下、一般式（１１）の化合物を溶媒量用い、加熱還流下に行うことが好ましい。   The reaction is preferably carried out with heating under reflux using a compound of the general formula (11) in a solvent amount in the presence of an inorganic base such as sodium alkoxide, potassium alkoxide, potassium hydride, preferably sodium hydride.

合成経路Eで一般式（８）で表される化合物は、上記一般式（２５）で表される化合物に前記一般式（７）で表される化合物と一般式（２７）   In the synthesis route E, the compound represented by the general formula (8) includes the compound represented by the general formula (7) and the compound represented by the general formula (25).

[式中、R₄及びXは前述の通り]
で表される化合物を塩基の存在下に作用させることによって製造することができる（工程E-５）。 [Wherein R ₄ and X are as described above]
In the presence of a base (Step E-5).

反応は、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシド、リチウムジイソプロピルアミド（LDA）、リチウム−２，２，６，６−テトラメチルピペリジド、リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミドを塩基として用い、反応溶媒としてはTHF、１，４−ジオキサン、１，２−ジメトキシエタンなどを用い、−７８℃〜常温下にて一般式（９）で表される化合物と反応させた後、同様にして再度塩基処理を行い一般式（２７）で表される化合物を次に反応させることができる。また、化合物の反応順序を逆にしてもよいし、各々の反応を連続的に行うのでなく、一段階ごとに反応を進める手法でも行える。   The reaction includes sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, lithium diisopropylamide (LDA), lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, Using potassium bistrimethylsilylamide as a base, THF, 1,4-dioxane, 1,2-dimethoxyethane or the like as a reaction solvent, and a compound represented by the general formula (9) at −78 ° C. to room temperature After the reaction, the base treatment is performed again in the same manner, and the compound represented by the general formula (27) can be reacted next. Further, the reaction order of the compounds may be reversed, and each reaction may be performed not only continuously but also by a method in which the reaction is advanced step by step.

前述一般式（４）で表される化合物の中、Ｒ₃、Ｒ₄が炭素数１〜４の低級アルキル基で次式一般式（２８） Among the compounds represented by the general formula (4), R ₃ and R ₄ are lower alkyl groups having 1 to ₄ carbon atoms, and the following general formula (28)

[式中、R₁、R₂及びR₇は前述の通り]
で表される化合物は、下記合成経路Ｆによっても製造することができる。 [Wherein R ₁ , R ₂ and R ₇ are as described above]
The compound represented by can also be manufactured by the following synthetic pathway F.

＜合成経路Ｆ＞ <Synthesis route F>

合成経路Ｆで一般式（３０）   In the synthesis route F, the general formula (30)

[式中、Ｒ₁及びＲ₂は前述の通り]
で表される化合物は一般式（２９） [Wherein R ₁ and R ₂ are as described above]
The compound represented by general formula (29)

[式中、Ｒ₁及びＲ₂は前述の通り]
で表される化合物をMSHと作用させることによって製造することができる（工程Ｆ-1）。 [Wherein R ₁ and R ₂ are as described above]
Can be produced by reacting with MSH (step F-1).

反応は（２９）を塩化メチレンに溶解させ、０℃〜常温下にてMSHの塩化メチレン溶液を作用させることが好ましい。   In the reaction, (29) is preferably dissolved in methylene chloride, and a methylene chloride solution of MSH is allowed to act at 0 ° C. to room temperature.

合成経路Ｆで前記一般式（２８）で表される化合物は上記一般式（３０）で表される化合物と一般式（３１）   In the synthesis route F, the compound represented by the general formula (28) is the same as the compound represented by the general formula (30) and the general formula (31).

[式中、Ｒ₇は前述の通り]
で表される化合物を反応させることによって製造することができる（工程Ｆ−２）。 [Wherein R ₇ is as described above]
It can manufacture by making the compound represented by (process F-2) react.

反応は、ピリジン溶媒中、場合によっては炭酸カリウムを加え加熱還流下に行うことが望ましい。   The reaction is desirably carried out in a pyridine solvent, optionally with potassium carbonate, with heating under reflux.

前述合成経路Ａで一般式（５）で表される化合物は前記一般式（３）で表される化合物と一般式（３２）   In the synthesis route A, the compound represented by the general formula (5) is the same as the compound represented by the general formula (3) and the general formula (32).

[Ｒ₃、Ｒ₄及びＲ₆は前述の通り]
で表される化合物と塩基の存在下に反応させることによっても製造することができる。 [R ₃ , R ₄ and R ₆ are as described above]
It can also manufacture by making it react with the compound represented by presence of a base.

反応は、メタノール、エタノール、１，４−ジオキサン、DMSO、DMF、THF、トルエン、ベンゼン、シクロヘキサン、シクロペンタン、塩化メチレン、クロロホルム、アセトニトリルなどを反応溶媒として用い、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸カリウムなどの無機塩基存在下、あるいはトリエチルアミンなどの有機塩基の存在下に、反応温度としては０℃、好適には常温下にて行うことができる。   For the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. are used as the reaction solvent. Sodium bicarbonate, sodium carbonate, bicarbonate The reaction can be carried out in the presence of an inorganic base such as potassium or potassium carbonate, or in the presence of an organic base such as triethylamine, at a reaction temperature of 0 ° C., preferably at room temperature.

一般式（１）で表される化合物の中、- -が単結合である化合物、即ち一般式（１ｂ）   Among the compounds represented by the general formula (1), a compound in which-is a single bond, that is, the general formula (1b)

[式中、R₁、R₂、R₃、Ｒ₄及びＲ₅は前述の通り]
で表される化合物は前記一般式（１ａ）で表される化合物と一般式（３３） [Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above]
The compound represented by the general formula (1a) and the compound represented by the general formula (33)

[式中、Ｒ₅及びＸは前述の通り]
で表される化合物を塩基の存在下に反応させることによって製造することができる。 [Wherein R ₅ and X are as described above]
Can be produced by reacting in the presence of a base.

反応は、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシドを塩基として用い、反応溶媒としてＴＨＦまたはＤＭＦを用いて０〜６０℃にて行うことが望ましい。   The reaction is desirably performed at 0 to 60 ° C. using sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide as a base and THF or DMF as a reaction solvent.

一般式（１）でＲ₅が水素原子で、- -が二重結合である化合物、即ち一般式（１ｃ） A compound in which R ₅ is a hydrogen atom and − − is a double bond in the general formula (1), that is, the general formula (1c)

[式中、R₁、R₂、R₃及びＲ₄は前述の通り]
で表される化合物は前記一般式（１ａ）で表される化合物を酸化することによって製造することができる。 [Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above]
The compound represented by can be produced by oxidizing the compound represented by the general formula (1a).

反応は酢酸溶媒中、臭素を作用させ５０〜６０℃にて反応させるか、アセトニトリル中、塩化銅（II）を常温〜加熱下に反応させることができる。また、ｍ−ニトロベンゼンスルホン酸ナトリウムを0.5mol/L水酸化ナトリウム水溶液中にて常温下〜加熱還流下に作用させることによっても製造することができる。   The reaction can be carried out by reacting bromine in an acetic acid solvent at 50 to 60 ° C., or copper (II) chloride in acetonitrile at room temperature to heating. It can also be produced by allowing sodium m-nitrobenzenesulfonate to act in a 0.5 mol / L aqueous sodium hydroxide solution at room temperature to under reflux with heating.

一般式（１）で- -が二重結合である化合物、即ち一般式（１ｄ）   A compound in which-is a double bond in the general formula (1), that is, the general formula (1d)

[式中、R₁、R₂、R₃、Ｒ₄及びＲ₅は前述の通り]
で表される化合物は前記一般式（１ｂ）で表される化合物を酸化することによって製造することができる。 [Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above]
Can be produced by oxidizing the compound represented by the general formula (1b).

反応は酢酸溶媒中、臭素を作用させ５０〜６０℃にて反応させるか、アセトニトリル中、塩化銅（II）を常温〜加熱下に反応させることができる。また、ｍ−ニトロベンゼンスルホン酸ナトリウムを0.5mol/L水酸化ナトリウム水溶液中にて常温下〜加熱還流下に作用させることによっても製造することができる。   The reaction can be carried out by reacting bromine in an acetic acid solvent at 50 to 60 ° C., or copper (II) chloride in acetonitrile at room temperature to heating. It can also be produced by allowing sodium m-nitrobenzenesulfonate to act in a 0.5 mol / L aqueous sodium hydroxide solution at room temperature to under reflux with heating.

次に本発明を具体例によって説明するが、これらの例によって本発明が限定されるものではない。 Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

＜実施例１＞
N-アミノ−３−クロロピリジニウムメシチレンスルホネート <Example 1>
N-amino-3-chloropyridinium mesitylene sulfonate

Ｎ−ヒドロキシアセトイミド酸エチル(47.2g) のDMF(200mL)溶液を０℃にて撹拌下、トリエチルアミン(70mL)、ついでメシチレンスルホニルクロリド(100g)をゆっくりと加えた。同温にて1.5時間撹拌後、氷水を加え、酢酸エチル：ヘキサン＝１：１の混液にて抽出後、水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥後、濃縮し無色固形物を得た。得られた固形物をジオキサン(100mL)に溶解し、０℃冷却撹拌下に70%HClO₄(40mL)をゆっくりと滴下した。滴下後、同温にて30分撹拌し、氷水を加え析出物を濾取し（注意：この固形物を完全に乾燥状態にしてしまうと爆発する）、水洗後ぬれた状態のままで塩化メチレン約300mLに溶解し、有機層を分取後、硫酸マグネシウムで乾燥した。３−クロロピリジン(43.0g)の塩化メチレン(40mL)溶液を０℃にて撹拌下、上記の硫酸マグネシウムで乾燥した塩化メチレン溶液に滴下した。その後、常温にて30分撹拌し約350mLのエーテルを加え、析出した結晶を濾取した。エーテルにて洗浄後、乾燥物(69.0g)を無色粉末として得た。
元素分析（％）：C₁₄H₁₇ClN₂O₃Sとして
C H N
計算値 51.14 5.21 8.52
実測値 51.20 5.10 8.47 While stirring a solution of ethyl N-hydroxyacetimidate (47.2 g) in DMF (200 mL) at 0 ° C., triethylamine (70 mL) and then mesitylenesulfonyl chloride (100 g) were slowly added. After stirring at the same temperature for 1.5 hours, ice water was added, and the mixture was extracted with a mixed solution of ethyl acetate: hexane = 1: 1, washed with water and then saturated brine, dried over anhydrous sodium sulfate, and concentrated to a colorless solid. Got. The obtained solid was dissolved in dioxane (100 mL), and 70% HClO ₄ (40 mL) was slowly added dropwise with stirring at 0 ° C. After dropwise addition, the mixture is stirred at the same temperature for 30 minutes, ice water is added, and the precipitate is collected by filtration (Caution: If this solid is completely dried, it explodes). After washing with water, methylene chloride remains wet. After dissolving in about 300 mL, the organic layer was separated and dried over magnesium sulfate. A solution of 3-chloropyridine (43.0 g) in methylene chloride (40 mL) was added dropwise to the methylene chloride solution dried over magnesium sulfate with stirring at 0 ° C. Thereafter, the mixture was stirred at room temperature for 30 minutes, about 350 mL of ether was added, and the precipitated crystals were collected by filtration. After washing with ether, a dried product (69.0 g) was obtained as a colorless powder.
Elemental analysis (%): as C ₁₄ H ₁₇ ClN ₂ O ₃ S
CHN
Calculated 51.14 5.21 8.52
Actual value 51.20 5.10 8.47

＜実施例２−７＞
３−フルオロピリジン、３，５−ジフルオロピリジン、３，５−ジクロロピリジン、３−メトキシピリジン、３−クロロ−５−メトキシピリジン、５−クロロ−α−ピコリンを用いて上記実施例と同様に反応させ表１に示す化合物を合成した。 <Example 2-7>
Reaction similar to the above Example using 3-fluoropyridine, 3,5-difluoropyridine, 3,5-dichloropyridine, 3-methoxypyridine, 3-chloro-5-methoxypyridine, 5-chloro-α-picoline The compounds shown in Table 1 were synthesized.

実施例２：¹H-NMR (400 MHz, DMSO-d₆) δ 2.17 (3H, s), 2.49 (6H, s), 6.74 (2H, s), 8.05-8.11 (1H, m), 8.28-8.32 (1H, m), 8.68 (1H, t, J=6.4Hz), 8.71(2H, br s), 9.06-9.08(1H, m). Example 2: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.49 (6H, s), 6.74 (2H, s), 8.05-8.11 (1H, m), 8.28- 8.32 (1H, m), 8.68 (1H, t, J = 6.4Hz), 8.71 (2H, br s), 9.06-9.08 (1H, m).

実施例３：¹H-NMR (400 MHz, DMSO-d₆) δ 2.16 (3H, s), 2.48 (3H, s), 2.49(6H, s), 6.73 (2H, br s), 8.59-8.65 (1H, m), 8.91 (2H, br s), 9.00-9.01(2H, m). Example 3: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.16 (3H, s), 2.48 (3H, s), 2.49 (6H, s), 6.73 (2H, br s), 8.59-8.65 (1H, m), 8.91 (2H, br s), 9.00-9.01 (2H, m).

実施例４：¹H-NMR (400 MHz, DMSO-d₆) δ 2.16 (3H, s), 2.48 (3H, s), 2.49(6H, s), 6.73 (2H, br s), 8.71 (2H, br s), 8.78-8.79 (1H, m), 9.01-9.02(1H, m). Example 4: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.16 (3H, s), 2.48 (3H, s), 2.49 (6H, s), 6.73 (2H, br s), 8.71 (2H , br s), 8.78-8.79 (1H, m), 9.01-9.02 (1H, m).

実施例５：¹H-NMR (400 MHz, DMSO-d₆) δ 2.17 (3H, s), 2.49 (6H, s), 3.98(3H, s), 6.74 (2H, s), 8.20-8.21 (1H, m), 8.58 (2H, br s), 8.59-8.60(1H, m), 8.67-8.68(1H, m). Example 5: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.49 (6H, s), 3.98 (3H, s), 6.74 (2H, s), 8.20-8.21 ( 1H, m), 8.58 (2H, br s), 8.59-8.60 (1H, m), 8.67-8.68 (1H, m).

実施例７：¹H-NMR (400 MHz, DMSO-d₆) δ 2.17 (3H, s), 2.49 (6H, s), 2.68(3H, s), 6.74 (2H, s), 8.00 (1H, d, J = 8.7 Hz), 8.38 (1H, dd, J=8.7, 1.8Hz), 9.04(1H, d, J=1.8Hz). Example 7: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.49 (6H, s), 2.68 (3H, s), 6.74 (2H, s), 8.00 (1H, d, J = 8.7 Hz), 8.38 (1H, dd, J = 8.7, 1.8Hz), 9.04 (1H, d, J = 1.8Hz).

＜実施例８＞
６−クロロ−２−エチル−３−プロピオニル−ピラゾロ[１，５−ａ]ピリジン <Example 8>
6-Chloro-2-ethyl-3-propionyl-pyrazolo [1,5-a] pyridine

３−ヘプチン−５−オン（18.8 g）および実施例１の化合物（84.2 g）をトルエン（450 mL）およびTHF（50mL）に溶解し、そこに炭酸カリウム（70.9 g）を少量ずつ加えていき、常温にて70時間攪拌した。その後、反応液にDMF（50mL）を加え、さらに常温にて98時間攪拌した。反応液を氷水中に注いだ後、ヘキサン：酢酸エチル ＝ 1：1で抽出し、有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 19：1）にて精製し、目的物（14.7 g）を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.25 (3H, t, J = 7.3 Hz), 1.39 (3H, t, J = 7.3 Hz), 2.91 (2H, q, J = 7.3 Hz), 3.12 (2H, q, J = 7.3 Hz), 7.37 (1H, dd, J = 1.8, 9.8 Hz), 8.18 (1H, d, J = 9.8 Hz), 8.49-8.50 (1H, m)
LRMS (EI+): 236 [M+] 3-Heptin-5-one (18.8 g) and the compound of Example 1 (84.2 g) were dissolved in toluene (450 mL) and THF (50 mL), and potassium carbonate (70.9 g) was gradually added thereto. The mixture was stirred at room temperature for 70 hours. Thereafter, DMF (50 mL) was added to the reaction solution, and the mixture was further stirred at room temperature for 98 hours. The reaction solution was poured into ice water, and extracted with hexane: ethyl acetate = 1: 1. The organic layer was washed with water and then saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain the desired product (14.7 g) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (3H, t, J = 7.3 Hz), 1.39 (3H, t, J = 7.3 Hz), 2.91 (2H, q, J = 7.3 Hz), 3.12 ( 2H, q, J = 7.3 Hz), 7.37 (1H, dd, J = 1.8, 9.8 Hz), 8.18 (1H, d, J = 9.8 Hz), 8.49-8.50 (1H, m)
LRMS (EI +): 236 [M +]

＜実施例９〜27＞
実施例１〜７の化合物を用い、各種アルキン誘導体と反応させ表２に示す化合物を得た。 <Examples 9 to 27>
Using the compounds of Examples 1 to 7 and reacting with various alkyne derivatives, the compounds shown in Table 2 were obtained.

実施例９：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.36(6H, d, J=6.7Hz), 3.79-3.86(1H, m), 5.38(2H, s), 7.29(1H, dd, J=1.8, 9.5Hz), 7.35-7.47(5H, m), 8.01(1H, dd, J=0.6, 9.5Hz), 8.50(1H, dd, J=0.6, 1.8Hz) Example 9: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (6H, d, J = 6.7Hz), 3.79-3.86 (1H, m), 5.38 (2H, s), 7.29 (1H, dd, J = 1.8, 9.5Hz), 7.35-7.47 (5H, m), 8.01 (1H, dd, J = 0.6, 9.5Hz), 8.50 (1H, dd, J = 0.6, 1.8Hz)

実施例10：淡黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.40 (3H, t, J = 7.3 Hz), 2.59 (3H, s), 3.12 (2H, q, J = 7.3 Hz), 7.38 (1H, dd, J = 1.8, 9.2 Hz), 8.19 (1H, d, J = 9.2 Hz), 8.50 (1H, d, J = 1.8 Hz) Example 10: Pale yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.59 (3H, s), 3.12 (2H, q, J = 7.3 Hz), 7.38 (1H, dd, J = 1.8, 9.2 Hz), 8.19 (1H, d, J = 9.2 Hz), 8.50 (1H, d, J = 1.8 Hz)

実施例11：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.35(3H, t, J=7.6Hz), 1.43(3H, t, J=7.0Hz), 3.11(2H, q, J=7.6Hz), 4.39(2H, q, J=7.0Hz), 7.32(1H, dd, J=1.8, 9.5Hz), 8.05(1H, dd, J=0.9, 9.5Hz), 8.48(1H, dd, J=0.9, 1.8Hz) Example 11: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, t, J = 7.6Hz), 1.43 (3H, t, J = 7.0Hz), 3.11 (2H, q, J = 7.6Hz), 4.39 ( 2H, q, J = 7.0Hz), 7.32 (1H, dd, J = 1.8, 9.5Hz), 8.05 (1H, dd, J = 0.9, 9.5Hz), 8.48 (1H, dd, J = 0.9, 1.8Hz )

実施例12：淡黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 2.67 (3H, s), 3.92 (3H, s), 7.33 (1H, dd, J = 1.8, 9.2 Hz), 8.04 (1H, d, J = 9.2 Hz), 8.46 (1H, d, J = 1.8 Hz) Example 12: Pale yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.67 (3H, s), 3.92 (3H, s), 7.33 (1H, dd, J = 1.8, 9.2 Hz), 8.04 (1H, d, J = 9.2 Hz ), 8.46 (1H, d, J = 1.8 Hz)

実施例13：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.30 (3H, t, J = 7.3 Hz), 4.44 (2H, q, J = 7.3 Hz), 7.48 (1H, dd, J = 1.8, 9.8 Hz), 8.25 (1H, d, J = 9.8 Hz), 8.59 (1H, brs) Example 13: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.30 (3H, t, J = 7.3 Hz), 4.44 (2H, q, J = 7.3 Hz), 7.48 (1H, dd, J = 1.8, 9.8 Hz), 8.25 (1H, d, J = 9.8 Hz), 8.59 (1H, brs)

実施例14：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.06 (3H, t, J = 7.3 Hz), 1.25 (3H, t, J = 7.3 Hz), 1.77-1.88 (2H, m), 2.91 (2H, q, J = 7.3 Hz), 3.04-3.08 (2H, m), 7.37 (1H, dd, J = 1.8, 9.2 Hz), 8.18 (1H, d, J = 9.2 Hz), 8.49 (1H, d, J = 1.8 Hz) Example 14: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.06 (3H, t, J = 7.3 Hz), 1.25 (3H, t, J = 7.3 Hz), 1.77-1.88 (2H, m), 2.91 (2H, q , J = 7.3 Hz), 3.04-3.08 (2H, m), 7.37 (1H, dd, J = 1.8, 9.2 Hz), 8.18 (1H, d, J = 9.2 Hz), 8.49 (1H, d, J = 1.8 Hz)

実施例15：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 2.56 (3H, s), 7.45 (1H, dd, J = 1.8, 9.2 Hz), 8.34 (1H, s), 8.35 (1H, d, J = 9.2 Hz), 8.59 (1H, d, J = 1.8 Hz) Example 15: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.56 (3H, s), 7.45 (1H, dd, J = 1.8, 9.2 Hz), 8.34 (1H, s), 8.35 (1H, d, J = 9.2 Hz ), 8.59 (1H, d, J = 1.8 Hz)

実施例16：橙色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.04-1.10 (2H, m), 1.27-1.32 (2H, m), 2.79-2.86 (1H, m), 5.40 (2H, s), 7.28-7.47 (6H, m), 7.97 (1H, d, J = 8.6 Hz), 8.39 (1H, d, J = 1.8 Hz) Example 16: Orange powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.04-1.10 (2H, m), 1.27-1.32 (2H, m), 2.79-2.86 (1H, m), 5.40 (2H, s), 7.28-7.47 ( 6H, m), 7.97 (1H, d, J = 8.6 Hz), 8.39 (1H, d, J = 1.8 Hz)

実施例17：淡黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.32(3H, t, J=7.0Hz), 1.40(3H, t, J=7.0Hz), 3.01(2H, q, J=7.0Hz), 3.96(3H, s), 4.36(2H, q, J=7.0Hz), 6.57(1H, d, J=1.5Hz), 8.12-8.13(1H, m) Example 17: Pale yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32 (3H, t, J = 7.0Hz), 1.40 (3H, t, J = 7.0Hz), 3.01 (2H, q, J = 7.0Hz), 3.96 ( 3H, s), 4.36 (2H, q, J = 7.0Hz), 6.57 (1H, d, J = 1.5Hz), 8.12-8.13 (1H, m)

実施例18：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.36(6H, d, J=7.0Hz), 3.80-3.87(1H, m), 5.38(2H, s), 7.20-7.27(1H, m), 7.32-7.47(5H, m), 8.05(1H, dd, J=5.8, 9.8Hz), 8.39-8.41(1H, m) Example 18: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (6H, d, J = 7.0Hz), 3.80-3.87 (1H, m), 5.38 (2H, s), 7.20-7.27 (1H, m), 7.32 -7.47 (5H, m), 8.05 (1H, dd, J = 5.8, 9.8Hz), 8.39-8.41 (1H, m)

実施例19：異性体との分離ができないため未精製のまま次工程へ Example 19: Since it cannot be separated from the isomer, the next step is left unpurified.

実施例20：淡黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.35(3H, t, J=7.6Hz), 1.43(3H, t, J=7.0Hz), 3.11(2H, q, J=7.6Hz), 4.39(2H, q, J=7.0Hz), 7.26-7.31(1H, m), 8.08-8.12(1H, m), 8.37-8.40(1H, m) Example 20: Pale yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, t, J = 7.6Hz), 1.43 (3H, t, J = 7.0Hz), 3.11 (2H, q, J = 7.6Hz), 4.39 ( 2H, q, J = 7.0Hz), 7.26-7.31 (1H, m), 8.08-8.12 (1H, m), 8.37-8.40 (1H, m)

実施例21：褐色油状物
¹H-NMR (400 MHz, CDCl₃) δ 1.22(3H, d, J=7.0Hz), 1.24-1.28(6H, m), 2.45(1H, dd, J=5.8, 16.5Hz), 2.97(1H, dd, J=8.3, 16.5Hz), 3.64(3H, s), 3.66-3.81(4H, m), 4.07-4.15(1H, m), 6.08(1H, s), 7.40(1H, dd, J=1.8, 9.8Hz), 8.29(1H, dd, J=0.6, 9.8Hz), 8.56(1H, dd, J=0.6, 1.8Hz) Example 21: Brown oil
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22 (3H, d, J = 7.0Hz), 1.24-1.28 (6H, m), 2.45 (1H, dd, J = 5.8, 16.5Hz), 2.97 (1H , dd, J = 8.3, 16.5Hz), 3.64 (3H, s), 3.66-3.81 (4H, m), 4.07-4.15 (1H, m), 6.08 (1H, s), 7.40 (1H, dd, J = 1.8, 9.8Hz), 8.29 (1H, dd, J = 0.6, 9.8Hz), 8.56 (1H, dd, J = 0.6, 1.8Hz)

実施例22：黄色油状物
¹H-NMR (400 MHz, CDCl₃) δ 0.12(3H, s), 0.14(3H, s), 0.92(9H, s), 1.24(3H, d, J=7.0Hz), 2.45(1H, dd, J=5.8, 16.8Hz), 2.98(1H, dd, J=8.6, 16.8Hz), 3.64(3H, s), 3.90-3.95(1H, s), 5.08(1H, d, J=13.5Hz), 5.20(1H, d, J=13.5Hz), 7.40(1H, dd, J=1.8, 9.5Hz), 8.25(1H, dd, J=0.9, 9.5Hz), 8.53(1H, dd, J=0.9, 1.8Hz) Example 22: Yellow oil
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.12 (3H, s), 0.14 (3H, s), 0.92 (9H, s), 1.24 (3H, d, J = 7.0Hz), 2.45 (1H, dd , J = 5.8, 16.8Hz), 2.98 (1H, dd, J = 8.6, 16.8Hz), 3.64 (3H, s), 3.90-3.95 (1H, s), 5.08 (1H, d, J = 13.5Hz) , 5.20 (1H, d, J = 13.5Hz), 7.40 (1H, dd, J = 1.8, 9.5Hz), 8.25 (1H, dd, J = 0.9, 9.5Hz), 8.53 (1H, dd, J = 0.9 , 1.8Hz)

実施例23：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.21 (3H, t, J = 7.3 Hz), 1.33 (3H, t, J = 7.3 Hz), 2.94-2.97 (2H, m), 3.05 (2H, q, J = 7.3 Hz), 7.04-7.09 (1H, m), 8.31-8.32 (1H, m)
LRMS (EI+): 238 [M+] Example 23: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21 (3H, t, J = 7.3 Hz), 1.33 (3H, t, J = 7.3 Hz), 2.94-2.97 (2H, m), 3.05 (2H, q , J = 7.3 Hz), 7.04-7.09 (1H, m), 8.31-8.32 (1H, m)
LRMS (EI +): 238 [M +]

実施例24：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.17 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.3 Hz), 2.88-2.95 (4H, m), 3.97 (3H, s), 6.56 (1H, d, J = 1.8 Hz), 8.15 (1H, d, J = 1.8 Hz)
LRMS (EI+): 266 [M+] Example 24: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.17 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.3 Hz), 2.88-2.95 (4H, m), 3.97 (3H, s ), 6.56 (1H, d, J = 1.8 Hz), 8.15 (1H, d, J = 1.8 Hz)
LRMS (EI +): 266 [M +]

実施例25：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.44 (3H, t, J = 7.3 Hz), 4.43 (2H, q, J = 7.3 Hz), 7.41 (1H, dd, J = 1.8, 9.2 Hz), 8.10 (1H, d, J = 9.2 Hz), 8.49 (1H, d, J = 1.8 Hz) Example 25: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.44 (3H, t, J = 7.3 Hz), 4.43 (2H, q, J = 7.3 Hz), 7.41 (1H, dd, J = 1.8, 9.2 Hz), 8.10 (1H, d, J = 9.2 Hz), 8.49 (1H, d, J = 1.8 Hz)

実施例26：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.23 (3H, t, J = 7.3 Hz), 1.32 (3H, t, J = 7.3 Hz), 2.83-2.94 (4H, m), 7.29 (1H, d, J = 1.8 Hz), 8.41 (1H, d, J = 1.8 Hz)LRMS (EI+): 220 [M+] Example 26: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, t, J = 7.3 Hz), 1.32 (3H, t, J = 7.3 Hz), 2.83-2.94 (4H, m), 7.29 (1H, d , J = 1.8 Hz), 8.41 (1H, d, J = 1.8 Hz) LRMS (EI +): 220 [M +]

実施例27：黄色粉末
¹H-NMR (400 MHz, CDCl₃) δ 1.42 (3H, t, J = 7.3 Hz), 4.42 (2H, q, J = 7.3 Hz), 7.42-7.48 (1H, m), 8.29-8.33 (1H, m), 8.49-8.50 (1H, m) Example 27: Yellow powder
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.42 (3H, t, J = 7.3 Hz), 4.42 (2H, q, J = 7.3 Hz), 7.42-7.48 (1H, m), 8.29-8.33 (1H , m), 8.49-8.50 (1H, m)

実施例21':黄色油状物
未精製のまま次の反応へ Example 21 ': yellow oil to the next reaction unpurified

＜実施例28＞
６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン <Example 28>
6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridine

実施例１０の化合物（16.0 g）を50%硫酸水溶液（300 mL）に溶解し、9時間加熱還流した。放冷後、反応液を氷水中に注ぎ、炭酸カリウムを加えて中和後、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 19：1）にて精製し、目的物（5.8 8 g）を淡黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.34 (3H, t, J = 7.3 Hz), 2.84 (2H, q, J = 7.3 Hz), 6.33 (1H, s), 7.13 (1H, dd, J = 1.8, 9.8 Hz), 7.37 (1H, d, J = 9.8 Hz), 8.41 (1H, d, J = 1.8 Hz) The compound of Example 10 (16.0 g) was dissolved in 50% aqueous sulfuric acid solution (300 mL) and heated to reflux for 9 hours. After allowing to cool, the reaction mixture was poured into ice water, neutralized with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain the desired product (5.8 8 g) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3 Hz), 2.84 (2H, q, J = 7.3 Hz), 6.33 (1H, s), 7.13 (1H, dd, J = 1.8, 9.8 Hz), 7.37 (1H, d, J = 9.8 Hz), 8.41 (1H, d, J = 1.8 Hz)

＜実施例29＞
６−クロロ−２−メチル−ピラゾロ[１，５−ａ]ピリジン <Example 29>
6-Chloro-2-methyl-pyrazolo [1,5-a] pyridine

実施例12の化合物（2.20 g）をエタノール（150 mL）に溶解し、そこに水酸化カリウム（1.10 g）および水（10mL）を加え、2.5時間加熱還流した。放冷後、溶媒留去し、残渣を47％臭化水素酸水溶液（50mL）に溶解し、1時間加熱還流した。反応液に20％水酸化ナトリウム水溶液を加えて中和後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、目的物（1.21 g, ）を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 2.47 (3H, s), 6.30 (1H, br s), 7.03 (1H, dd, J = 1.8, 9.2Hz), 7.35(1H, d, J=9.2Hz), 8.40 (1H, d, J = 1.8 Hz). The compound of Example 12 (2.20 g) was dissolved in ethanol (150 mL), potassium hydroxide (1.10 g) and water (10 mL) were added thereto, and the mixture was heated to reflux for 2.5 hours. After allowing to cool, the solvent was distilled off, and the residue was dissolved in 47% aqueous hydrobromic acid solution (50 mL) and heated to reflux for 1 hour. The reaction solution was neutralized with 20% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the desired product (1.21 g,) was obtained as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.47 (3H, s), 6.30 (1H, br s), 7.03 (1H, dd, J = 1.8, 9.2Hz), 7.35 (1H, d, J = 9.2 Hz), 8.40 (1H, d, J = 1.8 Hz).

＜実施例30〜33＞
実施例18、11、20および9の化合物を用い実施例29と同様に反応させ表３に示す化合物を合成した。 <Examples 30 to 33>
The compounds shown in Table 3 were synthesized by reacting in the same manner as in Example 29 using the compounds of Examples 18, 11, 20, and 9.

＜実施例34＞
６−クロロ−２−シクロプロピル−ピラゾロ[１，５−ａ]ピリジン <Example 34>
6-Chloro-2-cyclopropyl-pyrazolo [1,5-a] pyridine

実施例16の化合物（3.31 g）をエタノール（100 mL）に溶解し、そこに水酸化カリウム（2.83 g）および水（20 mL）を加え、3.5時間加熱還流した。放冷後、溶媒留去し、残渣を水で希釈後、濃塩酸により酸性とした。生じた固体を濾取し、水で洗浄後、得られた固体を47%臭化水素酸水溶液（80 mL）に溶解し、1時間加熱還流した。反応液に水酸化ナトリウム水溶液でアルカリ性とした後、酢酸エチルで抽出し、水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 19：1）にて精製し、目的物（1.33 g）を淡黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ0.85-0.89 (2H, m), 1.01-1.06 (2H, m), 2.06-2.10 (1H, m), 6.18 (1H, s), 7.01 (1H, dd, J = 1.8, 9.8 Hz), The compound of Example 16 (3.31 g) was dissolved in ethanol (100 mL), potassium hydroxide (2.83 g) and water (20 mL) were added thereto, and the mixture was heated to reflux for 3.5 hours. After cooling, the solvent was distilled off, and the residue was diluted with water and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration and washed with water. The obtained solid was dissolved in 47% aqueous hydrobromic acid solution (80 mL) and heated to reflux for 1 hour. The reaction mixture was made alkaline with aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain the desired product (1.33 g) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ0.85-0.89 (2H, m), 1.01-1.06 (2H, m), 2.06-2.10 (1H, m), 6.18 (1H, s), 7.01 (1H , dd, J = 1.8, 9.8 Hz),

＜実施例35＞
２−ブロモ−６−クロロ−ピラゾロ[１，５−ａ]ピリジン <Example 35>
2-Bromo-6-chloro-pyrazolo [1,5-a] pyridine

実施例25の化合物を上記実施例34と同様に反応させ目的物を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ1.44 (3H, t, J = 7.3 Hz), 4.43 (2H, q, J = 7.3 Hz), 7.41 (1H, dd, J = 1.8, 9.2 Hz), 8.10 (1H, d, J = 9.2 Hz), 8.49 (1H, d, J = 1.8 Hz). The compound of Example 25 was reacted in the same manner as in Example 34 to obtain the target product as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.44 (3H, t, J = 7.3 Hz), 4.43 (2H, q, J = 7.3 Hz), 7.41 (1H, dd, J = 1.8, 9.2 Hz) , 8.10 (1H, d, J = 9.2 Hz), 8.49 (1H, d, J = 1.8 Hz).

＜実施例36＞
６−クロロ−２−エチル−３−プロピオニル−ピラゾロ[１，５−ａ]ピリジン <Example 36>
6-Chloro-2-ethyl-3-propionyl-pyrazolo [1,5-a] pyridine

実施例28の化合物（5.88 g）をプロピオン酸無水物（50 mL）に溶解し、そこに濃硫酸を2滴加え、140℃で4時間攪拌した。放冷後、10％水酸化カリウム水溶液（100 mL）およびテトラヒドロフラン（50 mL）を加え、60℃で2時間攪拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 9：1）にて精製し、目的物（6.88 g）を淡黄色粉末として得た。実施例８とデータ同一。   The compound of Example 28 (5.88 g) was dissolved in propionic anhydride (50 mL), 2 drops of concentrated sulfuric acid was added thereto, and the mixture was stirred at 140 ° C. for 4 hours. After allowing to cool, 10% aqueous potassium hydroxide solution (100 mL) and tetrahydrofuran (50 mL) were added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (6.88 g) as a pale yellow powder. Same data as Example 8.

＜実施例37〜42＞
実施例29〜30、32〜35の化合物を用い実施例36と同様に反応させ表４に示す化合物を合成した。 <Examples 37 to 42>
The compounds shown in Table 4 were synthesized by reacting in the same manner as in Example 36 using the compounds of Examples 29-30 and 32-35.

＜実施例43＞
６−クロロ−２−トリフルオロロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イルカルボン酸 <Example 43>
6-Chloro-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-3-ylcarboxylic acid

実施例13の化合物（3.69 g）をエタノール（150 mL）に溶解し、そこに水酸化カリウム（2.12 g）および水（20 mL）を加え、1.5時間加熱還流した。放冷後、溶媒留去し、残渣を水で希釈後、濃塩酸により酸性とした。これを酢酸エチルで抽出し、有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、目的物（3.30 g）を茶褐色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 7.55 (1H, dd, J = 1.8, 9.8 Hz), 8.31 (1H, d, J = 9.8 Hz), 8. 63 (1H, d, J = 1.8 Hz). The compound of Example 13 (3.69 g) was dissolved in ethanol (150 mL), potassium hydroxide (2.12 g) and water (20 mL) were added thereto, and the mixture was heated to reflux for 1.5 hours. After cooling, the solvent was distilled off, and the residue was diluted with water and acidified with concentrated hydrochloric acid. This was extracted with ethyl acetate, and the organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the desired product (3.30 g) was obtained as a brown powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.55 (1H, dd, J = 1.8, 9.8 Hz), 8.31 (1H, d, J = 9.8 Hz), 8. 63 (1H, d, J = 1.8 Hz ).

＜実施例44＞
Ｎ−メチル−Ｎ−メトキシ−６−クロロ−２−トリフルオロロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イルカルボキサミド <Example 44>
N-methyl-N-methoxy-6-chloro-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-3-ylcarboxamide

上記実施例43の化合物（1.68 g）をN，N−ジメチルホルムアミド（50mL）に溶解し、N,O-ジメチルヒドロキシアミン塩酸塩（0.743 g）、シアノリン酸ジエチル（1.20 mL）を加えた後、氷冷下でトリエチルアミン（2.20 mL）をゆっくり滴下し、徐々に常温まで昇温させながら、6時間攪拌した。反応液を酢酸エチルで希釈後、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3：1 ）にて精製し、目的物（1.79 g）を淡黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 3.42 (3H, s), 3.46 (3H, s), 7.34 (1H, dd, J= 1.8, 9.2 Hz), 7.73 (1H, d, J = 9.2 Hz), 8.56 (1H, brs). The compound of Example 43 (1.68 g) was dissolved in N, N-dimethylformamide (50 mL), and N, O-dimethylhydroxyamine hydrochloride (0.743 g) and diethyl cyanophosphate (1.20 mL) were added. Triethylamine (2.20 mL) was slowly added dropwise under ice cooling, and the mixture was stirred for 6 hours while gradually warming to room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (1.79 g) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.42 (3H, s), 3.46 (3H, s), 7.34 (1H, dd, J = 1.8, 9.2 Hz), 7.73 (1H, d, J = 9.2 Hz ), 8.56 (1H, brs).

＜実施例45＞
Ｎ−メチル−Ｎ−メトキシ−６−フルオロ−２−トリフルオロロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イルカルボキサミド <Example 45>
N-methyl-N-methoxy-6-fluoro-2-trifluorolomethyl-pyrazolo [1,5-a] pyridin-3-ylcarboxamide

実施例27の化合物を用い、実施例43、44と同様に反応させ目的物を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 3.42 (3H, s), 3.47 (3H, s), 7.29-7.34 (1H, m), 7.75-7.79 (1H, m), 8.46-8.47 (1H, m). The target product was obtained as a yellow powder by reacting in the same manner as in Examples 43 and 44 using the compound of Example 27.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.42 (3H, s), 3.47 (3H, s), 7.29-7.34 (1H, m), 7.75-7.79 (1H, m), 8.46-8.47 (1H, m).

＜実施例46＞
６−クロロ−２−トリフルオロロメチル−３−プロピオニル−ピラゾロ[１，５−ａ]ピリジン <Example 46>
6-Chloro-2-trifluoromethyl-3-propionyl-pyrazolo [1,5-a] pyridine

アルゴン気流下、実施例44の化合物（0.53 g）をテトラヒドロフラン（20mL）に溶解し、氷冷下で0.86 mol/Lエチルマグネシウムブロミド/テトラヒドロフラン溶液（6.00 mL）をゆっくり滴下し、その後徐々に常温まで昇温させながら6時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝9：1）にて精製し、目的物（0.24 g）を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.23 (3H, t, J = 7.3 Hz), 2.50 (2H, q, J = 7.3 Hz), 7.51 (1H, dd, J= 1.8, 9.2 Hz), 8.43 (1H, d, J = 9.2 Hz), 8.58 (1H, d, J = 1.8 Hz). Under an argon stream, the compound of Example 44 (0.53 g) was dissolved in tetrahydrofuran (20 mL), and 0.86 mol / L ethylmagnesium bromide / tetrahydrofuran solution (6.00 mL) was slowly added dropwise under ice cooling, and then gradually to room temperature. The mixture was stirred for 6 hours while raising the temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (0.24 g) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, t, J = 7.3 Hz), 2.50 (2H, q, J = 7.3 Hz), 7.51 (1H, dd, J = 1.8, 9.2 Hz), 8.43 (1H, d, J = 9.2 Hz), 8.58 (1H, d, J = 1.8 Hz).

＜実施例47＞
６−フルオロ−２−トリフルオロロメチル−３−プロピオニル−ピラゾロ[１，５−ａ]ピリジン <Example 47>
6-Fluoro-2-trifluoromethyl-3-propionyl-pyrazolo [1,5-a] pyridine

実施例45の化合物を用い実施例46と同様に反応させ目的物を淡黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.23 (3H, t, J = 7.3 Hz), 3.01 (2H, q, J = 7.3 Hz), 7.45-7.50 (1H, m), 8.48-8.52 (1H, m), 8.52-8.53 (1H, m). The target product was obtained as a pale yellow powder by reacting in the same manner as in Example 46 using the compound of Example 45.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, t, J = 7.3 Hz), 3.01 (2H, q, J = 7.3 Hz), 7.45-7.50 (1H, m), 8.48-8.52 (1H , m), 8.52-8.53 (1H, m).

＜実施例48＞
２−エチル−６−フルオロ−４−メトキシ−３−プロピオニル−ピラゾロ[１，５−ａ]ピリジン <Example 48>
2-Ethyl-6-fluoro-4-methoxy-3-propionyl-pyrazolo [1,5-a] pyridine

実施例23の化合物（2.87 g）をメタノール（75 mL）に溶解し、ナトリウムメトキシド（3.30 g）を加え、2時間加熱還流した。反応液を溶媒留去した後、残渣を酢酸エチルに溶解し、水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル9：1）にて精製し、目的物（2.58 g）を黄色固体として得た。
LRMS (EI+):250 [M+]
¹H-NMR (400 MHz, CDCl₃): δ 1.18 (3H, t, J = 7.3 Hz), 1.29 (3H, t, J = 7.3 Hz), 2.88-2.95 (4H, m), 3.98 (3H, s), 6.55 (1H, dd, J = 1.8, 9.8 Hz), 8.07-8.08 (1H, m). The compound of Example 23 (2.87 g) was dissolved in methanol (75 mL), sodium methoxide (3.30 g) was added, and the mixture was heated to reflux for 2 hours. After the solvent of the reaction solution was distilled off, the residue was dissolved in ethyl acetate, washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 9: 1) to obtain the desired product (2.58 g) as a yellow solid.
LRMS (EI +): 250 [M +]
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (3H, t, J = 7.3 Hz), 1.29 (3H, t, J = 7.3 Hz), 2.88-2.95 (4H, m), 3.98 (3H, s), 6.55 (1H, dd, J = 1.8, 9.8 Hz), 8.07-8.08 (1H, m).

＜実施例49＞
２−ブロモ−１−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−プロパン−１−オン <Example 49>
2-Bromo-1- (6-chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -propan-1-one

実施例８の化合物（6.88 g）を酢酸エチル（100 mL）に溶解し、臭化第二銅（13.0 g）を加え、1時間加熱還流した。反応液をセライト濾過した後、濾液を酢酸エチルで希釈し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、目的物（5.18 g）を淡黄色粉末として得た。
LRMS (EI+): 314 [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.42 (3H, t, J = 7.3 Hz), 1.92 (3H, t, J = 6.7 Hz), 3.11-3.24 (2H, m), 5.02 (1H, q, J = 6.7 Hz), 7.45 (1H, dd, J = 1.8, 9.8 Hz), 8.20 (1H, d, J = 9.8 Hz), 8.54 (1H, d, J = 1.8 Hz). The compound of Example 8 (6.88 g) was dissolved in ethyl acetate (100 mL), cupric bromide (13.0 g) was added, and the mixture was heated to reflux for 1 hour. The reaction solution was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent, the desired product (5.18 g) was obtained as a pale yellow powder.
LRMS (EI +): 314 [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.42 (3H, t, J = 7.3 Hz), 1.92 (3H, t, J = 6.7 Hz), 3.11-3.24 (2H, m), 5.02 (1H, q , J = 6.7 Hz), 7.45 (1H, dd, J = 1.8, 9.8 Hz), 8.20 (1H, d, J = 9.8 Hz), 8.54 (1H, d, J = 1.8 Hz).

＜実施例50〜57＞
実施例23〜24、26、39、41〜42、47〜48の化合物を用い、実施例49と同様に反応させ表５に示す化合物を合成した。 <Examples 50 to 57>
Using the compounds of Examples 23 to 24, 26, 39, 41 to 42, and 47 to 48, the compounds shown in Table 5 were synthesized by reacting in the same manner as in Example 49.

＜実施例58＞
２−[２−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−１−メチル−２−オキソエチル]−マロン酸ジメチルエステル <Example 58>
2- [2- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -1-methyl-2-oxoethyl] -malonic acid dimethyl ester

アルゴン気流下、マロン酸ジメチル（2.40 mL）をN，N−ジメチルホルムアミド（50mL）に溶解し、氷冷下で60％水素化ナトリウム（0.84 g）を加え、常温で30分間攪拌した。その後、氷冷下で実施例49の化合物（5.18 g）のN，N−ジメチルホルムアミド（100 mL）溶液を滴下し、常温で3時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、ヘキサン：酢酸エチル ＝ 1：1で抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 4：1）にて精製し、目的物（5.58 g）を淡黄色粉末として得た。
LRMS (EI+): 366 (M+)
¹H-NMR (400 MHz, CDCl₃) δ 1.23 (3H, d, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz), 3.08-3.20 (2H, m), 3.68 (3H, s), 3.82 (3H, s), 4.08 (1H, d, J = 10.4 Hz), 7.39 (1H, dd, J = 1.8, 9.8 Hz), 8.15 (1H, d, J = 9.8 Hz), 8.51 (1H, d, J = 1.8 Hz). Under an argon stream, dimethyl malonate (2.40 mL) was dissolved in N, N-dimethylformamide (50 mL), 60% sodium hydride (0.84 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of the compound of Example 49 (5.18 g) in N, N-dimethylformamide (100 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with hexane: ethyl acetate = 1: 1. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (5.58 g) as a pale yellow powder.
LRMS (EI +): 366 (M +)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, d, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz), 3.08-3.20 (2H, m), 3.68 (3H, s ), 3.82 (3H, s), 4.08 (1H, d, J = 10.4 Hz), 7.39 (1H, dd, J = 1.8, 9.8 Hz), 8.15 (1H, d, J = 9.8 Hz), 8.51 (1H , d, J = 1.8 Hz).

＜実施例59〜66＞
表５の化合物を用い、上記実施例58と同様に反応させ表６に示す化合物を合成した。 <Examples 59 to 66>
The compounds shown in Table 6 were synthesized using the compounds shown in Table 5 in the same manner as in Example 58 above.

＜実施例67＞
３−（６−クロロ−２−メチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−メチル−３−オキソプロピオン酸メチルエステル <Example 67>
3- (6-Chloro-2-methyl-pyrazolo [1,5-a] pyridin-3-yl) -2-methyl-3-oxopropionic acid methyl ester

アルゴン気流下、実施例40の化合物（0.89 g）を炭酸ジメチル（15 mL）に溶解した後、60%水素化ナトリウム（0.48 g）を加え、3時間加熱還流した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝5：1）にて精製し、目的物（0.62 g）を白色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.52 (3H, d, J = 7.3 Hz), 2.73 (3H, s), 3.73 (3H, s), 4.25 (1H, q, J = 7.3 Hz), 7.43 (1H, dd, J = 1.8, 9.8 Hz), 8.26 (1H, d, J = 9.8 Hz), 8.48 (1H, d, J = 1.8 Hz). Under an argon stream, the compound of Example 40 (0.89 g) was dissolved in dimethyl carbonate (15 mL), 60% sodium hydride (0.48 g) was added, and the mixture was heated to reflux for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (0.62 g) as a white powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.52 (3H, d, J = 7.3 Hz), 2.73 (3H, s), 3.73 (3H, s), 4.25 (1H, q, J = 7.3 Hz), 7.43 (1H, dd, J = 1.8, 9.8 Hz), 8.26 (1H, d, J = 9.8 Hz), 8.48 (1H, d, J = 1.8 Hz).

＜実施例68〜75＞
実施例８、10、14〜15、３７〜３９、４６の化合物を用い上記実施例67と同様に反応させ表７に示す化合物を合成した。 <Examples 68 to 75>
The compounds shown in Table 7 were synthesized by reacting in the same manner as in Example 67 using the compounds of Examples 8, 10, 14-15, 37-39, and 46.

＜実施例76＞
３−（６−クロロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−メチル−３−オキソプロピオン酸メチルエステル <Example 76>
3- (6-Chloro-pyrazolo [1,5-a] pyridin-3-yl) -2-methyl-3-oxopropionic acid methyl ester

アルゴン気流下、実施例74の化合物（1.07 g）をN, N−ジメチルホルムアミド（30 mL）に溶解した後、氷冷下で60％水素化ナトリウム（0.15 g）を加え、常温にて1時間攪拌した。その後、氷冷下でヨードメタン（0.23 mL）を加え、常温でさらに6時間攪拌した。
反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝9：1）にて精製し、目的物（0.51 g）を白色固体として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.53 (3H, d, J = 7.3 Hz), 3.71 (3H, s), 4.21 (1H, q, J = 7.3 Hz), 7.49 (1H, dd, J = 1.8, 9.2 Hz), 8.37 (1H, d, J = 9.2 Hz), 8.43 (1H, s), 8.60 (1H, d, J = 1.8 Hz). In a stream of argon, the compound of Example 74 (1.07 g) was dissolved in N, N-dimethylformamide (30 mL), then 60% sodium hydride (0.15 g) was added under ice cooling, and the mixture was at room temperature for 1 hour. Stir. Thereafter, iodomethane (0.23 mL) was added under ice cooling, and the mixture was further stirred at room temperature for 6 hours.
A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (0.51 g) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.53 (3H, d, J = 7.3 Hz), 3.71 (3H, s), 4.21 (1H, q, J = 7.3 Hz), 7.49 (1H, dd, J = 1.8, 9.2 Hz), 8.37 (1H, d, J = 9.2 Hz), 8.43 (1H, s), 8.60 (1H, d, J = 1.8 Hz).

＜実施例77＞
３−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−メチル−３−オキソプロピオン酸メチルエステル <Example 77>
3- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2-methyl-3-oxopropionic acid methyl ester

実施例75の化合物を用い上記実施例76と同様に反応させ目的物を得た。得られた化合物は実施例70と同一。   The target product was obtained by reacting in the same manner as in Example 76 using the compound of Example 75. The resulting compound is identical to Example 70.

＜実施例78＞
４−（６−クロロ−２−メチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−３−メチル−４−オキソ酪酸 <Example 78>
4- (6-Chloro-2-methyl-pyrazolo [1,5-a] pyridin-3-yl) -3-methyl-4-oxobutyric acid

アルゴン気流下、実施例67の化合物（0.62 g）をN, N−ジメチルホルムアミド（20mL）に溶解した後、氷冷下で60％水素化ナトリウム（0.13 g）を加え、常温にて1時間攪拌した。その後、氷冷下でブロモ酢酸エチル (0.37 mL)を加え、常温でさらに7時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣を47％臭化水素酸水溶液（15 mL）に溶解し、1.5時間加熱還流した。反応液に20％水酸化ナトリウム水溶液を加えてアルカリ性とし、生じた不溶物を濾過にて除去した。この濾液を濃塩酸にて酸性にした後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、目的物（0.33 g）を白色固体として得た。
¹H-NMR (400 MHz, CDCl₃) δ1.29 (3H, d, J = 7.3 Hz), 2.55 (1H, dd, J = 5.6, 17.2 Hz), 3.02 (1H, dd, J = 8.6, 17.2 Hz), 3.64-3.74 (1H, m), 7.42 (1H, dd, J = 1.8, 9.8 Hz), 8.21 (1H, d, J = 9.8 Hz), 8.49 (1H, d, J = 1.8 Hz). In an argon stream, the compound of Example 67 (0.62 g) was dissolved in N, N-dimethylformamide (20 mL), and then 60% sodium hydride (0.13 g) was added under ice cooling, followed by stirring at room temperature for 1 hour. did. Thereafter, ethyl bromoacetate (0.37 mL) was added under ice cooling, and the mixture was further stirred at room temperature for 7 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was dissolved in 47% aqueous hydrobromic acid solution (15 mL) and heated to reflux for 1.5 hours. A 20% aqueous sodium hydroxide solution was added to the reaction solution to make it alkaline, and the resulting insoluble matter was removed by filtration. The filtrate was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the desired product (0.33 g) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.29 (3H, d, J = 7.3 Hz), 2.55 (1H, dd, J = 5.6, 17.2 Hz), 3.02 (1H, dd, J = 8.6, 17.2 Hz), 3.64-3.74 (1H, m), 7.42 (1H, dd, J = 1.8, 9.8 Hz), 8.21 (1H, d, J = 9.8 Hz), 8.49 (1H, d, J = 1.8 Hz).

＜実施例79〜85＞
実施例68〜73及び76の化合物を用い上記実施例77と同様に反応させ表８に示す化合物を合成した。 <Examples 79 to 85>
The compounds shown in Table 8 were synthesized by reacting the compounds of Examples 68 to 73 and 76 in the same manner as in Example 77.

＜実施例86＞
４−（６−クロロ−２−エトキシカルボニル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−３−メチル−４−オキソ酪酸メチルエステル <Example 86>
4- (6-Chloro-2-ethoxycarbonyl-pyrazolo [1,5-a] pyridin-3-yl) -3-methyl-4-oxobutyric acid methyl ester

実施例21の化合物(528mg)をアセトン(10mL)に溶解し、パラトルエンスルホン酸(30mg)を加え、40℃にて3時間撹拌した。放冷後、反応溶液に飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄した。無水硫酸ナトリウムで乾燥し溶媒留去後、残渣をショートシリカゲルカラムクロマトグラフィー(酢酸エチル)にて精製し、淡黄色油状物の2−アルデヒド体を得た。   The compound of Example 21 (528 mg) was dissolved in acetone (10 mL), paratoluenesulfonic acid (30 mg) was added, and the mixture was stirred at 40 ° C. for 3 hr. After allowing to cool, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate and evaporating the solvent, the residue was purified by short silica gel column chromatography (ethyl acetate) to obtain a 2-aldehyde form as a pale yellow oil.

これをイソプロパノール(15mL)及びジクロロメタン(2mL)に溶解し、2−メチルブテン(15mL)及び水(15mL)を加えた。更に亜塩素酸ナトリウム(1.56g)及びリン酸一ナトリウム・二水和物(1.51g)を順次加え、常温にて一終夜撹拌した。反応液を酢酸エチルで3回抽出し、有機層を合わせ、飽和食塩水にて洗浄した。無水硫酸ナトリウムで乾燥し、溶媒を留去することにより淡黄色粉末の2−カルボン酸体を得た。   This was dissolved in isopropanol (15 mL) and dichloromethane (2 mL) and 2-methylbutene (15 mL) and water (15 mL) were added. Further, sodium chlorite (1.56 g) and monosodium phosphate dihydrate (1.51 g) were sequentially added, and the mixture was stirred at room temperature overnight. The reaction solution was extracted three times with ethyl acetate, and the organic layers were combined and washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a 2-carboxylic acid compound as a pale yellow powder.

これをN, N−ジメチルホルムアミド(20mL)に溶解し、炭酸カリウム(276mg)及びヨウ化エチル(138μL)を順次加え、常温にて3時間撹拌した。反応液を氷水中に注ぎ、酢酸エチルにて抽出し、水(2回)及び飽和食塩水にて順次洗浄した。無水硫酸ナトリウムで乾燥し溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=5：1)にて精製し、目的物(288mg)を黄色油状物として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.24(3H, d, J=7.0Hz), 1.47(3H, t, J=7.0Hz), 2.46(1H, dd, J=6.1, 16.5Hz), 2.92(1H, dd, J=8.0, 16.5Hz), 3.63(1H, s), 3.93-4.01(1H, m), 4.50-4.56(1H, m), 7.43(1H, dd, J=1.8, 9.5Hz), 8.27(1H, d, J=9.5Hz), 8.58(1H, d, J=1.8Hz). This was dissolved in N, N-dimethylformamide (20 mL), potassium carbonate (276 mg) and ethyl iodide (138 μL) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed successively with water (twice) and saturated brine. After drying over anhydrous sodium sulfate and distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (288 mg) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.24 (3H, d, J = 7.0Hz), 1.47 (3H, t, J = 7.0Hz), 2.46 (1H, dd, J = 6.1, 16.5Hz), 2.92 (1H, dd, J = 8.0, 16.5Hz), 3.63 (1H, s), 3.93-4.01 (1H, m), 4.50-4.56 (1H, m), 7.43 (1H, dd, J = 1.8, 9.5 Hz), 8.27 (1H, d, J = 9.5Hz), 8.58 (1H, d, J = 1.8Hz).

＜実施例87＞
４−（６−クロロ−２−メトキシメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−３−メチル−４−オキソ酪酸メチルエステル <Example 87>
4- (6-Chloro-2-methoxymethyl-pyrazolo [1,5-a] pyridin-3-yl) -3-methyl-4-oxobutyric acid methyl ester

実施例22の化合物(1.06g)をテトラヒドロフラン(5mL)に溶解し、1.0mol/Lテトラブチルアンモニウムフルオリド/テトラヒドロフラン溶液(7.47mL)を加え、常温にて2時間撹拌した。反応液に水を加え、酢酸エチルにて抽出し、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=3：2)にて精製し、2-ヒドロキシメチル体(401mg)を淡黄色粉末として得た。   The compound of Example 22 (1.06 g) was dissolved in tetrahydrofuran (5 mL), 1.0 mol / L tetrabutylammonium fluoride / tetrahydrofuran solution (7.47 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. After drying over anhydrous sodium sulfate and evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 2-hydroxymethyl compound (401 mg) as a pale yellow powder.

これ(370mg)をアセトニトリル(10mL)に溶解し、酸化銀（I）(1.38g)及びヨウ化メチル(741μL)を加え、常温にて24時間撹拌した。セライトを用い不溶物を濾去後、濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=2：1)にて精製し、目的物(289mg)を淡黄色油状物として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.25(3H, d, J=7.3Hz), 2.45(1H, dd, J=5.8, 16.8Hz), 3.00(1H, dd, J=8.6, 16.8Hz), 3.51(3H, s), 3.66(3H, s), 3.75-3.80(1H, m), 4.90(1H, d, J=13.1Hz), 4.98(1H, d, J=13.1), 7.43(1H, dd, J=1.8, 9.5Hz), 8.21(1H, d, J=9.5Hz), 8.56(1H, d, J=1.8Hz). This (370 mg) was dissolved in acetonitrile (10 mL), silver (I) oxide (1.38 g) and methyl iodide (741 μL) were added, and the mixture was stirred at room temperature for 24 hours. The insoluble material was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (289 mg) as a pale yellow oil. It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (3H, d, J = 7.3Hz), 2.45 (1H, dd, J = 5.8, 16.8Hz), 3.00 (1H, dd, J = 8.6, 16.8Hz ), 3.51 (3H, s), 3.66 (3H, s), 3.75-3.80 (1H, m), 4.90 (1H, d, J = 13.1Hz), 4.98 (1H, d, J = 13.1), 7.43 ( 1H, dd, J = 1.8, 9.5Hz), 8.21 (1H, d, J = 9.5Hz), 8.56 (1H, d, J = 1.8Hz).

＜実施例88＞
６−（６−クロロ−２−メチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 88>
6- (6-Chloro-2-methyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例78の化合物（0.33 g）をエタノール（10mL）に溶解した後、ヒドラジン一水和物（0.12 mL）を加え、6時間加熱還流した。反応液をそのまま溶媒留去した後、ジエチルエーテルでトリチュレートし、固体を濾取した。得られた固体をジエチルエーテルで洗浄し、目的物（0.20 g）を淡黄色固体として得た。（方法Ａ）
HRMS (EI+): 276.0761 (-1.6 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.28 (3H, d, J = 7.3 Hz), 2.50 (1H, dd, J = 1.8, 17.1 Hz), 2.78 (1H, dd, J = 6.1, 17.1 Hz), 3.32-3.39 (1H, m), 7.22 (1H, dd, J = 1.8, 9.7 Hz), 7.96 (1H, d, J = 9.7 Hz), 8.43 (1H, brs), 8.44 (1H, brs).
m.p. 220-222 ℃ The compound of Example 78 (0.33 g) was dissolved in ethanol (10 mL), hydrazine monohydrate (0.12 mL) was added, and the mixture was heated to reflux for 6 hours. The solvent of the reaction solution was distilled off as it was, then triturated with diethyl ether, and the solid was collected by filtration. The obtained solid was washed with diethyl ether to obtain the desired product (0.20 g) as a pale yellow solid. (Method A)
HRMS (EI +): 276.0761 (-1.6 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.28 (3H, d, J = 7.3 Hz), 2.50 (1H, dd, J = 1.8, 17.1 Hz), 2.78 (1H, dd, J = 6.1, 17.1 Hz ), 3.32-3.39 (1H, m), 7.22 (1H, dd, J = 1.8, 9.7 Hz), 7.96 (1H, d, J = 9.7 Hz), 8.43 (1H, brs), 8.44 (1H, brs) .
mp 220-222 ℃

＜実施例89＞
６−（６−クロロ−２−ジエトキシメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 89>
6- (6-Chloro-2-diethoxymethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例21の化合物(460mg)をエタノール(2mL)及び水(1mL)に溶解し、水酸化カリウム(135mg)を加え、常温にて2時間撹拌した。反応溶媒を留去し、残渣を水に溶解し、希塩酸にて中和し、酢酸エチルで抽出後、水、飽和食塩水にて順次洗浄した。無水硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をエタノール(10mL)に溶解し、ヒドラジン一水和物(117μL)を加え、3時間加熱還流した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=3：2)にて精製し、目的物(385mg)を黄色アモルファスとして得た。(方法Ｂ)．
¹H-NMR (400 MHz, CDCl₃) δ 1.13(3H, d, J=7.3Hz), 1.23(3H, t, J=7.0Hz), 1.24(3H, t, J=7.0Hz), 2.45(1H, dd, J=1.5, 17.1Hz), 2.78(1H, dd, J=6.7, 17.1Hz), 3.52-3.62(2H, m), 3.63-3.80(2H, m), 3.85-3.90(1H, m), 5.74(1H, s), 7.22(1H, dd, J=1.8, 9.8Hz), 7.94(1H, dd, J=0.6, 9.8Hz), 8.47(1H, dd, J=0.6, 1.8Hz), 8.49(1H, s). The compound of Example 21 (460 mg) was dissolved in ethanol (2 mL) and water (1 mL), potassium hydroxide (135 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solvent was distilled off, the residue was dissolved in water, neutralized with dilute hydrochloric acid, extracted with ethyl acetate, and washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was dissolved in ethanol (10 mL), hydrazine monohydrate (117 μL) was added, and the mixture was heated to reflux for 3 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain the desired product (385 mg) as a yellow amorphous. (Method B).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.13 (3H, d, J = 7.3Hz), 1.23 (3H, t, J = 7.0Hz), 1.24 (3H, t, J = 7.0Hz), 2.45 ( 1H, dd, J = 1.5, 17.1Hz), 2.78 (1H, dd, J = 6.7, 17.1Hz), 3.52-3.62 (2H, m), 3.63-3.80 (2H, m), 3.85-3.90 (1H, m), 5.74 (1H, s), 7.22 (1H, dd, J = 1.8, 9.8Hz), 7.94 (1H, dd, J = 0.6, 9.8Hz), 8.47 (1H, dd, J = 0.6, 1.8Hz) ), 8.49 (1H, s).

＜実施例90＞
６−（６−クロロ−２−メトキシメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 90>
6- (6-Chloro-2-methoxymethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例87の化合物を用い上記実施例89と同様に反応させ目的物を淡黄色粉末として得た。
mp:164.0-166.0℃
HRMS (EI+): 306.0900 (+1.6mmu) [M+]
¹H-NMR (400 MHz, CDCl₃)δ 1.25(3H, d, J=7.3Hz), 2.49(1H, dd, J=1.5, 16.8Hz), 2.78(1H, dd, J=6.7, 16.8Hz), 3.43(3H, s), 3.43-3.50(1H, m), 4.71(1H, d, J=12.5Hz), 4.83(1H, d, J=12.5Hz), 7.24(1H, dd, J=1.5Hz, 9.5Hz), 8.02(1H, d, J=9.5Hz), 8.49(1H, d, J=1.5Hz), 8.64(1H, br s).
元素分析 (%) : C₁₄H₁₅ClN₄O₂として
C H N
計算値 54.82 4.93 18.26
実測値 54.73 4.92 18.17 The target product was obtained as a pale yellow powder by reacting in the same manner as in Example 89 using the compound of Example 87.
mp: 164.0-166.0 ℃
HRMS (EI +): 306.0900 (+ 1.6mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (3H, d, J = 7.3Hz), 2.49 (1H, dd, J = 1.5, 16.8Hz), 2.78 (1H, dd, J = 6.7, 16.8Hz ), 3.43 (3H, s), 3.43-3.50 (1H, m), 4.71 (1H, d, J = 12.5Hz), 4.83 (1H, d, J = 12.5Hz), 7.24 (1H, dd, J = 1.5Hz, 9.5Hz), 8.02 (1H, d, J = 9.5Hz), 8.49 (1H, d, J = 1.5Hz), 8.64 (1H, br s).
Elemental analysis (%): as C ₁₄ H ₁₅ ClN ₄ O ₂
CHN
Calculated 54.82 4.93 18.26
Actual value 54.73 4.92 18.17

＜実施例91＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 91>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例58の化合物（5.58 g）をエタノール（160 mL）に溶解し、そこに水酸化カリウム（2.56 g）および水（30 mL）を加え、2.5時間加熱還流した。放冷後、溶媒留去し、残渣を水で希釈後、濃塩酸により酸性とした。これを酢酸エチルにて2回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、得られた黄色油状物をエタノール（200 mL）に溶解し、63時間加熱還流した。その後、反応液にヒドラジン一水和物（2.00mL）を加え、さらに4時間加熱還流した。放冷後、反応液を溶媒留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 1：1）にて精製し目的物（3.00 g）を黄色固体として得た（方法Ｃ）。
mp:152.5-154.5℃
HRMS (EI+): 290.0946 (+1.1mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.25 (3H, d, J = 7.3 Hz), 1.36 (3H, t, J = 7.3 Hz), 2.51 (1H, dd, J = 1.8, 17.1 Hz), 2.78 (1H, dd, J = 6.7, 17.1 Hz), 2.99 (2H, q, J = 7.3 Hz), 3.26-3.34 (1H, m), 7.20 (1H, dd, J = 1.8, 9.2 Hz), 7.83 (1H, d, J = 9.2 Hz), 8.46 (1H, d, J = 1.8 Hz), 8.47 (1H, brs)．
元素分析 (%) : C₁₄H₁₅ClN₄Oとして
C H N
計算値 57.83 5.20 19.27
実測値 57.86 5.08 19.01 The compound of Example 58 (5.58 g) was dissolved in ethanol (160 mL), potassium hydroxide (2.56 g) and water (30 mL) were added thereto, and the mixture was heated to reflux for 2.5 hours. After cooling, the solvent was distilled off, and the residue was diluted with water and acidified with concentrated hydrochloric acid. This was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained yellow oil was dissolved in ethanol (200 mL) and heated to reflux for 63 hours. Thereafter, hydrazine monohydrate (2.00 mL) was added to the reaction solution, and the mixture was further heated to reflux for 4 hours. After allowing to cool, the reaction mixture was evaporated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (3.00 g) as a yellow solid (Method C).
mp: 152.5-154.5 ℃
HRMS (EI +): 290.0946 (+ 1.1mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (3H, d, J = 7.3 Hz), 1.36 (3H, t, J = 7.3 Hz), 2.51 (1H, dd, J = 1.8, 17.1 Hz), 2.78 (1H, dd, J = 6.7, 17.1 Hz), 2.99 (2H, q, J = 7.3 Hz), 3.26-3.34 (1H, m), 7.20 (1H, dd, J = 1.8, 9.2 Hz), 7.83 (1H, d, J = 9.2 Hz), 8.46 (1H, d, J = 1.8 Hz), 8.47 (1H, brs).
Elemental analysis (%): as C ₁₄ H ₁₅ ClN ₄ O
CHN
Calculated 57.83 5.20 19.27
Actual value 57.86 5.08 19.01

＜実施例92〜108＞
実施例21'、22、60〜66、79〜86を用い上記実施例と同様に反応させ表９に示す化合物を合成した。 <Examples 92 to 108>
The compounds shown in Table 9 were synthesized by reacting in the same manner as in the above Examples using Examples 21 ′, 22, 60 to 66, and 79 to 86.

実施例92: mp:130-132 ℃
HRMS (EI+): 304.1082 (-0.9 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.23(3H, d, J=7.3Hz),1.36(3H,d,J=7.0Hz),1.42(3H,d,J=7.0Hz), 2.51(1H,dd,J=2.4,16.8Hz),2.80(1H,dd,J=6.7,16.8Hz),3.20-3.30(1H,m),3.38-3.42(1H,m),7.17 (1H,dd,J=1.8,9.5Hz),7.69(1H,d,J=9.5Hz),8.46(1H,brs),8.47(1H,d,J=1.8Hz).
元素分析 (%) : C₁₅H₁₇ClN₄Oとして
C H N
計算値 59.11 5.62 18.38
実測値 59.14 5.55 18.26 Example 92: mp: 130-132 ° C
HRMS (EI +): 304.1082 (-0.9 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, d, J = 7.3Hz), 1.36 (3H, d, J = 7.0Hz), 1.42 (3H, d, J = 7.0Hz), 2.51 ( 1H, dd, J = 2.4,16.8Hz), 2.80 (1H, dd, J = 6.7,16.8Hz), 3.20-3.30 (1H, m), 3.38-3.42 (1H, m), 7.17 (1H, dd, J = 1.8, 9.5Hz), 7.69 (1H, d, J = 9.5Hz), 8.46 (1H, brs), 8.47 (1H, d, J = 1.8Hz).
Elemental analysis (%): as C ₁₅ H ₁₇ ClN ₄ O
CHN
Calculated 59.11 5.62 18.38
Actual value 59.14 5.55 18.26

実施例93: mp:154-156 ℃
HRMS (EI+): 288.1360 (-2.6 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.23(3H, d, J=7.3Hz),1.36(3H,d,J=6.7Hz),1.43(3H,d,J=6.7 Hz), 2.51(1H,dd,J=1.8,16.8Hz),2.80(1H,dd,J=6.8,16.8Hz),3.23-3.31(1H,m),3.35-3.42(1H,m),7.12- 7.17 (1H,m),7.74-7.78(1H,m), 8.37-8.39(1H,m) ,8.46(1H,brs).
元素分析 (%) : C₁₅H₁₇FN₄Oとして
C H N
計算値 62.49 5.95 19.43
実測値 62.51 5.91 19.29 Example 93: mp: 154-156 ° C
HRMS (EI +): 288.1360 (-2.6 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, d, J = 7.3Hz), 1.36 (3H, d, J = 6.7Hz), 1.43 (3H, d, J = 6.7 Hz), 2.51 ( 1H, dd, J = 1.8,16.8Hz), 2.80 (1H, dd, J = 6.8,16.8Hz), 3.23-3.31 (1H, m), 3.35-3.42 (1H, m), 7.12--7.17 (1H, m), 7.74-7.78 (1H, m), 8.37-8.39 (1H, m), 8.46 (1H, brs).
Elemental analysis (%): as C ₁₅ H ₁₇ FN ₄ O
CHN
Calculated 62.49 5.95 19.43
Actual value 62.51 5.91 19.29

実施例94: 実施例91に記載。 Example 94: described in Example 91.

実施例95: mp:151-153℃
HRMS (EI+): 274.1220 (-0.9mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.26 (3H, d, J = 7.3 Hz), 1.37 (3H, t, J = 7.6 Hz), 2.51 (1H, dd, J = 1.2, 16.8 Hz), 2.78 (1H, dd, J = 6.7, 16.8 Hz), 2.99 (2H, q, J = 7.6 Hz), 3.27-3.35 (1H, m), 7.15-7.20 (1H, m), 7.88-7.92 (1H, m), 8.35-37 (1H,m), 8.50 (1H, brs)。
元素分析 (%) : C₁₄H₁₅FN₄Oとして
C H N
計算値 61.30 5.51 20.43
実測値 61.24 5.45 20.39 Example 95: mp: 151-153 ° C
HRMS (EI +): 274.1220 (-0.9mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26 (3H, d, J = 7.3 Hz), 1.37 (3H, t, J = 7.6 Hz), 2.51 (1H, dd, J = 1.2, 16.8 Hz), 2.78 (1H, dd, J = 6.7, 16.8 Hz), 2.99 (2H, q, J = 7.6 Hz), 3.27-3.35 (1H, m), 7.15-7.20 (1H, m), 7.88-7.92 (1H, m), 8.35-37 (1H, m), 8.50 (1H, brs).
Elemental analysis (%): as C ₁₄ H ₁₅ FN ₄ O
CHN
Calculated 61.30 5.51 20.43
Actual value 61.24 5.45 20.39

実施例96: m.p. 174-176 ℃
HRMS (FAB+): 331.0575 (+0.1 mmu) [M+H]
¹H-NMR (400 MHz, CDCl₃) δ 1.17 (3H, d, J = 7.3 Hz), 2.52 (1H, dd, J = 2.5, 17.1 Hz), 2.81 (1H, dd, J = 6.7, 17.1 Hz), 3.29-3.28 (1H, m), 7.34 (1H, dd, J = 1.8, 9.8 Hz), 7.89 (1H, d, J = 9.8 Hz), 8.56 (1H, brs), 8.63 (1H, brs). Example 96: mp 174-176 ° C
HRMS (FAB +): 331.0575 (+0.1 mmu) [M + H]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.17 (3H, d, J = 7.3 Hz), 2.52 (1H, dd, J = 2.5, 17.1 Hz), 2.81 (1H, dd, J = 6.7, 17.1 Hz ), 3.29-3.28 (1H, m), 7.34 (1H, dd, J = 1.8, 9.8 Hz), 7.89 (1H, d, J = 9.8 Hz), 8.56 (1H, brs), 8.63 (1H, brs) .

実施例97: 元素分析 (%) : C₁₅H₁₇ClN₄Oとして
C H N
計算値 59.11 5.62 18.38
実測値 58.91 5.60 18.23
m.p. 138-140 ℃
HRMS (EI+): 304.1086 (-0.5 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.02 (3H, t, J = 8.0 Hz), 1.24 (3H, d, J = 7.3 Hz), 1.74-1.83 (2H, m), 2.51 (1H, dd, J = 1.9, 17.2 Hz), 2.78 (1H, dd, J = 6.8, 17.2 Hz), 3.25-3.32 (1H, m), 7.19 (1H, dd, J = 1.8, 9.8 Hz), 7.82 (1H, d, J = 9.8 Hz), 8.45 (1H, d, J = 1.8 Hz), 8.58 (1H, brs). Example 97: Elemental analysis (%): as C ₁₅ H ₁₇ ClN ₄ O
CHN
Calculated 59.11 5.62 18.38
Actual value 58.91 5.60 18.23
mp 138-140 ℃
HRMS (EI +): 304.1086 (-0.5 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.02 (3H, t, J = 8.0 Hz), 1.24 (3H, d, J = 7.3 Hz), 1.74-1.83 (2H, m), 2.51 (1H, dd , J = 1.9, 17.2 Hz), 2.78 (1H, dd, J = 6.8, 17.2 Hz), 3.25-3.32 (1H, m), 7.19 (1H, dd, J = 1.8, 9.8 Hz), 7.82 (1H, d, J = 9.8 Hz), 8.45 (1H, d, J = 1.8 Hz), 8.58 (1H, brs).

実施例98: 元素分析 (%) : C₁₂H₁₁ClN₄Oとして
C H N
計算値 54.87 4.22 21.33
実測値 54.78 4.19 21.42
m.p. 179-181 ℃
HRMS (EI+): 262.0640 (+1.9 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.32 (3H, d, J = 7.3 Hz), 2.50 (1H, d, J = 17.1 Hz), 2.79 (1H, dd, J = 7.3, 17.1 Hz), 3.23-3.30 (1H, m), 7.30 (1H, dd, J = 1.8, 9.8 Hz), 8.10 (1H, s), 8.23 (1H, d, J = 9.8 Hz), 8.50 (1H, brs), 8.56 (1H, d, J = 1.8Hz). Example 98: Elemental analysis (%): as C ₁₂ H ₁₁ ClN ₄ O
CHN
Calculated 54.87 4.22 21.33
Actual value 54.78 4.19 21.42
mp 179-181 ℃
HRMS (EI +): 262.0640 (+1.9 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32 (3H, d, J = 7.3 Hz), 2.50 (1H, d, J = 17.1 Hz), 2.79 (1H, dd, J = 7.3, 17.1 Hz), 3.23-3.30 (1H, m), 7.30 (1H, dd, J = 1.8, 9.8 Hz), 8.10 (1H, s), 8.23 (1H, d, J = 9.8 Hz), 8.50 (1H, brs), 8.56 (1H, d, J = 1.8Hz).

実施例99: mp >300℃
HRMS (EI+): 306.0559 (+3.9mmu)[M+]
¹H-NMR (400 MHz, DMSO-d⁶) δ 1.29(3H, d, J=7.0Hz), 2.52(1H, dd, J=6.1, 16.5Hz), 2.91(1H, dd, J=8.3, 16.5Hz), 3.75-3.83(1H, m), 7.83(1H, dd, J=1.8, 9.5Hz), 8.30(1H, d, J=9.5Hz), 9.53(1H, d, J=1.8Hz), 12.20(1H, br s), 12.50(1H, s). Example 99: mp> 300 ° C
HRMS (EI +): 306.0559 (+ 3.9mmu) [M +]
¹ H-NMR (400 MHz, DMSO-d ⁶ ) δ 1.29 (3H, d, J = 7.0Hz), 2.52 (1H, dd, J = 6.1, 16.5Hz), 2.91 (1H, dd, J = 8.3, 16.5Hz), 3.75-3.83 (1H, m), 7.83 (1H, dd, J = 1.8, 9.5Hz), 8.30 (1H, d, J = 9.5Hz), 9.53 (1H, d, J = 1.8Hz) , 12.20 (1H, br s), 12.50 (1H, s).

実施例100: ¹H-NMR (400 MHz, CDCl₃) δ 1.14(3H, d, J=7.3Hz), 1.24(6H, t, J=7.0Hz), 2.46(1H, dd, J=1.2, 16.8Hz), 2.78(1H, dd, J=6.7, 16.8Hz), 3.52-3.66(2H, m), 3.71-3.80(2H, m), 3.88-3.92(1H, m), 5,74(1H, s), 7.17-7.22(1H, m), 7.98-8.02(1H, m), 8.37-8.38(1H, m), 8.45(1H, br s) Example 100: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.14 (3H, d, J = 7.3 Hz), 1.24 (6H, t, J = 7.0 Hz), 2.46 (1H, dd, J = 1.2, 16.8Hz), 2.78 (1H, dd, J = 6.7, 16.8Hz), 3.52-3.66 (2H, m), 3.71-3.80 (2H, m), 3.88-3.92 (1H, m), 5,74 (1H , s), 7.17-7.22 (1H, m), 7.98-8.02 (1H, m), 8.37-8.38 (1H, m), 8.45 (1H, br s)

実施例101 : ¹H-NMR (400 MHz, CDCl₃) δ 0.05(3H, s), 0.10(3H, s), 0.88(9H, s), 1.23(3H, d, J=7.3Hz), 2.46(1H, dd, J=1.2, 16.8Hz), 2.76(1H, dd, J=6.7, 16.8Hz), 3.66-3.74(1H, m), 4.93(1H, d, J=12.8Hz), 5.00(1H, d, J=12.8Hz), 7.23(1H, dd, J=1.8, 9.5Hz), 8.06(1H, dd, J=0.9, 9.5Hz), 8.46(1H, dd, J=0.9, 1.8Hz), 8.48(1H, br s). Example 101: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.05 (3H, s), 0.10 (3H, s), 0.88 (9H, s), 1.23 (3H, d, J = 7.3 Hz), 2.46 (1H, dd, J = 1.2, 16.8Hz), 2.76 (1H, dd, J = 6.7, 16.8Hz), 3.66-3.74 (1H, m), 4.93 (1H, d, J = 12.8Hz), 5.00 ( 1H, d, J = 12.8Hz), 7.23 (1H, dd, J = 1.8, 9.5Hz), 8.06 (1H, dd, J = 0.9, 9.5Hz), 8.46 (1H, dd, J = 0.9, 1.8Hz) ), 8.48 (1H, br s).

実施例102: m.p. 172-174 ℃
元素分析（％）：C₁₃H₁₀F₄N₄Oとして
C H N
計算値 49.69 3.21 17.83
実測値 49.57 3.18 17.75
HRMS (EI+): 314.0786 (-0.4 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.17 (3H, d, J = 7.3 Hz), 2.53 (1H, dd, J = 2.5, 16.5 Hz), 2.81 (1H, dd, J = 6.7, 16.5 Hz), 3.21-3.29 (1H, m), 7.29-7.34 (1H, m), 7.93-7.97 (1H, m), 8.46-8.47 (1H, m), 8.62 (1H, brs). Example 102: mp 172-174 ° C
Elemental analysis (%): As C ₁₃ H ₁₀ F ₄ N ₄ O
CHN
Calculated 49.69 3.21 17.83
Actual value 49.57 3.18 17.75
HRMS (EI +): 314.0786 (-0.4 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.17 (3H, d, J = 7.3 Hz), 2.53 (1H, dd, J = 2.5, 16.5 Hz), 2.81 (1H, dd, J = 6.7, 16.5 Hz) ), 3.21-3.29 (1H, m), 7.29-7.34 (1H, m), 7.93-7.97 (1H, m), 8.46-8.47 (1H, m), 8.62 (1H, brs).

実施例103: m.p. 225-227 ℃
HRMS (EI+): 339.9745 (+1.8 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃)δ1.29 (3H, d, J = 7.3 Hz), 2.50 (1H, dd, J = 1.8, 17.1 Hz), 2.77 (1H, dd, J = 6.7, 17.1 Hz), 3.82-3.90 (1H, m), 7.30 (1H, dd, J = 1.8, 9.8 Hz), 8.14 (1H, d, J = 9.8 Hz), 8.45 (1H, d, J = 1.8 Hz), 8.50 (1H, brs). Example 103: mp 225-227 ° C
HRMS (EI +): 339.9745 (+1.8 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.29 (3H, d, J = 7.3 Hz), 2.50 (1H, dd, J = 1.8, 17.1 Hz), 2.77 (1H, dd, J = 6.7, 17.1 Hz), 3.82-3.90 (1H, m), 7.30 (1H, dd, J = 1.8, 9.8 Hz), 8.14 (1H, d, J = 9.8 Hz), 8.45 (1H, d, J = 1.8 Hz), 8.50 (1H, brs).

実施例104: 元素分析（％）：C₁₃H₁₀F₄N₄Oとして
C H N
計算値 49.69 3.21 17.83
実測値 49.57 3.18 17.75
m.p. 166-168 ℃
HRMS (EI+): 302.0969 (+3.5 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.00-1.14 (4H, m), 1.29 (3H, d, J = 7.3 Hz), 2.12-2.19 (1H, m), 2.51 (1H, dd, J = 1.8, 7.1 Hz), 2.79 (1H, dd, J = 7.1, 16.5 Hz), 3.66-3.69 (1H, m), 7.19 (1H, dd, J = 1.8, 9.8 Hz), 7.94 (1H, d, J = 9.8 Hz), 8.39 (1H, d, J = 1.8 Hz), 8.50 (1H, brs). Example 104: Elemental analysis (%): as _{C 13 H 10 F 4 N 4} O
CHN
Calculated 49.69 3.21 17.83
Actual value 49.57 3.18 17.75
mp 166-168 ℃
HRMS (EI +): 302.0969 (+3.5 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.00-1.14 (4H, m), 1.29 (3H, d, J = 7.3 Hz), 2.12-2.19 (1H, m), 2.51 (1H, dd, J = 1.8, 7.1 Hz), 2.79 (1H, dd, J = 7.1, 16.5 Hz), 3.66-3.69 (1H, m), 7.19 (1H, dd, J = 1.8, 9.8 Hz), 7.94 (1H, d, J = 9.8 Hz), 8.39 (1H, d, J = 1.8 Hz), 8.50 (1H, brs).

実施例105: m.p. 235-237 ℃
HRMS (EI+): 290.1197 (+1.8 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.35 (3H, d, J = 7.3 Hz), 1.40 (3H, t, J = 7.3 Hz), 2.51-2.56 (1H, m), 2.75 (1H, dd, J = 6.1, 16.5 Hz), 2.96-3.02 (2H, m), 3.56-3.64 (1H, m), 6.57 (1H, dd, J = 1.8, 10.4 Hz), 7.93-7.94 (1H, m), 8.31 (1H, brs), 13.1 (1H, brs).
実施例106: m.p. 205-207 ℃
元素分析（％）：C₁₄H₁₅ClN₄O₂として
C H N
計算値 54.82 4.93 18.26
実測値 54.53 4.79 18.20
HRMS (EI+): 306.0884 (+0.1 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.35 (3H, d, J = 7.3 Hz), 1.40 (3H, t, J = 7.3 Hz), 2.54 (1H, dd, J = 1.8, 17.1 Hz), 2.75 (1H, dd, J = 6.1, 17.1 Hz), 2.96-3.02 (2H, m), 3.57-3.61 (1H, m), 6.64 (1H, d, J = 1.8 Hz), 8.02 (1H, d, J = 1.8 Hz), 8.33 (1H, brs), 12.9 (1H, s). Example 105: mp 235-237 ° C
HRMS (EI +): 290.1197 (+1.8 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, d, J = 7.3 Hz), 1.40 (3H, t, J = 7.3 Hz), 2.51-2.56 (1H, m), 2.75 (1H, dd , J = 6.1, 16.5 Hz), 2.96-3.02 (2H, m), 3.56-3.64 (1H, m), 6.57 (1H, dd, J = 1.8, 10.4 Hz), 7.93-7.94 (1H, m), 8.31 (1H, brs), 13.1 (1H, brs).
Example 106: mp 205-207 ° C
Elemental analysis (%): as C ₁₄ H ₁₅ ClN ₄ O ₂
CHN
Calculated 54.82 4.93 18.26
Actual value 54.53 4.79 18.20
HRMS (EI +): 306.0884 (+0.1 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, d, J = 7.3 Hz), 1.40 (3H, t, J = 7.3 Hz), 2.54 (1H, dd, J = 1.8, 17.1 Hz), 2.75 (1H, dd, J = 6.1, 17.1 Hz), 2.96-3.02 (2H, m), 3.57-3.61 (1H, m), 6.64 (1H, d, J = 1.8 Hz), 8.02 (1H, d, J = 1.8 Hz), 8.33 (1H, brs), 12.9 (1H, s).

実施例107: m.p. 206-208 ℃
HRMS (EI+): 324.0551 (+0.6 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.10 (3H, t, J = 7.3 Hz), 1.34 (3H, t, J = 7.3 Hz), 2.47 (1H, dd, J = 4.9, 16.5 Hz), 2.79 (1H, q, J = 7.3 Hz), 2.86 (1H, dd, J = 6.7, 16.5 Hz), 3.06-3.14 (2H, m), 7.23 (1H, d, J = 1.2 Hz), 8.41 (1H, d, J = 1.2 Hz), 8.51 (1H, brs). Example 107: mp 206-208 ° C
HRMS (EI +): 324.0551 (+0.6 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.10 (3H, t, J = 7.3 Hz), 1.34 (3H, t, J = 7.3 Hz), 2.47 (1H, dd, J = 4.9, 16.5 Hz), 2.79 (1H, q, J = 7.3 Hz), 2.86 (1H, dd, J = 6.7, 16.5 Hz), 3.06-3.14 (2H, m), 7.23 (1H, d, J = 1.2 Hz), 8.41 (1H , d, J = 1.2 Hz), 8.51 (1H, brs).

実施例108: m.p. 165-167 ℃
HRMS (EI+): 292.1117 (-1.9 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.12 (3H, d, J = 7.3 Hz), 1.32 (3H, t, J = 7.3 Hz), 2.80-2.91 (3H, m), 3.08-3.12 (1H, m), 6.88-6.93 (1H, m), 8.27-8.28 (1H, m), 8.51 (1H, brs). Example 108: mp 165-167 ° C
HRMS (EI +): 292.1117 (-1.9 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.12 (3H, d, J = 7.3 Hz), 1.32 (3H, t, J = 7.3 Hz), 2.80-2.91 (3H, m), 3.08-3.12 (1H , m), 6.88-6.93 (1H, m), 8.27-8.28 (1H, m), 8.51 (1H, brs).

＜実施例109＞
６−（６−クロロ−２−ホルミル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 109>
6- (6-Chloro-2-formyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例89の化合物(1.87g)をアセトン(75mL)に溶解し、パラトルエンスルホン酸(100mg)を加え、常温にて3時間撹拌した。析出晶を濾取した後、濾液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をヘキサンに懸濁させ、結晶を濾取し、先に得られた結晶と合わせて乾燥し、目的物(1.39g)を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.12(3H, d, J=7.3Hz), 2.50(1H, dd, J=2.7, 7.1Hz), 2.98(1H, dd, J=7.0, 7.1Hz), 3.51-3.59(1H, m), 7.29(1H, dd, J=1.8, 9.8Hz), 7.93(1H, dd, J=0.9, 9.8Hz), 8.56(1H, dd, J=0.9, 1.8Hz), 8.64(1H, s), 10.24(1H, s). The compound of Example 89 (1.87 g) was dissolved in acetone (75 mL), paratoluenesulfonic acid (100 mg) was added, and the mixture was stirred at room temperature for 3 hours. Precipitated crystals were collected by filtration, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was suspended in hexane, and the crystals were collected by filtration and combined with the crystals obtained above and dried to obtain the desired product (1.39 g) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.12 (3H, d, J = 7.3Hz), 2.50 (1H, dd, J = 2.7, 7.1Hz), 2.98 (1H, dd, J = 7.0, 7.1Hz ), 3.51-3.59 (1H, m), 7.29 (1H, dd, J = 1.8, 9.8Hz), 7.93 (1H, dd, J = 0.9, 9.8Hz), 8.56 (1H, dd, J = 0.9, 1.8 Hz), 8.64 (1H, s), 10.24 (1H, s).

＜実施例110＞
６−[６−クロロ−２−（１−ヒドロキシエチル）−ピラゾロ[１，５−ａ]ピリジン−３−イル]−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 110>
6- [6-Chloro-2- (1-hydroxyethyl) -pyrazolo [1,5-a] pyridin-3-yl] -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

アルゴンガス気流下、メチルマグネシウムヨージド(0.86mL, 3.0mol/Lジエチルエーテル溶液)をテトラヒドロフラン(3mL)で希釈後、氷冷撹拌下、上記実施例109の化合物(150mg)のテトラヒドロフラン(20mL)溶液を滴下した。常温にて5時間撹拌後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1：1〜酢酸エチルのみ)で精製し、目的物(88.6mg)を淡黄色粉末として得た。
m.p. 192-194 ℃
元素分析（％）：C₁₄H₁₅ClN₄O₂として
C H N
計算値 54.82 4.93 18.26
実測値 54.84 4.78 18.11
LRMS (EI+): 306 [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.91-1.39(3H, m), 1.66-1.70(3H, m), 2.40-2.58(1H, m), 2.75-2.88(1H, m), 3.39-3.44(1H, m), 4.80(1H, br s), 5.05-5.12(1H, m), 7.22-7.30(1H, m), 7.60(1H, d, J=9.5Hz), 8.52-8.53(2H, m). In an argon gas stream, methyl magnesium iodide (0.86 mL, 3.0 mol / L diethyl ether solution) was diluted with tetrahydrofuran (3 mL), and then stirred under ice-cooling, a solution of the compound of Example 109 (150 mg) in tetrahydrofuran (20 mL). Was dripped. After stirring at room temperature for 5 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After sequentially washing with water and saturated brine, the solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-ethyl acetate alone) to obtain the desired product (88.6 mg) as a pale yellow powder.
mp 192-194 ℃
Elemental analysis (%): as C ₁₄ H ₁₅ ClN ₄ O ₂
CHN
Calculated 54.82 4.93 18.26
Actual value 54.84 4.78 18.11
LRMS (EI +): 306 [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.91-1.39 (3H, m), 1.66-1.70 (3H, m), 2.40-2.58 (1H, m), 2.75-2.88 (1H, m), 3.39- 3.44 (1H, m), 4.80 (1H, br s), 5.05-5.12 (1H, m), 7.22-7.30 (1H, m), 7.60 (1H, d, J = 9.5Hz), 8.52-8.53 (2H , m).

＜実施例111＞
６−[６−クロロ−２−（１−フルオロエチル）−ピラゾロ[１，５−ａ]ピリジン−３−イル]−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 111>
6- [6-Chloro-2- (1-fluoroethyl) -pyrazolo [1,5-a] pyridin-3-yl] -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例110の化合物(100mg)をジクロロメタン(15mL)に溶解し、氷冷撹拌下(ジエチルアミノ)スルファートリフルオリド(0.108mL)のジクロロメタン(5mL)溶液を滴下した。氷冷下30分撹拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。水、飽和食塩水にて順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1：1)で精製し、目的物(65.6mg)を黄色アモルファス状物として得た。
HRMS (EI+): 308.0842 (+0.2 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.20-1.26(3H, m), 1.82-1.89(3H, m), 2.48-2.54(1H, m), 2.77-2.85(1H, m), 3.30-3.41(1H, m), 6.00-6.17(1H, m), 7.22-7.26(1H, m), 7.78-7.84(1H, m), 8.50-8.53(1H, m), 8.79(1H, br s). The compound of Example 110 (100 mg) was dissolved in dichloromethane (15 mL), and a solution of (diethylamino) sulfur trifluoride (0.108 mL) in dichloromethane (5 mL) was added dropwise with ice-cooling and stirring. After stirring for 30 minutes under ice cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After sequentially washing with water and saturated brine, the solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (65.6 mg) as a yellow amorphous product.
HRMS (EI +): 308.0842 (+0.2 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.20-1.26 (3H, m), 1.82-1.89 (3H, m), 2.48-2.54 (1H, m), 2.77-2.85 (1H, m), 3.30- 3.41 (1H, m), 6.00-6.17 (1H, m), 7.22-7.26 (1H, m), 7.78-7.84 (1H, m), 8.50-8.53 (1H, m), 8.79 (1H, br s) .

＜実施例112＞
６−（２−アセチル−６−クロロ−ピラゾロ[１，５−ａ]ピリジン−３−イル]−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 112>
6- (2-acetyl-6-chloro-pyrazolo [1,5-a] pyridin-3-yl] -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

アルゴンガス気流下、オキザリルクロリド(0.171mL)をジクロロメタン(10mL)に溶解し、-78℃にてジメチルスルホキシド(0.187mL)のジクロロメタン(2mL)溶液を滴下した。同温にて30分撹拌後、実施例110(300mg)のジクロロメタン(50mL)溶液を滴下し、ゆっくりと‐40℃まで昇温し、トリエチルアミン(1.36mL)を加え、徐々に0℃まで昇温した。反応液を水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル＝1：1)で精製し、目的物(255mg)を淡黄色粉末として得た。
m.p. 185-187℃
元素分析（％）：C₁₄H₁₃ClN₄O₂として
C H N
計算値 55.18 4.30 18.39
実測値 54.99 4.19 18.24
HRMS (EI+): 304.0703 (-2.4 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.06(3H, d, J=7.6Hz), 2.48(1H, dd, J=3.1, 16.8Hz), 2.74(3H, s), 3.07(1H, dd, J=6.7, 16.8Hz), 3.21-3.29(1H, m), 7.23-7.26(1H, m), 7.70(1H, d, J=9.5Hz), 8.51-8.52(1H, m), 8.54(1H, br s). Under an argon gas stream, oxalyl chloride (0.171 mL) was dissolved in dichloromethane (10 mL), and a solution of dimethyl sulfoxide (0.187 mL) in dichloromethane (2 mL) was added dropwise at −78 ° C. After stirring at the same temperature for 30 minutes, a solution of Example 110 (300 mg) in dichloromethane (50 mL) was added dropwise, the temperature was slowly raised to −40 ° C., triethylamine (1.36 mL) was added, and the temperature was gradually raised to 0 ° C. did. The reaction solution was washed with water and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (255 mg) as a pale yellow powder.
mp 185-187 ° C
Elemental analysis (%): as C ₁₄ H ₁₃ ClN ₄ O ₂
CHN
Calculated 55.18 4.30 18.39
Actual value 54.99 4.19 18.24
HRMS (EI +): 304.0703 (-2.4 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.06 (3H, d, J = 7.6Hz), 2.48 (1H, dd, J = 3.1, 16.8Hz), 2.74 (3H, s), 3.07 (1H, dd , J = 6.7, 16.8Hz), 3.21-3.29 (1H, m), 7.23-7.26 (1H, m), 7.70 (1H, d, J = 9.5Hz), 8.51-8.52 (1H, m), 8.54 ( 1H, br s).

＜実施例113＞
６−[６−クロロ−２−（１−ヒドロキシ−１−メチルエチル）−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン <Example 113>
6- [6-Chloro-2- (1-hydroxy-1-methylethyl) -pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -Pyridazinone

アルゴンガス気流下、実施例112の化合物(60mg)をテトラヒドロフラン(5mL)に溶解し、氷冷撹拌下メチルマグネシウムブロミド(0.704mL, 1.4mol/Lテトラヒドロフラン‐トルエン溶液)を加え、同温にて1時間、更に常温にて2時間撹拌した。飽和塩化アンモニア水溶液を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1：1〜1：2)で精製し、目的物(39mg)を淡黄色粉末として得た。
m.p. 196-198℃
HRMS (EI+): 320.1032 (-0.8 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.29(3H, d, J=7.3Hz), 1.65(3H, s), 1.69(3H, s), 2.55(1H, dd, J=1.8, 16.8Hz), 2.83(1H, dd, J=6.4, 16.8Hz), 3.40-3.48(1H, m), 5.73(1H, br s), 7.23(1H, dd, J=1.8, 9.8Hz), 7.50(1H, d, J=9.8Hz), 8.50-8.51(1H, m), 8.71(1H, br s). Under an argon gas stream, the compound of Example 112 (60 mg) was dissolved in tetrahydrofuran (5 mL), and methylmagnesium bromide (0.704 mL, 1.4 mol / L tetrahydrofuran-toluene solution) was added under ice-cooling and stirring. The mixture was further stirred for 2 hours at room temperature. Saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 2) to obtain the desired product (39 mg) as a pale yellow powder.
mp 196-198 ℃
HRMS (EI +): 320.1032 (-0.8 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.29 (3H, d, J = 7.3Hz), 1.65 (3H, s), 1.69 (3H, s), 2.55 (1H, dd, J = 1.8, 16.8Hz ), 2.83 (1H, dd, J = 6.4, 16.8Hz), 3.40-3.48 (1H, m), 5.73 (1H, br s), 7.23 (1H, dd, J = 1.8, 9.8Hz), 7.50 (1H , d, J = 9.8Hz), 8.50-8.51 (1H, m), 8.71 (1H, br s).

＜実施例114＞
６−[６−クロロ−２−（１−メチルビニル）−ピラゾロ[１，５−ａ]ピリジン−３−イル]−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 114>
6- [6-Chloro-2- (1-methylvinyl) -pyrazolo [1,5-a] pyridin-3-yl] -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

アルゴンガス気流下、メチルトリフェニルホスホニウムブロミド(352mg)をテトラヒドロフラン(5mL)に懸濁し、氷冷撹拌下ｎ−ブチルリチウム(0.623mL, 1.58mol/Lヘキサン溶液)を滴下し、同温にて30分撹拌後、更に常温にて30分撹拌した。これに氷冷撹拌下、実施例112の化合物(60mg)のテトラヒドロフラン(10mL)溶液を加え、常温にて3時間撹拌した。飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=2：1)で精製し、目的物(29.5mg)を黄色粉末として得た。
m.p. 187-189℃
HRMS (EI+): 303.0983 (-3.0 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ1.08(3H, d, J=7.3Hz), 2.25(3H, s), 2.46(1H, dd, J=2.4, 16.8Hz), 2.72(1H, dd, J=6.7,16.8Hz), 3.28-3.36(1H, m), 5.31(1H, s), 5.43(1H, s), 7.20(1H, dd, J=1.8, 9.5Hz), 7.76(1H, dd, J=0.6, 9.5Hz), 8.47(1H, dd, J=0.6, 1.8Hz), 8.52(1H, br s). Under a stream of argon gas, methyltriphenylphosphonium bromide (352 mg) was suspended in tetrahydrofuran (5 mL), and n-butyllithium (0.623 mL, 1.58 mol / L hexane solution) was added dropwise with stirring under ice cooling. After stirring for 30 minutes, the mixture was further stirred at room temperature for 30 minutes. To this was added a solution of the compound of Example 112 (60 mg) in tetrahydrofuran (10 mL) with stirring under ice cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (29.5 mg) as a yellow powder.
mp 187-189 ℃
HRMS (EI +): 303.0983 (-3.0 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.08 (3H, d, J = 7.3Hz), 2.25 (3H, s), 2.46 (1H, dd, J = 2.4, 16.8Hz), 2.72 (1H, dd, J = 6.7,16.8Hz), 3.28-3.36 (1H, m), 5.31 (1H, s), 5.43 (1H, s), 7.20 (1H, dd, J = 1.8, 9.5Hz), 7.76 (1H , dd, J = 0.6, 9.5Hz), 8.47 (1H, dd, J = 0.6, 1.8Hz), 8.52 (1H, br s).

＜実施例115＞
６−（２−アセチル−６−クロロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−ｔ−ブトキシカルボニル−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 115>
6- (2-acetyl-6-chloro-pyrazolo [1,5-a] pyridin-3-yl) -2-t-butoxycarbonyl-5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例112の化合物(160mg)をジクロロメタン(10mL)に溶解し、ジ‐t-ブチルジカーボネート(172mg)、４−ジメチルアミノピリジン(10mg)及びトリエチルアミン(0.11mL)を順次加え、常温にて24時間撹拌した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=5：1)で精製し、目的物(198mg)を無色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.06(3H, d, J=7.6Hz), 1.62(9H, s), 2.58(1H, dd, J=2.7, 16.2Hz), 2.74(3H, s), 3.14(1H, dd, J=6.4, 16.2Hz), 3.42-3.50(1H, m), 7.27(1H, dd, J=1.5, 9.5Hz), 8.04(1H, dd, J=0.6, 9.5Hz), 8.52(1H, dd, J=0.6, 1.5Hz). The compound of Example 112 (160 mg) was dissolved in dichloromethane (10 mL), di-t-butyl dicarbonate (172 mg), 4-dimethylaminopyridine (10 mg) and triethylamine (0.11 mL) were sequentially added, and the mixture was stirred at room temperature for 24 hours. Stir for hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (198 mg) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.06 (3H, d, J = 7.6Hz), 1.62 (9H, s), 2.58 (1H, dd, J = 2.7, 16.2Hz), 2.74 (3H, s ), 3.14 (1H, dd, J = 6.4, 16.2Hz), 3.42-3.50 (1H, m), 7.27 (1H, dd, J = 1.5, 9.5Hz), 8.04 (1H, dd, J = 0.6, 9.5 Hz), 8.52 (1H, dd, J = 0.6, 1.5Hz).

＜実施例116＞
６−[６−クロロ−２−（１，１−ジフルオロエチル）−ピラゾロ[１，５−ａ]ピリジン−３−イル]−２−ｔ−ブトキシカルボニル−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 116>
6- [6-Chloro-2- (1,1-difluoroethyl) -pyrazolo [1,5-a] pyridin-3-yl] -2-t-butoxycarbonyl-5-methyl-4,5-dihydro- 3- (2H) -pyridazinone

アルゴンガス気流下、実施例115の化合物（174mg）をジクロロメタン（3mL）に溶解し、［ビス(2−メトキシエチル)アミノ］スルファートリフルオリド(3mL, 50%w/wテトラヒドロフラン溶液)及びエタノール（1滴）を加え、5日間加熱還流した。放冷後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=8：1）で精製し、目的物（91mg）を淡黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.14(3H, d, J=7.3Hz), 1.64(9H, s), 2.19(3H, t, J=19.3Hz), 2.59(1H, dd, J=1.8, 15.9Hz), 2.89(1H, dd, J=6.1, 15.9Hz), 3.56-3.66(1H, m), 7.29(1H, dd, J=1.5, 9.8Hz), 8.29(1H, d, J=9.8Hz), 8.49(1H, d, J=1.5Hz). Under an argon gas stream, the compound of Example 115 (174 mg) was dissolved in dichloromethane (3 mL), and [bis (2-methoxyethyl) amino] sulfur trifluoride (3 mL, 50% w / w tetrahydrofuran solution) and ethanol ( 1 drop) was added and heated to reflux for 5 days. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain the desired product (91 mg) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.14 (3H, d, J = 7.3Hz), 1.64 (9H, s), 2.19 (3H, t, J = 19.3Hz), 2.59 (1H, dd, J = 1.8, 15.9Hz), 2.89 (1H, dd, J = 6.1, 15.9Hz), 3.56-3.66 (1H, m), 7.29 (1H, dd, J = 1.5, 9.8Hz), 8.29 (1H, d, J = 9.8Hz), 8.49 (1H, d, J = 1.5Hz).

＜実施例117＞
６−[６−クロロ−２−（１，１−ジフルオロエチル）−ピラゾロ[１，５−ａ]ピリジン−３−イル]−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 117>
6- [6-Chloro-2- (1,1-difluoroethyl) -pyrazolo [1,5-a] pyridin-3-yl] -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例116の化合物（100mg）をジクロロメタンに溶解し、氷冷撹拌下トリフルオロ酢酸（1mL）を加え、常温にて1時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=3：1）で精製し、目的物（59.4mg）を無色粉末として得た。
ｍｐ：209-211℃
HRMS (EI+): 326.0763 (+2.3 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.13(3H, d, J=7.3Hz), 2.20(3H, t, J=19.3Hz), 2.48(1H, dd, J=2.4, 16.8Hz), 2.82(1H, dd, J=6.7, 16.8Hz), 3.40-3.48(1H, m), 7.26(1H, dd, J=1.8, 9.8Hz), 7.79(1H, d, J=9.8Hz), 8.48(1H, d, J=1.8Hz), 8.50(1H, br s). The compound of Example 116 (100 mg) was dissolved in dichloromethane, trifluoroacetic acid (1 mL) was added with ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (59.4 mg) as a colorless powder.
mp: 209-211 ° C
HRMS (EI +): 326.0763 (+2.3 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.13 (3H, d, J = 7.3Hz), 2.20 (3H, t, J = 19.3Hz), 2.48 (1H, dd, J = 2.4, 16.8Hz), 2.82 (1H, dd, J = 6.7, 16.8Hz), 3.40-3.48 (1H, m), 7.26 (1H, dd, J = 1.8, 9.8Hz), 7.79 (1H, d, J = 9.8Hz), 8.48 (1H, d, J = 1.8Hz), 8.50 (1H, br s).

＜実施例118＞
６−（６−フルオロ−２−ホルミル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 118>
6- (6-Fluoro-2-formyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例100の化合物(660mg)を用い、実施例109と同様の方法で目的物(520mg)を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.12(3H, d, J=7.3Hz), 2.50(1H, dd, J=2.4, 16.5Hz), 2.98(1H, dd, J=6.7, 16.5Hz), 3.54-3.62(1H, m), 7.25-7.30(1H, m), 8.00(1H, dd, J=5.5, 9.8Hz), 8.45-8.47(1H, m), 8.61(1H, br s), 10.24(1H, s). The target product (520 mg) was obtained as a yellow powder in the same manner as in Example 109, using the compound of Example 100 (660 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.12 (3H, d, J = 7.3Hz), 2.50 (1H, dd, J = 2.4, 16.5Hz), 2.98 (1H, dd, J = 6.7, 16.5Hz ), 3.54-3.62 (1H, m), 7.25-7.30 (1H, m), 8.00 (1H, dd, J = 5.5, 9.8Hz), 8.45-8.47 (1H, m), 8.61 (1H, br s) , 10.24 (1H, s).

＜実施例119＞
６−[６−フルオロ−２−（１−ヒドロキシエチル）−ピラゾロ[１，５−ａ]ピリジン−３−イル]−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 119>
6- [6-Fluoro-2- (1-hydroxyethyl) -pyrazolo [1,5-a] pyridin-3-yl] -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例118の化合物(540mg)を用いて、実施例110と同様の方法で目的物(195mg)を淡黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.28-1.40(3H, m), 1.67-1.71(3H, m), 2.52-2.58(1H, m), 2.77-2.86(1H, m), 3.38-3.47(1H, m), 4.69-4.73(1H, m), 5.01-5.12(1H, m), 7.21-7.26(1H, m), 7.64(1H, dd, J=5.2, 10.1Hz), 8.42-8.43(1H, m), 8.54(1H, br s). Using the compound of Example 118 (540 mg), the target product (195 mg) was obtained as a pale yellow powder in the same manner as in Example 110.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.28-1.40 (3H, m), 1.67-1.71 (3H, m), 2.52-2.58 (1H, m), 2.77-2.86 (1H, m), 3.38- 3.47 (1H, m), 4.69-4.73 (1H, m), 5.01-5.12 (1H, m), 7.21-7.26 (1H, m), 7.64 (1H, dd, J = 5.2, 10.1Hz), 8.42- 8.43 (1H, m), 8.54 (1H, br s).

＜実施例120＞
６−（６−クロロ−２−ヒドロキシメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 120>
6- (6-Chloro-2-hydroxymethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例101の化合物(1.99g)をテトラヒドロフラン(20mL) に溶解し、テトラブチルアンモニウムフルオリド(7.34mL, 1.0mol/Lテトラヒドロフラン溶液)を加え、常温にて1時間撹拌した。酢酸エチルで希釈後、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。残渣を酢酸エチル‐イソプロピルエーテル(1：20)に懸濁し、結晶を濾取した。濾液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)にて精製した。先に濾取した結晶と合わせ、乾燥することにより目的物(1.22g)を無
色粉末として得た。
m.p. 206−208℃
元素分析（％）：C₁₃H₁₃ClN₄O₂として
C H N
計算値 53.34 4.48 19.14
実測値 53.20 4.30 19.01
HRMS (EI+): 292.0721 (-0.6 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.36(3H, d, J=7.3Hz), 2.54(1H, dd, J=0.9, 16.8Hz), 2.81(1H, dd, J=6.4, 16.8Hz), 3.39-3.47(1H, m), 4.20(1H, br s), 4.83(2H, d, J=5.5Hz), 7.28(1H, dd, J=1.8, 9.8Hz), 7.67(1H, dd, J=0.6, 9.8Hz), 8.51(1H, dd, J=0.6, 1.8Hz), 8.56(1H, br s). The compound of Example 101 (1.99 g) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (7.34 mL, 1.0 mol / L tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was suspended in ethyl acetate-isopropyl ether (1:20), and the crystals were collected by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The target product (1.22 g) was obtained as a colorless powder by combining with the crystals collected earlier and drying.
mp 206-208 ° C
Elemental analysis (%): as C ₁₃ H ₁₃ ClN ₄ O ₂
CHN
Calculated 53.34 4.48 19.14
Actual value 53.20 4.30 19.01
HRMS (EI +): 292.0721 (-0.6 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, d, J = 7.3Hz), 2.54 (1H, dd, J = 0.9, 16.8Hz), 2.81 (1H, dd, J = 6.4, 16.8Hz ), 3.39-3.47 (1H, m), 4.20 (1H, br s), 4.83 (2H, d, J = 5.5Hz), 7.28 (1H, dd, J = 1.8, 9.8Hz), 7.67 (1H, dd , J = 0.6, 9.8Hz), 8.51 (1H, dd, J = 0.6, 1.8Hz), 8.56 (1H, br s).

＜実施例121＞
６−（６−クロロ−２−フルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 121>
6- (6-Chloro-2-fluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例120の化合物(100mg)を用い、実施例111と同様な方法で目的物(59mg)を黄色粉末として得た。
m.p. 211-213℃
HRMS (EI+): 294.0674 (-1.0 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.29(3H, d, J=7.3Hz), 2.52(1H, dd, J=1.5, 16.8Hz), 2.80(1H, dd, J=6.4, 16.8Hz), 3.35-3.42(1H, m), 5.63(1H, dd, J=11.6, 18.3Hz), 5.75(1H, dd, J=11.6, 18.3Hz), 7.28(1H, dd, J=1.2, 9.8Hz), 8.01(1H, d, J=9.8Hz), 8.51(1H, d, J=1.2Hz), 8.57(1H, br s). Using the compound of Example 120 (100 mg), the target product (59 mg) was obtained as a yellow powder in the same manner as in Example 111.
mp 211-213 ℃
HRMS (EI +): 294.0674 (-1.0 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.29 (3H, d, J = 7.3Hz), 2.52 (1H, dd, J = 1.5, 16.8Hz), 2.80 (1H, dd, J = 6.4, 16.8Hz ), 3.35-3.42 (1H, m), 5.63 (1H, dd, J = 11.6, 18.3Hz), 5.75 (1H, dd, J = 11.6, 18.3Hz), 7.28 (1H, dd, J = 1.2, 9.8 Hz), 8.01 (1H, d, J = 9.8Hz), 8.51 (1H, d, J = 1.2Hz), 8.57 (1H, br s).

＜実施例122＞
６−（６−クロロ−２−ビニル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 122>
6- (6-Chloro-2-vinyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例109の化合物(200mg)を出発原料とし、実施例114と同様な方法により目的物(97.5mg)を黄色粉末として得た。
m.p. 164-166℃
HRMS (FAB+): 289.0851 (-0.5 mmu) [M+H]
¹H-NMR (400 MHz, CDCl₃) δ 1.24(3H, d, J=7.3Hz), 2.50(1H, dd, J=2.1, 16.8Hz), 2.78(1H, dd, J=6.4, 16.8Hz), 3.28-3.36(1H, m), 5.58(1H, dd, J=1.5, 11.0Hz), 6.13(1H, dd, J=1.5, 17.4Hz), 6.98(1H, dd, J=11.0, 17.4Hz), 7.21(1H, dd, J=1.8, 9.5Hz), 7.87(1H, d, J=9.5Hz), 8.48-8.49(1H, m), 8.58(1H, br s). The compound of Example 109 (200 mg) was used as a starting material, and the target product (97.5 mg) was obtained as a yellow powder by the same method as in Example 114.
mp 164-166 ℃
HRMS (FAB +): 289.0851 (-0.5 mmu) [M + H]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.24 (3H, d, J = 7.3Hz), 2.50 (1H, dd, J = 2.1, 16.8Hz), 2.78 (1H, dd, J = 6.4, 16.8Hz ), 3.28-3.36 (1H, m), 5.58 (1H, dd, J = 1.5, 11.0Hz), 6.13 (1H, dd, J = 1.5, 17.4Hz), 6.98 (1H, dd, J = 11.0, 17.4) Hz), 7.21 (1H, dd, J = 1.8, 9.5Hz), 7.87 (1H, d, J = 9.5Hz), 8.48-8.49 (1H, m), 8.58 (1H, br s).

＜実施例123＞
６−（６−クロロ−２−ホルミル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−ｔ−ブトキシカルボニル−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 123>
6- (6-Chloro-2-formyl-pyrazolo [1,5-a] pyridin-3-yl) -2-t-butoxycarbonyl-5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例118の化合物(100mg)を用い、実施例115と同様の方法により目的物(104mg)を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃) δ1.13(3H, d, J=7.3Hz), 1.64(9H, s), 2.61(1H, dd, J=2.1, 16.2Hz), 3.01(1H, dd, J=6.4, 16.2Hz), 3.83-3.91(1H, m), 7.34(1H, dd, J=1.8, 9.8Hz), 8.39(1H, dd, J=0.9, 9.8Hz), 8.58(1H, dd, J=0.9, 1.8Hz), 10.24(1H, s). The target product (104 mg) was obtained as a yellow powder in the same manner as in Example 115, using the compound of Example 118 (100 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.13 (3H, d, J = 7.3Hz), 1.64 (9H, s), 2.61 (1H, dd, J = 2.1, 16.2Hz), 3.01 (1H, dd, J = 6.4, 16.2Hz), 3.83-3.91 (1H, m), 7.34 (1H, dd, J = 1.8, 9.8Hz), 8.39 (1H, dd, J = 0.9, 9.8Hz), 8.58 (1H , dd, J = 0.9, 1.8Hz), 10.24 (1H, s).

＜実施例124＞
６−（６−クロロ−２−ジフルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−ｔ−ブトキシカルボニル−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 124>
6- (6-Chloro-2-difluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -2-t-butoxycarbonyl-5-methyl-4,5-dihydro-3- (2H)- Pyridazinone

アルゴンガス気流下、実施例123の化合物(100mg)をジクロロメタン(2mL)に溶解し、氷冷撹拌下ジエチルアミノスルファートリフルオリド(0.0846mL)を加え、常温にて24時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出し、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル＝5：1)で精製し、目的物(90mg)を淡黄色アモルファス状物として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.22(3H, d, J=7.3Hz), 1.66(9H, s), 2.62(1H, dd, J=1.8, 15.9Hz), 2.89(1H, dd, J=6.1, 15.9Hz), 3.56-3.61(1H, m), 7.20(1H, dd, J=53.5, 54.7Hz), 7.35(1H, dd, J=1.8, 9.5Hz), 8.48(1H, dd, J=0.6, 9.5Hz), 8.52(1H, dd, J=0.6, 1.8Hz). Under an argon gas stream, the compound of Example 123 (100 mg) was dissolved in dichloromethane (2 mL), diethylaminosulfur trifluoride (0.0846 mL) was added with stirring under ice cooling, and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (90 mg) as a pale yellow amorphous product.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22 (3H, d, J = 7.3Hz), 1.66 (9H, s), 2.62 (1H, dd, J = 1.8, 15.9Hz), 2.89 (1H, dd , J = 6.1, 15.9Hz), 3.56-3.61 (1H, m), 7.20 (1H, dd, J = 53.5, 54.7Hz), 7.35 (1H, dd, J = 1.8, 9.5Hz), 8.48 (1H, dd, J = 0.6, 9.5Hz), 8.52 (1H, dd, J = 0.6, 1.8Hz).

＜実施例125＞
６−（６−クロロ−２−ジフルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 125>
6- (6-Chloro-2-difluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例124の化合物(90mg)を酢酸エチル(1mL)に溶解し、1mol/L塩酸‐メタノール(10mL)を加え、常温にて2時間撹拌した。溶媒を留去し、残渣を酢酸エチルに溶解し、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル＝2：1)で精製し、目的物(29.1mg)を無色粉末として得た。
m.p. 169-171℃
MS (FAB+): 313 [M+H]
¹H-NMR (400 MHz, CDCl₃) δ1.22(3H, d, J=7.3Hz), 2.49-2.54(1H, m), 2.81(1H, dd, J=6.7, 17.1Hz), 3.42-3.50(1H, m), 7.00(1H, dd, J=53.2), 7.31(1H, dd, J=1.8, 9.5Hz), 8.02(1H, dd, J=0.6, 9.5Hz), 8.50(1H, br s), 8.51(1H, dd, J=0.6, 1.8Hz). The compound of Example 124 (90 mg) was dissolved in ethyl acetate (1 mL), 1 mol / L hydrochloric acid-methanol (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (29.1 mg) as a colorless powder.
mp 169-171 ℃
MS (FAB +): 313 [M + H]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.22 (3H, d, J = 7.3Hz), 2.49-2.54 (1H, m), 2.81 (1H, dd, J = 6.7, 17.1Hz), 3.42- 3.50 (1H, m), 7.00 (1H, dd, J = 53.2), 7.31 (1H, dd, J = 1.8, 9.5Hz), 8.02 (1H, dd, J = 0.6, 9.5Hz), 8.50 (1H, br s), 8.51 (1H, dd, J = 0.6, 1.8Hz).

＜実施例126＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−（ピリジン−２−イルメチル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 126>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2- (pyridin-2-ylmethyl) -5-methyl-4,5-dihydro-3- (2H ) -Pyridazinone

アルゴン気流下にて、実施例91の化合物（30.0 mg）をN, N−ジメチルホルムアミド（2 mL）に溶解した後、氷冷下で60％水素化ナトリウム（8.20 mg）を加え、常温にて30分間攪拌した。その後、氷冷下で2−クロロメチルピリジン塩酸塩（18.6 mg）を加え、60℃でさらに4.5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）にて精製し、目的物（11.4 mg）を黄色油状物として得た。
HRMS (EI+): 381.1340 (-1.7 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.22-1.29 (6H, m), 2.60 (1H, dd, J = 1.8, 16.5 Hz), 2.83-2.90 (3H, m), 3.27-3.34 (1H, m), 5.06 (1H, d, J = 15.4 Hz), 5.39 (1H, d, J = 15.4 Hz), 7.08 (1H, dd, J = 1.8, 9.8 Hz), 7.20 (1H, dd, J = 4.9, 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.57 (1H, d, J = 9.8 Hz), 7.64-7.68 (1H, m), 8.40 (1H, d, J = 1.8 Hz), 8.59 (1H, d, J = 4.9 Hz). In an argon stream, the compound of Example 91 (30.0 mg) was dissolved in N, N-dimethylformamide (2 mL), and then 60% sodium hydride (8.20 mg) was added under ice-cooling at room temperature. Stir for 30 minutes. Thereafter, 2-chloromethylpyridine hydrochloride (18.6 mg) was added under ice cooling, and the mixture was further stirred at 60 ° C. for 4.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (11.4 mg) as a yellow oil.
HRMS (EI +): 381.1340 (-1.7 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22-1.29 (6H, m), 2.60 (1H, dd, J = 1.8, 16.5 Hz), 2.83-2.90 (3H, m), 3.27-3.34 (1H, m), 5.06 (1H, d, J = 15.4 Hz), 5.39 (1H, d, J = 15.4 Hz), 7.08 (1H, dd, J = 1.8, 9.8 Hz), 7.20 (1H, dd, J = 4.9 , 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.57 (1H, d, J = 9.8 Hz), 7.64-7.68 (1H, m), 8.40 (1H, d, J = 1.8 Hz), 8.59 (1H, d, J = 4.9 Hz).

＜実施例127＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−（ピリジン−３−イルメチル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 127>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2- (pyridin-3-ylmethyl) -5-methyl-4,5-dihydro-3- (2H ) -Pyridazinone

実施例91の化合物(400mg)と３−クロロメチルピリジン塩酸塩を用いて、実施例126と同様の方法により、目的物(330mg)を黄色油状物として得た。
¹H-NMR (400 MHz, CDCl₃) δ 1.16(3H, d, J=7.3Hz), 1.29(3H, t, J=7.3Hz), 2.56(1H, dd, J=1.8, 16.5Hz), 2.79(1H, dd, J=6.4, 16.5Hz), 2.90(2H, q, J=7.3Hz), 3.24-3.31(1H, m), 4.90(1H, d, J=14.4Hz), 5.23(1H, d, J=14.4Hz), 7.14(1H, dd, J=1.8, 9.5Hz), 7.28(1H, dd, J=4.9, 7.6Hz), 7.51(1H, d, J=9.5Hz), 7.74(1H, d, J=7.6Hz), 8.42-
8.43(1H, m), 8.55-8.56(1H, m), 8.68(1H, d, J=1.8Hz). The target product (330 mg) was obtained as a yellow oil in the same manner as in Example 126 using the compound of Example 91 (400 mg) and 3-chloromethylpyridine hydrochloride.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.16 (3H, d, J = 7.3Hz), 1.29 (3H, t, J = 7.3Hz), 2.56 (1H, dd, J = 1.8, 16.5Hz), 2.79 (1H, dd, J = 6.4, 16.5Hz), 2.90 (2H, q, J = 7.3Hz), 3.24-3.31 (1H, m), 4.90 (1H, d, J = 14.4Hz), 5.23 (1H , d, J = 14.4Hz), 7.14 (1H, dd, J = 1.8, 9.5Hz), 7.28 (1H, dd, J = 4.9, 7.6Hz), 7.51 (1H, d, J = 9.5Hz), 7.74 (1H, d, J = 7.6Hz), 8.42-
8.43 (1H, m), 8.55-8.56 (1H, m), 8.68 (1H, d, J = 1.8Hz).

＜実施例128＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−（ピリジン−４−イルメチル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 128>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2- (pyridin-4-ylmethyl) -5-methyl-4,5-dihydro-3- (2H ) -Pyridazinone

アルゴン気流下にて、実施例91（30.0 mg）をN, N−ジメチルホルムアミド（2 mL）に溶解した後、氷冷下で60％水素化ナトリウム（8.20 mg）を加え、常温にて30分間攪拌した。その後、氷冷下で4−クロロメチルピリジン塩酸塩（18.6 mg）を加え、60℃でさらに4.5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）にて精製し、目的物（20.0 mg）を黄色油状物として得た。
HRMS (EI+): 381.1400 (+4.4 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.21 (3H, d, J = 7.3 Hz), 1.29 (3H, d, J = 7.3 Hz), 2.59 (1H, dd, J = 1.8, 16.5 Hz), 2.83 (1H, dd, J = 6.7, 16.5 Hz), 2.88-2.93 (2H, m), 3.28-3.36 (1H, m), 7.12 (1H, dd, J = 1.8, 9.8 Hz), 7.29 (1H, d, J = 5.5 Hz), 7.48 (1H, d, J = 9.8 Hz), 8.43 (1H, m), 8.59 (1H, d, J = 1.8 Hz) Example 91 (30.0 mg) was dissolved in N, N-dimethylformamide (2 mL) under an argon stream, and then 60% sodium hydride (8.20 mg) was added under ice cooling, followed by 30 minutes at room temperature. Stir. Thereafter, 4-chloromethylpyridine hydrochloride (18.6 mg) was added under ice cooling, and the mixture was further stirred at 60 ° C. for 4.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (20.0 mg) as a yellow oil.
HRMS (EI +): 381.1400 (+4.4 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21 (3H, d, J = 7.3 Hz), 1.29 (3H, d, J = 7.3 Hz), 2.59 (1H, dd, J = 1.8, 16.5 Hz), 2.83 (1H, dd, J = 6.7, 16.5 Hz), 2.88-2.93 (2H, m), 3.28-3.36 (1H, m), 7.12 (1H, dd, J = 1.8, 9.8 Hz), 7.29 (1H, d, J = 5.5 Hz), 7.48 (1H, d, J = 9.8 Hz), 8.43 (1H, m), 8.59 (1H, d, J = 1.8 Hz)

＜実施例129＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−（２−モルホリン−４−イルエチル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 129>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2- (2-morpholin-4-ylethyl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

アルゴン気流下にて、実施例91の化合物（30.0 mg）をN, N−ジメチルホルムアミド（2 mL）に溶解した後、氷冷下で60％水素化ナトリウム（8.20 mg）を加え、常温にて30分間攪拌した。その後、氷冷下でN−クロロエチルモルホリン塩酸塩（21.0 mg）を加え、60℃でさらに4.5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→1：2）にて精製し、目的物（5.50 mg）を黄色油状物として得た。
HRMS (EI+): 403.1761 (-1.4 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.25 (3H, d, J = 7.3 Hz), 1.34 (3H, t, J = 7.3 Hz), 2.47-2.78 (8H, m), 2.97-3.03 (2H, m), 3.21-3.29 (1H, m), 3.67-3.69 (4H, m), 3.76-3.83 (1H, m), 4.24-4.31 (1H, m), 7.20 (1H, dd, J = 1.8, 9.2 Hz), 7.82 (1H, d, J = 9.2 Hz), 8.46 (1H, d, J = 1.8 Hz) In an argon stream, the compound of Example 91 (30.0 mg) was dissolved in N, N-dimethylformamide (2 mL), and then 60% sodium hydride (8.20 mg) was added under ice-cooling at room temperature. Stir for 30 minutes. Thereafter, N-chloroethylmorpholine hydrochloride (21.0 mg) was added under ice cooling, and the mixture was further stirred at 60 ° C. for 4.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 2) to obtain the desired product (5.50 mg) as a yellow oil.
HRMS (EI +): 403.1761 (-1.4 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (3H, d, J = 7.3 Hz), 1.34 (3H, t, J = 7.3 Hz), 2.47-2.78 (8H, m), 2.97-3.03 (2H , m), 3.21-3.29 (1H, m), 3.67-3.69 (4H, m), 3.76-3.83 (1H, m), 4.24-4.31 (1H, m), 7.20 (1H, dd, J = 1.8, 9.2 Hz), 7.82 (1H, d, J = 9.2 Hz), 8.46 (1H, d, J = 1.8 Hz)

＜実施例130＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−シクロプロピルメチル−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 130>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2-cyclopropylmethyl-5-methyl-4,5-dihydro-3- (2H) -pyridazinone

アルゴン気流下にて、実施例91の化合物（30.0 mg）をN, N−ジメチルホルムアミド（2 mL）に溶解した後、氷冷下で60％水素化ナトリウム（4.10 mg）を加え、常温にて1時間攪拌した。その後、氷冷下でブロモメチルシクロプロパン（0.01mL）を加え、60℃でさらに5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）にて精製し、目的物（15.5 mg）を黄色油状物として得た。
HRMS (EI+): 344.1435 (+3.1 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 0.38-0.39 (2H, m), 0.49-0.55 (2H, m), 1.22-1.24 (1H, m), 1.23 (3H, d, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 2.52 (1H, dd, J = 1.8, 16.5 Hz), 2.77 (1H, dd, J = 6.7, 16.5 Hz), 2.98-3.04 (2H, m), 3.21-3.29 (1H, m), 3.64 (1H, dd, J = 7.3, 14.1 Hz), 3.87 (1H, dd, J = 7.3, 14.1 Hz), 7.21 (1H, dd,
J = 1.8, 9.8 Hz), 7.79 ( 1H, J = 9.8 Hz), 8.46 (1H, d, J = 1.8 Hz). In an argon stream, the compound of Example 91 (30.0 mg) was dissolved in N, N-dimethylformamide (2 mL), and then 60% sodium hydride (4.10 mg) was added under ice cooling, and at room temperature. Stir for 1 hour. Thereafter, bromomethylcyclopropane (0.01 mL) was added under ice cooling, and the mixture was further stirred at 60 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (15.5 mg) as a yellow oil.
HRMS (EI +): 344.1435 (+3.1 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.38-0.39 (2H, m), 0.49-0.55 (2H, m), 1.22-1.24 (1H, m), 1.23 (3H, d, J = 7.3 Hz) , 1.37 (3H, t, J = 7.3 Hz), 2.52 (1H, dd, J = 1.8, 16.5 Hz), 2.77 (1H, dd, J = 6.7, 16.5 Hz), 2.98-3.04 (2H, m), 3.21-3.29 (1H, m), 3.64 (1H, dd, J = 7.3, 14.1 Hz), 3.87 (1H, dd, J = 7.3, 14.1 Hz), 7.21 (1H, dd,
J = 1.8, 9.8 Hz), 7.79 (1H, J = 9.8 Hz), 8.46 (1H, d, J = 1.8 Hz).

＜実施例131＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−シクロヘキシルメチル−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 131>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2-cyclohexylmethyl-5-methyl-4,5-dihydro-3- (2H) -pyridazinone

アルゴン気流下にて、実施例91の化合物（30.0 mg）をN, N−ジメチルホルムアミド（2 mL）に溶解した後、氷冷下で60％水素化ナトリウム（4.10 mg）を加え、常温にて1時間攪拌した。その後、氷冷下でブロモメチルシクロヘキサン (0.02mL)を加え、60℃でさらに5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）にて精製し、目的物（20.4 mg）を黄色油状物として得た。
HRMS (EI+): 386.1897 (+2.4 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.04-1.07 (2H, m), 1.21 (3H, d, J = 7.3 Hz), 1.36 (3H, t, J = 7.3 Hz), 1.59-1.88 (9H, m), 2.51 (1H, dd, J = 1.8, 16.5 Hz), 2.76 (1H, dd, J = 6.7, 16.5 Hz), 2.97-3.03 (2H, m), 3.21-3.29 (1H, m), 3.54 (1H, dd, J = 7.5, 13.5 Hz), 3.89 (1H, dd, J = 7.5, 13.5 Hz), 7.21 (1H, dd, J = 1.8, 9.8 Hz), 7
.79 (1H, d, J = 9.8 Hz), 8.46 (1H, d, J = 1.8 Hz)． In an argon stream, the compound of Example 91 (30.0 mg) was dissolved in N, N-dimethylformamide (2 mL), and then 60% sodium hydride (4.10 mg) was added under ice cooling, and at room temperature. Stir for 1 hour. Thereafter, bromomethylcyclohexane (0.02 mL) was added under ice cooling, and the mixture was further stirred at 60 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (20.4 mg) as a yellow oil.
HRMS (EI +): 386.1897 (+2.4 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.04-1.07 (2H, m), 1.21 (3H, d, J = 7.3 Hz), 1.36 (3H, t, J = 7.3 Hz), 1.59-1.88 (9H , m), 2.51 (1H, dd, J = 1.8, 16.5 Hz), 2.76 (1H, dd, J = 6.7, 16.5 Hz), 2.97-3.03 (2H, m), 3.21-3.29 (1H, m), 3.54 (1H, dd, J = 7.5, 13.5 Hz), 3.89 (1H, dd, J = 7.5, 13.5 Hz), 7.21 (1H, dd, J = 1.8, 9.8 Hz), 7
.79 (1H, d, J = 9.8 Hz), 8.46 (1H, d, J = 1.8 Hz).

＜実施例132＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−シクロペンチルメチル−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 132>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -2-cyclopentylmethyl-5-methyl-4,5-dihydro-3- (2H) -pyridazinone

アルゴン気流下にて、実施例91の化合物（30.0 mg）をN, N−ジメチルホルムアミド（2 mL）に溶解した後、氷冷下で60％水素化ナトリウム（4.10 mg）を加え、常温にて1時間攪拌した。その後、氷冷下でブロモメチルシクロペンタン (48.0 mg)を加え、60℃でさらに5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）にて精製し、目的物（18.9 mg）を黄色油状物として得た。
HRMS (EI+): 372.1709 (-0.8 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.21 (3H, d, J = 6.7 Hz), 1.36 (3H, t, J = 7.3 Hz), 1.55-1.79 (8H, m), 2.38-2.46 (1H, m), 2.50 (1H, dd, J = 1.8, 16.5 Hz), 2.75 (1H, dd, J = 6.7, 16.5 Hz), 2.97-3.03 (2H, m), 3.21-3.28 (1H, m), 3.59 (1H, dd, J = 7.3, 13.5 Hz), 4.05 (1H, dd, J = 7.3, 13.5 Hz), 7.21 (1H, dd, J = 1.8, 9.8 Hz), 7.82 (1H, d, J = 9.8 Hz), 8.45 (1H, d, J = 1.8 Hz). In an argon stream, the compound of Example 91 (30.0 mg) was dissolved in N, N-dimethylformamide (2 mL), and then 60% sodium hydride (4.10 mg) was added under ice cooling, and at room temperature. Stir for 1 hour. Thereafter, bromomethylcyclopentane (48.0 mg) was added under ice cooling, and the mixture was further stirred at 60 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (18.9 mg) as a yellow oil.
HRMS (EI +): 372.1709 (-0.8 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21 (3H, d, J = 6.7 Hz), 1.36 (3H, t, J = 7.3 Hz), 1.55-1.79 (8H, m), 2.38-2.46 (1H , m), 2.50 (1H, dd, J = 1.8, 16.5 Hz), 2.75 (1H, dd, J = 6.7, 16.5 Hz), 2.97-3.03 (2H, m), 3.21-3.28 (1H, m), 3.59 (1H, dd, J = 7.3, 13.5 Hz), 4.05 (1H, dd, J = 7.3, 13.5 Hz), 7.21 (1H, dd, J = 1.8, 9.8 Hz), 7.82 (1H, d, J = 9.8 Hz), 8.45 (1H, d, J = 1.8 Hz).

＜実施例133＞
６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−３−（２Ｈ）−ピリダジノン <Example 133>
6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-3- (2H) -pyridazinone

実施例９１の化合物（72.0 mg）を酢酸（2.0 mL）に溶解し、そこに臭素（0.02mL）を加え、65℃にて5時間攪拌した。放冷後、反応液を氷水中に注ぎ、酢酸エチルで抽出し、有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 1：1）にて精製し、目的物（35.2 mg）を黄色粉末として得た。
HRMS (EI+): 288.0765 (-1.3 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.28 (3H, t, J = 7.3 Hz), 2.04 (3H, s), 2.77 (2H, q, J = 7.3 Hz), 6.89 (1H, brs), 7.13-7.23 (2H, m), 8.49 (1H, brs), 10.6 (1H, brs). The compound of Example 91 (72.0 mg) was dissolved in acetic acid (2.0 mL), bromine (0.02 mL) was added thereto, and the mixture was stirred at 65 ° C. for 5 hours. After allowing to cool, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (35.2 mg) as a yellow powder.
HRMS (EI +): 288.0765 (-1.3 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.28 (3H, t, J = 7.3 Hz), 2.04 (3H, s), 2.77 (2H, q, J = 7.3 Hz), 6.89 (1H, brs), 7.13-7.23 (2H, m), 8.49 (1H, brs), 10.6 (1H, brs).

＜実施例134および135＞
（＋）−６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン及び（−）−６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン
実施例91を高速液体クロマトグラフィー（Daicel Chiralpak AS-H column, eluent: n-hexane / EtOH = 20 / 80, flow rate: 3.00 ml / min, detection: 293 nm）により光学分割を行い、前溶出分から（＋）体実施例134、後溶出部分から（−）体実施例135を各々淡黄色粉末として得た。
実施例134: [α]_D +263 °(c = 0.52, CHCl₃)
HRMS(EI+): 290.0923(-1.2mmu)[M+]
実施例135: [α]_D -253 °(c = 0.50, CHCl₃)
元素分析（％）：C₁₄H₁₅ClN₄Oとして
C H N
計算値 57.83 5.20 19.27
実測値 57.58 5.17 19.17 <Examples 134 and 135>
(+)-6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone and (- ) -6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone Perform optical resolution by liquid chromatography (Daicel Chiralpak AS-H column, eluent: n-hexane / EtOH = 20/80, flow rate: 3.00 ml / min, detection: 293 nm), and perform (+) body from the pre-elution fraction Example 134 From the post-elution portion, (-) body Example 135 was obtained as a pale yellow powder.
Example 134: [α] _D + 263 ° (c = 0.52, CHCl ₃ )
HRMS (EI +): 290.0923 (-1.2mmu) [M +]
Example 135: [α] _D −253 ° (c = 0.50, CHCl ₃ )
Elemental analysis (%): as C ₁₄ H ₁₅ ClN ₄ O
CHN
Calculated 57.83 5.20 19.27
Actual value 57.58 5.17 19.17

＜実施例136および137＞
（＋）−６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン及び（−）−６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン
実施例95を高速液体クロマトグラフィー（Daicel Chiralpak AS-H column, eluent: n-hexane / EtOH = 25 / 75, flow rate: 3.00 ml / min, detection: 293 nm）により光学分割を行い、前溶出分から（＋）体実施例136、後溶出部分から（−）体実施例137を各々淡黄色粉末として得た。 <Examples 136 and 137>
(+)-6- (2-Ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone and (- ) -6- (2-Ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone Perform optical resolution by liquid chromatography (Daicel Chiralpak AS-H column, eluent: n-hexane / EtOH = 25/75, flow rate: 3.00 ml / min, detection: 293 nm), and carry out (+) bodies from the pre-elution fraction Example 136, (-) Form Example 137 was obtained as a pale yellow powder from the post-elution part.

実施例136: [α]_D +271 °(c = 1.06, CHCl₃)
HRMS(EI+): 274.1219(-1.1mmu)[M+] Example 136: [α] _D + 271 ° (c = 1.06, CHCl ₃ )
HRMS (EI +): 274.1219 (-1.1mmu) [M +]

実施例137: [α]_D -273 °(c = 1.10, CHCl₃)
HRMS(EI+): 274.1227(-0.2mmu)[M+] Example 137: [α] _D −273 ° (c = 1.10, CHCl ₃ )
HRMS (EI +): 274.1227 (-0.2mmu) [M +]

＜実施例138＞
６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−３−（２Ｈ）−ピリダジノン <Example 138>
6- (2-Ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-3- (2H) -pyridazinone

実施例95の化合物を用い、実施例133と同様に反応させ、目的物を淡黄色粉末として得た。
HRMS (EI+): 272.1082 (0.9 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.27(3H, t, J=7.3Hz), 2.06(3H, d, J=1.2Hz), 2.77(2H, q, J=7.3Hz), 6.90(1H, d, J=1.2Hz), 7.10-7.15(1H, m), 7.22(1H, dd, J=5.5, 10.8Hz), 8.40-8.42(1H, m), 11.14(1H, br s) The target product was obtained as a pale yellow powder by reacting in the same manner as in Example 133 using the compound of Example 95.
HRMS (EI +): 272.1082 (0.9 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3Hz), 2.06 (3H, d, J = 1.2Hz), 2.77 (2H, q, J = 7.3Hz), 6.90 ( 1H, d, J = 1.2Hz), 7.10-7.15 (1H, m), 7.22 (1H, dd, J = 5.5, 10.8Hz), 8.40-8.42 (1H, m), 11.14 (1H, br s)

＜実施例139＞
６−（６−クロロ−２−フルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−（ピリジン−３−イルメチル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 139>
6- (6-Chloro-2-fluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -2- (pyridin-3-ylmethyl) -5-methyl-4,5-dihydro-3- ( 2H) -Pyridazinone

実施例121の化合物を用い、実施例133と同様に反応させ、目的物を淡黄色アモルファス状物として得た。
HRMS (EI+): 385.1137(3.2 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.19(3H, d, J=7.3Hz), 2.54(1H, dd, J=1.8, 16.5Hz), 2.80(1H, dd, J=6.4, 16.5Hz), 3.33-3.37(1H, m), 4.94(1H, d, J=14.7Hz), 5.20(1H, d, J=14.7), 5.55(1H, dd, J=11.6, 16.5Hz), 5.68(1H, dd, J=11.6, 16.5Hz), 7.22(1H, dd, J=1.8, 9.5Hz), 7.29(1H, dd, J=4.9, 7.9Hz), 7.70(1H, dd, J=0.6, 9.5Hz), 7.74(1H, td, J=1.8,7.9Hz), 8.48(1H, d, J=1.5Hz), 8.56(1H, dd, J=1.5, 4.9Hz), 8.68(1H, d, J=1.8Hz) The target product was obtained as a pale yellow amorphous product by reacting in the same manner as in Example 133 using the compound of Example 121.
HRMS (EI +): 385.1137 (3.2 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.19 (3H, d, J = 7.3Hz), 2.54 (1H, dd, J = 1.8, 16.5Hz), 2.80 (1H, dd, J = 6.4, 16.5Hz ), 3.33-3.37 (1H, m), 4.94 (1H, d, J = 14.7Hz), 5.20 (1H, d, J = 14.7), 5.55 (1H, dd, J = 11.6, 16.5Hz), 5.68 ( 1H, dd, J = 11.6, 16.5Hz), 7.22 (1H, dd, J = 1.8, 9.5Hz), 7.29 (1H, dd, J = 4.9, 7.9Hz), 7.70 (1H, dd, J = 0.6, 9.5Hz), 7.74 (1H, td, J = 1.8, 7.9Hz), 8.48 (1H, d, J = 1.5Hz), 8.56 (1H, dd, J = 1.5, 4.9Hz), 8.68 (1H, d, (J = 1.8Hz)

＜実施例140＞
６−（６−クロロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−２−（ピリジン−３−イルメチル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 140>
6- (6-Chloro-pyrazolo [1,5-a] pyridin-3-yl) -2- (pyridin-3-ylmethyl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

実施例121の化合物を用い、実施例133と同様に反応させ、目的物を黄色アモルファス状物として得た。
HRMS (EI+): 353.1077(3.4 mmu) [M+]
¹H-NMR (400 MHz, CDCl₃) δ 1.22(3H, d, J=7.3Hz), 2.55(1H, dd, J=1.5, 16.8Hz), 2.79(1H, dd, J=6.7, 16.8Hz), 3.20-3.26(1H, m), 5.01(1H, d, J=14.4Hz), 5.14(1H, d, J=14.4Hz), 7.25-7.29(1H, m), 7.75(1H, td, J=1.8, 7.9Hz), 8.02(1H, dd, J=0.9, 9.5Hz), 8.07(1H, s), 8.54(1H, dd, J=0.9, 1.8Hz), 8.70(1H, s) The target product was obtained as a yellow amorphous product by reacting in the same manner as in Example 133 using the compound of Example 121.
HRMS (EI +): 353.1077 (3.4 mmu) [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22 (3H, d, J = 7.3Hz), 2.55 (1H, dd, J = 1.5, 16.8Hz), 2.79 (1H, dd, J = 6.7, 16.8Hz ), 3.20-3.26 (1H, m), 5.01 (1H, d, J = 14.4Hz), 5.14 (1H, d, J = 14.4Hz), 7.25-7.29 (1H, m), 7.75 (1H, td, J = 1.8, 7.9Hz), 8.02 (1H, dd, J = 0.9, 9.5Hz), 8.07 (1H, s), 8.54 (1H, dd, J = 0.9, 1.8Hz), 8.70 (1H, s)

＜実施例141＞
実施例110（６−[６−クロロ−２−（１−ヒドロキシエチル）−ピラゾロ[１，５−ａ]ピリジン−３−イル]−５−メチル−４，５−ジヒドロ-３−（２Ｈ）−ピリダジノン）の光学活性体
実施例110のシルルエーテル保護体を合成し、粒径50μmの球状シリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル＝ 2 : 1 v/v)によりジアステレオマーＡとＢに分割した。そしてジアステレオマーＡはDaicel Chiralcel AD-H column(Hex:EtOH=40:60, 3.00mL/min))により光学分割し、ジアステレオマーＢはDaicel Chiralcel AS-H column (Hex:EtOH = 75:25, 3.00mL/min)により光学分割した。分割した４種の光学異性体を脱シリル化し、光学活性な目的物を各々得た。 <Example 141>
Example 110 (6- [6-Chloro-2- (1-hydroxyethyl) -pyrazolo [1,5-a] pyridin-3-yl] -5-methyl-4,5-dihydro-3- (2H) -Pyridazinone) optically active form The silyl ether protected form of Example 110 was synthesized and separated into diastereomers A and B by spherical silica gel column chromatography (hexane: ethyl acetate = 2: 1 v / v) having a particle size of 50 μm. did. Diastereomer A is optically resolved by Daicel Chiralcel AD-H column (Hex: EtOH = 40: 60, 3.00 mL / min)), and diastereomer B is Daicel Chiralcel AS-H column (Hex: EtOH = 75: 25, 3.00 mL / min). The four separated optical isomers were desilylated to obtain optically active target compounds.

異性体１：白色結晶, ¹H-NMR (400 MHz, CDCl3) δ1.29 (3H, d, J = 7.3 Hz), 1.67 (3H, d, J = 6.7 Hz), 2.55 (1H, dd, J = 17.1, 1.8 Hz), 2.83 (1H, dd, J = 17.1, 6.7 Hz), 3.37−3.47 (1H, m), 4.76 (1H, br s), 5.05−5.13 (1H, m), 7.24−7.27 (1H, m), 7.60 (1H, d, J = 9.8 Hz), 8.50 (1H, br s), 8.52 (1H, d, J = 1.8 Hz).
[α]^D ₂₅ : -176 (CHCl₃, c:0.690)
LRMS (EI+): 306 (M⁺)
元素分析 : C₁₄H₁₅ClN₄O₂ calcd (%) C : 54.82, H : 4.93, N : 18.26
found (%) C : 54.64, H : 4.88, N : 18.18 Isomer 1: white crystals, ¹ H-NMR (400 MHz, CDCl3) δ 1.29 (3H, d, J = 7.3 Hz), 1.67 (3H, d, J = 6.7 Hz), 2.55 (1H, dd, J = 17.1, 1.8 Hz), 2.83 (1H, dd, J = 17.1, 6.7 Hz), 3.37−3.47 (1H, m), 4.76 (1H, br s), 5.05−5.13 (1H, m), 7.24−7.27 (1H, m), 7.60 (1H, d, J = 9.8 Hz), 8.50 (1H, br s), 8.52 (1H, d, J = 1.8 Hz).
[α] ^D ₂₅ : -176 (CHCl ₃ , c: 0.690)
LRMS (EI +): 306 (M ⁺ )
Elemental analysis: C ₁₄ H ₁₅ ClN ₄ O ₂ calcd (%) C: 54.82, H: 4.93, N: 18.26
found (%) C: 54.64, H: 4.88, N: 18.18

異性体２：白色結晶、¹H-NMR (400 MHz, CDCl₃)δ 1.29 (3H, d, J = 7.3 Hz), 1.67 (3H, d, J = 6.7 Hz), 2.55 (1H, dd, J = 17.1, 1.2 Hz), 2.83 (1H, dd, J = 16.5, 6.7 Hz), 3.37−3.48 (1H, m), 4.80 (1H, br s), 5.10 (1H, q, J = 6.7 Hz), 7.23−7.28 (1H, m), 7.60 (1H, d, J = 8.6 Hz), 8.52 (1H, d, J = 1.8 Hz), 8.59 (1H, br s).
[α]^D ₂₅ : -180 (CHCl₃, c:0.600)
LRMS (EI+): 306(M⁺)
元素分析 : C₁₄H₁₅ClN₄O₂ calcd (%) C : 54.82, H : 4.93, N : 18.26
found (%) C : 54.70, H : 4.86, N : 18.30 Isomer 2: white crystals, ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.29 (3H, d, J = 7.3 Hz), 1.67 (3H, d, J = 6.7 Hz), 2.55 (1H, dd, J = 17.1, 1.2 Hz), 2.83 (1H, dd, J = 16.5, 6.7 Hz), 3.37−3.48 (1H, m), 4.80 (1H, br s), 5.10 (1H, q, J = 6.7 Hz), 7.23-7.28 (1H, m), 7.60 (1H, d, J = 8.6 Hz), 8.52 (1H, d, J = 1.8 Hz), 8.59 (1H, br s).
[α] ^D ₂₅ : -180 (CHCl ₃ , c: 0.600)
LRMS (EI +): 306 (M ⁺ )
Elemental analysis: C ₁₄ H ₁₅ ClN ₄ O ₂ calcd (%) C: 54.82, H: 4.93, N: 18.26
found (%) C: 54.70, H: 4.86, N: 18.30

異性体３：白色結晶
¹H-NMR (400 MHz, CDCl₃)δ 1.38 (3H, d, J = 7.3 Hz), 1.69 (3H, d, J = 6.7 Hz), 2.54 (1H, dd, J = 17.1, 1.2 Hz), 2.80 (1H, dd, J = 17.1, 6.1 Hz), 3.35−3.46 (1H, m), 4.81 (1H, br s), 5.02−5.12 (1H, m), 7.24−7.29 (1H, m), 7.60 (1H, d, J = 9.8 Hz), 8.53 (1H, d, J = 1.2 Hz), 8.56 (1H, s).
[α]^D ₂₅ : +274 (CHCl₃, c:0.610)
LRMS (EI+): 306(M⁺) Isomer 3: white crystals
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, d, J = 7.3 Hz), 1.69 (3H, d, J = 6.7 Hz), 2.54 (1H, dd, J = 17.1, 1.2 Hz), 2.80 (1H, dd, J = 17.1, 6.1 Hz), 3.35−3.46 (1H, m), 4.81 (1H, br s), 5.02−5.12 (1H, m), 7.24−7.29 (1H, m), 7.60 (1H, d, J = 9.8 Hz), 8.53 (1H, d, J = 1.2 Hz), 8.56 (1H, s).
[α] ^D ₂₅ : +274 (CHCl ₃ , c: 0.610)
LRMS (EI +): 306 (M ⁺ )

異性体４：白色結晶
¹H-NMR (400 MHz, CDCl₃)δ 1.38 (3H, d, J = 7.3 Hz), 1.69 (3H, d, J = 6.7 Hz), 2.54 (1H, dd, J = 17.1, 1.2 Hz), 2.80 (1H, dd, J = 17.1, 6.7 Hz), 3.33−3.45 (1H, m), 4.85 (1H, br s), 5.04−5.12 (1H, m), 7.24−7.28 (1H, m), 7.59 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 1.8 Hz), 8.66 (1H, br s).
[α]^D ₂₅ : -282 (CHCl₃, c:0.770)
LRMS (EI+): 306(M⁺) Isomer 4: white crystals
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, d, J = 7.3 Hz), 1.69 (3H, d, J = 6.7 Hz), 2.54 (1H, dd, J = 17.1, 1.2 Hz), 2.80 (1H, dd, J = 17.1, 6.7 Hz), 3.33−3.45 (1H, m), 4.85 (1H, br s), 5.04−5.12 (1H, m), 7.24−7.28 (1H, m), 7.59 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 1.8 Hz), 8.66 (1H, br s).
[α] ^D ₂₅ : -282 (CHCl ₃ , c: 0.770)
LRMS (EI +): 306 (M ⁺ )

＜実施例142＞
６−（２−エチル−６−メトキシ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３−（２Ｈ）−ピリダジノン <Example 142>
6- (2-Ethyl-6-methoxy-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3- (2H) -pyridazinone

３−メトキシピリジンを実施例１と同様に反応させＮ−アミニウム塩を合成した後、実施例10と同様に反応させピラゾロピリジン誘導体へと変換した。以下、実施例67、76、78、88と同様に順次反応させ目的物を黄色粉末として得た。
¹H-NMR (400 MHz, CDCl₃): δ 1.26 (3H, d, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 2.49 (1H, dd, J = 1.8, 17.1 Hz), 2.77 (1H, dd, J = 6.7, 17.1 H), 2.97 (2H, q, J = 7.3Hz), 3.27-3.36 (1H, m), 3.84 (3H, s), 7.04 (1H, dd, J = 1.8, 9.8 Hz), 7.78 (1H, d, J =9.8 Hz), 8.03 (1H, d, J = 1.8 Hz), 8.43 (1H, brs)．
元素分析（％）：C₁₅H₁₈N₄O₂として
C H N
計算値 62.92 6.34 19.57
実測値 62.64 6.32 19.14 3-methoxypyridine was reacted in the same manner as in Example 1 to synthesize an N-aminium salt, and then reacted in the same manner as in Example 10 to convert to a pyrazolopyridine derivative. Thereafter, the target product was obtained as a yellow powder by sequentially reacting in the same manner as in Examples 67, 76, 78 and 88.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.26 (3H, d, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 2.49 (1H, dd, J = 1.8, 17.1 Hz) , 2.77 (1H, dd, J = 6.7, 17.1 H), 2.97 (2H, q, J = 7.3Hz), 3.27-3.36 (1H, m), 3.84 (3H, s), 7.04 (1H, dd, J = 1.8, 9.8 Hz), 7.78 (1H, d, J = 9.8 Hz), 8.03 (1H, d, J = 1.8 Hz), 8.43 (1H, brs).
Elemental analysis (%): as C ₁₅ H ₁₈ N ₄ O ₂
CHN
Calculated 62.92 6.34 19.57
Actual value 62.64 6.32 19.14

次に本発明化合物について、有用性を裏付ける成績を実験例によって示す。   Next, the results of supporting the usefulness of the compounds of the present invention are shown by experimental examples.

＜実験例１＞ ホスホジエステラーゼ阻害活性
PDE3A触媒領域（以下Catと略す）, PDE4BCat, PDE5ACat, PDE10A1の cDNAはヒト由来のRNAよりそれぞれRT-PCRを行い単離した。各単離したcDNA断片をGateway system (Invitrogen社製)及びBac-to-Bac（登録商標） Baculovirus Expression system (Invitrogen社製)で昆虫細胞Sf9に導入し、目的の各PDEタンパクを発現させた。これら組み換えPDE3ACat, PDE4BCat, PDE5ACat, PDE10A1はこれらPDEタンパクを高発現したSf9細胞の培養上清もしくは細胞抽出液からそれぞれイオン交換クロマトグラフィーで精製し,以下に示す実験に用いた。 <Experimental Example 1> Phosphodiesterase inhibitory activity
The PDE3A catalytic region (hereinafter abbreviated as Cat), PDE4BCat, PDE5ACat, and PDE10A1 cDNAs were isolated from human-derived RNA by RT-PCR. Each isolated cDNA fragment was introduced into insect cells Sf9 by Gateway system (Invitrogen) and Bac-to-Bac (registered trademark) Baculovirus Expression system (Invitrogen) to express each target PDE protein. These recombinant PDE3ACat, PDE4BCat, PDE5ACat, and PDE10A1 were purified by ion exchange chromatography from the culture supernatant or cell extract of Sf9 cells that highly expressed these PDE proteins, respectively, and used in the following experiments.

被験化合物は4 mmol/L溶液を段階的に15％DMSO溶液で4倍希釈し、15 nmol/Lから4 mmol/Lまでの濃度の溶液を用意した（実験での最終濃度は1.5 nmol/Lから400μmol/L）。これら被験化合物溶液 10μLを表１０に示した濃度に緩衝液[40 mmol/LTris-HCl (pH7.4), 10 mmol/L MgCl₂ ]で希釈した[³H] cAMPもしくは[³H] ｃGMP 50 μL及び表１０に示したunit量の各ヒト由来組み換えPDEタンパク40 μLを96穴プレートに添加し、30℃で20分間反応した。その後65℃で2分間反応させた後、1 mg/m L 5'nucleotidase（Crotalus atrox venom, Sigma社製） 25 μLを添加し、30℃で10分間反応した。反応終了後、Dowex溶液[300 mg/m L Dowex 1x8-400 (Sigma Aldrich社製), 33% Ethanol] 200μLを添加し、4℃で20分間振動混合した後MicroScint 20（Packard社製） 200μLを添加し、シンチレーションカウンター（Topcount, Packard社製）を用いて測定した。IC₅₀値の算出はGraphPad Prism v3.03 (GraphPad Software社製)を用いて行った。 For the test compound, a 4 mmol / L solution was diluted 4-fold with a 15% DMSO stepwise to prepare a solution having a concentration from 15 nmol / L to 4 mmol / L (the final concentration in the experiment was 1.5 nmol / L). To 400 μmol / L). [ ³ H] cAMP or [ ³ H] cGMP 50 diluted with a buffer solution [40 mmol / LTris-HCl (pH 7.4), 10 mmol / L MgCl ₂ ] to a concentration shown in Table 10 for 10 μL of these test compound solutions. μL and 40 μL of each human-derived recombinant PDE protein in the unit amount shown in Table 10 were added to a 96-well plate and reacted at 30 ° C. for 20 minutes. After reacting at 65 ° C. for 2 minutes, 25 μL of 1 mg / mL 5 ′ nucleotidase (Crotalus atrox venom, Sigma) was added and reacted at 30 ° C. for 10 minutes. After completion of the reaction, 200 μL of Dowex solution [300 mg / ml L Dowex 1x8-400 (Sigma Aldrich), 33% Ethanol] was added, mixed by shaking at 4 ° C. for 20 minutes, and then 200 μL of MicroScint 20 (Packard) It was added and measured using a scintillation counter (Topcount, Packard). The IC ₅₀ value was calculated using GraphPad Prism v3.03 (GraphPad Software).

結果を表１１に示す。   The results are shown in Table 11.

＜実験例２＞ 摘出モルモット気管筋のヒスタミン収縮に対する弛緩作用
モルモットを脱血致死させ、素早く気管を摘出し、2〜3軟骨分を単位とした気管リング標本を作製した。この標本を、95%O₂+5%CO₂混合ガスを通気し、37℃で保温した10 m LのTyrode液中にて懸垂した。Tyrode液の組成(mmol/L)はNaCl: 136.9, KCl :2.7, CaCl₂ :1.8, MgCl₂ :1.0, NaH₂PO₄:0.4, NaHCO₃ :11.9, Gucose :5.6とした。収縮反応はアイソメトリックトランスデューサー（UM-203 KISHIMOTO）を介して測定し、レコーダー（GRAPHTEC SERVOCORDER SR6221）上に記録した。1.5 gの負荷をかけ、約1時間平衡化した後、ヒスタミン（10^-5mol/L）を添加し,収縮反応を確認した後、Tyrodeで洗い（10mLで3回）、インドメタシン（10^-5mol/L）を添加し、1.5 gの負荷をかけて30分以上平衡化を行った。そして、再度ヒスタミン（10^-5mol/L）を添加し、収縮が安定した後、化合物を累積的に添加した（10^-8mol/L−3×10^-5mol/L）。化合物はDMSOで10^-1mol/Lの溶液を作製し、蒸留水で希釈したものを用いた。化合物添加終了後、パパベリン（10^-4mol/L）を添加して最大弛緩を求めた。被験化合物の弛緩作用はパパベリンによる最大弛緩に対する弛緩率（％）で示し、50％の弛緩に要した化合物濃度をIC₅₀値として求めた。対照としてDMSOを使用した。 <Experimental example 2> Relaxing action on histamine contraction of isolated guinea pig tracheal muscles The guinea pig was lethal and lethal, and the trachea was quickly removed to produce a tracheal ring specimen in units of 2 to 3 cartilage. This specimen was suspended in 10 mL of Tyrode solution which was aerated with 95% O ₂ + 5% CO ₂ mixed gas and kept at 37 ° C. The composition of the Tyrode solution (mmol / L) is NaCl: 136.9, KCl: 2.7, CaCl 2: 1.8, MgCl 2: 1.0, NaH 2 PO 4: 0.4, NaHCO 3: 11.9, Gucose: was 5.6. Contractile response was measured via an isometric transducer (UM-203 KISHIMOTO) and recorded on a recorder (GRAPHTEC SERVOCORDER SR6221). After applying a load of 1.5 g and equilibrating for about 1 hour, histamine (10 ^-5 mol / L) was added, and after confirming the contraction reaction, it was washed with Tyrode (3 times with 10 mL) and indomethacin (10 ^-5 mol / L) was added and equilibrated for 30 minutes or more with a load of 1.5 g. And histamine (10 ^<-5 > mol / L) was added again, and after shrinkage | contraction became stable, the compound was added cumulatively (10 < ^-8 > mol / L-3 * 10 < ^-5 > mol / L). As the compound, a 10 ⁻¹ mol / L solution prepared with DMSO and diluted with distilled water was used. After completion of compound addition, papaverine (10 ^-4 mol / L) was added to determine maximum relaxation. The relaxation effect of the test compound was expressed as a relaxation rate (%) with respect to the maximum relaxation by papaverine, and the compound concentration required for 50% relaxation was determined as an IC ₅₀ value. DMSO was used as a control.

結果を表１２に示す。   The results are shown in Table 12.

＜実験例３＞モルモットにおけるヒスタミン誘発気道収縮反応
モルモットをペントバルビタール(30mg/kg,i.p.)で麻酔し、左外頚静脈に静脈投与用カニューレ、 右内頚動脈に採血および血圧測定用カニューレ、気管に気管カニューレを挿入した。60 times/min、 10 mL/kg/strokeの条件で人工呼吸し、気管カニューレの側枝からオーバフローする空気 (エアフロー)をbronchospasm transducer(Ugo-Basile)にて測定し、Power Lab (ADInstruments Japan)を介してコンピューターに記録した。ガラミン(10mg/kg,i.v.)にて不動化した後、10分おきにヒスタミン (12.5μg/kg,i.v.)を投与した。ヒスタミンによる気道収縮が安定した後、化合物(1mg/kg,i.v.)を投与し、投与30秒後のヒスタミンによる気道収縮反応を測定し, 化合物の気道収縮抑制作用を調べた。気道収縮をエアフロー値で記録し、結果は投与30秒後のヒスタミンによるエアフローの最大値を投与前の最大値に対する割合で表した。なお被検化合物はDMSOで溶解し, 10mg/mLに調製した。ガラミンは生理食塩液で溶解し、10mg/mLに調整した。ヒスタミンは生理食塩液に溶解し、1mg/mLにした後、生理食塩液で62.5μg/mLに希釈して用いた。 <Experimental Example 3> Histamine-induced airway contraction in guinea pigs Guinea pigs are anesthetized with pentobarbital (30 mg / kg, ip), the left external jugular vein is a cannula for intravenous administration, the right internal carotid artery is a blood collection and blood pressure measurement cannula, the trachea A tracheal cannula was inserted. After artificial respiration under conditions of 60 times / min and 10 mL / kg / stroke, the air (airflow) overflowing from the side branch of the tracheal cannula was measured with a bronchospasm transducer (Ugo-Basile), and via Power Lab (AD Instruments Japan) Recorded on a computer. After immobilization with gallamine (10 mg / kg, iv), histamine (12.5 μg / kg, iv) was administered every 10 minutes. After the airway contraction by histamine was stabilized, the compound (1 mg / kg, iv) was administered, and the airway contraction response by histamine 30 seconds after administration was measured to examine the inhibitory effect of the compound on the airway contraction. Airway contraction was recorded as an airflow value, and the result was expressed as a ratio of the maximum value of histamine airflow 30 seconds after administration to the maximum value before administration. The test compound was dissolved in DMSO and adjusted to 10 mg / mL. Galamine was dissolved in physiological saline and adjusted to 10 mg / mL. Histamine was dissolved in physiological saline to 1 mg / mL, and then diluted to 62.5 μg / mL with physiological saline.

結果を表１３に示す。   The results are shown in Table 13.

以上のように、一般式（１）で表される本発明化合物はＰＤＥ阻害活性を有し、各種動
物実験モデルにおいてその有効性が確認された。 As described above, the compound of the present invention represented by the general formula (1) has PDE inhibitory activity, and its effectiveness has been confirmed in various animal experimental models.

上述のように、本発明は、新規なハロゲノピラゾロピリジンピリダジノン誘導体とその付加塩が優れたPDE阻害作用を有することを見出したものである。このようなPDE阻害剤作用を有する化合物は、狭心症、心不全、高血圧症などの治療薬や血小板凝集抑制薬あるいは気管支喘息、慢性閉塞性肺疾患（COPD）、間質性肺炎、アレルギー性鼻炎、アトピー性皮膚炎、関節リウマチ、多発性硬化症、ハンチントン、アルツハイマー、認知症、パーキンソン病、精神***症などの各種精神障害等の予防または治療薬ならびに男性性機能障害治療薬として有用である。
As described above, the present invention has been found that a novel halogenopyrazolopyridine pyridazinone derivative and its addition salt have an excellent PDE inhibitory action. Such compounds with PDE inhibitor activity include therapeutic agents for angina pectoris, heart failure, hypertension, platelet aggregation inhibitors or bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis It is useful as a prophylactic or therapeutic agent for various psychiatric disorders such as atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Huntington, Alzheimer, dementia, Parkinson's disease, schizophrenia, etc., and as a therapeutic agent for male sexual dysfunction.

Claims (8)

一般式（１）

[式中、R₁はハロゲン原子又は炭素数１〜４の低級アルコキシ基を、
R₂は水素原子、ハロゲン原子、ヒドロキシ基又は炭素数１〜４の低級アルコキシ基を、
R₃は水素原子、ハロゲン原子、置換基を有しても良い炭素数１〜４の低級アルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜４の低級アルケニル基、炭素数１〜４の低級アルコキシ基、炭素数１〜４の低級アルカノイル基、ヒドロキシ基又はカルボキシル基を、
R₄は炭素数１〜４の低級アルキル基を、
R₅は水素原子又はR₆-(CH₂)m-（式中、R₆は炭素数３〜８のシクロアルキル基、１〜２個の複素原子を含んでいても良い芳香族複素環又は飽和複素環を、mは１〜２の整数を示す）を、
- -は単結合又は二重結合を示す]
で表されることを特徴とするハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物。
General formula (1)

[Wherein R ₁ represents a halogen atom or a lower alkoxy group having 1 to 4 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a hydroxy group or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ is a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms, or 1 carbon atom. -4 lower alkoxy group, 1 to 4 carbon lower alkanoyl group, hydroxy group or carboxyl group,
R ₄ represents a lower alkyl group having 1 to ₄ carbon atoms,
R ₅ is a hydrogen atom or R ₆ — (CH ₂ ) m — (wherein R ₆ is a cycloalkyl group having 3 to 8 carbon atoms, an aromatic heterocycle optionally containing 1 to 2 heteroatoms, or A saturated heterocyclic ring, m represents an integer of 1 to 2),
--Indicates a single bond or a double bond]
A halogenopyrazolopyridine pyridazinone derivative, its optical isomers and pharmacologically acceptable salts, and hydrates thereof, characterized in that
前記一般式（１）で表される化合物が、一般式（１ａ）

[式中、R₁、R₂、R₃及びR₄は前記定義に同じ]
で表されることを特徴とする請求項１記載のハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物。 The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
The halogenopyrazolopyridine pyridazinone derivative according to claim 1, its optical isomer, pharmacologically acceptable salt, and hydrate thereof, wherein 前記一般式（１ａ）においてR₁が塩素原子であることを特徴とする請求項２に記載のハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物。 3. The halogenopyrazolopyridine pyridazinone derivative according to claim 2, wherein R ₁ is a chlorine atom in the general formula (1a), optical isomers and pharmacologically acceptable salts thereof, and water thereof Japanese products. 前記一般式（１ａ）においてR₁がフッ素原子であることを特徴とする請求項２に記載のハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物。 3. The halogenopyrazolopyridine pyridazinone derivative according to claim 2, the optical isomer, a pharmacologically acceptable salt thereof and water thereof, wherein R ₁ in the general formula (1a) is a fluorine atom. Japanese products. 前記一般式（１）で示される化合物が、
１） ６−（６−クロロ−２−エチル-ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（＋）−６−（６−クロロ−２−エチル-ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（−）−６−（６−クロロ−２−エチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（＋）−６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
（−）−６−（２−エチル−６−フルオロ−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン、
６−（６−クロロ−２−トリフルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノン又は
６−（６−フルオロ−２−トリフルオロメチル−ピラゾロ[１，５−ａ]ピリジン−３−イル）−５−メチル−４，５−ジヒドロ−３（２H）−ピリダジノンである請求項１記載のハロゲノピラゾロピリジンピリダジノン誘導体、及び薬理学的に許容しうる塩並びにその水和物。 The compound represented by the general formula (1) is
1) 6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(+)-6- (6-chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(−)-6- (6-Chloro-2-ethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
6- (2-ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(+)-6- (2-ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
(−)-6- (2-ethyl-6-fluoro-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
6- (6-Chloro-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone or 6- (6- The halogenopyrazolopyridine of claim 1, which is fluoro-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-3-yl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone. Pyridazinone derivatives, and pharmacologically acceptable salts and hydrates thereof. 一般式（１）

[式中、R₁はハロゲン原子又は炭素数１〜４の低級アルコキシ基を、
R₂は水素原子、ハロゲン原子、ヒドロキシ基又は炭素数１〜４の低級アルコキシ基を、
R₃は水素原子、ハロゲン原子、置換基を有しても良い炭素数１〜４の低級アルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜４の低級アルケニル基、炭素数１〜４の低級アルコキシ基、炭素数１〜４の低級アルカノイル基、ヒドロキシ基又はカルボキシル基を、
R₄は炭素数１〜４の低級アルキル基を、
R₅は水素原子又はR₆-(CH₂)m-（式中、R₆は炭素数３〜８のシクロアルキル基、１〜２個の複素原子を含んでいても良い芳香族複素環又は飽和複素環を、mは１〜２の整数を示す）を、
- -は単結合又は二重結合を示す]
で表されることを特徴とするハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とするホスホジエステラーゼ（PDE）阻害剤。 General formula (1)

[Wherein R ₁ represents a halogen atom or a lower alkoxy group having 1 to 4 carbon atoms,
R ₂ represents a hydrogen atom, a halogen atom, a hydroxy group or a lower alkoxy group having 1 to 4 carbon atoms,
R ₃ is a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms, or 1 carbon atom. -4 lower alkoxy group, 1 to 4 carbon lower alkanoyl group, hydroxy group or carboxyl group,
R ₄ represents a lower alkyl group having 1 to ₄ carbon atoms,
R ₅ is a hydrogen atom or R ₆ — (CH ₂ ) m — (wherein R ₆ is a cycloalkyl group having 3 to 8 carbon atoms, an aromatic heterocycle optionally containing 1 to 2 heteroatoms, or A saturated heterocyclic ring, m represents an integer of 1 to 2),
--Indicates a single bond or a double bond]
A phosphodiesterase (PDE) comprising at least one of halogenopyrazolopyridine pyridazinone derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof, characterized in that Inhibitor. 前記一般式（１）で示される化合物が、一般式（１ａ）

[式中、R₁、R₂、R₃及びR₄は前記定義に同じ]
で表されるハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とすることを特徴とする請求項６に記載のPDE阻害剤。 The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
The active ingredient is at least one of a halogenopyrazolopyridine pyridazinone derivative represented by the following formula, an optical isomer, a pharmacologically acceptable salt thereof, and a hydrate thereof. The PDE inhibitor described. 請求項１〜５のいずれか１項に記載されたハロゲノピラゾロピリジンピリダジノン誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分として含有する医薬。 The halogenopyrazolopyridine pyridazinone derivative according to any one of claims 1 to 5, an optical isomer, a pharmacologically acceptable salt thereof, and a hydrate thereof as an active ingredient. Contains medicines.