JP7361013B2 - Pharmaceutical composition containing polycyclic carbamoylpyridone derivative - Google Patents

Description

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

Among viruses, Human Immunodeficiency Virus (hereinafter referred to as HIV), which is a type of retrovirus, is a cause of acquired immunodeficiency syndrome (hereinafter referred to as AIDS). It has been known. Currently, there are various combination drugs for the treatment of AIDS that combine an integrase inhibitor (such as dolutegravir) as the main drug with two nucleic acid reverse transcriptase inhibitors with different resistance profiles (ABC + 3TC, FTC + TAF, etc.). Recommended for naïve patients in guidelines. Because of its strong medicinal efficacy and high safety, satisfaction rates are higher than with earlier therapeutic drugs. On the other hand, since safe drugs have been developed and the prognosis is good, it is now recommended to start treatment as soon as HIV infection is detected, and the average life expectancy of people infected with HIV is approaching that of healthy people. The period of drug administration is becoming longer. If side effects of nucleic acid reverse transcriptase inhibitors or resistant viruses appear due to long-term medication, there is no simple treatment available, so it is best to leave nucleic acid reverse transcriptase inhibitors unused. There is a movement to do so. Therefore, it is desired to establish a two-drug therapy using two main drugs, and there is a desire to develop a main drug that can be combined with an integrase inhibitor. In addition, in order to improve the patient's QOL (Quality of Life), such as relieving fatigue caused by long-term medication use and enjoying daily life more, we recommend using therapeutic drugs that require longer dosing intervals, i.e. once at intervals of one month or more. There is a desire to develop a long-acting injection that can complete the treatment once injected.

In order to meet such needs, the integrase inhibitor cabotegravir is currently under development as a long-acting injection at Ph3. Rilpivirine, a non-nucleic acid reverse transcriptase inhibitor, is also being developed as a long-acting injection, and efforts are being made to establish a treatment method using these two drugs. However, these drugs require injections once every one or two months, and require three to four painful injections in total. Therefore, in order to further improve patients' QOL, it is desired to develop a drug that is less painful at a lower dose and can be treated with injections once every three months.
As integrase inhibitors, raltegravir and elvitegravir are already on the market as first generation oral agents, and dolutegravir as second generation. When dolutegravir is used in naïve patients, no resistance mutations emerge, but when dolutegravir is used to treat patients infected with viruses resistant to first-generation integrase inhibitors, additional resistance mutations are added and may no longer work. Therefore, it is desired to develop an inhibitor with a higher resistance barrier than dolutegravir.

In addition, bicyclic or more carbamoylpyridone derivatives are known as anti-HIV drugs having an integrase inhibitory effect (Patent Documents 1 to 29). Among these, Patent Document 3 describes carbamoylpyridotriazine derivatives. However, the optically active tricyclic or more-cyclic carbamoylpyridotriazine derivative, which is the compound of the present application, is not described.

International Publication No. 2006/088173 pamphlet International Publication No. 2006/116764 pamphlet International Publication No. 2007/049675 pamphlet International Publication No. 2011/129095 pamphlet International Publication No. 2014/099586 pamphlet International Publication No. 2014/100323 pamphlet International Publication No. 2014/104279 pamphlet International Publication No. 2014/183532 pamphlet International Publication No. 2014/200880 pamphlet International Publication No. 2015/039348 pamphlet International Publication No. 2015/048363 pamphlet International Publication No. 2015/089847 pamphlet International Publication No. 2015/095258 pamphlet International Publication No. 2015/006731 pamphlet International Publication No. 2015/006733 pamphlet International Publication No. 2015/199167 pamphlet International Publication No. 2016/090545 pamphlet International Publication No. 2016/094198 pamphlet International Publication No. 2016/094197 pamphlet International Publication No. 2016/106237 pamphlet International Publication No. 2016/154527 pamphlet International Publication No. 2016/161382 pamphlet International Publication No. 2016/187788 pamphlet International Publication No. 2016/191239 pamphlet International Publication No. 2017/087256 pamphlet International Publication No. 2017/087257 pamphlet International Publication No. 2017/106071 pamphlet International Publication No. 2017/113288 pamphlet International Publication No. 2017/116928 pamphlet

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

As a result of extensive studies, the present inventors found that a novel carbamoylpyridone derivative has an integrase inhibitory effect with a high resistance barrier. Furthermore, the pharmaceutical composition of the present invention may be an antiviral drug (e.g., an antiretroviral drug, an anti-HIV drug, an anti-HTLV-1 (Human T cell leukemia virus type 1) drug, an anti-FIV drug, (Feline immunodeficiency virus: Feline AIDS virus) drug, anti-SIV (Simian immunodeficiency virus: Simian AIDS virus) drug), especially as an anti-HIV drug, anti-AIDS drug, or a therapeutic drug for related diseases, etc. The present invention shown in FIG.

（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、ピリジン環または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^２ａおよびＲ^２ｂは隣接する炭素原子と一緒になって非芳香族炭素環または非芳香族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；
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、Ｓ、Ｓ（＝Ｏ）またはＳ（＝Ｏ）_２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、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非芳香族炭素環式基であり；
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、それぞれ独立して、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芳香族炭素環、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］Ａ環が、以下のいずれかの環であり；

Ｘ１が、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が、それぞれ独立して、水素、ハロゲン、アルキル、アルキルオキシ、アルキルオキシアルキルまたは３－６員の非芳香族炭素環式基であり；
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が、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が、それぞれ独立して、水素、ハロゲン、アルキル、アルキルオキシ、アルキルオキシアルキルまたは３－６員の非芳香族炭素環式基であり；
Ｒ^Ａ８ａおよびＲ^Ａ１０ａが、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が、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が、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環が、ベンゼン環またはピリジン環であり；
Ｒ^１が、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が、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が、アルキルまたはハロアルキルであり；
Ｒ^４が、水素またはアルキルであり；および
ｎが、１～３の整数である、［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。
［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、かつ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、［１］～［３］、または［５］～［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］Ｒ^２ａが水素であり、Ｒ^２ｂが水素またはアルキルである、［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。
［１２］Ｃ環が、ベンゼン環またはピリジン環である、［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。
［１３］化合物Ｉ－２、Ｉ－６、Ｉ－１１、Ｉ－１５、ＩＩ－４、ＩＩ－８、ＩＩ－９、ＩＩ－１５、ＩＩ－１８、ＩＩ－２０、ＩＩ－２１、ＩＩ－２２、ＩＩ－２３、ＩＩ－２４、ＩＩ－２６、ＩＩ－２８、ＩＩ－３１、ＩＩ－３７、ＩＩ－４０、ＩＩ－４１、ＩＩ－４２、ＩＩ－４４、ＩＩ－４６、ＩＩ－４９、ＩＩ－５１、ＩＩ－５３、ＩＩ－５７、ＩＩ－６０、ＩＩ－６６、ＩＩ－７０、ＩＩ－７１、ＩＩ－８７、ＩＩ－９０、ＩＩ－９９、ＩＩ－１０６、ＩＩ－１１２、ＩＩ－１３３、ＩＩ－１３６、ＩＩ－１５３およびＩＩ－１５６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。
［１３－１］化合物Ｉ－２、Ｉ－６、Ｉ－１１およびＩ－１５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。
［１３－２］化合物ＩＩ－４、ＩＩ－８、ＩＩ－９、ＩＩ－１５、ＩＩ－１８、ＩＩ－２０、ＩＩ－２１、ＩＩ－２２、ＩＩ－２３、ＩＩ－２４、ＩＩ－２６、ＩＩ－２８、ＩＩ－３１、ＩＩ－３７、ＩＩ－４０、ＩＩ－４１、ＩＩ－４２、ＩＩ－４４、ＩＩ－４６、ＩＩ－４９、ＩＩ－５１、ＩＩ－５３、ＩＩ－５７、ＩＩ－６０、ＩＩ－６６、ＩＩ－７０、ＩＩ－７１、ＩＩ－８７、ＩＩ－９０、ＩＩ－９９、ＩＩ－１０６、ＩＩ－１１２、ＩＩ－１３３、ＩＩ－１３６、ＩＩ－１５３およびＩＩ－１５６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］、［１３－１］および［１３－２］のいずれかに記載の医薬組成物。
［１５］［１］～［１４］、［１３－１］および［１３－２］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。 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.
Formula (I):

(In the formula,
Ring A is a substituted or unsubstituted non-aromatic heterocycle;
Ring C is a benzene ring, a pyridine ring or a 5-membered aromatic heterocycle;
each R ¹ is independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
R ^2a and R ^2b are each independently hydrogen, alkyl or haloalkyl;
R ^2a and R ^2b may be combined with adjacent carbon atoms to form a non-aromatic carbocycle or a non-aromatic heterocycle;
R ³ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
R ³ and R ⁴ , or R ³ and the substituents on the A ring, together with adjacent atoms, may 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.

(In the formula,
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
Dashed lines represent the presence or absence of a bond;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c , S, S(=O) or S(=O) ₂ , where the number of heteroatoms constituting the ring structure of ring A in 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 between R ⁴ and Z ⁵ , a substituted or unsubstituted C1-C4 bridge may be formed, which may include one hetero atom selected from NR ^5c , O and S. often;
R ^5a and R ^5b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclic group;
R ^5a and R ^5b on the same carbon atom may be taken together to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;
R ^5c is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbon a cyclic group, a substituted or 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 described in [1] or a pharmaceutically acceptable salt thereof, wherein ring A is any of the following rings.

(In the formula,
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
Dashed lines represent the presence or absence of a bond;
Ring B is a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, or a substituted or unsubstituted non-aromatic heterocycle;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , C, O, N, NR ^5c or S (provided that 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 between R ⁴ and Z ⁵ , a substituted or unsubstituted C2-C4 bridge may be formed, which may include one hetero atom selected from NR ^5c , O and S. well;
R ^5a and R ^5b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy;
R ^5a and R ^5b on the same carbon atom may be taken together 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 or 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] Ring A is any of the following rings;

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, halogen, alkyl, alkyloxy, alkyloxyalkyl or a 3-6 membered non-aromatic carbocyclic group; can be;
R ^A5a and R ^A6a , or R ^A6a and R ^A7a together with adjacent atoms represent an aromatic carbocyclic ring which may be substituted with halogen, a 3-6 membered non-ring which may be substituted with halogen; An aromatic carbocycle or a 4- to 6-membered non-aromatic heterocycle optionally substituted with halogen may be formed (however, in the case of forming an aromatic carbocycle, R ^A5b and R ^A6b , or R ^A6b and R ^A7b together form a bond);
R ^A5b and R ^A6b may be taken together 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, halogen, alkyl, alkyloxy, alkyloxyalkyl or 3-6 membered non-aromatic is a group carbocyclic group;
R ^A8a and R ^A10a may together form a C1-C3 bridge;
R ^A10a and R ^A11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocycle;
R ^A9a and R ^A9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocycle or a 5-membered non-aromatic heterocycle;
R ^A8a and R ^A9a may be taken together to form a bond;
C ring is a benzene ring or a pyridine ring;
R ¹ is each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
R ^2a and R ^2b are each independently hydrogen, alkyl or haloalkyl;
R ³ is alkyl or haloalkyl;
A pharmaceutical composition containing the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen or alkyl; and n is an integer of 1 to 3. thing.
[5] A pharmaceutical composition containing the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl or haloalkyl.
[6] A pharmaceutical composition containing the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl.
[7] A pharmaceutical composition containing the compound according to any one of [1] to [3], [5] or [6], or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen or alkyl.
[8] A pharmaceutical composition containing the compound according to any one of [1] to [7], or a pharmaceutically acceptable salt thereof, wherein R ¹ is each independently halogen, alkyl, or haloalkyl.
[9] A pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [7], wherein each R ¹ is independently a halogen.
[10] R ^2a is hydrogen, and R ^2b is hydrogen or alkyl,
or the compound according to any one of [1] to [3] or [5] to [9], in which R ^2a and R ^2b form a C3-C4 carbocycle together with adjacent carbon atoms; A pharmaceutical composition containing a pharmaceutically acceptable salt.
[11] A pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [9], wherein R ^2a is hydrogen and R ^2b is hydrogen or alkyl.
[12] Contains the compound according to any one of [1] to [3], or [5] to [11], or a pharmaceutically acceptable salt thereof, wherein the C ring is a benzene ring or a pyridine ring; Pharmaceutical composition.
[13] Compounds I-2, I-6, I-11, I-15, II-4, II-8, II-9, II-15, II-18, II-20, II-21, II- 22, II-23, II-24, II-26, II-28, II-31, II-37, II-40, II-41, II-42, II-44, II-46, II-49, II-51, II-53, II-57, II-60, II-66, II-70, II-71, II-87, II-90, II-99, II-106, II-112, II- 133, II-136, II-153 and II-156. A pharmaceutical composition containing the compound according to [1] or a pharmaceutically acceptable salt thereof.
[13-1] A pharmaceutical composition containing the compound described in [1] or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds I-2, I-6, I-11 and I-15. .
[13-2] Compounds II-4, II-8, II-9, II-15, II-18, II-20, II-21, II-22, II-23, II-24, II-26, II-28, II-31, II-37, II-40, II-41, II-42, II-44, II-46, II-49, II-51, II-53, II-57, II- From 60, II-66, II-70, II-71, II-87, II-90, II-99, II-106, II-112, II-133, II-136, II-153 and II-156 A pharmaceutical composition containing the compound according to [1] or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
[14] The pharmaceutical composition according to any one of [1] to [13], [13-1] and [13-2], which is an anti-HIV agent.
[15] An HIV integrase inhibitor containing the compound according to any one of [1] to [14], [13-1] and [13-2] or a pharmaceutically acceptable salt thereof.

（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、ピリジン環または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^２ａおよびＲ^２ｂは隣接する炭素原子と一緒になって非芳香族炭素環または非芳香族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；
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、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、それぞれ独立して、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芳香族炭素環、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’］Ａ環が、以下のいずれかの環であり；

Ｘ１が、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が、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が、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が、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が、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が、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が、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環が、ベンゼン環またはピリジン環であり；
Ｒ^１が、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が、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が、アルキルまたはハロアルキルであり；
Ｒ^４が、水素またはアルキルであり；および
ｎが、１～３の整数である、［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。
［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、かつ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、［１’］～［３’］、または［５’］～［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’］Ｒ^２ａが水素であり、Ｒ^２ｂが水素またはアルキルである、［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。
［１２’］Ｃ環が、ベンゼン環またはピリジン環である、［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。
［１３’］化合物Ｉ－２、Ｉ－６、Ｉ－１１およびＩ－１５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’］化合物ＩＩ－４、ＩＩ－８、ＩＩ－９、ＩＩ－１５、ＩＩ－１８、ＩＩ－２０、ＩＩ－２１、ＩＩ－２２、ＩＩ－２３、ＩＩ－２４、ＩＩ－２６、ＩＩ－２８、ＩＩ－３１、ＩＩ－３７、ＩＩ－４０、ＩＩ－４１、ＩＩ－４２、ＩＩ－４４、ＩＩ－４６、ＩＩ－４９、ＩＩ－５１、ＩＩ－５３、ＩＩ－５７、ＩＩ－６０、ＩＩ－６６、ＩＩ－７０、ＩＩ－７１、ＩＩ－８７、ＩＩ－９０、ＩＩ－９９、ＩＩ－１０６、ＩＩ－１１２、ＩＩ－１３３、ＩＩ－１３６、ＩＩ－１５３およびＩＩ－１５６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。
［１５’］抗ＨＩＶ剤である、［１’］～［１４’］のいずれかに記載の医薬組成物。
［１６’］［１’］～［１４’］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'] A pharmaceutical composition containing a compound represented by the following formula or a pharmaceutically acceptable salt thereof.
Formula (I):

(In the formula,
Ring A is a substituted or unsubstituted non-aromatic heterocycle;
Ring C is a benzene ring, a pyridine ring or a 5-membered aromatic heterocycle;
each R ¹ is independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
R ^2a and R ^2b are each independently hydrogen, alkyl or haloalkyl;
R ^2a and R ^2b may be combined with adjacent carbon atoms to form a non-aromatic carbocycle or a non-aromatic heterocycle;
R ³ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
R ³ and R ⁴ , or R ³ and the substituents on the A ring, together with adjacent atoms, may 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.

(In the formula,
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
Dashed lines represent the presence or absence of a bond;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c or S, where Z ¹ , Z ² , Z ³ , The number of heteroatoms constituting the ring structure of ring A in 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 between R ⁴ and Z ⁵ , a substituted or unsubstituted C1-C4 bridge may be formed, which may include one hetero atom selected from NR ^5c , O and S. often;
R ^5a and R ^5b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy;
R ^5a and R ^5b on the same carbon atom may be taken together to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;
R ^5c is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbon a cyclic group, a substituted or 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 described in [1'] or a pharmaceutically acceptable salt thereof, wherein ring A is any of the following rings.

(In the formula,
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
Dashed lines represent the presence or absence of a bond;
Ring B is a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, or a substituted or unsubstituted non-aromatic heterocycle;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , C, O, N, NR ^5c or S (provided that 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 between R ⁴ and Z ⁵ , a substituted or unsubstituted C2-C4 bridge may be formed, which may include one hetero atom selected from NR ^5c , O and S. well;
R ^5a and R ^5b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy;
R ^5a and R ^5b on the same carbon atom may be taken together 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 or 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'] Ring A is any of the following rings;

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 alkyloxyalkyl;
R ^A5a and R ^A6a , or R ^A6a and R ^A7a together with adjacent atoms represent an aromatic carbocyclic ring which may be substituted with halogen, a 3-6 membered non-ring which may be substituted with halogen; An aromatic carbocycle or a 4- to 6-membered non-aromatic heterocycle optionally substituted with halogen may be formed (however, in the case of forming an aromatic carbocycle, R ^A5b and R ^A6b , or R ^A6b and R ^A7b together form a bond);
R ^A5b and R ^A6b may be taken together 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 alkyloxyalkyl;
R ^A8a and R ^A10a may together form a C1-C3 bridge;
R ^A10a and R ^A11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocycle;
R ^A9a and R ^A9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocycle or a 5-membered non-aromatic heterocycle;
R ^A8a and R ^A9a may be taken together to form a bond;
C ring is a benzene ring or a pyridine ring;
R ¹ is each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy;
R ^2a and R ^2b are each independently hydrogen, alkyl or haloalkyl;
R ³ is alkyl or haloalkyl;
R ⁴ is hydrogen or alkyl; and n is an integer of 1 to 3, containing the compound according to any one of [1'] to [3'] or a pharmaceutically acceptable salt thereof; Pharmaceutical composition.
[5'] A pharmaceutical composition containing the compound according to any one of [1'] to [3'] or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl or haloalkyl.
[6'] A pharmaceutical composition containing the compound according to any one of [1'] to [4'] or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl.
[7'] Contains the compound according to any one of [1'] to [3'], [5'] or [6'], or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen or alkyl , pharmaceutical composition.
[8'] A pharmaceutical composition containing the compound according to any one of [1'] to [7'] or a pharmaceutically acceptable salt thereof, wherein R ¹ is each independently halogen, alkyl, or haloalkyl. thing.
[9'] A pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof according to any one of [1'] to [7'], wherein R ¹ is each independently a halogen.
[10'] R ^2a is hydrogen, and R ^2b is hydrogen or alkyl,
or any one of [1'] to [3'] or [5'] to [9'], in which R ^2a and R ^2b form a C3-C4 carbocycle together with adjacent carbon atoms or a pharmaceutically acceptable salt thereof.
[11'] A pharmaceutical composition containing the compound according to any one of [1'] to [9'] or a pharmaceutically acceptable salt thereof, wherein R ^2a is hydrogen and R ^2b is hydrogen or alkyl. thing.
[12'] The compound according to any one of [1'] to [3'] or [5'] to [11'], wherein the C ring is a benzene ring or a pyridine ring, or a pharmaceutically acceptable compound thereof A pharmaceutical composition containing a salt.
[13'] A pharmaceutical composition containing the compound described in [1'] or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds I-2, I-6, I-11 and I-15. .
[14'] Compounds II-4, II-8, II-9, II-15, II-18, II-20, II-21, II-22, II-23, II-24, II-26, II -28, II-31, II-37, II-40, II-41, II-42, II-44, II-46, II-49, II-51, II-53, II-57, II-60 , II-66, II-70, II-71, II-87, II-90, II-99, II-106, II-112, II-133, II-136, II-153 and II-156 A pharmaceutical composition containing the compound described in [1'] or a pharmaceutically acceptable salt thereof selected from the group.
[15'] The pharmaceutical composition according to any one of [1'] to [14'], which is an anti-HIV agent.
[16'] An HIV integrase inhibitor containing the compound according to any one of [1'] to [14'] or a pharmaceutically acceptable salt thereof.

（式中、
Ａ環は、置換もしくは非置換の複素環であり；
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；
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；
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^５d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^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）
［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^５ｃ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^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^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^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；
Ｒ^１、Ｒ^２ａ、Ｒ^２ｂ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、［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’’］以下の化合物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。

［１１’’］抗ＨＩＶ剤である、［１’’］～［９’’］のいずれかに記載の医薬組成物。
［１２’’］ＨＩＶインテグラーゼ阻害剤である、［１’’］～［９’’］のいずれかに記載の医薬組成物。 [1''] A pharmaceutical composition containing a compound represented by the following formula or a pharmaceutically acceptable salt thereof.
Formula (I'):

(In the formula,
Ring A is a substituted or unsubstituted heterocycle;
each R ¹ is independently halogen, alkyl, haloalkyl, alkyloxy, nitrile, or haloalkyloxy;
R ^2a and R ^2b are each independently hydrogen, alkyl, or haloalkyl;
R ^2a and R ^2b may be taken together with adjacent carbon atoms to form a carbocycle or a heterocycle;
R ³ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
R ³ and R ⁴ , or R ³ and the substituents on the A ring, together with adjacent atoms, may form a substituted or unsubstituted 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.

(In the formula,
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
Dashed lines represent the presence or absence of a bond;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c , S, S(=O), S(=O) ₂ , or S(=O)=NR ^5d , where the number of heteroatoms among 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 A substituted or unsubstituted C2-C4 bridge may be formed between and Z ⁴ or R ⁴ and Z ⁵ ;
R ^5a and R ^5b are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted ureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted 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 unsubstituted non-aromatic heterocyclic oxy;
R ^5a and R ^5b on the same carbon atom may be taken together 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 carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl; non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or 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 carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl; non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
The 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)
[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.

(In the formula,
R ⁴ is hydrogen or substituted or unsubstituted alkyl;
Dashed lines represent the presence or absence of a bond;
Ring B is a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , C, O, N, NR ^5c , S, S(=O), S(=O) ₂ , or S(=O)=NR ^5c (however, when it is a constituent atom of ring B, it is 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 A substituted or unsubstituted C2-C4 bridge may be formed between and Z ⁴ or R ⁴ and Z ⁵ ;
R ^5a and R ^5b are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted ureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted 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 unsubstituted non-aromatic heterocyclic oxy;
R ^5a and R ^5b on the same carbon atom may be taken together 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 carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl; non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
The 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.
Formula (I-2):

(In the formula,
R ³ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
R ⁴ is hydrogen or 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 each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl oxy, or substituted or unsubstituted amino;
R ^6b and R ^9b , R ^9b and R ^7b , or R ^7b and R ^8b together with adjacent atoms may form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle. ;
R ⁴ and R ^7b or R ^6b and R ^8b may be taken together to form a substituted or unsubstituted C2-C4 bridge;
R ^6b and R ¹⁰ or R ¹⁰ and R ^7b may be taken together with adjacent atoms to form a substituted or unsubstituted heterocycle;
R ³ and R ⁴ or R ³ and R ^6b may be taken together with adjacent atoms to form a substituted or unsubstituted heterocycle;
^R10 is 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 carbocycle carbonyl, substituted or unsubstituted aromatic heterocycle carbonyl, substituted or unsubstituted non-aromatic heterocycle carbonyl, substituted or unsubstituted aromatic carbocycle oxycarbonyl, substituted or unsubstituted non-aromatic group carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
R ¹¹ is 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 carbocycle carbonyl, substituted or unsubstituted aromatic heterocycle carbonyl, substituted or unsubstituted non-aromatic heterocycle carbonyl, substituted or unsubstituted aromatic carbocycle oxycarbonyl, substituted or unsubstituted non-aromatic group carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl;
R ¹ , R ^2a , R ^2b and n have the same meaning as [1''])
[5''] A pharmaceutical composition containing the compound according to any one of [1''] to [4''] or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl or haloalkyl.
[6''] A pharmaceutical composition containing the compound according to any one of [1''] to [5''] or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.
[7''] The compound according to any one of [1''] to [6''], wherein n is an integer of 2 or 3, and R ¹ is each independently halogen, alkyl, or haloalkyl. or a pharmaceutically acceptable salt thereof.
[8''] R ^2a is hydrogen and R ^2b is hydrogen or alkyl,
or the compound according to any one of [1''] to [7''], wherein R ^2a and R ^2b together with adjacent carbon atoms form a C3-C4 carbocyclic ring, or a pharmaceutically acceptable compound thereof A pharmaceutical composition containing a salt.
[9''] A pharmaceutical composition containing the compound described in [1''] or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds.

[11''] The pharmaceutical composition according to any one of [1''] to [9''], which is an anti-HIV agent.
[12''] The pharmaceutical composition according to any one of [1''] to [9''], 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 pharmaceutical composition to a human.
The present invention further provides the above pharmaceutical composition for use as an anti-HIV drug.

The compounds according to the present invention have integrase inhibitory activity and/or cell growth inhibitory activity against viruses, particularly HIV and its resistant viruses. Therefore, it is useful for the prevention or treatment of various diseases and viral infections (eg, AIDS) involving integrase. More preferably, compounds according to the invention are useful as long-acting integrase inhibitors. Furthermore, it has an excellent resistance profile, such as being difficult to generate new HIV-resistant viruses. More preferably, the compounds according to the present invention also have prophylactic or therapeutic effects against HIV drug-resistant viruses. Even more preferably, the compound according to the present invention has low clearance, long half-life in the body, excellent solubility, metabolic stability, or bioavailability, and has low cytotoxicity and side effects (for example, mutagenicity). It is also useful as a drug with little concern about electrocardiogram QT interval prolongation, arrhythmia).

The meaning of each term used in this specification will be explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms.
The term "consisting of" means having only the constituent features.
The term "comprising" is meant to be non-limiting and does not exclude elements not listed.

"Halogen" includes fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms. Particularly preferred are fluorine atoms and chlorine atoms.

"Alkyl" includes a straight chain or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. 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, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

"Alkenyl" has one or more double bonds at any position and has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. straight-chain or branched hydrocarbon groups. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl. etc.
Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl.

"Aromatic carbocyclic group" means a monocyclic or two or more ring cyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl, and the like.
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 term "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 ring in the above-mentioned "aromatic carbocyclic group" fused to a monocyclic or two-ring or more non-aromatic carbocyclic group.
Furthermore, the "non-aromatic carbocyclic group" also includes a group that is bridged as described below 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 even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
The non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, and the like.

"Aromatic heterocyclic group" means a monocyclic or bicyclic or more aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N in the ring. do.
The aromatic heterocyclic group having two or more rings includes those in which the ring in the above "aromatic carbocyclic group" is fused to a monocyclic or two or more ring aromatic heterocyclic group, and the bond is It may be present in either ring.
The monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 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, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazo Lyle, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. can be mentioned.
The aromatic heterocyclic group having 3 or more rings is preferably 13 to 15 members. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and the like.

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。 "Non-aromatic heterocyclic group" refers to a mono- or bi- or more-ring non-aromatic cyclic group having one or more same or different heteroatoms arbitrarily selected from O, S, and N in the ring. means. A non-aromatic heterocyclic group with two or more rings is a monocyclic or a non-aromatic heterocyclic group with 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 the ring in the "aromatic heterocyclic group" is condensed to a monocyclic or two or more non-aromatic carbocyclic group. The bond may be present in any ring.
Furthermore, the "non-aromatic heterocyclic group" also includes a group that is bridged as described below 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 3-membered non-aromatic heterocyclic group include thiiranyl, oxiranyl, 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, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, 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, dihydroxazinyl, and tetrahydropyridazinyl. Examples include hexahydropyrimidinyl, dioxazinyl, thiinyl, 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. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl, and the like.

"Aromatic carbocycle," "non-aromatic carbocycle," "aromatic heterocycle," and "non-aromatic heterocycle" refer to the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and "non-aromatic carbocyclic group," respectively. "group", "aromatic heterocyclic group" and "non-aromatic heterocyclic group".

"Carbocycle" means the above-mentioned "aromatic carbocycle" or "non-aromatic carbocycle."

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

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

As used herein, "may be substituted with substituent group α" means "may be substituted with one or more groups selected from substituent group α". The same applies to "may be substituted with substituent group β", "may be substituted with substituent group γ", and "may be substituted with substituent group γ'".

The substituents for "substituted alkyl", "substituted alkyloxy", "substituted alkylcarbonyl", "substituted alkyloxycarbonyl", "substituted C1-C4 bridge" and "substituted C2-C4 bridge" include the following substituent groups: An example is A. A carbon atom at any 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,
Alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkyloxycarbonyl which may be 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 Alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α,
Amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, and optionally substituted with substituent group β. sulfamoyl, ureido optionally substituted with substituent group β;
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic carbocyclic group optionally substituted with substituent group γ group heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy which may be substituted with substituent group γ, aromatic heterocyclic oxy which may be substituted with substituent group γ', non-aromatic heterocyclic oxy which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocycle optionally substituted with substituent group γ Ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, unsubstituted with substituent group γ' Non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ, aromatic heterocyclic carbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', substituent group γ Aromatic carbocyclic oxycarbonyl optionally substituted with , non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ Carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, substituted with substituent group γ' Non-aromatic carbocyclic alkyloxy, optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy, optionally substituted with substituent group γ', 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 heterocyclic alkyloxycarbonyl group, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituent group γ' Optionally substituted non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', Aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocycle optionally substituted with substituent group γ Ring sulfinyl, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, even if substituted with substituent group γ' Good non-aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

Substituent group 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, alkyl carbonyl optionally substituted with substituent group α, 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 , alkenylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic carbocyclic group optionally substituted with substituent group γ 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 with substituent group γ, non-aromatic heterocyclic alkyl which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyl optionally substituted with group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ , non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' Non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituted with substituent group γ' Non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, aromatic heterocyclyl sulfanyl optionally substituted with substituent group γ', substituent Aromatic carbocyclic sulfinyl optionally substituted with group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ , non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ' Aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with 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 carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocycle oxy", "substituted aromatic heterocycle oxy", "Aromatic carbocycle" and "Aromatic heterocycle" in "Substituted aromatic carbocycle carbonyl", "Substituted aromatic heterocycle carbonyl", "Substituted aromatic carbocycle oxycarbonyl" and "Substituted aromatic heterocycle oxycarbonyl" Examples of the substituent on the ring include the following substituent group B. An atom at any 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, optionally substituted with substituent group α Good alkenyloxy, optionally substituted alkylcarbonyloxy with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, substituent Alkenylcarbonyl optionally substituted with group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl 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, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, substituent Alkylsulfonyl optionally substituted with group α, alkenylsulfonyl optionally substituted with substituent group α,
Amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, and optionally substituted with substituent group β. sulfamoyl, ureido optionally substituted with substituent group β;
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic carbocyclic group optionally substituted with substituent group γ group heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy which may be substituted with substituent group γ, aromatic heterocyclic oxy which may be substituted with substituent group γ', non-aromatic heterocyclic oxy which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocycle optionally substituted with substituent group γ Ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, unsubstituted with substituent group γ' Non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ, aromatic heterocyclic carbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', substituent group γ Aromatic carbocyclic oxycarbonyl optionally substituted with , non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ Carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, even if substituted with substituent group γ' Good non-aromatic 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 aromatic carbocyclic alkyloxy which may be substituted with the substituent group γ', non-aromatic carbocyclic alkyloxy which may be substituted with the substituent group γ', Non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, even substituted with substituent group γ' Good non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', Aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', even substituted with substituent group γ Good aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituent group Non-aromatic carbocyclic sulfanyl optionally substituted with γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic ring optionally substituted with substituent group γ' Sulfanyl, aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ group heterocyclic sulfinyl, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, substituent group γ' non-aromatic carbocyclic sulfonyl which may be optionally substituted, aromatic heterocyclic sulfonyl which may be optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl which may be optionally substituted with substituent group γ'.

"Substituted carbocyclic", "substituted heterocyclic", "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocyclic oxy", "substituted non-aromatic heterocyclic group""ringoxy","substituted non-aromatic carbocyclic carbonyl", "substituted non-aromatic heterocyclic carbonyl", "substituted non-aromatic carbocyclic oxycarbonyl" and "substituted non-aromatic heterocyclic oxycarbonyl" Examples of substituents on the rings of "carbocycle" and "non-aromatic heterocycle" include the following substituent group C. An atom at any 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 substituents for "substituted amino", "substituted carbamoyl", and "substituted ureido" include the following substituent group D. It may be substituted with one or two groups selected from substituent group D.
Substituent group D: alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkyl carbonyl optionally substituted with substituent group α, 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 , alkenylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic carbocyclic group optionally substituted with substituent group γ 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 with substituent group γ, non-aromatic heterocyclic alkyl which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyl optionally substituted with group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ , non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, optionally 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, 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 if substituted with substituent group γ Good aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and substituent group γ' Optionally substituted non-aromatic heterocyclic sulfonyl.

Preferred embodiments of each symbol in the compound represented by formula (I) or (I') are shown below. As the compound represented by formula (I) or (I'), all combinations of the specific examples shown below are exemplified.

Ring A includes substituted or unsubstituted non-aromatic heterocycles.
Ring A 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 above-mentioned non-aromatic heterocycle. selected. One of the preferred embodiments of ring A is the following ring (a), (b) or (c), more preferably ring (a) or (b).

Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c , S, S(=O) or S(=O) ₂ Here, the number of heteroatoms constituting the ring structure of ring A in Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is 0 to 3.
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each independently CR ^5a R ^5b , CR ^5a , O, N, NR ^5c or S, where Z ¹ , Z ² , Z ³ , The number of heteroatoms constituting the ring structure of ring A in Z ⁴ and Z ⁵ 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 , more preferably CR ^5a R ^5b , O or NR ^5c , and particularly preferred CR ^5a R ^5b or O.
One of the other preferred embodiments of Z ² is CR ^5a R ^5b , O, S, S(=O), S(=O) ₂ or NR ^5c , CR ^5a R ^5b , O, S, S( =O) ₂ or NR ^5c is more preferred, and CR ^5a R ^5b , O, S or S(=O) ₂ is 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 , A substituted or unsubstituted C1-C4 bridge may be formed between R ⁴ and Z ⁴ or R ⁴ and Z ⁵ . ^{Preferably , substituted or unsubstituted ( C1 _ _ _ _ _} -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 shown below. In this case, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ constituting Ring B are each independently CR ^5a , C or N.

Ring A is more preferably a ring (a1), (b1), (c1) or (e1), particularly preferably a ring (a1) or (b1).
Ring B is preferably a substituted or unsubstituted 3- to 7-membered carbon ring (examples of substituents: alkyl, halogen, hydroxy, haloalkyl) or a substituted or unsubstituted 4- to 7-membered heterocycle (examples of substituents: Examples: alkyl, halogen, hydroxy, haloalkyl), and more preferably a benzene ring, a 5- to 6-membered unsubstituted carbocycle, 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、以下のいずれかの環である。

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

can be mentioned.
One of the more preferred embodiments of ring A is any of the following rings.

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

Examples of X1 include CR ^A9a R ^A9b , O, NR ^A9c , S, S(=O) or S(=O) ₂ .
One of the preferred embodiments of X1 is CR ^A9a R ^A9b or O.
Another preferred embodiment of X1 is CR ^A9a R ^A9b , O, S or S(=O) ₂ .

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 R ^A14b or O.
However, when either 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 , R ^A7a and R ^A7b each independently represent hydrogen, halogen, alkyl, alkyloxy, alkyloxyalkyl, or a 3- to 6-membered non-aromatic carbocyclic group. can be mentioned.
R ^A5a , R ^A5b , R ^A6a , R ^A6b , R ^A7a and R ^A7b each independently include hydrogen, alkyl, alkyloxy or alkyloxyalkyl.
One of the preferred embodiments of R ^A5a is hydrogen or alkyl, preferably hydrogen.
One of the preferred embodiments of R ^A5b is hydrogen or alkyl, preferably hydrogen.
One of the preferred embodiments of R ^A6a is hydrogen, halogen, alkyl, alkyloxyalkyl or a 3-6 membered non-aromatic carbocyclic group, preferably hydrogen.
Another preferred embodiment of R ^A6a is hydrogen, alkyl or alkyloxyalkyl, preferably hydrogen.
One of the preferred embodiments of R ^A6b is hydrogen.
One of the preferred embodiments of R ^A7a is hydrogen, halogen, alkyl or alkyloxyalkyl, preferably alkyloxyalkyl.
One of the preferred embodiments of R ^A7b is hydrogen.
R ^A5a and R ^A6a , or R ^A6a and R ^A7a together with adjacent atoms represent an aromatic carbocyclic ring which may be substituted with halogen, a 3-6 membered non-ring which may be substituted with halogen; An aromatic carbocycle or a 4- to 6-membered non-aromatic heterocycle optionally substituted with halogen may be formed (however, in the case of forming an aromatic carbocycle, R ^A5b and R ^A6b , or R ^A6b and R ^A7b together form a bond).
R ^A5b and R ^A6b may be taken together to form a bond.
R ^A6a and R ^A6b may be combined with adjacent atoms to form a 3- to 6-membered non-aromatic carbocycle or a 4- to 6-membered non-aromatic heterocycle.

R ^A8a , R ^A8b , R ^A9a , R ^A9b , R ^A10a , R ^A10b , R ^A11a and R ^A11b each independently include hydrogen, alkyl, haloalkyl, alkyloxy or alkyloxyalkyl.
R ^A8a , R ^A8b , R ^A9a , R ^A9b , R ^A10a , R ^A10b , R ^A11a and R ^A11b each independently represent hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl or 3-6 membered non-aromatic carbocyclic groups.
One of the preferred embodiments of R ^A8a is hydrogen or alkyl, preferably hydrogen.
One of the preferred embodiments of R ^A8b is hydrogen or alkyl, preferably hydrogen.
One of the preferred embodiments of R ^A9a is hydrogen, alkyl or alkyloxyalkyl.
Another preferred embodiment of R ^A9a is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl or a 3-6 membered non-aromatic carbocyclic group.
One of the preferred embodiments of R ^A9b is hydrogen or alkyl, preferably hydrogen.
One of the preferred embodiments of R ^A10a is hydrogen, alkyl or alkyloxy, preferably hydrogen.
Another preferred embodiment of R ^A10a is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl or a 3-6 membered non-aromatic carbocyclic group.
One of the preferred embodiments of R ^A10b is hydrogen.
One of the preferred embodiments of R ^A11a is hydrogen or alkyl, preferably hydrogen.
Another preferred embodiment of R ^A11a is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl or a 3-6 membered non-aromatic carbocyclic group.
One of the preferred embodiments of R ^A11b is hydrogen.
R ^A8a and R ^A10a or R ^A8a and R ^A11a may be taken together to form a C1-C3 bridge.
R ^A10a and R ^A11a may be combined with adjacent atoms to form a 5-membered non-aromatic carbocycle.
R ^A9a and R ^A9b may be combined with adjacent atoms to form a 4-membered non-aromatic carbocycle or a 5-membered non-aromatic heterocycle.
R ^A8a and R ^A9a may be taken together to form a bond.
R ^A9c is hydrogen, alkyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbamoyl, aromatic carbocyclic group, aromatic heterocyclic group, aromatic carbocyclyl alkyl, or aromatic heterocyclyl alkyl.

R ^A12a , R ^A12b , R ^A13a , R ^A13b , R ^A14a , R ^A14b , R ^A15a , R ^A15b , R ^A16a and R ^A16b are each independently hydrogen, alkyl, alkyloxy or alkyloxyalkyl.
R ^A12a , R ^A12b , R ^A13a , R ^A13b , R ^A14a , R ^A14b , R ^A15a , R ^A15b , R ^A16a and R ^A16b each independently represent hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxy It is an alkyl or 3-6 membered non-aromatic carbocyclic group.
R ^A13c or R ^A14c is each independently alkyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbamoyl, aromatic carbocyclic group, aromatic heterocyclic group, aromatic carbocyclic alkyl, or aromatic heterocyclic group It is an alkyl.

R ¹ each independently includes halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy.
One preferred embodiment of R ¹ is each independently halogen, alkyl or haloalkyl.
R ¹ is preferably each independently halogen.

R ^2a and R ^2b each independently include hydrogen, alkyl, or haloalkyl.
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 carbocycle taken together with adjacent carbon atoms.
R ^2a is preferably hydrogen.
R ^2b is preferably hydrogen or methyl, more preferably hydrogen.
R ^2a and R ^2b are preferably C3-C4 non-aromatic carbocycles taken together with adjacent carbon atoms.

^R3 is 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 of the preferred embodiments of R ³ is alkyl or haloalkyl.
R ³ is preferably alkyl.

Examples of R ⁴ include hydrogen or alkyl.
One preferred embodiment of R ⁴ is hydrogen or methyl, and a more preferred embodiment is hydrogen.

R ^5a and R ^5b each independently represent hydrogen, halogen, substituted or unsubstituted alkyl (examples of substituents: halogen, alkyloxy), substituted or unsubstituted alkyloxy (examples of substituents: halogen) or a substituted or unsubstituted non-aromatic carbocyclic group, in which R ^5a and R ^5b on the same carbon atom are together a substituted or unsubstituted non-aromatic carbocyclic group (example of substituent: halogen) Alternatively, a substituted or unsubstituted non-aromatic heterocycle (example of substituent: halogen) may be formed.
One preferred embodiment of R ^5a and R ^5b is each independently hydrogen, alkyl, or alkyloxyalkyl.

R ^5c each independently represents hydrogen, substituted or unsubstituted alkyl (examples of substituents: alkyloxy, aromatic carbocyclic group, aromatic heterocyclic group), substituted or unsubstituted alkylcarbonyl, Substituted 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 or an unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
One preferred embodiment of R ^5c is each independently hydrogen or substituted or unsubstituted alkyl (example of substituent: alkyloxy).

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

Examples of the C ring include a benzene ring, a pyridine ring, and a 5-membered aromatic heterocycle.
One preferred embodiment of ring C is a benzene ring or a pyridine ring, preferably a benzene ring.

Furthermore, the compound represented by formula (I') is preferably a compound represented by formula (I-2) below.

Preferred embodiments of each symbol in the compound represented by formula (I-2) are shown below. As the compound represented by formula (I-2), all combinations of the specific examples shown below are exemplified.
R ¹ , R ^2a , R ^2b , R ³ , R ⁴ and n are the same as the preferred embodiments of the compound represented by formula (I') above.

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 preferred embodiment 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 each independently hydrogen, or substituted or unsubstituted alkyl (example of substituent: halogen ), with hydrogen or methyl being particularly preferred.

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

（式中、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））
C環は、ベンゼン環であり；
Ｒ^１は、それぞれ独立して、ハロゲンであり；
Ｒ^２ａおよびＲ^２ｂは、それぞれ独立して、水素であり；
Ｒ^３は、アルキルであり；
Ｒ^４は、水素またはアルキルであり；および
ｎは、１～３の整数である。 One of the preferred embodiments of the compound represented by formula (I) is
The A ring is the following ring;

(wherein R ^A5a , R ^A5b , R ^A6a , R ^A6b , R ^A7a and R ^A7b are each independently hydrogen, alkyl, alkyloxy or alkyloxyalkyl;
R ^A5a and R ^A6a , or R ^A6a and R ^A7a together with adjacent atoms represent an aromatic carbon ring which may be substituted with halogen, a 3-6 membered non-ring which may be substituted with halogen; An aromatic carbocycle or a 4- to 6-membered non-aromatic heterocycle optionally substituted with halogen may be formed (however, in the case of forming an aromatic carbocycle, R ^A5b and R ^A6b , or R ^A6b and R ^A7b together form a bond))
C ring is a benzene ring;
each R ¹ is independently a halogen;
R ^2a and R ^2b are each independently hydrogen;
R ³ is alkyl;
R ⁴ is hydrogen or alkyl; and n is an integer from 1 to 3.

The compound of the present invention is characterized by its excellent resistance profile, pharmacokinetics, and safety by fixing the A ring in a specific steric position in formula (I), (I'), or formula (I-2). The point is that In addition, the characteristics of the compound of the present invention are that, in formula (I), (I') or formula (I-2), it is an optically active tricyclic or more-cyclic carbamoylpyridotriazine derivative, resulting in a resistance profile, It has excellent pharmacokinetics and safety.

Unless otherwise specified, the compounds according to the invention are not limited to a particular isomer, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, (optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

Pharmaceutically acceptable salts of the compound according to the present invention include, for example, the compound according to the present invention, an alkali metal (e.g., lithium, sodium, potassium, etc.), an alkaline earth metal (e.g., calcium, barium, etc.), Magnesium, transition metals (e.g. zinc, iron, etc.), ammonia, organic bases (e.g. trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids. salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, etc.). Acid, lactic acid, 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.). These salts can be formed by conventional methods.

The compound according to the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate, etc.), a co-crystal, and/or a crystal polymorph, and the present invention covers such various types. Also included are solvates, co-crystals and polymorphs. A "solvate" may be coordinated with any number of solvent molecules (eg, water molecules, etc.) 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, adhere to adsorbed water, or form a hydrate. Moreover, crystal polymorphs 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 the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.

The compound according to the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs. Prodrugs are derivatives of the compounds of the invention which have groups that can be chemically or metabolically degradable and which, upon solvolysis or under physiological conditions, become pharmaceutically active compounds of the invention in vivo. . Prodrugs are compounds that undergo enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo and are converted into compounds represented by formula (I), (I') or formula (I-2); It includes compounds that are hydrolyzed by gastric acid or the like and converted into compounds represented by formula (I), (I') or formula (I-2). Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.

When the compound represented by formula (I), (I') or formula (I-2) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable prodrugs such as acyloxy derivatives and sulfonyloxy derivatives prepared by reacting with a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride and a mixed anhydride, or by reacting with a condensing agent. Illustrated. 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 -, and 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；ＲおよびＲ’はカルボキシ保護基；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、Ｐ^２、ＲおよびＲ’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り、ＲおよびＲ’はアルキル等である；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ａをカルボキシ保護基の一般的な脱保護反応に付すことにより、化合物ａ１を得ることができる。
工程２
化合物ａ１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ａ２および、トリエチルアミン、Ｎ－メチルモルホリン、ピリジン、ＤＩＥＡ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ａ３を得ることができる。
工程３
化合物ａ３に、ＴＨＦ、メタノール、エタノール、クロロホルム、ジクロロメタン、ＴＨＦ等の溶媒の存在下、化合物ａ４を加え、６０℃～１２０℃、好ましくは８０℃～１００℃にて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ａ５を得ることができる。
工程４
化合物ａ５を、アミノ保護基の一般的な脱保護反応に付すことにより、化合物ａ６を得ることができる。
工程５
化合物ａ６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ａ７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ａ８を得ることができる。
工程６
化合物ａ８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ａ９を得ることができる。
工程７
化合物ａ９はキラルＳＦＣによって、ａ１０に分割することができる。
工程８
化合物ａ１０を、ヒドロキシ保護基の一般的な脱保護反応に付すことにより、化合物Ｉａを得ることができる。 (Method for producing the compound according to the present invention)
The compound according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by the treatments normally performed in organic chemistry experiments.
The compounds according to the present invention can be synthesized with reference to techniques known in the art.
(Production method 1)

(wherein, P ¹ is a hydroxy protecting group; P ² is an amino protecting group; R and R' are carboxy protecting groups; Z is Z ² , Z ³ , Z ⁴ or Z ⁵ ; m is an integer from 1 to 4; Hal is a halogen; P ¹ , P ² , R and R' may be any group that can be protected and/or deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc., e.g. P ¹ is aromatic carbocyclic alkyl, etc., P ² is alkyloxycarbonyl, etc., R and R' are alkyl, etc.; other symbols have the same meanings as above)
Process 1
Compound a1 can be obtained by subjecting compound a, which is commercially available or can be prepared by a known method, to a general deprotection reaction of the carboxy protecting group.
Process 2
Compound a2, which can be prepared by a commercially available or known method, by adding a condensing agent such as HATU, WSC/HCl, PyBOP to compound a1 in the presence of a solvent such as DMF, DMA, NMP, THF, chloroform, dichloromethane, etc., and triethylamine, By adding a tertiary amine such as N-methylmorpholine, pyridine, or DIEA, and reacting at 10°C to 60°C, preferably 20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours. , compound a3 can be obtained.
Process 3
Compound a4 is added to compound a3 in the presence of a solvent such as THF, methanol, ethanol, chloroform, dichloromethane, THF, etc., and the mixture is heated at 60°C to 120°C, preferably 80°C to 100°C for 0.5 to 24 hours. Compound a5 can be obtained by reacting preferably for 1 to 12 hours.
Process 4
Compound a6 can be obtained by subjecting compound a5 to a general deprotection reaction of an amino protecting group.
Process 5
Compound a6, in the presence of a solvent such as dichloromethane, dichloroethane, chloroform, methanol, ethanol, toluene, DMF, DMA, THF, etc., compound a7, which is commercially available or can be prepared by a known method, and acetic acid, p-toluenesulfonic acid, methane. Compound a8 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. .
Process 6
A base such as cesium carbonate or potassium carbonate, and a salt such as sodium iodide or potassium iodide are added to compound a8 in the presence of a solvent such as DMF, DMA, NMP, or THF, and the mixture is heated at 0°C to 60°C, preferably 0°C. Compound a9 can be obtained by reacting at a temperature of 0.1 to 24 hours, preferably 1 to 12 hours, at a temperature of 0.degree. to 40.degree.
Process 7
Compound a9 can be resolved into a10 by chiral SFC.
Process 8
Compound Ia can be obtained by subjecting compound a10 to a general deprotection reaction of the hydroxy protecting group.

（式中、各記号は前記と同意義。）
工程１
化合物ａ５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、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、市販または、公知の方法で調製できる化合物ｂ１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ｂ２を得ることができる。
工程２
化合物ｂ２をアセタールの一般的な脱保護反応に付すことにより、化合物ｂ３を得ることができる。
工程３
化合物ｂ３に、ジクロロメタン、ジクロロエタン、クロロホルム、アセトニトリル、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、メタンスルホン酸、トリフルオロ酢酸等の酸を加え、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ａ９を得ることができる。
工程４
化合物Ｉａは、上記製法１の工程７および８に従い合成することができる。 (Production method 2)

(In the formula, each symbol has the same meaning as above.)
Process 1
Add a base such as cesium carbonate, potassium carbonate, or triethylamine to compound a5 in the presence of a solvent such as DMF, DMA, NMP, or THF, and a salt such as sodium iodide or potassium iodide when Hal is chloro, and prepare a commercially available product. Alternatively, compound b2, which can be prepared by a known method, is added and reacted at 0°C to 60°C, preferably 20°C to 40°C, for 0.1 to 24 hours, preferably 1 hour to 12 hours. can be obtained.
Process 2
Compound b3 can be obtained by subjecting compound b2 to a general deprotection reaction of acetal.
Process 3
Add an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid to compound b3 in the presence of a solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, toluene, DMF, DMA, THF, etc. Compound a9 can be obtained by reacting at 20° C. to 130° C., preferably 80° C. to 120° C., for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Process 4
Compound Ia can be synthesized according to steps 7 and 8 of Production Method 1 above.

（式中、各記号は前記と同意義。）
工程１
化合物ａ５に、ＴＨＦ、トルエン等の溶媒の存在下、市販または、公知の方法で調製できる化合物ｃ１を加え、ＤＥＡＤ／ＰＰｈ_３、ＤＩＡＤ／ＰＰｈ_３、ＤＭＥＡＤ／ＰＰｈ_３、ＡＤＤＰ／ｎ－Ｂｕ_３Ｐ等の光延試薬を加えて０℃～１００℃、好ましくは２０℃～８０℃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ｃ２を得ることができる。
工程２
化合物ｃ２を、アルケンの一般的な酸化開裂反応に付すことにより、化合物ｃ３を得ることができる。例えば，オゾン分解やＫ_２ＯｓＯ_４／ＮａＩＯ_４等が使用される。
工程３
化合物ｃ３を、製法２の工程３と同様の条件で反応させることにより、化合物ａ９を得ることができる。
工程４
化合物Ｉａは、製法１の工程７および８に従い合成することができる。 (Production method 3)

(In the formula, each symbol has the same meaning as above.)
Process 1
Compound c1, which is commercially available or can be prepared by a known method, is added to compound a5 in the presence of a solvent such as THF or toluene to form DEAD/PPh ₃ , DIAD/PPh ₃ , DMEAD/PPh ₃ , ADDP/n-Bu ₃ P Compound c2 can be obtained by adding a Mitsunobu reagent such as and reacting at 0° C. to 100° C., preferably 20° C. to 80° C., for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Process 2
Compound c3 can be obtained by subjecting compound c2 to a general oxidative cleavage reaction of alkenes. For example, _ozonolysis , _K2OsO4 / _NaIO4 , etc. are used.
Process 3
Compound a9 can be obtained by reacting compound c3 under the same conditions as in step 3 of manufacturing method 2.
Process 4
Compound Ia can be synthesized according to Steps 7 and 8 of Production Method 1.

（式中、各記号は前記と同意義。）
工程１
化合物ａ５および化合物ｄ１を、製法３の工程１と同様の条件で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、ヒドロキシ保護基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を水酸基の一般的な酸化反応に付すことにより、化合物ｄ４を得ることができる。
工程４
化合物ｄ４を、製法２の工程３と同様の条件で反応させることにより、化合物ａ９を得ることができる。
工程５
化合物Ｉａは、製法１の工程７および８に従い合成することができる。 (Production method 4)

(In the formula, each symbol has the same meaning as above.)
Process 1
Compound d2 can be obtained by reacting compound a5 and compound d1 under the same conditions as in step 1 of production method 3.
Process 2
Compound d3 can be obtained by subjecting compound d2 to a general deprotection reaction of a hydroxy protecting group.
Process 3
Compound d4 can be obtained by subjecting compound d3 to a general oxidation reaction of the hydroxyl group.
Process 4
Compound a9 can be obtained by reacting compound d4 under the same conditions as in step 3 of manufacturing method 2.
Process 5
Compound Ia can be synthesized according to Steps 7 and 8 of Production Method 1.

（式中、各記号は前記と同意義。）
工程１
化合物ａ５および化合物ｅ１を、製法１の工程５と同様の条件で反応させることにより、化合物ｅ２を得ることができる。
工程２
化合物ｅ２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ｅ３を得ることができる。
工程３
ヒドロキシ保護基の一般的な脱保護反応に付すことにより、化合物ｅ４を得ることができる。
工程４
化合物ｅ４に、ＴＨＦ，トルエン等の溶媒の存在下、ＤＥＡＤ／ＰＰｈ_３、ＤＩＡＤ／ＰＰｈ_３、ＤＭＥＡＤ／ＰＰｈ_３、ＡＤＤＰ／ｎ－Ｂｕ_３Ｐ等の光延試薬を加えて０℃～１００℃、好ましくは２０℃～８０℃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ａ９を得ることができる。
工程５
化合物Ｉａは、製法１の工程７および８に従い合成することができる。 (Production method 5)

(In the formula, each symbol has the same meaning as above.)
Process 1
Compound e2 can be obtained by reacting compound a5 and compound e1 under the same conditions as in step 5 of production method 1.
Process 2
A base such as cesium carbonate or potassium carbonate is added to compound e2 in the presence of a solvent such as DMF, DMA, NMP, or THF, and the mixture is heated at 0°C to 60°C, preferably 0°C to 40°C for 0.1 to 24 hours. Compound e3 can be obtained by reacting for a period of time, preferably from 1 hour to 12 hours.
Process 3
Compound e4 can be obtained by subjecting the hydroxy protecting group to a general deprotection reaction.
Process 4
A Mitsunobu reagent such as DEAD/PPh ₃ , DIAD/PPh ₃ , DMEAD/PPh ₃ , ADDP/n-Bu ₃ P is added to compound e4 in the presence of a solvent such as THF or toluene, and the mixture is heated at 0°C to 100°C, preferably. Compound a9 can be obtained by reacting at 20° C. to 80° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Process 5
Compound Ia can be synthesized according to Steps 7 and 8 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, if a reactive functional group (eg, OH, COOH, NH ₂ ) is present in a side chain moiety, it may be protected before the reaction and deprotected after the reaction, if desired.
Protective groups (amino protecting group, hydroxy protecting group, etc.) include, for example, ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc., as described in Protective Groups in Organic Synthesis, T. W. Written by John Wiley & Sons Inc. (1991) and the like can be mentioned. The method for introducing and removing a protecting group is a method commonly used in organic synthetic chemistry [for example, Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1991)] or according to the method described therein. In addition to the above-mentioned production method, the functional group contained in each substituent may be transformed by a known method [for example, Comprehensive Organic Transformations, R. C. (1989) etc.], and some of the compounds according to the present invention can be used as synthetic intermediates to lead to further novel derivatives. Intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do. Further, the intermediate can also be subjected to the next reaction without being particularly purified.

The pharmaceutical composition of the present invention is useful, for example, as a medicine such as an antiviral drug. The compounds according to the present invention have a significant 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 viruses that produce at least integrase and proliferate in animal cells upon infection, such as retroviruses (e.g., HIV -1, HIV-2, HTLV-1, SIV, FIV, etc.), and is useful as an anti-HIV drug. More preferred compounds according to the present invention have characteristics such as high blood concentration, long duration of effect, and/or remarkable tissue distribution in terms of pharmacokinetics. Also, preferred compounds according to the invention are safe in terms of side effects (eg, inhibition of CYP enzymes, mutagenicity, electrocardiogram QT interval prolongation, arrhythmia).

The pharmaceutical composition of the present invention can also be used in combination therapy in combination with anti-HIV drugs having different mechanisms of action, such as reverse transcriptase inhibitors, protease inhibitors and/or entry inhibitors.
Furthermore, the above-mentioned uses include not only use as an anti-HIV combination drug, but also use as a combination drug that increases the anti-HIV activity of other anti-HIV drugs, such as in cocktail therapy.
In addition, the pharmaceutical composition of the present invention can be used in the field of gene therapy to prevent retroviral vector infection from spreading to tissues other than the target tissue when using retroviral vectors based on HIV or MLV. can be used. In particular, when cells, etc. are infected with a vector in vitro and then returned to the body, administering the pharmaceutical composition of the present invention in advance can prevent unnecessary infection within the body. .

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

For oral administration, solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.), liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, etc.) are prepared according to conventional methods. The drug may be administered in any commonly used dosage form, such as a limonade, an alcoholic beverage, an aromatic perfume, an extract, a decoction, a tincture, etc.). The tablets may be sugar-coated, film-coated, enteric-coated, extended-release, troches, sublingual, buccal, chewable or orally disintegrating tablets; powders and granules may be dry syrups; Alternatively, the capsules may be soft capsules, microcapsules or sustained release capsules.

For parenteral administration, injections, drops, external preparations (e.g. eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, gargles, enemas, It can be suitably administered in any commonly used dosage form such as ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.). The injection may be an emulsion of O/W, W/O, O/W/O, W/O/W type, or the like.

A pharmaceutical composition can be prepared by mixing an effective amount of the compound according to the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, as necessary. can. Furthermore, by appropriately changing the effective amount, dosage form, and/or various pharmaceutical additives of the compound according to the present invention, the pharmaceutical composition can be made into a pharmaceutical composition for children, the elderly, critically ill patients, or surgery. It can also be a thing. For example, pediatric pharmaceutical compositions may be used for neonates (less than 4 weeks after birth), infants (from 4 weeks after birth to less than 1 year), infants (from 1 year to 7 years), children (from 7 years old to less than 15 years), or children (from 7 years old to less than 15 years old). It can be administered to patients between the ages of 18 and 18. For example, geriatric pharmaceutical compositions may be administered to patients 65 years of age or older.

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

Examples are shown below.
<Abbreviation>
ADDP: 1,1'-(azodicarbonyl)dipiperidine Bn: Benzyl DEAD: Diethyl azodicarboxylate DIAD: Diisopropylazodicarboxylate DIEA: N,N-diisopropylethylamine DMA: Dimethylacetamide DMEAD: Di-2-methoxyethyl Azodicarboxylate DMF: dimethylformamide DMSO: dimethyl sulfoxide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate NMP: N- Methylpyrrolidone PyBOP: Tripyrrolidinophosphonium hexafluorophosphate (benzotriazol-1-yloxy) TBAF: Tetrabutylammonium fluoride THF: Tetrahydrofuran WSC/HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

NMR analysis obtained in each example was performed at 300 MHz or 400 MHz, and was measured using DMSO-d ₆ and CDCl ₃ . Furthermore, when NMR data is shown, there are cases where not all measured peaks are listed.
In the examples, "No." represents the compound number, "Structure" represents the chemical structure, and "MS" represents the molecular weight determined by LC/MS (liquid chromatography/mass spectrometry).

(Measurement condition)
(A) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters)
Flow rate: 0.8 mL/min; UV detection wavelength: 254 nm;
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid [B] is an acetonitrile solution containing 0.1% formic acid After performing a linear gradient from 5% to 100% solvent [B] in 3.5 minutes, 0. 100% solvent [B] was maintained for 5 minutes.
(B) Column: Shim-pack XR-ODS (2.2μm, i.d.50x3.0mm) (Shimadzu)
Flow rate: 1.6 mL/min; UV detection wavelength: 254 nm;
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10% to 100% solvent [B] is performed in 3 minutes, and 0. 100% solvent [B] was maintained for 5 minutes.
(C) Column: Shim-pack XR-ODS (2.2μm, i.d.50x3.0mm) (Shimadzu)
Flow rate: 1.6 mL/min; UV detection wavelength: 254 nm;
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10% to 100% solvent [B] is performed in 8 minutes, and 0. 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（９．５９ｇ、２２．２ｍｍｏｌ）をジクロロメタン（１８０ｍｌ）に溶解させ、（２，４－ジフルオロフェニル）メタンアミン（４．７７ｇ、３３．３ｍｍｏｌ）、ＰｙＢＯＰ（１３．９ｇ，２６．７ｍｍｏｌ）およびＤＩＥＡ（１１．７ｍｌ、６６．７ｍｍｏｌ）を加えて室温で１８時間撹拌した。反応液を水と飽和食塩水で洗浄し、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３（１１．５ｇ、収率９３％）を得た。
1H-NMR(CDCl₃)δ: 10.20(t, J=5.8Hz, 1H), 8.54(brs, 1H), 8.49(s, 1H), 7.38(m, 5H), 6.87-6.79(m, 2H), 6.61(t, J=5.5Hz, 1H), 5.28(s, 2H), 4.64(d, J=5.9Hz, 2H), 3.18(ddt, J=18.8, 10.2, 3.8Hz, 3H), 1.83-1.80(m, 1H), 1.43(s, 9H), 0.99(t, J=7.3Hz, 3H).
工程３
化合物３（１１．５ｇ、９．５４ｍｍｏｌ）をジオキサン（５７．５ｍｌ）に溶解させ、４ｍｏｌ／Ｌ塩酸／ジオキサン溶液（３００ｍｌ）を加えて室温で４時間撹拌した。反応液の溶媒を減圧留去した後、飽和炭酸ナトリウム水溶液を加え、クロロホルム-メタノールで抽出した。有機層を硫酸ナトリウムで乾燥した後、溶媒を留去して得られた粗生成物をジイソプロピルエーテルから固体化させ、化合物４（７．８０ｇ、収率８３％）を得た。
1H-NMR(CDCl₃)δ: 10.33(s, 1H), 8.60(s, 1H), 7.39(m, 5H), 6.83(m, 3H), 5.82(s, 2H), 5.26(s, 2H), 4.64(d, J=5.8Hz, 2H), 3.28-3.21(m, 2H), 1.02(t, J=7.3Hz, 3H).
工程４
化合物４（２００ｍｇ、０．４３８ｍｍｏｌ）をジクロロメタン（４ｍｌ）に溶解させ、化合物５（１１１ｍｇ、０．９２０ｍｍｏｌ）と酢酸（触媒量）を加えて室温で１９時間撹拌した。反応液を減圧濃縮後、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６（２６５ｍｇ、収率１００％）を得た。
MS: m/z = 559 [M+H]+
工程５
化合物６（２４５ｍｇ、０．４３８ｍｍｏｌ）をＤＭＦ（５ｍｌ）に溶解させ、炭酸セシウム（４２８ｍｇ、１．３１ｍｍｏｌ）を０℃で加えて室温で１８時間撹拌した。反応液に希塩酸を加え、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）により精製し、ラセミ混合物（１３９ｍｇ、収率６０％）を得た。
得られたラセミ混合物をＳＦＣにより光学分割し、化合物７を得た。
カラム：ＣＨＩＲＡＬＰＡＫ ＩＡ／ＳＦＣ （５μｍ、ｉ．ｄ．２５０ｘ２０ｍｍ）
流速：30 ｍＬ／分
ＵＶ検出波長：250ｎｍ
分取条件：MeOH/CO₂=45/55の組成比を維持して、21分間送液した。
1H-NMR(CDCl₃)δ: 10.46(s, 1H), 8.51(s, 1H), 7.58(m, 2H), 7.34(m, 4H), 6.81(m, 2H), 5.41(d, J=10.4Hz, 1H), 5.26(d, J=10.4Hz, 1H), 4.91(s, 1H), 4.64(m, 2H), 4.39(dd, J=14.3, 7.2Hz, 1H), 3.18-2.88(m, 3H), 2.24(d, J=14.7Hz, 1H), 2.00(m, 1H), 1.85(m, 2H), 1.72(d, J=13.6Hz, 1H), 1.38(m, 1H), 1.16(t, J=7.1Hz, 3H).
工程６
化合物７（４４．０ｍｇ、０．０８４０ｍｍｏｌ）をＤＭＦ（０．８８ｍｌ）に溶解させ、塩化リチウム（３５．７ｍｇ、０．８４２ｍｍｏｌ）を加えて９０℃で１．５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（１９ｍｇ、収率５２％）を得た。
1H-NMR(CDCl₃)δ: 11.98(s, 1H), 10.42(s, 1H), 8.46(s, 1H), 7.36(dd, J=15.2, 8.6Hz, 1H), 6.83-6.77(m, 2H), 5.06(s, 1H), 4.64(m, 2H), 4.35(td, J=14.2, 6.9Hz, 1H), 3.20-3.09(m, 2H), 3.00(d, J=10.8Hz, 1H), 2.31(d, J=15.4Hz, 1H), 2.06(m, 1H), 1.89(m, 2H), 1.76(m, 1H), 1.42-1.36(m, 1H), 1.24(t, J=7.1Hz, 4H). 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 the solvent of the reaction solution was distilled off under reduced pressure, diluted hydrochloric acid was added to make it acidic, and the mixture was extracted with ethyl acetate. After drying the organic layer with sodium sulfate, 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).
Process 2
Compound 2 (9.59 g, 22.2 mmol) was dissolved in dichloromethane (180 ml), (2,4-difluorophenyl)methanamine (4.77 g, 33.3 mmol), PyBOP (13.9 g, 26.7 mmol) and DIEA (11.7 ml, 66.7 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was washed with water and saturated brine, and the organic layer was dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 3 (11.5 g, yield 93%).
1H-NMR(CDCl ₃ )δ: 10.20(t, J=5.8Hz, 1H), 8.54(brs, 1H), 8.49(s, 1H), 7.38(m, 5H), 6.87-6.79(m, 2H) , 6.61(t, J=5.5Hz, 1H), 5.28(s, 2H), 4.64(d, J=5.9Hz, 2H), 3.18(ddt, J=18.8, 10.2, 3.8Hz, 3H), 1.83- 1.80(m, 1H), 1.43(s, 9H), 0.99(t, J=7.3Hz, 3H).
Process 3
Compound 3 (11.5 g, 9.54 mmol) was dissolved in dioxane (57.5 ml), 4 mol/L hydrochloric acid/dioxane solution (300 ml) was added, and the mixture was stirred at room temperature for 4 hours. After the solvent of the reaction solution was distilled off under reduced pressure, a saturated aqueous sodium carbonate solution was added, and the mixture was extracted with chloroform-methanol. After drying the organic layer with sodium sulfate, the solvent was distilled off, and the resulting crude product was solidified from diisopropyl ether to obtain Compound 4 (7.80 g, yield 83%).
1H-NMR(CDCl ₃ )δ: 10.33(s, 1H), 8.60(s, 1H), 7.39(m, 5H), 6.83(m, 3H), 5.82(s, 2H), 5.26(s, 2H) , 4.64(d, J=5.8Hz, 2H), 3.28-3.21(m, 2H), 1.02(t, J=7.3Hz, 3H).
Process 4
Compound 4 (200 mg, 0.438 mmol) was dissolved in dichloromethane (4 ml), compound 5 (111 mg, 0.920 mmol) and acetic acid (catalytic amount) were added, and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 6 (265 mg, yield 100%).
MS: m/z = 559 [M+H]+
Process 5
Compound 6 (245 mg, 0.438 mmol) was dissolved in DMF (5 ml), cesium carbonate (428 mg, 1.31 mmol) was added at 0°C, and the mixture was stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a racemic mixture (139 mg, yield 60%).
The obtained racemic mixture was optically resolved by SFC to obtain Compound 7.
Column: CHIRALPAK IA/SFC (5μm, i.d.250x20mm)
Flow rate: 30 mL/min UV detection wavelength: 250 nm
Preparation conditions: The composition ratio of MeOH/CO ₂ =45/55 was maintained and the solution was pumped for 21 minutes.
1H-NMR(CDCl ₃ )δ: 10.46(s, 1H), 8.51(s, 1H), 7.58(m, 2H), 7.34(m, 4H), 6.81(m, 2H), 5.41(d, J= 10.4Hz, 1H), 5.26(d, J=10.4Hz, 1H), 4.91(s, 1H), 4.64(m, 2H), 4.39(dd, J=14.3, 7.2Hz, 1H), 3.18-2.88( m, 3H), 2.24(d, J=14.7Hz, 1H), 2.00(m, 1H), 1.85(m, 2H), 1.72(d, J=13.6Hz, 1H), 1.38(m, 1H), 1.16(t, J=7.1Hz, 3H).
Process 6
Compound 7 (44.0 mg, 0.0840 mmol) was dissolved in DMF (0.88 ml), lithium chloride (35.7 mg, 0.842 mmol) was added, and the mixture was stirred at 90°C for 1.5 hours. Water was added to the reaction solution, 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 then the solvent was distilled off. The obtained crude product was solidified from diethyl ether to obtain Compound I-2 (19 mg, yield 52%).
1H-NMR(CDCl ₃ )δ: 11.98(s, 1H), 10.42(s, 1H), 8.46(s, 1H), 7.36(dd, J=15.2, 8.6Hz, 1H), 6.83-6.77(m, 2H), 5.06(s, 1H), 4.64(m, 2H), 4.35(td, J=14.2, 6.9Hz, 1H), 3.20-3.09(m, 2H), 3.00(d, J=10.8Hz, 1H) ), 2.31(d, J=15.4Hz, 1H), 2.06(m, 1H), 1.89(m, 2H), 1.76(m, 1H), 1.42-1.36(m, 1H), 1.24(t, J= 7.1Hz, 4H).

工程１
窒素雰囲気下、マグネシウム（３２２ｍｇ、１３．３ｍｍｏｌ）のＴＨＦ（３．０ｍＬ）溶液に、化合物８（１．３ｍＬ、１１．１ｍｍｏｌ）のＴＨＦ（７．０ｍＬ）溶液を滴下し、室温で３０分間撹拌した。反応液を０℃まで冷却し、ヨウ化銅（２１０ｍｇ、１．１ｍｍｏｌ）を加え、化合物９（１．２ｍＬ、１６．６ｍｍｏｌ）のＴＨＦ（６．０ｍＬ）溶液を滴下し、室温に昇温して２時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。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１０（１９２ｍｇ、収率１１％）を得た。
1H-NMR(CDCl₃)δ: 4.86(t, J=4.8Hz, 1H), 3.99-3.96(m, 2H), 3.90-3.79(m, 3H), 1.72-1.67(m, 2H), 1.55-1.48(m, 4H), 1.36(d, J=4.5Hz, 1H), 1.20(d, J=6.3Hz, 3H).
工程２
化合物１１（３３４ｍｇ、０．６０ｍｍｏｌ）のＴＨＦ（２．０ｍＬ）溶液に、化合物１０（１９２．２ｍｇ、１．２ｍｍｏｌ）、トリフェニルホスフィン（３１５ｍｇ、１．２ｍｍｏｌ）およびアゾジカルボン酸ビス(２－メトキシエチル)（２８１ｍｇ、１．０ｍｍｏｌ）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）により粗精製した。
MS: m/z = 699 [M+H]+
工程３
第２工程で得られた粗精製物（１００ｍｇ）のアセトニトリル（１．０ｍＬ）溶液に、パラトルエンスルホン酸水和物（４５．１ｍｇ、０．２４２ｍｍｏｌ）を加え、２１０分間加熱還流した。反応液を室温まで放冷し、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ＤＭＦ（１．０ｍＬ）に溶解させ、炭酸セシウム（１４０ｍｇ、０．４３ｍｍｏｌ）およびベンジルブロミド（３４．１μＬ、０．２９ｍｍｏｌ）を加え、室温で３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１３（６５．１ｍｇ）を得た。
MS: m/z = 537 [M+H]+
工程４
実施例１の工程６と同様の反応を行い、化合物Ｉ－５０（３１ｍｇ、収率５７％）を得た。
1H-NMR(CDCl₃)δ: 11.93(s, 1H), 10.40(s, 1H), 8.39(s, 1H), 7.40-7.34(m, 1H), 6.84-6.77(m, 2H), 5.11-5.09(m, 1H), 4.64(d, J=5.8Hz, 2H), 4.40-4.31(m, 1H), 3.27-3.21(m, 1H), 3.13-3.06(m, 1H), 2.32-2.28(m, 1H), 2.12-2.04(m, 1H), 1.86-1.83(m, 1H), 1.79-1.75(m, 1H), 1.63-1,48(m, 2H), 1.21(t, J=7.2Hz, 3H), 0.89(d, J=6.3Hz, 3H). Example 2

Process 1
Under a nitrogen atmosphere, a THF (7.0 mL) solution of compound 8 (1.3 mL, 11.1 mmol) was added dropwise to a THF (3.0 mL) solution of magnesium (322 mg, 13.3 mmol), and the mixture was stirred at room temperature for 30 minutes. did. The reaction solution was cooled to 0°C, copper iodide (210 mg, 1.1 mmol) was added, a solution of compound 9 (1.2 mL, 16.6 mmol) in THF (6.0 mL) was added dropwise, and the temperature was raised to room temperature. The mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 10 (192 mg, yield 11%).
1H-NMR(CDCl ₃ )δ: 4.86(t, J=4.8Hz, 1H), 3.99-3.96(m, 2H), 3.90-3.79(m, 3H), 1.72-1.67(m, 2H), 1.55- 1.48(m, 4H), 1.36(d, J=4.5Hz, 1H), 1.20(d, J=6.3Hz, 3H).
Process 2
A solution of Compound 11 (334 mg, 0.60 mmol) in THF (2.0 mL) was added with Compound 10 (192.2 mg, 1.2 mmol), triphenylphosphine (315 mg, 1.2 mmol), and bis(2-methoxy azodicarboxylate). ethyl) (281 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was roughly purified by silica gel column chromatography (hexane-ethyl acetate).
MS: m/z = 699 [M+H]+
Process 3
Para-toluenesulfonic acid hydrate (45.1 mg, 0.242 mmol) was added to a solution of the crude product (100 mg) obtained in the second step in acetonitrile (1.0 mL), and the mixture was heated under reflux for 210 minutes. The reaction solution was allowed to cool to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was dissolved in DMF (1.0 mL), cesium carbonate (140 mg, 0.43 mmol) and benzyl bromide (34.1 μL, 0.29 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 13 (65.1 mg).
MS: m/z = 537 [M+H]+
Process 4
The same reaction as in Step 6 of Example 1 was carried out to obtain Compound I-50 (31 mg, yield 57%).
1H-NMR(CDCl ₃ )δ: 11.93(s, 1H), 10.40(s, 1H), 8.39(s, 1H), 7.40-7.34(m, 1H), 6.84-6.77(m, 2H), 5.11- 5.09(m, 1H), 4.64(d, J=5.8Hz, 2H), 4.40-4.31(m, 1H), 3.27-3.21(m, 1H), 3.13-3.06(m, 1H), 2.32-2.28( m, 1H), 2.12-2.04(m, 1H), 1.86-1.83(m, 1H), 1.79-1.75(m, 1H), 1.63-1,48(m, 2H), 1.21(t, J=7.2 Hz, 3H), 0.89(d, J=6.3Hz, 3H).

工程１
化合物１１（３５２ｍｇ、０．６２９ｍｍｏｌ）のＤＭＦ（３．５ｍｌ）溶液に、炭酸カリウム（２６１ｍｇ、１．８９ｍｍｏｌ）と４－ブロモブテン（１４７ｍｇ、０．９４３ｍｍｏｌ）を加え、室温で一晩反応させた。反応液に水を加え、酢酸エチルで抽出した。有機層を水、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。
MS: m/z = 611 [M+H]+
工程２
工程１で得られた粗生成物に４ｍｏｌ／Ｌ塩酸／ジオキサン溶液（３．１５ｍｌ）を加え、室温で２時間撹拌した。反応液に飽和重曹水を加え、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。
MS: m/z = 511 [M+H]+
工程３
工程２で得られた粗生成物、アクロレイン（１０２ｍｇ、１．８３ｍｍｏｌ）、パラトルエンスルホン酸水和物（１１．６ｍｇ、０．０６１ｍｍｏｌ）をジクロロエタン（９．６ｍＬ）に溶解させ、１００℃で６時間撹拌した。反応液を室温まで放冷後、水と飽和重曹水を加え、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１６（１１５ｍｇ）を得た。
MS: m/z = 549 [M+H]+
工程４
化合物１６（６６．４ｍｇ、０．１２１ｍｍｏｌ）、Ｈｏｖｅｙｄａ―Ｇｒｕｂｂｓ 第二世代触媒（６０ｍｇ、０．１３９ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶解させ、６時間加熱還流させた。反応液の溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル－メタノール）により粗精製した。
MS: m/z = 521 [M+H]+
工程５
工程４で得られた化合物１７をＳＦＣにより光学分割し、化合物１８を得た。
カラム：ＣＨＩＲＡＬＰＡＫ ＩＣ／ＳＦＣ （５μｍ、ｉ．ｄ．２５０ｘ２０ｍｍ）
流速：20 ｍＬ／分
ＵＶ検出波長：220ｎｍ
分析条件：MeOH/CO₂=70/30の組成比を維持して、21分間送液した。
工程６
実施例１の工程６と同様の反応を行い、化合物ＩＩ－７２（１１ｍｇ、収率７４％）を得た。
1H-NMR(CDCl₃)δ: 11.93(s, 1H), 10.42(t, J=5.6Hz, 1H), 8.50(s, 1H), 7.40-7.33(m, 1H), 6.84-6.77(m, 2H), 6.28-6.24(m, 1H), 5.96-5.91(m, 1H), 5.32(d, J=5.2Hz, 1H), 4.68(dd, J=15.2, 6.0Hz, 1H), 4.61(dd, J=15.6, 6.0Hz, 1H), 3.83(dt, J=21.2, 7.2Hz, 1H), 3.53(dt, J=20.8, 6.8Hz, 1H), 3.39(td, J=11.2, 4.4Hz, 1H), 3.04(dd, J=10.8, 6.8Hz, 1H), 2.77-2.68(m, 1H), 2.35(dt, J=18.8, 4.8Hz, 1H), 1.23(t, J=7.2Hz, 3H). Example 3

Process 1
Potassium carbonate (261 mg, 1.89 mmol) and 4-bromobutene (147 mg, 0.943 mmol) were added to a solution of Compound 11 (352 mg, 0.629 mmol) in DMF (3.5 ml), and the mixture was reacted overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off.
MS: m/z = 611 [M+H]+
Process 2
A 4 mol/L hydrochloric acid/dioxane solution (3.15 ml) was added to the crude product obtained in Step 1, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate 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 then the solvent was distilled off.
MS: m/z = 511 [M+H]+
Process 3
The crude product obtained in step 2, acrolein (102 mg, 1.83 mmol), and paratoluenesulfonic acid hydrate (11.6 mg, 0.061 mmol) were dissolved in dichloroethane (9.6 mL), and the mixture was heated at 100°C for 6 mL. Stir for hours. After the reaction solution was allowed to cool to room temperature, water and saturated aqueous sodium bicarbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 16 (115 mg).
MS: m/z = 549 [M+H]+
Process 4
Compound 16 (66.4 mg, 0.121 mmol) and Hoveyda-Grubbs second generation catalyst (60 mg, 0.139 mmol) were dissolved in dichloromethane (10 mL) and heated under reflux for 6 hours. The solvent of the reaction solution was distilled off, and the resulting residue was roughly purified by silica gel column chromatography (ethyl acetate-methanol).
MS: m/z = 521 [M+H]+
Process 5
Compound 17 obtained in Step 4 was optically resolved by SFC to obtain Compound 18.
Column: CHIRALPAK IC/SFC (5μm, i.d.250x20mm)
Flow rate: 20 mL/min UV detection wavelength: 220 nm
Analysis conditions: The composition ratio of MeOH/CO ₂ =70/30 was maintained and the solution was pumped for 21 minutes.
Process 6
The same reaction as in Step 6 of Example 1 was carried out to obtain Compound II-72 (11 mg, yield 74%).
1H-NMR(CDCl ₃ )δ: 11.93(s, 1H), 10.42(t, J=5.6Hz, 1H), 8.50(s, 1H), 7.40-7.33(m, 1H), 6.84-6.77(m, 2H), 6.28-6.24(m, 1H), 5.96-5.91(m, 1H), 5.32(d, J=5.2Hz, 1H), 4.68(dd, J=15.2, 6.0Hz, 1H), 4.61(dd , J=15.6, 6.0Hz, 1H), 3.83(dt, J=21.2, 7.2Hz, 1H), 3.53(dt, J=20.8, 6.8Hz, 1H), 3.39(td, J=11.2, 4.4Hz, 1H), 3.04(dd, J=10.8, 6.8Hz, 1H), 2.77-2.68(m, 1H), 2.35(dt, J=18.8, 4.8Hz, 1H), 1.23(t, J=7.2Hz, 3H) ).

工程１
化合物１１（３２６ｍｇ、０．５９ｍｍｏｌ）、化合物１９（８７ｍｇ、０．７７ｍｍｏｌ）およびトリフェニルホスフィン（３０７ｍｇ、１．１８ｍｍｏｌ）のＴＨＦ（３．５ｍL）溶液に、０℃にて、アゾジカルボン酸ジ―２―メトキシエチル（２７４ｍｇ、１．１８ｍｍｏｌ）を加え１２時間室温で静置した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、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２０（２９３ｍｇ、収率７７％）を得た。
MS: m/z = 653 [M+H]+
工程２
化合物２０（２８７ｍｇ、０．４４ｍｍｏｌ）をジオキサン（３．４ｍL）、水（２．３ｍL）に懸濁させ、０℃にて、２、６－ルチジン（０．１０ｍＬ）、過ヨウ素酸水素ナトリウム（２８２ｍｇ、１．３２ｍｍｏｌ）、オスミウム（ＶＩ）酸カリウム二水和物（８．０ｍｇ、０．０２ｍｍｏｌ）を加え、０℃から室温に５時間かけて昇温した。反応液をセライト（登録商標）でろ過し、１０％チオ硫酸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、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２１（２２３ｍｇ、収率７８％）を得た。
MS: m/z = 655 [M+H]+
工程３
化合物２１（１９２ｍｇ、０．２９ｍｍｏｌ）を４ｍｏｌ／Ｌ塩酸／ジオキサン溶液（１．４７ｍｌ）に溶解させ、室温にて２時間撹拌した。溶媒を留去し、得られた粗生成物をトルエン（２．０ｍｌ）に溶解させ、酢酸を触媒量加え、９０℃で２時間撹拌した。反応溶液に飽和重曹水を加え、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により精製し、ジアステレオマー混合物を得た。得られたジアステレオマー混合物をＳＦＣにより光学分割し、化合物２２（６９ｍｇ、収率４４％）を得た。
カラム：ＣＨＩＲＡＬＰＡＫ ＩC／ＳＦＣ （５μｍ、ｉ．ｄ．２５０ｘ２０ｍｍ）を２本直列で使用
流速：20 ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：MeOH/CO₂=65/35の組成比を維持して、35分間送液した。
MS: m/z = 537 [M+H]+
工程４
実施例１の工程６と同様の反応を行い、化合物ＩＩ－４０を得た。
MS: m/z = 447 [M+H]+ Example 4

Process 1
Azodicarboxylic acid di- 2-Methoxyethyl (274 mg, 1.18 mmol) was added and the mixture was allowed to stand at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 20 (293 mg, yield 77%).
MS: m/z = 653 [M+H]+
Process 2
Compound 20 (287 mg, 0.44 mmol) was suspended in dioxane (3.4 mL) and water (2.3 mL), and 2,6-lutidine (0.10 mL), sodium hydrogen periodate ( 282 mg, 1.32 mmol) and potassium osmate (VI) dihydrate (8.0 mg, 0.02 mmol) were added, and the temperature was raised from 0° C. to room temperature over 5 hours. The reaction solution was filtered through Celite (registered trademark), a 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 21 (223 mg, yield 78%).
MS: m/z = 655 [M+H]+
Process 3
Compound 21 (192 mg, 0.29 mmol) was dissolved in a 4 mol/L hydrochloric acid/dioxane solution (1.47 ml) and stirred at room temperature for 2 hours. The solvent was distilled off, and the resulting crude product was dissolved in toluene (2.0 ml), a catalytic amount of acetic acid was added, and the mixture was stirred at 90°C for 2 hours. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain a diastereomer mixture. The resulting diastereomer mixture was optically resolved by SFC to obtain Compound 22 (69 mg, yield 44%).
Column: Two CHIRALPAK IC/SFC (5 μm, i.d. 250 x 20 mm) used in series Flow rate: 20 mL/min UV detection wavelength: 220 nm
Preparation conditions: The composition ratio of MeOH/CO ₂ =65/35 was maintained and the solution was pumped for 35 minutes.
MS: m/z = 537 [M+H]+
Process 4
A reaction similar to Step 6 of Example 1 was carried out to obtain Compound II-40.
MS: m/z = 447 [M+H]+

工程１
化合物２３（１.５９ｇ、１２．２ｍｍｏｌ）のＤＭＦ（１６．０ｍＬ）溶液に、０℃にてイミダゾール（０．９９８ｇ、１４．６６ｍｍｏｌ）、ｔ－ブチルジメチルシリルクロリド（１．８４ｇ、１２．２１ｍｍｏｌ）を加え、室温で３時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水と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２４（１.３９ｇ、収率４７％）を得た。
1H-NMR(CDCl₃)δ: 3.47-3.55(m, 4H), 2.09-2.15(m, 2H), 1.88-1.95(s, 1H), 1.65-1.79(m, 2H), 1.32-1.42(m, 2H), 0.88-0.89(m, 1H), 0.85(s, 9H), 0.039(s, 6H).
工程２
化合物２４（４００ｍｇ、０．１６４ｍｍｏｌ）、化合物１１（７００ｍｇ、１．２６ｍｍｏｌ）およびトリフェニルホスフィン（６６０ｍｇ、２．５２ｍｍｏｌ）のＴＨＦ（７ｍＬ）溶液に、０℃にてアゾジカルボン酸ジ－２－メトキシエチル（５８９ｍｇ、２．５２ｍｍｏｌ）を加え１２時間室温で静置した。反応液に水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、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）により粗精製した。
工程３
化合物２５（１.０６ｇ、１.３５ｍｍｏｌ）のＴＨＦ（１０．０ｍＬ）溶液に１ｍｏｌ／Ｌ ＴＢＡＦ／ＴＨＦ溶液（１．６３ｍｌ、１．６３ｍｍｏｌ）を加え、室温で１２時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水と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（７２０ｍｇ、収率８０％）を得た。
MS: m/z = 669 [M+H]+
工程４
化合物２６（７２０ｍｇ、１.０８ｍｍｏｌ）のジクロロメタン（８．０ｍＬ）溶液に、０℃にてデス-マーチンペルヨージナンを加え、室温で１時間撹拌した。反応液に１０％チオ硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を水と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２７（３９３ｍｇ、収率５５％）を得た。
MS: m/z = 667 [M+H]+
工程５
化合物２７（３９３ｍｇ、０.５９ｍｍｏｌ）のアセトニトリル（８．０ｍＬ）溶液を６０℃加温し８０分撹拌した。反応液に飽和炭酸水素ナトリム水溶液を加え、酢酸エチルで抽出した。有機層を水と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。得られた粗生成物をＤＭＦ（４．０ｍＬ）に溶解させ、０℃にて炭酸セシウム（５７６ｍｇ、１.７７ｍｍｏｌ）、ベンジルブロミド（０．２１ｍＬ、１．７７ｍｍｏｌ）を加え、室温にて終夜攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水と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、ＳＦＣ光学分割し、化合物２８（８９ｍｇ、収率２８％）を得た。
カラム：ＣＨＩＲＡＬＰＡＫ ＩC／ＳＦＣ （５μｍ、ｉ．ｄ．２５０ｘ２０ｍｍ）を２本直列で使用
流速：20ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：MeOH/CO₂=75/25の組成比を維持して、45分間送液した。
MS: m/z = 549 [M+H]+
工程６
実施例１の工程６と同様の反応を行い、化合物ＩＩ－４（１１ｍｇ、収率７４％）を得た。
MS: m/z = 459 [M+H]+ Example 5

Process 1
To a solution of compound 23 (1.59 g, 12.2 mmol) in DMF (16.0 mL) at 0°C were added imidazole (0.998 g, 14.66 mmol) and t-butyldimethylsilyl chloride (1.84 g, 12.21 mmol). ) and stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 24 (1.39 g, yield 47%).
1H-NMR(CDCl ₃ )δ: 3.47-3.55(m, 4H), 2.09-2.15(m, 2H), 1.88-1.95(s, 1H), 1.65-1.79(m, 2H), 1.32-1.42(m , 2H), 0.88-0.89(m, 1H), 0.85(s, 9H), 0.039(s, 6H).
Process 2
Di-2-methoxy azodicarboxylate was added to a THF (7 mL) solution of compound 24 (400 mg, 0.164 mmol), compound 11 (700 mg, 1.26 mmol) and triphenylphosphine (660 mg, 2.52 mmol) at 0°C. Ethyl (589 mg, 2.52 mmol) was added and allowed to stand at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was roughly purified by silica gel column chromatography (hexane-ethyl acetate).
Process 3
A 1 mol/L TBAF/THF solution (1.63 ml, 1.63 mmol) was added to a THF (10.0 mL) solution of Compound 25 (1.06 g, 1.35 mmol), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 26 (720 mg, yield 80%).
MS: m/z = 669 [M+H]+
Process 4
Dess-Martin periodinane was added to a solution of Compound 26 (720 mg, 1.08 mmol) in dichloromethane (8.0 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 27 (393 mg, yield 55%).
MS: m/z = 667 [M+H]+
Process 5
A solution of Compound 27 (393 mg, 0.59 mmol) in acetonitrile (8.0 mL) was heated to 60° C. and stirred for 80 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained crude product was dissolved in DMF (4.0 mL), cesium carbonate (576 mg, 1.77 mmol) and benzyl bromide (0.21 mL, 1.77 mmol) were added at 0°C, and the mixture was stirred at room temperature overnight. did. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and subjected to SFC optical resolution to obtain Compound 28 (89 mg, yield 28%).
Column: Two CHIRALPAK IC/SFC (5μm, i.d. 250x20mm) used in series Flow rate: 20mL/min UV detection wavelength: 220nm
Preparation conditions: The composition ratio of MeOH/CO ₂ =75/25 was maintained and the solution was pumped for 45 minutes.
MS: m/z = 549 [M+H]+
Process 6
The same reaction as in Step 6 of Example 1 was carried out to obtain Compound II-4 (11 mg, yield 74%).
MS: m/z = 459 [M+H]+

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

Physical data for each compound is shown below.

Below, biological test examples of compounds according to the present invention will be described.
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, and still more preferably 5 nM.

Test Example 1: Anti-HIV activity A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL/well). After dispensing 100 μL/well of MT-4 cell suspension of 2.5×10 ⁵ cells/mL into the plate containing the test sample, 50 μL/well of HIV virus solution was dispensed. 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-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution was dispensed into each well. The reaction was performed in a CO ₂ incubator for 1 hour. 150 μL of supernatant was removed from each well without aspirating cells. 150 μL of cell lysis solution was added and mixed well using a plate mixer until all the cells were lysed. The absorbance of the mixed plate was measured using a microplate reader at two wavelengths of 560 nm and 690 nm. The 50% HIV inhibitory concentration (EC50) was determined from the concentration dependence curve using the 4-parameter logistic curve fitting model shown below.
y=A+((B-A)/(1+(C/x) ^D ))

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

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 the test sample was prepared in a 384-well microplate using a dispenser. After dispensing 6.25 x ¹⁰⁴ cells/mL of MT-4 cell suspension at 20 μL/well into the plate containing the test sample, the HIV virus solution was dispensed at 20 μL/well. The mixture was mixed with a plate mixer and cultured in a CO ₂ incubator for 4 days. On the fourth day of culture, 20 μL of CellTiter-Glo or CellTiter-Glo 2.0 was dispensed into each well. The reaction was allowed to proceed at room temperature for about 15 minutes while stirring with a plate mixer. After the reaction, the amount of luminescence of the plate was measured using a microplate reader. The 50% HIV inhibitory concentration (EC50) was determined from the concentration dependence curve using the 4-parameter logistic curve fitting model shown below.
y=A+((B-A)/(1+((C/x) ^D )))

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

(result)

From the above test results, it was revealed that the compound according to the present invention exhibited high anti-HIV activity, and therefore, the pharmaceutical composition of the present invention has utility as an HIV drug.

変異株３（Ｅ９２Ｑ／Ｅ１３８Ｋ／Ｇ１４０Ｓ／Ｑ１４８Ｈ）に対するＦＣ
化合物Ｉ－１５：７．７
変異株（Ｔ９７Ａ／Ｅ１３８Ｔ／Ｇ１４０Ｓ／Ｑ１４８Ｈ）に対するＦＣ
化合物Ｉ－１５：１０
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 the test sample was prepared in a 96-well microplate (50 μL/well). After dispensing 100 μL/well of 2.5×10 ⁵ cells/mL HeLa-CD4 cell suspension to the plate containing the test sample, dispense 50 μL/well of HIV virus solution (wild strain and mutant strain). I noted it. The mixture was mixed with a plate mixer and cultured in a CO ₂ incubator for 3 days. The culture supernatant from each well was removed by suction, and 100 μL of the cell lysis buffer in the reporter measurement kit was dispensed and frozen in a freezer (-80°C). The plates frozen in the freezer were thawed at room temperature, mixed using a plate mixer, and centrifuged at 1,200 rpm for 5 minutes. 20 μL of the supernatant from each well was dispensed into a 96-well microplate (BLACK). The chemiluminescence reagent in the reporter assay kit was dispensed in 100 μL portions and reacted at room temperature for about 1 hour, and then the amount of luminescence was measured using MicroBeta TRILUX. The 50% HIV inhibitory concentration (EC50) was determined from the concentration dependence curve using the four-parameter logistic curve fitting model shown below.
y=A+((B-A)/(1+(C/x) ^D ))

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

Furthermore, the degree of resistance (Fold change (FC)) of each mutant strain was calculated based on the following calculation formula.
FC = EC50 of mutant strain/EC50 of wild strain
(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 against mutant strain 3 (E92Q/E138K/G140S/Q148H)
Compound I-15: 7.7
FC against mutant strain (T97A/E138T/G140S/Q148H)
Compound I-15:10
The above test results revealed that the compound according to the present invention has a high resistance barrier and is difficult to generate HIV-resistant viruses.

Test Example 3: CYP inhibition test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin, which is a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), was performed. (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), The degree to which the amount of each metabolite produced was inhibited by the compound according to the present invention was evaluated.
The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenytoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenadine (CYP3A4); Reaction time, 15 minutes; Reaction temperature, 37°C; Enzyme, pooled human liver microsomes 0.2 mg protein/mL; Compound concentration according to the present invention, 1, 5, 10, 20 μmol/L (4 point).
Add each of the five substrates, human liver microsomes, and the compound according to the present invention in the above composition to a 96-well plate in 50 mmol/L Hepes buffer, add the coenzyme NADPH, and 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, resorufin (CYP1A2 metabolite) in the centrifuged supernatant was quantified using a fluorescence multilabel counter or LC/MS/MS, and tolbutamide hydroxylated form (CYP2C9 metabolite) and mephenytoin 4' hydroxylated terfenadine alcohol (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.
A control (100%) in which only DMSO, a solvent in which the compound was dissolved, was added to the reaction solution instead of the compound according to the present invention, the residual activity (%) was calculated, and using the concentration and inhibition rate, the logistic _IC50 was calculated by inverse estimation using the model.

Test Example 4: CYP3A4 (MDZ) MBI test This is a test to evaluate the Mechanism based inhibition (MBI) ability of the compound of the present invention regarding CYP3A4 inhibition from the enhancement of the inhibitory effect caused by the metabolic reaction of the compound of the present invention. CYP3A4 inhibition was evaluated using pooled human liver microsomes using the 1-hydroxylation reaction of midazolam (MDZ) as an indicator.
The reaction conditions were as follows: substrate, 10 μmol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg/mL during pre-reaction; 0.05 mg/mL during reaction (when diluted 10 times); Concentration during pre-reaction of the compound 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 a compound solution according to the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the above pre-reaction composition, and K-Pi buffer containing the substrate was added to another 96-well plate. -Transfer a portion of the sample so that it is diluted 1/10 with Pi buffer, add the coenzyme NADPH to start the reaction as an indicator (no pre-reaction: Preincubation 0 min), and after the reaction for a predetermined time. The reaction was stopped by adding methanol/acetonitrile=1/1 (V/V) solution. In addition, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (with pre-reaction: Preincubation 30 min), and after pre-reaction for a predetermined time, the solution was diluted 1/10 with K-Pi buffer containing the substrate on another plate. We have started a reaction to move some of the substances and use them as indicators. After reacting for a predetermined time, the reaction was stopped by adding methanol/acetonitrile=1/1 (V/V) solution. After centrifuging the plate on which each index reaction was performed at 3000 rpm for 15 minutes, the amount of 1-midazolam hydroxide in the centrifuged supernatant was determined by LC/MS/MS.
A control (100%) in which only DMSO, a solvent in which the compound was dissolved, was added to the reaction solution instead of the compound according to the present invention, and residual activity (%) when each concentration of the compound according to the present invention was added. is calculated, and IC is calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The IC at Preincubation 0 min/IC at Preincubation 30 min is taken as the Shifted IC value, and if the Shifted IC is 1.5 or more, it is taken as positive (+), and if the Shifted IC is 1.0 or less, it is taken as negative (-).
(result)
Compound I-15: (-)
Compound II-066: (-)

Test Example 5: BA Test Examination of Oral Absorption Experimental Materials and Methods (1) Animals Used: Rats were used.
(2) Breeding conditions: Rats were allowed free access to solid food and sterile tap water.
(3) Setting of dosage and group division: Oral and intravenous administration was carried out at predetermined dosages. The groups were set up as follows. (Dosage may vary depending on compound)
Oral administration 2-60μmol/kg or 1-30mg/kg (n=2-3)
Intravenous administration 1-30μmol/kg or 0.5-10mg/kg (n=2-3)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. For intravenous administration, the drug was solubilized and administered.
(5) Administration method: For oral administration, the drug was forcibly administered into the stomach using an oral probe. Intravenous administration was performed through the tail vein using a syringe with an injection needle attached.
(6) Evaluation items: 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: The area under the plasma concentration-time curve (AUC) was calculated using the moment analysis method regarding the concentration change of the compound according to the present invention in plasma, and the dose ratio and AUC of the oral administration group and intravenous administration group were calculated. 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 free access to solid food and sterile tap water.
(3) Setting of dosage and group division: Intravenous administration was performed at a predetermined dosage. The groups were set up as follows.
Intravenous administration 1 μmol/kg (n=2)
(4) Preparation of administration solution: Solubilized using dimethyl sulfoxide/propylene glycol = 1/1 solvent and administered.
(5) Administration method: Administration was carried out through the tail vein using a syringe fitted with an injection needle.
(6) Evaluation items: 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 concentration change of the compound according to the present invention in plasma, the whole body clearance (CLtot) and elimination half-life (t1/2) were calculated by moment analysis method.
Compound I-15: 0.111mL/min/kg, 12.3hr
Compound II-028: 0.102mL/min/kg, 26.7hr
From the above results, it was revealed that the compound according to the present invention has a low clearance and a long elimination half-life, and therefore the pharmaceutical composition of the present invention is useful as a long-lasting integrase inhibitor.

Test example 7 (metabolic stability test)
Commercially available pooled human liver microsomes and the compound according to the present invention were reacted for a certain period of time, and the residual rate was calculated by comparing the reacted sample and the unreacted sample, and the extent to which the compound according to the present invention was metabolized in the liver was evaluated.
Human liver microsomes were cultured in 0.2 mL of 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 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 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 centrifuged 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 calculated as the amount of compound at 0 minute reaction. Calculations were made with 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 compounds according to the invention was evaluated.
20 μL of frozen Salmonella typhimurium (TA98 strain, TA100 strain) was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and cultured at 37° C. for 10 hours before shaking. For the TA98 strain, 7.70 to 8.00 mL of the bacterial solution was centrifuged (2000×g, 10 minutes) to remove the culture solution. 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, tricitric acid) in the same volume as the bacterial solution used for centrifugation. Suspend the bacteria in 120 mL of Exposure medium (biotin: 8 μg/ _mL , histidine: 0.2 _μg /mL, Glucose: MicroF buffer containing 8 mg/mL). For the TA100 strain, 3.10 to 3.42 mL of bacterial suspension was added to 120 to 130 mL of Exposure medium to prepare a test bacterial suspension. The compound according to the present invention in DMSO solution (several dilutions in 2-3 folds from the highest dose of 50 mg/mL), DMSO as a negative control, and 50 μg/mL for TA98 strain as a positive control under non-metabolic activation conditions. 4-nitroquinoline-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 For the TA98 strain, 40 μg/mL 2-aminoanthracene DMSO solution, for the TA100 strain, 12 μL each of 20 μg/mL 2-aminoanthracene DMSO solution 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 with shaking at 37° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was transferred to Indicator medium (MicroF buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, bromocresol purple: 37.5 μg/mL). ), 50 μL each was dispensed into 48 wells/dose of a microplate, and cultured stationary at 37° C. for 3 days. Wells containing bacteria that have acquired the ability to proliferate due to mutations in the amino acid (histidine) synthase gene change color from purple to yellow due to pH changes, so the number of wells with bacterial growth that turned yellow out of 48 wells per dose was counted. , evaluated in comparison with a negative control group. Mutagenicity is shown as negative (-) and positive (+).

Test Example 9: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound according to the present invention, we investigated the ventricular repolarization process using CHO cells expressing human ether-a-go-go related gene (hERG) channels. The effect of the compound according to the present invention on the delayed rectification K ⁺ current (I _Kr ), which plays an important role in the present invention, was investigated.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A/S), the cells were held at a membrane potential of -80 mV by the whole cell patch clamp method, a leak potential of -50 mV was applied, and then a depolarizing stimulus of +20 mV was applied. was applied for 2 seconds, and then a −50 mV repolarizing stimulus was applied for 2 seconds, and the induced I _Kr was recorded. Extracellular fluid adjusted to 0.1% with dimethyl sulfoxide (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-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH = 7.4) was used as a medium, An extracellular solution in which the compound of the invention is dissolved at a desired concentration is applied to the cells at room temperature for 7 minutes or more. From the obtained I _Kr , using analysis software (QPatch Assay software; Sophion Bioscience A/S), the absolute value of the maximum tail current was measured based on the current value at the retained membrane potential. Furthermore, the maximum tail current after application of the compound according to the present invention relative to the maximum tail current after application of the medium was calculated as an inhibition rate, 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 addition of 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 for 1 hour at room temperature, the mixture was filtered with suction. The filtrate was diluted 10 or 100 times with methanol/water = 1/1 (V/V) or acetonitrile/methanol/water = 1/1/2 (V/V/V), and analyzed by LC/MS using the absolute calibration curve method. Alternatively, the concentration in the filtrate was measured using solid phase extraction (SPE)/MS.
The composition of JP-1 liquid 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 JP-2 liquid is as follows.
Add 1 volume of water to 1 volume of 1000 mL of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water.

Test Example 11: Powder Solubility Test Put an appropriate amount of the compound according to the present invention into a suitable container, and add JP-1 solution (add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL) and JP-1 solution to each container. 2 liquid (add 1 volume of water to 1 volume of 1000 mL of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water), 20 mmol/L Sodium taurocholate (TCA)/JP -2 solution (JP-2 solution was added to 1.08 g of TCA to make 100 mL) was added in 200 μL portions. If the entire amount was dissolved after addition of the test solution, the compound according to the present invention was added as appropriate. The mixture was sealed and shaken at 37° C. for 1 hour, then filtered, and 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution ratio was changed as necessary. After checking for bubbles and precipitates, the container was sealed and shaken. Compounds according to the present invention were quantified using HPLC using the absolute calibration curve method.

Test Example 12: Ames test Mutagenicity of the compound according to the present invention was determined by Ames test using Salmonella typhimurium TA98 strain, TA100 strain, TA1535 strain, TA1537 strain and Escherichia coli WP2uvrA strain as test strains. rate do. 0.1 mL of a DMSO solution of the compound of the present invention was mixed 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 overlaying soft agar containing biotin or tryptophan. At the same time, for the negative control substance (DMSO) and the positive control substance (2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene) will be carried out in the same manner. After culturing at 37°C for 48 hours, the revertant colonies that appeared are counted and evaluated in comparison with the negative control group. If the number of revertant colonies increases in a concentration-dependent manner and is at least twice the number of colonies in the negative control group, it is determined to be positive (+).

Test Example 13: Nav Test For the purpose of evaluating the arrhythmogenic risk of the compound according to the present invention, myocardial depolarization was performed using HEK cells expressing the voltage gated sodium channel (Nav1.5 channel) encoded by the SCN5A gene. The effect of the compounds according to the invention on the Na ⁺ current (I _Na ), which plays an important role in the process, was investigated.
Using a fully automated patch clamp system (QPatch; Sophion Bioscience A/S), cells were held at a membrane potential of -100 mV and induced by applying a -10 mV depolarizing stimulus for 20 ms by whole cell patch clamp method. The _INa obtained was recorded. Extracellular solution containing 0.3% dimethyl sulfoxide (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-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, TEA (Tetraethylammonium Hydroxide) e): 10 mmol/L, pH=7. 4) was used as a medium, and the medium and an extracellular solution in which the compound of the present invention was dissolved at a desired concentration were each applied to the cells at room temperature for 5 minutes or more. From the obtained _INa , the absolute value of the maximum peak current was measured using analysis software (QPatch Assay software; Sophion Bioscience A/S) based on the current value at the holding membrane potential. Furthermore, the ratio of the maximum peak current when applying the compound according to the present invention to the maximum peak current when applying the medium was calculated, and the influence of the compound according to the present invention on I _Na was evaluated.
(result)
Compound I-2 101%
Compound I-15 92.1%
Compound II-31 79%
From the above results, no obvious increase in current was observed, and it was found that the pharmaceutical composition of the present invention is less likely to cause arrhythmia due to an increase in Na current.

Test Example 14: Anti-HIV activity evaluation test using peripheral blood mononuclear cells (PBMC) of healthy individuals A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL/well). PBMC stimulated with 1.0 x 10 ⁵ cells/well of Phytohemagglutinin (PHA) and HIV virus solution were mixed for the required number of wells and allowed to react at 37°C for 1 hour. After the reaction, centrifuge the cell suspension, discard the supernatant, disperse the infected cells in the culture medium for the required number of wells at 150 μL/well, and dispense 150 μL/well into the 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. Reverse transcriptase activity in the culture solution was measured. The 90% HIV inhibitory concentration (EC90) was determined from the concentration dependence curve using the 4-parameter logistic curve fitting model shown below.
y=A+((B-A)/(1+(C/x) ^D ))

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

(result)
Compound II-31 0.73nM
Compound II-51 3.3nM

Test Example 15: Anti-HIV activity evaluation test in the presence of human serum protein A serial dilution series of the test sample was prepared in 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 into 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 allowed to react at 37° C. for 1 hour. After the reaction, the cell suspension is centrifuged, the supernatant is discarded, the infected cells are dispersed in the culture medium for the required number of wells at 50 μL/well, and 50 μL/well is added to a 96-well microplate containing the test sample and human serum protein. It was dispensed into each well (final human serum protein concentration: 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-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution was dispensed into each well. The reaction was performed in a CO ₂ incubator for 1 hour. 150 μL of supernatant was removed from each well without aspirating cells. 150 μL of cell lysis solution was added and mixed well using a plate mixer until all the cells were lysed. The absorbance of the mixed plate was measured using a microplate reader at two wavelengths of 560 nm and 690 nm. The 50% HIV inhibitory concentration (EC50) was determined from the concentration dependence curve using the 4-parameter logistic curve fitting model shown below.
y=A+((B-A)/(1+(C/x) ^D ))

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

Furthermore, the potency whip (PS) was calculated based on the following calculation formula. Note that 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)
The table shows PS in the presence of human serum proteins (100% extrapolated value).
Compound II-31 364
Compound II-51 236

Formulation Examples The compounds according to the invention may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of an injection solution or suspension. It can be administered as a pharmaceutical composition, topically, for example in the form of a lotion, gel, ointment or cream, or in nasal or suppository form. Pharmaceutical compositions containing a compound according to the invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be prepared by mixing in a conventional manner. , granulation or coating methods. For example, the oral composition may be a tablet, granule, or capsule containing an excipient, a disintegrant, a binder, a lubricant, etc., and an active ingredient. In addition, the composition for injection may be in the form of a solution or suspension, may be sterilized, and may contain a preservative, a stabilizing agent, a buffering agent, and the like.

The compounds according to the present invention have integrase inhibitory activity and/or cell growth inhibitory activity against viruses, particularly HIV. Therefore, the pharmaceutical composition of the present invention is useful for preventing or treating various diseases and viral infections (eg, AIDS) involving integrase.

Claims (10)

A pharmaceutical composition comprising a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. The formula below:
A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof. The formula below:
A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof. The formula below:
A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof. The formula below:
A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing a compound selected from the group consisting of: The formula below:
A pharmaceutical composition containing a compound represented by: The formula below:
A pharmaceutical composition containing a compound represented by: The formula below:
A pharmaceutical composition containing a compound represented by: The formula below:
A pharmaceutical composition containing a compound represented by: