JP2014214138A - Piperazine derivative having hydroxyl group and salt of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound which has an Akt inhibitory effect and a cell growth inhibitory effect and a medicine useful in prevention and/or remedy of Akt-related diseases, especially cancer, based on the Akt inhibitory effect.SOLUTION: Piperazine derivatives of formula (I) having a hydroxyl group or their salts are provided. In formula (I), Rto Rare as defined in the specification.

Description

  The present invention relates to a novel piperazine derivative having an Akt inhibitory action, which is a serine / threonine kinase, and a pharmaceutical composition containing these as active ingredients.

  Akt kinase (hereinafter referred to as “Akt”) is a serine / threonine kinase also called PKB, and is a molecule that plays a central role in cell survival, proliferation, metabolism, and the like (Non-patent Document 1). .

  Abnormal activation of Akt and mutation of the Akt gene itself are observed in various types of cancer, and it is strongly suggested that Akt is involved in the development, maintenance and expression of traits ( Non-patent documents 2, 3).

  To date, several inhibitors targeting Akt have been developed and reported for their anti-tumor effects. However, these inhibitors do not exhibit a sufficient antitumor effect as a single agent in a non-clinical model, and it is not possible to obtain a strong cytocidal effect at a low concentration or a strong antitumor effect in vivo. Not done (Non-Patent Documents 4 and 5) In addition, clinical effects have not been confirmed for these inhibitors.

  Moreover, as a piperazine derivative which has Akt inhibitory activity, although the compound described in patent documents 1-3 is reported, all have the antitumor effect inadequate.

  Furthermore, the cancer types for which the Akt inhibitor has shown a certain effect in the previous reports are limited to cells and models such as breast cancer, prostate cancer, glioma (Non-patent Documents 4 and 6), and other cancers. There are no examples showing strong effects on species such as colon cancer.

  Therefore, in the field of cancer treatment, it is still desired to develop an Akt inhibitor that exhibits a powerful antitumor effect as a single agent and is effective against a wide range of cancer types.

International Publication No. WO2005 / 051304 International Publication No. WO2008 / 006040 International Publication No. WO2009 / 089453

J Cell Sci. 2005 118: 5675-8 Curr Cancer Drug Targets. 2008 8: 27-36 Nature. 2007 448: 439-44. Mol Cancer Ther. 2005 4: 977-86 Mol Cancer Ther. 2010 9: 1956-67 Rhodes N et al, Cancer Res. 2008 68: 2366-74

  An object of the present invention is to provide a novel compound or a salt thereof that strongly inhibits Akt.

  As a result of intensive studies to solve the above problems, the inventors of the present invention have a piperazine derivative as a basic structure, and 5,6-dihydro-7H-pyrrolo [2,3-d] pyrimidine-6 at the 1-position of piperazine. -A compound group having an ON and having aminohydroxypropanone at the 4-position of piperazine has an excellent inhibitory activity against Akt and a cancer cell growth inhibitory effect, and various diseases (especially cancer) in which Akt is involved As a result, the present invention has been completed.

［式中、
Ｒ_１及びＲ_２は、同一又は異なって、水素原子であるか、又はＲ_ａにより置換されていてもよいＣ_１−Ｃ_６アルキル基であるか、或いは、Ｒ_１及びＲ_２は、それらが結合する炭素原子と一緒になってＣ_３−Ｃ_１０シクロアルキレン（ここでＣ_３−Ｃ_１０シクロアルキレンは、Ｒ_ｂで置換されていてもよい）を形成し；
Ｒ_３は、Ｒ_ｃにより置換されていてもよいＣ_６−Ｃ_１４芳香族炭化水素基、又はＲ_ｃにより置換されていてもよい４〜１０員の不飽和複素環式基であり；
Ｒ_４及びＲ_５は、同一又は異なって、水素原子であるか、又はＲ_ａにより置換されていてもよいＣ_１−Ｃ_６アルキル基、Ｒ_ａにより置換されていてもよいＣ_２−Ｃ_６アルケニル基、Ｒ_ａにより置換されていてもよいＣ_２−Ｃ_６アルキニル基、Ｒ_ｃにより置換されていてもよいＣ_３−Ｃ_１０シクロアルキル基、Ｒ_ｃにより置換されていてもよいＣ_６−Ｃ_１４芳香族炭化水素基、若しくはＲ_ｃにより置換されていてもよい４〜１０員の飽和若しくは不飽和複素環式基であるか、或いは、Ｒ_４及びＲ_５は、それらが結合する窒素原子と一緒になって４〜１０員の飽和複素環式基（ここで４〜１０員の飽和複素環式基は、Ｒ_ｂにより置換されていてもよい）を形成し；
Ｒ_６及びＲ_７は、同一又は異なって、水素原子であるか、又はＲ_ａにより置換されていてもよいＣ_１−Ｃ_６アルキル基、又はＲ_ａにより置換されていてもよいＣ_１−Ｃ_６アルコキシ基であるか、或いは、Ｒ_６及びＲ_７は、それらが結合する炭素原子と一緒になってＣ_３−Ｃ_１０シクロアルキレン（ここでＣ_３−Ｃ_１０シクロアルキレンは、Ｒ_ｂにより置換されていてもよい）を形成し；
Ｒ_ａは、重水素原子、ハロゲン原子、ヒドロキシル基、アミノ基、シアノ基、ニトロ基、Ｃ_３−Ｃ_１０シクロアルキル基、Ｃ_６−Ｃ_１４芳香族炭化水素基、又は４〜１０員の飽和若しくは不飽和複素環式基であり；
Ｒ_ｂは、重水素原子、ハロゲン原子、ヒドロキシル基、アミノ基、シアノ基、ニトロ基、オキソ基、オキシド基、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロアルキル基、Ｃ_２−Ｃ_６アルケニル基、Ｃ_２−Ｃ_６アルキニル基、Ｃ_３−Ｃ_１０シクロアルキル基、Ｃ_６−Ｃ_１４芳香族炭化水素基、又は４〜１０員の飽和若しくは不飽和複素環式基であり；
Ｒ_ｃは、重水素原子、ハロゲン原子、シアノ基、ニトロ基、オキソ基、オキシド基、
−Ｃ（＝Ｏ）Ｒ_ｘ、−Ｃ（＝Ｏ）ＯＲ_ｘ、−Ｃ（＝Ｏ）Ｎ（Ｒ_ｘ）（Ｒ_ｙ）、−Ｃ（＝Ｏ）ＳＲ_ｘ、−Ｃ（＝Ｓ）ＯＲ_ｘ、−Ｃ（＝Ｏ）ＯＮ（Ｒ_ｘ）（Ｒ_ｙ）、−Ｎ（Ｒ_ｘ）（Ｒ_ｙ）、−ＮＲ_ｘＣ（＝Ｏ）Ｒ_ｙ、−ＮＲ_ｘＳＯ_２Ｒ_ｙ、−ＮＲ_ｘＣ（＝Ｏ）ＯＲ_ｙ、−ＮＲ_ｘＣ（＝Ｏ）Ｎ（Ｒ_ｙ）（Ｒ_ｚ）、−ＮＲ_ｘＳＯ_２Ｎ（Ｒ_ｙ）（Ｒ_ｚ）、−Ｎ（Ｒ_ｘ）−ＯＲ_ｙ、＝ＮＲ_ｘ、＝Ｎ−ＯＲ_ｘ、−ＯＲ_ｘ、−ＯＣ（＝Ｏ）Ｒ_ｘ、−ＯＣ（＝Ｓ）Ｒ_ｘ、−ＯＣ（＝Ｏ）ＯＲ_ｘ、−ＯＣ（＝Ｏ）Ｎ（Ｒ_ｘ）（Ｒ_ｙ）、−ＯＣ（＝Ｓ）ＯＲ_ｘ、−ＳＲ_ｘ、−ＳＯ_２Ｒ_ｘ、−ＳＯ_２Ｎ（Ｒ_ｘ）（Ｒ_ｙ）、Ｒ_ａにより置換されていてもよいＣ_１−Ｃ_６アルキル基、Ｒ_ａにより置換されていてもよいＣ_２−Ｃ_６アルケニル基、Ｒ_ａにより置換されていてもよいＣ_２−Ｃ_６アルキニル基、Ｒ_ｂにより置換されていてもよいＣ_３−Ｃ_１０シクロアルキル基、Ｒ_ｂにより置換されていてもよいＣ_６−Ｃ_１４芳香族炭化水素基、Ｒ_ｂにより置換されていてもよい４〜１０員の飽和若しくは不飽和複素環式基であり；
Ｒ_ｘ、Ｒ_ｙ及びＲ_ｚは、同一又は異なって、水素原子、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロアルキル基、Ｃ_２−Ｃ_６アルケニル基、Ｃ_２−Ｃ_６アルキニル基、Ｃ_３−Ｃ_１０シクロアルキル基、Ｃ_６−Ｃ_１４芳香族炭化水素基、又は４〜１０員の飽和若しくは不飽和複素環式基である。］
で表される、化合物又はその塩。
［２］ Ｒ_１及びＲ_２のいずれか一方が水素原子であり、他方がＣ_１−Ｃ_６アルキル基である、［１］に記載の化合物又はその塩。
［３］ Ｒ_３が、Ｒ_ｃにより置換されていてもよいＣ_６−Ｃ_１４芳香族炭化水素基、又はＮ、Ｓ及びＯから選択される１〜３個のヘテロ原子を有し、かつＲ_ｃにより置換されていてもよい４〜６員の単環式の不飽和複素環式基である、［１］又は［２］記載の化合物又はその塩。
［４］ Ｒ_３が、同一又は異なった１〜５個のＲ_ｃにより置換されていてもよいＣ_６−Ｃ_１４芳香族炭化水素基であり、かつＲ_ｃが
（１）ハロゲン原子；
（２）Ｃ_６−Ｃ_１４芳香族炭化水素オキシ基；
（３）Ｃ_２−Ｃ_６アルキニル基；
（４）Ｃ_６−Ｃ_１４芳香族炭化水素基；及び
（５）オキソ基及びＣ_１−Ｃ_６アルキル基からなる群から選択される同一又は異なった１〜３個の基により置換されていてもよい４〜１０員の不飽和複素環式基；
からなる群から選択されるか、或いは
Ｒ_３が、１〜５個のＲ_ｃにより置換されていてもよい、Ｎ、Ｓ及びＯから選択される１〜３個のヘテロ原子を有する４〜６員の単環式の不飽和複素環式基であり、かつＲ_ｃがハロゲン原子である、［１］〜［３］のいずれかに記載の化合物またはその塩。
［５］ Ｒ_４及びＲ_５が、同一又は異なって、水素原子であるか、又はＲ_ａにより置換されていてもよいＣ_１−Ｃ_６アルキル基、Ｒ_ｃにより置換されていてもよいＣ_３−Ｃ_１０シクロアルキル基、又はＲ_ｃにより置換されていてもよいＮ、Ｓ及びＯから選択される１〜３個のヘテロ原子を有する４〜６員の単環式の飽和複素環式基であるか、或いは、Ｒ_４及びＲ_５が、それらが結合する窒素原子と一緒になってＮ、Ｓ及びＯから選択される１〜３個のヘテロ原子を有する４〜６員の単環式の飽和複素環式基（ここで飽和複素環式基は、Ｒ_ｂで置換されていてもよい）を形成する、［１］〜［４］のいずれかに記載の化合物又はその塩。
［６］ Ｒ_６及びＲ_７のいずれか一方が水素原子であり、他方が水素原子又はＣ_１−Ｃ_６アルキル基であるか、或いは、Ｒ_６及びＲ_７が、それらが結合する炭素原子と一緒になってＣ_３−Ｃ_１０シクロアルキレン（ここでＣ_３−Ｃ_１０シクロアルキレンは、Ｒ_ｂにより置換されていてもよい）を形成する、［１］〜［５］のいずれかに記載の化合物又はその塩。
［７］ Ｒ_１及びＲ_２のいずれか一方が水素原子であり、他方がＣ_１−Ｃ_６アルキル基であり、
Ｒ_３が、同一又は異なった１〜５個のＲ_ｃにより置換されていてもよいＣ_６−Ｃ_１４芳香族炭化水素基であり、かつＲ_ｃが
（１）ハロゲン原子；
（２）Ｃ_６−Ｃ_１４芳香族炭化水素オキシ基；
（３）Ｃ_２−Ｃ_６アルキニル基；
（４）Ｃ_６−Ｃ_１４芳香族炭化水素基；及び
（５）オキソ基及びＣ_１−Ｃ_６アルキル基からなる群から選択される同一又は異なった１〜３個の基により置換されていてもよい４〜１０員の不飽和複素環式基；
からなる群から選択されるか、或いは
Ｒ_３が、１〜５個のＲ_ｃにより置換されていてもよい、Ｎ、Ｓ及びＯから選択される１〜３個のヘテロ原子を有する４〜６員の単環式の不飽和複素環式基であり、かつＲ_ｃがハロゲン原子であり、
Ｒ_４及びＲ_５が、同一又は異なって、水素原子；Ｃ_３−Ｃ_１０シクロアルキル基により置換されていてもよいＣ_１−Ｃ_６アルキル基；Ｃ_１−Ｃ_６アルコキシ基により置換されていてもよいＣ_３−Ｃ_１０シクロアルキル基；又はＮ、Ｓ及びＯから選択される１〜３個のヘテロ原子を有する４〜６員の単環式の飽和複素環式基であるか、或いは、Ｒ_４及びＲ_５が、それらが結合する窒素原子と一緒になってＮ、Ｓ及びＯから選択される１〜３個のヘテロ原子を有する４〜６員の単環式の飽和複素環を形成し、
Ｒ_６及びＲ_７のいずれか一方が水素原子であり、他方が水素原子又はＣ_１−Ｃ_６アルキル基であるか、或いは、Ｒ_６及びＲ_７が、それらが結合する炭素原子と一緒になってＣ_３−Ｃ_１０シクロアルキレンを形成する、［１］〜［６］のいずれかに記載の化合物又はその塩。
［８］ 以下の化合物群から選択される、［１］〜［７］のいずれかに記載の化合物又はその塩：
（１）４−（４−（（Ｒ）−２−（４−クロロフェニル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（２）４−（４−（（Ｒ）−２−（４−クロロフェニル）−３−（ジメチルアミノ）−２−ヒドロキシプロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（３）４−（４−（（Ｒ）−２−（４−クロロフェニル）−３−（エチルアミノ）−２−ヒドロキシプロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（４）４−（４−（（Ｒ）−２−（５−クロロチオフェン−２−イル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（５）４−（４−（（Ｒ）−２−（４−クロロ−３−フルオロフェニル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（６）４−（（Ｒ）−４−（（Ｒ）−２−（４−クロロ−３−フルオロフェニル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）−３−メチルピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（７）４−（４−（（Ｒ）−２−（５−クロロチオフェン−２−イル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）−４，７−ジアザスピロ［２．５］オクタン−７−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（８）４−（４−（（Ｒ）−２−（４−クロロ−３−フルオロフェニル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）−４，７−ジアザスピロ［２．５］オクタン−７−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（９）４−（４−（（Ｒ）−２−（［１，１’−ビフェニル］−４−イル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（１０）４−（４−（（Ｒ）−３−（アゼチジン−１−イル）−２−（４−クロロフェニル）−２−ヒドロキシプロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（１１）４−（４−（（Ｒ）−２−（４−クロロフェニル）−２−ヒドロキシ−３−（ピロリジン−１−イル）プロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、
（１２）４−（４−（（Ｒ）−２−（４−エチニルフェニル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン、及び
（１３）４−（４−（（Ｒ）−２−（４−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル）−２−ヒドロキシ−３−（イソプロピルアミノ）プロパノイル）ピペラジン−１−イル）−５−メチル−５Ｈ−ピロロ［２，３−ｄ］ピリミジン−６（７Ｈ）−オン。
［９］ ［１］〜［８］のいずれかに記載の化合物又はその塩を有効成分とするＡｋｔ阻害剤。
［１０］ ［１］〜［８］のいずれかに記載の化合物又はその塩を有効成分として含有する、Ａｋｔが関与する疾患を治療するための医薬組成物。
［１１］ ［１］〜［８］のいずれかに記載の化合物又はその塩を有効成分とする抗腫瘍剤。 The present invention includes the following.
[1] The following formula (I)

[Where:
R ₁ and R ₂ are the same or different and are a hydrogen atom or _a C ₁ -C ₆ alkyl group optionally substituted by R _a , or R ₁ and R ₂ are _C 3 _{-C 10} cycloalkylene (wherein _C 3 _{-C 10} cycloalkylene may be substituted by _{R b)} taken together with the carbon atom bonded to the formation;
R ₃ is an unsaturated heterocyclic group _R may be substituted by _{c C} 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered optionally substituted by _{R c;}
R ₄ and R ₅ are the same or different and are a hydrogen atom or _a C ₁ -C ₆ alkyl group optionally substituted by R _a , C ₂ -C ₆ optionally substituted by R _a alkenyl group, optionally substituted by _{R a C} 2 -C ₆ alkynyl group, _{R c} by optionally substituted _C 3 _-C even though ₁₀ cycloalkyl group, optionally substituted by _{R c C 6} - A C ₁₄ aromatic hydrocarbon group, or a 4-10 membered saturated or unsaturated heterocyclic group optionally substituted by R _c , or R ₄ and R ₅ are the nitrogen atoms to which they are attached. Together with a 4- to 10-membered saturated heterocyclic group, wherein the 4- to 10-membered saturated heterocyclic group may be substituted by R _b ;
R ₆ and _{R 7} are the same or different, is a hydrogen atom, or _{R a} with substituted _C 1 -C ₆ alkyl group or _{R a} optionally _C 1 -C be substituted by, ₆ alkoxy groups or R ₆ and R ₇ together with the carbon atom to which they are attached are C ₃ -C ₁₀ cycloalkylene (where C ₃ -C ₁₀ cycloalkylene is substituted by R _b May be formed);
R _a is a deuterium atom, halogen atom, hydroxyl group, amino group, cyano group, nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₄ aromatic hydrocarbon group, or 4-10 membered saturation Or an unsaturated heterocyclic group;
R _b is a deuterium atom, halogen atom, hydroxyl group, amino group, cyano group, nitro group, oxo group, oxide group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₂ -C _6. alkenyl _group, a C 2 -C ₆ alkynyl _group, C 3 _{-C 10} cycloalkyl _group, C 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered saturated or unsaturated heterocyclic group;
R _c is a deuterium atom, halogen atom, cyano group, nitro group, oxo group, oxide group,
_{-C (= O) R x,} -C (= O) OR x, -C (= O) N (R x) (R y), - C (= O) SR x, -C (= S) OR _{x, -C (= O) ON} (R x) (R y), - N (R x) (R y), - NR x C (= O) R y, -NR x SO 2 R y, -NR _{x C (= O) OR y} , -NR x C (= O) N (R y) (R z), - NR x SO 2 N (R y) (R z), - N (R x) -OR _{y, = NR x, = N} -OR x, -OR x, -OC (= O) R x, -OC (= S) R x, -OC (= O) OR x, -OC (= O) N (R _x ) (R _y ), —OC (═S) OR _x , —SR _x , —SO ₂ R _x , —SO ₂ N (R _x ) (R _y ), R _a may be substituted. C ₁ -C ₆ alkyl group, optionally substituted by _{R a} Which may _C 2 -C ₆ alkenyl group, _{R a} by optionally substituted _C 2 -C ₆ alkynyl group, _{R b} by optionally substituted _C 3 _-C even though ₁₀ cycloalkyl group, substituted by _{R b} which may be C ₆ -C ₁₄ aromatic hydrocarbon group, a saturated or unsaturated heterocyclic group having 4 to 10 membered optionally substituted by R _b;
R _x , R _y and R _z are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, C ₃ -C ₁₀ cycloalkyl _group, a saturated or unsaturated heterocyclic group C 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered. ]
Or a salt thereof.
[2] The compound or a salt thereof according to [1], wherein either _one of R ₁ and R ₂ is a hydrogen atom, and the other is a C ₁ -C ₆ alkyl group.
[3] R ₃ has a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by R _c , or 1 to 3 heteroatoms selected from N, S and O, and R 3 The compound or a salt thereof according to [1] or [2], which is a 4- to 6-membered monocyclic unsaturated heterocyclic group optionally substituted by _c .
[4] R ₃ is a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by 1 to 5 identical or different R _{c s} , and R _c is (1) a halogen atom;
(2) a C ₆ -C ₁₄ aromatic hydrocarbon oxy group;
₍₃₎ C 2 -C ₆ alkynyl group;
₍₄₎ C 6 _{-C 14} aromatic hydrocarbon group; and (5) optionally substituted by the same or different 1 to 3 groups selected from the group consisting of oxo group and _C 1 -C ₆ alkyl group A 4-10 membered unsaturated heterocyclic group;
4 to 6 having 1 to 3 heteroatoms selected from N, S and O, wherein R ₃ is selected from the group consisting of: or R ₃ is optionally substituted by 1 to 5 R _c The compound or salt thereof according to any one of [1] to [3], which is a membered monocyclic unsaturated heterocyclic group and R _c is a halogen atom.
[5] _{R 4} and _{R 5} are the same or different, is a hydrogen atom, or optionally substituted by _{R a C} 1 -C ₆ alkyl group, optionally substituted by _{R c C 3} -C ₁₀ cycloalkyl group, or R may be substituted by _c N, 4-6 membered monocyclic saturated heterocyclic group having 1 to 3 heteroatoms selected from S and the O Or alternatively, R ₄ and R ₅ are 4-6 membered monocyclic having 1 to 3 heteroatoms selected from N, S and O together with the nitrogen atom to which they are attached. The compound or salt thereof according to any one of [1] to [4], which forms a saturated heterocyclic group (wherein the saturated heterocyclic group may be substituted with _Rb ).
[6] Either one of R ₆ and R ₇ is a hydrogen atom and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ are a carbon atom to which they are bonded, and _C 3 _{-C 10} cycloalkylene (wherein _C 3 _{-C 10} cycloalkylene may be substituted by _{R b)} taken together to form a, according to any one of [1] to [5] Compound or salt thereof.
[7] Either _one of R ₁ and R ₂ is a hydrogen atom, and the other is a C ₁ -C ₆ alkyl group,
R ₃ is a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by 1 to 5 different or identical R _{c s} , and R _c is (1) a halogen atom;
(2) a C ₆ -C ₁₄ aromatic hydrocarbon oxy group;
₍₃₎ C 2 -C ₆ alkynyl group;
₍₄₎ C 6 _{-C 14} aromatic hydrocarbon group; and (5) optionally substituted by the same or different 1 to 3 groups selected from the group consisting of oxo group and _C 1 -C ₆ alkyl group A 4-10 membered unsaturated heterocyclic group;
4 to 6 having 1 to 3 heteroatoms selected from N, S and O, wherein R ₃ is selected from the group consisting of: or R ₃ is optionally substituted by 1 to 5 R _c A membered monocyclic unsaturated heterocyclic group, and R _c is a halogen atom,
R ₄ and R ₅ are the same or different and are each a hydrogen atom; a C ₁ -C ₆ alkyl group optionally substituted by a C ₃ -C ₁₀ cycloalkyl group; and a C ₁ -C ₆ alkoxy group. which may C ₃ -C ₁₀ cycloalkyl group; or N, or a monocyclic saturated heterocyclic group having 4-6 members with 1-3 heteroatoms selected from S and O, or, R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic saturated heterocycle having 1 to 3 heteroatoms selected from N, S and O And
One of R ₆ and R ₇ is a hydrogen atom and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ are combined with the carbon atom to which they are attached. Te to form a _C 3 _{-C 10} cycloalkylene, the compound or salt thereof according to any one of [1] to [6].
[8] The compound or salt thereof according to any one of [1] to [7], selected from the following compound group:
(1) 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2, 3-d] pyrimidin-6 (7H) -one,
(2) 4- (4-((R) -2- (4-Chlorophenyl) -3- (dimethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one,
(3) 4- (4-((R) -2- (4-chlorophenyl) -3- (ethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one,
(4) 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(5) 4- (4-((R) -2- (4-Chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(6) 4-((R) -4-((R) -2- (4-chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -3-methylpiperazine-1- Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(7) 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] octane -7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(8) 4- (4-((R) -2- (4-Chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] octane -7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(9) 4- (4-((R) -2-([1,1′-biphenyl] -4-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5 -Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(10) 4- (4-((R) -3- (azetidin-1-yl) -2- (4-chlorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H- Pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(11) 4- (4-((R) -2- (4-Chlorophenyl) -2-hydroxy-3- (pyrrolidin-1-yl) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(12) 4- (4-((R) -2- (4-ethynylphenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one, and (13) 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -2-Hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one.
[9] An Akt inhibitor comprising the compound or salt thereof according to any one of [1] to [8] as an active ingredient.
[10] A pharmaceutical composition for treating a disease involving Akt, comprising the compound or salt thereof according to any one of [1] to [8] as an active ingredient.
[11] An antitumor agent comprising the compound or salt thereof according to any one of [1] to [8] as an active ingredient.

  According to the present invention, a novel compound represented by the above formula (I) or a salt thereof useful as an Akt inhibitor is provided.

  It became clear that this invention compound or its salt has the outstanding Akt inhibitory activity, and shows the growth inhibitory effect with respect to a cancer cell line. Therefore, the compound of the present invention or a salt thereof is useful as a preventive and / or therapeutic agent for diseases involving Akt such as cancer.

  The compound represented by the above formula (I) of the present invention has 5,6-dihydro-7H-pyrrolo [2,3-d] pyrimidin-6-one at the 1-position of the piperazine skeleton, and the 4-position thereof. Is a novel compound not described in any of the above-mentioned prior art documents.

  In the present specification, specific examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  In the present specification, the “alkyl group” is a linear or branched alkyl group, specifically a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, Examples thereof include a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group.

  In the present specification, the “alkenyl group” is a linear or branched alkenyl group containing at least one carbon-carbon double bond, and specifically includes a vinyl group, an allyl group, a methylvinyl group, and a propenyl. Group, butenyl group, pentenyl group, hexenyl group and the like.

  In the present specification, the “alkynyl group” is a linear or branched alkynyl group containing at least one carbon-carbon triple bond, and specific examples thereof include an ethynyl group and a 2-propynyl group.

  In the present specification, the “haloalkyl group” is a group in which one to all hydrogen atoms of the alkyl group are substituted with halogen atoms, and specifically includes a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group. Group, 1-fluoroethyl group, 2-fluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2-difluoroethyl group and the like.

  In the present specification, the “alkoxy group” is an oxy group to which the alkyl group is bonded, specifically, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, Examples thereof include a tert-butoxy group.

  In the present specification, the “cycloalkyl group” is a monocyclic or polycyclic alkyl group, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a decalyl group, an adamantyl group. Groups and the like.

  In the present specification, the “aromatic hydrocarbon group” is a monocyclic or polycyclic aromatic hydrocarbon group, and only a part of the rings may be a group exhibiting aromaticity. Specific examples include a phenyl group, a naphthyl group, and a tetrahydronaphthyl group.

  In the present specification, the “saturated heterocyclic group” is a monocyclic or polycyclic saturated heterocyclic group having a heteroatom selected from N, S and O, specifically a pyrrolidinyl group, Examples include a piperidinyl group, a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperazinyl group, an oxetanyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group.

  As used herein, the term “unsaturated heterocyclic group” means a monocyclic or polycyclic, fully unsaturated or partially unsaturated heterocyclic group having a heteroatom selected from N, S and O Specifically, imidazolyl group, thienyl group, furyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group , Pyridazinyl group, indolyl group, isoindolyl group, indazolyl group, triazolopyridyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzothienyl group, benzofuranyl group, purinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl Group, methylenedioxyphenyl , Ethylenedioxy phenyl group, dihydrobenzofuranyl group and the like.

  In the present specification, the “aromatic hydrocarbon oxy group” is an oxy group to which the aromatic hydrocarbon group is bonded. Specific examples include a phenyloxy group and a naphthyloxy group.

In the description of the substituents in the present specification, the "C _x -C _y" indicates that the carbon number of substituents X to Y. For example, “C ₁ -C ₆ alkyl group” represents an alkyl group having 1 to 6 carbon atoms, and “C ₆ -C ₁₄ aromatic hydrocarbon oxy group” represents an aromatic hydrocarbon group having 6 to 14 carbon atoms. A bonded oxy group is shown. The “X to Y member” indicates that the number of atoms constituting the ring (the number of ring members) is X to Y. For example, “4 to 10-membered saturated heterocyclic group” means a saturated heterocyclic group having 4 to 10 ring members.

In the present specification, R _a is a deuterium atom, halogen atom, hydroxyl group, amino group, cyano group, nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₄ aromatic hydrocarbon group, or 4 It is a 10-membered saturated or unsaturated heterocyclic group.

In the present specification, R _b represents a deuterium atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, an oxo group, an oxide group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, C ₂ -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 3 _{-C 10} cycloalkyl _group, C 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered saturated or unsaturated heterocyclic group It is.

In the present specification, R _c represents a deuterium atom, a halogen atom, a cyano group, a nitro group, an oxo group, an oxide group, —C (═O) R _x , —C (═O) OR _x , —C (= _{O) N (R x) (} R y), - C (= O) SR x, -C (= S) OR x, -C (= O) ON (R x) (R y), - N (R _{x) (R y), -} NR x C (= O) R y, -NR x SO 2 R y, -NR x C (= O) OR y, -NR x C (= O) N (R y) _{(R z), - NR x} SO 2 N (R y) (R z), - N (R x) -OR y, = NR x, = N-OR x, -OR x, -OC (= O) R _x , —OC (═S) R _x , —OC (═O) OR _x , —OC (═O) N (R _x ) (R _y ), —OC (═S) OR _x , —SR _x , _{-SO 2 R x, -SO 2 N} (R _x ) (R _y ), _a C ₁ -C ₆ alkyl group optionally substituted by R _a , _a C ₂ -C ₆ alkenyl group optionally substituted by R _a , and optionally substituted by R _a C ₂ -C ₆ alkynyl group, optionally substituted by _{R b C} 3 _{-C 10} cycloalkyl group, optionally substituted by _{R b C} 6 _{-C 14} aromatic hydrocarbon group, substituted by _{R b} A 4- to 10-membered saturated or unsaturated heterocyclic group which may be substituted. _Here, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 3 _{-C 10} cycloalkyl _group, C 6 _{-C 14} aromatic hydrocarbon group, and 4 relates saturated or unsaturated heterocyclic group having 10-membered, when substituted by R _a or R _b, the number of R _a and R _b are bonded is not particularly limited, 1-5 each independently, especially A range of 1 to 3, particularly 1 to 2 is preferable.

In the present specification, R _x , R _y and R _z are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₂ -C ₆ alkenyl group, a C _2- C ₆ alkynyl _group, a C 3 _{-C 10} cycloalkyl _group, C 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered saturated or unsaturated heterocyclic group.

In the compound represented by the formula (I) of the present invention, R ₁ and R ₂ are the same or different and each is a hydrogen atom or _a C ₁ -C ₆ alkyl group which may be substituted with _Ra. Or R ₁ and R ₂ together with the carbon atom to which they are attached are C ₃ -C ₁₀ cycloalkylene (wherein the C ₃ -C ₁₀ cycloalkylene may be substituted with R _b Good).

In the “C ₁ -C ₆ alkyl group optionally substituted by R _a ” represented by R ₁ or R ₂ , the “C ₁ -C ₆ alkyl group” is preferably a C ₁ -C ₄ alkyl group. More preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

In the “C ₁ -C ₆ alkyl group optionally substituted by R _a ” represented by R ₁ or R ₂ , R _a is preferably a halogen atom. The number of _Ra is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3, and particularly preferably unsubstituted.

R ₁ and R _{2 form} “C ₃ -C ₁₀ cycloalkylene together with the carbon atom to which they are attached, where C ₃ -C ₁₀ cycloalkylene may be substituted with R _b” In this case, “C ₃ -C ₁₀ cycloalkylene” is preferably C ₃ -C ₇ cycloalkylene, more preferably cyclopropylene, cyclobutylene or cyclopentylene, and particularly preferably cyclopropylene.

R ₁ and R _{2 form} “C ₃ -C ₁₀ cycloalkylene together with the carbon atom to which they are attached, where C ₃ -C ₁₀ cycloalkylene may be substituted with R _b” In this case, R _b is preferably a halogen atom. Here, the number of R _b is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3, and particularly preferably unsubstituted.

Preferably, R ₁ and R ₂ are the same or different and are a hydrogen atom or _a C ₁ -C ₆ alkyl group optionally substituted by _Ra , more preferably a hydrogen atom or C _1- C ₆ alkyl group. More preferably, _one of R ₁ and R ₂ is a hydrogen atom or a C ₁ -C ₆ alkyl group, and the other is a C ₁ -C ₆ alkyl group. Particularly preferably, _one of R ₁ and R ₂ is a hydrogen atom and the other is a C ₁ -C ₆ alkyl group.

In the compounds of the formula (I) of the present invention, R ₃ is optionally substituted by R _{c C 6} -C ₁₄ aromatic hydrocarbon group, or a 4 to which may optionally be substituted by R _c It is a 10-membered unsaturated heterocyclic group.

In the “C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by R _c ” represented by R ₃ , the “C ₆ -C ₁₄ aromatic hydrocarbon group” is preferably C ₆ -C _14. An aromatic hydrocarbon group, more preferably a phenyl group or a naphthyl group, and particularly preferably a phenyl group.

In the “C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted with R _c ” represented by R ₃ , R _c is preferably substituted with _a halogen atom, —OR _x , or R _a. good _C 1 -C ₆ alkyl group, optionally substituted by _{R a C} 2 -C ₆ alkenyl group, _{R a} by optionally substituted _C 2 -C ₆ alkynyl group, optionally substituted by _{R b} also a good _C 6 _{-C 14} aromatic hydrocarbon group, an unsaturated heterocyclic group having 4 to 10 membered optionally substituted by _{R b.} R _c is more preferably a halogen atom; a C ₆ -C ₁₄ aromatic hydrocarbon oxy group; a C ₂ -C ₆ alkynyl group; a C ₆ -C ₁₄ aromatic hydrocarbon group; an oxo group and C ₁ -C _6. It is a 4- to 10-membered unsaturated heterocyclic group which may be substituted with 1 to 3 groups which are the same or different and selected from the group consisting of alkyl groups. R _c is particularly preferably 4 having 1 to 3 heteroatoms selected from a halogen atom, a C ₂ -C ₆ alkynyl group, a C ₆ -C ₁₄ aromatic hydrocarbon group, or N, S and O. A 6-membered monocyclic unsaturated heterocyclic group. The number of R _c is not particularly limited, but is preferably 1 to 5, and particularly preferably 1 to 3.

In the “4- to 10-membered unsaturated heterocyclic group optionally substituted by R _c ” represented by R ₃ , the “4- to 10-membered unsaturated heterocyclic group” is preferably N, S And a 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic group having 1 to 3 heteroatoms selected from O and O, more preferably 1 selected from N, S and O A 4-6 membered monocyclic unsaturated heterocyclic group having 3 heteroatoms, particularly preferably a 4-6 membered monocyclic unsaturated heterocyclic ring having one S as a heteroatom A formula group, particularly preferably a thienyl group.

In the “4- to 10-membered unsaturated heterocyclic group optionally substituted by R _c ” represented by R ₃ , R _c is preferably C ₁ optionally substituted by _a halogen atom or R _a. A —C ₆ alkyl group, more preferably a halogen atom or a C ₁ -C ₆ alkyl group, and particularly preferably a halogen atom. The number of R _c is not particularly limited, but is preferably 1 to 5, and particularly preferably 1 to 3.

Preferably, _{R 3} is 1 to 3 groups selected substituted _C 6 _{-C 14} aromatic hydrocarbon group, or _R may be substituted by _c N, S and O by _{R c} 4-6 membered monocyclic unsaturated heterocyclic group having a heteroatom.

More preferably, R ₃ is a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by 1 to 5 R _c, which are the same or different, and R _c is (1) a halogen atom;
(2) a C ₆ -C ₁₄ aromatic hydrocarbon oxy group;
₍₃₎ C 2 -C ₆ alkynyl group;
₍₄₎ C 6 _{-C 14} aromatic hydrocarbon group; and (5) optionally substituted by the same or different 1 to 3 groups selected from the group consisting of oxo group and _C 1 -C ₆ alkyl group A 4-10 membered unsaturated heterocyclic group;
R ₃ is selected from the group consisting of 4 to 6 having 1 to 3 heteroatoms selected from N, S and O, optionally substituted by 1 to 5 R _c Membered monocyclic unsaturated heterocyclic group, and R _c is a halogen atom.

Particularly preferably, R ₃ is selected from (1) a halogen atom; (3) a C ₂ -C ₆ alkynyl group; (4) a C ₆ -C ₁₄ aromatic hydrocarbon group; and (5) N, S and O A phenyl group optionally substituted by 1 to 5 R _c selected from the group consisting of 4 to 6-membered monocyclic unsaturated heterocyclic groups having 1 to 3 heteroatoms, Alternatively, it is a thienyl group optionally substituted by 1 to 5 halogen atoms.

In the compound represented by the formula (I) of the present invention, R ₄ and R ₅ are the same or different and each is a hydrogen atom or _a C ₁ -C ₆ alkyl group optionally substituted by R _a , R may be substituted by _{a C} 2 -C ₆ alkenyl group, optionally substituted by _{R a C} 2 -C ₆ alkynyl group, optionally substituted by _{R c C} 3 _{-C 10} cycloalkyl group, or a saturated or unsaturated heterocyclic group represented by R may be substituted by _c C ₆ -C ₁₄ aromatic hydrocarbon group, or a 4-10 membered optionally substituted by R _c, or , R ₄ and R ₅ together with the nitrogen atom to which they are attached are 4-10 membered saturated heterocycles (wherein the 4-10 membered saturated heterocycle may be substituted with R _b ) Form.

In the “C ₁ -C ₆ alkyl group optionally substituted by R _a ” represented by R ₄ or R ₅ , the “C ₁ -C ₆ alkyl group” is preferably a C ₁ -C ₄ alkyl group. More preferably a methyl group, an ethyl group or an isopropyl group, and particularly preferably an isopropyl group.

In the “C ₁ -C ₆ alkyl group optionally substituted by R _a ” represented by R ₄ or R ₅ , R _a is preferably a halogen atom or a C ₃ -C ₁₀ cycloalkyl group, particularly preferably a _C 3 _{-C 10} cycloalkyl. Here, the number of _Ra is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3.

In the “C ₂ -C ₆ alkenyl group optionally substituted by R _a ” represented by R ₄ or R ₅ , the “C ₂ -C ₆ alkenyl group” is preferably a vinyl group.

In the “C ₂ -C ₆ alkenyl group optionally substituted by R _a ” represented by R ₄ or R ₅ , R _a is preferably a halogen atom. Here, the number of _Ra is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3.

In the “C ₂ -C ₆ alkynyl group optionally substituted by _Ra ” represented by R ₄ or R ₅ , the “C ₂ -C ₆ alkynyl group” is preferably an ethynyl group.

In the “C ₂ -C ₆ alkynyl group optionally substituted by R _a ” represented by R ₄ or R ₅ , R _a is preferably a halogen atom. Here, the number of _Ra is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3.

In the “C ₃ -C ₁₀ cycloalkyl group optionally substituted by R _c ” represented by R ₄ or R ₅ , the “C ₃ -C ₁₀ cycloalkyl group” is preferably a cyclopropyl group, a cyclobutyl group , A cyclopentyl group or a cyclohexyl group, particularly preferably a cyclobutyl group or a cyclohexyl group.

In the “C ₃ -C ₁₀ cycloalkyl group optionally substituted by R _c ” represented by R ₄ or R ₅ , R _c is preferably a halogen atom or —OR _x , particularly preferably C _1. -C ₆ alkoxy group. Here, the number of R _c is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3.

In the “C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by R _c ” represented by R ₄ or R ₅ , the “C ₆ -C ₁₄ aromatic hydrocarbon group” is preferably a phenyl group is there.

In the “C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by R _c ” represented by R ₄ or R ₅ , R _c is preferably a halogen atom. Here, the number of R _c is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3.

“4- to 10-membered saturated or unsaturated heterocyclic group” in “4 to 10-membered saturated or unsaturated heterocyclic group optionally substituted by R _c ” represented by R ₄ or R ₅ is , Preferably a 4-10 membered saturated heterocyclic group, more preferably a 4-6 membered monocyclic saturated heterocyclic group having 1-3 heteroatoms selected from N, S and O. Group, particularly preferably a tetrahydropyranyl group.

In the “4- to 10-membered saturated or unsaturated heterocyclic group optionally substituted by R _c ” represented by R ₄ or R ₅ , R _c is preferably a halogen atom. Here, the number of R _c is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3.

R ₄ and R ₅ are “a 4- to 10-membered saturated heterocycle together with the nitrogen atom to which they are attached (where the 4- to 10-membered saturated heterocycle may be substituted with R _b ) In the "forming" case, "4-10 membered saturated heterocycle" is preferably a 4-6 membered monocyclic saturated heterocycle having 1-3 heteroatoms selected from N, S and O More preferred is azetidine, pyrrolidine or piperidine, and particularly preferred is azetidine or pyrrolidine.

R ₄ and R ₅ are “a 4- to 10-membered saturated heterocycle together with the nitrogen atom to which they are attached (where the 4- to 10-membered saturated heterocycle may be substituted with R _b )” In the “forming” case, R _b is preferably a halogen atom. Here, the number of R _b is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3.

Preferably, R ₄ and R ₅ are the same or different and are a hydrogen atom, _a C ₁ -C ₆ alkyl group optionally substituted by R _a , or _a C ₃ -C ₁₀ cyclo optionally substituted by R _c. alkyl group, or R _c may be substituted by N, or a 4-6 membered saturated heterocyclic group monocyclic having 1-3 heteroatoms selected from S and O, or , R ₄ and R ₅ are 4-6 membered monocyclic saturated heterocycles having 1-3 heteroatoms selected from N, S and O together with the nitrogen atom to which they are attached ( Where the saturated heterocycle is optionally substituted with R _b ).

More preferably, R ₄ and R ₅ are the same or different and are each a hydrogen atom; a C ₁ -C ₆ alkyl group optionally substituted by a C ₃ -C ₁₀ cycloalkyl group; and a C ₁ -C ₆ alkoxy group. is 4-6 membered monocyclic saturated heterocyclic group with or N, 1 to 3 heteroatoms selected from S and O; optionally substituted C ₃ -C ₁₀ cycloalkyl group also be Or R ₄ and R ₅ are 4-6 membered monocyclic saturated having 1-3 heteroatoms selected from N, S and O together with the nitrogen atom to which they are attached. Heterocycle is formed.

Particularly preferably, _{R 4} and _{R 5,} either one is a hydrogen atom or a _C 1 -C ₆ alkyl group, the other is _C 3 _{-C 10} cycloalkyl substituted _C 1 optionally -C by group ₆ An alkyl group or a 4-6 membered monocyclic saturated heterocyclic group having 1-3 heteroatoms selected from N, S and O, or R ₄ and R ₅ are Together with the nitrogen atom to which is attached forms a 4-6 membered monocyclic saturated heterocycle having 1-3 heteroatoms selected from N, S and O.

In the compound represented by the formula (I) of the present invention, R ₆ and R ₇ are the same or different and are a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted by R _a , or Or a C ₁ -C ₆ alkoxy group optionally substituted by R _a , or R ₆ and R ₇ together with the carbon atom to which they are attached are C ₃ -C ₁₀ cycloalkylene (where C ₃ -C ₁₀ cycloalkylene forms a _{R b} may be substituted with).

In the “C ₁ -C ₆ alkyl group optionally substituted by R _a ” represented by R ₆ or R ₇ , the “C ₁ -C ₆ alkyl group” is preferably a C ₁ -C ₄ alkyl group. More preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

In the “C ₁ -C ₆ alkyl group optionally substituted by R _a ” represented by R ₆ or R ₇ , R _a is preferably a halogen atom. Here, the number of _Ra is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3, and particularly preferably unsubstituted.

In the “C ₁ -C ₆ alkoxy group optionally substituted by R _a ” represented by R ₆ or R ₇ , the “C ₁ -C ₆ alkoxy group” is preferably a C ₁ -C ₄ alkoxy group. More preferably a methoxy group or an ethoxy group, and particularly preferably a methoxy group.

In the “C ₁ -C ₆ alkoxy group optionally substituted by R _a ” represented by R ₆ or R ₇ , R _a is preferably a halogen atom. Here, the number of _Ra is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3, and particularly preferably unsubstituted.

R ₆ and R _{7 form} “C ₃ -C ₁₀ cycloalkylene, where the C ₃ -C ₁₀ cycloalkylene may be substituted with R _b , together with the carbon atom to which they are attached. In this case, “C ₃ -C ₁₀ cycloalkylene” is preferably C ₃ -C ₇ cycloalkylene, more preferably cyclopropylene, cyclobutylene or cyclopentylene, and particularly preferably cyclopropylene.

R ₆ and R _{7 form} “C ₃ -C ₁₀ cycloalkylene, where the C ₃ -C ₁₀ cycloalkylene may be substituted with R _b , together with the carbon atom to which they are attached. In this case, R _b is preferably a halogen atom. Here, the number of R _b is not particularly limited, but is preferably 0, that is, unsubstituted or 1 to 3, and particularly preferably unsubstituted.

Preferably, R ₆ and R ₇ are the same or different and are a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ together with the carbon atom to which they are attached. It is to form a _C 3 _{-C 10} cycloalkylene.

More preferably, one of R ₆ and R ₇ is a hydrogen atom and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ are carbon atoms to which they are bonded. Together with C ₃ -C ₁₀ cycloalkylene.

Particularly preferably, one of R ₆ and R ₇ is a hydrogen atom, and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group.

In the compound represented by the formula (I) of the present invention,
One of R ₁ and R ₂ is a hydrogen atom, the other is a C ₁ -C ₆ alkyl group,
R ₃ is optionally substituted by _{R c C} 6 _{-C 14} aromatic hydrocarbon group, or optionally substituted by _{R c} N, 1 to 3 heteroatoms selected from S and O A 4-6 membered monocyclic unsaturated heterocyclic group having
R ₄ and _{R 5} are the same or different, is a hydrogen atom, optionally substituted by _{R a C} 1 -C ₆ alkyl group, optionally substituted by _{R c C} 3 _{-C 10} cycloalkyl alkyl group, or R _c may be substituted by N, or a 4-6 membered saturated heterocyclic group monocyclic having 1-3 heteroatoms selected from S and O, or , R ₄ and R ₅ together with the nitrogen atom to which they are attached, a 4-6 membered monocyclic saturated heterocycle having 1 to 3 heteroatoms selected from N, S and O ( Where the saturated heterocycle is optionally substituted with R _b ),
R ₆ and R ₇ are the same or different and are a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ together with the carbon atom to which they are attached. it is preferable to form a C ₃ -C ₁₀ cycloalkylene.

In the compound represented by the formula (I) of the present invention,
One of R ₁ and R ₂ is a hydrogen atom, the other is a C ₁ -C ₆ alkyl group,
R ₃ is a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by 1 to 5 different or identical R _c , and R _c is (1) a halogen atom;
(2) a C ₆ -C ₁₄ aromatic hydrocarbon oxy group;
₍₃₎ C 2 -C ₆ alkynyl group;
₍₄₎ C 6 _{-C 14} aromatic hydrocarbon group; and (5) optionally substituted by the same or different 1 to 3 groups selected from the group consisting of oxo group and _C 1 -C ₆ alkyl group A 4-10 membered unsaturated heterocyclic group;
R ₃ is selected from the group consisting of 4 to 6 having 1 to 3 heteroatoms selected from N, S and O, optionally substituted by 1 to 5 R _c Membered monocyclic unsaturated heterocyclic group, R _c is a halogen atom,
R ₄ and R ₅ are the same or different and are each a hydrogen atom; a C ₁ -C ₆ alkyl group optionally substituted by a C ₃ -C ₁₀ cycloalkyl group; and a C ₁ -C ₆ alkoxy group. which may C ₃ -C ₁₀ cycloalkyl group; or N, or a monocyclic saturated heterocyclic group having 4-6 members with 1-3 heteroatoms selected from S and O, or, R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic saturated heterocycle having 1 to 3 heteroatoms selected from N, S and O And
Either one of R ₆ and R ₇ is a hydrogen atom and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ are carbon atoms to which they are bonded. More preferably together with C ₃ -C ₁₀ cycloalkylene.

In the compound represented by the formula (I) of the present invention,
One of R ₁ and R ₂ is a hydrogen atom, the other is a C ₁ -C ₆ alkyl group,
R ₃ is selected from (1) a halogen atom; (3) a C ₂ -C ₆ alkynyl group; (4) a C ₆ -C ₁₄ aromatic hydrocarbon group; and (5) N, S and O A phenyl group optionally substituted by 1 to 5 R _c selected from the group consisting of 4 to 6-membered monocyclic unsaturated heterocyclic groups having 3 heteroatoms, or 1 to 5 A thienyl group optionally substituted by one halogen atom,
One of R ₄ and R ₅ is a hydrogen atom or a C ₁ -C ₆ alkyl group, and the other is a C ₁ -C ₆ alkyl group optionally substituted by a C ₃ -C ₁₀ cycloalkyl group, or N 4 to 6-membered monocyclic saturated heterocyclic group having 1 to 3 heteroatoms selected from S and O, or R ₄ and R ₅ are nitrogen atoms to which they are bonded. Together with 4 to 6-membered monocyclic saturated heterocycle having 1 to 3 heteroatoms selected from N, S and O;
It is particularly preferable that either one of R ₆ and R ₇ is a hydrogen atom, and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group.

  Specific examples of the compound of the present invention include, but are not limited to, compounds produced in Examples described later.

Suitable examples of the compound of the present invention include the following:
(1) 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2, 3-d] pyrimidin-6 (7H) -one (Example 4 compound)
(2) 4- (4-((R) -2- (4-Chlorophenyl) -3- (dimethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one (Example 5 compound)
(3) 4- (4-((R) -2- (4-chlorophenyl) -3- (ethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one (Compound of Example 6)
(4) 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Compound of Example 10)
(5) 4- (4-((R) -2- (4-Chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Compound of Example 13)
(6) 4-((R) -4-((R) -2- (4-chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -3-methylpiperazine-1- Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Example 14 compound)
(7) 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] octane -7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Compound of Example 18)
(8) 4- (4-((R) -2- (4-Chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] octane -7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Compound of Example 19)
(9) 4- (4-((R) -2-([1,1′-biphenyl] -4-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5 -Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound of Example 21)
(10) 4- (4-((R) -3- (azetidin-1-yl) -2- (4-chlorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H- Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Example 23 compound)
(11) 4- (4-((R) -2- (4-Chlorophenyl) -2-hydroxy-3- (pyrrolidin-1-yl) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Example 24 compound)
(12) 4- (4-((R) -2- (4-ethynylphenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one (Example 25 compound)
(13) 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazine- 1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Example 30 compound)

  Next, the manufacturing method of the compound based on this invention is demonstrated.

  The compound represented by the formula (I) of the present invention can be produced, for example, by the following production method or the method shown in the examples. However, the production method of the compound represented by the formula (I) of the present invention is not limited to these reaction examples.

［式中、Ｒ_１、Ｒ_２、Ｒ_６、及びＲ_７は、前記と同義である。ＰＧ_１、及びＰＧ_２は、保護基を示す。］ Manufacturing method 1

[Wherein, R ₁ , R ₂ , R ₆ , and R ₇ are as defined above. PG ₁ and PG ₂ represent protecting groups. ]

(Step 1) This step is a step for producing a compound represented by the formula (IV) by an S _N Ar reaction between a compound represented by the formula (II) and a compound represented by the formula (III). .

PG ₁ and PG ₂ are not particularly limited as long as they are commonly used amino-protecting groups, but PG ₁ includes 2,4,6-trimethoxybenzyl group, 2,4-dimethoxybenzyl group or 4-methoxy group. A benzyl group is preferred, and PG ₂ is preferably a Boc group, a benzyloxycarbonyl group, or a 4-methoxybenzyl group.

  This step is usually performed using 0.5 mol to 5 mol, preferably 1 to 2 mol, of the compound represented by the formula (III) with respect to 1 mol of the compound represented by the formula (II).

  Examples of the base used in this step include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldiethyl. Organic bases such as silazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride It can be illustrated.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl Pyrrolidinone, dimethyl sulfoxide or the like or a mixed solvent thereof is preferred.

  The reaction temperature is generally 0 ° C. to 200 ° C., preferably 80 ° C. to 180 ° C. The reaction time is usually 10 minutes to 3 days, preferably 1 hour to 10 hours.

  The compound represented by the formula (IV) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

  (Step 2) This step is a step of treating the compound represented by the formula (IV) with a base and an alkylating agent to produce the compound represented by the formula (V) by an alkylation reaction.

  Examples of the base used in this step include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium Organic bases such as hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, and butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride It can be illustrated.

The alkylating agent used in this step is not particularly limited as long as R ₁ and R ₂ can be introduced, but iodomethane, iodoethane, 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromo An example is butane.

  In this step, the base is usually 0.5 mol to 5 mol, preferably 1 to 2 mol, the alkylating agent is 0.5 mol to 5 mol, relative to 1 mol of the compound represented by formula (IV), Preferably 1 to 3 moles are used.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl Pyrrolidinone, dimethyl sulfoxide or the like or a mixed solvent thereof is preferred.

  The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 1 hour.

  The compound represented by the formula (V) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

  (Step 3) This step is a step of producing a compound represented by the formula (VI) by deprotecting the compound represented by the formula (V).

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide N-methylpyrrolidinone. , Dimethyl sulfoxide, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like, or mixed solvents thereof are preferred.

  The reaction temperature is generally −78 ° C. to 200 ° C., preferably 80 ° C. to 160 ° C. The reaction time is usually 10 minutes to 3 days, preferably 1 hour to 10 hours.

  Moreover, the said reaction can use a cation scavenger as needed. An anisole can be illustrated here as a cation scavenger.

  The compound represented by the formula (VI) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

［式中、Ｒ_３は、前記と同義である。Ｒ_８はアルキル基或いはベンジル基、ＰＧ_３は、保護基を示す。］ Manufacturing method 2

[Wherein, R ₃ has the same meaning as described above. R ₈ represents an alkyl group or a benzyl group, and PG ₃ represents a protecting group. ]

  (Step 4) This step is a step of producing a compound represented by the formula (VIII) by treating the compound represented by the formula (VII) with nitromethane and a base.

  This step can be carried out by using, for example, a suitable base catalyst such as triethylamine, N, N-diisopropylethylamine, or a known document (Hongming Li, Baomin Wang, and Li Deng; J. Am. Chem. Soc., 2006, 128 (3), pp. 732-733).

  In this step, the base is usually 0.1 mol to 5 mol, preferably 0.2 to 2 mol, and nitromethane is 1 mol to excess, preferably 1 mol, relative to 1 mol of the compound represented by formula (VII). This is done using an excess.

  The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, preferably -30 ° C to room temperature. The reaction time is usually 1 hour to 24 hours.

  The compound represented by the formula (VIII) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

  (Step 5) This step is a step for producing a compound represented by the formula (IX) by a reduction reaction of the compound represented by the formula (VIII).

  This step can be performed by a hydrogenation reaction or a reaction using, for example, zinc or iron as a reducing agent under acidic conditions. Examples of the catalyst used for the hydrogenation reaction include catalysts such as palladium, nickel, and rhodium.

  The solvent in the hydrogenation reaction is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, dimethylformamide, and acetic acid.

  Examples of the acid used in the reduction reaction using, for example, zinc or iron as a reducing agent under acidic conditions include acids such as acetic acid and ammonium chloride.

  The reaction solvent in the reduction reaction using, for example, zinc or iron as a reducing agent under acidic conditions is not particularly limited as long as it does not hinder the reaction. For example, acetic acid, ethanol, methanol, or a mixed solvent thereof or the like Is preferred.

  The reaction temperature is generally 0 ° C. to 200 ° C., preferably room temperature to reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.

  The compound represented by the formula (IX) thus obtained is isolated or purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

  (Step 6) This step is a step for producing a compound represented by the formula (X) by introducing a protecting group into the amino group of the compound represented by the formula (IX).

PG ₃ is not particularly limited as long as it is a commonly used amino-protecting group, but Boc group, benzyloxycarbonyl group, 4-nitrobenzenesulfonyl group, 2-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, Or a 4-methoxybenzyl group is preferable.

  Examples of the reagent used in this step include di-tert-butyl dicarbonate, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride and the like.

  The compound represented by the formula (X) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

［式中、Ｒ_３，Ｒ_８，ＰＧ_３は前記と同義であり、Ｒ_４ａはＲ_ａにより置換されていてもよいＣ_１−Ｃ_６アルキル基、Ｒ_ａにより置換されていてもよいＣ_２−Ｃ_６アルケニル基、Ｒ_ａにより置換されていてもよいＣ_２−Ｃ_６アルキニル基、または、Ｒ_ｃにより置換されていてもよいＣ_３−Ｃ_１０シクロアルキル基である。］ Production method 3

_{Wherein, R 3, R 8, PG} 3 are as defined _{above, R 4a} is _{R a} by optionally substituted _C 1 -C ₆ alkyl group, optionally substituted by _{R a C 2} It is a -C ₆ alkenyl group, _a C ₂ -C ₆ alkynyl group optionally substituted by R a, or a C ₃ -C ₁₀ cycloalkyl group optionally substituted by R _c . ]

(Step 7) This step is a step of producing a compound represented by the formula (XII) from a compound represented by the formula (XI) by an alkylation reaction.

  Examples of the base used in this step include potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. Examples thereof include organic bases such as lithium diisopropylamide and butyl lithium, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride.

  Examples of the alkylating agent used in this step include iodomethane and iodoethane.

  In this step, the base is usually 0.5 mol to 5 mol, preferably 1 to 2 mol, the alkylating agent is 0.5 mol to 5 mol, relative to 1 mol of the compound represented by formula (XI), Preferably 1 to 3 moles are used.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl Pyrrolidinone, dimethyl sulfoxide or the like or a mixed solvent thereof is preferred.

  The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 1 hour.

  The compound represented by the formula (XII) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

［式中、Ｒ_３、Ｒ_８は前記と同義であり、Ｒ_４ｂ及びＲ_５ｂは、Ｒ_４ｂ及びＲ_５ｂが結合する窒素原子と一緒になって４〜１０員の飽和複素環（ここで４〜１０員の飽和複素環は、Ｒ_ｂで置換されていてもよい）を形成する。］ Manufacturing method 4

[Wherein R ₃ and R ₈ have the same meanings as defined above, and R _4b and R _5b together with a nitrogen atom to which R _4b and R _5b are bonded are 4- to 10-membered saturated heterocycles (where 4 A 10-membered saturated heterocycle may be substituted with R _b ). ]

  (Step 8) This step is a step of producing a compound represented by the formula (XIV) by an alkylation reaction of the compound represented by the formula (XIII).

  Examples of the base used in this step include potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. Examples thereof include organic bases such as lithium diisopropylamide and butyl lithium, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride.

  Examples of the alkylating agent used in this step include 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane and the like.

  In this step, the base is usually 0.5 mol to 5 mol, preferably 1 to 3 mol, the alkylating agent 0.5 mol to 5 mol, relative to 1 mol of the compound represented by the formula (XIII). Preferably 1 to 3 moles are used.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, ethanol, isopropanol, tert-butyl alcohol, acetoyl tolyl, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, Preference is given to dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide and the like, or mixed solvents thereof.

  The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 1 hour.

  The compound represented by the formula (XIV) thus obtained is isolated or purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

［式中、Ｒ_４、Ｒ_８、ＰＧ_３は前記と同義である。Ｒ_３ａは、ハロゲン原子が置換した芳香族炭化水素基又は不飽和複素環式基であり、Ｒ_３ｂは、Ｒ_ｃのうちハロゲン原子を除いた基により置換されていてもよい芳香族炭化水素基又は不飽和複素環式基である。］ Manufacturing method 5

[Wherein, R ₄ , R ₈ and PG ₃ have the same meanings as described above. R _3a is an aromatic hydrocarbon group or unsaturated heterocyclic group substituted with a halogen atom, and R _3b is an aromatic hydrocarbon group optionally substituted by a group other than the halogen atom in R _c Or it is an unsaturated heterocyclic group. ]

  (Step 9) This step is a step of producing a compound represented by the formula (XVI) by a cross-coupling reaction of the compound represented by the formula (XV).

  For example, this process is a known Suzuki coupling reaction, Negishi reaction, Sonogashira reaction, Ullmann reaction or Goldberg reaction using Cu as a catalyst, and aryl halides and amines in the presence of a palladium catalyst reported by Buchwald and Hartwig et al. Aromatic amine synthesis method from the above, catalytic cyanation method and the like can be applied.

  This reaction can be performed, for example, by heating in a suitable solvent within a range of 20 ° C. to 200 ° C. in the presence or absence of a palladium catalyst.

  Examples of the palladium catalyst that can be used include palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, Examples thereof include dichlorobisacetonitrile palladium and tris (dibenzylideneacetone) dipalladium (0).

  The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 1 mol with respect to 1 mol of the compound represented by the formula (XV).

  If necessary, as a ligand for palladium, 1-1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2 ′ , 4 ′, 6′-triisopropylbiphenyl and the like can be used.

  The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, hydrocarbons such as benzene and toluene, acetonitrile, dimethyl sulfoxide, water, or a mixed solvent thereof.

  The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.

  The compound represented by the formula (XVI) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

［式中、Ｒ_３ａ、Ｒ_４、Ｒ_８、及びＰＧ_３は、前記と同義である。Ｒ_９はＣ_１−Ｃ_６アルキル基である（２個の−ＯＲ_９が結合するボロン原子と一緒になって環を形成してもよい（環上には置換基を有しても良い)）。Ｒ_３ｃはホウ酸エステル基で置換された芳香族炭化水素基又は不飽和複素環式基であり、Ｘはハロゲン原子であり、ＡｒはＲ_ｂにより置換されていてもよい芳香族炭化水素基、又はＲ_ｂにより置換されていてもよい飽和若しくは不飽和複素環式基であり、Ｒ_３ｄはＲ_ｂにより置換されていてもよい芳香族炭化水素基及びＲ_ｂにより置換されていてもよい飽和若しくは不飽和複素環式基からなる群から選ばれた基で置換された芳香族炭化水素基又は不飽和複素環式基である。］ Manufacturing method 6

[Wherein, R _3a , R ₄ , R ₈ , and PG ₃ are as defined above. R ₉ is a C ₁ -C ₆ alkyl group (may form a ring together with a boron atom to which two —OR ₉ bonds) (may have a substituent on the ring) ). R _3c is an aromatic hydrocarbon group or unsaturated heterocyclic group substituted with a borate group, X is a halogen atom, Ar is an aromatic hydrocarbon group optionally substituted by R _b , or be substituted by R _b are also be saturated or unsaturated heterocyclic group, R _3d is saturated may be substituted by an optionally substituted aromatic hydrocarbon group and R _b or a R _b An aromatic hydrocarbon group or an unsaturated heterocyclic group substituted with a group selected from the group consisting of unsaturated heterocyclic groups. ]

  (Step 10) This step is a step of producing a compound represented by the formula (XIX) by reacting a compound represented by the formula (XVII) with a compound represented by the formula (XVIII).

  This reaction is usually performed in an inert solvent in the presence of a metal catalyst. At this time, a base may be added.

  Examples of the metal catalyst include zero-valent palladium, divalent palladium, and zero-valent nickel. Here, examples of the zero-valent palladium catalyst include tetrakis (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium, and examples of the divalent palladium catalyst include palladium acetate, palladium chloride, and dichlorobis ( Triphenylphosphine) palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium and the like, and examples of the zero-valent nickel catalyst include 1,1′-bis (diphenylphosphino) ferrocene nickel and the like. Can be mentioned.

  If necessary, palladium ligands include triphenylphosphine, tris (ortho-tolyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, diphenylphosphinopropane, diphenylphosphinobutane, 4,5-bis ( Diphenylphosphino) -9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1, A ligand such as 1′-biphenyl may be added.

  Examples of the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkali metal acetates such as sodium acetate and potassium acetate, and tripotassium phosphate. Examples include alkali metal phosphates.

  The amount of the metal catalyst used is, for example, 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent, relative to the compound represented by the formula (XVII). The amount of the base to be used is 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to the compound represented by formula (XVII).

  The reaction temperature is usually from room temperature to the reflux temperature of the solvent. Examples of the inert solvent include alcohols such as methanol, ethanol, isopropanol and tert-butanol, ethers such as tetrahydrofuran and 1,4-dioxane, esters such as ethyl acetate, dichloromethane, chloroform, dichloroethane and carbon tetrachloride. Halogenated hydrocarbons such as hexane, benzene, toluene, xylene and other hydrocarbons, N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide and other amides, acetonitrile and other nitriles, dimethyl Sulfoxides such as sulfoxide, water, and the like are used, and these may be mixed and used at an appropriate ratio.

  The usage-amount of the compound represented by Formula (XVIII) is 1-10 equivalent with respect to the compound represented by Formula (XVII), Preferably it is 1-3 equivalent.

  (Step 11) This step is a step of producing a compound represented by the formula (XXI) by reacting a compound represented by the formula (XIX) with a compound represented by the formula (XX).

  This reaction is usually performed in an inert solvent in the presence of a metal catalyst. At this time, a base may be added.

  Examples of the metal catalyst include zero-valent palladium, divalent palladium, and zero-valent nickel. Here, examples of the zero-valent palladium catalyst include tetrakis (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium, and examples of the divalent palladium catalyst include palladium acetate and dichlorobis (triphenylphosphine). ) Palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, etc. Examples of the zero-valent nickel catalyst include 1,1′-bis (diphenylphosphino) ferrocene nickel.

  If necessary, palladium ligands include triphenylphosphine, tris (ortho-tolyl) phosphine, diphenylphosphinopropane, diphenylphosphinobutane, 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis ( Diphenylphosphino) -9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1, A ligand such as 1′-biphenyl and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2 ′, 4 ′, 6′-triisopropylbiphenyl may be added.

  Examples of the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkali metal acetates such as sodium acetate and potassium acetate, and tripotassium phosphate. Examples include alkali metal phosphates.

The amount of the metal catalyst to be used is, for example, 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent, relative to the compound represented by the formula (XIX). The amount of the base to be used is 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to the compound represented by formula (XIX).
The reaction temperature is usually from room temperature to the reflux temperature of the solvent.

  Examples of the inert solvent include alcohols such as methanol, ethanol, isopropanol and tert-butanol, ethers such as tetrahydrofuran and 1,4-dioxane, esters such as ethyl acetate, dichloromethane, chloroform, dichloroethane and carbon tetrachloride. Halogenated hydrocarbons such as hexane, benzene, toluene, xylene and other hydrocarbons, N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide and other amides, acetonitrile and other nitriles, dimethyl Sulfoxides such as sulfoxide, water, and the like are used, and these may be mixed and used at an appropriate ratio.

The usage-amount of the compound represented by Formula (XX) is 1-10 equivalent with respect to the compound represented by Formula (XIX), Preferably it is 1-3 equivalent.
The reaction temperature is usually from room temperature to the reflux temperature of the solvent.

［式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_６、Ｒ_７及びＲ_８は、前記と同義である。Ｒ_４ｃ、Ｒ_５ｃは、それぞれＲ_４、Ｒ_５と同義であるか、又は、保護基である。］ Manufacturing method 7

[Wherein, R ₁ , R ₂ , R ₃ , R ₆ , R ₇ and R ₈ have the same meanings as described above. R _4c and R _5c have the same meanings as R ₄ and R ₅ , respectively, or are protecting groups. ]

  (Step 12) This step is a step of producing a compound represented by the formula (XXIII) from a compound represented by the formula (XXII) by a hydrolysis reaction.

  Examples of the base used in this step include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

As the solvent used in this step, methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, or a mixed solvent thereof is preferable.
The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent.

  (Step 13) This step is a step of producing a compound represented by the formula (Ia) by a condensation reaction of the compound represented by the formula (VI) and the compound represented by the formula (XXIII).

  This step is usually performed using 0.5 mol to 5 mol, preferably 1 to 2 mol, of the compound represented by the formula (XXVIII) with respect to 1 mol of the compound represented by the formula (VI).

  Examples of the condensing agent used in this step include diphenyl phosphate azide, N, N′-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, 4- (4,6-dimethoxy-1,3,5). -Triazin-2-yl) -4-methylmorpholinium chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzo Combination of triazole, 2-chloro-1,3-dimethylimidazolinium chloride, O- (7-azabenzotriazo-1-yl) -N, N, N ′, N′-tetramethylhexauronium hexafluoro A phosphate etc. can be illustrated.

  Examples of the base used in this step include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldiethyl. Organic bases such as silazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride It can be illustrated.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl Pyrrolidinone, dimethyl sulfoxide or the like or a mixed solvent thereof is preferred.

The reaction temperature is usually -78 ° C to 200 ° C of the solvent, preferably 0 ° C to 50 ° C.
The reaction time is usually 10 minutes to 3 days, preferably 1 hour to 10 hours.

  The compound represented by the formula (Ia) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

［式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_６、Ｒ_７、及びＰＧ_３は、前記と同義である。］ Manufacturing method 8

[Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , and PG ₃ have the same meanings as described above. ]

  (Step 14) This step is a step of producing a compound represented by the formula (Ib) by deprotecting the compound represented by the formula (XXIV).

  The reaction conditions used in this step are the methods described in the literature [Protective Groups in Organic Synthesis], T.M. W. According to Green (TW Green, John Wiley & Sons (1981)] or a method similar thereto.

The compound represented by the formula (I _b ) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be applied to the next step without separation and purification.

［式中、Ｒ_１，Ｒ_２、Ｒ_３ａ、Ｒ_３ｃ、Ｒ_４，Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_９及びＡｒは前記と同義である。］ Manufacturing method 9

[Wherein, R ₁ , R ₂ , R _3a , R _3c , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ and Ar are as defined above] ]

(Step 15) This step is a step of producing a compound represented by the formula (I _c ) by a cross-coupling reaction between a compound represented by the formula (XXV) and a compound represented by the formula (XXVI). .

  This reaction is usually performed in an inert solvent in the presence of a metal catalyst. At this time, a base may be added.

  Examples of the metal catalyst include zero-valent palladium, divalent palladium, and zero-valent nickel. Here, examples of the zero-valent palladium catalyst include tetrakis (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium, and examples of the divalent palladium catalyst include palladium acetate and dichlorobis (triphenylphosphine). ) Palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, etc. Examples of the zero-valent nickel catalyst include 1,1′-bis (diphenylphosphino) ferrocene nickel.

  If necessary, as a ligand for palladium, triphenylphosphine, tris (ortho-tolyl) phosphine, diphenylphosphinopropane, diphenylphosphinobutane, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, Even if ligands such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl and 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl are added. good.

  Examples of the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkali metal acetates such as sodium acetate and potassium acetate, and tripotassium phosphate. Examples include alkali metal phosphates.

The amount of the metal catalyst used is, for example, 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent, relative to the compound represented by the formula (XXV). The amount of the base to be used is 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to the compound represented by formula (XXV).
The reaction temperature is usually from room temperature to the reflux temperature of the solvent.

  Examples of the inert solvent include alcohols such as methanol, ethanol, isopropanol and tert-butanol, ethers such as tetrahydrofuran and 1,4-dioxane, esters such as ethyl acetate, dichloromethane, chloroform, dichloroethane and carbon tetrachloride. Halogenated hydrocarbons such as hexane, benzene, toluene, xylene and other hydrocarbons, N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide and other amides, acetonitrile and other nitriles, dimethyl Sulfoxides such as sulfoxide, water, and the like are used, and these may be mixed and used at an appropriate ratio.

  The usage-amount of the compound represented by Formula (XXVI) is 1-10 equivalent with respect to the compound represented by Formula (XXV), Preferably it is 1-3 equivalent.

［式中、Ｒ_１、Ｒ_２，Ｒ_３、Ｒ_４，Ｒ_５、Ｒ_６及びＲ_７は、前記と同義である。］ Manufacturing method 10

[Wherein, R ₁ , R ₂ , R _3, R ₄ , R _5, R ₆ and R ₇ are as defined above]. ]

(Step 16) This step is a step of producing a compound represented by formula (I) from a compound represented by formula (I _d ) using an aldehyde or a ketone and a reducing agent.

  Examples of the reducing agent used in this step include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. Of these, sodium cyanoborohydride or sodium triacetoxyborohydride is preferred.

  The solvent used in this step is not particularly limited as long as it is inert to the reaction. For example, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, n-propanol, 2 -Pulpanol etc. can be used alone or in combination.

  In this step, an acid can be used as an additive. Examples of the acid used as the additive include strong rubonic acids such as acetic acid, formic acid, furopionic acid and trifluoroacetic acid, mineral acids such as hydrochloric acid, and Lewis acids such as zinc chloride.

The reaction temperature is a temperature between room temperature and the boiling point of the solvent used, preferably 20 ° C to 200 ° C.
The reaction time is usually 0.5 to 24 hours.

  In addition, in the said manufacturing methods 1-10, the compound represented by Formula (II) can be manufactured by the method according to literature description (US2010-0120801) or a method according to these methods.

  The compound of the present invention can be easily isolated and purified by ordinary separation means. Examples of such means include solvent extraction, recrystallization, preparative reverse phase high performance liquid chromatography, column chromatography, preparative thin layer chromatography and the like.

  When the compound of the present invention has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, a tautomer, etc., any isomer or mixture is also included in the compound of the present invention. . For example, when an optical isomer exists in the compound of the present invention, an optical isomer resolved from a racemate is also included in the compound of the present invention.

The compound of the present invention or a salt thereof may be in the form of a crystal, and it is included in the compound of the present invention or a salt thereof regardless of whether the crystal form is single or polymorphic. The crystal can be produced by crystallization by applying a crystallization method known per se. The compound of the present invention or a salt thereof may be a solvate (such as a hydrate) or a non-solvate, and both are included in the compound of the present invention or a salt thereof. A compound labeled with an isotope (eg, deuterium, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) is also encompassed in the compound of the present invention or a salt thereof.

  A prodrug of the compound of the present invention or a salt thereof is a compound that is converted into the compound of the present invention or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed, The compound which changes into this invention compound or its salt, the compound which raise | generates a hydrolysis etc. by stomach acid etc., and changes into this invention compound or its salt. Further, the prodrug of the compound of the present invention or a salt thereof can be converted into the compound of the present invention or a salt thereof under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, pages 163 to 198. It may change.

  The salt of the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and means a conventional salt used in the field of organic chemistry. For example, when it has a carboxyl group, the base in the carboxyl group Examples thereof include salts of acid addition salts in the amino group or basic heterocyclic group in the case of having an addition salt or an amino group or a basic heterocyclic group.

  Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt and ethanolamine. Examples thereof include organic amine salts such as salts, diethanolamine salts, triethanolamine salts, procaine salts, and N, N′-dibenzylethylenediamine salts.

  Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, acetate, formate, maleate, fumarate, tartrate, citric acid Organic acid salts such as salts, ascorbates and trifluoroacetates; for example, sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.

  The compound of the present invention or a salt thereof has excellent Akt inhibitory activity. As used herein, “Akt” includes human or non-human mammal Akt, preferably human Akt. “Akt” includes a plurality of isoforms. For example, when Akt is human Akt, Akt1, Akt2, and Akt3 are included. The compound of the present invention or a salt thereof has inhibitory activity against at least one of these isoforms, preferably 2 or more, more preferably 3 or more, and more preferably all isoforms. The inhibitory activity of the compound of the present invention against Akt can be measured by a general method known in the art (Biochem. J. vol. 385, pp 399-408 (2005) and Cancer Res. Vol. 68, pp 2366). -2374 (2008)).

  Moreover, this invention compound or its salt is useful as a pharmaceutical for the prevention or treatment of the disease in which Akt is related by the outstanding Akt inhibitory activity. The “disease in which Akt is involved” includes a disease in which the rate of onset is reduced, symptoms are ameliorated, alleviated, and / or completely cured by deleting, suppressing, and / or inhibiting the function of Akt. Examples of such diseases include, but are not limited to, cancer and autoimmune diseases. The target cancer is not particularly limited. Cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, bone / soft tissue sarcoma, blood cancer, multiple myeloma, primary macroglobulinemia, skin cancer, brain tumor, mesothelioma, etc. Can be mentioned.

  The target autoimmune disease is not particularly limited, and examples thereof include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis / dermatomyositis, Sjogren's syndrome, Behcet's disease and the like.

  When the compound of the present invention or a salt thereof is used as a medicine, a pharmaceutical carrier can be blended as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. Any of injections, suppositories, ointments, inhalants, patches and the like may be used, and oral preparations are preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

  As the pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants in solid preparations, solvents in liquid preparations, solubilizers, suspensions It is blended as an agent, isotonic agent, buffer, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.

  When preparing an oral solid preparation, an excipient, if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. are added to the compound of the present invention. Tablets, coated tablets, granules, powders, capsules and the like can be produced by the method.

  When preparing an injection, a pH adjuster, buffer, stabilizer, tonicity agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods. Can be manufactured.

  The amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptom of the patient to which this compound is to be applied, or its dosage form, but generally it is about an oral dosage form per dosage unit form. 0.05 to 1000 mg, about 0.01 to 500 mg for injections, and about 1 to 1000 mg for suppositories are desirable.

  In addition, the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally. The dose may be 0.05 to 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into about 2 to 3 times a day.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

  Various reagents used in the examples were commercially available unless otherwise specified. For silica gel column chromatography, Moritex Pref Pack (registered trademark) SI, Biotage KP-Sil (registered trademark) Silica prepacked column, or Biotage HP-Sil (registered trademark) Silica prepacked column are used. Using. For basic silica gel column chromatography, Moripex Prefpack (registered trademark) NH or Biotage KP-NH (registered trademark) prepacked column was used. The NMR spectrum was measured using AL400 (400 MHz; JEOL) or Mercury 400 (400 MHz; Varian) type spectrometer. When tetramethylsilane was included in the heavy solvent, tetramethylsilane was used as an internal standard. In other cases, measurement was performed using an NMR solvent as an internal standard, and all δ values were expressed in ppm. The microwave reaction was performed using Initiator (registered trademark) manufactured by Biotage.

The LCMS spectrum was measured using SQD manufactured by Waters under the following conditions.
Column: Accuracy BEH C18.1 × 50 mm, 1.7 μm
MS detection: ESI positive
UV detection: 254 and 210 nm
Column flow rate: 0.5 mL / min Mobile phase: water / acetonitrile (0.1% formic acid)
Injection volume: 1 μL
Gradient time (min) Water Acetonitrile 0 95 5
0.1 95 5
1.1 5 95
2.0 Stop

Reverse phase preparative HPLC purification was performed under the following conditions.
Column: YMC YMC-Actus Trial C18, 30 × 50 mm, 5 μm
UV detection: 254 nm
Column flow rate: 40 mL / min Mobile phase: water / acetonitrile (0.1% trifluoroacetic acid)
Injection volume: 1.0 mL

The meanings of the abbreviations are shown below.
s: singlet d: doublet t: triplet q: quartet dd: double doublet dt: double triplet td: triple doublet tt: triple triplet ddd: double double doublet ddt: double double triplet dtd: double triple doublet tdd: triple double doublet m: Multiplet br: broad DMSO-D ₆ : deuterated dimethyl sulfoxide CDCl ₃ : deuterated chloroform CD ₃ OD: deuterated methanol THF: tetrahydrofuran DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide TFA: trifluoroacetic acid HATU: O- (7 -Azabenzotriazo-1-yl) -N, N, N ', N'-tetramethylhexauronium hexafluorophosphate

Example 1: 4- (4-((R) -3-Amino-2- (4-chlorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3 -D] pyrimidin-6 (7H) -one (1)
(Step 1) 4-chloro-7- (2,4-dimethoxybenzyl) -5H-pyrrolo [2,3-d] pyrimidine-6 (7H)-synthesized according to the method described in US2010-0120801 Triethylamine (9.57 ml) was added to a DMSO solution (50 ml) of 10.0 g of ON and 6.39 g of tert-butylpiperazine-1-carboxylate, and the reaction solution was stirred at 100 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate), and tert-butyl 4- (7- (2,4-dimethoxybenzyl). ) -6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperazine-1-carboxylate (1a) was obtained as a pale pink solid.

  (Step 2) After adding iodomethane (1 ml) to 580 mg of THF solution (10 ml) of compound (1a), 1M-hexamethyldisilazane lithium THF solution (1.24 ml) was added dropwise while stirring the reaction solution. Then, it stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate), and tert-butyl-4- (7- (2,4-dimethoxy). (Benzyl) -5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperazine-1-carboxylate (1b) was obtained as a pale yellow amorphous.

  (Step 3) After adding anisole (1 ml) to a TFA solution (25 ml) of 2.16 g of compound (1b), the reaction solution was stirred at 140 ° C. for 10 minutes in a microwave reactor. After the solvent was distilled off under reduced pressure, water was added to the residue to form an aqueous solution, which was then washed with ethyl acetate, and the aqueous solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound (1c) as a white solid. To the resulting white solid was added 10% hydrochloric acid methanol, and the mixture was concentrated under reduced pressure. This operation was repeated twice to obtain hydrochloride of 5-methyl-4- (piperazin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (1c) as a white solid. It was.

  (Step 4) 500 mg of commercially available ethyl 2- (4-chlorophenyl) -2-oxoacetic acid was dissolved in a mixed solvent of dichloromethane (2.6 ml) and nitromethane (1.3 ml) at 0 ° C., and then Hongming Li, Bamin Wang , And Li Deng; Am. Chem. Soc. , 2006, 128 (3), pp. 49 mg of (R)-(6-hydroxyquinolin-4-yl) ((1S, 2S, 4S, 5R) -5-vinylquinuclidin-2-yl) methyl benzoate synthesized by the method described in 732 The mixture was further stirred for 20 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with a mixed solvent of hexane-ethyl acetate (1: 1). The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain (R) -ethyl 2- (4-chlorophenyl) -2-hydroxy-3-propionic acid (1d) as a colorless oily substance. .

  (Step 5) 634 mg of the compound (1d) was dissolved in acetic acid (6 ml), and 1.5 g of zinc dust was slowly added. The resulting mixture was stirred for 7 hours, diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was concentrated to give (R) -ethyl 3-amino-2- (4-chlorophenyl) -2-hydroxypropanoic acid (1e) as a colorless oil.

  (Step 6) 380 mg of compound (1e), 4.5 ml of chloroform and 0.5 ml of methanol were mixed, and 2 ml of saturated aqueous sodium hydrogen carbonate was added. To the resulting mixture, 0.4 ml of di-tert-butyl dicarbonate was added and stirred at room temperature for 1 hour. The organic layer was separated and concentrated, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) and concentrated. The obtained residue was crystallized from hexane to obtain (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2- (4-chlorophenyl) -2-hydroxypropanoic acid (1f) as a white solid. .

  (Step 7) Compound (1f) (3.0 g) was dissolved in a mixture of tetrahydrofuran (20 ml), methanol (20 ml), and 2M aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 40 minutes. After adding 4.5M of 5M hydrochloric acid to the reaction mixture, the organic solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and (R) -3-((tert-butoxycarbonyl) amino) -2- (4-chlorophenyl) -2-hydroxypropanoic acid ( 1 g) was obtained as a white amorphous solid.

  (Step 8) To a mixture of 2.8 g of the hydrochloride of compound (1c), 3.0 g of compound (1 g), 3.3 g of HATU, and 40 ml of DMF at 0 ° C., 5.0 ml of triethylamine was added. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and tert-butyl ((2R) -2- (4-chlorophenyl) -2-hydroxy-3- (4- (5-methyl-6). -Oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperazin-1-yl) -3-oxopropyl) carbamate (1h) was obtained as a white amorphous solid.

  (Step 9) 270 mg of the compound (1h) was dissolved in 5 ml of chloroform, and 5 ml of TFA was added. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure to obtain the TFA salt of compound (1) as a white amorphous solid. The obtained residue was dissolved in 5 ml of chloroform and 2 ml of triethylamine and concentrated. The obtained residue was purified by silica gel column chromatography (NH silica, ethyl acetate-methanol) to obtain compound (1) as a white amorphous solid.

Example 2: 4- (4-((R) -3-Amino-2- (5-chlorothiophen-2-yl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H- Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (2)
According to Example 1 (Steps 4 to 9), instead of ethyl 2- (4-chlorophenyl) -2-oxoacetic acid, commercially available ethyl 2- (5-chlorothiophen-2-yl) -2-oxoacetic acid was used. The TFA salt of compound (2) was obtained as a white amorphous solid. To the obtained solid was added hydrochloric acid methanol solution (5-10%) and concentrated. Hydrochloric acid methanol solution (5-10%) was added again, concentrated, and dried under reduced pressure to obtain hydrochloride of compound (2).

Example 3: 4- (4-((R) -3-amino-2- (4-chloro-3-fluorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H- Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (3)
According to Example 1 (Steps 4 to 9), instead of ethyl 2- (4-chlorophenyl) -2-oxoacetic acid, commercially available ethyl 2- (4-chloro-3-fluorophenyl) -2-oxoacetic acid was used. After obtaining the TFA salt of compound (3) as a white amorphous solid, the hydrochloride of compound (3) was obtained according to Example 2.

Example 4: 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one (4)
A mixture of 7.6 g of the TFA salt of compound (1), 100 ml of methanol, 10 ml of acetic acid and 1.8 g of sodium acetate was stirred, 13 ml of acetone was added at 0 ° C., and then 340 mg of sodium cyanoborohydride was added. The reaction mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 30 minutes, and then concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain compound (4) as a white amorphous solid.

Example 5: 4- (4-((R) -2- (4-chlorophenyl) -3- (dimethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [ 2,3-d] pyrimidin-6 (7H) -one (5)
According to Example 4, a formalin aqueous solution was used in place of acetone to obtain Compound (5) as a white amorphous solid.

Example 6: 4- (4-((R) -2- (4-chlorophenyl) -3- (ethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [ 2,3-d] pyrimidin-6 (7H) -one (6)
According to Example 4, an acetaldehyde aqueous solution was used in place of acetone to obtain Compound (6) as a white amorphous solid.

Example 7: 4- (4-((R) -2- (4-chlorophenyl) -3-((cyclopropylmethyl) amino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl- 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (7)
In accordance with Example 4, cyclopropanecarbaldehyde was used in place of acetone to obtain Compound (7) as a white amorphous solid.

Example 8: 4- (4-((R) -3-amino-2- (4-fluorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2, 3-d] pyrimidin-6 (7H) -one (8)
In accordance with Example 1 (steps 4 to 9), using commercially available ethyl 2- (4-fluorophenyl) -2-oxoacetic acid instead of ethyl 2- (4-chlorophenyl) -2-oxoacetic acid, compound (8 ) Was obtained as a white solid.

Example 9: 4- (4-((R) -2- (4-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [ 2,3-d] pyrimidin-6 (7H) -one (9)
According to Example 4, the compound (8) was used in place of the compound (1), and the compound (9) was obtained as a white amorphous solid.

Example 10: 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl- 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (10)
According to Example 4, the compound (2) was used instead of the compound (1), and the compound (10) was obtained as a white amorphous solid.

Example 11: 4-((R) -4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -3-methylpiperazin-1-yl) -5 -Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (11)
According to Example 1 (Steps 1 to 9), (R) -tert-butyl 2-methylpiperazine-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate, and 4-((R)- 4-((R) -3-amino-2- (4-chlorophenyl) -2-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] Pyrimidin-6 (7H) -one (11a) was obtained. Furthermore, according to Example 4, the compound (11a) was used instead of the compound (1) to obtain the compound (11) as a white amorphous solid.

Example 12: 4-((S) -4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -3-methylpiperazin-1-yl) -5 -Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (12)
According to Example 1 (Steps 1 to 9), (S) -tert-butyl 2-methylpiperazine-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate, and 4-((S)- 4-((R) -3-amino-2- (4-chlorophenyl) -2-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] Pyrimidin-6 (7H) -one (12a) was obtained. Furthermore, according to Example 4, the compound (12a) was used instead of the compound (1) to obtain the compound (12) as a white amorphous solid.

Example 13: 4- (4-((R) -2- (4-chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl- 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (13)
According to Example 4, the compound (3) was used in place of the compound (1) to obtain the compound (13) as a white amorphous solid.

Example 14: 4-((R) -4-((R) -2- (4-chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -3-methylpiperazine-1 -Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (14)
According to Example 1 (Steps 1 to 9), (R) -tert-butyl 2-methylpiperazine-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate, and ethyl 2- (4-chlorophenyl) was used. ) -2-Oxoacetic acid instead of commercially available ethyl 2- (4-chloro-3-fluorophenyl) -2-oxoacetic acid, and 4-((R) -4-((R) -3-amino- 2- (4-Chloro-3-fluorophenyl) -2-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidine-6 (7H) -On (14a) was obtained. Furthermore, according to Example 4, the compound (14a) was used instead of the compound (1) to obtain the compound (14) as a white amorphous solid.

Example 15: 4-((R) -4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) -3-methylpiperazine-1 -Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (15)
According to Example 1 (Steps 1 to 9), (R) -tert-butyl 2-methylpiperazine-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate, and ethyl 2- (4-chlorophenyl) was used. ) -2-oxoacetic acid instead of commercially available ethyl 2- (5-chlorothiophen-2-yl) -2-oxoacetic acid, and 4-((R) -4-((R) -3-amino- 2- (5-Chlorothiophen-2-yl) -2-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidine-6 (7H) -On (15a) was obtained. Furthermore, according to Example 4, the compound (15a) was used instead of the compound (1), and the compound (15) was obtained as a white amorphous solid.

Example 16: 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] octane-7-yl ) -5-Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (16)
According to Example 1 (Steps 1 to 9), instead of tert-butylpiperazine-1-carboxylate, 4,7-diazaspiro [2.5] octane was used and 4- (4-((R) -3) -Amino-2- (4-chlorophenyl) -2-hydroxypropanoyl) -4,7-diazaspiro [2.5] octane-7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidine -6 (7H) -one (16a) was obtained. Furthermore, according to Example 4, the compound (16a) was used instead of the compound (1), and the compound (16) was obtained as a white amorphous solid.

Example 17: 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3-((tetrahydro-2H-pyran-4-yl) amino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (17)
According to Example 4, dihydro-2H-pyran-4 (3H) -one was used in place of acetone to obtain compound (17) as a white amorphous solid.

Example 18: 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] Octane-7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (18)
According to Example 1 (Steps 1 to 9), instead of tert-butylpiperazine-1-carboxylate, 4,7-diazaspiro [2.5] octane was used and ethyl 2- (4-chlorophenyl) -2-oxo Commercially available ethyl 2- (5-chlorothiophen-2-yl) -2-oxoacetic acid was used instead of acetic acid, and 4- (4-((R) -3-amino-2- (5-chlorothiophene-2) was used. -Yl) -2-hydroxypropanoyl) -4,7-diazaspiro [2.5] octane-7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (18a) was obtained. Furthermore, according to Example 4, the compound (18a) was used in place of the compound (1) to obtain the compound (18) as a white amorphous solid.

Example 19: 4- (4-((R) -2- (4-chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] Octane-7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (19)
According to Example 1 (Steps 1 to 9), instead of tert-butylpiperazine-1-carboxylate, 4,7-diazaspiro [2.5] octane was used and ethyl 2- (4-chlorophenyl) -2-oxo Instead of acetic acid, commercially available ethyl 2- (4-chloro-3-fluorophenyl) -2-oxoacetic acid was used and 4- (4-((R) -3-amino-2- (4-chloro-3- Fluorophenyl) -2-hydroxypropanoyl) -4,7-diazaspiro [2.5] octane-7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (19a) was obtained. Furthermore, according to Example 4, the compound (19a) was used in place of the compound (1) to obtain the compound (19) as a white amorphous solid.

Example 20: 4- (4- (2- (4-chlorophenyl) -2-hydroxy-3- (isopropyl (methyl) amino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2, 3-d] pyrimidin-6 (7H) -one (20)
(R)-(6-Hydroxyquinolin-4-yl) ((1S, 2S, 4S, 5R) -5-vinylquinuclidin-2-yl) methyl benzoate according to Example 1 (Steps 4 to 9) Triethylamine was used in place of the acid salt and 4- (4- (3-amino-2- (4-chlorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2, 3-d] pyrimidin-6 (7H) -one (20a) was obtained. Furthermore, according to Example 4, the compound (20a) was used instead of the compound (1), and 4- (4- (2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazine- After obtaining 1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (20b), compound (1) was used instead of compound (1) according to Example 4. 20b) was used, and a formalin aqueous solution was used in place of acetone to obtain compound (20) as a white amorphous solid.

Example 21: 4- (4-((R) -2-([1,1′-biphenyl] -4-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl)- 5-Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (21)
Compound (4) 31 mg, phenylboric acid 16 mg, cesium carbonate aqueous solution (2M, 70 μL), 1,4-dioxane 1 ml, palladium acetate 2.69 mg, 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1, After stirring a mixture of 14 mg of 1′-biphenyl at 100 ° C. for 1 hour under a nitrogen atmosphere, 16 mg of phenylboric acid, 2.69 mg of palladium acetate, 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1 , 1'-biphenyl was added, and the mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. Ethyl acetate and anhydrous sodium sulfate were added to the reaction mixture, and after filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol) to obtain compound (21) as a white amorphous solid.

Example 22: 4- (4-((R) -2-hydroxy-3- (isopropylamino) -2- (4- (2-oxopyrrolidin-1-yl) phenyl) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (22)
Compound (4) 28 mg, 2-pyrrolidone 50 μL, tris (dibenzylideneacetone) dipalladium (0) 5.4 mg, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2 ′, A mixture of 14 mg of 4 ′, 6′-triisopropylbiphenyl, 25 mg of tripotassium phosphate and 0.2 ml of tert-butanol was stirred at 100 ° C. for 2.5 hours under a nitrogen atmosphere. To the reaction mixture was added 0.2 ml of ethyl acetate, and after filtration, the filtrate was purified by silica gel column chromatography (NH, ethyl acetate-methanol) to obtain compound (22) as a white amorphous solid.

Example 23: 4- (4-((R) -3- (azetidin-1-yl) -2- (4-chlorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (23)
(Step 1) Compound (1f) 500 mg was dissolved in chloroform 5 ml, and TFA 2 ml was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to convert the TFA salt of (R) -ethyl 3-amino-2- (4-chlorophenyl) -2-hydroxypropanoic acid (23a) into a white amorphous Obtained as a solid.

  (Step 2) 360 mg of the compound (23a) TFA salt was dissolved in 5 ml of ethanol, 1 ml of diisopropylethylamine was added, 150 μL of 1,3-dibromopropane was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was stirred at 70 ° C. for 12 hours under microwave irradiation, hydrochloric acid (1M, 15 ml) was added to the resulting mixture and washed twice with hexane. Saturated aqueous sodium bicarbonate was added to the aqueous layer to adjust the pH to 9, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), and (R) -ethyl 3- (azetidin-1-yl) -2- (4-chlorophenyl) -2-hydroxypropanoic acid (23b). Was obtained as a colorless oil.

  (Step 3) According to Example 1 (Steps 7 to 9), Compound (23b) was used instead of Compound (1f) to obtain Compound (23) as a white amorphous solid.

Example 24: 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (pyrrolidin-1-yl) propanoyl) piperazin-1-yl) -5-methyl-5H- Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (24)
Compound (1) 150 mg of TFA salt was dissolved in 2 ml of acetonitrile, and 33 μL of 1,4-dibromobutane and 199 μL of diisopropylethylamine were sequentially added. The resulting mixture was stirred at room temperature for 15 hours and at 100 ° C. for 1 hour under microwave irradiation. After cooling, the mixture was diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (24) as a pale yellow solid.

Example 25: 4- (4-((R) -2- (4-ethynylphenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [ 2,3-d] pyrimidin-6 (7H) -one (25)
(Step 1) Compound (1f) 78 mg, cesium carbonate 232 mg, 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl 59 mg, dichlorobisacetonitrile palladium 10 mg, acetonitrile 1 ml The mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, 250 μL of ethynyltrimethylsilane was added, and the mixture was stirred at 90 ° C. for 4 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2-hydroxy-2- (4-((trimethylsilyl) ethynyl). ) Phenyl) propanoic acid (25a) was obtained as a colorless oil.

  (Step 2) According to Example 1 (Steps 7 to 9), the compound (25a) was used instead of the compound (1f), and 4- (4-((R) -3-amino-2- (4-ethynyl) was used. Phenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (25b) was obtained. Furthermore, according to Example 4, the compound (25b) was used instead of the compound (1), and the compound (25) was obtained as a white amorphous solid.

Example 26: 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (methylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one (26)
(Step 1) To a mixture of 360 mg of the TFA salt of compound (23a), 483 mg of p-nitrobenzenesulfonyl chloride and 10 ml of chloroform, 808 μl of triethylamine was added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and (R) -ethyl 2- (4-chlorophenyl) -2-hydroxy-3- ( 4-Nitrophenylsulfonamido) propanoic acid (26a) was obtained as a pale yellow amorphous solid.

  (Step 2) To a mixture of 567 mg of the compound (26a), 165 μL of methyl iodide, and 5 ml of DMF, 365 mg of potassium carbonate was added at room temperature. The resulting mixture was stirred at room temperature for 15 hours, diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and (R) -ethyl 2- (4-chlorophenyl) -2-hydroxy-3- (N-methyl-4-nitrophenylsulfonamide). ) Propanoic acid (26b) was obtained as a pale yellow amorphous solid.

  (Step 3) According to Example 1 (7 to 9), using compound (26b) instead of compound (1f), N-((2R) -2- (4-chlorophenyl) -2-hydroxy-3- (4- (5-Methyl-6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperazin-1-yl) -3-oxopropyl) -N-methyl -4-Nitrobenzenesulfonamide (26c) was obtained as a pale yellow amorphous solid.

  (Step 4) To a mixture of 770 mg of compound (26c), 127 μL of mercaptoacetic acid and 10 mL of acetonitrile, 547 μL of 1,8-diazabicyclo [5.4.0] undec-7-ene was added at 0 ° C., and then at room temperature. Stir for 1 hour. The obtained mixture was diluted with ethyl acetate, and washed successively with saturated aqueous sodium chloride solution, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform-methanol). The obtained crude product was purified by silica gel column chromatography (NH, ethyl acetate-methanol) to obtain compound (26) as a pale yellow amorphous solid.

Example 27: 4- (4-((R) -2-([1,1′-biphenyl] -4-yl) -3- (methylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (27)
(Step 1) Compound (1f) 750 mg, phenylboric acid 533 mg, aqueous cesium carbonate (2M, 2.2 ml), palladium acetate 39 mg, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl 179 mg, 1,4-dioxane 17 ml of the mixture was stirred for 1 hour at 100 ° C. under microwave irradiation. Ethyl acetate and water were added to the reaction mixture, and after filtration, the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and (R) -ethyl 2-([1,1′-biphenyl] -4-yl) -3-((tert-butoxycarbonyl) was obtained. ) Amino) -2-hydroxypropanoic acid (27a) was obtained as a white amorphous solid.

  (Step 2) According to Example 23 (Step 1), instead of compound (1f), compound (27a) was used and (R) -ethyl 2-([1,1′-biphenyl] -4-yl)- 3-Amino-2-hydroxypropanoic acid (27b) was obtained. Furthermore, according to Example 26 (Steps 1 to 4), Compound (27b) was used instead of Compound (23a) to obtain Compound (27) as a white amorphous solid.

Example 28: 4- (4-((R) -2-([1,1′-biphenyl] -4-yl) -3- (ethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (28)
According to Example 27 (Steps 1 and 2), compound (28) was obtained as a white amorphous solid by using ethyl iodide instead of methyl iodide.

Example 29: 4- (4-((R) -2- (4- (1H-pyrazol-1-yl) phenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl)- 5-Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (29)
(Step 1) Compound (1f) 100 mg, pyrazole 40 mg, tris (dibenzylideneacetone) dipalladium (0) 13 mg, tripotassium phosphate 130 mg, 2-di-tert-butylphosphino-3,4,5,6- A mixture of 35 mg of tetramethyl-2 ′, 4 ′, 6′-triisopropylbiphenyl and 1 ml of tert-butanol was stirred at 120 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and (R) -ethyl 2- (4- (1H-pyrazol-1-yl) phenyl) -3-((tert-butoxycarbonyl) was obtained. Amino) -2-hydroxypropanoic acid (29a) was obtained as a pale yellow oil.

  (Step 2) According to Example 1 (Steps 7 to 9), compound (29a) was used instead of compound (1f), and 4- (4-((R) -2- (4- (1H-pyrazole-) 1-yl) phenyl) -3-amino-2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (29b) Obtained. Furthermore, according to Example 4, the compound (29b) was used in place of the compound (1) to obtain the compound (29) as a white amorphous solid.

Example 30: 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazine -1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (30)
(Step 1) Tris (dibenzylideneacetone) dipalladium (0) 92 mg, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2 ′, 4 ′, 6′-triisopropylbiphenyl A mixture of 115 mg, toluene 4.2 ml, and 1,4-dioxane 0.9 ml was stirred at 120 ° C. for 3 minutes under microwave irradiation and nitrogen atmosphere. The obtained solution was poured into a mixture of 340 mg of compound (1f), 83 mg of triazole, and 425 mg of tripotassium phosphate under a nitrogen atmosphere, and stirred at 120 ° C. for 5 hours under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and (R) -ethyl 2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -3- ( (Tert-Butoxycarbonyl) amino) -2-hydroxypropanoic acid (30a) was obtained as a pale yellow oil.

  (Step 2) According to Example 1 (Steps 7 to 9), compound (30a) was used instead of compound (1f), and 4- (4-((R) -2- (4- (2H-1, 2,3-triazol-2-yl) phenyl) -3-amino-2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidine-6 (7H) -On (30b) was obtained. Furthermore, according to Example 4, the compound (30b) was used instead of the compound (1), and the compound (30) was obtained as a white amorphous solid.

Example 31: 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -3- (cyclobutylamino) -2-hydroxypropanoyl ) Piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (31)
According to Example 4, compound (30b) was used instead of compound (1), and cyclobutanone was used instead of acetone to obtain compound (31) as a white amorphous solid.

Example 32: 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -3- (dicyclobutylamino) -2-hydroxyprop Noyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (32)
According to Example 4, compound (30b) was used instead of compound (1), and cyclobutanone was used instead of acetone to obtain compound (32) as a white amorphous solid.

Example 33: 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -2-hydroxy-3-((tetrahydro-2H-pyran) -4-yl) amino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (33)
According to Example 4, compound (30b) was used instead of compound (1), and dihydro-2H-pyran-4 (3H) -one was used instead of acetone to obtain compound (33).

Example 34: 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -2-hydroxy-3-((4-methoxycyclohexyl) Amino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (34)
According to Example 4, the compound (30b) was used instead of the compound (1), and 4-methoxycyclohexanone was used instead of acetone to obtain the compound (34).

Example 35: 4- (4-((R) -2-hydroxy-3- (isopropylamino) -2- (4- (thiazol-2-yl) phenyl) propanoyl) piperazin-1-yl) -5- Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (35)
(Step 1) Compound (1f) 1.4 g, bis (neopentylglycolate) diboron 1.2 g, potassium acetate 0.6 g, 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl- A mixture of 0.4 g of 1,1′-biphenyl, 0.19 g of tris (dibenzylideneacetone) dipalladium (0) and 40 ml of 1,4-dioxane was stirred at 90 ° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2- (4- (5,5-dimethyl-1) was obtained. , 3-Dioxane-2-yl) phenyl) -2-hydroxypropanoic acid (35a) was obtained.

  (Step 2) A mixture of 100 mg of compound (35a), 60 mg of 2-bromothiazole, 17 mg of dichlorobis (triphenylphosphine) palladium, 98 mg of potassium carbonate, 1 ml of 1,4-dioxane, and 0.2 ml of water was subjected to 140 irradiation under microwave irradiation. Stir at 15 ° C. for 15 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, filtered, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2-hydroxy-2- (4- (thiazole-2-) was obtained. Yl) phenyl) propanoic acid (35b) was obtained as a pale yellow amorphous substance.

  (Step 3) According to Example 1 (Steps 7 to 9), instead of compound (1f), compound (35b) was used, and 4- (4-((R) -3-amino-2-hydroxy-2-phenyl) was used. (4- (Thiazol-2-yl) phenyl) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (35c) was obtained. Furthermore, according to Example 4, the compound (35c) was used instead of the compound (1) to obtain a compound (35).

Example 36: 4- (4-((R) -2-hydroxy-3- (isopropylamino) -2- (4-phenoxyphenyl) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [ 2,3-d] pyrimidin-6 (7H) -one (36)
(Step 1) Compound (1f) 200 mg, phenol 110 mg, palladium acetate 13 mg, tripotassium phosphate 310 mg, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2 ′, 4 ′, A mixture of 42 mg of 6′-triisopropylbiphenyl and 5.5 ml of toluene was stirred at 100 ° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and adjusted to pH 3 with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (chloroform-methanol), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2-hydroxy-2- (4-phenoxyphenyl) propanoic acid ( 36a) was obtained as a brown oil.

  (Step 2) According to Example 1 (Steps 7 to 9), instead of compound (1f), compound (36a) was used, and 4- (4-((R) -3-amino-2-hydroxy-2-phenyl) was used. (4-Phenoxyphenyl) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (36b) was obtained. Furthermore, according to Example 4, the compound (36b) was used instead of the compound (1), and the compound (36) was obtained as a white amorphous solid.

Example 37: 4- (4-((R) -2-hydroxy-3- (isopropylamino) -2- (4- (pyrimidin-4-yl) phenyl) piperazin-1-yl) -5-methyl- 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (37)
(Step 1) A mixture of 100 mg of compound (35a), 100 mg of 2,4-dichloropyrimidine, 17 mg of dichlorobis (triphenylphosphine) palladium, 98 mg of potassium carbonate, 1 ml of 1,4-dioxane, and 0.2 ml of water was irradiated under microwave irradiation. The mixture was stirred at 120 ° C. for 1 hour and at 130 ° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, filtered, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (chloroform-methanol), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2- (4- (2-chloropyrimidin-4-yl) was obtained. Phenyl) -2-hydroxypropanoic acid (37a) was obtained as a pale yellow amorphous substance.

  (Step 2) Compound (37a) was dissolved in 5 ml of ethanol, 30 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. After replacing hydrogen with nitrogen, the reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate) to give (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2-hydroxy-2- (4- (pyrimidine-4- Yl) phenyl) propanoic acid (37b) was obtained as a pale yellow amorphous substance.

  (Step 3) According to Example 1 (Steps 7 to 9), instead of compound (1f), compound (37b) was used, and 4- (4-((R) -3-amino-2-hydroxy-2-phenyl) was used. (4- (Pyrimidin-4-yl) phenyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (37c) was obtained. According to Example 4, the compound (37c) was used in place of the compound (1) to obtain the compound (37) as a white amorphous solid.

Example 38: 4- (4-((R) -2-hydroxy-3- (isopropylamino) -2- (4- (1-methyl-1H-pyrazol-3-yl) phenyl) piperazin-1-yl ) -5-Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (38)
(Step 1) A mixture of compound (35a) 89 mg, 3-iodo-1-methyl-1H-pyrazole 60 mg, dichlorobis (triphenylphosphine) palladium 15 mg, potassium carbonate 90 mg, 1,4-dioxane 1 ml, water 0.2 ml. The mixture was stirred at 120 ° C. for 1.5 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, the organic layer was filtered and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2-hydroxy-2- (4- (1-methyl-) was obtained. 1H-pyrazol-3-yl) phenyl) propanoic acid (38a) was obtained as a colorless oil.

  (Step 2) According to Example 1 (Steps 7 to 9), compound (38a) was used instead of compound (1f), and 4- (4-((R) -3-amino-2-hydroxy-2-phenyl) was used. (4- (1-Methyl-1H-pyrazol-3-yl) phenyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (38b) Furthermore, according to Example 4, the compound (38b) was used instead of the compound (1) to obtain the compound (38) as a white amorphous solid.

Example 39: 4- (4-((R) -2-hydroxy-3- (isopropylamino) -2- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) -5-methyl- 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (39)
(Step 1) Compound (35a) 200 mg, 2-chloropyrimidine 81 mg, palladium acetate 11 mg, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl 39 mg, 4M lithium hydroxide aqueous solution 0.47 ml, 1,4-dioxane 3 ml of the mixture was stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and adjusted to pH 2 with dilute hydrochloric acid. The obtained mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (chloroform-methanol), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2-hydroxy-2- (4- (pyrimidin-2-yl) was obtained. ) Phenyl) propanoic acid (39a) was obtained as a yellow oil.

  (Step 2) According to Example 1 (Steps 7 to 9), compound (39a) was used instead of compound (1f), and 4- (4-((R) -3-amino-2-hydroxy-2-phenyl) was used. (4- (Pyrimidin-2-yl) phenyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (39b) was obtained. According to Example 4, compound (39b) was used instead of compound (1) to obtain compound (39) as a white amorphous solid.

Example 40 4- (4-((R) -3-amino-2-hydroxy-2- (4- (3-methyl-1,2,4-thiadiazol-5-yl) phenyl) piperazine-1- Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (40)
(Step 1) 265 mg of compound (35a), 100 mg of 3-methyl-5-chloro-1,2,4-thiadiazole, 23 mg of bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium, cesium fluoride A mixture of 191 mg, 1,4-dioxane 3 ml, and water 0.3 ml was stirred at 80 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and adjusted to pH 2 with dilute hydrochloric acid. The obtained mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and (R) -ethyl 3-((tert-butoxycarbonyl) amino) -2-hydroxy-2- (4- (3-methyl- 1,2,4-thiadiazol-5-yl) phenyl) propanoic acid (40a) was obtained as a yellow oil.

  (Step 2) According to Example 1 (Steps 7 to 9), compound (40a) was used instead of compound (1f), and 4- (4-((R) -3-amino-2-hydroxy-2-phenyl) was used. (4- (3-Methyl-1,2,4-thiadiazol-5-yl) phenyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidine-6 (7H)- After obtaining the on (40) TFA salt as a white amorphous solid, the hydrochloride of the compound (40) was obtained according to Example 2.

Example 41 4- (4-((R) -2-hydroxy-3- (isopropylamino) -2- (4- (3-methyl-1,2,4-thiadiazol-5-yl) phenyl) piperazine -1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (41)
According to Example 4, the compound (40) was used in place of the compound (1), and the compound (41) was obtained as a white amorphous solid.

  The structural formulas and physical property values of Compounds 1-41 are shown in Table 1.

Test Example 1: Confirmation of Akt1 Kinase Activity Inhibitory Activity Preparation of Akt1 and measurement of the inhibitory activity of the compounds of the present invention against the kinase activity of Akt1 in vitro are described in Biochem. J. et al. vol. 385, pp 399-408 (2005) and Cancer Res. vol. 68, pp 2366-2374 (2008). In the preparation of Akt1, first, human Akt1 to which a Middle T antigen tag was added was expressed in insect cells Sf9, and then Akt1 was prepared through affinity purification and activation with PDK1, until the inhibitory activity of the compound was measured. Stored at ° C. In measuring the inhibitory activity of a compound, first, Akt1 and the compound of the present invention were preincubated for 120 minutes at 25 ° C. in a reaction buffer (15 mM Tris-HCl pH 7.5, 0.01% Tween-20, 2 mM DTT). . Next, biotinylated Crosstide (biotin-KGSGSGPRTSFAEG, manufactured by Millipore), MgCl ₂ and ATP as a substrate were added to final concentrations of 500 nM, 10 mM and 150 μM, respectively, and reacted at 25 ° C. for 60 minutes. The reaction was terminated by adding EDTA to a final concentration of 40 mM, and then Eu-labeled anti-phosphorylated Crosstide antibody (PerkinElmer) and SureLight APC-SA (PerkinElmer) were each added at a final concentration of 0.5 nM. And a detection solution containing 62.5 nM were added and reacted at room temperature for 2 hours. Finally, the amount of fluorescence when irradiated with excitation light having a wavelength of 337 nm was measured at two wavelengths of 620 nm and 665 nm using PHERAstar FS (manufactured by BMG LABTECH) or PHERAstar (manufactured by BMG LABTECH). The amount of phosphorylation reaction was determined from the ratio of fluorescence amounts of two wavelengths, and the compound concentration capable of suppressing the phosphorylation reaction by 50% was defined as IC ₅₀ value (nM) and is shown in Table 2 below.

Test Example 2: Cell Proliferation Inhibition Test An in vitro cell proliferation suppression test for RKO cells (human colorectal cancer cell line) was performed under the following conditions.

Cultured in MEM medium (GIBCO, Cat #: 10370-088) containing 10% FBS, 1 mM L-glutamine (GIBCO, Cat #: 25030) and 1 mM sodium pyruvate (GIBCO, Cat #: 11360). RKO cells (ATCC, Cat #: CRL-2577) are seeded at 2 × 10 ³ (100 μl) in each well of a 96-well flat bottom microplate (COSTAR, Cat #: 3904) at 37 ° C., 5% carbon dioxide gas Cultivated in the containing incubator for 1 day. The compound of the present invention serially diluted with dimethyl sulfoxide or only dimethyl sulfoxide was added to MEM medium containing 10% FBS, 1 mM L-glutamine, and 1 mM sodium pyruvate. 100 μl of this was added to each well of the above-mentioned RKO cell culture plate to give a final compound concentration of 20, 6, 2, 0.6, 0.2, 0.06, 0.02, 0.0. 006, 0 μM. In addition, a separately prepared RKO cell culture plate was allowed to stand at room temperature for 30 minutes, and then 100 μl of CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat #: G7573) was added to each well. After leaving it in the dark for 10 minutes, the amount of luminescence derived from living cells in the well at the time of compound addition was measured with a microplate reader (PerkinElmer, ARVOsx). Cells to which only the compound or dimethyl sulfoxide was added were further cultured for 3 days in an incubator containing 37% at 5% carbon dioxide gas. After incubation, the mixture was left at room temperature for 30 minutes, and 100 μl of the supernatant was removed from each well so that 100 μl of cell culture medium remained. An equivalent amount of CellTiter-Glo Luminescent Cell Viability Assay was added to 100 μl of the remaining cell culture solution. After leaving it in the dark for 10 minutes, the amount of luminescence derived from living cells in each well was measured with a microplate reader. The cell growth rate was calculated from the following formula, and the concentration at which the cell growth rate was 50%, that is, the concentration of the compound of the present invention that inhibits cell growth by 50% (GI ₅₀ value (μM)) was determined.

Cell growth rate (%) = (T−C ₀ ) / (C−C ₀ ) × 100; if T ≧ C ₀ , cell growth rate (%) = (T−C ₀ ) / C ₀ × 100; T < for C _{0 C 0:} amount of light emission of the wells during compound addition (count per second)
C: luminescence amount of wells to which only dimethyl sulfoxide was added (count per second)
T: luminescence amount of well added with test compound (count per second)

As control compounds, piperazine derivatives A, B, C, D and E having the following known Akt inhibitory activities (A: WO2005 / 051304 (Example 76), B: WO2008 / 006040 (Example 14), C: WO2009 / 088943 (Example 1)) was used.

The GI ₅₀ values of representative compounds and control compounds in the present invention against RKO cells were evaluated, and the results are shown in Table 3 below.

  From this result, it was clarified that the compound of the present invention has significantly higher cell growth inhibitory activity than the piperazine derivative having known Akt inhibitory activity.

Claims (11)

Formula (I)

[Where:
R ₁ and R ₂ are the same or different and are a hydrogen atom or _a C ₁ -C ₆ alkyl group optionally substituted by R _a , or R ₁ and R ₂ are _C 3 _{-C 10} cycloalkylene (wherein _C 3 _{-C 10} cycloalkylene may be substituted by _{R b)} taken together with the carbon atom bonded to the formation;
R ₃ is an unsaturated heterocyclic group _R may be substituted by _{c C} 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered optionally substituted by _{R c;}
R ₄ and R ₅ are the same or different and are a hydrogen atom or _a C ₁ -C ₆ alkyl group optionally substituted by R _a , C ₂ -C ₆ optionally substituted by R _a alkenyl group, optionally substituted by _{R a C} 2 -C ₆ alkynyl group, _{R c} by optionally substituted _C 3 _-C even though ₁₀ cycloalkyl group, optionally substituted by _{R c C 6} - A C ₁₄ aromatic hydrocarbon group, or a 4-10 membered saturated or unsaturated heterocyclic group optionally substituted by R _c , or R ₄ and R ₅ are the nitrogen atoms to which they are attached. Together with a 4- to 10-membered saturated heterocyclic group, wherein the 4- to 10-membered saturated heterocyclic group may be substituted by R _b ;
R ₆ and _{R 7} are the same or different, is a hydrogen atom, or _{R a} with substituted _C 1 -C ₆ alkyl group or _{R a} optionally _C 1 -C be substituted by, ₆ alkoxy groups or R ₆ and R ₇ together with the carbon atom to which they are attached are C ₃ -C ₁₀ cycloalkylene (where C ₃ -C ₁₀ cycloalkylene is substituted by R _b May be formed);
R _a is a deuterium atom, halogen atom, hydroxyl group, amino group, cyano group, nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₄ aromatic hydrocarbon group, or 4-10 membered saturation Or an unsaturated heterocyclic group;
R _b is a deuterium atom, halogen atom, hydroxyl group, amino group, cyano group, nitro group, oxo group, oxide group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₂ -C _6. alkenyl _group, a C 2 -C ₆ alkynyl _group, C 3 _{-C 10} cycloalkyl _group, C 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered saturated or unsaturated heterocyclic group;
R _c is a deuterium atom, halogen atom, cyano group, nitro group, oxo group, oxide group,
_{-C (= O) R x,} -C (= O) OR x, -C (= O) N (R x) (R y), - C (= O) SR x, -C (= S) OR _{x, -C (= O) ON} (R x) (R y), - N (R x) (R y), - NR x C (= O) R y, -NR x SO 2 R y, -NR _{x C (= O) OR y} , -NR x C (= O) N (R y) (R z), - NR x SO 2 N (R y) (R z), - N (R x) -OR _{y, = NR x, = N} -OR x, -OR x, -OC (= O) R x, -OC (= S) R x, -OC (= O) OR x, -OC (= O) N (R _x ) (R _y ), —OC (═S) OR _x , —SR _x , —SO ₂ R _x , —SO ₂ N (R _x ) (R _y ), R _a may be substituted. C ₁ -C ₆ alkyl group, optionally substituted by _{R a} Which may _C 2 -C ₆ alkenyl group, _{R a} by optionally substituted _C 2 -C ₆ alkynyl group, _{R b} by optionally substituted _C 3 _-C even though ₁₀ cycloalkyl group, substituted by _{R b} which may be C ₆ -C ₁₄ aromatic hydrocarbon group, a saturated or unsaturated heterocyclic group having 4 to 10 membered optionally substituted by R _b;
R _x , R _y and R _z are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, C ₃ -C ₁₀ cycloalkyl _group, a saturated or unsaturated heterocyclic group C 6 _{-C 14} aromatic hydrocarbon group, or a 4-10 membered. ]
Or a salt thereof. The compound according to claim 1 or a salt thereof, wherein _one of R ₁ and R ₂ is a hydrogen atom, and the other is a C ₁ -C ₆ alkyl group. R ₃ has a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by R _c , or 1 to 3 heteroatoms selected from N, S and O, and is substituted by R _c The compound or a salt thereof according to claim 1 or 2, which is a 4 to 6-membered monocyclic unsaturated heterocyclic group which may be used. R ₃ is a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by 1 to 5 different or identical R _{c s} , and R _c is (1) a halogen atom;
(2) a C ₆ -C ₁₄ aromatic hydrocarbon oxy group;
₍₃₎ C 2 -C ₆ alkynyl group;
₍₄₎ C 6 _{-C 14} aromatic hydrocarbon group; and (5) optionally substituted by the same or different 1 to 3 groups selected from the group consisting of oxo group and _C 1 -C ₆ alkyl group A 4-10 membered unsaturated heterocyclic group;
4 to 6 having 1 to 3 heteroatoms selected from N, S and O, wherein R ₃ is selected from the group consisting of: or R ₃ is optionally substituted by 1 to 5 R _c The compound or a salt thereof according to any one of claims 1 to 3, which is a membered monocyclic unsaturated heterocyclic group, and _Rc is a halogen atom. R ₄ and R ₅ are the same or different and are a hydrogen atom or _a C ₁ -C ₆ alkyl group optionally substituted by R a, C ₃ -C ₁₀ optionally substituted by R _c cycloalkyl group, or R _c may be substituted by N, or a 4-6 membered saturated heterocyclic group monocyclic having 1-3 heteroatoms selected from S and O, Alternatively, R ₄ and R _5, 4-6 membered monocyclic saturated heterocyclic ring having 1-3 heteroatoms they are selected from the nitrogen atom together N, S and O that binds The compound or salt thereof according to any one of claims 1 to 4, which forms a formula group (wherein the saturated heterocyclic group may be substituted with _Rb ). One of R ₆ and R ₇ is a hydrogen atom and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ are combined with the carbon atom to which they are attached. Te to form a _C 3 _{-C 10} cycloalkylene, or a salt thereof according to any one of claims 1-5. One of R ₁ and R ₂ is a hydrogen atom, the other is a C ₁ -C ₆ alkyl group,
R ₃ is a C ₆ -C ₁₄ aromatic hydrocarbon group optionally substituted by 1 to 5 different or identical R _{c s} , and R _c is (1) a halogen atom;
(2) a C ₆ -C ₁₄ aromatic hydrocarbon oxy group;
₍₃₎ C 2 -C ₆ alkynyl group;
₍₄₎ C 6 _{-C 14} aromatic hydrocarbon group; and (5) optionally substituted by the same or different 1 to 3 groups selected from the group consisting of oxo group and _C 1 -C ₆ alkyl group A 4-10 membered unsaturated heterocyclic group;
4 to 6 having 1 to 3 heteroatoms selected from N, S and O, wherein R ₃ is selected from the group consisting of: or R ₃ is optionally substituted by 1 to 5 R _c A membered monocyclic unsaturated heterocyclic group, and R _c is a halogen atom,
R ₄ and R ₅ are the same or different and are each a hydrogen atom; a C ₁ -C ₆ alkyl group optionally substituted by a C ₃ -C ₁₀ cycloalkyl group; and a C ₁ -C ₆ alkoxy group. which may C ₃ -C ₁₀ cycloalkyl group; or N, or a monocyclic saturated heterocyclic group having 4-6 members with 1-3 heteroatoms selected from S and O, or, R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic saturated heterocycle having 1 to 3 heteroatoms selected from N, S and O And
One of R ₆ and R ₇ is a hydrogen atom and the other is a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₆ and R ₇ are combined with the carbon atom to which they are attached. Te to form a _C 3 _{-C 10} cycloalkylene, or a salt thereof according to any one of claims 1-6. The compound or a salt thereof according to any one of claims 1 to 7, which is selected from the following compound group:
(1) 4- (4-((R) -2- (4-chlorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2, 3-d] pyrimidin-6 (7H) -one,
(2) 4- (4-((R) -2- (4-Chlorophenyl) -3- (dimethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one,
(3) 4- (4-((R) -2- (4-chlorophenyl) -3- (ethylamino) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one,
(4) 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(5) 4- (4-((R) -2- (4-Chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(6) 4-((R) -4-((R) -2- (4-chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -3-methylpiperazine-1- Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(7) 4- (4-((R) -2- (5-chlorothiophen-2-yl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] octane -7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(8) 4- (4-((R) -2- (4-Chloro-3-fluorophenyl) -2-hydroxy-3- (isopropylamino) propanoyl) -4,7-diazaspiro [2.5] octane -7-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(9) 4- (4-((R) -2-([1,1′-biphenyl] -4-yl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5 -Methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(10) 4- (4-((R) -3- (azetidin-1-yl) -2- (4-chlorophenyl) -2-hydroxypropanoyl) piperazin-1-yl) -5-methyl-5H- Pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(11) 4- (4-((R) -2- (4-Chlorophenyl) -2-hydroxy-3- (pyrrolidin-1-yl) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one,
(12) 4- (4-((R) -2- (4-ethynylphenyl) -2-hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2 , 3-d] pyrimidin-6 (7H) -one, and (13) 4- (4-((R) -2- (4- (2H-1,2,3-triazol-2-yl) phenyl) -2-Hydroxy-3- (isopropylamino) propanoyl) piperazin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one.   The Akt inhibitor which uses the compound or its salt of any one of Claims 1-8 as an active ingredient.   A pharmaceutical composition for treating a disease involving Akt, comprising the compound according to any one of claims 1 to 8 or a salt thereof as an active ingredient.   The antitumor agent which uses the compound or its salt of any one of Claims 1-8 as an active ingredient.