JP2021091671A - Pharmaceutical composition containing polycyclic pyridone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having an anti-HIV action. A pharmaceutical composition containing a compound represented by the formula (I). (In the formula, ring A is a substituted or unsubstituted non-aromatic heterocycle; ring C is a benzene ring or the like; Q is a 5-membered aromatic heterocycle or the like; R1 is independent of each other. Then, halogen or the like; L is a substituted or unsubstituted alkylene; R3 is a substituted or unsubstituted alkyl or the like; R4 is hydrogen or the like; n is an integer of 1 to 3 Yes) [Selection diagram] None

Description

The present invention relates to a novel compound having an antiviral effect, more particularly to a pharmaceutical composition containing a polycyclic pyridone derivative having an HIV integrase inhibitory activity, particularly an anti-HIV drug.

Among the viruses, human immunodeficiency virus (Human Immunodeficiency Virus, hereinafter abbreviated as HIV), which is a kind of retrovirus, causes acquired immunodeficiency syndrome (Acquired immunodeficiency syndrome, hereinafter abbreviated as AIDS). It has been known. As therapeutic agents for AIDS, there are currently various combinations of integrase inhibitors (dolutegravir, etc.) as the main agents and two nucleic acid-based reverse transcriptase inhibitors (ABC + 3TC, FTC + TAF, etc.) with different resistance profiles. Recommended for naive patients in the guidelines. It has a strong medicinal effect and is highly safe, so it is more satisfying than the initial therapeutic drugs. On the other hand, because of the availability of safe drugs and the good prognosis, it is recommended to start treatment as soon as HIV infection is known, and the life expectancy of HIV-infected persons is approaching that of healthy people. The medication period is getting longer. Once the side effects of the nucleic acid reverse transcriptase inhibitor or the emergence of a resistant virus due to long-term administration, there is no convenient treatment after that, so leave the nucleic acid reverse transcriptase inhibitor unused. There is a movement to try. Therefore, it is desired to establish a two-drug treatment with two major drugs, and it is desired to develop a major drug that can be combined with an integrase inhibitor. In addition, a therapeutic drug with a longer dosing interval, that is, once at intervals of one month or more, for improving the patient's QOL (Quality of Life), such as improving the fatigue of taking the drug by taking the drug for a long period of time and enjoying more daily life. It is desired to develop a long-acting injection that completes treatment by injection.

To meet these demands, the integrase inhibitor cabotegravir is under development at Ph3 as a sustained injection. In addition, the non-nucleic acid reverse transcriptase inhibitor rilpivirine has also been developed as a long-acting injection, and the aim is to establish a therapeutic method using these two agents. However, these drugs are injected once every one or two months and require a total of three to four painful injections. Therefore, in order to further improve the QOL of patients, it is desired to develop a drug that is less painful at a lower dose and can be treated by injection once every three months.
As integrase inhibitors, raltegravir and elvitegravir are already on the market as the first generation of oral preparations, and dolutegravir as the second generation. When dolutegravir is used by naive patients, resistance mutations do not appear, but when dolutegravir is used to treat patients infected with a virus resistant to first-generation integrase inhibitors, additional resistance mutations are added to dolutegravir. May not work. Therefore, it is also desired to develop an inhibitor having a higher resistance barrier than dolutegravir.

Further, as one of the anti-HIV agents having an integrase inhibitory action, a pyridone derivative having a heterocyclic side chain is known (Patent Documents 1 to 13). Of these, Patent Document 6 describes a fused tricyclic pyridopyrazine derivative. Further, Patent Document 4 describes a condensed tricyclic pyridopyrazine derivative and a condensed tricyclic pyridotriazine derivative.

International Publication No. 2005/016927 Pamphlet International Publication No. 2011/105590 Pamphlet International Publication No. 2013/054862 Pamphlet International Publication No. 2014/099586 Pamphlet International Publication No. 2014/183532 Pamphlet International Publication No. 2014/200080 Pamphlet International Publication No. 2015/089847 Pamphlet International Publication No. 2015/09525 Pamphlet International Publication No. 2016/0278779 Pamphlet International Publication No. 2016/094197 Pamphlet International Publication No. 2016/187788 Pamphlet International Publication No. 2016/191239 Pamphlet International Publication No. 2017/106071 Pamphlet

An object of the present invention is to provide a pharmaceutical composition containing a compound having a novel long-acting integrase inhibitory activity having a high resistance barrier.

As a result of diligent studies, the present inventors have found that a novel carbamoylpyridone derivative has an integrase inhibitory effect having a high resistance barrier. Furthermore, the pharmaceutical composition of the present invention is an antiviral drug (eg, antiretroviral drug, anti-HIV drug, anti-HTLV-1 (Human T cell leukemia virus type 1: human T cell leukemia virus type 1) drug, anti-FIV. (Feline immunodeficiency virus: feline AIDS virus) drug, anti-SIV (Siman immunodeficiency virus: sal AIDS virus) drug, especially anti-HIV drug, anti-AIDS drug, or a therapeutic drug for related diseases, etc. The present invention shown in is completed.

（式中、
Ａ環は、置換もしくは非置換の非芳香族複素環であり；
Ｃ環は、ベンゼン環またはピリジン環であり；
Ｑは、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、およびアルキルアミノからなる群から選択される１以上の置換基で置換されていてもよい５員または６員の芳香族複素環であり；
Ｒ^１は、それぞれ独立して、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、シアノまたはハロアルキルオキシであり；
Ｌは、置換もしくは非置換のアルキレンであり；
Ｒ^３は、置換もしくは非置換のアルキル、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基であり；
Ｒ^４は、水素または置換もしくは非置換のアルキルであり；
Ｒ^３およびＲ^４、またはＲ^３およびＡ環上の置換基が、隣接する原子と一緒になって、置換もしくは非置換の非芳香族複素環を形成してもよく；
ｎは、１〜３の整数である）
［２］Ａ環が、以下のいずれかの環である［１］記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。

（式中、
Ｒ^４は、水素または置換もしくは非置換のアルキルであり；
破線は、結合の存在または非存在を表し；
Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４およびＺ^５は、それぞれ独立してＣＲ^５ａＲ^５ｂ、ＣＲ^５ａ、Ｏ、Ｎ、ＮＲ^５ｃまたはＳであり、ここでＺ^１、Ｚ^２、Ｚ^３、Ｚ^４およびＺ^５においてＡ環の環構造を構成するヘテロ原子の数は０または１個であり；
Ｚ^１とＺ^３、Ｚ^１とＺ^４、Ｚ^１とＺ^５、Ｚ^２とＺ^４、Ｚ^２とＺ^５、Ｚ^３とＺ^５、Ｒ^４とＺ^２、Ｒ^４とＺ^３、Ｒ^４とＺ^４もしくはＲ^４とＺ^５の間には、ＮＲ^５ｃ、ＯおよびＳから選択されるヘテロ原子が１個介在していてもよい置換もしくは非置換のＣ１−Ｃ４架橋が形成されていてもよく；
Ｒ^５ａおよびＲ^５ｂは、それぞれ独立して、水素、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルキルオキシであり；
同一炭素原子上のＲ^５ａおよびＲ^５ｂが一緒になって置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
Ｒ^５ｃは、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基であり；
Ｒ^３およびＲ^４が、隣接する原子と一緒になって、置換もしくは非置換の非芳香族複素環を形成してもよい）
［３］Ａ環が、以下のいずれかの環である、［１］記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。

（式中、
Ｒ^４は、水素または置換もしくは非置換のアルキルであり；
破線は、結合の存在または非存在を表し；
Ｂ環は、置換もしくは非置換の炭素環または置換もしくは非置換の複素環であり；
Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４およびＺ^５は、それぞれ独立してＣＲ^５ａＲ^５ｂ、ＣＲ^５ａ、Ｃ、Ｏ、Ｎ、ＮＲ^５ｃまたはＳであり（ただし、Ｂ環の構成原子である場合は、ＣＲ^５ａ、ＣまたはＮである）；
Ｚ^１とＺ^３、Ｚ^１とＺ^４、Ｚ^１とＺ^５、Ｚ^２とＺ^４、Ｚ^２とＺ^５、Ｚ^３とＺ^５、Ｒ^４とＺ^２、Ｒ^４とＺ^３、Ｒ^４とＺ^４もしくはＲ^４とＺ^５の間には、ＮＲ^５ｃ、ＯおよびＳから選択されるヘテロ原子が１個介在していてもよい置換もしくは非置換のＣ２−Ｃ４架橋が形成されていても良く；
Ｒ^５ａおよびＲ^５ｂは、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルキルオキシであり；
同一炭素原子上のＲ^５ａおよびＲ^５ｂが一緒になって置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
Ｒ^５ｃは、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基であり；
Ｒ^３およびＲ^４が、隣接する原子と一緒になって、置換もしくは非置換の非芳香族複素環を形成してもよい）
［４］以下の式で示される［１］〜［３］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
式（ＩＩ）：

（式中、
Ａ環は、以下の環であり；

Ｘ１は、ＣＲ^Ａ９ａＲ^Ａ９ｂまたはＯであり；
Ｒ^Ａ５ａ、Ｒ^Ａ５ｂ、Ｒ^Ａ６ａ、Ｒ^Ａ６ｂ、Ｒ^Ａ７ａおよびＲ^Ａ７ｂは、それぞれ独立して、水素、アルキル、アルキルオキシまたはアルキルオキシアルキルであり；
Ｒ^Ａ５ａおよびＲ^Ａ６ａ、またはＲ^Ａ６ａおよびＲ^Ａ７ａが、隣接する原子と一緒になって、ハロゲンで置換されていてもよい芳香族炭素環、ハロゲンで置換されていてもよい３−６員の非芳香族炭素環またはハロゲンで置換されていてもよい４−６員の非芳香族複素環を形成してもよく（ただし、芳香族炭素環を形成する場合は、Ｒ^Ａ５ｂおよびＲ^Ａ６ｂ、またはＲ^Ａ６ｂおよびＲ^Ａ７ｂは一緒になって結合を形成する）；
Ｒ^Ａ５ｂおよびＲ^Ａ６ｂは、一緒になって結合を形成してもよく；
Ｒ^Ａ８ａ、Ｒ^Ａ８ｂ、Ｒ^Ａ９ａ、Ｒ^Ａ９ｂ、Ｒ^Ａ１０ａ、Ｒ^Ａ１０ｂ、Ｒ^Ａ１１ａおよびＲ^Ａ１１ｂは、それぞれ独立して、水素、アルキル、アルキルオキシまたはアルキルオキシアルキルであり；
Ｒ^Ａ８ａおよびＲ^Ａ１０ａは、一緒になってＣ１−Ｃ３架橋を形成してもよく；
Ｒ^Ａ１０ａおよびＲ^Ａ１１ａは、隣接する原子と一緒になって、５員の非芳香族炭素環を形成してもよく；
Ｒ^Ａ９ａおよびＲ^Ａ９ｂは、隣接する原子と一緒になって、４員の非芳香族炭素環または５員の非芳香族複素環を形成してもよく；
Ｒ^Ａ８ａおよびＲ^Ａ９ａが、一緒になって結合を形成してもよく；
C環は、ベンゼン環またはピリジン環であり；
Qは、５員の芳香族複素環であり；
Ｒ^１は、それぞれ独立して、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、シアノまたはハロアルキルオキシであり；
Ｒ^２ａおよびＲ^２ｂは、それぞれ独立して、水素、アルキルまたはハロアルキルであり；
Ｒ^３は、アルキルまたはハロアルキルであり；
Ｒ^４は、水素またはアルキルであり；
ｎは、１〜３の整数である）
［５］Ｒ^３がアルキルまたはハロアルキルである、［１］〜［３］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［６］Ｒ^３がアルキルである、［１］〜［４］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［７］Ｒ^４が水素またはアルキルである、［１］〜［３］、［５］または［６］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［８］Ｒ^１がそれぞれ独立して、ハロゲン、アルキルまたはハロアルキルである、［１］〜［７］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［９］Ｒ^１がそれぞれ独立して、ハロゲンである、［１］〜［７］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［１０］Ｒ^２ａが水素であり、Ｒ^２ｂが水素またはアルキルである、［４］、［６］〜［９］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［１１］Ｑが５員の芳香族複素環である、［１］〜［３］または［５］〜［１０］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［１２］Ｒ^４に隣接する炭素原子の立体が以下である、［１］〜［３］または［５］〜［１１］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。

（式中、Ａ環およびＲ^４は、［１］と同意義である）
［１３］化合物Ｉ−２、Ｉ−６、Ｉ−８、ＩＩ−３、ＩＩ−１８、ＩＩ−２３、ＩＩ−２４、ＩＩ−２７、ＩＩ−２９、ＩＩ−３３、ＩＩ−３７、ＩＩ−３８、ＩＩ−４４、ＩＩ−４８、ＩＩ−５０、ＩＩ−５１、ＩＩ−５２、ＩＩ−５４、ＩＩ−５５、ＩＩ−５６、ＩＩ−５７、ＩＩ−５８、ＩＩ−６１、ＩＩ−６２、ＩＩ−６３、ＩＩ−６５、ＩＩ−６７およびＩＩ−６８からなる群から選択される、［１］記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［１４］抗ＨＩＶ剤である、［１］〜［１３］のいずれかに記載の医薬組成物。
［１５］［１］〜［１３］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、ＨＩＶインテグラーゼ阻害剤。

［１’］以下の式で示される化合物またはその製薬上許容される塩を含有する、医薬組成物。
式（Ｉ’）：

（式中、
Ａ環は、置換もしくは非置換の複素環であり；
Ｑは、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、またはアルキルアミノで置換されていてもよい複素環であり；
Ｒ^１は、それぞれ独立して、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、ニトリル、またはハロアルキルオキシであり；
Ｌは、置換もしくは非置換のアルキレンであり；
Ｒ^３は、置換もしくは非置換のアルキル、置換もしくは非置換の非芳香族炭素環式基、または置換もしくは非置換の非芳香族複素環式基であり；
Ｒ^４は、水素、または置換もしくは非置換のアルキルであり；
Ｒ^３およびＲ^４、またはＲ^３およびＡ環上の置換基が、隣接する原子と一緒になって、置換もしくは非置換の複素環を形成してもよく；
ｎは、１〜３の整数である）
［２’］Ａ環が、以下のいずれかの環である［１’］記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。

（式中、
Ｒ^４は、水素、または置換もしくは非置換のアルキルであり；
破線は、結合の存在または非存在を表し；
Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４およびＺ^５は、それぞれ独立してＣＲ^５ａＲ^５ｂ、ＣＲ^５ａ、Ｏ、Ｎ、ＮＲ^５ｃ、Ｓ、Ｓ（＝Ｏ）、Ｓ（＝Ｏ）_２、またはＳ（＝Ｏ）＝ＮＲ^５ｃであり、ここでＺ^１、Ｚ^２、Ｚ^３、Ｚ^４およびＺ^５のうちヘテロ原子の数は０または１個であり；
Ｚ^１とＺ^３、Ｚ^１とＺ^４、Ｚ^１とＺ^５、Ｚ^２とＺ^４、Ｚ^２とＺ^５、Ｚ^３とＺ^５、Ｒ^４とＺ^２、Ｒ^４とＺ^３、Ｒ^４とＺ^４もしくはＲ^４とＺ^５の間には、置換もしくは非置換のＣ２−Ｃ４架橋が形成されていてもよく；
Ｒ^５ａおよびＲ^５ｂは、それぞれ独立して、水素、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のウレイド、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、または置換もしくは非置換の非芳香族複素環オキシであり；
同一炭素原子上のＲ^５ａおよびＲ^５ｂが一緒になってオキソ、チオキソもしくは置換もしくは非置換のスピロ環を形成してもよく；
Ｒ^５ｃは、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、または置換もしくは非置換の非芳香族複素環オキシカルボニルであり；
Ｒ^３およびＲ^４、またはＲ^３およびＺ^１上の置換基が、隣接する原子と一緒になって、置換もしくは非置換の複素環を形成してもよい）
［３’］Ａ環が、以下のいずれかの環である、［１’］記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。

（式中、
Ｒ^４は、水素、または置換もしくは非置換のアルキルであり；
破線は、結合の存在または非存在を表し；
Ｂ環は、置換もしくは非置換の炭素環または置換もしくは非置換の複素環であり；
Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４およびＺ^５は、それぞれ独立してＣＲ^５ａＲ^５ｂ、ＣＲ^５ａ、Ｃ、Ｏ、Ｎ、ＮＲ^５ｃ、Ｓ、Ｓ（＝Ｏ）、Ｓ（＝Ｏ）_２、またはＳ（＝Ｏ）＝ＮＲ^５ｄであり（ただし、Ｂ環の構成原子である場合は、ＣＲ^５ａ、ＣまたはＮである）；
Ｚ^１とＺ^３、Ｚ^１とＺ^４、Ｚ^１とＺ^５、Ｚ^２とＺ^４、Ｚ^２とＺ^５、Ｚ^３とＺ^５、Ｒ^４とＺ^２、Ｒ^４とＺ^３、Ｒ^４とＺ^４もしくはＲ^４とＺ^５の間には、置換もしくは非置換のＣ２−Ｃ４架橋が形成されていても良く；
Ｒ^５ａおよびＲ^５ｂは、それぞれ独立して、水素、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のウレイド、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、または置換もしくは非置換の非芳香族複素環オキシであり；
同一炭素原子上のＲ^５ａおよびＲ^５ｂが一緒になってオキソ、チオキソもしくは置換もしくは非置換のスピロ環を形成してもよく；
Ｒ^５ｃは、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、または置換もしくは非置換の非芳香族複素環オキシカルボニルであり；
Ｒ^５ｄは、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、または置換もしくは非置換の非芳香族複素環オキシカルボニルであり；
Ｒ^３およびＲ^４、またはＲ^３およびＺ^１上の置換基が、隣接する原子と一緒になって、置換もしくは非置換の複素環を形成してもよい）
［４’］以下の式で示される［１’］〜［３’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
式（Ｉ−２）：

（式中、
Ｒ^２ａおよびＲ^２ｂは、それぞれ独立して、水素、アルキル、またはハロアルキルであり；
Ｒ^２ａおよびＲ^２ｂは隣接する炭素原子と一緒になって炭素環または複素環を形成してもよく；
Ｒ^３は、置換もしくは非置換のアルキル、置換もしくは非置換の非芳香族炭素環式基、または置換もしくは非置換の非芳香族複素環式基であり；
Ｒ^４は、水素、または置換もしくは非置換のアルキルであり；
Ｘは、ＣＲ^９ａＲ^９ｂ、ＮＲ^１０、Ｏ、Ｓ、Ｓ（＝Ｏ）、Ｓ（＝Ｏ）_２、またはＳ（＝Ｏ）＝ＮＲ^１１であり；
Ｒ^６ａ、Ｒ^６ｂ、Ｒ^７ａ、Ｒ^７ｂ、Ｒ^８ａ、Ｒ^８ｂ、Ｒ^９ａ、およびＲ^９ｂは、それぞれ独立して、水素、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノであり；
Ｒ^６ｂおよびＲ^９ｂ、Ｒ^９ｂおよびＲ^７ｂ、またはＲ^７ｂおよびＲ^８ｂが、隣接する原子と一緒になって、置換もしくは非置換の炭素環または置換もしくは非置換の複素環を形成してもよく；
Ｒ^４およびＲ^７ｂ、またはＲ^６ｂおよびＲ^８ｂは、一緒になって置換もしくは非置換のＣ２−Ｃ４架橋を形成してもよく；
Ｒ^６ｂおよびＲ^１０、またはＲ^１０およびＲ^７ｂが、隣接する原子と一緒になって、置換もしくは非置換の複素環を形成してもよく；
Ｒ^３およびＲ^４、またはＲ^３およびＲ^６ｂが、隣接する原子と一緒になって、置換もしくは非置換の複素環を形成してもよく；
Ｒ^１０は、置換もしくは非置換のアルキル、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環アルキルカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、または置換もしくは非置換の非芳香族複素環オキシカルボニルであり；
Ｒ^１１は、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、または置換もしくは非置換の非芳香族複素環オキシカルボニルであり；
Ｑ、Ｒ^１およびｎは、［１’］と同意義である）
［５’］Ｒ^３がアルキル、またはハロアルキルである、［１’］〜［４’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［６’］Ｒ^４が水素である、［１’］〜［５’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［７’］ｎが２または３の整数であり、Ｒ^１がそれぞれ独立して、ハロゲン、アルキル、またはハロアルキルである、［１’］〜［６’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［８’］Ｒ^２ａが水素であり、Ｒ^２ｂが水素、またはアルキルであるか、
またはＲ^２ａおよびＲ^２ｂが隣接する炭素原子と一緒になってＣ３−Ｃ４炭素環を形成する、［４’］〜［７’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［９’］Ｑがハロゲン、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、またはアルキルアミノで置換されていてもよい５員または６員の芳香族複素環である、［１’］〜［８’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［１０’］Ｒ^４に隣接する炭素原子の立体が以下である、［１’］〜［９’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。

（式中、Ａ環およびＲ^４は、［１’］と同意義である）
［１１’］化合物Ｉ−２、Ｉ−４、Ｉ−５、Ｉ−６およびＩ−８からなる群から選択される、［１］記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［１２’］抗ＨＩＶ剤である、［１’］〜［１１’］のいずれかに記載の医薬組成物。
［１３’］ＨＩＶインテグラーゼ阻害剤である、［１’］〜［１１’］のいずれかに記載の医薬組成物。 The present invention provides the inventions shown below.
[1] A pharmaceutical composition containing a compound represented by the following formula or a pharmaceutically acceptable salt thereof.
Equation (I):

(During the ceremony,
Ring A is a substituted or unsubstituted non-aromatic heterocycle;
The C ring is a benzene ring or a pyridine ring;
Q is a 5- or 6-membered aromatic heterocycle optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, haloalkyls, alkyloxys, haloalkyloxys, and alkylaminos;
R ^1s are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
L is a substituted or unsubstituted alkylene;
R ³ is a substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
Substituents on the R ³ and R ⁴ , or R ³ and A rings may combine with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle;
n is an integer from 1 to 3)
[2] A pharmaceutical composition containing the compound according to [1] or a pharmaceutically acceptable salt thereof, wherein ring A is any of the following rings.

(During the ceremony,
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
The dashed line represents the presence or absence of a bond;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c or S, where Z ¹ , Z ² , Z ³ , In Z ⁴ and Z ⁵ , the number of heteroatoms constituting the ring structure of the A ring is 0 or 1;
Z ¹ and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ , Z ³ and Z ⁵ , R ⁴ and Z ² , R ⁴ and Z ³ , R ⁴ And Z ⁴ or R ⁴ and Z ^{5 may be} interspersed with one heteroatom selected from NR 5c, O and S, even if a substituted or unsubstituted C1-C4 crosslink is formed. Often;
R ^5a and R ^5b are independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
^{R 5a} and R ^5b on the same carbon atom may be combined to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;
R ^5c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted. Alternatively, it is an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ³ and R ⁴ may be combined with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle)
[3] A pharmaceutical composition containing the compound according to [1] or a pharmaceutically acceptable salt thereof, wherein ring A is any of the following rings.

(During the ceremony,
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
The dashed line represents the presence or absence of a bond;
Ring B is a substituted or unsubstituted carbon ring or a substituted or unsubstituted heterocycle;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are independently CR ^5a R ^5b , CR ^5a , C, O, N, NR ^5c or S (provided that they are constituent atoms of the B ring). If CR ^5a , C or N);
Z ¹ and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ , Z ³ and Z ⁵ , R ⁴ and Z ² , R ⁴ and Z ³ , R ⁴ And Z ⁴ or R ⁴ and Z ^{5 may be} interspersed with one heteroatom selected from NR 5c, O and S, even if a substituted or unsubstituted C2-C4 crosslink is formed. well;
R ^5a and R ^5b are independently hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
^{R 5a} and R ^5b on the same carbon atom may be combined to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;
R ^5c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted. Alternatively, it is an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ³ and R ⁴ may be combined with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle)
[4] A pharmaceutical composition containing the compound according to any one of [1] to [3] represented by the following formula or a pharmaceutically acceptable salt thereof.
Equation (II):

(During the ceremony,
Ring A is the following ring;

X1 is CR ^A9a R ^A9b or O;
^{R A5a, R A5b, R A6a} , R A6b, R A7a and ^{R A7b} are each independently hydrogen, alkyl, alkyloxy or alkyloxy alkyl;
R ^A5a and ^{R A6a} or ^{R A6a} and ^{R A7a,} together with the adjacent atoms, an aromatic carbon ring which may be substituted by halogen, non-3-6 membered optionally substituted by halogen It may form a 4-6 member non-aromatic heterocycle which may be substituted with an aromatic carbocycle or halogen (provided that an aromatic carbocycle is formed, ^RA5b and ^RA6b , or R. ^A6b and ^RA7b together form a bond);
^RA5b and ^RA6b may be combined to form a bond;
^{R A8a, R A8b, R A9a} , R A9b, R A10a, R A10b, R A11a and ^{R A11b} are each independently hydrogen, alkyl, alkyloxy or alkyloxy alkyl;
R ^{A 8a} and ^{R A 10a} may form a C1-C3 bridge together;
R ^{A 10a} and ^{R A 11a,} together with the adjacent atoms may form a non-aromatic carbocyclic ring of 5 members;
^RA9a and ^RA9b may be combined with adjacent atoms to form a 4-membered non-aromatic carbocycle or a 5-membered non-aromatic heterocycle;
^RA8a and ^RA9a may come together to form a bond;
The C ring is a benzene ring or a pyridine ring;
Q is a 5-membered aromatic heterocycle;
R ^1s are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
R ^2a and R ^2b are independently hydrogen, alkyl or haloalkyl;
R ³ is alkyl or haloalkyl;
R ⁴ is hydrogen or alkyl;
n is an integer from 1 to 3)
[5] R ³ is alkyl or haloalkyl, [1] to a compound according to any one of [3] or containing a pharmaceutically acceptable salt, pharmaceutical compositions.
[6] R ³ is alkyl, [1] ~ comprising a compound or a pharmaceutically acceptable salt thereof according to any one of [4], a pharmaceutical composition.
[7] R ⁴ is hydrogen or alkyl, [1] to [3], [5] or a compound according to any one of [6] or containing a pharmaceutically acceptable salt, pharmaceutical compositions.
[8] A pharmaceutical composition comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein ^{R 1 is independently halogen, alkyl or haloalkyl.}
[9] A pharmaceutical composition containing the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein ^{R 1 is an independent halogen.}
[10] A medicament containing the compound according to any one of [4], [6] to [9] or a pharmaceutically acceptable salt thereof, ^{wherein R 2a} is hydrogen and R ^{2b is hydrogen or alkyl.} Composition.
[11] A medicament containing the compound according to any one of [1] to [3] or [5] to [10] or a pharmaceutically acceptable salt thereof, wherein Q is a 5-membered aromatic heterocycle. Composition.
[12] steric carbon atom adjacent to R ⁴ is not more than, containing [1] to [3] or [5] to the compound or a pharmaceutically acceptable salt thereof according to any one of [11] , Pharmaceutical composition.

(In the formula, A ring and ^{R 4} are as defined as [1])
[13] Compounds I-2, I-6, I-8, II-3, II-18, II-23, II-24, II-27, II-29, II-33, II-37, II- 38, II-44, II-48, II-50, II-51, II-52, II-54, II-55, II-56, II-57, II-58, II-61, II-62, A pharmaceutical composition comprising the compound according to [1] or a pharmaceutically acceptable salt thereof selected from the group consisting of II-63, II-65, II-67 and II-68.
[14] The pharmaceutical composition according to any one of [1] to [13], which is an anti-HIV agent.
[15] An HIV integrase inhibitor containing the compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof.

[1'] A pharmaceutical composition containing a compound represented by the following formula or a pharmaceutically acceptable salt thereof.
Equation (I'):

(During the ceremony,
Ring A is a substituted or unsubstituted heterocycle;
Q is a heterocycle that may be substituted with halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkylamino;
R ^1s are each independently halogen, alkyl, haloalkyl, alkyloxy, nitrile, or haloalkyloxy;
L is a substituted or unsubstituted alkylene;
R ³ is a substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
Substituents on the R ³ and R ⁴ , or R ³ and A rings may combine with adjacent atoms to form a substituted or unsubstituted heterocycle;
n is an integer from 1 to 3)
[2'] A pharmaceutical composition containing the compound according to [1'], which is any of the following rings, or a pharmaceutically acceptable salt thereof.

(During the ceremony,
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
The dashed line represents the presence or absence of a bond;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c , S, S (= O), S (= O) ₂ , Or S (= O) = NR ^5c , where ^{the number of heteroatoms of Z 1} , Z ² , Z ³ , Z ⁴ and Z ⁵ is 0 or 1;
Z ¹ and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ , Z ³ and Z ⁵ , R ⁴ and Z ² , R ⁴ and Z ³ , R ⁴ And Z ⁴ or R ⁴ and Z ⁵ may have a substituted or unsubstituted C2-C4 crosslink formed;
R ^5a and R ^5b are independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted, respectively. Alternatively, an unsubstituted carbamoyl, a substituted or unsubstituted ureido, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, Substituent or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or It is an unsubstituted non-aromatic heterocyclic oxy;
^{R 5a} and R ^5b on the same carbon atom may be combined to form an oxo, thioxo or substituted or unsubstituted spiro ring;
R ^5c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or Unsubstituted non-aromatic carbocyclic carbonyls, substituted or unsubstituted aromatic heterocyclic carbonyls, substituted or unsubstituted non-aromatic heterocyclic carbonyls, substituted or unsubstituted aromatic carbocyclic oxycarbonyls, substituted or unsubstituted A non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
Substituents on R ³ and R ⁴ , or R ³ and Z ¹ may be combined with adjacent atoms to form a substituted or unsubstituted heterocycle).
A pharmaceutical composition comprising the compound according to [1'] or a pharmaceutically acceptable salt thereof, wherein the ring [3'] A is any of the following rings.

(During the ceremony,
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
The dashed line represents the presence or absence of a bond;
Ring B is a substituted or unsubstituted carbon ring or a substituted or unsubstituted heterocycle;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are independently CR ^5a R ^5b , CR ^5a , C, O, N, NR ^5c , S, S (= O), S (= O). ₂ or S (= O) = NR ^{5d (where CR 5a} , C or N if it is a constituent atom of the B ring);
Z ¹ and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ , Z ³ and Z ⁵ , R ⁴ and Z ² , R ⁴ and Z ³ , R ⁴ And Z ⁴ or R ⁴ and Z ⁵ may have a substituted or unsubstituted C2-C4 crosslink formed;
R ^5a and R ^5b are independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted, respectively. Alternatively, an unsubstituted carbamoyl, a substituted or unsubstituted ureido, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, Substituent or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or It is an unsubstituted non-aromatic heterocyclic oxy;
^{R 5a} and R ^5b on the same carbon atom may be combined to form an oxo, thioxo or substituted or unsubstituted spiro ring;
R ^5c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or Unsubstituted non-aromatic carbocyclic carbonyls, substituted or unsubstituted aromatic heterocyclic carbonyls, substituted or unsubstituted non-aromatic heterocyclic carbonyls, substituted or unsubstituted aromatic carbocyclic oxycarbonyls, substituted or unsubstituted A non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
R ^5d is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or Unsubstituted non-aromatic carbocyclic carbonyls, substituted or unsubstituted aromatic heterocyclic carbonyls, substituted or unsubstituted non-aromatic heterocyclic carbonyls, substituted or unsubstituted aromatic carbocyclic oxycarbonyls, substituted or unsubstituted A non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
Substituents on R ³ and R ⁴ , or R ³ and Z ¹ may be combined with adjacent atoms to form a substituted or unsubstituted heterocycle).
[4'] A pharmaceutical composition containing the compound according to any one of [1'] to [3'] represented by the following formula or a pharmaceutically acceptable salt thereof.
Equation (I-2):

(During the ceremony,
R ^2a and R ^2b are independently hydrogen, alkyl, or haloalkyl;
R ^2a and R ^2b may be combined with adjacent carbon atoms to form a carbon ring or heterocycle;
R ³ is a substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
X is CR ^9a R ^9b , NR ¹⁰ , O, S, S (= O), S (= O) ₂ , or S (= O) = NR ¹¹ ;
R ^6a , R ^6b , R ^7a , R ^7b , R ^8a , R ^8b , R ^9a , and R ^9b are independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl, respectively. Oxy, or substituted or unsubstituted amino;
R ^6b and R ^9b , R ^9b and R ^7b , or R ^7b and R ^8b may be combined with adjacent atoms to form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle. ;
R ⁴ and ^{R 7b} or ^{R 6b} and ^{R 8b,} it may form a C2-C4 bridge substituted or unsubstituted together;
R ^6b and R ¹⁰ or R ¹⁰ and R ^7b may be combined with adjacent atoms to form a substituted or unsubstituted heterocycle;
R ³ and R ⁴ , or R ³ and R ^6b may be combined with adjacent atoms to form a substituted or unsubstituted heterocycle;
R ¹⁰ is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted alkyloxycarbonyl, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted aromatic carbon. Ring carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic alkylcarbonyl , Substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl It is carbonyl;
R ¹¹ is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkylcarbonyl, a substituted or unsubstituted alkyloxycarbonyl, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted aromatic carbocyclic carbonyl, a substituted or unsubstituted. Non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic A group carbocyclic oxycarbonyl, a substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
Q, ^{R 1} and n are as defined as [1 '])
[5 '] R ³ is alkyl or haloalkyl, [1'] A compound according to any one of - [4 '] or containing a pharmaceutically acceptable salt, pharmaceutical compositions.
[6 '] R ⁴ is hydrogen, [1'] A compound according to any one of - [5 '] or containing a pharmaceutically acceptable salt, pharmaceutical compositions.
The compound according to any one of [1'] to [6'], wherein [7'] n is an integer of 2 or 3, and R ^{1 is an independent halogen, alkyl, or haloalkyl, respectively, or a pharmaceutical product thereof.} A pharmaceutical composition containing an acceptable salt.
[8'] ^{Whether R 2a} is hydrogen and R ^2b is hydrogen or alkyl,
Alternatively, the compound according to any one of [4'] to [7'] or a pharmaceutically acceptable salt thereof, wherein R ^2a and R ^{2b form a C3-C4 carbon ring together with adjacent carbon atoms.} Contains, pharmaceutical composition.
[9'] Q is a 5- or 6-membered aromatic heterocycle optionally substituted with halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkylamino, [1'] to [8']. A pharmaceutical composition containing the compound according to any one of the above or a pharmaceutically acceptable salt thereof.
[10 '] stereoisomers of the carbon atom adjacent to R ⁴ is not more than, [1'] - containing a compound or a pharmaceutically acceptable salt thereof according to any one of [9 '], a pharmaceutical composition.

(In the equation, ring A and R ⁴ have the same meaning as [1'])
[11'] Contains the compound according to [1] or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds I-2, I-4, I-5, I-6 and I-8. Pharmaceutical composition.
[12'] The pharmaceutical composition according to any one of [1'] to [11'], which is an anti-HIV agent.
[13'] The pharmaceutical composition according to any one of [1'] to [11'], which is an HIV integrase inhibitor.

The present invention further provides a method for preventing or treating HIV, which comprises administering an effective amount of the above-mentioned pharmaceutical composition to a person.
The present invention further provides the above-mentioned pharmaceutical composition for use as an anti-HIV drug.

The compound according to the present invention has integrase inhibitory activity and / or cell proliferation inhibitory activity against viruses, particularly HIV and resistant viruses thereof. Therefore, it is useful for the prevention or treatment of various diseases associated with integrase and viral infections (for example, AIDS). More preferably, the compound according to the present invention is useful as a long-acting integrase inhibitor. Furthermore, it is also excellent in terms of resistance profile, such as being less likely to generate a new HIV-resistant virus. More preferably, the compound according to the present invention also has a prophylactic or therapeutic effect on HIV drug resistant virus. Even more preferably, the compound according to the present invention has a small clearance, a long half-life in the body, excellent solubility, metabolic stability, bioavailability, etc., and also has cytotoxicity and side effects (for example, mutagenicity). , ECG QT interval prolongation, arrhythmia) is also useful as a drug with little concern.

The meaning of each term used in the present specification will be described below. Unless otherwise specified, each term is used interchangeably when used alone or in combination with other terms.
The term "consisting of" means having only constituent requirements.
The term "contains" means that it is not limited to the constituent requirements and does not exclude elements that are not described.

"Halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In particular, fluorine atoms and chlorine atoms are preferable.

The "alkyl" includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and further preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl. , Isooctyl, n-nonyl, n-decyl and the like.
Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl and tert-butyl.

The "alkenyl" has 1 or more double bonds at arbitrary positions and has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms. Includes linear or branched hydrocarbon groups of. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenylate, butazienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetra. And so on.
Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, butenyl.

The "alkylene" is a linear or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and further preferably 1 to 4 carbon atoms. Includes groups. For example, methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like can be mentioned.
Furthermore, "alkylene" also includes groups that are crosslinked as follows.

The "aromatic carbocyclic group" means a cyclic aromatic hydrocarbon group having a single ring or two or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

単環の非芳香族炭素環式基としては、炭素数３〜１６が好ましく、より好ましくは炭素数３〜１２、さらに好ましくは炭素数４〜８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
２環以上の非芳香族炭素環式基としては、炭素数８〜２０が好ましく、より好ましくは炭素数８〜１６である。例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The "non-aromatic carbocyclic group" means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having a single ring or two or more rings. The "non-aromatic carbocyclic group" having two or more rings also includes a monocyclic or two or more non-aromatic carbocyclic groups in which the rings in the "aromatic carbocyclic group" are condensed.
Furthermore, the "non-aromatic carbocyclic group" also includes a group that is crosslinked as follows, or a group that forms a spiro ring.

The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and further preferably 4 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like can be mentioned.
The non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, and more preferably 8 to 16 carbon atoms. For example, indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.

The "aromatic heterocyclic group" means a monocyclic or two or more aromatic cyclic groups having one or more identical or different heteroatoms arbitrarily selected from O, S and N in the ring. To do.
The aromatic heterocyclic group having two or more rings also includes a monocyclic or two or more aromatic heterocyclic groups in which the rings in the above-mentioned "aromatic carbocyclic group" are condensed, and the binding agent It may be contained in any ring.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, frill, thienyl, isooxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridadinyl, pyrimidinyl, pyrazineyl, triazinyl and the like.
The two-ring aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members. For example, indolyl, isoindrill, indazolyl, indridinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyldinyl, quinoxalinyl, prynyl, pteridinyl, benzimidazolyl, benzisooxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl. Lil, benzothiazolyl, benzothiasiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazolipyryl, triazolopyridyl, imidazolithazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. Can be mentioned.
The aromatic heterocyclic group having 3 or more rings is preferably 13 to 15 members. For example, carbazolyl, acridinyl, xanthenyl, phenothiazine, phenoxatinyl, phenoxadinyl, dibenzofuryl and the like can be mentioned.

単環の非芳香族複素環式基としては、３〜８員が好ましく、より好ましくは５員または６員である。
３員非芳香族複素環式基としては、例えば、チイラニル、オキシラニル、アジリジニルが挙げられる。４員非芳香族複素環式基としては、例えば、オキセタニル、アゼチジニルが挙げられる。５員非芳香族複素環式基としては、例えば、オキサチオラニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、テトラヒドロフリル、ジヒドロチアゾリル、テトラヒドロイソチアゾリル、ジオキソラニル、ジオキソリル、チオラニル等が挙げられる。６員非芳香族複素環式基としては、例えば、ジオキサニル、チアニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロピラニル、ジヒドロオキサジニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキサジニル、チイニル、チアジニル等が挙げられる。７員非芳香族複素環式基としては、例えば、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、オキセパニルが挙げられる。
２環以上の非芳香族複素環式基としては、８〜２０員が好ましく、より好ましくは８〜１０員である。例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。 A "non-aromatic heterocyclic group" is a monocyclic or two or more non-aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S and N in the ring. Means. The non-aromatic heterocyclic group having two or more rings is a monocyclic or non-aromatic heterocyclic group having two or more rings, and the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", and / Or each ring in the "aromatic heterocyclic group" is condensed, and further, the ring in the above "aromatic heterocyclic group" is condensed with a monocyclic or two or more non-aromatic carbocyclic groups. The binding hand may be held in any ring.
Furthermore, the "non-aromatic heterocyclic group" also includes a group that is crosslinked as follows, or a group that forms a spiro ring.

The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
Examples of the three-membered non-aromatic heterocyclic group include thiylanyl, oxylanyl and aziridinyl. Examples of the 4-membered non-aromatic heterocyclic group include oxetanyl and azetidinyl. Examples of the 5-membered non-aromatic heterocyclic group include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolydinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxoril, thiolanyl and the like. Can be mentioned. Examples of the 6-membered non-aromatic heterocyclic group include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxadinyl, tetrahydropyridadini. Examples thereof include le, hexahydropyrimidinyl, dioxadinyl, tiinyl, thiazinyl and the like. Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazepinyl, tetrahydrodiazepinyl and oxepanyl.
The non-aromatic heterocyclic group having two or more rings is preferably 8 to 20 members, more preferably 8 to 10 members. For example, indolinyl, isoindolinyl, chromanyl, isochromanyl and the like can be mentioned.

The "aromatic carbocycle", "non-aromatic carbocycle", "aromatic heterocycle" and "non-aromatic heterocycle" are the above-mentioned "aromatic carbocyclic group" and "non-aromatic carbocyclic ring", respectively. It means a ring derived from "group", "aromatic heterocyclic group" and "non-aromatic heterocyclic group".

The "carbon ring" means the above-mentioned "aromatic carbocycle" or "non-aromatic carbocycle".

The "heterocycle" means the above-mentioned "aromatic heterocycle" or "non-aromatic heterocycle".

The "spiro ring" means the above-mentioned "non-aromatic carbocycle" or "non-aromatic heterocycle".

In the present specification, "may be substituted with a substituent group α" means "may be substituted with one or more groups selected from the substituent group α". The same applies to "may be substituted with the substituent group β", "may be substituted with the substituent group γ", and "may be substituted with the substituent group γ'".

The substituents of "substituted alkyl", "substituted alkyloxy", "substituted alkylcarbonyl", "substituted alkyloxycarbonyl", "substituted C1-C4 crosslinks", "substituted C2-C4 crosslinks" and "substituted alkylene" are The following substituent group A can be mentioned. The carbon atom at an arbitrary position may be bonded to one or more groups selected from the following substituent group A.
Substituent group A: Halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, substitution Alkyloxy which may be substituted with the group α, alkenyloxy which may be substituted with the substituent group α, alkylcarbonyloxy which may be substituted with the substituent group α, and substituted with the substituent group α. May be alkenylcarbonyloxy, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, Alkenyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, substituted with substituent group α Alkyl sulfinyl may be substituted, alkenyl sulfinyl optionally substituted with substituent group α, alkyl sulfonyl optionally substituted with substituent group α, alkenyl sulfonyl optionally substituted with substituent group α, substituted Amino which may be substituted with a group β, imino which may be substituted with a substituent group β, carbamoyl which may be substituted with a substituent group β, sulfamoyl which may be substituted with a substituent group β. , Ureid which may be substituted with substituent group β, aromatic carbocyclic group which may be substituted with substituent group γ, non-aromatic carbocyclic type which may be substituted with substituent group γ'. Group, aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', even substituted with substituent group γ Good aromatic carbocyclic oxy, non-aromatic carbocyclic oxy which may be substituted with substituent group γ', aromatic heterocyclic oxy which may be substituted with substituent group γ, substitution with substituent group γ' Non-aromatic heterocyclic oxy which may be substituted, aromatic carbocyclic carbonyloxy which may be substituted with the substituent group γ, non-aromatic carbocyclic carbonyloxy which may be substituted with the substituent group γ', Aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ Group carbocyclic carbonyl, may be substituted with substituent group γ' Non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', substituted with substituent group γ Aromatic carbocyclic oxycarbonyl may be substituted, non-aromatic carbocyclic oxycarbonyl may be substituted with substituent group γ', aromatic heterocyclic oxycarbonyl may be substituted with substituent group γ, It may be substituted with a non-aromatic heterocyclic oxycarbonyl that may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxy that may be substituted with a substituent group γ, or a substituent group γ'. Non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', substituent group γ Aromatic carbocyclic alkyloxycarbonyl optionally substituted with, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic which may be substituted with substituent group γ. Ring alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituted with substituent group γ' Non-aromatic carbocyclic sulfanyl which may be substituted, aromatic heterocyclic sulfanyl which may be substituted by substituent group γ, non-aromatic heterocyclic sulfanyl which may be substituted by substituent group γ', substituent. Aromatic carbocyclic sulfinyl which may be substituted by group γ, non-aromatic carbocyclic sulfinyl which may be substituted by substituent group γ', aromatic heterocyclic sulfinyl which may be substituted by substituent group γ. , Non-aromatic heterocyclic sulfinyl which may be substituted with substituent group γ', aromatic carbocyclic sulfonyl which may be substituted with substituent group γ, non-aromatic heterocyclic ring which may be substituted with substituent group γ'. Aromatic carbocyclic sulfonyls, aromatic heterocyclic sulfonyls optionally substituted with substituents γ, and non-aromatic heterocyclic sulfonyls optionally substituted with substituents γ'.

Substituents α: Halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, sulfanyl, cyano, nitro, and guanidino.

Substituent group β: Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, substituent group α Alkenylcarbonyl that may be substituted, alkylsulfanyl that may be substituted with the substituent group α, alkenylsulfanyl that may be substituted with the substituent group α, alkylsulfinyl that may be substituted with the substituent group α. , Alkenyl sulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, substituted with substituent group γ Aromatic carbocyclic groups which may be present, non-aromatic carbocyclic groups which may be substituted with the substituent group γ', aromatic heterocyclic groups which may be substituted with the substituent group γ, substitutions. A non-aromatic heterocyclic group which may be substituted with a group γ', an aromatic carbocyclic alkyl which may be substituted with a substituent group γ, and a non-aromatic group which may be substituted with a substituent group γ'. Group carbocyclic alkyl, aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituted with substituent group γ May be aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, substituent group γ' Non-aromatic heterocyclic carbonyl that may be substituted, aromatic carbocyclic oxycarbonyl that may be substituted with the substituent group γ, non-aromatic carbocyclic oxycarbonyl that may be substituted with the substituent group γ'. , Aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' Group carbocyclic sulfanyl, aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', substituted with substituent group γ May be aromatic carbocyclic sulfinyl, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, substituent group γ' Non-aromatic heterocyclic sulfinyl which may be substituted, aromatic carbocyclic sulfonyl which may be substituted by the substituent group γ, non-aromatic carbocyclic sulfonyl which may be substituted by the substituent group γ', substitution. Substituted by group γ Aromatic heterocyclic sulfonyls that may be present, and non-aromatic heterocyclic sulfonyls that may be substituted with the substituent group γ'.

Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkylcarbonyl, haloalkylcarbonyl, and alkenylcarbonyl.

Substituent group γ': Substituent group γ and oxo.

"Substituted Carbocycle", "Substituted Heterocycle", "Substituted Aromatic Heterocyclic Group", "Substituted Aromatic Heterocyclic Group", "Substituted Aromatic Heterocyclic Oxygen", "Substituted Aromatic Heterocyclic Oxygen", "Aromatic Carbocycle" and "Aromatic Heterocycle" of "Substituted Aromatic Carbocyclic carbonyl", "Substituted Aromatic Heterocyclic carbonyl", "Substituted Aromatic Carbocycle Oxycarbonyl" and "Substituted Aromatic Heterocyclic Oxycarbonyl" Examples of the substituent on the ring of "" include the following substituent group B. An atom at an arbitrary position on the ring may be bonded to one or more groups selected from the following substituent group B.
Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, and guanidino, Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, even substituted with substituent group α Good alkenyloxy, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, substituents Alkenylcarbonyl optionally substituted with group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, substituted with substituent group α Alkyl sulfanyl may be substituted, alkenyl sulfanyl optionally substituted with substituent group α, alkyl sulfinyl optionally substituted with substituent group α, alkenyl sulfinyl optionally substituted with substituent group α, substituents. Alkylsulfonyl optionally substituted with group α, alkenylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, optionally substituted with substituent group β Imino, carbamoyl which may be substituted with the substituent group β, sulfamoyl which may be substituted with the substituent group β, ureido which may be substituted with the substituent group β, and substituted with the substituent group γ. May be aromatic carbocyclic group, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, substituent group Non-aromatic heterocyclic group optionally substituted with γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbon optionally substituted with substituent group γ' Ring oxy, aromatic heterocyclic oxy which may be substituted with substituent group γ, non-aromatic heterocyclic oxy which may be substituted with substituent group γ', may be substituted with substituent group γ. Aromatic carbocyclic carbonyloxy, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ, substituent group γ' Non-aromatic heterocyclic carbonyl oxy which may be substituted with B, an aromatic carbocyclic carbonyl that may be substituted with the substituent group γ, a non-aromatic carbocyclic carbonyl that may be substituted with the substituent group γ', and an aromatic that may be substituted with the substituent group γ. Group heterocyclic carbonyl, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, substituted with substituent group γ' Non-aromatic carbocyclic oxycarbonyl which may be present, aromatic heterocyclic oxycarbonyl which may be substituted with the substituent group γ, non-aromatic heterocyclic oxycarbonyl which may be substituted with the substituent group γ', An aromatic carbocyclic alkyl that may be substituted with the substituent group γ, a non-aromatic carbocyclic alkyl that may be substituted with the substituent group γ', and an aromatic complex that may be substituted with the substituent group γ. Ring alkyl, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, substituted with substituent group γ' May be a non-aromatic carbocyclic alkyloxy, an aromatic heterocyclic alkyloxy optionally substituted with a substituent group γ, a non-aromatic heterocyclic alkyloxy optionally substituted with a substituent group γ', a substituent. Aromatic carbocyclic alkyloxycarbonyl optionally substituted with group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ Group heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, substituent group Non-aromatic carbocyclic alkyloxyalkyl which may be substituted with γ', aromatic heterocyclic alkyloxyalkyl which may be substituted by substituent group γ, non-aromatic which may be substituted by substituent group γ'. Aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', substituted with substituent group γ Aromorphic heterocyclic sulfanyl which may be substituted, a non-aromatic heterocyclic sulfanyl which may be substituted with the substituent group γ', an aromatic carbocyclic sulfinyl which may be substituted with the substituent group γ, a substituent group. Non-aromatic carbocyclic sulfinyl optionally substituted with γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic ring optionally substituted with substituent group γ' Su Rufynyl, an aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ', and an aromatic which may be substituted with a substituent group γ. Group heterocyclic sulfonyls, and non-aromatic heterocyclic sulfonyls that may be substituted with the substituent group γ'.

"Substituted Carbocycle", "Substituted Heterocycle", "Substituted Non-Aromatic Heterocyclic Group", "Substituted Non-Aromatic Heterocyclic Group", "Substituted Non-Aromatic Heterocyclic Oxygen", "Substituted Non-Aromatic Heterocycle""Non-aromatic" of "Ring Oxy", "Substituted Non-Aromatic Heterocyclic carbonyl", "Substituted Non-Aromatic Heterocyclic carbonyl", "Substituted Non-Aromatic Heterocyclic Oxycarbonyl" and "Substituted Non-Aromatic Heterocyclic Oxycarbonyl" Examples of the substituents on the rings of the "carbon ring" and the "non-aromatic heterocycle" include the following substituent group C. An atom at an arbitrary position on the ring may be bonded to one or more groups selected from the following substituent group C.
Substituent group C: Substituent group B and oxo.

Examples of the substituent of "substituted amino", "substituted carbamoyl", and "substituted ureido" include the following substituent group D. It may be substituted with 1 or 2 groups selected from the substituent group D.
Substituent group D: Alkyl which may be substituted by the substituent group α, alkenyl which may be substituted by the substituent group α, alkylcarbonyl which may be substituted by the substituent group α, and the substituent group α. Alkenylcarbonyl optionally substituted, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α , Alkenyl sulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α,
Aromatic carbocyclic groups optionally substituted with substituent group γ, non-aromatic carbocyclic groups optionally substituted with substituent group γ', aromatics optionally substituted with substituent group γ Group heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, substituted with substituent group γ' Non-aromatic carbocyclic alkyl which may be substituted, aromatic heterocyclic alkyl which may be substituted by substituent group γ, non-aromatic heterocyclic alkyl which may be substituted by substituent group γ', substituent. Aromatic carbocyclic carbonyls that may be substituted with group γ, non-aromatic carbocyclic carbonyls that may be substituted with substituents γ', aromatic heterocyclic carbonyls that may be substituted with substituents γ. , Non-aromatic heterocyclic carbonyl that may be substituted with substituent group γ', aromatic carbocyclic oxycarbonyl that may be substituted with substituent group γ, may be substituted with substituent group γ'. Non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', substituent group γ Aromatic carbocyclic sulfanyl optionally substituted with, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, substituted Non-aromatic heterocyclic sulfanyl optionally substituted with group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' Carbocyclic sulfinyl, aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', even substituted with substituent group γ Good aromatic carbocyclic sulfonyls, non-aromatic carbocyclic sulfonyls optionally substituted with substituents γ', aromatic heterocyclic sulfonyls optionally substituted with substituents γ, and substituents γ'. A non-aromatic heterocyclic sulfonyl that may be substituted.

Preferred embodiments of the symbols in the compounds represented by the formulas (I), (I') or (II) are shown below. As the compound represented by the formula (I), (I') or (II), all combinations of the specific examples shown below are exemplified.
Examples of the A ring include a substituted or unsubstituted non-aromatic heterocycle.
The A ring is preferably a 5 to 7-membered ring containing 1 to 3, preferably 1 to 2 O, S and / or N atoms, and more preferably from the non-aromatic heterocycle. Be selected. One of the preferred embodiments of the A ring is the ring (a), (b) or (c) below, and more preferably the ring (a) or (b).

Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c or S, where Z ¹ , Z ² , Z ³ , In Z ⁴ and Z ⁵ , the number of heteroatoms constituting the ring structure of the A ring is 0 or 1.
^One of the preferred embodiments of Z ^{1 is CR 5a} R ^5b , O, S or NR ^5c , with CR ^5a R ^5b being more preferred.
One of the preferred embodiments of Z ^{2 is CR 5a} R ^5b , O, S or NR ^5c , with CR ^5a R ^5b , O or NR ^5c being more preferred, with CR ^5a R ^5b or O particularly preferred.
One of the preferred embodiments of Z ^{3 is CR 5a} R ^5b , O, S or NR ^5c , with CR ^5a R ^5b or O being more preferred, and CR ^5a R ^5b being particularly preferred.
One of the preferred embodiments of Z ^{4 is CR 5a} R ^5b , O, S or NR ^5c , with CR ^5a R ^5b being more preferred.
One of the preferred embodiments of Z ^{5 is CR 5a} R ^5b , O, S or NR ^5c , with CR ^5a R ^5b being more preferred.
Or Z ¹ and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ , Z ³ and Z ⁵ , R ⁴ and Z ² , R ⁴ and Z ³ , Substituted or unsubstituted C1-C4 crosslinks may be formed between R ⁴ and Z ⁴ or R ⁴ and Z ^5. Preferably, there is a substituted or unsubstituted (C1) between ^{Z 1} and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ or Z ³ and Z ^5. -C4) A crosslink may be formed.

Ａ環は、より好ましくは、（ａ１）、（ｂ１）、（ｃ１）または（ｅ１）の環であり、特に好ましくは（ａ１）または（ｂ１）の環である。
Ｂ環は、好ましくは、置換もしくは非置換の３〜７員の炭素環（置換基の例：アルキル、ハロゲン、ヒドロキシ、ハロアルキル）または置換もしくは非置換の４〜７員の複素環（置換基の例：アルキル、ハロゲン、ヒドロキシ、ハロアルキル）であり、より好ましくは、ベンゼン環、５〜６員の非置換炭素環または５〜６員の非置換複素環である。 The A ring may further have a B ring as follows. In this case, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ constituting the B ring are independently CR ^5a , C or N, respectively.

The A ring is more preferably the ring of (a1), (b1), (c1) or (e1), and particularly preferably the ring of (a1) or (b1).
The B ring is preferably a substituted or unsubstituted 3- to 7-membered carbocyclic ring (examples of substituents: alkyl, halogen, hydroxy, haloalkyl) or a substituted or unsubstituted 4- to 7-membered heterocycle (substituent of substituents). Examples: alkyl, halogen, hydroxy, haloalkyl), more preferably a benzene ring, a 5- to 6-membered unsubstituted carbon ring or a 5- to 6-membered unsubstituted heterocycle.

が挙げられる。
Ａ環の更に好ましい態様の１つは、以下の環である。

Ａ環のより好ましい態様は、上記（ａ２）または（ｂ３）の環である。 One of the other preferred embodiments of the A ring is the following ring:

Can be mentioned.
One of the more preferred embodiments of the A ring is the following ring.

A more preferred embodiment of the A ring is the ring of (a2) or (b3) above.

^{Examples of} X1 include CR A9a R ^A9b , O or NR ^A9c .
One of the preferred embodiments of X1 is CR ^A9a R ^A9b or O.

^{Examples of} X2 include CR A13a R ^A13b , O or NR ^A13c .
One of the preferred embodiments of X2 is CR ^A13a R ^A13b or O.
^{Examples of} X3 include CR ^A14a R A9b, O or NR ^A14c .
One of the preferred embodiments of X3 is CR ^{A14a RA14b} or O.
However, when either one of X2 or X3 is NR ^A13c , NR ^A14c or O, the other of X2 or X3 is CR ^A13a R ^A13b or CR ^A14a R ^A14b .

^{R A5a, R A5b, R A6a} , R A6b, as ^{R A7a} and ^{R A7b} are each independently hydrogen, alkyl, and alkyloxy or alkyloxyalkyl.
^{One of the preferred embodiments of RA5a} is hydrogen or alkyl, preferably hydrogen.
^{One of the preferred embodiments of RA5b} is hydrogen or alkyl, preferably hydrogen.
^{One of the preferred embodiments of RA6a} is hydrogen, alkyl or alkyloxyalkyl, preferably hydrogen.
One of the preferred embodiments of ^{RA6b is hydrogen.
One} of the preferred embodiments of RA7a is hydrogen, alkyl or alkyloxyalkyl, preferably alkyloxyalkyl.
^One of the preferred embodiments of RA7b is hydrogen.
R ^A5a and ^{R A6a} or ^{R A6a} and ^{R A7a,} together with the adjacent atoms, an aromatic carbon ring which may be substituted by halogen, non-3-6 membered optionally substituted by halogen It may form a 4-6 member non-aromatic heterocycle which may be substituted with an aromatic carbocycle or halogen (provided that an aromatic carbocycle is formed, ^RA5b and ^RA6b , or R. ^A6b and ^RA7b together form a bond).
^RA5b and ^RA6b may be combined to form a bond.
^RA6a and ^RA6b may be combined with adjacent atoms to form a 3-6 member non-aromatic carbocycle or a 4-6 member non-aromatic heterocycle.

^{R A8a, R A8b, R A9a} , R A9b, R A10a, R A10b, as ^{R A 11a} and ^{R A11b} are each independently hydrogen, alkyl, haloalkyl, alkyl alkyloxy or alkyloxyalkyl.
^One of the preferred embodiments of RA8a is hydrogen or alkyl, preferably hydrogen.
^One of the preferred embodiments of RA8b is hydrogen or alkyl, preferably hydrogen.
^One of the preferred embodiments of RA9a is hydrogen, alkyl or alkyloxyalkyl.
^One of the preferred embodiments of RA9b is hydrogen or alkyl, preferably hydrogen.
^{One of the preferred embodiments of RA10a} is hydrogen, alkyl or alkyloxy, preferably hydrogen.
^One of the preferred embodiments of RA10b is hydrogen.
^One of the preferred embodiments of RA11a is hydrogen or alkyl, preferably hydrogen.
^One of the preferred embodiments of RA11b is a hydrogen atom.
R ^{A 8a} and ^{R A 10a} or ^{R A 8a} and ^{R A 11a} may form a C1-C3 bridge together.
R ^{A 10a} and ^{R A 11a,} together with the adjacent atoms may form a non-aromatic carbocyclic ring of 5 members.
^RA9a and ^RA9b may be combined with adjacent atoms to form a 4-membered non-aromatic carbocycle or a 5-membered non-aromatic heterocycle.
^RA8a and ^RA9a may be combined to form a bond.
^RA9c is a hydrogen, alkyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbamoyl, aromatic carbocyclic group, aromatic heterocyclic group, aromatic carbocyclic alkyl, or aromatic heterocyclic alkyl.

The R ^A12a , R ^A12b , R ^A13a , R ^A13b , R ^A14a , R ^A14b , R ^A15a , R ^A15b , R ^A16a and R ^A16b are independently hydrogen, alkyl, alkyloxy or alkyloxyalkyl, respectively.
^RA13c or ^RA14c are independently alkyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbamoyl, aromatic carbocyclic groups, aromatic heterocyclic groups, aromatic carbocyclic alkyl, or aromatic heterocycles, respectively. It is alkyl.

より好ましくは、ハロゲン、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、またはアルキルアミノで置換されていてもよい以下の環である（左側の結合手はＬと結合する）；

Ｑの別の好ましい態様の１つは、以下の環である（左側の結合手はＬと結合する）；

Ｑのさらに好ましい態様の１つは、上記（１）で示される環である。 Q includes, or a 5-membered aromatic heterocycle.
One preferred embodiment of Q is a 5- to 6-membered heterocycle that may be substituted with halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkylamino.
Q is preferably the following ring, which may be substituted with halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkylamino (however, the bond on the left side binds to L);

More preferably, it is the following ring, which may be substituted with halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkylamino (the left bond binds to L);

One of the other preferred embodiments of Q is the ring below (the left bond binds to L);

One of the more preferable aspects of Q is the ring shown in (1) above.

Examples of R ¹ include halogen, alkyl, haloalkyl, alkyloxy, cyano and haloalkyloxy, respectively.
^One of the preferred embodiments of R 1 is halogen, alkyl or haloalkyl.
R ¹ is preferably a halogen.

L is a substituted or unsubstituted alkylene (example of a substituent: halogen), more preferably methylene.

Examples of R ³ include substituted or unsubstituted alkyl (examples of substituents: halogen, alkyloxy, haloalkyloxy, non-aromatic cyclic group, non-aromatic heterocyclic group), substituted or unsubstituted non-aromatic carbon. It is a cyclic group (example of substituent: halogen) or a substituted or unsubstituted non-aromatic heterocyclic group (example of substituent: halogen).
One preferred embodiment of R ³ is alkyl or haloalkyl.
R ³ is preferably alkyl.

The R ^4, include hydrogen or alkyl.
One preferred embodiment of R ⁴ is hydrogen or methyl, as a further preferred embodiment is a hydrogen.

R ^5a and R ^5b are independently hydrogen, halogen, substituted or unsubstituted alkyl (substituent example: halogen, alkyloxy) or substituted or unsubstituted alkyloxy (substituent example: halogen). ^{, And R 5a} and R ^5b on the same carbon atom together are substituted or unsubstituted non-aromatic carbocycles (examples of substituents: halogen) or substituted or unsubstituted non-aromatic heterocycles (substitution). Examples of groups: halogen) may be formed.
One of the preferred embodiments of R ^5a and R ^5b is each independently hydrogen, alkyl, or alkyloxyalkyl.

R ^5c includes hydrogen, substituted or unsubstituted alkyl (examples of substituents: alkyloxy, aromatic carbocyclic group, aromatic heterocyclic group), substituted or unsubstituted alkylcarbonyl, respectively. Substituent or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl (example of substituent: alkyl), substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted Alternatively, an unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group can be mentioned.
One of the preferred embodiments of R ^5c is hydrogen, or substituted or unsubstituted alkyl (example of substituent: alkyloxy), respectively.

Examples of n include integers 1 to 3.
One of the preferred embodiments of n is an integer of 2-3.
One of the more preferred embodiments of n is an integer of 1-2.

（式中、各記号は、上記と同意義） It is preferable that the three-dimensional shape of the carbon atom adjacent to ^{R 4 is as follows.}

(In the formula, each symbol has the same meaning as above)

Examples of the C ring include a benzene ring and a pyridine ring.
One of the preferred embodiments of the C ring is a benzene ring.

The compound represented by the formula (I') is preferably a compound represented by the following formula (I-2).

Preferred embodiments of each symbol in the compound represented by the formula (I-2) are shown below. Examples of the compound represented by the formula (I-2) include all combinations of the specific examples shown below.
The steric structure of the carbon atoms adjacent to R ¹ , R ³ , R ⁴ , Q, n and R ⁴ is the same as in the preferred embodiment of the compound represented by the above formula (I').

One of the preferred embodiments of R ^2a and R ^{2b is hydrogen.}
One ^{of the other preferred embodiments of R 2a} and R ^2b is a carbon ring along with adjacent carbon atoms.
R ^2a is preferably hydrogen.
R ^2b is preferably hydrogen or methyl.
R ^2a and R ^2b are preferably C3-C4 non-aromatic carbon rings, together with adjacent carbon atoms.

One of the preferred embodiments of X is CR ^9a R ^9b , NR ¹⁰ , or O, with CR ^9a R ^9b or NR ¹⁰ being more preferred, and CR ^9a R ^9b being particularly preferred.

One of the preferred embodiments of R ^6a , R ^6b , R ^7a , R ^7b , R ^8a , R ^8b , R ^9a , and R ^9b is each independently hydrogen, or substituted or unsubstituted alkyl.
R ^6a , R ^6b , R ^7a , R ^7b , R ^8a , R ^8b , R ^9a , and R ^9b are preferably hydrogen or substituted or unsubstituted alkyl (example of substituent: halogen) independently of each other. ), And hydrogen or methyl is particularly preferable.

One of the preferred embodiments of R ¹⁰ is a substituted or unsubstituted alkyl.

The characteristics of the compound according to the present invention are that the resistance profile, pharmacokinetics and safety are excellent by forming the A ring in the formula (I), (I'), (I-2) or (II). It is a point. Furthermore, by defining the solid shape of the A ring, it has an excellent resistance profile.

Unless otherwise specified, the compounds according to the present invention are not limited to specific isomers, and all possible isomers (for example, keto-enol isomer, imine-enamine isomer, diastereo isomer, etc.) Optical isomers, rotational isomers, etc.), racemates or mixtures thereof.

Examples of pharmaceutically acceptable salts of the compound according to the present invention include the compound according to the present invention, alkali metals (for example, lithium, sodium, potassium, etc.), alkaline earth metals (for example, calcium, barium, etc.), and the like. With magnesium, transition metals (eg zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumin, ethylenediamine, pyridine, picolin, quinoline, etc.) and amino acids Salts or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitrate, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citrate) Acids, lactic acids, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid Etc.) and salt. These salts can be formed by conventional methods.

The compounds according to the present invention or pharmaceutically acceptable salts thereof may form solvates (eg, hydrates, etc.), co-crystals and / or polymorphs of crystals, and the present invention has various such types. Also includes solvates, co-crystals and polymorphs. The "solvate" may be coordinated with any number of solvent molecules (eg, water molecules) with respect to the compound according to the present invention. When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water and adsorbed water may adhere to it or form a hydrate. In addition, a polymorph may be formed by recrystallizing the compound according to the present invention or a pharmaceutically acceptable salt thereof. "Co-crystal" means that the compound or salt according to the present invention and a counter molecule are present in the same crystal lattice, and may be formed with an arbitrary number of counter molecules.

The compounds according to the present invention or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention also includes various such prodrugs. A prodrug is a derivative of a compound of the present invention having a chemically or metabolically degradable group, which is a compound according to the present invention that is pharmaceutically active in vivo by solvolysis or under physiological conditions. .. The prodrug is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo and converted into a compound represented by the formula (I), (I'), (I-2) or (II). This includes compounds that are hydrolyzed by gastric acid or the like and converted into compounds represented by the formulas (I), (I'), (I-2) or (II). Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may have activity on their own.

When the compound represented by the formula (I), (I'), (I-2) or (II) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and a suitable acyl Such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting halides, suitable acid anhydrides, suitable sulfonyl chlorides, suitable sulfonylan hydrides and mixed hydrides, or by reacting with condensing agents. Prodrugs are exemplified. For example, CH ₃ COO-, C ₂ H ₅ COO-, tert-BuCOO-, C ₁₅ H ₃₁ COO-, PhCOO-, (m-NaOOCPh) COO-, NaOOCCH ₂ CH ₂ COO-, CH ₃ CH (NH _2). ) COO-, CH ₂ N (CH ₃ ) ₂ COO-, CH ₃ SO _3- , CH ₃ CH ₂ SO _3- , CF ₃ SO _3- , CH ₂ FSO _3- , CF ₃ CH ₂ SO _3- , p -CH ₃ O-PhSO _3- , PhSO _3- , p-CH ₃ PhSO _3- .

（式中、Ｐ^１はヒドロキシ保護基；Ｐ^２はアミノ保護基；ＺはＺ^２、Ｚ^３、Ｚ^４またはＺ^５；ｍは１〜４の整数；Ｈａｌはハロゲン；Ｐ^１およびＰ^２は、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ、 Ｔｈｅｏｄｏｒａ Ｗ Ｇｒｅｅｎ（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ）等に記載の方法で保護および／または脱保護できる基であればよく、例えばＰ^１は芳香族炭素環アルキル等であり、Ｐ^２はアルキルオキシカルボニル等である；その他の記号は前記と同意義）

工程１
市販または公知の方法により調製できる化合物ｃ１に、ＤＭＦ、ＤＭＡ、ＮＭＰ、ＴＨＦ、クロロホルム、ジクロロメタン等の溶媒の存在下、ＨＡＴＵ、ＷＳＣ・ＨＣｌ、ＰｙＢＯＰ等の縮合剤を加え、市販または公知の方法により調製できる化合物ｃ２および、トリエチルアミン、Ｎ−メチルモルホリン、ピリジン，ジイソプロピルエチルアミン等の３級アミンを加え、１０℃〜６０℃、好ましくは２０℃〜４０℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｃ３を得ることができる。
工程２
化合物ｃ３にＤＭＦ、ＤＭＡ、ＮＭＰ等の溶媒の存在下、市販または、公知の方法で調製できる化合物ｃ４および、酢酸，p-トルエンスルホン酸ピリジニウム，p-トルエンスルホン酸．メタンスルホン酸などの酸を加え，２０℃〜１２０℃、好ましくは６０℃〜１００℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｃ５を得ることができる。
工程３
化合物ｃ５を、アミノ保護基の公知の一般的な脱保護反応に付すことにより、化合物ｃ６を得ることができる。
工程４
化合物ｃ６に、ジクロロメタン、ジクロロエタン、クロロホルム、メタノール、エタノール、トルエン、ＤＭＦ、ＤＭＡ、ＴＨＦ等の溶媒の存在下、市販または、公知の方法で調製できる化合物ｃ７および、酢酸、p-トルエンスルホン酸、メタンスルホン酸等の酸を加え、２０℃〜１３０℃、好ましくは２０℃〜１００℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｃ８を得ることができる。
工程５
化合物ｃ８に、ＤＭＦ、ＤＭＡ、ＮＭＰ、ＴＨＦ等の溶媒の存在下、炭酸セシウムや炭酸カリウム等の塩基と、ヨウ化ナトリウムやヨウ化カリウム等の塩を加え、０℃〜６０℃、好ましくは０℃〜４０℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｃ９を得ることができる。
工程６
ジクロロメタン、ジクロロエタン、アセトニトリル、ＤＭＦ等の溶媒中において、化合物ｃ９に、臭素やＮＢＳ、ＮＣＳ、ＮＩＳなどのハロゲン化試薬を加え、Ｈａｌがブロモの場合、−３０℃〜５０℃、好ましくは−１０℃〜２０℃、０．１時間〜１０時間、好ましくは０．５時間〜２時間反応することによってＪを得ることができる。Halがクロロまたはヨードの場合、１０℃〜１５０℃、好ましくは６０℃〜１２０℃、０．５時間〜２４時間、好ましくは１時間〜６時間反応することによって、化合物ｃ１０を得ることができる。
工程７
化合物ｃ１０をジオキサン、ＤＭＦ、ＤＭＥ、ＴＨＦ、ＤＭＳＯ等の溶媒あるいは混合溶媒中において、Ｐｄ（ＰＰｈ_３）_４、Ｐｄ（ＯＡｃ）_２、Ｐｄ（ＰＰｈ_３）_２Ｃｌ_２、Ｐｄ（ｄｐｐｆ）_２Ｃｌ_２やＰｄ（ｄｔｂｐｆ）等のパラジウム触媒と、酢酸カリウム、酢酸ナトリウム、炭酸カリウムやリン酸カリウム等の塩基と、ｂｉｓ（ｐｉｎａｃｏｌａｔｏ）ｄｉｂｏｒｏｎを加え、窒素雰囲気下にて、０℃〜１５０℃、好ましくは６０℃〜１２０℃で、０．５時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｃ１１を得ることができる。
工程８
化合物ｃ１１をジオキサン、ＤＭＦ、ＤＭＥ、ＴＨＦ、水等の溶媒あるいは混合溶媒中において、Ｐｄ（ＰＰｈ_３）_４、Ｐｄ（ＯＡｃ）_２、Ｐｄ（ＰＰｈ_３）_２Ｃｌ_２、Ｐｄ（ｄｐｐｆ）_２Ｃｌ_２やＰｄ（ｄｔｂｐｆ）等のパラジウム触媒と、炭酸カリウム、炭酸ナトリウム、炭酸セシウムやリン酸カリウム等の塩基と、市販または公知の方法により調整した化合物ｃ１２加え、窒素雰囲気下にて、０℃〜１５０℃、好ましくは６０℃〜１２０℃で、０．５時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｃ１３を得ることができる。
工程９
化合物ｃ１３を、ヒドロキシ保護基の公知の一般的な脱保護反応に付すことにより、化合物Ｉｃを得ることができる。 (Method for producing a compound according to the present invention)
The compound according to the present invention can be produced, for example, by the general synthetic method shown below. Extraction, purification, and the like may be carried out in ordinary organic chemistry experiments.
The compound according to the present invention can be synthesized with reference to a method known in the art.
(Manufacturing method 1)

(In the formula, P ¹ is a hydroxy protecting group; P ² is an amino protecting group; Z is Z ² , Z ³ , Z ⁴ or Z ⁵ ; m is an integer of 1 to 4; H is halogen; P ¹ and P ² are , Protective Groups in Organic Synthesis, Theodora W Green (John Willey & Sons), etc., as long as it is a group that can be protected and / or deprotected by the method described in, for example, P ¹ is an aromatic carbocyclic alkyl or the like, and P ² Is alkyloxycarbonyl, etc;; other symbols have the same meaning as above)

Process 1
To compound c1 which can be prepared by a commercially available or known method, a condensing agent such as HATU, WSC / HCl, PyBOP is added in the presence of a solvent such as DMF, DMA, NMP, THF, chloroform, and dichloromethane, and by a commercially available or known method. The compound c2 that can be prepared and a tertiary amine such as triethylamine, N-methylmorpholine, pyridine, or diisopropylethylamine are added, and the temperature is 10 ° C to 60 ° C, preferably 20 ° C to 40 ° C for 0.1 to 24 hours, preferably 0.1 to 24 hours. Compound c3 can be obtained by reacting for 1 to 12 hours.
Step 2
Compound c4, which can be commercially available or prepared by a known method in the presence of a solvent such as DMF, DMA, or NMP, and acetic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid. Compound c5 can be obtained by adding an acid such as methanesulfonic acid and reacting at 20 ° C. to 120 ° C., preferably 60 ° C. to 100 ° C. for 0.1 to 24 hours, preferably 1 to 12 hours. it can.
Process 3
Compound c6 can be obtained by subjecting compound c5 to a known general deprotection reaction of an amino protecting group.
Step 4
Compound c6 contains compound c7 that can be commercially available or prepared by a known method in the presence of solvents such as dichloromethane, dichloroethane, chloroform, methanol, ethanol, toluene, DMF, DMA, and THF, and acetic acid, p-toluenesulfonic acid, and methane. Compound c8 can be obtained by adding an acid such as sulfonic acid and reacting at 20 ° C to 130 ° C, preferably 20 ° C to 100 ° C for 0.1 to 24 hours, preferably 1 to 12 hours. ..
Step 5
A base such as cesium carbonate or potassium carbonate and a salt such as sodium iodide or potassium iodide are added to compound c8 in the presence of a solvent such as DMF, DMA, NMP or THF, and the temperature is 0 ° C to 60 ° C, preferably 0. Compound c9 can be obtained by reacting at ° C. to 40 ° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Step 6
In a solvent such as dichloromethane, dichloroethane, acetonitrile, DMF, etc., a halogenating reagent such as bromine, NBS, NCS, NIS is added to compound c9, and when Hall is bromo, -30 ° C to 50 ° C, preferably -10 ° C. J can be obtained by reacting at ~ 20 ° C. for 0.1 to 10 hours, preferably 0.5 to 2 hours. When Hal is chloro or iodine, compound c10 can be obtained by reacting at 10 ° C. to 150 ° C., preferably 60 ° C. to 120 ° C. for 0.5 to 24 hours, preferably 1 to 6 hours.
Step 7
Compound c10 in a solvent such as dioxane, DMF, DME, THF, DMSO or a mixed solvent, Pd (PPh ₃ ) ₄ , Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd (dppf) ₂ Cl ₂ Palladium catalyst such as Pd (dtbpf), bases such as potassium acetate, sodium acetate, potassium carbonate and potassium phosphate, and bis (pinacolato) diboron are added, and the temperature is 0 ° C. to 150 ° C., preferably 0 ° C. to 150 ° C. under a nitrogen atmosphere. Compound c11 can be obtained by reacting at 60 ° C. to 120 ° C. for 0.5 hours to 24 hours, preferably 1 hour to 12 hours.
Step 8
Compound c11 in a solvent such as dioxane, DMF, DME, THF, water, or a mixed solvent, Pd (PPh ₃ ) ₄ , Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd (dppf) ₂ Cl ₂ Palladium catalyst such as Pd (dtbpf), bases such as potassium carbonate, sodium carbonate, cesium carbonate and potassium phosphate, and compound c12 prepared by a commercially available or known method are added, and the temperature is 0 ° C. to 150 in a nitrogen atmosphere. Compound c13 can be obtained by reacting at ° C., preferably 60 ° C. to 120 ° C., for 0.5 hours to 24 hours, preferably 1 hour to 12 hours.
Step 9
Compound Ic can be obtained by subjecting compound c13 to a known general deprotection reaction of a hydroxy protecting group.

（式中、各記号は前記と同意義）
工程１
化合物ｃ５に、ＤＭＦ、ＤＭＡ、ＮＭＰ、ＴＨＦ等の溶媒の存在下、炭酸セシウムや炭酸カリウム、トリエチルアミン等の塩基と、市販または、公知の方法で調製できる化合物ｄ１を加え、さらにＨａｌがクロロの場合はヨウ化ナトリウムやヨウ化カリウム等の塩を加え、０℃〜６０℃、好ましくは２０℃〜４０℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｄ２を得ることができる。
工程２
化合物ｄ２をアセタールの公知の一般的な脱保護反応に付すことにより、化合物ｄ３を得ることができる。
工程３
化合物ｄ３に、ジクロロメタン、ジクロロエタン、クロロホルム、メタノール、エタノール、トルエン、ＤＭＦ、ＤＭＡ、ＴＨＦ等の溶媒の存在下、酢酸、p-トルエンスルホン酸、メシル酸等の酸を加え、２０℃〜１３０℃、好ましくは８０℃〜１２０℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｄ４を得ることができる。
工程４
化合物Ｉｄは、上記製法１の工程６〜９に従い合成することができる。 (Manufacturing method 2)

(In the formula, each symbol has the same meaning as above)
Process 1
In the presence of a solvent such as DMF, DMA, NMP, or THF, a base such as cesium carbonate, potassium carbonate, or triethylamine and compound d1 that can be commercially available or prepared by a known method are added to compound c5, and when Hall is chloro. Is a compound by adding a salt such as sodium iodide or potassium iodide and reacting at 0 ° C to 60 ° C, preferably 20 ° C to 40 ° C for 0.1 to 24 hours, preferably 1 to 12 hours. d2 can be obtained.
Step 2
Compound d3 can be obtained by subjecting compound d2 to a known general deprotection reaction of acetals.
Process 3
Acids such as acetic acid, p-toluenesulfonic acid and mesylic acid are added to compound d3 in the presence of solvents such as dichloromethane, dichloroethane, chloroform, methanol, ethanol, toluene, DMF, DMA and THF, and the temperature is adjusted to 20 ° C to 130 ° C. Compound d4 can be obtained by reacting at 80 ° C. to 120 ° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Step 4
Compound Id can be synthesized according to steps 6 to 9 of the above-mentioned production method 1.

（式中、その他の記号は前記と同意義。）
工程１
化合物ｇに、ジクロロメタン，ジクロロエタン，クロロホルム，ＤＭＦ、ＤＭＡ、ＮＭＰ、ＴＨＦ等の溶媒の存在下、トリエチルアミンやジイソプロピルエチルアミン等の塩基と、クロロ蟻酸エチル等を加えて酸クロライドとした後、市販または、公知の方法で調製できる化合物ｇ１を加え、０℃〜６０℃、好ましくは０℃〜２０℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｇ２を得ることができる。
工程２
化合物ｇ２に，酢酸エチル，ジクロロメタン，ジクロロエタン，クロロホルム，ジオキサン，ＤＭＦ、ＤＭＡ、ＴＨＦ等の溶媒の存在下、Ｔ３Ｐ，トリフルオロ酢酸、リン酸、塩酸、硫酸、臭化水素酸などの酸を作用させ，２０℃〜１３０℃、好ましくは６０℃〜１００℃にて０．１時間〜２４時間、好ましくは１時間〜１２時間反応させることにより、化合物ｇ３を得ることができる。
工程３
化合物Ｉｃは、製法１の工程９に従い合成することができる。 (Manufacturing method 3)

(In the formula, other symbols have the same meaning as above.)
Process 1
In the presence of a solvent such as dichloromethane, dichloroethane, chloroform, DMF, DMA, NMP, THF, etc. to compound g, a base such as triethylamine or diisopropylethylamine and ethyl chloroatelate are added to obtain acid chloride, which is then commercially available or known. Compound g1 prepared by the above method is added and reacted at 0 ° C to 60 ° C, preferably 0 ° C to 20 ° C for 0.1 to 24 hours, preferably 1 to 12 hours to obtain compound g2. Can be done.
Step 2
Acids such as T3P, trifluoroacetic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and hydrobromic acid are allowed to act on compound g2 in the presence of solvents such as ethyl acetate, dichloromethane, dichloroethane, chloroform, dioxane, DMF, DMA, and THF. , 20 ° C. to 130 ° C., preferably 60 ° C. to 100 ° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours to obtain compound g3.
Process 3
Compound Ic can be synthesized according to step 9 of production method 1.

The compound according to the present invention obtained above may be further chemically modified to synthesize another compound. Further, in the above reaction, when a reactive functional group (eg, OH, COOH, NH ₂ ) is present in the side chain portion or the like, it may be protected before the reaction and deprotected after the reaction, if desired.
Protecting groups (amino protecting groups, hydroxy protecting groups, etc.) include, for example, ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like, Protective Groups in Organic Synthesis, T.I. W. By Green, John
Wiley & Sons Inc. Protecting groups described in (1991) and the like can be mentioned. Protecting group introduction and elimination methods are commonly used in synthetic organic chemistry [eg, Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991)] and the like, or can be obtained according to them. Further, the conversion of the functional group contained in each substituent is carried out by a known method other than the above-mentioned production method [for example, Comprehensive Organic Transitions, R. et al. C. It can also be carried out by Larock (1989), etc.], and some of the compounds according to the present invention can be used as synthetic intermediates to lead to further novel derivatives. The intermediates and target compounds in each of the above production methods are isolated and purified by subjecting them to purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. can do. Further, the intermediate can be subjected to the next reaction without any particular purification.

The pharmaceutical composition of the present invention is useful as a medicine such as an antiviral drug. The compound according to the present invention has a remarkable inhibitory effect on viral integrase. Therefore, the pharmaceutical composition of the present invention can be expected to have a preventive or therapeutic effect on various diseases caused by a virus that produces at least integrase and proliferates in animal cells at the time of infection. For example, a retrovirus (eg, HIV). -1, HIV-2, HTLV-1, SIV, FIV, etc.) is useful as an integrase inhibitor, and is useful as an anti-HIV drug and the like. More preferable compounds according to the present invention have features such as high blood concentration, long duration of effect, and / or remarkable tissue migration as pharmacokinetics. In addition, the preferred compounds according to the present invention are safe in terms of side effects (eg, inhibition of CYP enzyme, mutagenicity, ECG QT interval prolongation, arrhythmia).

The pharmaceutical composition of the present invention can also be used in combination therapy in combination with an anti-HIV drug having a different mechanism of action such as a reverse transcriptase inhibitor, a protease inhibitor and / or an invasion inhibitor.
Furthermore, the above-mentioned use includes not only use as a combination drug for anti-HIV, but also use as a concomitant drug that increases the anti-HIV activity of other anti-HIV drugs such as cocktail therapy.
Further, the pharmaceutical composition of the present invention is used in the field of gene therapy in order to prevent infection of the retroviral vector from spreading to other than the target tissue when the retroviral vector based on HIV or MLV is used. Can be used. In particular, in the case where cells or the like are infected with a vector in vitro and then returned to the body, administration of the pharmaceutical composition of the present invention in advance can prevent unnecessary infection in the body. ..

The pharmaceutical composition of the present invention can be administered by either an oral method or a parenteral method. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drops, ear drops, and intravaginal administration.

In the case of oral administration, according to the conventional method, solid preparations for internal use (for example, tablets, powders, granules, capsules, pills, film preparations, etc.), liquids for internal use (eg, suspensions, emulsions, elixirs, syrups, etc.) It may be prepared and administered in any commonly used dosage form such as an agent, a limonade agent, a liquor agent, an aromatic water agent, an extract agent, a decoction agent, a tincture agent, etc. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules are dry syrups. Capsules may be soft capsules, microcapsules or sustained release capsules.

For parenteral administration, injections, instillations, topical agents (eg, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injectables, ointments, mouthwashes, enemas, etc. Any commonly used dosage form such as ointment, ointment, jelly, cream, patch, poultice, external powder, suppository, etc. can be suitably administered. The injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type or the like.

Various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form may be mixed with the effective amount of the compound according to the present invention as necessary to prepare a pharmaceutical composition. it can. Further, the pharmaceutical composition is a pharmaceutical composition for children, the elderly, critically ill patients or for surgery by appropriately changing the effective amount, dosage form and / or various pharmaceutical additives of the compound according to the present invention. It can also be a thing. For example, pediatric pharmaceutical compositions include newborns (4 weeks to less than 1 year old), infants (4 weeks to less than 1 year old), infants (1 to 7 years old), children (7 to less than 15 years old) or 15 It can be administered to patients aged 18 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to a patient aged 65 years or older.

The dose of the pharmaceutical composition of the present invention is preferably set in consideration of the age, body weight, type and degree of disease, administration route, etc. of the patient, but in the case of oral administration, it is usually 0.05 to 100 mg / mg. It is kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, it is usually 0.005 to 10 mg / kg / day, preferably in the range of 0.01 to 1 mg / kg / day, although it varies greatly depending on the administration route. This may be administered once a day to once a month or once every three months.

An example is shown below.
<Abbreviation>
Bn: benzyl DMA: Dimethylacetamide DME: Dimethoxyethane DMF: Dimethylformamide DMSO: Dimethyl sulfoxide HATU: O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexa Fluorophosphate NBS: N-Bromosuccinimide NCS: N-Chlorosuccinimide NIS: N-iodosuccinimide NMP: N-Methylpyrrolidone PyBOP: Hexafluorophosphate (benzotriazol-1-yloxy) Trypyrrolidinophosphonium THF: tetrahydrofuran WSC. HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

The NMR analysis obtained in each example was performed at 300 MHz or 400 MHz and measured using _{DMSO-d 6} and CDCl _3. Further, when showing NMR data, there are cases where all the measured peaks are not described.
In the examples, "No." represents the compound number, "Structure" represents the chemical structure, and "MS" represents the molecular weight in LC / MS (liquid chromatography / mass spectrometry).

(Measurement condition)
(A) Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)
Flow velocity: 0.8 mL / min; UV detection wavelength: 254 nm;
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution [B] is a 0.1% formic acid-containing acetonitrile solution. After linear gradient of 5% -100% solvent [B] for 3.5 minutes, 0. The 100% solvent [B] was maintained for 5 minutes.

(B) Column: Sim-pack XR-ODS (2.2 μm, id 50x3.0 mm) (Shimadzu)
Flow velocity: 1.6 mL / min; UV detection wavelength: 254 nm;
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution gradient: Linear gradient of 10% -100% solvent [B] is performed in 3 minutes, and 0. The 100% solvent [B] was maintained for 5 minutes.

工程１
化合物１（１．５０ｇ、３．５９ｍｍｏｌ）に２ｍｏｌ／Ｌエチルアミンのメタノール溶液（１７．９ｍｌ、３５．９ｍｍｏｌ）を加え、マイクロウエーブ照射下１００℃で１時間撹拌した。反応液の溶媒を減圧留去した後、希塩酸を加えて酸性にし、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、化合物２（１．１５ｇ、収率７４％）を得た。
1H-NMR(CDCl₃)δ: 14.53(s, 1H), 8.64(brs, 1H), 8.46(s, 1H), 7.37(m, 5H), 6.57(brs, 1H), 5.38(s, 2H), 3.24(dt, J=14.0, 6.6Hz, 2H), 1.45(s, 9H), 1.02(t, J=7.3Hz, 4H).
工程２
化合物２（３ｇ、６．９５ｍｍｏｌ）のＤＭＦ（６０ｍｌ）溶液に、炭酸カリウム（２．０２ｇ、１４．６ｍｍｏｌ）と２−（４−ブロモブチル）−１，３−ジオキソラン（２．５３ｍｌ、１６．７ｍｍｏｌ）を加えて室温で一晩反応させた。反応液を１ｍｏｌ／Ｌ塩酸で中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去し、化合物３を得た。
MS: m/z = 688 [M+H]+
工程３
化合物３のＴＨＦ（４７．８ｍＬ）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１７．３８ｍｌ、１３９ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液に２ｍｏｌ／Ｌ塩酸を少しずつ加えて中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去し、化合物４を得た。
MS: m/z = 560 [M+H]+
工程４
化合物４の１，４−ジオキサン（５ｍＬ）溶液に、４ｍｏｌ／Ｌの塩化水素（１，４−ジオキサン溶液、３４．８ｍｌ、１３９ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液の溶媒を留去し、トルエンを加えて再度留去し、化合物５を得た。
MS: m/z = 416 [M+H]+
工程５
化合物５のトルエン（５０ｍＬ）溶液に、酢酸を数滴加え、１１０℃で３０分撹拌した。反応液の溶媒を留去し、得られた残渣をエタノール/イソプロピルエーテルで固体化させ、化合物６（２．４４ｇ、４工程収率８８％）を得た。
¹H-NMR（CDCl₃）δ：15.1(s, 1H), 8.48(s, 1H), 7.57-7.55(m, 2H), 7.36-7.29(m, 3H), 5.53(d, J=10.4Hz, 1H), 5.36(d, J=10.4Hz 1H), 4.93-4.91(m, 1H), 4.20(td, J=21.6, 7.2Hz, 1H), 3.24-3.02(m, 3H), 2.28-1.73(m, 5H), 1.41-1.31(m, 1H), 1.18(t, J=7.2Hz, 3H).工程６
化合物６（３００ｍｇ、０．７５５ｍｍｏｌ）のジクロロメタン（３ｍｌ）溶液に、０℃でトリエチルアミン（０．４１９ｍｌ、３．０２ｍｍｏｌ）とクロロ蟻酸エチル（９０．０ｍｇ、０．８３０ｍｍｏｌ）を加え、室温で３０分間撹拌した。反応液へ化合物７（２１６ｍｇ、０．９０６ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、化合物８（４６６ｍｇ、収率１００％）を得た。
MS: m/z = 582 [M+H]+
工程７
化合物８（４３９ｍｇ、０．７５５ｍｍｏｌ）の酢酸エチル（６ｍｌ）溶液に、５０％Ｔ３Ｐ／酢酸エチル溶液（２．２５ｍｌ，７，５５ｍｍｏｌ）を加えて１００℃で１時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）に付し、により精製し、ラセミ混合物である化合物９（３００ｍｇ、収率７１％）を得た。
1H-NMR (CDCl3) δ: 8.80 (s, 1H), 7.60 (m, 2H), 7.34-7.27 (m, 4H), 6.85 (t, J = 8.9 Hz, 2H), 5.55 (d, J = 10.3 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 4.97 (m, 1H), 4.46 (s, 2H), 4.40 (m, 1H), 3.23 (m, 1H), 3.10-3.03 (m, 2H), 2.24 (m, 1H), 2.02 (m, 1H), 1.89 (m, 2H), 1.72 (m, 1H), 1.42 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H).
工程８
化合物９をＳＦＣにより光学分割し、化合物１０および１１を得た。
カラム：CHIRALPAK IA/SFC （5μｍ、ｉ．ｄ．250ｘ20ｍｍ）
流速：20ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：MeOH/CO2=65/35の組成比を維持して、25分間送液した。
工程９
化合物１１（１１０ｍｇ、０．１９５ｍｍｏｌ）をＤＭＦ（１．１ｍｌ）に溶解させ、塩化リチウム（８３．０ｍｇ、１．９５ｍｍｏｌ）を加えて９０℃で２時間撹拌した。反応液に水を加え、１０％クエン酸水溶液で酸性にし、酢酸エチルで抽出した。有機層を水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。得られた粗生成物をジエチルエーテルから固体化させ、化合物Ｉ−２（６３ｍｇ、収率６８％）を得た。
MS: m/z = 474 [M+H]+
1H-NMR (CDCl3) δ: 12.04 (s, 1H), 8.73 (s, 1H), 7.31 (m, 1H), 6.84 (t, J = 8.6 Hz, 2H), 5.14 (s, 1H), 4.45 (s, 2H), 4.36 (m, 1H), 3.26-3.04 (m, 3H), 2.33 (d, J = 14.9 Hz, 1H), 2.08 (t, J = 14.7 Hz, 1H), 1.91 (m, 3H), 1.42 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).
また、化合物１０も同様の反応条件に付すことにより、化合物Ｉ−１を得た。
MS: m/z = 474 [M+H]+ Example 1

Process 1
A methanol solution of 2 mol / L ethylamine (17.9 ml, 35.9 mmol) was added to compound 1 (1.50 g, 3.59 mmol), and the mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. After distilling off the solvent of the reaction solution under reduced pressure, dilute hydrochloric acid was added to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 2 (1.15 g, yield 74%).
1H-NMR (CDCl ₃ ) δ: 14.53 (s, 1H), 8.64 (brs, 1H), 8.46 (s, 1H), 7.37 (m, 5H), 6.57 (brs, 1H), 5.38 (s, 2H) , 3.24 (dt, J = 14.0, 6.6Hz, 2H), 1.45 (s, 9H), 1.02 (t, J = 7.3Hz, 4H).
Step 2
Potassium carbonate (2.02 g, 14.6 mmol) and 2- (4-bromobutyl) -1,3-dioxolane (2.53 ml, 16.7 mmol) in a solution of compound 2 (3 g, 6.95 mmol) in DMF (60 ml). ) Was added and reacted overnight at room temperature. The reaction mixture was neutralized with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated to give compound 3.
MS: m / z = 688 [M + H] +
Process 3
A 2 mol / L aqueous sodium hydroxide solution (17.38 ml, 139 mmol) was added to a solution of Compound 3 in THF (47.8 mL), and the mixture was stirred at room temperature for 2 hours. 2 mol / L hydrochloric acid was added little by little to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 4.
MS: m / z = 560 [M + H] +
Step 4
4 mol / L hydrogen chloride (1,4-dioxane solution, 34.8 ml, 139 mmol) was added to a solution of compound 4 in 1,4-dioxane (5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off, toluene was added, and the mixture was distilled off again to obtain Compound 5.
MS: m / z = 416 [M + H] +
Step 5
A few drops of acetic acid were added to a solution of compound 5 in toluene (50 mL), and the mixture was stirred at 110 ° C. for 30 minutes. The solvent of the reaction solution was distilled off, and the obtained residue was solidified with ethanol / isopropyl ether to obtain Compound 6 (2.44 g, yield of 4 steps: 88%).
^{1 1} H-NMR (CDCl ₃ ) δ: 15.1 (s, 1H), 8.48 (s, 1H), 7.57-7.55 (m, 2H), 7.36-7.29 (m, 3H), 5.53 (d, J = 10.4Hz , 1H), 5.36 (d, J = 10.4Hz 1H), 4.93-4.91 (m, 1H), 4.20 (td, J = 21.6, 7.2Hz, 1H), 3.24-3.02 (m, 3H), 2.28-1.73 (m, 5H), 1.41-1.31 (m, 1H), 1.18 (t, J = 7.2Hz, 3H). Step 6
Triethylamine (0.419 ml, 3.02 mmol) and ethyl chloroatelate (90.0 mg, 0.830 mmol) were added to a solution of compound 6 (300 mg, 0.755 mmol) in dichloromethane (3 ml) at 0 ° C. for 30 minutes at room temperature. Stirred. Compound 7 (216 mg, 0.906 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 8 (466 mg, 100% yield).
MS: m / z = 582 [M + H] +
Step 7
A 50% T3P / ethyl acetate solution (2.25 ml, 7,55 mmol) was added to a solution of compound 8 (439 mg, 0.755 mmol) in ethyl acetate (6 ml), and the mixture was stirred at 100 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (chloroform-methanol) and purified by purification to obtain compound 9 (300 mg, yield 71%) as a racemic mixture.
1H-NMR (CDCl3) δ: 8.80 (s, 1H), 7.60 (m, 2H), 7.34-7.27 (m, 4H), 6.85 (t, J = 8.9 Hz, 2H), 5.55 (d, J = 10.3 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 4.97 (m, 1H), 4.46 (s, 2H), 4.40 (m, 1H), 3.23 (m, 1H), 3.10-3.03 (m) , 2H), 2.24 (m, 1H), 2.02 (m, 1H), 1.89 (m, 2H), 1.72 (m, 1H), 1.42 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H) ..
Step 8
Compound 9 was optically resolved by SFC to obtain compounds 10 and 11.
Column: CHIRALPAK IA / SFC (5 μm, id 250 x 20 mm)
Flow velocity: 20 mL / min UV detection wavelength: 220 nm
Preparation conditions: The liquid was sent for 25 minutes while maintaining the composition ratio of MeOH / CO2 = 65/35.
Step 9
Compound 11 (110 mg, 0.195 mmol) was dissolved in DMF (1.1 ml), lithium chloride (83.0 mg, 1.95 mmol) was added, and the mixture was stirred at 90 ° C. for 2 hours. Water was added to the reaction mixture, acidified with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off. The resulting crude product was solidified from diethyl ether to give compound I-2 (63 mg, 68% yield).
MS: m / z = 474 [M + H] +
1H-NMR (CDCl3) δ: 12.04 (s, 1H), 8.73 (s, 1H), 7.31 (m, 1H), 6.84 (t, J = 8.6 Hz, 2H), 5.14 (s, 1H), 4.45 ( s, 2H), 4.36 (m, 1H), 3.26-3.04 (m, 3H), 2.33 (d, J = 14.9 Hz, 1H), 2.08 (t, J = 14.7 Hz, 1H), 1.91 (m, 3H) ), 1.42 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).
Further, compound I-1 was obtained by subjecting compound 10 to the same reaction conditions.
MS: m / z = 474 [M + H] +

工程１
化合物１２（１２ｇ、４８．７ｍｍｏｌ）のＤＭＦ（６０ｍＬ）溶液を０℃に冷却し、ＨＯＢｔ（７．９ｇ、５８．５ｍｍｏｌ）、ＥＤＣ（１１．２ｇ、５８．５ｍｍｏｌ）、トリエチルアミン（８．１ｍＬ、５８．５ｍｍｏｌ）およびエチルアミン塩酸塩（４．８ｇ、５８．５ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた固体をイソプロピルエーテルに懸濁し、濾取することで化合物１３（１０．７ｇ、収率８０％）を得た。
1H-NMR (CDCl3) δ: 7.84 (d, J = 5.8 Hz, 1H), 7.69 (s, 1H), 7.41-7.39 (m, 5H), 6.49 (d, J = 5.5 Hz, 1H), 5.41 (s, 2H), 3.29-3.26 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H).
工程２
化合物１３（１０ｇ、３６．６ｍｍｏｌ）をＤＭＡ（１００ｍＬ）に溶解させ、パラトルエンスルホン酸ピリジニウム（２７．６ｇ、１０９．８ｍｍｏｌ）を加えたのち６０℃に加熱した。反応液に、カルバジン酸ｔ−Ｂｕ（８．７ｇ、６５．９ｍｍｏｌ）を１時間おきに６回に分けて加えた。反応液を室温まで放冷後、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加えて塩基性にし、ジエチルエーテルで洗浄した。水層に２ｍｏｌ／Ｌ塩酸を加えて酸性にしたのち、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた固体を酢酸エチル／ジイソプロピルエーテルで洗浄することで化合物１４（６．３ｇ、収率４４％）を得た。
1H-NMR (CDCl3) δ: 8.31 (br s, 1H), 7.36-7.34 (m, 6H), 6.59 (s, 1H), 6.40 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H), 3.21-3.17 (m, 2H), 1.43 (s, 9H), 0.99 (t, J = 7.3 Hz, 3H).
工程３
化合物１４（０．５ｇ、１．３ｍｍｏｌ）を４ｍｏｌ／Ｌ塩化水素−酢酸エチル溶液（５ｍＬ）に溶解させ、室温で３０分撹拌した。溶媒を減圧留去し、化合物１５の粗生成物を得た。
MS: m/z = 288 [M+H]+
工程４
化合物１５の粗生成物（０．１３ｇ）をジクロロメタン（１ｍＬ）に溶解させ、化合物１６（４６．２ｍｇ、０．３８ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液の溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、化合物１７（０．１３ｇ、収率９６％）を得た。
MS: m/z = 390 [M+H]+
工程５
化合物１７（０．１３ｇ、３３．３ｍｍｏｌ）をＤＭＦ（１．０ｍＬ）に溶解させ、炭酸セシウム（０．３４ｇ、１．０ｍｍｏｌ）およびヨウ化ナトリウム（０．１６ｇ、１．０ｍｍｏｌ）を加え、５０℃で終夜撹拌した。反応液に酢酸エチルを加え、生じた固体を濾去したのち、溶媒を減圧留去した。得られた粗精製物をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、化合物１８（５２ｍｇ、収率４４％）を得た。
1H-NMR (CDCl3) δ: 7.60 (d, J = 7.0 Hz, 2H), 7.32-7.28 (m, 4H), 6.40 (d, J = 7.5 Hz, 1H), 5.48 (d, J = 10.5 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.88-4.90 (m, 1H), 4.43-4.39 (m, 1H), 3.12-2.97 (m, 3H), 2.24-2.20 (m, 1H), 1.98-1.91 (m, 1H), 1.83-1.80 (m, 2H), 1.71-1.67 (m, 1H), 1.40-1.38 (m, 1H), 1.14 (t, J = 7.0 Hz, 3H).
工程６
化合物１８（１．０ｇ、２．８ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液を０℃に冷却し、ＮＢＳ（０．５６ｇ、３．１ｍｍｏｌ）を加え、室温で終夜撹拌した。反応液の溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）により精製し、化合物１９（１．４ｇ、収率９３％）を得た。
1H-NMR (CDCl3) δ: 7.83 (s, 1H), 7.64 (d, J = 7.0 Hz, 2H), 7.34-7.27 (m, 3H), 5.48 (d, J = 10.3 Hz, 1H), 5.26 (d, J = 10.3 Hz, 1H), 4.92-4.90 (m, 1H), 4.43-4.39 (m, 1H), 3.20-3.14 (m, 1H), 3.05-2.98 (m, 2H), 2.26-2.22 (m, 1H), 1.97-1.94 (m, 1H), 1.84-1.82 (m, 2H), 1.73-1.69 (m, 1H), 1.41-1.39 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H).
工程７
化合物１９をＳＦＣにより光学分割し、化合物２０と２１を得た。
カラム：CHIRALPAK IB/SFC （5μｍ、ｉ．ｄ．250ｘ20ｍｍ）
流速：30 ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：MeOH/CO2=35/65の組成比を維持して、21分間送液した。
工程８
化合物２１（２５０ｍｇ、０．５８ｍｍｏｌ）をトルエンに溶解させ、化合物２２（１８３ｍｇ、０．８７ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１３．０ｍｇ、０．０６ｍｍｏｌ）、２−ジシクロヘキシルホスフィノ−２’−（Ｎ，Ｎ−ジアミノ）ビフェニル（４６ｍｇ、０．１２ｍｍｏｌ）および炭酸セシウム（５６５ｍｇ、１．７ｍｍｏｌ）を加えて封緘し、１４０℃で２時間撹拌した。室温まで放冷し、不溶物をセライト濾過で除き、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により粗精製し、逆相精製することで化合物２３（４０ｍｇ、収率１２％）を得た。
1H-NMR (CDCl3) δ: 8.63 (s, 1H), 7.64-7.61 (m, 3H), 7.34-7.19 (m, 4H), 6.83-6.79 (m, 2H), 5.58 (d, J = 10.3 Hz, 1H), 5.33 (d, J = 10.3 Hz, 1H), 4.96-4.94 (m, 1H), 4.44-4.40 (m, 1H), 4.19 (s, 2H), 3.22-3.18 (m, 1H), 3.09-3.02 (m, 2H), 2.27-2.23 (m, 1H), 2.01-1.97 (m, 1H), 1.86-1.84 (m, 2H), 1.74-1.70 (m, 1H), 1.43-1.40 (m, 1H), 1.17 (t, J = 7.0 Hz, 3H).
工程９
化合物２３（４０ｍｇ、０．０７１ｍｍｏｌ）を、実施例１の工程９と同様の反応条件に付すことにより、化合物Ｉ−４（２２ｍｇ、収率６７％）を得た。
1H-NMR (CDCl3) δ:11.81 (br s, 1H), 8.59 (s, 1H), 7.54 (s, 1H), 7.20-7.18 (m, 1H), 6.83-6.78 (m, 2H), 5.11-5.09 (m, 1H), 4.40-4.31 (m, 1H), 4.18 (s, 2H), 3.24-3.02 (m, 3H), 2.34-2.29 (m, 1H), 2.09-2.01 (m, 1H), 1.90-1.85 (m, 2H), 1.78-1.74 (m, 1H), 1.46-1.36 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H). Example 2

Process 1
A solution of compound 12 (12 g, 48.7 mmol) in DMF (60 mL) was cooled to 0 ° C. and HOBt (7.9 g, 58.5 mmol), EDC (11.2 g, 58.5 mmol), triethylamine (8.1 mL, 58.5 mmol) and ethylamine hydrochloride (4.8 g, 58.5 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was suspended in isopropyl ether and collected by filtration to obtain Compound 13 (10.7 g, yield 80%).
1H-NMR (CDCl3) δ: 7.84 (d, J = 5.8 Hz, 1H), 7.69 (s, 1H), 7.41-7.39 (m, 5H), 6.49 (d, J = 5.5 Hz, 1H), 5.41 ( s, 2H), 3.29-3.26 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H).
Step 2
Compound 13 (10 g, 36.6 mmol) was dissolved in DMA (100 mL), pyridinium paratoluenesulfonate (27.6 g, 109.8 mmol) was added, and the mixture was heated to 60 ° C. To the reaction mixture, t-Bu carbazic acid (8.7 g, 65.9 mmol) was added in 6 portions every hour. The reaction mixture was allowed to cool to room temperature, basicized by adding 1 mol / L aqueous sodium hydroxide solution, and washed with diethyl ether. The aqueous layer was acidified by adding 2 mol / L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate / diisopropyl ether to obtain Compound 14 (6.3 g, yield 44%).
1H-NMR (CDCl3) δ: 8.31 (br s, 1H), 7.36-7.34 (m, 6H), 6.59 (s, 1H), 6.40 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H) , 3.21-3.17 (m, 2H), 1.43 (s, 9H), 0.99 (t, J = 7.3 Hz, 3H).
Process 3
Compound 14 (0.5 g, 1.3 mmol) was dissolved in a 4 mol / L hydrogen chloride-ethyl acetate solution (5 mL) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain a crude product of compound 15.
MS: m / z = 288 [M + H] +
Step 4
The crude product of compound 15 (0.13 g) was dissolved in dichloromethane (1 mL), compound 16 (46.2 mg, 0.38 mmol) was added and stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 17 (0.13 g, yield 96%).
MS: m / z = 390 [M + H] +
Step 5
Compound 17 (0.13 g, 33.3 mmol) is dissolved in DMF (1.0 mL), cesium carbonate (0.34 g, 1.0 mmol) and sodium iodide (0.16 g, 1.0 mmol) are added, and 50 Stirred overnight at ° C. Ethyl acetate was added to the reaction mixture, the resulting solid was filtered off, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 18 (52 mg, yield 44%).
1H-NMR (CDCl3) δ: 7.60 (d, J = 7.0 Hz, 2H), 7.32-7.28 (m, 4H), 6.40 (d, J = 7.5 Hz, 1H), 5.48 (d, J = 10.5 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.88-4.90 (m, 1H), 4.43-4.39 (m, 1H), 3.12-2.97 (m, 3H), 2.24-2.20 (m, 1H) , 1.98-1.91 (m, 1H), 1.83-1.80 (m, 2H), 1.71-1.67 (m, 1H), 1.40-1.38 (m, 1H), 1.14 (t, J = 7.0 Hz, 3H).
Step 6
A solution of compound 18 (1.0 g, 2.8 mmol) in dichloromethane (10 mL) was cooled to 0 ° C., NBS (0.56 g, 3.1 mmol) was added and the mixture was stirred overnight at room temperature. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 19 (1.4 g, yield 93%).
1H-NMR (CDCl3) δ: 7.83 (s, 1H), 7.64 (d, J = 7.0 Hz, 2H), 7.34-7.27 (m, 3H), 5.48 (d, J = 10.3 Hz, 1H), 5.26 ( d, J = 10.3 Hz, 1H), 4.92-4.90 (m, 1H), 4.43-4.39 (m, 1H), 3.20-3.14 (m, 1H), 3.05-2.98 (m, 2H), 2.26-2.22 ( m, 1H), 1.97-1.94 (m, 1H), 1.84-1.82 (m, 2H), 1.73-1.69 (m, 1H), 1.41-1.39 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H).
Step 7
Compound 19 was optically resolved by SFC to obtain compounds 20 and 21.
Column: CHIRALPAK IB / SFC (5 μm, id 250 x 20 mm)
Flow velocity: 30 mL / min UV detection wavelength: 220 nm
Preparation conditions: The liquid was sent for 21 minutes while maintaining the composition ratio of MeOH / CO2 = 35/65.
Step 8
Compound 21 (250 mg, 0.58 mmol) was dissolved in toluene and compound 22 (183 mg, 0.87 mmol), Pd (OAc) ₂ (13.0 mg, 0.06 mmol), 2-dicyclohexylphosphino-2'-( N, N-diamino) biphenyl (46 mg, 0.12 mmol) and cesium carbonate (565 mg, 1.7 mmol) were added, sealed, and stirred at 140 ° C. for 2 hours. The mixture was allowed to cool to room temperature, the insoluble material was removed by filtration through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate) and reverse-phase purified to obtain Compound 23 (40 mg, yield 12%).
1H-NMR (CDCl3) δ: 8.63 (s, 1H), 7.64-7.61 (m, 3H), 7.34-7.19 (m, 4H), 6.83-6.79 (m, 2H), 5.58 (d, J = 10.3 Hz) , 1H), 5.33 (d, J = 10.3 Hz, 1H), 4.96-4.94 (m, 1H), 4.44-4.40 (m, 1H), 4.19 (s, 2H), 3.22-3.18 (m, 1H), 3.09-3.02 (m, 2H), 2.27-2.23 (m, 1H), 2.01-1.97 (m, 1H), 1.86-1.84 (m, 2H), 1.74-1.70 (m, 1H), 1.43-1.40 (m) , 1H), 1.17 (t, J = 7.0 Hz, 3H).
Step 9
Compound I-4 (22 mg, yield 67%) was obtained by subjecting Compound 23 (40 mg, 0.071 mmol) to the same reaction conditions as in Step 9 of Example 1.
1H-NMR (CDCl3) δ: 11.81 (br s, 1H), 8.59 (s, 1H), 7.54 (s, 1H), 7.20-7.18 (m, 1H), 6.83-6.78 (m, 2H), 5.11- 5.09 (m, 1H), 4.40-4.31 (m, 1H), 4.18 (s, 2H), 3.24-3.02 (m, 3H), 2.34-2.29 (m, 1H), 2.09-2.01 (m, 1H), 1.90-1.85 (m, 2H), 1.78-1.74 (m, 1H), 1.46-1.36 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H).

工程１
化合物２４（５２８ｍｇ、２．１０ｍｍｏｌ）のＴＨＦ（５．０ｍＬ）溶液に、０℃にて水素化ナトリウム（６０ｗｔ％、１３５ｍｇ、３．３８ｍｍｏｌ）を加え、０℃で１０分間撹拌した。反応液に化合物２５（５００ｍｇ、２．４１５ｍｍｏｌ）を加え、室温まで昇温し一晩反応させた。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）により精製し、化合物２６（５１７ｍｇ、収率６７％）を得た。
MS: m/z = 321 [M+H]+
工程２
化合物２６（８９ｍｇ、０．２７８ｍｍｏｌ）、化合物２１（６０ｍｇ、０．１３９ｍｍｏｌ）、炭酸セシウム（６８ｍｇ、０．２０８ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１６ｍｇ、０．０１４ｍｍｏｌ）をジオキサン（１．８ｍＬ）に溶解させ、９０℃で７時間反応させた。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル−メタノール）により粗精製した。
MS: m/z = 546 [M+H]+
工程３
実施例１の工程９と同様の方法により、化合物ＩＩ−６を得た。
1H-NMR(CDCl3)δ: 8.66(s, 1H), 7.77(s, 1H), 7.72(s, 1H), 7.20-7.15(m, 1H), 6.86-6.80(m, 2H), 5.35(s, 2H), 5.08(s, 1H), 4.40-4.30(m, 1H), 3.20-2.95(m, 3H), 2.35-2.25(m, 1H), 2.01-1.40(m, 6H), 1.22(t, J=7.2Hz, 3H). Example 3

Process 1
Sodium hydride (60 wt%, 135 mg, 3.38 mmol) was added to a solution of compound 24 (528 mg, 2.10 mmol) in THF (5.0 mL) at 0 ° C. and the mixture was stirred at 0 ° C. for 10 minutes. Compound 25 (500 mg, 2.415 mmol) was added to the reaction solution, the temperature was raised to room temperature, and the reaction was allowed to proceed overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 26 (517 mg, yield 67%).
MS: m / z = 321 [M + H] +
Step 2
Compound 26 (89 mg, 0.278 mmol), compound 21 (60 mg, 0.139 mmol), cesium carbonate (68 mg, 0.208 mmol), tetrakistriphenylphosphine palladium (16 mg, 0.014 mmol) in dioxane (1.8 mL). It was dissolved and reacted at 90 ° C. for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was crudely purified by silica gel column chromatography (ethyl acetate-methanol).
MS: m / z = 546 [M + H] +
Process 3
Compound II-6 was obtained in the same manner as in Step 9 of Example 1.
1H-NMR (CDCl3) δ: 8.66 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.20-7.15 (m, 1H), 6.86-6.80 (m, 2H), 5.35 (s) , 2H), 5.08 (s, 1H), 4.40-4.30 (m, 1H), 3.20-2.95 (m, 3H), 2.35-2.25 (m, 1H), 2.01-1.40 (m, 6H), 1.22 (t) , J = 7.2Hz, 3H).

The compounds shown below were also synthesized in the same manner.

The physical data of each compound is shown below.

Examples of biological tests of the compounds according to the present invention are described below.
The compound according to the present invention may be any compound that significantly inhibits viral integrase.
Specifically, in the evaluation method described below, the EC50 is preferably 100 nM or less, more preferably 10 nM or less, still more preferably 5 nM or less.

以上の試験結果から、本発明に係る化合物は高い抗ＨＩＶ活性を示したため、本発明の医薬組成物はＨＩＶ薬として有用性を有することが明らかになった。 Test Example 1 (anti-HIV activity)
A serial dilution series of test samples was made on 96-well microplates (50 μL / well). A 2.5 x 10 ⁵ cells / mL MT-4 cell suspension was dispensed into a plate containing the test sample at a rate of 100 μL / well, and then the HIV virus solution was dispensed at a rate of 50 μL / well. The mixture was mixed with a plate mixer and _{cultured in a CO 2} incubator for 4 days. 30 μL of MTT (3- (4,5-dimethylthialzol-2-yl) -2,5-diphenyltetrazolium bromide) solution was dispensed into each well. The reaction was carried out in a _{CO 2 incubator for 1 hour.} 150 μL of supernatant was removed from each well to avoid sucking cells. 150 μL of cytolyte was added and mixed well with a plate mixer until all the cells were lysed. The absorbance of the mixed plate was measured with a microplate reader at two wavelengths of 560 nm / 690 nm. The 50% HIV inhibition concentration (EC50) was determined from the concentration-dependent curve using the 4-parameter logistic curve fitting model shown below.
y = A + ((BA) / (1+ (C / x) ^D ))

A = minimum inhibition rate (negative control, 0%)
B = maximum inhibition rate (positive control, 100%)
C = Compound concentration at inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%)
(result)

From the above test results, it was clarified that the pharmaceutical composition of the present invention has usefulness as an HIV drug because the compound according to the present invention showed high anti-HIV activity.

変異株３（Ｅ９２Ｑ／Ｅ１３８Ｋ／Ｇ１４０Ｓ／Ｑ１４８Ｈ）に対するＦＣ
化合物Ｉ−２：７．７
変異株４（Ｔ９７Ａ／Ｅ１３８Ｔ／Ｇ１４０Ｓ／Ｑ１４８Ｈ）に対するＦＣ
化合物Ｉ−２：３．２
以上の試験結果から、本発明に係る化合物は耐性バリアが高く、ＨＩＶ耐性ウイルスを発生させにくいことが明らかになった。 Test Example 2: Resistance Evaluation Test A serial dilution series of test samples was prepared on a 96-well microplate (50 μL / wel). After dispensing 2.5 × 10 ⁵ cells / mL HeLa-CD4 cell suspension into a plate containing the test sample at 100 μL / well, the HIV virus solution (wild strain and mutant strain) was dispensed at 50 μL / well. Noted. The mixture was mixed with a plate mixer and _{cultured in a CO 2} incubator for 3 days. The culture supernatant of each well was removed by suction, 100 μL of the cell lysis buffer in the reporter measurement kit was dispensed, and the cells were frozen in a freezer (-80 ° C). The plate frozen in the freezer was thawed at room temperature, mixed with a plate mixer, and centrifuged at 1,200 rpm for 5 minutes. 20 μL of the supernatant of each well was dispensed into a 96-well microplate (BLACK). 100 μL of the chemiluminescent reagent in the reporter assay kit was dispensed, reacted at room temperature for about 1 hour, and then the amount of luminescence was measured with MicroBeta TRILLUX. The 50% HIV inhibition concentration (EC50) was determined from the concentration-dependent curve using the 4-parameter logistic curve fitting model shown below.
y = A + ((BA) / (1+ (C / x) ^D ))

A = minimum inhibition rate (negative control, 0%)
B = maximum inhibition rate (positive control, 100%)
C = Compound concentration at inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%)

In addition, the resistance degree (Fold change (FC)) of each mutant strain was calculated based on the following formula.
FC = mutant EC50 / wild EC50
(result)
The FC for mutant strain 1 (E138K / G140S / Q148H / N155H) and the FC for mutant strain 2 (E92Q / E138T / G140S / Q148H) are shown in the table.

FC for mutant strain 3 (E92Q / E138K / G140S / Q148H)
Compound I-2: 7.7
FC for mutant strain 4 (T97A / E138T / G140S / Q148H)
Compound I-2: 3.2
From the above test results, it was clarified that the compound according to the present invention has a high resistance barrier and is unlikely to generate an HIV resistant virus.

Test Example 3: CYP inhibition test
Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorphin (CYP1A2), which is a typical substrate metabolic reaction of the major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), torubutamide. Methyl-hydroxylation (CYP2C9), mephenitoin 4'-hydroxylation (CYP2C19), dexstrometolphan O demethylation (CYP2D6), and terfenazine hydroxylation (CYP3A4) are used as indicators, and the amount of each metabolite produced is The degree of inhibition by the compound according to the present invention was evaluated.

The reaction conditions are as follows: Substrate, 0.5 μmol / L ethoxyresorphin (CYP1A2), 100 μmol / L tolubutamide (CYP2C9), 50 μmol / L S-mephenitoin (CYP2C19), 5 μmol / L dextrometholphan (CYP2D6), 1 μmol / L terphenazine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration according to the present invention 1, 5, 10, 20 μmol / L (4) point).

Five kinds of substrates, human liver microsomes, and the compound according to the present invention were added to a 96-well plate in 50 mmol / L Hepes buffer with the above composition, and the coenzyme NADPH was added to start the metabolic reaction as an index. did. After reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resolver fins (CYP1A2 metabolites) in the centrifugation supernatant were quantified with a fluorescent multi-label counter or LC / MS / MS, and tolubutamide hydroxylate (CYP2C9 metabolites) and mephenytoin 4'hydroxylite. The body (CYP2C19 metabolite), dextrolphan (CYP2D6 metabolite), and terphenazine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

Using only DMSO, which is a solvent in which the compound is dissolved, is added to the reaction solution instead of the compound according to the present invention as a control (100%), the residual activity (%) is calculated, and the concentration and the suppression rate are used to logistically. _{IC 50} was calculated by inverse estimation by the model.

Test Example 4: CYP3A4 (MDZ) MBI test Regarding the inhibition of CYP3A4 of the compound of the present invention, it is a test for evaluating the Mechanism-based inhibition (MBI) ability from the enhancement of the inhibitory action caused by the metabolic reaction of the compound according to the present invention. CYP3A4 inhibition was evaluated using pooled human liver microsomes using the 1-hydroxylation reaction of midazolam (MDZ) as an index.

Reaction conditions are as follows: Substrate, 10 μmol / L MDZ; Prereaction time, 0 or 30 minutes; Substrate metabolism reaction time, 2 minutes; Reaction temperature, 37 ° C.; Pooled human liver microsomes, 0.5 mg / mL during prereaction, 0.05 mg / mL during reaction (when diluted 10-fold); concentration during compound pre-reaction according to the present invention 1, 5, 10, 20 μmol / L (4 points) or 0.83, 5, 10, 20 μmol / L (4 points).

Pooled human liver microsomes and the compound solution according to the present invention are added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above pre-reaction composition, and another 96-well plate contains the substrate. Part of it was transferred so as to be diluted 1/10 with −Pi buffer solution, and the coenzyme NADPH was added to start the reaction as an index (no prereaction: Preincubation 0 min), and after the reaction for a predetermined time. , Methanol / acetonitrile = 1/1 (V / V) solution was added to terminate the reaction. NADPH was also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction: Preincubation 30 min), and after the pre-reaction for a predetermined time, it was diluted 1/10 with K-Pi buffer containing the substrate on another plate. As a result, a part of the reaction was started as an index. After the reaction for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging the plate subjected to each index reaction at 3000 rpm for 15 minutes, 1-hydroxide midazolam in the centrifugal supernatant was quantified by LC / MS / MS.

The control (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved, to the reaction solution instead of the compound according to the present invention, and the residual activity (%) when the compound according to the present invention was added at each concentration. Was calculated, and the IC was calculated by reverse estimation using a logistic model using the concentration and the inhibition rate. A IC of 0 min of Preincubation / an IC of 30 min of Preincubation is defined as a Shifted IC value, a positive (+) is set when the Shifted IC is 1.5 or more, and a negative (-) is set when the Shifted IC is 1.0 or less.
(result)
Compound II-37: (-)
Compound II-51: (-)

Test Example 5: BA test Examination of oral absorbability Experimental materials and methods (1) Animals used: Rats were used.
(2) Breeding conditions: Rats were allowed to freely ingest solid feed and sterile tap water.
(3) Dosage and grouping settings: Oral administration and intravenous administration were performed at predetermined doses. The group was set as follows. (Dose may change for each compound)
Oral administration 2 to 60 μmol / kg or 1 to 30 mg / kg (n = 2 to 3)
Intravenous administration 1 to 30 μmol / kg or 0.5 to 10 mg / kg (n = 2 to 3)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was forcibly administered into the stomach by an oral sonde. Intravenous administration was performed from the tail vein with a syringe equipped with an injection needle.
(6) Evaluation item: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: Regarding the transition of the compound concentration according to the present invention in plasma, the area under the plasma concentration-time curve (AUC) was calculated by the moment analysis method, and the dose ratio between the oral administration group and the intravenous administration group and the AUC. The bioavailability (BA) of the compound according to the present invention was calculated from the ratio.

Test Example 6: Clearance evaluation test Experimental materials and methods (1) Animals used: Rats were used.
(2) Breeding conditions: Rats were allowed to freely ingest solid feed and sterile tap water.
(3) Dosage and grouping settings: Intravenous administration was administered at a predetermined dose. The group was set as follows.
Intravenous administration 1 μmol / kg (n = 2)
(4) Preparation of administration solution: Dimethyl sulfoxide / propylene glycol = 1/1 solvent was used to solubilize and administer.
(5) Administration method: Administration was performed from the tail vein using a syringe equipped with an injection needle.
(6) Evaluation item: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: Regarding the transition of the compound concentration according to the present invention in plasma, the whole body clearance (CLtot) and the elimination half-life (t1 / 2) were calculated by the moment analysis method.
(result)
Compound II-13: 0.0226 mL / min / kg, 35.4 hr
Compound II-24: 0.0364 mL / min / kg, 23.6 hr
From the above results, it was found that the pharmaceutical composition of the present invention is useful as a long-acting integrase inhibitor because the compound according to the present invention has a small clearance and a long elimination half-life.

Test Example 7: Metabolic stability test A commercially available pooled human liver microsome was reacted with the compound according to the present invention for a certain period of time, the residual rate was calculated by comparing the reaction sample and the unreacted sample, and the compound according to the present invention was metabolized in the liver. The degree of metabolism was evaluated.

In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL of human liver microsomes, in the presence of 1 mmol / L NADPH The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound according to the present invention in the centrifugal supernatant is quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the residual amount of the compound according to the present invention after the reaction is the amount of the compound at the time of 0 minute reaction. Was calculated as 100%.
(Results) The residual rate at a compound concentration of 0.5 μmol / L is shown in the table below.

Test Example 8: Fluctuation Ames Test
The mutagenicity of the compound according to the present invention was evaluated.
20 μL of cryopreserved Salmonella typhimurium TA98 strain, TA100 strain was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient birth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, the culture solution was removed by centrifuging 7.70 to 8.00 mL of the bacterial solution (2000 × g, 10 minutes). _{Micro F buffer (K 2} HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, tricitrate) having the same volume as the bacterial solution used for centrifugation. sodium _{dihydrate: 0.25g / L, MgSO 4 ·} 7H 2 O: 0.1g / L) in the cells were suspended, 120 mL of Exposure medium (biotin: 8 [mu] g / mL, histidine: 0.2 [mu] g / mL, Glucose: added to MicroF buffer (MicroF buffer) containing 8 mg / mL. For the TA100 strain, a test bacterial solution was prepared by adding 3.1 to 3.42 mL of the bacterial solution to 120 to 130 mL of Exposure medium. The compound DMSO solution according to the present invention (diluted in several steps from the maximum dose of 50 mg / mL in a 2-3-fold common ratio), DMSO as a negative control, and 50 μg / mL for the TA98 strain under non-metalytic activation conditions as a positive control 4-Nitroquinolin-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, metabolic activation conditions Then, 40 μg / mL 2-aminoanthracene DMSO solution for TA98 strain, 12 μL of 2-aminoanthracene DMSO solution of 20 μg / mL for TA100 strain, and 588 μL of test bacterial solution (498 μL of test bacterial solution under metabolic activation conditions). And S9 mix (90 μL of mixed solution) were mixed and cultured at 37 ° C. for 90 minutes with shaking. MicroF buffer containing 460 μL of the bacterial solution exposed to the compound according to the present invention in an indicator medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). ) The mixture was mixed with 2300 μL, 50 μL was dispensed into 48 wells / dose of microplate, and the mixture was statically cultured at 37 ° C. for 3 days. Wells containing bacteria that have acquired proliferative potential due to mutations in the amino acid (histidine) synthase gene change color from purple to yellow due to pH changes, so the number of bacterial growth wells that turned yellow out of 48 wells per dose was counted. , Evaluated in comparison with the negative control group. Those with negative mutagenicity are shown as (-), and those with positive mutagenicity are shown as (+).

Test Example 9: hERG test For the purpose of assessing the risk of ECG QT interval prolongation of the compound according to the present invention, a ventricular repolarization process using CHO cells expressing a human ether-a-go-go related gene (herG) channel. The effect of the compound according to the present invention on ^{delayed rectification K +} current (I _Kr ), which plays an important role in the above, was investigated.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), cells are held at a membrane potential of -80 mV by the whole cell patch clamp method, a leak potential of -50 mV is applied, and then a depolarization stimulus of +20 mV is applied. _{I Kr} was recorded for 2 seconds and when a repolarization stimulus of -50 mV was applied for 2 seconds. Extracellular fluid adjusted to 0.1% of dimethylsulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ₂ : 2 mmol / L, MgCl ₂ : 1 mmol / L, glucose: 10 mmol / L , HEPES (4- (2-hydroxyethyl) -1-piperazineethanetic acid, 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid): 10 mmol / L, pH = 7.4) as a medium, and the medium and the present. The extracellular fluid in which the compound according to the invention is lysed at the desired concentration is applied to the cells under normal temperature conditions for 7 minutes or longer. From the obtained I _Kr , the absolute value of the maximum tail current was measured using analysis software (QPatch Assay software; Sophion Bioscience A / S) with reference to the current value at the holding membrane potential. Further, the maximum tail current after application of the compound according to the present invention was calculated as an inhibition rate with respect to the maximum tail current after application of the medium, and the influence of the _{compound according to the present invention on I Kr was evaluated.}

Test Example 10: Solubility test The solubility of the compound according to the present invention was determined under the condition of adding 1% DMSO. A 10 mmol / L compound solution was prepared in DMSO. 2 μL of the compound solution according to the present invention was added to 198 μL of JP-1 solution and JP-2 solution, respectively. After shaking at room temperature for 1 hour, the mixed solution was suction filtered. The filtrate is diluted 10 or 100 times with methanol / water = 1/1 (V / V) or acetonitrile / methanol / water = 1/1/2 (V / V / V) and LC / MS by absolute calibration curve method. Alternatively, the concentration in the filtrate was measured using solid phase extraction (SPE) / MS.

The composition of the JP-1 solution is as follows.
Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
The composition of the JP-2 solution is as follows.
1.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate are dissolved in water to make 1000 mL, and 1 volume of water is added to 1 volume.

Test Example 11: Powder solubility test Put an appropriate amount of the compound according to the present invention in an appropriate container, and add JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid and water to make 1000 mL) in each container, JP- 2 liquids (3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to make 1000 mL, add 1 volume of water to 1 volume), 20 mmol / L sodium taurocholate (TCA) / JP Solution 2 (add solution JP-2 to 1.08 g of TCA to make 100 mL) was added in an amount of 200 μL each. When the entire amount was dissolved after the addition of the test solution, the compound according to the present invention was added as appropriate. The mixture was sealed, shaken at 37 ° C. for 1 hour, filtered, and 100 μL of methanol was added to 100 μL of each filtrate for 2-fold dilution. The dilution ratio was changed as needed. It was checked for air bubbles and precipitates, sealed and shaken. The compound according to the present invention was quantified by the absolute calibration curve method using HPLC.

Test Example 12: Ames test The mutagenicity of the compound according to the present invention is evaluated by the Ames test using Salmonella typhimurium TA98 strain, TA100 strain, TA1535 strain, TA1537 strain and Escherichia coli WP2uvrA strain as test strains. To do. Histidine is mixed with 0.1 mL of DMSO solution of the compound according to the present invention with 0.5 mL of S9mix under metabolic activation conditions, 0.5 mL of phosphate buffer and 0.1 mL of test bacterial solution under non-metabolic activation conditions. And 2 mL of layered soft agar containing biotin or tryptophan is layered on a minimal glucose agar plate. At the same time, for negative control substances (DMSO) and positive control substances (2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene) Will be carried out in the same way. After culturing at 37 ° C. for 48 hours, the emerging mutant colonies are counted and evaluated in comparison with the negative control group. When the number of reverted mutant colonies increases in a concentration-dependent manner and becomes more than twice the number of colonies in the negative control group, it is judged as positive (+).

Test Example 13: Nav test For the purpose of assessing the risk of arrhythmia of the compound according to the present invention, depolarization of the myocardium using HEK cells expressing Voltage gated sodium channel (Nav1.5 channel) encoded by the SCN5A gene. The action of the compound according to the present invention on ^{Na +} current ( _INA ), which plays an important role in the process, was investigated.
Using a fully automatic patch clamp system (QPatch; Sodium Bioscience A / S), cells are held at a membrane potential of -100 mV by the whole cell patch clamp method and induced when a depolarizing stimulus of -10 mV is applied for 20 milliseconds. I _Na was recorded. Extracellular fluid adjusted to 0.3% of dimethylsulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ₂ : 2 mmol / L, MgCl ₂ : 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxythyl) -1-piperazine molar compound, 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid): 10 mmol / L, TEA (Tetramethylmolarium Hydroxide): 10 mmol / L, pH = 7. Using 4) as a medium, extracellular fluid in which the medium and the compound according to the present invention were dissolved at the desired concentrations were applied to cells at room temperature for 5 minutes or longer. From the resulting _{I Na,} analysis software; using (QPatch Assay software Sophion Bioscience A / S), the absolute value of the maximum peak current based on the current value in the holding membrane potential was measured. Moreover, to calculate the ratio of the maximum peak current during the compounds applied according to the present invention with respect to the maximum peak current at medium applied to evaluate the effect on I _Na of the compounds according to the present invention.
(result)
Compound I-8 103%
Compound I-2 102%
Compound I-12 97.1%
Compound II-3 96.7%
Compound II-18 109%
Compound II-23 93.3%
Compound II-24 89.3%
Compound II-37 88.8%
Compound II-38 86.2%
Compound II-41 78.8%
Compound II-33 90.7%
From the above results, no obvious increase in current was observed, and it was found that the pharmaceutical composition of the present invention has little concern about arrhythmia due to an increase in Na current.

Test Example 14: Anti-HIV activity evaluation test using peripheral blood mononuclear cells (PBMC) of healthy subjects A serial dilution series of test samples was prepared on a 96-well microplate (50 μL / well). The 1.0 x 10 ⁵ cells / well Virus solution of PBMC and HIV stimulated with Phytohemagglutinin (PHA), and mixed several minutes required well and allowed to react for 1 hour at 37 ° C.. After the reaction, the cell suspension is centrifuged to discard the supernatant, the infected cells are dispersed at 150 μL / well in the culture medium for the required number of wells, and 150 μL / well is dispensed into a 96-well microplate containing the test sample. did. The mixture was mixed with a plate mixer and _{cultured in a CO 2} incubator for 4 days. The reverse transcriptase activity in the culture medium was measured. The 90% HIV inhibition concentration (EC90) was determined from the concentration-dependent curve using the 4-parameter logistic curve fitting model shown below.
y = A + ((BA) / (1+ (C / x) ^D ))

A = minimum inhibition rate (negative control, 0%)
B = maximum inhibition rate (positive control, 100%)
C = Compound concentration at inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%)

(result)
Compound I-8 1.0 nM
Compound II-23 1.7 nM

Test Example 15: Anti-HIV activity evaluation test in the presence of human serum protein A serial dilution series of test samples was prepared on a 96-well microplate (50 μL / well). A human serum protein solution (human serum protein concentration 50%) was dispensed at 100 μL / well into a 96-well microplate containing a test sample, and allowed to stand at room temperature for 1 hour. The culture solution was dispensed at 100 μL / well on the serum-free plate. 3.0 x 10 ⁵ cells / well of MT-4 cells and 3 μL / well of HIV virus solution were mixed for the required number of wells and reacted at 37 ° C. for 1 hour. After the reaction, the cell suspension is centrifuged to discard the supernatant, the infected cells are dispersed in the culture medium for the required number of wells at 50 μL / well, and 50 μL / in a 96-well microplate containing the test sample and human serum protein. Wells were dispensed one by one (final concentration of human serum protein: 25%). The mixture was mixed with a plate mixer and _{cultured in a CO 2} incubator for 4 days. 30 μL of MTT (3- (4,5-dimethylthialzol-2-yl) -2,5-diphenyltetrazolium bromide) solution was dispensed into each well. The reaction was carried out in a _{CO 2 incubator for 1 hour.} 150 μL of supernatant was removed from each well to avoid sucking cells. 150 μL of cytolyte was added and mixed well with a plate mixer until all the cells were lysed. The absorbance of the mixed plate was measured with a microplate reader at two wavelengths of 560 nm / 690 nm. The 50% HIV inhibition concentration (EC50) was determined from the concentration-dependent curve using the 4-parameter logistic curve fitting model shown below.
y = A + ((BA) / (1+ (C / x) ^D ))

A = minimum inhibition rate (negative control, 0%)
B = maximum inhibition rate (positive control, 100%)
C = Compound concentration at inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%)

In addition, potency with (PS) was calculated based on the following formula. PS is an extrapolated value of 100% human serum protein concentration.
PS = 4 x (EC50 in the presence of 25% human serum protein / EC50 in the absence of human serum protein)

(result)
PS in the presence of human serum protein is shown in the table (100% extrapolated value).
Compound I-8 116
Compound II-23 56

Pharmaceutical Examples The compounds according to the invention can be prepared by any conventional route, in particular enteral, eg, orally, eg, in the form of tablets or capsules, or parenterally, eg, in the form of injectables or suspensions. It can be administered topically, for example, in the form of a lotion, gel, ointment or cream, or in the form of a nasal or capsule as a pharmaceutical composition. Pharmaceutical compositions comprising a compound according to the invention in free form or in pharmaceutically acceptable salt form, together with at least one pharmaceutically acceptable carrier or diluent, are mixed in a conventional manner. Can be manufactured by granulation or coating methods. For example, the oral composition can be a tablet, a granule, or a capsule containing an excipient, a disintegrant, a binder, a lubricant, an active ingredient, or the like. In addition, the composition for injection may be a solution or a suspension, may be sterilized, or may contain a preservative, a stabilizer, a buffer, or the like.

The compound according to the present invention has integrase inhibitory activity and / or cell proliferation inhibitory activity against viruses, particularly HIV. Therefore, the pharmaceutical composition of the present invention is useful for the prevention or treatment of various diseases associated with integrase and viral infections (eg, AIDS).

Claims (15)

A pharmaceutical composition containing a compound represented by the following formula or a pharmaceutically acceptable salt thereof.
Equation (I):

(During the ceremony,
Ring A is a substituted or unsubstituted non-aromatic heterocycle;
The C ring is a benzene ring or a pyridine ring;
Q is a 5- or 6-membered aromatic heterocycle optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, haloalkyls, alkyloxys, haloalkyloxys, and alkylaminos;
R ^1s are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
L is a substituted or unsubstituted alkylene;
R ³ is a substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
Substituents on the R ³ and R ⁴ , or R ³ and A rings may combine with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle;
n is an integer from 1 to 3)
A pharmaceutical composition comprising the compound according to claim 1, wherein the ring A is any of the following rings, or a pharmaceutically acceptable salt thereof.

(During the ceremony,
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
The dashed line represents the presence or absence of a bond;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c or S, where Z ¹ , Z ² , Z ³ , In Z ⁴ and Z ⁵ , the number of heteroatoms constituting the ring structure of the A ring is 0 or 1;
Z ¹ and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ , Z ³ and Z ⁵ , R ⁴ and Z ² , R ⁴ and Z ³ , R ⁴ And Z ⁴ or R ⁴ and Z ^{5 may be} interspersed with one heteroatom selected from NR 5c, O and S, even if a substituted or unsubstituted C1-C4 crosslink is formed. Often;
R ^5a and R ^5b are independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
^{R 5a} and R ^5b on the same carbon atom may be combined to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;
R ^5c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted. Alternatively, it is an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ³ and R ⁴ may be combined with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle)
A pharmaceutical composition containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring A is any of the following rings.

(During the ceremony,
R ⁴ is hydrogen or a substituted or unsubstituted alkyl;
The dashed line represents the presence or absence of a bond;
Ring B is a substituted or unsubstituted carbon ring or a substituted or unsubstituted heterocycle;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are independently CR ^5a R ^5b , CR ^5a , C, O, N, NR ^5c or S (provided that they are constituent atoms of the B ring). If CR ^5a , C or N);
Z ¹ and Z ³ , Z ¹ and Z ⁴ , Z ¹ and Z ⁵ , Z ² and Z ⁴ , Z ² and Z ⁵ , Z ³ and Z ⁵ , R ⁴ and Z ² , R ⁴ and Z ³ , R ⁴ And Z ⁴ or R ⁴ and Z ^{5 may be} interspersed with one heteroatom selected from NR 5c, O and S, even if a substituted or unsubstituted C2-C4 crosslink is formed. well;
R ^5a and R ^5b are independently hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
^{R 5a} and R ^5b on the same carbon atom may be combined to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;
R ^5c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted. Alternatively, it is an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ³ and R ⁴ may be combined with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle)
A pharmaceutical composition containing the compound according to any one of claims 1 to 3 represented by the following formula or a pharmaceutically acceptable salt thereof.
Equation (II):

(During the ceremony,
Ring A is the following ring;

X1 is CR ^A9a R ^A9b or O;
^{R A5a, R A5b, R A6a} , R A6b, R A7a and ^{R A7b} are each independently hydrogen, alkyl, alkyloxy or alkyloxy alkyl;
R ^A5a and ^{R A6a} or ^{R A6a} and ^{R A7a,} together with the adjacent atoms, an aromatic carbon ring which may be substituted by halogen, non-3-6 membered optionally substituted by halogen It may form a 4-6 member non-aromatic heterocycle which may be substituted with an aromatic carbocycle or halogen (provided that an aromatic carbocycle is formed, ^RA5b and ^RA6b , or R. ^A6b and ^RA7b together form a bond);
^RA5b and ^RA6b may be combined to form a bond;
^{R A8a, R A8b, R A9a} , R A9b, R A10a, R A10b, R A11a and ^{R A11b} are each independently hydrogen, alkyl, alkyloxy or alkyloxy alkyl;
R ^{A 8a} and ^{R A 10a} may form a C1-C3 bridge together;
R ^{A 10a} and ^{R A 11a,} together with the adjacent atoms may form a non-aromatic carbocyclic ring of 5 members;
^RA9a and ^RA9b may be combined with adjacent atoms to form a 4-membered non-aromatic carbocycle or a 5-membered non-aromatic heterocycle;
^RA8a and ^RA9a may come together to form a bond;
The C ring is a benzene ring or a pyridine ring;
Q is a 5-membered aromatic heterocycle;
R ^1s are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
R ^2a and R ^2b are independently hydrogen, alkyl or haloalkyl;
R ³ is alkyl or haloalkyl;
R ⁴ is hydrogen or alkyl;
n is an integer from 1 to 3)
A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ^{R 3 is alkyl or haloalkyl.}
A pharmaceutical composition containing the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is alkyl.}
A pharmaceutical composition comprising the compound according to any one of claims 1, 3, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein ^{R 4 is hydrogen or alkyl.}
A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ^{R 1 is independently halogen, alkyl or haloalkyl.}
A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ^{R 1 is an independent halogen.}
A pharmaceutical composition comprising the compound according to any one of claims 4 and 6 to 9, wherein ^{R 2a is hydrogen and R 2b is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof.}
A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or 5 to 10 or a pharmaceutically acceptable salt thereof, wherein Q is a 5-membered aromatic heterocycle.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or 5 to 11 or a pharmaceutically acceptable salt thereof, wherein the stericity of the carbon atom adjacent to ^{R 4 is as follows.}

(In the formula, A ring and R ⁴ are as defined in claim 1)
Compounds I-2, I-6, I-8, II-3, II-18, II-23, II-24, II-27, II-29, II-33, II-37, II-38, II -44, II-48, II-50, II-51, II-52, II-54, II-55, II-56, II-57, II-58, II-61, II-62, II-63 , II-65, II-67 and II-68, the pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to any one of claims 1 to 13, which is an anti-HIV agent.
An HIV integrase inhibitor comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.