JP4993205B2 - Pyrimidine derivatives having tyrosine kinase inhibitory action - Google Patents

Description

  The present invention relates to a compound that inhibits both EGF receptor tyrosine kinase and HER2 tyrosine kinase, and a pharmaceutical composition containing them as active ingredients.

Tyrosine kinase is an enzyme that phosphorylates tyrosine residues in proteins, and is known to play an important role in cell differentiation / proliferation and intracellular signal transduction system. In particular, HER2 (also referred to as ErbB2 or Neu) and growth factor receptor tyrosine kinase (hereinafter referred to as receptor tyrosine kinase) such as EGF receptor are deeply involved in the formation of cancer, and receptor tyrosine kinase activity in human cancer Is known to be enhanced (Non-Patent Document 1, Non-Patent Document 2, and Non-Patent Document 3). Furthermore, these receptor tyrosine kinases have been shown to be overexpressed in tumors in the brain, lung, stomach, intestine, pancreas, head and neck, esophagus, bladder, kidney, prostate, ovary, breast, uterus, thyroid, etc. (Non-patent Document 4 and Patent Document 1). Therefore, tyrosine kinase inhibitors are considered useful as anticancer agents with few side effects that can be applied to many cancer types. As tyrosine kinase inhibitors, compounds described in Patent Literature 2, Patent Literature 3, Patent Literature 4, Patent Literature 5, Patent Literature 6, Patent Literature 7, and the like are known.
In addition, it is known that co-expression of the EGF receptor and HER2 further accelerates canceration by the EGF receptor alone (Non-patent Document 5). Furthermore, there is a report that the prognosis is poor when there is co-expression of the EGF receptor and HER2 in breast cancer, oral cancer, lung cancer and the like (Non-patent Document 6). As drugs that inhibit both EGF receptor tyrosine kinase and HER2 tyrosine kinase, compounds described in Patent Document 8, Patent Document 9 and the like are known.
Pyrimidine derivatives having an EGF receptor tyrosine kinase inhibitory action are described in Non-Patent Document 7 and Patent Document 9, and pyrimidine derivatives having a cell growth inhibitory action are described in Patent Document 10. In addition, a pyrimidine derivative having an effect on a central disease is described in Patent Document 11, and a pyrimidine derivative having an effect as an agricultural fungicide is described in Patent Document 12.
Cancer Res. 1991, 51, p.4430-4435 Cancer Res. 1992, Volume 52, p.3636-3641 Cancer Chemother. Pharmacol., 1993, Volume 32, p.1-19 Expert Opin. Invest. Drugs 1994, Volume 3, Issue 6, p. 577-595 Cell 1987, Vol. 58, p.287-292 Clinical Cancer Research 1999, Vol. 5, pp. 4164-4174 Journal of Heterocyclic Chemistry 2004, Vol. 41, No. 3, p.355-358 Japanese Patent Laid-Open No. 5-208911 International Publication No. 92/20642 Pamphlet European Patent Application Publication No. 92305703.8 European Patent Application No. 0 566 266 European Patent Application No. 0602851 European Patent Application Publication No. 0520722 International Publication No. 98/02434 Pamphlet International Publication No. 02/066445 Pamphlet International Publication No. 05/016914 Pamphlet International Publication No. 02/032872 Pamphlet International Publication No. 02/008205 Pamphlet JP-A-7-224046

  Compared with a compound that acts only on a single kinase, the dual inhibitor of EGF receptor and HER2 is superior in that it has a wide range of indications and a stronger therapeutic effect can be obtained by the synergistic action of dual inhibition. Accordingly, there has been a need for compounds that inhibit both EGF receptor tyrosine kinase and HER2 tyrosine kinase.

［式中、Ｒ^１は、Ｃ１−Ｃ３アルキル、Ｃ１−Ｃ３アルキルオキシ、Ｃ１−Ｃ３アルキルチオ、またはＣ１−Ｃ３アルキルアミノ；
Ｒ^２は、式：

（式中、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^９、Ｒ^４４、およびＲ^４５は、それぞれ独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、ハロゲン、アルキルオキシ、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ａｒ^１、Ａｒ^２およびＡｒ^３は、アリレンまたはヘテロアリレン；
Ｒ^６およびＲ⁷は、置換されていてもよいアルキル、アルキルオキシ、アルコキシカルボニル、またはホルミル；
Ｒ^１０、Ｒ^１１およびＲ^１４は、水素原子、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、置換されていてもよいアリール、置換されていてもよいヘテロアリール、アルキルスルフィニル、アルキルスルホニル、ヒドロキシ、またはアルキルオキシ；
Ｘ^１、Ｘ^２およびＸ^４は、−Ｃ（＝Ｏ）−Ｎ（Ｒ^１５）−、−Ｎ（Ｒ^１６）−Ｃ（＝Ｏ）−、または−Ｃ（＝Ｏ）−Ｎ（Ｒ^１５）−、−Ｎ（Ｒ^１６）−Ｃ（＝Ｏ）−、−Ｎ（Ｒ^１７）−、−Ｏ−、−Ｓ−、フェニレン、もしくはヘテロアリレンを介在していてもよく置換されていてもよいアルキレン；Ｒ^１５、Ｒ^１６およびＲ^１７は、それぞれ独立して、水素原子、アルキル、またはアシル；
Ｒ^１２、Ｒ^４６、およびＲ^５０は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいシクロアルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ｘ^３、Ｘ^１１、およびＸ^１２は、−Ｏ−、−Ｎ（Ｒ^１８）−、または−Ｏ−もしくは−Ｎ（Ｒ^１９）−を介在してもよく置換されていてもよいアルキレン；Ｒ^１８およびＲ^１９は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^１３、Ｒ^４７、およびＲ^５１は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアリール、または置換されていてもよい非芳香族含窒素複素環基；および
Ｒは、それぞれ独立して、置換されていてもよいアルキル、アルキルオキシ、アルキルオキシカルボニル、置換されていてもよいアルケニル、アルケニルオキシ、置換されていてもよいアルキニル、アルキニルオキシ、ハロゲン、ニトロ、シアノ、または置換されていてもよいアミノ；ｎは０〜２の整数）で表される基；
Ｙは、−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^２０）−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^２１）−を介在してもよいアルキレン；Ｒ^２０およびＲ^２１は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；および
Ｒ^３は、式：

（式中、Ｒ^２２は、水素原子、ハロゲン、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、または式：−Ｚ−Ｒ^２５（式中、Ｚは−Ｏ−、−Ｓ−、または−Ｎ（Ｒ^２６）−を介在してもよいアルキレン；Ｒ^２５は置換されていてもよいアリールまたは置換されていてもよいヘテロアリール；Ｒ^２６は水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル）で表される基；
Ｒ^２３およびＲ^２４は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ；
Ｒ^４９は置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、または式：

（式中Ｒ^２２、Ｒ^２３、およびＲ^２４は前記と同意義）で表される基；
ＱはＮまたはＣＨ）で表される基］
で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物、に関する。As a result of intensive studies, the present inventors have found that a pyrimidine derivative having a certain substituent at the 5-position has an excellent EGF receptor and HER2 dual inhibitory action.
That is, the present invention
(1) Formula (I):

[Wherein R ¹ represents C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 alkylthio, or C1-C3 alkylamino;
R ² has the formula:

(Wherein R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ⁴⁴ , and R ⁴⁵ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, halogen, alkyloxy, substituted Optionally substituted aryl, or optionally substituted heteroaryl;
Ar ¹ , Ar ² and Ar ³ are allylene or heteroarylene;
R ⁶ and R ⁷ are optionally substituted alkyl, alkyloxy, alkoxycarbonyl, or formyl;
R ¹⁰ , R ¹¹ and R ¹⁴ are each a hydrogen atom, an optionally substituted amino group, an optionally substituted non-aromatic nitrogen-containing heterocyclic group, an optionally substituted aryl group, or an optionally substituted group. Heteroaryl, alkylsulfinyl, alkylsulfonyl, hydroxy, or alkyloxy;
X ¹ , X ² and X ^{4 each} represent —C (═O) —N (R ¹⁵ ) —, —N (R ¹⁶ ) —C (═O) —, or —C (═O) —N (R ¹⁵ )-, -N (R < ¹⁶ >)-C (= O)-, -N (R < ¹⁷ >)-, -O-, -S-, phenylene, or heteroarylene, or may be substituted. Alkylene; R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently a hydrogen atom, alkyl, or acyl;
R ¹² , R ⁴⁶ , and R ⁵⁰ are each a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, or a substituted Optionally substituted aryl, or optionally substituted heteroaryl;
X ³ , X ¹¹ and X ¹² are —O—, —N (R ¹⁸ ) —, or —O— or —N (R ¹⁹ ) — which may be interposed or substituted alkylene; R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl;
R ¹³ , R ⁴⁷ , and R ⁵¹ are each a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, or an optionally substituted non-aromatic nitrogen-containing And R each independently represents an optionally substituted alkyl, an alkyloxy, an alkyloxycarbonyl, an optionally substituted alkenyl, an alkenyloxy, an optionally substituted alkynyl, an alkynyloxy, A group represented by halogen, nitro, cyano, or optionally substituted amino; n is an integer of 0 to 2;
Y is —O—, —S—, or —N (R ²⁰ ) —, or alkylene that may be mediated by —O—, —S—, or —N (R ²¹ ) —; R ²⁰ and R ²¹ Each independently represents a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl; and R ³ is of the formula:

(Wherein R ²² represents a hydrogen atom, a halogen, an optionally substituted alkyloxy, an optionally substituted alkenyloxy, an optionally substituted alkynyloxy, or a formula: —Z—R ²⁵ (formula In the formula, Z is alkylene which may be mediated by —O—, —S—, or —N (R ²⁶ ) —; R ²⁵ is optionally substituted aryl or optionally substituted heteroaryl; R ²⁶ Is a group represented by a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl);
R ²³ and R ²⁴ are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkyloxy, a substituted Optionally substituted alkenyloxy, optionally substituted alkynyloxy, halogen, hydroxy, mercapto, or optionally substituted amino;
R ⁴⁹ can be an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, or the formula:

A group represented by the formula: wherein R ²² , R ²³ , and R ²⁴ are as defined above;
Q is a group represented by N or CH)
Or a pharmaceutically acceptable salt thereof or a solvate thereof.

［式中、Ｒ^４およびＲ^５は、それぞれ独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ａｒ^１、Ａｒ^２およびＡｒ^３は、式：

（式中、Ｒは、それぞれ独立して、置換されていてもよいアルキル、アルキルオキシ、アルキルオキシカルボニル、置換されていてもよいアルケニル、アルケニルオキシ、置換されていてもよいアルキニル、アルキニルオキシ、ハロゲン、ニトロ、シアノ、または置換されていてもよいアミノ；ｎは０〜２の整数）で表される基；
Ｒ^６およびＲ⁷は、置換基群Ａ（置換基群Ａ：置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、アルコキシイミノ、およびヒドロキシ）から選択される置換基で置換されていてもよいアルキル、アルキルオキシ、またはアルコキシカルボニル；
Ｘ^４は、−Ｃ（＝Ｏ）−Ｎ（Ｒ^１５）−または−Ｎ（Ｒ^１６）−Ｃ（＝Ｏ）−を介在していてもよく置換されていてもよいアルキレン；Ｒ^１５およびＲ^１６は、それぞれ独立して、水素原子、アルキル、またはアシル；および
Ｒ^１４は、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、アルキルスルフィニル、アルキルスルホニル、ヒドロキシ、またはアルキルオキシ］で表される基である、（１）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。More specifically, it relates to the following (2) to (14).
(2) R ² is represented by the formula:

[Wherein, R ⁴ and R ⁵ each independently represents a hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
Ar ¹ , Ar ² and Ar ³ have the formula:

(In the formula, each R independently represents an optionally substituted alkyl, an alkyloxy, an alkyloxycarbonyl, an optionally substituted alkenyl, an alkenyloxy, an optionally substituted alkynyl, an alkynyloxy, or a halogen. , Nitro, cyano, or optionally substituted amino; n is an integer of 0 to 2);
R ⁶ and R ⁷ are selected from the substituent group A (substituent group A: optionally substituted amino, optionally substituted non-aromatic nitrogen-containing heterocyclic group, alkoxyimino, and hydroxy). Alkyl, alkyloxy, or alkoxycarbonyl optionally substituted with substituents;
X ⁴ is an alkylene which may be optionally substituted by —C (═O) —N (R ¹⁵ ) — or —N (R ¹⁶ ) —C (═O) —; R ¹⁵ and R ¹⁶ is each independently a hydrogen atom, alkyl, or acyl; and R ¹⁴ is an optionally substituted amino, an optionally substituted non-aromatic nitrogen-containing heterocyclic group, an alkylsulfinyl, an alkylsulfonyl, Or a pharmaceutically acceptable salt thereof or a solvate thereof.

［式中、Ｒ^８、Ｒ^９、Ｒ^１２、Ｒ^４４、Ｒ^４５、Ｒ^４６、およびＲ^５０は、それぞれ独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ｘ^１およびＸ^２は、−Ｃ（＝Ｏ）−Ｎ（Ｒ^１５）−または−Ｎ（Ｒ^１６）−Ｃ（＝Ｏ）−を介在していてもよく置換されていてもよいアルキレン；Ｒ^１５およびＲ^１６は、それぞれ独立して、水素原子、アルキル、またはアシル；
Ｘ^３、Ｘ^１１、およびＸ^１２は、−Ｏ−または−Ｎ（Ｒ^１８）−；Ｒ^１８は、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^１０およびＲ^１１は、置換されていてもよいアミノ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、または置換されていてもよい非芳香族含窒素複素環基；
Ｒ^１３、Ｒ^４７、およびＲ^５１は、置換されていてもよいアミノで置換されたアルキル、または置換されていてもよい非芳香族含窒素複素環基で置換されたアルキル］である、（１）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。(3) R ⁶ and R ⁷ are substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted) Aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Alkyl substituted with amino, or substituent group C (substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted alkyl, alkyloxy Alkyl, shear (1) or an alkyl substituted with a non-aromatic nitrogen-containing heterocyclic group which may be substituted with a substituent selected from (A), alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl), (2) The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(4) R ² has the formula:

[Wherein R ⁸ , R ⁹ , R ¹² , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , and R ⁵⁰ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, substituted Optionally substituted aryl, or optionally substituted heteroaryl;
X ¹ and X ² are each an alkylene optionally intervening or substituted with —C (═O) —N (R ¹⁵ ) — or —N (R ¹⁶ ) —C (═O) —; R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, alkyl, or acyl;
X ³ , X ¹¹ , and X ¹² are —O— or —N (R ¹⁸ ) —; R ¹⁸ is a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl;
R ¹⁰ and R ¹¹ are an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic nitrogen-containing heterocyclic group;
R ¹³ , R ⁴⁷ , and R ⁵¹ are an alkyl substituted with an optionally substituted amino, or an alkyl substituted with an optionally substituted non-aromatic nitrogen-containing heterocyclic group], (1 Or a pharmaceutically acceptable salt thereof or a solvate thereof.

(5) R ¹⁰ and R ¹¹ are substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted) Aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Amino, or substituent group C (substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted with alkyloxy, alkyloxyalkyl, cyano, alkyls (1) or (4) or a pharmaceutical thereof, which is a non-aromatic nitrogen-containing heterocyclic group which may be substituted with a substituent selected from sulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl) Top acceptable salts or solvates thereof.
(6) R ¹³ , R ⁴⁷ , and R ⁵¹ are substituted with a substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, substituted) Optionally substituted aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Alkyl substituted with amino which may be substituted, or Substituent group C (Substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy may be substituted. Alkyl, alkylo Alkyl substituted with a non-aromatic nitrogen-containing heterocyclic group which may be substituted with a substituent selected from (Cialkyl, cyano, alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl). The compound of 1) or (4) or a pharmaceutically acceptable salt thereof or a solvate thereof.
(7) The compound according to any one of (1) to (6), or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Y is —NH—.

（式中、Ｒ^２２は、水素原子またはハロゲン；Ｒ^２３は、ハロゲンまたはアルキニル；およびＲ^２４は水素原子）で表される基である、（１）〜（７）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（９） Ｒ^３が、式：

［式中、Ｒ^２２は、置換基群Ｄ（置換基群Ｄ：カルボキシ、アルキルオキシカルボニル、および置換されていてもよいアミノカルボニル）から選択される置換基で置換されていてもよいアルキルオキシ、置換基群Ｄから選択される置換基で置換されていてもよいアルケニルオキシ、または置換基群Ｄから選択される置換基で置換されていてもよいアルキニルオキシ；Ｒ^２３は、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^２４は水素原子］で表される基である、（１）〜（７）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１０） Ｒ^３が、式：

［式中、Ｒ^２２は、式：−Ｚ−Ｒ^２５（式中、Ｚは、−Ｏ−を介在してもよいアルキレン；Ｒ^２５は、置換基群Ｅ（置換基群Ｅ：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基で置換されていてもよいフェニル、置換基群Ｅから選択される置換基で置換されていてもよいピリジル、置換基群Ｅから選択される置換基で置換されていてもよいフリル、置換基群Ｅから選択される置換基で置換されていてもよいチエニル、置換基群Ｅから選択される置換基で置換されていてもよいチアゾリル、または置換基群Ｅから選択される置換基で置換されていてもよいオキサゾリル）で表される基；Ｒ^２３が、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^２４が水素原子］で表される基である、（１）〜（７）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１１） 式：

で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１２） 式：

で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１３） （１）〜（１２）のいずれかに記載の化合物を有効成分として含有する医薬組成物。
（１４） （１）〜（１２）のいずれかに記載の化合物を有効成分として含有する抗癌剤。
（１５） （１）〜（１２）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする癌の予防および／または治療方法。
（１６） 癌の予防および／または治療剤を製造するための（１）〜（１２）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。(8) R ³ is represented by the formula:

The compound according to any one of (1) to (7), wherein R ²² is a hydrogen atom or halogen; R ²³ is halogen or alkynyl; and R ²⁴ is a hydrogen atom. Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(9) R ³ is represented by the formula:

[Wherein, R ²² represents alkyloxy optionally substituted with a substituent selected from substituent group D (substituent group D: carboxy, alkyloxycarbonyl, and optionally substituted aminocarbonyl), Alkenyloxy which may be substituted with a substituent selected from Substituent Group D, or alkynyloxy which may be substituted with a substituent selected from Substituent Group D; R ²³ may be substituted good alkynyl, optionally alkyloxy substituted or halogen; and R ²⁴ is a group represented by hydrogen atom, (1) to (7) compound or a pharmaceutically acceptable according to any one of Salts or solvates thereof.
(10) R ³ is represented by the formula:

[Wherein R ²² represents a group represented by the formula: —Z—R ²⁵ (wherein Z represents an alkylene which may intervene —O—; R ²⁵ represents a substituent group E (substituent group E: halogen, , Alkyl, haloalkyl, hydroxyalkyl, alkyloxy, alkyloxycarbonyl, and optionally substituted phenyl, optionally substituted with a substituent selected from substituent group E Optionally substituted pyridyl, furyl optionally substituted with a substituent selected from substituent group E, thienyl optionally substituted with a substituent selected from substituent group E, substituent group E group represented by which may thiazolyl also be or may oxazolyl optionally substituted with a substituent selected from substituent group E,) substituted with a substituent selected from; R ²³ is replaced There may be an alkynyl, optionally substituted alkyloxy or halogen; a group and R ²⁴ is represented by a hydrogen atom], (1) a compound according to any one of (1) to (7) or a pharmaceutically Acceptable salts or solvates thereof.
(11) Formula:

Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(12) Formula:

Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(13) A pharmaceutical composition comprising the compound according to any one of (1) to (12) as an active ingredient.
(14) An anticancer agent comprising the compound according to any one of (1) to (12) as an active ingredient.
(15) A method for preventing and / or treating cancer, which comprises administering the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof or a solvate thereof.
(16) Use of the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of an agent for preventing and / or treating cancer.

［式中、Ｒ^１は、Ｃ１−Ｃ３アルキル、Ｃ１−Ｃ３アルキルオキシ、Ｃ１−Ｃ３アルキルチオ、またはＣ１−Ｃ３アルキルアミノ；
Ｒ^２は、式：

（式中、Ｒ^４、Ｒ^５、Ｒ^８およびＲ^９は、それぞれ独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、ハロゲン、アルキルオキシ、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ａｒ^１、Ａｒ^２およびＡｒ^３は、アリレンまたはヘテロアリレン；
Ｒ^６およびＲ⁷は、置換されていてもよいアルキル、アルキルオキシ、またはアルコキシカルボニル；
Ｒ^１０、Ｒ^１１およびＲ^１４は、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、アルキルスルフィニル、アルキルスルホニル、ヒドロキシ、またはアルキルオキシ；
Ｘ^１、Ｘ^２およびＸ^４は、−Ｃ（＝Ｏ）−Ｎ（Ｒ^１５）−、−Ｎ（Ｒ^１６）−Ｃ（＝Ｏ）−、または−Ｎ（Ｒ^１７）−、−Ｏ−、−Ｓ−、フェニレン、またはヘテロアリレンを介在していてもよく置換されていてもよいアルキレン；Ｒ^１５、Ｒ^１６およびＲ^１７は、それぞれ独立して、水素原子、アルキル、またはアシル；
Ｒ^１２は、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ｘ^３は、−Ｏ−または−Ｎ（Ｒ^１８）−；Ｒ^１８は、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^１３は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよい非芳香族含窒素複素環基；および
Ｒは、それぞれ独立して、置換されていてもよいアルキル、アルキルオキシ、アルキルオキシカルボニル、置換されていてもよいアルケニル、アルケニルオキシ、置換されていてもよいアルキニル、アルキニルオキシ、ハロゲン、ニトロ、シアノ、または置換されていてもよいアミノ；ｎは０〜２の整数）で表される基；
Ｙは、−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^２０）−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^２１）−を介在してもよいアルキレン；Ｒ^２０およびＲ^２１は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；および
Ｒ^３は、式：

（式中、Ｒ^２２は、水素原子、ハロゲン、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、または式：−Ｚ−Ｒ^２５（式中、Ｚは−Ｏ−、−Ｓ−、または−Ｎ（Ｒ^２６）−を介在してもよいアルキレン；Ｒ^２５は置換されていてもよいアリールまたは置換されていてもよいヘテロアリール；Ｒ^２６は水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル）で表される基；
Ｒ^２３およびＲ^２４は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ）で表される基］
で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Moreover, this invention includes invention of the following (I)-(XIV) as another aspect.
(I) Formula (I):

[Wherein R ¹ represents C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 alkylthio, or C1-C3 alkylamino;
R ² has the formula:

(Wherein R ⁴ , R ⁵ , R ⁸ and R ⁹ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, halogen, alkyloxy, optionally substituted aryl, Or an optionally substituted heteroaryl;
Ar ¹ , Ar ² and Ar ³ are allylene or heteroarylene;
R ⁶ and R ⁷ are optionally substituted alkyl, alkyloxy, or alkoxycarbonyl;
R ¹⁰ , R ¹¹ and R ¹⁴ are optionally substituted amino, optionally substituted non-aromatic nitrogen-containing heterocyclic group, alkylsulfinyl, alkylsulfonyl, hydroxy, or alkyloxy;
X ¹ , X ² and X ⁴ are —C (═O) —N (R ¹⁵ ) —, —N (R ¹⁶ ) —C (═O) —, or —N (R ¹⁷ ) —, —O—. , -S-, phenylene, or heteroarylene, optionally substituted alkylene; R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently a hydrogen atom, alkyl, or acyl;
R ¹² represents a hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
X ³ represents —O— or —N (R ¹⁸ ) —; R ¹⁸ represents a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl;
R ¹³ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted non-aromatic nitrogen-containing heterocyclic group; and R is each independently substituted Optionally substituted alkyl, alkyloxy, alkyloxycarbonyl, optionally substituted alkenyl, alkenyloxy, optionally substituted alkynyl, alkynyloxy, halogen, nitro, cyano, or optionally substituted amino; n is an integer of 0 to 2);
Y is —O—, —S—, or —N (R ²⁰ ) —, or alkylene that may be mediated by —O—, —S—, or —N (R ²¹ ) —; R ²⁰ and R ²¹ Each independently represents a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl; and R ³ is of the formula:

(Wherein R ²² represents a hydrogen atom, a halogen, an optionally substituted alkyloxy, an optionally substituted alkenyloxy, an optionally substituted alkynyloxy, or a formula: —Z—R ²⁵ (formula In the formula, Z is alkylene which may be mediated by —O—, —S—, or —N (R ²⁶ ) —; R ²⁵ is optionally substituted aryl or optionally substituted heteroaryl; R ²⁶ Is a group represented by a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl);
R ²³ and R ²⁴ are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkyloxy, a substituted Optionally substituted alkenyloxy, optionally substituted alkynyloxy, halogen, hydroxy, mercapto, or optionally substituted amino)]
Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｒ^４およびＲ^５は、それぞれ独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ａｒ^１、Ａｒ^２およびＡｒ^３は、式：

（式中、Ｒは、それぞれ独立して、置換されていてもよいアルキル、アルキルオキシ、アルキルオキシカルボニル、置換されていてもよいアルケニル、アルケニルオキシ、置換されていてもよいアルキニル、アルキニルオキシ、ハロゲン、ニトロ、シアノ、または置換されていてもよいアミノ；ｎは０〜２の整数）で表される基；
Ｒ^６およびＲ⁷は、置換基群Ａ’（置換基群Ａ’：置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、アルコキシイミノ、およびヒドロキシ）から選択される置換基で置換されていてもよいアルキル、アルキルオキシ、またはアルコキシカルボニル；
Ｘ^４は、−Ｃ（＝Ｏ）−Ｎ（Ｒ^１５）−または−Ｎ（Ｒ^１６）−Ｃ（＝Ｏ）−を介在していてもよく置換されていてもよいアルキレン；Ｒ^１５およびＲ^１６は、それぞれ独立して、水素原子、アルキル、またはアシル；および
Ｒ^１４は、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、アルキルスルフィニル、アルキルスルホニル、ヒドロキシ、またはアルキルオキシ］で表される基である、（Ｉ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。(II) R ² has the formula:

[Wherein, R ⁴ and R ⁵ each independently represents a hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
Ar ¹ , Ar ² and Ar ³ have the formula:

(In the formula, each R independently represents an optionally substituted alkyl, an alkyloxy, an alkyloxycarbonyl, an optionally substituted alkenyl, an alkenyloxy, an optionally substituted alkynyl, an alkynyloxy, or a halogen. , Nitro, cyano, or optionally substituted amino; n is an integer of 0 to 2);
R ⁶ and R ⁷ are selected from the substituent group A ′ (substituent group A ′: optionally substituted amino, optionally substituted non-aromatic nitrogen-containing heterocyclic group, alkoxyimino, and hydroxy). Alkyl, alkyloxy, or alkoxycarbonyl optionally substituted with such substituents;
X ⁴ is an alkylene which may be optionally substituted by —C (═O) —N (R ¹⁵ ) — or —N (R ¹⁶ ) —C (═O) —; R ¹⁵ and R ¹⁶ is each independently a hydrogen atom, alkyl, or acyl; and R ¹⁴ is an optionally substituted amino, an optionally substituted non-aromatic nitrogen-containing heterocyclic group, an alkylsulfinyl, an alkylsulfonyl, Or a pharmaceutically acceptable salt or solvate thereof according to (I), which is a group represented by hydroxy or alkyloxy].

［式中、Ｒ^８、Ｒ^９およびＲ^１２は、それぞれ独立して、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ｘ^１およびＸ^２は、−Ｃ（＝Ｏ）−Ｎ（Ｒ^１５）−または−Ｎ（Ｒ^１６）−Ｃ（＝Ｏ）−を介在していてもよく置換されていてもよいアルキレン；Ｒ^１５およびＲ^１６は、それぞれ独立して、水素原子、アルキル、またはアシル；
Ｘ^３は、−Ｏ−または−Ｎ（Ｒ^１８）−；Ｒ^１８は、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^１０およびＲ^１１は、置換されていてもよいアミノまたは置換されていてもよい非芳香族含窒素複素環基；
Ｒ^１３は、置換されていてもよいアミノで置換されたアルキル、または置換されていてもよい非芳香族含窒素複素環基で置換されたアルキル］である、（Ｉ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。(III) R ⁶ and R ⁷ are the substituent group B ′ (substituent group B ′: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, substituted Optionally substituted aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Alkyl substituted by amino, or substituent group C ′ (substituent group C ′: oxo, optionally substituted aminocarbonyl, alkyloxycarbonyl, alkyl optionally substituted by cyano or alkyloxy, Alkyloxyalkyl, cyano, The compound according to (II), which is an alkyl substituted with a non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent selected from alkylsulfonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl) Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(IV) R ² is of the formula:

[Wherein R ⁸ , R ⁹ and R ¹² each independently represent a hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, an optionally substituted aryl, or an optionally substituted hetero Aryl;
X ¹ and X ² are each an alkylene optionally intervening or substituted with —C (═O) —N (R ¹⁵ ) — or —N (R ¹⁶ ) —C (═O) —; R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, alkyl, or acyl;
X ³ represents —O— or —N (R ¹⁸ ) —; R ¹⁸ represents a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl;
R ¹⁰ and R ¹¹ are an optionally substituted amino or an optionally substituted non-aromatic nitrogen-containing heterocyclic group;
R ¹³ is an alkyl substituted with an optionally substituted amino, or an alkyl substituted with an optionally substituted non-aromatic nitrogen-containing heterocyclic group], or a pharmaceutical thereof, or a pharmaceutical thereof Top acceptable salts or solvates thereof.

(V) R ¹⁰ and R ¹¹ are a substituent group B ′ (substituent group B ′: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, substituted Optionally substituted aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Amino, or substituent group C ′ (substituent group C ′: oxo, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted with alkyloxy, alkyloxyalkyl, cyano Alkylsulfonyl, A compound or a pharmaceutically acceptable salt thereof according to (IV), which is a non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent selected from alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl), or Their solvates.
(VI) R ¹³ is substituent group B ′ (substituent group B ′: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted amino) Carbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl) optionally substituted amino. Or a substituent group C ′ (substituent group C ′: oxo, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted alkyl, alkyloxyalkyl , Cyano, alkyls A compound substituted with a non-aromatic nitrogen-containing heterocyclic group which may be substituted with a substituent selected from sulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl]. Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(VII) The compound according to any one of (I) to (VI), or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Y is —NH—.

（式中、Ｒ^２２は、水素原子またはハロゲン；Ｒ^２３は、ハロゲンまたはアルキニル；およびＲ^２４は水素原子）で表される基である、（Ｉ）〜（ＶＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＩＸ） Ｒ^３が、式：

［式中、Ｒ^２２は、置換基群Ｄ’（置換基群Ｄ’：カルボキシ、アルキルオキシカルボニル、および置換されていてもよいアミノカルボニル）から選択される置換基で置換されていてもよいアルキルオキシ、置換基群Ｄ’から選択される置換基で置換されていてもよいアルケニルオキシ、または置換基群Ｄ’から選択される置換基で置換されていてもよいアルキニルオキシ；Ｒ^２３は、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^２４は水素原子］で表される基である、（Ｉ）〜（ＶＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（Ｘ） Ｒ^３が、式：

［式中、Ｒ^２２は、式：−Ｚ−Ｒ^２５（式中、Ｚは、−Ｏ−を介在してもよいアルキレン；Ｒ^２５は、置換基群Ｅ’（置換基群Ｅ’：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基で置換されていてもよいフェニル、置換基群Ｅ’から選択される置換基で置換されていてもよいピリジル、置換基群Ｅ’から選択される置換基で置換されていてもよいフリル、置換基群Ｅ’から選択される置換基で置換されていてもよいチエニル、置換基群Ｅ’から選択される置換基で置換されていてもよいチアゾリル、または置換基群Ｅ’から選択される置換基で置換されていてもよいオキサゾリル）で表される基；Ｒ^２３が、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^２４が水素原子］で表される基である、（Ｉ）〜（ＶＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＸＩ） （Ｉ）〜（Ｘ）のいずれかに記載の化合物を有効成分として含有する医薬組成物。
（ＸＩＩ） （Ｉ）〜（Ｘ）のいずれかに記載の化合物を有効成分として含有する抗癌剤。
（ＸＩＩＩ） （Ｉ）〜（Ｘ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする癌の予防および／または治療方法。
（ＸＩＶ） 癌の予防および／または治療剤を製造するための（Ｉ）〜（Ｘ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。(VIII) R ³ is of the formula:

(Wherein R ²² is a hydrogen atom or halogen; R ²³ is halogen or alkynyl; and R ²⁴ is a hydrogen atom), and the compound according to any one of (I) to (VII) Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(IX) R ³ is of the formula:

[Wherein R ²² represents an alkyl optionally substituted with a substituent selected from substituent group D ′ (substituent group D ′: carboxy, alkyloxycarbonyl, and optionally substituted aminocarbonyl). oxy, 'which do may be alkenyloxy substituted with a substituent selected from or substituent group D,' substituent group D may alkynyl optionally substituted with a substituent selected from oxy; R ²³ is substituted which may alkynyl optionally, optionally substituted alkyloxy or halogen; and R ²⁴ is a group represented by hydrogen atom, or a compound according to any one of (I) ~ (VII) A pharmaceutically acceptable salt or a solvate thereof.
(X) R ³ is represented by the formula:

[In the formula, R ²² is a group represented by the formula: —Z—R ²⁵ (wherein Z is an alkylene which may interpose —O—; R ²⁵ is a substituent group E ′ (substituent group E ′: halogen) , Carboxy, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, alkyloxycarbonyl, and optionally substituted phenyl), optionally substituted phenyl, selected from substituent group E ′ Pyridyl which may be substituted with a substituent, furyl which may be substituted with a substituent selected from substituent group E ′, and thienyl which may be substituted with a substituent selected from substituent group E ′ , 'thiazolyl optionally substituted with a substituent selected from or substituent group E,' substituent group E be substituted with a substituent selected from the group represented by the good oxazolyl); R ²³ Is replaced Which may alkynyl optionally, an optionally substituted alkyloxy, or halogen; and R ²⁴ is a group represented by a hydrogen atom] The compound or thereof according to any one of (I) ~ (VII) A pharmaceutically acceptable salt or a solvate thereof.
(XI) A pharmaceutical composition comprising the compound according to any one of (I) to (X) as an active ingredient.
(XII) An anticancer agent comprising the compound according to any one of (I) to (X) as an active ingredient.
(XIII) A method for preventing and / or treating cancer, comprising administering the compound according to any one of (I) to (X) or a pharmaceutically acceptable salt or solvate thereof.
(XIV) Use of the compound according to any one of (I) to (X) or a pharmaceutically acceptable salt thereof or a solvate thereof for producing a preventive and / or therapeutic agent for cancer.

  In the present specification, “halogen” means fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred.

In the present specification, “alkyl” used alone or in combination with other terms includes straight-chain or branched monovalent hydrocarbon groups having 1 to 10 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, Examples include n-nonanyl and n-decanyl. Preferably, C1-C10 alkyl is mentioned. More preferably, C1-C6 alkyl is mentioned. Most preferably, C1-C4 alkyl is mentioned.
In the present specification, the term “haloalkyl” used alone or in combination with other terms includes the “alkyl” substituted with 1 to 8 positions, preferably 1 to 5 positions, with the “halogen”. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl and the like can be mentioned. Preferably, C1-C6 alkyl substituted by 1-5 places by the said "halogen" is mentioned. In particular, C1-C3 alkyl substituted with 1 to 3 sites by the “halogen” is preferable. Most preferably, trifluoromethyl is used.
In the present specification, examples of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like. Preferably, C1-C6 alkylsulfonyl is mentioned. In particular, C1-C3 alkylsulfonyl is preferable.
In the present specification, examples of the “alkylsulfonylalkyl” include methylsulfonylmethyl, methylsulfonylethyl, methylsulfonylpropyl, methylsulfonylbutyl, methylsulfonylpropyl and the like. Preferably, C1-C6 alkylsulfonyl C1-C6 alkyl is mentioned. In particular, C1-C3 alkylsulfonyl C1-C4 alkyl is preferable.

In the present specification, as "alkyloxy", methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, n-hexyloxy, Examples include n-heptyloxy, n-octyloxy, n-nonanyloxy, n-decanyloxy and the like. Preferably, C1-C6 alkyloxy is mentioned. In particular, C1-C3 alkyloxy is preferable.
In the present specification, examples of “alkyloxyalkyl” include methyloxymethyl, methyloxyethyl, methyloxypropyl, ethyloxymethyl, ethyloxyethyl, ethyloxypropyl, and the like. Preferably, C1-C6 alkyloxy C1-C6 alkyl is mentioned. In particular, C1-C3 alkyloxy C1-C4 alkyl is preferable.
In the present specification, “alkyloxycarbonyl” includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, t-butyloxycarbonyl, n-pentyloxycarbonyl and the like. Can be mentioned. Preferably, C1-C6 alkyloxycarbonyl is mentioned. In particular, C1-C3 alkyloxycarbonyl is preferable.
In the present specification, examples of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, t-butylcarbonyl, n-pentylcarbonyl and the like. Preferably, C1-C6 alkylcarbonyl is mentioned. In particular, C1-C3 alkylcarbonyl is preferable.
In the present specification, examples of “haloalkyloxy” include trifluoromethyloxy, trichloromethyloxy, difluoroethyloxy, trifluoroethyloxy, dichloroethyloxy, trichloroethyloxy and the like. Preferably, halo C1-C6 alkyloxy is mentioned. Particularly preferred is halo C1-C3 alkyloxy. Most preferably, trifluoromethyloxy is mentioned.
In the present specification, examples of “aminocarbonylalkyl” include aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylbutyl and the like. Preferably, aminocarbonyl C1-C6 alkyl is mentioned. In particular, aminocarbonyl C1-C3 alkyl is preferable.
In the present specification, examples of “aminocarbonylalkyloxy” include aminocarbonylmethyloxy, aminocarbonylethyloxy, aminocarbonylpropyloxy, aminocarbonylbutyloxy and the like. Preferably, aminocarbonyl C1-C6 alkyloxy is mentioned. In particular, aminocarbonyl C1-C3 alkyloxy is preferable.
In the present specification, examples of “hydroxyalkyl” include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like. Preferably, hydroxy C1-C6 alkyl is mentioned. In particular, hydroxy C1-C3 alkyl is preferable.
In the present specification, examples of “alkylthio” include methylthio, ethylthio, propylthio, butylthio and the like. Preferably, C1-C6 alkylthio is mentioned. In particular, C1-C3 alkylthio is preferable.

In the present specification, the “alkylene” used alone or in combination with other terms includes a linear or branched divalent hydrocarbon group having 1 to 4 carbon atoms. For example, methylene, ethylene, propylene, butylene and the like can be mentioned. Preferably, C1-C3 alkylene is mentioned. In particular, C1-C2 alkylene is preferable.
Examples of the “alkylene which may intervene —O— or —N (R ¹⁹ ) —” in X ³ , X ¹¹ and X ¹² include —CH ₂ —O—, —O—CH ₂ — and —CH _{2. ^{-N (R 19) -, -}} N (R 19) -CH 2 -, - (CH 2) 2 -O -, - O- (CH 2) 2 -, - (CH 2) 2 -N (R 19 ^{) -, - N (R 19} ) - including such - _{(CH 2)} 2.
Examples of the “alkylene which may intervene —O—, —S—, or —N (R ²¹ ) —” in Y include —CH ₂ —O—, —O—CH ₂ —, —CH ₂ —S—. _{^{, -S-CH 2 -, -}} CH 2 -N (R 21) -, - N (R 21) -CH 2 -, - (CH 2) 2 -O -, - O- (CH 2) 2 -, _{- (CH 2) 2 -S -} , - S- (CH 2) 2 -, - (CH 2) 2 -N (R 21) -, - N (R 21) - encompass such - _{(CH 2) 2} To do.
Examples of the “alkylene optionally intervening —O—, —S—, or —N (R ²⁶ ) —” in Z include —CH ₂ —O—, —O—CH ₂ —, —CH ₂ —S—. _{^{, -S-CH 2 -, -}} CH 2 -N (R 26) -, - N (R 26) -CH 2 -, - (CH 2) 2 -O -, - O- (CH 2) 2 -, _{- (CH 2) 2 -S -} , - S- (CH 2) 2 -, - (CH 2) 2 -N (R 26) -, - N (R 26) - encompass such - _{(CH 2) 2} To do.
“—C (═O) —N (R ¹⁵ ) —, —N (R ¹⁶ ) —C (═O) —, —N (R ¹⁷ ) —, —O— in X ¹ , X ² and X ⁴ , -S-, phenylene or as alkylene "be interposed a is _{heteroarylene,, - (CH 2) 0-4} -C (= O) -N (R 15) - (CH 2) 0-4 -, — (CH ₂ ) _0-4 —O— (CH ₂ ) _1-4 —C (═O) —N (R ¹⁵ ) — (CH ₂ ) _0-4 —, — (CH ₂ ) _0-4 —S — (CH ₂ ) _1-4 —C (═O) —N (R ¹⁵ ) — (CH ₂ ) _0-4- —, — (CH ₂ ) _0-4 —N (R ¹⁷ ) — (CH ₂ ) _{1 -4} -C (= O) -N (R ¹⁵ )-(CH ₂ ) _0-4 -,-(CH ₂ ) _{0 -4-} (phenylene)-(CH ₂ ) _1-4 -C (= O) -N ^{(R 15)} _{(CH 2) 0-4 -, -} (CH 2) 0-4 - ( _{heteroarylene) - (CH 2) 1-4 -C} (= O) -N (R 15) - (CH 2) 0-4 - , — (CH ₂ ) _0-4 —O- (phenylene)-(CH ₂ ) _1-4 —C (═O) —N (R ¹⁵ ) — (CH ₂ ) _0-4 —, — (CH ₂ ) _0-4 -O- (CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _1-4 -C (= O) -N (R ¹⁵ )-(CH ₂ ) _0-4 -,-(CH ₂ ) _0-4 -S- (phenylene)-(CH ₂ ) _1-4 -C (= O) -N (R ¹⁵ )-(CH ₂ ) _0-4 --,-(CH ₂ ) _0-4- S- (CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _1-4 -C (= O) -N (R ¹⁵ )-(CH ₂ ) _0-4 -,-(CH ₂ ) _{0- 4} -N ^{(R 17} - _{^{(phenylene) - (CH 2) 1-4 -C}} (= O) -N (R 15) - (CH 2) 0-4 -, - (CH 2) 0-4 -N (R 17) - ( CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _1-4 -C (= O) -N (R ¹⁵ )-(CH ₂ ) _0-4 --,-(CH ₂ ) _0-4 -O -(Heteroarylene)-(CH ₂ ) _1-4 -C (= O) -N (R ¹⁵ )-(CH ₂ ) _0-4 --,-(CH ₂ ) _0-4 -O- (CH ₂ ) _{1 -4} - ^{_{(heteroarylene) - (CH 2) 1-4 -C}} (= O) -N (R 15) - (CH 2) 0-4 -, - (CH 2) 0-4 -S- ( heteroarylene) — (CH ₂ ) _1-4 —C (═O) —N (R ¹⁵ ) — (CH ₂ ) _0-4- —, — (CH ₂ ) _0-4 —S— (CH ₂ ) _1-4 — ( Hetero ant _{^{Ren) - (CH 2) 1-4 -C}} (= O) -N (R 15) - (CH 2) 0-4 -, - (CH 2) 0-4 -N (R 17) - ( heteroarylene) — (CH ₂ ) _1-4 —C (═O) —N (R ¹⁵ ) — (CH ₂ ) _0-4- —, — (CH ₂ ) _0-4 —N (R ¹⁷ ) — (CH ₂ ) _{1 -4} - _{^{(heteroarylene) - (CH 2) 1-4 -C}} (= O) -N (R 15) - (CH 2) 0-4 - ;-( CH 2) 0-4 -N (R 16) _{-C (= O) - (CH} 2) 0-4 -, - (CH 2) 0-4 -O- (CH 2) 1-4 -N (R 16) -C (= O) - (CH 2 ) _0-4 -,-(CH ₂ ) _0-4 -S- (CH ₂ ) _1-4 -N (R ¹⁶ ) -C (= O)-(CH ₂ ) _0-4 -,-(CH _{2 ^{) 0-4 -N (R 17) -}} (C ^{_{2) 1-4 -N (R 16)}} -C (= O) - (CH 2) 0-4 -, - (CH 2) 0-4 - ( _{phenylene) - (CH 2) 1-4 -N} ( _{^{R 16) -C (= O)}} - (CH 2) 0-4 -, - (CH 2) 0-4 - ( ^{_{heteroarylene) - (CH 2) 1-4 -N}} (R 16) -C (= O )-(CH ₂ ) _0-4 -,-(CH ₂ ) _0-4 -O- (phenylene)-(CH ₂ ) _1-4 -N (R ¹⁶ ) -C (= O)-(CH ₂ ) _0-4 -,-(CH ₂ ) _0-4 -O- (CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _1-4 -N (R ¹⁶ ) -C (= O)-(CH _{2) 0-4 -, - (CH} 2) 0-4 -S- ( ^{_{phenylene) - (CH 2) 1-4 -N}} (R 16) -C (= O) - (CH 2) 0-4 - , - _{(CH 2) 0 4 -S- (CH 2) 1-4 -} ( ^{_{phenylene) - (CH 2) 1-4 -N}} (R 16) -C (= O) - (CH 2) 0-4 -, - (CH 2) _0-4 -N (R ¹⁷ )-(phenylene)-(CH ₂ ) _1-4 -N (R ¹⁶ ) -C (= O)-(CH ₂ ) _0-4 -,-(CH ₂ ) _{0- 4-} N (R ¹⁷ )-(CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _1-4 -N (R ¹⁶ ) —C (═O) — (CH ₂ ) _0-4- −, − _{(CH 2)} 0-4 -O- ^{_{(heteroarylene) - (CH 2) 1-4 -N}} (R 16) -C (= O) - (CH 2) 0-4 -, - (CH 2) 0- _{4 -O- (CH 2) 1-4 -} ( ^{_{heteroarylene) - (CH 2) 1-4 -N}} (R 16) -C (= O) - (CH 2) 0-4 -, - (CH 2) _0-4 -S -(Heteroarylene)-(CH ₂ ) _1-4 -N (R ¹⁶ ) -C (= O)-(CH ₂ ) _0-4 -,-(CH ₂ ) _0-4 -S- (CH ₂ ) _{1 -4} - _{^{(heteroarylene) - (CH 2) 1-4 -N}} (R 16) -C (= O) - (CH 2) 0-4 -, - (CH 2) 0-4 -N (R 17) - _{^{(heteroarylene) - (CH 2) 1-4 -N}} (R 16) -C (= O) - (CH 2) 0-4 -, - (CH 2) 0-4 -N (R 17) - ( CH _{2) 1-4} - ^{_{(heteroarylene) - (CH 2) 1-4 -N}} (R 16) -C (= O) - (CH 2) 0-4 - ;-( CH 2) 0-4 -O — (CH ₂ ) _0-4 —, — (CH ₂ ) _0-4 —O— (CH ₂ ) _1-4 —O— (CH ₂ ) _0-4 —, — (CH ₂ ) _0-4 —S - (CH _{) 1-4 -O- (CH 2) 0-4} -, - (CH 2) 0-4 -N (R 17) - (CH 2) 1-4 -O- (CH 2) 0-4 -, - _{(CH 2) 0-4} - _{(phenylene) - (CH 2) 1-4 -O-} (CH 2) 0-4 -, - (CH 2) 0-4 - ( _{heteroarylene)} - _(CH 2) _{1 -4-} O- (CH ₂ ) _0-4 -,-(CH ₂ ) _0-4 -O- (phenylene)-(CH ₂ ) _1-4 -O- (CH ₂ ) _0-4 -,-( _{CH 2) 0-4 -O- (CH 2} ) 1-4 - ( _{phenylene) - (CH 2) 1-4 -O-} (CH 2) 0-4 -, - (CH 2) 0-4 -S -(Phenylene)-(CH ₂ ) _1-4 -O- (CH ₂ ) _0-4 -,-(CH ₂ ) _0-4 -S- (CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _{1-4 -O- (CH 2) 0-4 -} , - (CH 2) 0-4 -N (R 17) - ( _{phenylene) - (CH 2) 1-4 -O-} (CH 2) 0- ^{_{4 -, - (CH 2)}} 0-4 -N (R 17) - (CH 2) 1-4 - ( _{phenylene) - (CH 2) 1-4 -O-} (CH 2) 0-4 -, - _{(CH 2)} 0-4 -O- _{(heteroarylene) - (CH 2) 1-4 -O-} (CH 2) 0-4 -, - (CH 2) 0-4 -O- (CH 2) 1- ₄ - _{(heteroarylene) - (CH 2) 1-4 -O-} (CH 2) 0-4 -, - (CH 2) 0-4 -S- ( _{heteroarylene)} - _{(CH 2)} 1-4 -O- _{(CH 2) 0-4 -, -} (CH 2) 0-4 -S- (CH 2) 1-4 - ( _{heteroarylene) - (CH 2) 1-4 -O-} (CH 2) _{-4 -, - (CH 2)} 0-4 -N (R 17) - ( _{heteroarylene) - (CH 2) 1-4 -O-} (CH 2) 0-4 -, - (CH 2) 0-4 _{^{-N (R 17) - (CH}} 2) 1-4 - ( _{heteroarylene) - (CH 2) 1-4 -O-} (CH 2) 0-4 - ;-( CH 2)
_0-4 -S- (CH ₂ ) _0-4 --,-(CH ₂ ) _0-4 -O- (CH ₂ ) _1-4 -S- (CH ₂ ) _0-4 --,-(CH ₂ ) _0-4 -S- (CH ₂ ) _1-4 -S- (CH ₂ ) _0-4 --,-(CH ₂ ) _{0 -4} -N (R ¹⁷ )-(CH ₂ ) _1-4 -S- (CH ₂ ) _0-4 --,-(CH ₂ ) _0-4- (phenylene)-(CH ₂ ) _1-4 -S- (CH ₂ ) _0-4 --,-(CH ₂ ) _0-4- (Heteroarylene)-(CH ₂ ) _1-4 -S- (CH ₂ ) _0-4 --,-(CH ₂ ) _0-4- O- (phenylene)-(CH ₂ ) _1-4 -S- (CH _{2) 0-4 -, - (CH} 2) 0-4 -O- (CH 2) 1-4 - ( _{phenylene) - (CH 2) 1-4 -S-} (CH 2) 0-4 -, - _{(CH 2) 0-4} S- _{(phenylene) - (CH 2) 1-4 -S-} (CH 2) 0-4 -, - (CH 2) 0-4 -S- (CH 2) 1-4 - ( phenylene) - (CH _{2) 1-4 -S- (CH 2)} 0-4 -, - (CH 2) 0-4 -N (R 17) - ( _{phenylene) - (CH 2) 1-4 -S-} (CH 2) _0-4 -,-(CH ₂ ) _0-4- N (R ¹⁷ )-(CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _1-4 -S- (CH ₂ ) _{0-4- , - (CH 2) 0-4 -O-} ( _{heteroarylene) - (CH 2) 1-4 -S-} (CH 2) 0-4 -, - (CH 2) 0-4 -O- (CH 2) _1-4 - _{(heteroarylene) - (CH 2) 1-4 -S-} (CH 2) 0-4 -, - (CH 2) 0-4 -S- ( heteroarylene) - (CH _{2 ) 1-4 -S- (CH 2) 0-4} -, - (CH 2) 0-4 -S- (CH 2) 1-4 - ( _{heteroarylene) - (CH 2) 1-4 -S-} ( _{CH 2) 0-4 -, - (} CH 2) 0-4 -N (R 17) - ( _{heteroarylene) - (CH 2) 1-4 -S-} (CH 2) 0-4 -, - (CH 2 ^{_{) 0-4 -N (R 17) -}} (CH 2) 1-4 - ( _{heteroarylene) - (CH 2) 1-4 -S-} (CH 2) 0-4 - ;-( CH 2) 0-4 _{^{-N (R 17) - (CH}} 2) 0-4 -, - (CH 2) 0-4 -O- (CH 2) 1-4 -N (R 17) - (CH 2) 0-4 -, _{- (CH 2) 0-4 -S- (} CH 2) 1-4 -N (R 17) - (CH 2) 0-4 -, - (CH 2) 0-4 -N (R 17) - ( CH _{2) ^{-4 -N (R 17) - (}} CH 2) 0-4 -, - (CH 2) 0-4 - ( ^{_{phenylene) - (CH 2) 1-4 -N}} (R 17) - (CH 2) 0 _{-4 -, - (CH 2)} 0-4 - ( _{^{heteroarylene) - (CH 2) 1-4 -N}} (R 17) - (CH 2) 0-4 -, - (CH 2) 0-4 -O -(Phenylene)-(CH ₂ ) _1-4 -N (R ¹⁷ )-(CH ₂ ) _0-4 -,-(CH ₂ ) _0-4 -O- (CH ₂ ) _1-4- (phenylene) -(CH ₂ ) _1-4 -N (R ¹⁷ )-(CH ₂ ) _0-4 -,-(CH ₂ ) _{0 -4} -S- (phenylene)-(CH ₂ ) _1-4 -N (R _{^{17) - (CH 2) 0-4}} -, - (CH 2) 0-4 -S- (CH 2) 1-4 - ( _{phenylene) - (CH 2) 1-4 -N} (R 17) _{- (CH 2) 0-4 -,} - (CH 2) 0-4 -N (R 17) - ( ^{_{phenylene) - (CH 2) 1-4 -N}} (R 17) - (CH 2) 0-4 -,-(CH ₂ ) _0-4 -N (R ¹⁷ )-(CH ₂ ) _1-4- (phenylene)-(CH ₂ ) _1-4 -N (R ¹⁷ )-(CH ₂ ) _{0-4 -, - (CH 2) 0-4} -O- ( _{^{heteroarylene) - (CH 2) 1-4 -N}} (R 17) - (CH 2) 0-4 -, - (CH 2) 0-4 -O - _{(CH 2) 1-4} - _{^{(heteroarylene) - (CH 2) 1-4 -N}} (R 17) - (CH 2) 0-4 -, - (CH 2) 0-4 -S- ( heteroarylene) — (CH ₂ ) _1-4 —N (R ¹⁷ ) — (CH ₂ ) _0-4 —, — (CH ₂ ) _0-4 —S— (CH ₂ ) _1-4 — (heteroary _{^{Ren) - (CH 2) 1-4 -N}} (R 17) - (CH 2) 0-4 -, - (CH 2) 0-4 -N (R 17) - ( _{heteroarylene)} - _(CH 2) _{1 ^{-4 -N (R 17) - (}} CH 2) 0-4 -, - (CH 2) 0-4 -N (R 17) - (CH 2) 1-4 - ( _{heteroarylene)} - _(CH 2) _{1 ^{-4 -N (R 17) - (}} CH 2) 0-4 - , and the like.
In the above-described substituent, when a — (CH ₂ ) _1-4 — group is not present in each substituent, [for example, — (CH ₂ ) _0-4- C (═O) —N (R ¹⁵ ) — (CH ₂ ) _0-4- group], — (CH ₂ ) _0-4- group is not a — (CH ₂ ) ₀ — group.

In the present specification, “cycloalkyl” used alone or in combination with other terms includes cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably C5-C6 cycloalkyl is mentioned.
In this specification, “alkenyl” includes straight or branched monovalent hydrocarbon groups having 2 to 8 carbon atoms and having one or more double bonds. To do. You may have a triple bond in the chain. Examples include vinyl, allyl, 1-propenyl, 2-propenyl, various butenyl isomers, and the like. Preferably, C2-C6 alkenyl is mentioned. More preferably, C2-C4 alkenyl is mentioned.
In the present specification, “alkenyloxy” includes vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy and various butenyloxy. Preferably, C2-C6 alkenyloxy is mentioned. In particular, C2-C4 alkenyloxy is preferable.
In the present specification, “alkynyl” includes straight or branched monovalent hydrocarbon groups having 2 to 8 carbon atoms and having one or more triple bonds. . Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, various pentynyl isomers, and the like. Preferably, C2-C6 alkynyl is mentioned. More preferably, C2-C4 alkynyl is mentioned.
In the present specification, “alkynyloxy” includes ethynyloxy, propynyloxy, butynyloxy, pentynyloxy and the like. Preferably, C2-C6 alkynyloxy is mentioned. In particular, C2-C4 alkynyloxy is preferable.

In the present specification, “aryl” used alone or in combination with other terms includes monocyclic or condensed cyclic aromatic hydrocarbons. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned.
In the present specification, “aralkyl” includes the above “alkyl” in which one or more “aryl” is substituted, and these can be substituted at all possible positions. For example, benzyl, phenylethyl (eg, 2-phenylethyl), phenylpropyl (eg, 3-phenylpropyl), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.), anthrylmethyl (eg, , 9-anthrylmethyl and the like). Preferably, benzyl and phenylethyl are used.
In the present specification, the “arylalkyl” includes those in which the “aryl” is substituted with one or more of the “alkyl”, and these can be substituted at all possible positions. For example, benzyl, phenylethyl (eg, 2-phenylethyl), phenylpropyl (eg, 3-phenylpropyl), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.), anthrylmethyl (eg, , 9-anthrylmethyl and the like). Preferably, benzyl and phenylethyl are used.
As the “arylalkyl” in the substituent group B, benzyl, phenylethyl and the like are preferable.

In the present specification, the term “non-aromatic heterocyclic group” used alone or in combination with other terms refers to any non-optionally selected oxygen atom, sulfur atom or nitrogen atom in the ring. A group derived from an aromatic 5- to 7-membered ring or a ring in which two or more of them are condensed is included. For example, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolinyl (eg, 3-pyrrolinyl), imidazolidinyl (eg, 2-imidazolidinyl), imidazolinyl (eg, imidazolinyl), pyrazolidinyl (eg, 1-pyrazolidinyl, 2- Pyrazolidinyl), pyrazolinyl (eg pyrazolinyl), piperidyl (eg piperidino, 2-piperidyl), piperazinyl (eg 1-piperazinyl, 2-piperazinyl), indolinyl (eg 1-indolinyl), isoindolinyl (eg isoindolinyl), Morpholinyl (eg, morpholino, 2-morpholinyl, 3-morpholinyl), tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, dioxolanyl, tetrahydrothie , Dihydrothiopyranyl, tetrahydrothiofuranyl, decahydroisoquinolyl, azepinyl, oxepinyl, dihydrooxepinyl, tetrahydrooxepinyl, oxepanyl, 4,5,6,7-tetrahydrothieno [3,2] pyridyl 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, hexahydropyrazyl [2.1-b] [1,3] oxazin-8-yl, and the like.
In the present specification, the term “non-aromatic nitrogen-containing heterocyclic group” used alone or in combination with other terms includes at least one nitrogen atom in the ring, and optionally from an oxygen atom and a sulfur atom. It includes a group derived from a non-aromatic 4- to 7-membered ring which may contain one or more selected atoms in the ring or a ring in which two or more thereof are condensed. For example, azetidinyl (eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), pyrrolinyl (eg, 3-pyrrolinyl), imidazolidinyl (eg, 2 -Imidazolidinyl), imidazolinyl (eg, imidazolinyl), pyrazolidinyl (eg, 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (eg, pyrazolinyl), piperidyl (eg, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl), Piperazinyl (eg 1-piperazinyl, 2-piperazinyl), indolinyl (eg 1-indolinyl), isoindolinyl (eg isoindolinyl), morpholinyl (eg morpholino, 2- Morpholinyl, 3-morpholinyl), 1,4-thiazinyl (eg, 1,4-thiazin-1-yl, 1,4-thiazin-2-yl,), thiomorpholinyl (eg, 1-thiomorpholinyl, 2-thiomorpholinyl), Decahydroisoquinolyl (eg 2-decahydroisoquinolyl), azepinyl (eg 1-azepinyl), diazepinyl, 4,5,6,7-tetrahydrothieno [3,2] pyridyl, 2-oxa-5-aza -Bicyclo [2.2.1] hept-5-yl, hexahydropyrazyl [2.1-b] [1,3] oxazin-8-yl and the like.
Examples of the “non-aromatic nitrogen-containing heterocyclic group” in R ¹⁰ , R ¹¹ , R ¹³ and R ¹⁴ include azetidinyl (eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl (eg, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl), piperazinyl (eg, 1-piperazinyl), morpholinyl (eg, morpholino, 3-morpholinyl), thiomorpholinyl ( For example, 1-thiomorpholinyl and 2-thiomorpholinyl) are preferable.
Examples of the “non-aromatic nitrogen-containing heterocyclic group” in Substituent Group A include azetidinyl (eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl). ), Piperidyl (eg piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl), piperazinyl (eg 1-piperazinyl), morpholinyl (eg morpholino, 3-morpholinyl), thiomorpholinyl (eg 1-thiomorpholinyl, 2 -Thiomorpholinyl) is preferred.
In the alkyl substituted with the non-aromatic nitrogen-containing heterocyclic group optionally substituted with the substituent selected from the substituent group C of R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ , “non-aromatic nitrogen-containing heterocycle” As the `` ring group '', azetidinyl (for example, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl (for example, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl), piperazinyl (eg 1-piperazinyl), morpholinyl (eg morpholino, 3-morpholinyl), thiomorpholinyl (eg 1-thiomorpholinyl, 2-thiomorpholinyl) are preferred.

In the present specification, the term “heteroaryl” used alone or in combination with other terms refers to a 5- to 6-membered aromatic containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring. Includes cyclic groups. This may be condensed with the “cycloalkyl”, the “aryl”, the “non-aromatic heterocyclic group”, or other heteroaryl at all possible positions. Whether the heteroaryl is a single ring or a fused ring, it can be attached at all possible positions. For example, pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), imidazolyl (eg, 2 -Imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl), oxazolyl (eg 2-oxazolyl), thiazolyl ( For example, 2-thiazolyl, 5-thiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (eg, 2-pyrazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl), Pyridazinyl (eg 3-pyridazinyl) Triazolyl, tetrazolyl (eg, 1H-tetrazolyl), oxadiazolyl (eg, 1,3,4-oxadiazolyl), thiadiazolyl (eg, 1,3,4-thiadiazolyl), indolizinyl (eg, 2-indolidinyl, 6-indolidinyl), Isoindolyl (eg, 2-isoindolyl), indolyl (eg, 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (eg, 3-indazolyl), purinyl (eg, 8-prinyl), quinolidinyl (eg, 2-indolyl) Quinolidinyl), isoquinolyl (eg, 3-isoquinolyl), quinolyl (eg, 2-quinolyl, 5-quinolyl), phthalazinyl (eg, 1-phthalazinyl), naphthyridinyl (eg, 2-naphthyridinyl), quinolanyl (eg, , 2-quinolinyl), quinazolinyl (eg, 2-quinazolinyl), cinnolinyl (eg, 3-cinnolinyl), pteridinyl (eg, 2-pteridinyl), carbazolyl (eg, 2-carbazolyl, 4-carbazolyl), phenanthridinyl (Eg 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (eg 1-acridinyl, 2-acridinyl), dibenzofuranyl (eg 1-dibenzofuranyl, 2-dibenzofuranyl), Benzimidazolyl (eg, 2-benzimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxazolyl), benzoxazolyl (eg, 2-benzoxazolyl), benzooxadiazolyl (eg, 4-benzoimidazolyl) Benzoxadiazolyl), benzoisothiazoly (Eg, 3-benzoisothiazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzofuryl (eg, 3-benzofuryl), benzothienyl (eg, 2-benzothienyl), 4,5-dihydronaphtho [1, 2-d] thiazolyl, 4H-chromeno [4,3-d] thiazolyl, 4H-thiochromeno [4,3-d] thiazolyl, 4,5-dihydrothiazolo [5,4-c] quinolyl, 8H-indeno [ 1,2-d] thiazolyl, 5,6-dihydro-4H-3-thia-1-aza-benzo [e] azulenyl and the like.
The “heteroaryl” in R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ⁴⁴ , and R ⁴⁵ is preferably pyridyl, furyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, triazolyl, or the like. More preferred are pyridyl, furyl, thienyl, thiazolyl and the like.
As the “heteroaryl” in R ¹² , R ⁴⁶ and R ⁵⁰ , pyridyl, furyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, triazolyl and the like are preferable. More preferred are pyridyl, furyl, thienyl, thiazolyl and the like.
As the “heteroaryl” for R ²⁵ , pyridyl, furyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, triazolyl and the like are preferable. More preferred are pyridyl, furyl, thienyl, thiazolyl and the like.

In the present specification, the “heteroarylene” includes the divalent group of the “heteroaryl”. For example, pyrrole diyl (e.g., 2,3-pyrrole diyl, 2,4-pyrrole diyl, 2,5-pyrrole diyl, 3,4-pyrrole diyl), flangeyl (e.g., 2,3-flangeyl, 2,4-flangeyl, 2,5-furandiyl, 3,4-furandiyl), thiophenediyl (for example, 2,3-thiophenediyl, 2,4-thiophenediyl, 2,5-thiophenediyl, 3,4-thiophenediyl), imidazole Diyl (eg, 2,4-imidazolediyl, 2,5-imidazolediyl), pyrazoldiyl (eg, 3,4-pyrazoldiyl, 3,5-pyrazoldiyl), isothiazoldiyl (eg, 3,4 4-isothiazoldiyl, 3,5-isothiazoldiyl), isoxazolediyl (e.g. 3 4-isoxazolediyl, 3,5-isoxazolediyl), oxazolediyl (eg, 2,4-oxazoldiyl, 2,5-oxazolediyl), thiazolediyl (eg, 2,4-thiazoldiyl, 2,5 -Thiazolediyl), pyridinediyl (eg 2,3-pyridinediyl, 2,4-pyridinediyl, 2,5-pyridinediyl), pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazolediyl, tetrazolediyl, oxadiazolediyl , Thiadiazole diyl and the like.
Examples of “heteroarylene” in Ar ¹ , Ar ² and Ar ³ include frangiyl, thiophenediyl, oxazolediyl, thiazolediyl and the like.
“Heteroarylene” in the definition of X ¹ , X ² and X ⁴ includes frangyl, thiophenediyl, oxazolediyl, thiazolediyl and the like.
In the present specification, “heteroarylalkyl” includes those in which “heteroaryl” is substituted at any position of the “alkyl” by one or more, and these are substituted at all possible positions. sell. For example, thienylmethyl (eg 2-thienylmethyl), thienylethyl (eg 2- (thiophen-2-yl) ethyl), furylmethyl (eg 2-furylmethyl), furylethyl (eg 2- (furan- 2-yl) ethyl), pyrrolylmethyl (eg 2-pyrrolylmethyl), pyrrolylethyl (eg 2- (pyrrol-2-yl) ethyl), imidazolylmethyl (eg 2-imidazolylmethyl, 4-imidazolylmethyl), imidazolylethyl (Eg 2- (imidazol-2-yl) ethyl), pyrazolylmethyl (eg 3-pyrazolylmethyl), pyrazolylethyl (eg 2- (pyrazol-3-yl) ethyl), thiazolylmethyl (eg 2-thiazolylmethyl) ), Thiazolylethyl (for example, 2- (thiazo L-2-yl) ethyl), isothiazolylmethyl (eg 3-isothiazolylmethyl), isoxazolylmethyl (eg 3-isoxazolylmethyl), oxazolylmethyl (eg 2- Oxazolylmethyl), oxazolylethyl (eg 2- (oxazol-2-yl) ethyl), pyridylmethyl (eg 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl), pyridylethyl (eg , 2-pyridylethyl) and the like.
As the “heteroarylalkyl” in the substituent group B, thienylmethyl, furylmethyl, pyrrolylmethyl, pyridylmethyl and the like are preferable.

In this specification, the term “acyl” used alone or in combination with other terms means alkylcarbonyl whose alkyl moiety is the aforementioned “alkyl”, haloalkylcarbonyl whose haloalkyl moiety is the aforementioned “haloalkyl”, The alkenylcarbonyl which is the “alkenyl”, the aralkylcarbonyl whose aralkyl moiety is the “aralkyl”, or the arylcarbonyl whose aryl moiety is the “aryl” are included. Examples include acetyl, propionyl, butyroyl, trifluoromethylcarbonyl, vinylcarbonyl, phenylacetyl, benzoyl and the like. “Alkyl”, “alkenyl”, and “aryl” may be substituted by respective substituents described later.
As “acyl” in R ¹⁵ and R ¹⁶ , acetyl, benzoyl, phenylacetyl and the like are preferable.
“Acyl” in R ¹⁸ and R ¹⁹ is preferably acetyl, benzoyl, phenylacetyl or the like.
“Acyl” in R ²⁰ and R ²¹ is preferably acetyl, benzoyl, phenylacetyl or the like.
As “acyl” in R ²⁶ , acetyl, benzoyl, phenylacetyl and the like are preferable.
In the present specification, “acyloxy” includes acetyloxy, propionyloxy, benzoyloxy and the like.

In the present specification, the term “optionally substituted amino” used alone or in combination with other terms is the above “alkyl”, “alkylsulfonylalkyl”, “alkyloxycarbonyl”, “ “Aminocarbonyloxyalkyl”, “alkyloxyalkyl”, “cycloalkyl”, “aryl”, “aralkyl”, “heteroaryl”, “heteroarylalkyl”, “acyl”, substituent group The “aminocarbonylalkyl” optionally substituted with a substituent selected from G, or the “aminoalkylcarbonyl” optionally substituted with a substituent selected from substituent group G, wherein the alkenyloxy moiety is “Alkenyloxycarbonyl” which is the above “alkenyloxy”, aralkyl Carboxymethyl moiety wherein encompasses "aralkyloxy" in which "aralkyloxycarbonyl" in one or two places an amino optionally substituted (substituent group G: alkyl, alkenyl, and aralkyl). For example, amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, diisopropylamino, benzylamino, acetylamino, trifluoromethylcarbonylamino, benzoylamino, methyloxycarbonylamino, ethyloxycarbonylamino, n-propyloxycarbonylamino Isopropyloxycarbonylamino, n-butyloxycarbonylamino, isobutyloxycarbonylamino, sec-butyloxycarbonylamino, tert-butyloxycarbonylamino, allyloxycarbonylamino, benzyloxycarbonylamino, cyclopentylamino, cyclohexylamino and the like It is done.
As the substituent of “optionally substituted amino” in R ²³ and R ²⁴ , alkyl and the like are preferable.
Examples of the substituent of “optionally substituted amino” in the substituent group A include alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, alkenyloxycarbonyl, aralkyloxycarbonyl, Cycloalkyl, arylalkyl, heteroarylalkyl, aminocarbonylalkyl optionally substituted with a substituent selected from substituent group G, aminocarbonyl optionally substituted with a substituent selected from substituent group G Preferred are oxyalkyl, alkyloxyalkyl, and aminoalkylcarbonyl which may be substituted with a substituent selected from substituent group G.
In the present specification, the substituent in “optionally substituted aminocarbonyl” is preferably alkyl, alkenyl, aralkyl and the like. In particular, alkyl is preferable.
In the substituent group C, the substituent in the “optionally substituted aminocarbonyl” is preferably alkyl, alkenyl, aralkyl and the like.
In the substituent group H, the substituent in the “optionally substituted aminocarbonyl” is preferably alkyl, alkenyl, aralkyl and the like.
In the present specification, as a substituent in “optionally substituted aminocarbonylalkyl”, alkyl, alkenyl, aralkyl and the like are preferable. In particular, alkyl is preferable.
As the substituent in the “optionally substituted aminocarbonylalkyl” in the substituent group B, alkylalkenyl, aralkyl and the like are preferable.
In the present specification, as a substituent in “optionally substituted aminocarbonyloxyalkyl”, alkyl, alkenyl, aralkyl and the like are preferable. In particular, alkyl is preferable.
As the substituent in the “optionally substituted aminocarbonyloxyalkyl” in the substituent group B, alkyl, alkenyl, aralkyl and the like are preferable.
In the present specification, the substituent in “optionally substituted aminoalkylcarbonyl” is preferably alkyl, alkenyl, aralkyl and the like. In particular, alkyl is preferable.
In the substituent group B, the substituent in the “optionally substituted aminoalkylcarbonyl” is preferably alkyl, alkenyl, aralkyl and the like.
In the present specification, the term “optionally substituted ureido” refers to the “alkyl”, the “aryl”, the “aralkyl”, the “heteroaryl”, the “heteroarylalkyl”, or the “acyl”. Includes ureido optionally substituted at one or more positions.

In the present specification, the substituent in the “optionally substituted alkyl” includes amino which may be substituted, non-aromatic nitrogen-containing heterocyclic group which may be substituted, non-substituted which may be substituted. Aromatic nitrogen-containing heterocyclic carbonyl, alkyl, alkyloxy, cyano, alkylsulfonyl, cycloalkyl, alkenyl, heteroaryl, heteroaryloxy, hydroxy, mercapto, alkylthio, halogen, nitro, carboxy, alkyloxycarbonyl, hydroxyalkyl, haloalkyl , Haloalkyloxy, alkylcarbonyloxy, carbamoyloxy, optionally substituted aminocarbonyl, aminocarbonylalkyloxy, acyl, acyloxy, aryloxy, aralkyl, aralkyloxy, optionally substituted group Nijino, azo groups, ureido, and the like may be substituted. These can be substituted one or more at all possible positions.
As the substituent of “optionally substituted alkyl” in R ⁶ , R ⁷ , R ¹³ , R ⁴⁷ , and R ⁵¹ , substituent group A (substituent group A: optionally substituted amino, substituted Substituents selected from non-aromatic nitrogen-containing heterocyclic groups, alkoxyimino, and hydroxy) which may be used are preferred. In particular, the substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted aminocarbonylalkyl, substituted Amino optionally substituted with a substituent selected from aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl), substituent group C (substituted) Group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted with alkyloxy, alkyloxyalkyl, cyano, alkylsulfonyl, alkylcarbonyl, Luque sulfonyl carbonyl, and alkylsulfonyl alkylcarbonyl) non-aromatic and may be substituted with a substituent selected from nitrogen-containing heterocyclic group is preferred.
As the substituent of “optionally substituted alkyl” in R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ⁴⁴ , and R ⁴⁵ , substituent group A (substituent group A: optionally substituted) A substituent selected from amino, an optionally substituted non-aromatic nitrogen-containing heterocyclic group, alkoxyimino, and hydroxy) is preferred. Particularly, amino optionally substituted with alkyl, alkylsulfonylalkyl, alkyloxycarbonyl, cyano or alkyl optionally substituted with alkyloxy and the like can be mentioned.

In the present specification, the substituents in “optionally substituted alkenyl” and “optionally substituted alkynyl” include amino which may be substituted and non-aromatic nitrogen-containing heterocycle which may be substituted. Ring group, cycloalkyl, hydroxy, alkyloxy, mercapto, alkylthio, halogen, nitro, cyano, carboxy, alkyloxycarbonyl, haloalkyl, haloalkyloxy, optionally substituted aminocarbonyl, acyl, acyloxy, aryl, aryloxy, Examples thereof include aralkyl, aralkyloxy, alkylsulfonyl, guanidino, azo group, ureido which may be substituted. These can be substituted one or more at all possible positions.
^Examples of the substituent of “optionally substituted alkenyl” in R ¹³ , R ⁴⁷ and R ⁵¹ include substituent group A (substituent group A: optionally substituted amino, optionally substituted non-substituted). Substituents selected from aromatic nitrogen-containing heterocyclic groups, alkoxyimino, and hydroxy) are preferred. In particular, the substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted aminocarbonylalkyl, substituted Amino optionally substituted with a substituent selected from aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl), substituent group C (substituted) Group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted with alkyl, alkyloxyalkyl, cyano, alkylsulfonyl, alkylcarbonyl, a Ke alkenyl carbonyl, and alkylsulfonyl alkylcarbonyl) non-aromatic and may be substituted with a substituent selected from nitrogen-containing heterocyclic group is preferred.

In the present specification, the substituents in “optionally substituted alkyloxy”, “optionally substituted alkenyloxy”, and “optionally substituted alkynyloxy” include cycloalkyl, alkenyl, hydroxy Alkyloxy, mercapto, alkylthio, halogen, nitro, cyano, carboxy, alkyloxycarbonyl, haloalkyl, haloalkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, acyloxy, substituted And non-aromatic heterocyclic group, aryloxy, aralkyloxy, alkylsulfonyl, guanidino, azo group, ureido which may be substituted, and the like. These can be substituted one or more at all possible positions. Preferably, halogen etc. are mentioned.
As the substituent of “optionally substituted alkyloxy”, “optionally substituted alkenyloxy”, and “optionally substituted alkynyloxy” in R ²² , substituent group D (substituent) Substituents selected from group D: carboxy, alkyloxycarbonyl, and optionally substituted aminocarbonyl) are preferred.
As the substituents of “optionally substituted alkyloxy”, “optionally substituted alkenyloxy”, and “optionally substituted alkynyloxy” in R ²³ and R ²⁴ , alkyloxy, cyano , Alkyloxycarbonyl, optionally substituted aminocarbonyl and the like are preferable.

In the present specification, as the substituent in the “optionally substituted non-aromatic nitrogen-containing heterocyclic group”, an aminocarbonyl optionally substituted with a substituent selected from alkyloxycarbonyl and substituent group G , Cyano, substituent group I (substituent group I: alkyl, alkyloxyalkyl, alkyl optionally substituted with a substituent selected from cyano, hydroxy, carboxy, aminocarbonyl, alkyloxycarbonyl, and alkyloxy) Sulfonyl, alkylsulfonylalkylcarbonyl, cycloalkyl, hydroxy, alkyloxy, mercapto, alkylthio, halogen, nitro, carboxy, haloalkyl, haloalkyloxy, acyl, acyloxy, aryl, aryloxy (eg, phenyloxy), aralkyl, araalkyl Kiruokishi (e.g., benzyloxy), a non-aromatic nitrogen-containing heterocyclic group, alkylcarbonylamino, aminocarbonylamino, amino, oxo, guanidino, azo group, ureido, and the like may be substituted.
Examples of the substituent of the “optionally substituted non-aromatic nitrogen-containing heterocyclic group” in R ¹⁰ , R ¹¹ and R ¹⁴ include alkyloxycarbonyl, optionally substituted aminocarbonyl, cyano, hydroxyalkyl, cyano Alternatively, alkyl optionally substituted with alkyloxy, alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, alkylsulfonylalkylcarbonyl, aralkyl optionally substituted, and the like are preferable. In particular, the substituents mentioned in the substituent group C are preferable.
As the substituent of the “optionally substituted non-aromatic nitrogen-containing heterocyclic group” in the substituent group A, it may be substituted with an optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy. Preferred alkyl, alkyloxyalkyl, cyano, alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, alkylsulfonylalkylcarbonyl and the like are preferable.

In the present specification, “optionally substituted aryl”, “optionally substituted phenyl”, “optionally substituted heteroaryl”, “optionally substituted pyridyl”, “substituted” "Optionally substituted furyl", "optionally substituted thienyl", "optionally substituted thiazolyl", "optionally substituted oxazolyl", "optionally substituted non-aromatic heterocyclic group" , "Optionally substituted cycloalkyl", "optionally substituted aralkyl", and "optionally substituted heteroarylalkyl" include an optionally substituted alkyl (substituent) As halogen, hydroxy, nitro, cyano, carboxy, alkyloxy, alkyloxycarbonyl, acyl, etc.), cycloalkyl, alkenyl, Lucinyl, hydroxy, alkyloxy, aralkyloxy, mercapto, alkylthio, halogen, nitro, cyano, carboxy, alkyloxycarbonyl, aryloxycarbonyl, haloalkyl, haloalkyloxy, optionally substituted amino, optionally substituted amino Carbonyl, acyl, acyloxy, optionally substituted aryl (substituents include halogen, hydroxy, nitro, cyano, carboxy, alkyloxy, alkyloxycarbonyl, acyl, etc.), optionally substituted heteroaryl ( Examples of the substituent include halogen, hydroxy, nitro, cyano, carboxy, alkyloxy, alkyloxycarbonyl, acyl, and the like, an optionally substituted non-aromatic heterocyclic group (the substituent includes halogen, Droxy, nitro, cyano, carboxy, alkyloxy, alkyloxycarbonyl, acyl, etc.), optionally substituted aralkyl (substituents are halogen, hydroxy, nitro, cyano, carboxy, alkyloxy, alkyloxycarbonyl, acyl) Etc.), alkylsulfonyl, guanidino, azo group, -N = N- (optionally substituted phenyl), or optionally substituted ureido. These can be substituted one or more at all possible positions.
Examples of the substituent of “optionally substituted aryl” and “optionally substituted heteroaryl” in R ²⁵ include alkyloxycarbonyl, optionally substituted aminocarbonyl, cyano, halogen, alkyloxy, alkylthio. Etc. are preferred. Particularly, substituents mentioned in Substituent Group F (Substituent Group F: halogen, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, alkyloxycarbonyl, and optionally substituted amino) are preferable.

In the present specification, the term “anticancer agent” and “cancer therapeutic agent” means brain tumor (eg glioblastoma type), urinary cancer (eg bladder cancer, kidney cancer), genital cancer (eg prostate cancer, ovarian cancer, uterus). Cancer), lymphoid tumor, gastrointestinal cancer (eg gastric cancer, colon cancer), throat cancer, lung cancer (eg lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer), pancreatic cancer, breast cancer, head and neck cancer, esophageal cancer, Includes therapeutic agents for thyroid cancer. In particular, it is preferably used as a therapeutic agent for breast cancer, brain tumor, bladder cancer, kidney cancer, prostate cancer, ovarian cancer, uterine cancer, lung cancer, pancreatic cancer, colon cancer, and head and neck cancer.
The present invention includes a method of treating or preventing cancer in a mammal in need of treating or preventing cancer, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I). Become. Preferred cancers to treat are brain tumors (eg glioblastoma types), urological cancers (eg bladder cancer, kidney cancer), genital cancers (eg prostate cancer, ovarian cancer, uterine cancer), lymphoid tumors, digestive organ cancers (Eg stomach cancer), throat cancer, lung cancer (eg lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer), pancreatic cancer, breast cancer, colon cancer, head and neck cancer, esophageal cancer, thyroid cancer. More preferred are breast cancer, brain tumor, bladder cancer, kidney cancer, prostate cancer, ovarian cancer, uterine cancer, lung cancer, pancreatic cancer, colon cancer, and head and neck cancer.

  The compound of the present invention has an excellent EGF receptor and HER2 inhibitory action and is highly safe, and thus is useful as a pharmaceutical, particularly a cancer therapeutic agent.

（式中、Ｈａｌ^１およびＨａｌ^２はそれぞれ独立してハロゲン；Ｒ^１、Ｒ^２２、Ｒ^２３、およびＲ^２４は前記（１）と同意義；Ａ^１は、Ｒ^２における置換基）
（第１工程）
Chem. Pharm. Bull., 30(7), 2410-2416等に記載の方法に従って合成できるまたは市販品として入手可能な出発原料（Ｓ．Ｍ．）とＷＯ９８／０２４３４等に記載の方法に従って合成できるまたは市販品として入手できる化合物（ｉｉ）を反応させることにより、化合物（ｉｉｉ）を合成する工程である。
出発原料（Ｓ．Ｍ．）と化合物（ｉｉ）を、テトラヒドロフラン、アセトニトリル等の溶媒中、２０℃〜加熱還流下、好ましくは６０℃〜加熱還流下で反応させることにより化合物（ｉｉｉ）を得ることができる。
（第２工程）
化合物（ｉｉｉ）を、薗頭反応に付して目的の化合物（ｉｖ）を得ることができる。
化合物（ｉｉｉ）を、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセタミド、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ジメチルスルホキシド等の溶媒中、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、[1,1'-ビス（ジフェニルフォスフィノ）フェロセン]ジクロロパラジウム、酢酸パラジウム＋トリフェニルホスフィン等のパラジウム触媒等のパラジウム触媒、ヨウ化銅、およびトリエチルアミン、ジ（イソプロピル）エチルアミン等の塩基の存在下、50℃〜150℃、好ましくは70℃〜90℃で反応させることにより化合物（ｉｖ）を得ることができる。The compound (I) of the present invention can be synthesized by any one of the methods A to E described below. Moreover, since the synthesis method of a pyrimidine derivative is described in Chem. Pharm. Bull., 30 (7), 2410-2416, 1982, EP606011, etc., it can also synthesize | combine according to these. When the compound has a group that affects each reaction, it can be protected with an appropriate protecting group and deprotected at an appropriate stage.
(Method A)

(In the formula, Hal ¹ and Hal ² are each independently halogen; R ¹ , R ²² , R ²³ , and R ²⁴ are as defined above (1); A ¹ is a substituent in R ² )
(First step)
Chem. Pharm. Bull., 30 (7), 2410-2416, etc., can be synthesized according to the method described in WO98 / 02434, etc. Or it is the process of synthesize | combining compound (iii) by making compound (ii) which can be obtained as a commercial item react.
Compound (iii) is obtained by reacting starting material (SM) and compound (ii) in a solvent such as tetrahydrofuran or acetonitrile at 20 ° C. to heating under reflux, preferably 60 ° C. to heating under reflux. Can do.
(Second step)
Compound (iii) can be subjected to Sonogashira reaction to obtain the target compound (iv).
Compound (iii) is dissolved in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, dimethyl sulfoxide, dichlorobis (triphenylphosphine) palladium, tetrakis (tri (Phenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium, palladium catalysts such as palladium acetate + triphenylphosphine, etc., palladium iodide, copper iodide, Compound (iv) can be obtained by reacting at 50 ° C. to 150 ° C., preferably 70 ° C. to 90 ° C., in the presence of a base such as triethylamine or di (isopropyl) ethylamine.

（式中、Ｈａｌ^２はハロゲン；Ｒ^１、Ｒ^１３、Ｒ^２２、Ｒ^２３、およびＲ^２４は前記（１）と同意義；Ｒ^Ａはアルキル）
（第１工程）
本工程は、Ａ法第１工程と同様の方法で行うことができる。EP606011等に記載の方法に従って合成できるまたは市販品として入手可能な出発原料（Ｓ．Ｍ．）を用いる。
（第２工程）
本工程は、通常行われるエステルからアルコールへの還元反応により行うことができる。
化合物（ｖ）を、テトラヒドロフラン、ジエチルエーテル等の溶媒中、水素化リチウムアルミニウム等の還元剤の存在下、−８０℃〜５０℃、好ましくは−１０℃〜３０℃で反応させることにより化合物（ｖｉ）を得ることができる。
（第３工程）
本工程は、通常行われるアルコールからアルデヒドへの酸化反応により行うことができる。
化合物（ｖｉ）を、クロロホルム、ジクロロメタン等の溶媒中、二酸化マンガン等の参加剤の存在下、０℃〜１００℃、好ましくは０℃〜５０℃で反応させることにより化合物（ｖｉｉ）を得ることができる。
（第４工程）
本工程は、化合物（ｖｉｉ）と式：Ｒ^１３−Ｏ−ＮＨ_２（式中、Ｒ^１３は上記（１）と同意義）で表される化合物を反応させることにより、目的とする化合物（ｖｉｉｉ）を合成する工程である。
出発原料（ｖｉｉ）と式：Ｒ^１３−Ｏ−ＮＨ_２（式中、Ｒ^１３は上記（１）と同意義）で表される化合物またはその塩を、テトラヒドロフラン、ジオキサン、メタノール等の溶媒中、またはそれらと水の混合溶媒中、０℃〜加熱還流下、好ましくは２０℃〜５０℃で反応させることにより化合物（ｖｉｉｉ）を得ることができる。(Method B)

(In the formula, Hal ² is halogen; R ¹ , R ¹³ , R ²² , R ²³ , and R ²⁴ are as defined above (1); R ^A is alkyl)
(First step)
This step can be performed by the same method as the first step of Method A. A starting material (SM) that can be synthesized according to the method described in EP606011 or the like or that is commercially available is used.
(Second step)
This step can be performed by a usual reduction reaction from ester to alcohol.
Compound (v) is reacted by reacting compound (v) in a solvent such as tetrahydrofuran or diethyl ether in the presence of a reducing agent such as lithium aluminum hydride at −80 ° C. to 50 ° C., preferably −10 ° C. to 30 ° C. ) Can be obtained.
(Third step)
This step can be performed by a usual oxidation reaction from alcohol to aldehyde.
Compound (vii) can be obtained by reacting compound (vi) in a solvent such as chloroform or dichloromethane in the presence of a participant such as manganese dioxide at 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C. it can.
(4th process)
This step is performed by reacting the compound (vii) with a compound represented by the formula: R ¹³ —O—NH ₂ (wherein R ¹³ has the same meaning as (1) above) to give the target compound (viii) ).
A starting material (vii) and a compound represented by the formula: R ¹³ —O—NH ₂ (wherein R ¹³ is the same as defined in (1) above) or a salt thereof in a solvent such as tetrahydrofuran, dioxane, methanol, Alternatively, compound (viii) can be obtained by reacting them in a mixed solvent of water and water at 0 ° C. to heating under reflux, preferably at 20 ° C. to 50 ° C.

（式中、Ｈａｌ^１はハロゲン；Ｒ^１、Ｒ^１３、Ｒ^２２、Ｒ^２３、およびＲ^２４は前記（１）と同意義；Ｒ^Ｂはアルキル；Ａ^２−ＮＨ−Ｃ（＝Ｏ）−基は、Ｒ^２における（Ｒ^１０−Ｘ^１）−で表される基）
（第１工程）
本工程は、Ａ法で得られた化合物（ｉｉｉ）をHeck反応に付することにより、目的とする化合物（ｉｘ）を合成する工程である。
化合物（ｉｉｉ）をアセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセタミド、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ジメチルスルホキシド、テトラヒドロフラン、トルエン等の溶媒中等の溶媒中、トリエチルアミン、ジイソプロピルエチルアミン、炭酸カリウム、炭酸ナトリウム等の塩基および塩化パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、[1,1'-ビス（ジフェニルフォスフィノ）フェロセン]ジクロロパラジウム、酢酸パラジウム＋トリフェニルホスフィン等の触媒の存在下、アクリル酸エチル、アクリル酸メチル等のアクリル酸誘導体と０℃〜150℃、好ましくは50℃〜100℃で反応させることにより、化合物（ｉｘ）を得ることができる。
（第２工程）
本工程は、通常行われるエステルからカルボン酸への加水分解反応により行うことができる。
化合物（ｉｘ）をテトラヒドロフラン、メタノールまたはそれらの混合溶媒等の溶媒中、水酸化ナトリウム水溶液等により、０℃〜８０℃、好ましくは０℃〜３０℃で加水分解することにより、化合物（ｘ）を得ることができる。
（第３工程）
本工程は、通常行われるアミド結合生成反応により行うことができる。
化合物（ｘ）をジクロロメタン、テトラヒドロフラン，等の溶媒中、ＷＳＣＤ（（1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride））およびＨＯＢｔ（N-Hydroxybenztriazole）の存在下、Ａ^２−ＮＨ_２と0℃〜100℃、好ましくは10℃〜50℃で反応させることにより、化合物（ｘｉ）を得ることができる。(Method C)

(Wherein, Hal ¹ is ^{halogen; R 1, R 13, R} 22, R 23, and ^{R 24} are as defined with the (1); ^{R B} is ^{alkyl; A 2 -NH-C (=} O) - group Is a group represented by (R ¹⁰ -X ¹ )-in R ² )
(First step)
This step is a step of synthesizing the target compound (ix) by subjecting the compound (iii) obtained by Method A to Heck reaction.
Compound (iii) is triethylamine, diisopropyl in a solvent such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, dimethyl sulfoxide, tetrahydrofuran, toluene and the like. Bases such as ethylamine, potassium carbonate, sodium carbonate and palladium chloride, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, [1,1'-bis (diphenylphosphino ) Ferrocene] In the presence of a catalyst such as dichloropalladium, palladium acetate + triphenylphosphine, the reaction is carried out with an acrylic acid derivative such as ethyl acrylate or methyl acrylate at 0 ° C to 150 ° C, preferably 50 ° C to 100 ° C. Thus, compound (ix) can be obtained.
(Second step)
This step can be performed by a usual hydrolysis reaction from ester to carboxylic acid.
Compound (x) is hydrolyzed at 0 ° C. to 80 ° C., preferably 0 ° C. to 30 ° C., with a sodium hydroxide aqueous solution or the like in a solvent such as tetrahydrofuran, methanol or a mixed solvent thereof to obtain compound (x). Obtainable.
(Third step)
This step can be performed by a amide bond formation reaction that is usually performed.
Compound (x) dichloromethane, tetrahydrofuran, in a solvent like, WSCD ((1-Ethyl- 3- (3-dimethylaminopropyl) carbodiimidehydrochloride)) and the presence of ^{HOBt (N-Hydroxybenztriazole), A} 2 -NH 2 and 0 ℃ Compound (xi) can be obtained by reaction at -100 ° C, preferably 10-50 ° C.

（式中、Ｈａｌ^１はハロゲン；Ｒ^１、Ｒ^６、Ｒ^２２、Ｒ^２３、およびＲ^２４は前記（１）と同意義；Ｒ^Ｃはアルキル）
（第１工程）
本工程は、Ａ法で得られた化合物（ｉｉｉ）と化合物（ｘｉｉ）を鈴木反応に付することにより、目的とする化合物（ｘｉｉｉ）を合成する工程である。
化合物（ｉｉｉ）を、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセタミド、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ジメチルスルホキシド等の溶媒中、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、[1,1'-ビス（ジフェニルフォスフィノ）フェロセン]ジクロロパラジウム、酢酸パラジウム＋トリフェニルホスフィン等のパラジウム触媒等のパラジウム触媒およびトリエチルアミン、ジイソプロピルアミン、炭酸カリウム化合物等の塩基の存在下、化合物（ｘｉｉ）と、0℃〜150℃、好ましくは50℃〜10 0℃で反応させることにより、化合物（ｘｉｉｉ）を得ることができる。
（第２工程）
Ｂ法第２工程と同様の反応により行うことができる。
（第３工程）
Ｂ法第３工程と同様の反応により行うことができる。
（第４工程）
本工程は、フェニル基上のアルデヒド基を用いてＲ^６へと変換する工程である。
化合物（ｘｖ）を、ジクロロメタン、クロロホルム，テトラヒドロフラン等の溶媒中、トリアセトキシホウ素ナトリウム、シアノボロハイドライド等の還元剤の存在下、モルホリン等の１級または２級アミンと、０℃〜１００℃、好ましくは０℃〜１００℃で反応させることにより、化合物（ｘｖｉ）を得ることができる。(Method D)

(In the formula, Hal ¹ is halogen; R ¹ , R ⁶ , R ²² , R ²³ , and R ²⁴ are as defined above (1); R ^C is alkyl)
(First step)
This step is a step of synthesizing the target compound (xiii) by subjecting compound (iii) and compound (xii) obtained by Method A to the Suzuki reaction.
Compound (iii) is dissolved in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, dimethyl sulfoxide, dichlorobis (triphenylphosphine) palladium, tetrakis (tri Palladium catalysts such as phenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium, palladium catalysts such as palladium acetate + triphenylphosphine, and triethylamine, diisopropylamine In the presence of a base such as a potassium carbonate compound, the compound (xiii) can be reacted with the compound (xii) at 0 ° C to 150 ° C, preferably 50 ° C to 100 ° C.
(Second step)
The reaction can be carried out in the same manner as in the second step of Method B.
(Third step)
The reaction can be carried out by the same reaction as in the third step of Method B.
(4th process)
This step is a step of converting to R ⁶ using an aldehyde group on the phenyl group.
Compound (xv) is mixed with a primary or secondary amine such as morpholine in a solvent such as dichloromethane, chloroform or tetrahydrofuran in the presence of a reducing agent such as sodium triacetoxyborohydride or cyanoborohydride. Can be reacted at 0 ° C. to 100 ° C. to obtain compound (xvi).

（式中、Ｈａｌ^１はハロゲン；Ｒ^１、Ｒ^１４、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ａｒ^３、Ｘ^４、Ｒおよびｎは前記（１）と同意義）
（第１工程）
Ｄ法第１工程と同様の方法で行うことができる。(E method)

(In the formula, Hal ¹ is halogen; R ¹ , R ¹⁴ , R ²² , R ²³ , R ²⁴ , Ar ³ , X ⁴ , R and n are as defined above (1)).
(First step)
It can carry out by the method similar to D method 1st process.

［式中、Ｒ^４２およびＲ^４３は、ヒドロキシ、アルキル、ハロゲン、アルキルオキシ、フェニル、ピリジル、フリル、チエニル、チアゾリル、またはアルキルで置換されていてもよいアミノアルキル；
Ａｒ^４は、式：

で表される基、
Ｒ’は、それぞれ独立してハロゲン、アルキル、アルキルオキシ、アルキルアミノ、またはシアノ；
ｎは、０〜２の整数；
Ｒ^２７は、置換基群Ｂ（置換基群Ｂ：アルキル、アルキルスルホニルアルキル、ハロゲンで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、シクロアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、置換されていてもよいアミノアルキルカルボニル、アリールアルキル、およびヘテロアリールアルキル）から選択される置換基で置換されていてもよいアミノで置換されたアルキルまたは置換基群Ｃ（置換基群Ｃ：オキソ、ヒドロキシ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、シアノもしくはアルキルオキシで置換されていてもよいアルキル、アルキルオキシアルキル、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、およびアルキルスルホニルアルキルカルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）で置換されたアルキル；
Ｒ^２８は、Ｃ１−Ｃ３アルキル、Ｃ１−Ｃ３アルキルオキシ、またはＣ１−Ｃ３アルキルアミノ；
Ｒ^２９は、水素原子、アルキル、またはアシル；および
Ｒ^３０およびＲ^３１は、それぞれ独立して、水素原子、ハロゲンまたはアルキニル］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Among the compounds represented by the formula (I), compounds represented by the following formulas (IA) to (I-AR) are preferable.
Formula (IA):

Wherein R ⁴² and R ⁴³ are hydroxy, alkyl, halogen, alkyloxy, phenyl, pyridyl, furyl, thienyl, thiazolyl, or aminoalkyl optionally substituted with alkyl;
Ar ⁴ has the formula:

A group represented by
Each R ′ is independently halogen, alkyl, alkyloxy, alkylamino, or cyano;
n is an integer of 0 to 2;
R ²⁷ is substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted aminocarbonylalkyl, substituted Optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl) substituted with amino optionally substituted with amino Or substituent group C (substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted alkyl, alkyloxyalkyl, cyano, alkylsulfur A non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent selected from sulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl (wherein the non-aromatic nitrogen-containing heterocyclic group is pyrrolidinyl, Alkyl substituted with (selected from piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl);
R ²⁸ is C1-C3 alkyl, C1-C3 alkyloxy, or C1-C3 alkylamino;
R ²⁹ is a hydrogen atom, alkyl, or acyl; and R ³⁰ and R ³¹ are each independently a hydrogen atom, halogen, or alkynyl], or a pharmaceutically acceptable salt thereof, or a solvate thereof. object.

［式中、Ｒ^４２、Ｒ^４３、Ａｒ^４、Ｒ’、Ｒ^２７、Ｒ^２８、Ｒ^２９、およびＲ^３１は前記と同意義；
ｎは、０〜２の整数；
Ｚ^１は、Ｃ１〜Ｃ３アルキレン；および
Ｒ^３２、Ｒ^３３、およびＲ^３４は、それぞれ独立して、水素原子または置換基群Ｆ（置換基群Ｆ：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IB):

[Wherein, R ⁴² , R ⁴³ , Ar ⁴ , R ′, R ²⁷ , R ²⁸ , R ²⁹ , and R ³¹ are as defined above;
n is an integer of 0 to 2;
Z ¹ is C1-C3 alkylene; and R ³² , R ³³ , and R ³⁴ are each independently a hydrogen atom or a substituent group F (substituent group F: halogen, carboxy, alkyl, haloalkyl, hydroxyalkyl, A substituent selected from alkyloxy, alkyloxycarbonyl, and optionally substituted amino)], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｒ’、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ａｒ^５は、式：

で表される基、および
ｎは、０または１］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IC):

[Wherein, R ⁴² , R ⁴³ , R ′, R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
Ar ⁵ has the formula:

And n is 0 or 1] or a pharmaceutically acceptable salt thereof or a solvate thereof.

［式中、Ｒ^４２、Ｒ^４３、Ａｒ^５、Ｒ’、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義；
ｎは、０または１］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (ID):

[Wherein, R ⁴² , R ⁴³ , Ar ⁵ , R ′, R ²⁷ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above;
n is a compound represented by 0 or 1] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ａｒ^４、Ｒ’、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；および
ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IE):

[Wherein Ar ⁴ , R ′, R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above; and n is an integer of 0 to 2] or a pharmaceutical thereof Acceptable salts or solvates thereof.

［式中、Ａｒ^４、Ｒ’、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義；ｎは、０〜２の整数；］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IF):

[In the formula, Ar ⁴ , R ′, R ²⁷ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above; n is an integer of 0 to 2; Or a pharmaceutically acceptable salt thereof or a solvate thereof.

［式中、Ａｒ^５、Ｒ’、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；およびｎは、０または１］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IG):

[Wherein Ar ⁵ , R ′, R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above; and n is 0 or 1] or a pharmaceutically acceptable salt thereof Salts or solvates thereof.

［式中、Ａｒ^５、Ｒ’、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義；およびｎは、０または１］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IH):

[Wherein Ar ⁵ , R ′, R ²⁷ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above; and n is 0 or 1] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ｒ^３５は、ヒドロキシ、アルキル、ハロゲン、アルキルオキシ、フェニル、ピリジル、フリル、チエニル、チアゾリル、またはアルキルで置換されていてもよいアミノアルキル；および
Ｒ^３６は、置換基群Ｂ（置換基群Ｂ：アルキル、アルキルスルホニルアルキル、ハロゲンで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、シクロアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、置換されていてもよいアミノアルキルカルボニル、アリールアルキル、およびヘテロアリールアルキル）から選択される置換基で置換されていてもよいアミノで置換されたアルキル、置換基群Ｃ（置換基群Ｃ：オキソ、ヒドロキシ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、シアノもしくはアルキルオキシで置換されていてもよいアルキル、アルキルオキシアルキル、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、およびアルキルスルホニルアルキルカルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）で置換されたアルキル、または置換基群Ｈ（置換基群Ｈ：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、およびシアノ）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、アゼチジニル、ピロリジニル、およびピペリジルから選択される）］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (II):

[Wherein, R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
R ³⁵ is hydroxy, alkyl, halogen, alkyloxy, phenyl, pyridyl, furyl, thienyl, thiazolyl, or aminoalkyl optionally substituted with alkyl; and R ³⁶ is substituent group B (substituent group B: Alkyl, alkylsulfonylalkyl, optionally substituted alkylcarbonyl, alkyloxycarbonyl, cycloalkyl, optionally substituted aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, substituted Alkyl substituted by amino optionally substituted with a substituent selected from aminoalkylcarbonyl, arylalkyl and heteroarylalkyl which may be substituted, substituent group C (substituent group C: oxo, hydroxy) , Replace Optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyl optionally substituted with alkyloxy, alkyloxyalkyl, cyano, alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl). An alkyl substituted with a non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent (wherein the non-aromatic nitrogen-containing heterocyclic group is selected from pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl) Or a non-aromatic nitrogen-containing heterocyclic group which may be substituted with a substituent selected from the substituent group H (substituent group H: alkyloxycarbonyl, optionally substituted aminocarbonyl, and cyano) Where non-aromatic nitrogen-containing complex The ring group is selected from azetidinyl, pyrrolidinyl, and piperidyl))] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ｒ^３５、Ｒ^３６、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-J):

[Wherein R ³⁵ , R ³⁶ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above] or a pharmaceutically acceptable compound thereof Salts or solvates thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ｘ^５は、単結合またはＣ１−Ｃ３アルキレン；
Ｒ^３７は、水素原子、アルキル、またはアシル；
Ｘ^６は、式：

で表される基を介在していてもよいＣ１−Ｃ３アルキレン；
Ｒ’は、前記と同意義；
ｎは、０〜２の整数；および
Ｒ^３８は、置換基群Ｂ（置換基群Ｂ：アルキル、アルキルスルホニルアルキル、ハロゲンで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、シクロアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、置換されていてもよいアミノアルキルカルボニル、アリールアルキル、およびヘテロアリールアルキル）から選択される置換基で置換されていてもよいアミノまたは置換基群Ｃ（置換基群Ｃ：オキソ、ヒドロキシ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、シアノもしくはアルキルオキシで置換されていてもよいアルキル、アルキルオキシアルキル、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、およびアルキルスルホニルアルキルカルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IK):

[Wherein, R ⁴² , R ⁴³ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
X ⁵ is a single bond or C1-C3 alkylene;
R ³⁷ represents a hydrogen atom, alkyl, or acyl;
X ⁶ represents the formula:

A C1-C3 alkylene optionally having a group represented by:
R ′ is as defined above;
n is an integer of 0 to 2; and R ³⁸ is a substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, substituted). Optionally substituted aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Optionally substituted amino or substituent group C (substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted alkyl, alkyloxyalkyl, Cyano, alkyl Non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent selected from rusulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl (wherein the non-aromatic nitrogen-containing heterocyclic group is pyrrolidinyl) , Piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl)) or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｘ^５、Ｒ^３７、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IL):

[Wherein, R ⁴² , R ⁴³ , X ⁵ , R ³⁷ , X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｘ^５、Ｒ^３７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ｘ^７は、式：

で表される基を介在していてもよいＣ１−Ｃ３アルキレン；
Ｒ’は、前記と同意義；および
ｎは、０または１］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IM):

[Wherein, R ⁴² , R ⁴³ , X ⁵ , R ³⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
X ⁷ has the formula:

A C1-C3 alkylene optionally having a group represented by:
R ′ is as defined above; and n is 0 or 1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｘ^５、Ｒ^３７、Ｘ^７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IN):

[Wherein, R ⁴² , R ⁴³ , X ⁵ , R ³⁷ , X ⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｘ^５、Ｒ^３７、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IO):

[Wherein X ⁵ , R ³⁷ , X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above] or a pharmaceutically acceptable salt thereof or a salt thereof Solvate.

［式中、Ｘ^５、Ｒ^３７、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IP):

Wherein X ⁵ , R ³⁷ , X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above, or The pharmaceutically acceptable salt or solvate thereof.

［式中、Ｘ^５、Ｒ^３７、Ｘ^７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-Q):

[Wherein X ⁵ , R ³⁷ , X ⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above] or a pharmaceutically acceptable salt thereof or a salt thereof Solvate.

［式中、Ｘ^５、Ｒ^３７、Ｘ^７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IR):

Wherein X ⁵ , R ³⁷ , X ⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above, or The pharmaceutically acceptable salt or solvate thereof.

［式中、Ｒ’、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ａｒ^６は、式：

で表される基、
ｎは、０〜２の整数；および
Ｒ^３９は、置換基群Ｂ（置換基群Ｂ：アルキル、アルキルスルホニルアルキル、ハロゲンで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、シクロアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、置換されていてもよいアミノアルキルカルボニル、アリールアルキル、およびヘテロアリールアルキル）から選択される置換基で置換されていてもよいアミノで置換されたアルキルまたは置換基群Ｃ（置換基群Ｃ：オキソ、ヒドロキシ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、シアノもしくはアルキルオキシで置換されていてもよいアルキル、アルキルオキシアルキル、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、およびアルキルスルホニルアルキルカルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）で置換されたアルキル］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IS):

[Wherein, R ′, R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
Ar ⁶ has the formula:

A group represented by
n is an integer of 0 to 2; and R ³⁹ is a substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, substituted). Optionally substituted aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Alkyl substituted with an optionally substituted amino group or a substituent group C (Substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy substituted alkyl , Alkyloxyal A non-aromatic nitrogen-containing heterocyclic group (here, a non-aromatic nitrogen-containing heterocyclic ring), which may be substituted with a substituent selected from a group selected from the group consisting of alkyl, cyano, alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl) Or a pharmaceutically acceptable salt or solvate thereof. The group is an alkyl substituted with pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl.

［式中、Ａｒ^６、Ｒ’、Ｒ^３９、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義；ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IT):

[In the formula, Ar ⁶ , R ′, R ³⁹ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above; n is an integer of 0 to 2] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｒ’、Ｒ^３９、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ａｒ^７は、式：

で表される基；および
ｎは、０または１］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-U):

[Wherein, R ′, R ³⁹ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
Ar ⁷ has the formula:

And n is 0 or 1] or a pharmaceutically acceptable salt thereof or a solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｒ^３９、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義；ｎは、０または１］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IV):

[Wherein Ar ⁷ , R ′, R ³⁹ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above; n is 0 or 1] Or a pharmaceutically acceptable salt thereof or a solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
ｎは、０〜２の整数；
Ｘ^８は、単結合またはＣ１−Ｃ３アルキレン；
Ｒ^４０は、水素原子、アルキル、またはアシル；
Ｘ^９は、式：

で表される基を介在していてもよいＣ１−Ｃ３アルキレン；
Ｒ’’は、それぞれ独立してハロゲン、アルキル、アルキルオキシ、アルキルアミノ、またはシアノ；
ｍは、０〜２の整数；および
Ｒ^４１は、置換基群Ｂ（置換基群Ｂ：アルキル、アルキルスルホニルアルキル、ハロゲンで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、シクロアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、置換されていてもよいアミノアルキルカルボニル、アリールアルキル、およびヘテロアリールアルキル）から選択される置換基で置換されていてもよいアミノまたは置換基群Ｃ（置換基群Ｃ：オキソ、ヒドロキシ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、シアノもしくはアルキルオキシで置換されていてもよいアルキル、アルキルオキシアルキル、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、およびアルキルスルホニルアルキルカルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-W):

[Wherein Ar ⁷ , R ′, R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
n is an integer of 0 to 2;
X ⁸ is a single bond or C1-C3 alkylene;
R ⁴⁰ represents a hydrogen atom, alkyl, or acyl;
X ⁹ is the formula:

A C1-C3 alkylene optionally having a group represented by:
Each R ″ is independently halogen, alkyl, alkyloxy, alkylamino, or cyano;
m is an integer of 0 to 2; and R ⁴¹ is a substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, substituted). Optionally substituted aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Optionally substituted amino or substituent group C (substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted alkyl, alkyloxyalkyl, Cyano, alkyl Non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent selected from rusulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl (wherein the non-aromatic nitrogen-containing heterocyclic group is pyrrolidinyl) , Piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl)) or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｘ^８、Ｒ^４０、Ｘ^９、Ｒ^４１、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義；ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (IX):

[Wherein, Ar ⁷ , R ′, X ⁸ , R ⁴⁰ , X ⁹ , R ⁴¹ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above; n is an integer of 0 to 2] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｘ^８、Ｒ^４０、Ｒ^４１、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ｘ^１０は、式：

で表される基を介在していてもよいＣ１−Ｃ３アルキレン；
Ｒ’’は、前記と同意義；
ｍは０または１；および
ｎは、０〜２の整数；］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-Y):

[Wherein, Ar ⁷ , R ′, X ⁸ , R ⁴⁰ , R ⁴¹ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
X ¹⁰ represents the formula:

A C1-C3 alkylene optionally having a group represented by:
R ″ is as defined above;
m is 0 or 1; and n is an integer of 0 to 2; or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｘ^８、Ｒ^４０、Ｘ^１０、Ｒ^４１、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３およびＲ^３４は、前記と同意義；ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-Z):

[In the formula, Ar ⁷ , R ′, X ⁸ , R ⁴⁰ , X ¹⁰ , R ⁴¹ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ and R ³⁴ are as defined above; n Is an integer from 0 to 2, or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｘ^５、Ｒ^３７、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AA):

Wherein R ⁴² , R ⁴³ , X ⁵ , R ³⁷ , X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above, or a pharmaceutically acceptable compound thereof Salts or solvates thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｘ^５、Ｒ^３７、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AB):

[Wherein R ⁴² , R ⁴³ , X ⁵ , R ³⁷ , X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ and R ³⁴ are as defined above] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｘ^５、Ｒ^３７、Ｘ^７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AC):

Wherein R ⁴² , R ⁴³ , X ⁵ , R ³⁷ , X ⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above, or a pharmaceutically acceptable compound thereof Salts or solvates thereof.

［式中、Ｒ^４２、Ｒ^４３、Ｘ^５、Ｒ^３７、Ｘ^７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AD):

[Wherein R ⁴² , R ⁴³ , X ⁵ , R ³⁷ , X ⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ and R ³⁴ are as defined above] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｘ^５、Ｒ^３７、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AE):

[Wherein X ⁵ , R ³⁷ , X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above] or a pharmaceutically acceptable salt thereof or a salt thereof Solvate.

［式中、Ｘ^５、Ｒ^３７、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AF):

[Wherein X ⁵ , R ³⁷ , X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ and R ³⁴ are as defined above] or a compound thereof A pharmaceutically acceptable salt or a solvate thereof.

［式中、Ｘ^５、Ｒ^３７、Ｘ^７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AG):

[Wherein X ⁵ , R ³⁷ , X ⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above] or a pharmaceutically acceptable salt thereof or a salt thereof Solvate.

［式中、Ｘ^５、Ｒ^３７、Ｘ^７、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AH):

Wherein X ⁵ , R ³⁷ , X ⁷ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above, or The pharmaceutically acceptable salt or solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｘ^８、Ｒ^４０、Ｒ^４１、Ｘ^９、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；および
ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AI):

[Wherein Ar ⁷ , R ′, X ⁸ , R ⁴⁰ , R ⁴¹ , X ⁹ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above; and n is an integer of 0 to 2] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｘ^８、Ｒ^４０、Ｘ^９、Ｒ^４１、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義；ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AJ):

[Wherein, Ar ⁷ , R ′, X ⁸ , R ⁴⁰ , X ⁹ , R ⁴¹ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above; n is an integer of 0 to 2] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｘ^８、Ｒ^４０、Ｘ^１０、Ｒ^４１、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；および
ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AK):

[Wherein Ar ⁷ , R ′, X ⁸ , R ⁴⁰ , X ¹⁰ , R ⁴¹ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above; and n is an integer of 0 to 2] Or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ａｒ^７、Ｒ’、Ｘ^８、Ｒ^４０、Ｘ^１０、Ｒ^４１、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３およびＲ^３４は、前記と同意義；ｎは、０〜２の整数］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AL):

[In the formula, Ar ⁷ , R ′, X ⁸ , R ⁴⁰ , X ¹⁰ , R ⁴¹ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ and R ³⁴ are as defined above; n Is an integer from 0 to 2, or a pharmaceutically acceptable salt or solvate thereof.

［式中、Ｘ^６、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ｘ^１５は、−Ｎ（Ｒ^５２）−、−Ｏ−、または−Ｓ−を介在していてもよいＣ１−Ｃ３アルキレン；Ｒ^５２は、水素原子、アルキル、またはアシル］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AM):

[Wherein, X ⁶ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
X ¹⁵ represents C1-C3 alkylene optionally having —N (R ⁵² ) —, —O—, or —S—; R ⁵² represents a hydrogen atom, alkyl, or acyl] The pharmaceutically acceptable salt or solvate thereof.

［式中、Ｘ^６、Ｘ^１５、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AN):

[Wherein X ⁶ , X ¹⁵ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ and R ³⁴ are as defined above] or a pharmaceutically acceptable compound thereof Salts or solvates thereof.

［式中、Ｘ^７、Ｘ^１５、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AO):

[Wherein X ⁷ , X ¹⁵ , R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above] or a pharmaceutically acceptable salt thereof, or a solvate thereof. .

［式中、Ｘ^７、Ｘ^１５、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AP):

[Wherein X ⁷ , X ¹⁵ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above] or a pharmaceutical thereof Acceptable salts or solvates thereof.

［式中、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３０およびＲ^３１は、前記と同意義；
Ｘ^１３は単結合またはＣ１−Ｃ３アルキレン］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AQ):

[Wherein, R ³⁸ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ are as defined above;
X ¹³ is a single bond or C1-C3 alkylene], a pharmaceutically acceptable salt thereof, or a solvate thereof.

［式中、Ｘ^１３、Ｒ^３８、Ｒ^２８、Ｒ^２９、Ｒ^３１、Ｚ^１、Ｒ^３２、Ｒ^３３、およびＲ^３４は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。Formula (I-AR):

Wherein X ¹³ , R ³⁸ , R ²⁸ , R ²⁹ , R ³¹ , Z ¹ , R ³² , R ³³ , and R ³⁴ are as defined above, or a pharmaceutically acceptable salt thereof. Salts or solvates thereof.

で表される基（式中Ｒ’はハロゲン；ｎは０または１）；
Ｒ^２７が置換基群Ｃから選択される置換基で置換されていてもよいピロリジニルで置換されたアルキル；
Ｒ^２８がＣ１〜Ｃ３アルキル；
Ｒ^２９が水素原子；
Ｒ^３１がハロゲン；
Ｚ^１がＣ１〜Ｃ３アルキレン；
Ｒ^３２がハロゲン；
Ｒ^３３およびＲ^３４が水素原子、
で表される化合物が好ましい。In particular, in formula (IF), Ar ⁴ represents the formula:

Wherein R ′ is halogen; n is 0 or 1;
R ²⁷ is an alkyl substituted with pyrrolidinyl optionally substituted with a substituent selected from substituent group C;
R ²⁸ is C1-C3 alkyl;
R ²⁹ is a hydrogen atom;
R ³¹ is halogen;
Z ¹ is C1-C3 alkylene;
R ³² is halogen;
R ³³ and R ³⁴ are hydrogen atoms,
The compound represented by these is preferable.

In the present specification, the “solvate” includes, for example, solvates with organic solvents, hydrates and the like. When forming a hydrate, any number of water molecules may be coordinated.
The term “the compound of the present invention” includes pharmaceutically acceptable salts or hydrates thereof. For example, alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) And salts with organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). These salts can be formed by a commonly performed method.
The compounds of the present invention are not limited to specific isomers, but include all possible isomers and racemates. In particular, even when the compound has a double bond and one of the E-form and Z-form is indicated, the other isomer is included.
The compound of the present invention exhibits excellent cell growth inhibitory activity as described in the experimental examples described later, and can be used as an “anticancer agent” and a “cancer therapeutic agent”.
When the compound of the present invention is administered to humans for the purpose of treating the above-mentioned diseases, it can be administered orally as a powder, granule, tablet, capsule, pill, liquid, or injection, suppository, or transdermal absorption. It can be administered parenterally as an agent, an inhalant and the like. In addition, excipients, binders, wetting agents, disintegrants, lubricants and other pharmaceutical additives suitable for the dosage form may be mixed with an effective amount of the present compound as necessary to obtain a pharmaceutical preparation. it can. In the case of an injection, it is sterilized with an appropriate carrier to obtain a preparation.
The dose varies depending on the disease state, administration route, patient age, or body weight, but is usually 0.1 to 100 mg / kg / day, preferably 1 to 20 mg / kg / day when orally administered to an adult. Day.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
In the examples, the following abbreviations are used.
Me: methyl Et: ethyl Boc: t-butoxycarbonyl

Example 1

Step 1 Preparation of (3-Chloro-4- (3-fluorobenzyloxy) phenyl)-(5-iodo-6-methylpyrimidin-4-yl) -amine (3)
7.4 g of 4-chloro-5-iodo-6-methylpyrimidine (1) and 7.3 g of 3-chloro-4- (3-fluorobenzyloxy) aniline (2) were dissolved in 90 mL of ethanol and heated to reflux for 3 hours. . Thereafter, a saturated aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine and then dried over magnesium sulfate. The dried solution was filtered, concentrated, triturated with ethyl acetate, and collected by filtration to give (3-chloro-4- (3-fluorobenzyloxy) phenyl)-(5-iodo-6-methylpyrimidin-4-yl) ) -Amine (3) 8.2 g was obtained as a light gray solid.
¹ H NMR (CDCl ₃ , δ): 8.40 (1H, s), 7.67 (1H, d, J = 3.0Hz), 7.36 (1H, dd, J = 3.0Hz, J = 8.7Hz), 7.26-7.16 ( 3H, m), 7.02 (1H, t, J = 8.7Hz), 6.95 (1H, d, J = 8.7Hz), 5.15 (2H, s), 2.66 (3H, s).

Second Step (3-Chloro-4- (3-fluorobenzyloxy) phenyl)-(6-methyl-5- (4-morpholin-4-ylbut-1-ynyl) -pyrimidin-4-yl) amine (II -1) Preparation
Dissolve 14 mg of (3-chloro-4- (3-fluorobenzyloxy) phenyl)-(5-iodo-6-methylpyrimidin-4-yl) -amine (3) in 0.3 mL of dimethylformamide and add 4-but- 6 mg of 3-ynylmorpholine (4-1), 1 mg of dichlorobis (triphenylphosphine) palladium, 0.6 mg of copper iodide, and 17 μL of triethylamine were added. The reaction solution was degassed and then heated and stirred at 50 ° C. for 1 hour in a nitrogen atmosphere. Thereafter, 0.1 M aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine and then dried over magnesium sulfate. After concentration, purification by preparative HPLC (water-acetonitrile) gave 4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) -5- (4-morpholino-1-butynyl) -6- Methyl pyrimidine (II-1) 9.3 mg was obtained as a white solid.
¹ H NMR (CDCl ₃ , δ): 8.49 (1H, s), 7.63 (1H, d, J = 2.7 Hz), 7.52 (1H, s), 7.42 (1H, dd, J = 2.7 Hz, J = 8.7 Hz), 7.39-7.32 (1H, m), 7.26-7.05 (2H, m), 7.04-6.94 (2H, m), 5.15 (2H, s), 3.69-3.67 (4H, m), 2.77 (4H, dd, J = 5.1Hz, J = 15.0Hz), 2.56-2.52 (7H, m).

The following compounds were synthesized by the same method as above.

Example 2

Step 1 Preparation of ethyl 4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidine-5-carboxylate (6)
Dissolve 14.2 g of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate (5) and 17.8 g of 3-chloro-4- (3-fluorobenzyloxy) aniline (2) in 60 mL of toluene, and add N-diisopropylethylamine. 12.2 mL was added and heated to reflux overnight. Thereafter, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with water and brine and then dried over magnesium sulfate. After concentration, the product was purified by silica gel chromatography (chloroform-ethyl acetate), and the resulting solid was recrystallized with a mixed system of chloroform-ethyl acetate-hexane to give 4- (3-chloro-4- (3-fluorobenzyloxy). 19.8 g of ethyl (6) phenylamino) -6-methylpyrimidine-5-carboxylate was obtained.
¹ H NMR (CDCl ₃ , δ): 8.55 (1H, s), 7.72 (1H, d, J = 2.1Hz), 7.39-7.33 (2H, m), 7.24-7.18 (2H, m), 7.04 (1H , dt, J = 2.1Hz, J = 7.5Hz,), 6.93 (1H, d, J = 8.3Hz), 5.14 (2H, s), 4.45 (2H, q, J = 7.5Hz), 2.71 (3H, s), 1.45 (3H, t, J = 7.5Hz).

Step 2 Preparation of 4- (3-Chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidin-5-ylmethanol (7)
6.8 g of ethyl 4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidine-5-carboxylate (6) was dissolved in 30 mL of tetrahydrofuran and cooled on ice, then lithium aluminum hydride 0.6 g was added over 20 minutes, and the mixture was stirred for 2 hours under ice cooling. Then, 2 mL of water was added dropwise, and the mixture was stirred for 20 minutes. After concentration, the obtained solid was washed with a mixed solvent of hexane-ethyl acetate (1: 1) to give 4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidine- 4.3 g of 5-ylmethanol (7) was obtained.
¹ H NMR (CDCl ₃ , δ): 8.48 (1H, s), 8.11 (1H, s), 7.69 (1H, d, J = 2.1Hz), 7.39-7.33 (2H, m), 7.24-7.18 (2H , m), 7.04 (1H, dt, J = 2.1Hz, J = 8.2Hz), 6.90 (1H, d, J = 8.2Hz), 5.21 (2H, s), 4.81 (2H, s), 2.37 (3H , s).

Step 3 Preparation of 4- (3-Chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidine-5-carbaldehyde (8)
4- (3-Chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidin-5-ylmethanol (7) 100 mg was dissolved in 2 mL of chloroform, and 117 mg of manganese dioxide was added and reacted at room temperature overnight. did. Thereafter, the reaction solution was filtered through Celite, and the solution was concentrated and purified by silica gel chromatography (hexane-ethyl acetate) to give 4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino)- 44 mg of 6-methylpyrimidine-5-carbaldehyde (8) was obtained as a yellow solid.
¹ H NMR (CDCl ₃ , δ): 10.94 (1H, brs), 10.43 (1H, s), 8.65 (1H, s), 7.83 (1H, d, J = 2.1Hz), 7.44-7.20 (4H, m ), 7.05-6.96 (2H, m), 5.16 (2H, s), 2.77 (3H, s).

Step 4 4- (3-Chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidine-5-carbaldehyde O- (2-morpholin-4-ylethyl) oxime (III-1) Preparation
4- (3-Chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidine-5-carbaldehyde (8) 23 mg and 2- (1-morpholinyl) ethoxyamine dihydrochloride (9- 1) 41 mg was dissolved in a mixture of tetrahydrofuran (1 ml) and water (0.05 ml), and reacted at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. After concentration, purification by ODS chromatography (water-acetonitrile) gave 4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) -6-methylpyrimidine-5-carbaldehyde O- (2 28 mg of -morpholin-4-ylethyl) oxime (III-1) were obtained as a white solid.
¹ H NMR (CDCl ₃ , δ): 10.07 (1H, brs), 8.58 (1H, s), 8.53 (1H, s), 7.72 (1H, d, J = 2.4Hz), 7.45 (1H, dd, J = 2.4Hz, J = 8.7Hz), 7.40-7.19 (3H, m), 7.05-7.00 (1H, m), 6.94 (1H, d, J = 8.7Hz), 5.16 (2H, s), 4.42 (2H , brs), 3.77 (4H, brs), 2.80 (2H, brs), 2.65-2.55 (7H, m).

The following compounds were synthesized by the same method as above.

Example 3

Step 1 (E) -3- {4- [3-Chloro-4- (3-fluorobenzyloxy) phenylamino] -6-methyl-pyrimidin-5-yl} ethyl acrylate (10) Preparation
[3-Chloro-4- (3-fluorobenzyloxy) phenyl]-(5-iodo-6-methylpyrimidin-4-yl) amine (3) 423 mg, ethyl acrylate 0.38 ml, acetonitrile 3.7 ml and triethylamine 3.7 ml After adding 16 mg of palladium chloride, the mixture was heated to reflux for 4 hours under nitrogen. Then, it was returned to room temperature, concentrated and purified by silica gel chromatography to obtain (E) -3- {4- (E) -3- {4- [3-chloro-4- (3-fluorobenzyloxy) phenyl Amino] -6-methyl-pyrimidin-5-yl} ethyl acrylate (10) was obtained as a yellow solid.
¹ H NMR (d ₆ -DMSO, δ): 8.78 (1H, s), 8.37 (1H, s), 8.94 (1H, s), 7.67 (1H, d, J = 2.7Hz,), 7.61 (1H, d, J = 16.2Hz), 7.45-7.41 (2H, m), 7.32-7.22 (2H, m), 7.21-7.10 (2H, m), 6.39 (1H, d, J = 16.2Hz), 5.22 (2H , s), 4.22 (2H, q, J = 7.2), 2.39 (3H, s), 1.30 (3H, t, J = 7.2).

Step 2 (E) -3- {4- [3-Chloro-4- (3-fluorobenzyloxy) phenylamino] -6-methyl-pyrimidin-5-yl} acrylic acid (11)
(E) -3- {4- [3-Chloro-4- (3-fluorobenzyloxy) phenylamino] -6-methyl-pyrimidin-5-yl} ethyl acrylate (10) 150 mg of THF-methanol (1 1) Dissolved in 4 ml, added 0.34 ml of 2 mol / L sodium hydroxide aqueous solution, and stirred at room temperature for 2 hours. Thereafter, the pH was adjusted to 3 with 2 mol / L hydrochloric acid, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. Filtration and solvent concentration gave (E) -3- {4- [3-chloro-4- (3-fluorobenzyloxy) phenylamino] -6-methyl-pyrimidin-5-yl} acrylic acid (11) 153 mg Got.
¹ H NMR (d ₆ -DMSO, δ): 12.5 (1H, br), 8.71 (1H, s), 8.37 (1H, s), 7.69 (1H, d, J = 2.4 Hz), 7.55 (1H, d , J = 15.9Hz), 7.60-7.10 (m, 6H), 6.29 (1H, d, J = 15.9Hz), 5.22 (2H, s), 2.39 (3H, s).

Third Step (E) -3- {4- [3-Chloro-4- (3-fluorobenzyloxy) phenylamino] -6-methyl-pyrimidin-5-yl} -N- (2-morpholine-4- Preparation of (ylethyl) acrylic acid amide (IV-1)
(E) -3- {4- [3-Chloro-4- (3-fluorobenzyloxy) phenylamino] -6-methyl-pyrimidin-5-yl} acrylic acid (11) 44 mg suspended in methylene chloride WSCD · HCl 20 mg and HOBt 16 mg were added. Further, 14 μl of N-aminoethylmorpholine was added and stirred for 2 hours. Then, after adding ethyl acetate and water and extracting with ethyl acetate, the organic layer was dried with anhydrous sodium sulfate. After filtration and solvent concentration, the product was purified by silica gel column chromatography (amino-modified silica gel filler), and (E) -3- {4- [3-chloro-4- (3-fluorobenzyloxy) phenylamino]- 30 mg of 6-methyl-pyrimidin-5-yl} -N- (2-morpholin-4-ylethyl) acrylic acid amide (IV-1) was obtained as a yellow solid.
¹ H NMR (CDCl3, δ): 8.51 (1H, s), 7.62 (1H, d, J = 15.6Hz), 7.63 (1H, d, J = 2.4Hz), 7.40-7.15 (4H, m), 7.05 -6.95 (1H, m), 6.91 (1H, d, J = 8.7Hz), 6.83 (1H, s), 5.12 (2H, s), 3.71 (4H, t, J = 4.8Hz)), 3.51 (2H , q, 6.0 Hz), 2.56 (2H, t, J = 6.0 Hz), 2.48 (4H, t, J = 4.8 Hz), 2.44 (3H, s).

The following compounds were synthesized by the same method as above.

Example 4

First Step ((E) -3- {4- [3-Chloro-4- (3-fluorobenzyloxy) phenylamino] -6-methylpyrimidin-5-yl} allyl) carbamate tert-butyl (IV- 4) Preparation
[3-Chloro-4- (3-fluorobenzyloxy) -phenyl]-(5-iodo-6-methylpyrimidin-4-yl) -amine (3) 50 mg and [(E) -3- (4,4 , 5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -allyl] -carbamate tert-butyl (12) 120mg dissolved in dryDMF1.5ml, 2.4mg palladium acetate and triphenylphosphine After adding 7.2 mg and 0.21 ml of 2M aqueous potassium carbonate solution, the mixture was heated at 100 ° C. for 12 hours under nitrogen. The reaction mixture was diluted with ethyl acetate, neutralized with the addition of 0.4 ml of 2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated with a solvent. The obtained residue was purified by silica gel column chromatography, and ((E) -3- {4- [3-chloro-4- (3-fluoro There were obtained 39 mg of benzyloxy) phenylamino] -6-methylpyrimidin-5-yl} allyl) carbamate tert-butyl (IV-4) as a brown solid.
¹ H NMR (CDCl3, δ): 8.53 (1H, s), 7.77-7.10 (5H, m), 7.05-6.95 (1, m), 6.91 (1H, d, J = 9.0Hz), 6.33 (1H, d, J = 16.5Hz), 5.96 (1H, m), 5.14 (2H, s), 5.05 (1H, br), 3.90 (2H, m), 2.44 (3H, s), 1.42 (s, 9H).

Example 5

First Step 4-((E) -2- {4- [3-Chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methylpyridin-5-yl} -vinyl) -methyl benzoate Preparation of (V-1)
[3-Chloro-4- (3-fluorobenzyloxy) -phenyl]-(5-iodo-6-methylpyrimidin-4-yl) -amine (3) 1 g and 4-[(E) -2- (4 , 4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -vinyl] -benzoic acid methyl ester (13) 920 mg was dissolved in dryDMF 30 ml, palladium acetate 52 mg and triphenylphosphine 167 mg, After adding 4.3 ml of 2M aqueous potassium carbonate solution, the mixture was heated at 100 ° C. for 12 hours under nitrogen. The solution was neutralized by adding 17 ml of 0.5 M citric acid, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in a solvent. Since the obtained residue was a mixture of a methyl ester form and a carboxylic acid, it was dissolved in 20 ml of ethyl acetate, and diazomethane was added thereto to completely convert it into a methyl ester form. The reaction solution was concentrated and purified by silica gel column chromatography, and 4-((E) -2- {4- [3-chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methylpyridine- 700 mg of methyl 5-yl} -vinyl) -benzoate (V-1) were obtained.
¹ H NMR (CDCl3, δ): 8.56 (1H, s), 8.09 (1H, d, J = 8.1 Hz), 7.63 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.1 Hz) ), 7.40-7.20 (m, 2H), 7.25-7.15 (m, 2H), 7.10-6.90 (m, 5H), 5.14 (2H, s), 3.95 (3H, s), 2.54 (3H, s).

Second Step 4-((E) -2- {4- [3-Chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methylpyrimidin-5-yl} -vinyl) -phenyl]- Preparation of methanol (V-2)
4-((E) -2- {4- [3-Chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methyl-pyrimidin-5-yl} -vinyl) -methyl benzoate (V -1) 463 mg was dissolved in 10 ml of THF, and after adding 49 mg of lithium aluminum hydride under ice cooling, the mixture was warmed to room temperature and stirred for 1 hour. Thereafter, 50 μl of water, 50 μl of 10% NaOHaq and 150 μl of water were sequentially added, and the precipitated solid was filtered and washed with a small amount of THF. The obtained filtrate was concentrated and purified by silica gel column chromatography to obtain 4-((E) -2- {4- [3-chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methylpyrimidine. 340 mg of -5-yl} -vinyl) -phenyl] -methanol (V-2) was obtained as a yellow solid.
¹ H NMR (CDCl3, δ): 8.54 (1H, s), 7.65 (1H, d, J = 2.4Hz), 7.55 (2H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz ), 7.40-7.30 (2H, m), 7.25-7.15 (2H, m), 7.05-6.80 (5H, m), 5.14 (2H, s), 4.76 (2H, d, J = 5.4Hz), 2.47 ( 3H, s).

Step 3 4-((E) -2- {4- [3-Chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methylpyrimidin-5-yl} -vinyl) -benzaldehyde (V -3) Preparation
4-((E) -2- {4- [3-Chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methylpyrimidin-5-yl} -vinyl) -phenyl] -methanol (V -2) 309 mg was dissolved in 5 ml of THF, 507 mg of manganese dioxide was added, and the mixture was stirred for 72 hours at room temperature. Thereafter, the mixture was filtered through Celite, and the filtrate was concentrated. The resulting residue was dissolved in a small amount of ethyl acetate and pulverized by adding hexane, and 4-((E) -2- {4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl Amino] -6-methylpyrimidin-5-yl} -vinyl) -benzaldehyde (V-3) 230 mg was obtained as a yellow solid.
¹ H NMR (CDCl3, δ): 10.05 (1H, s), 8.56 (1H, s), 7.94 (2H, d, J = 8.1Hz), 7.69 (2H, d, J = 8.1Hz), 7.63 (1H , d, J = 2.4Hz), 7.40-7.30 (2H, m), 7.25-7.10 (2H, m), 7.10-6.90 (5H, m), 5.14 (2H, s), 2.51 (3H, s).

Fourth Step [3-Chloro-4- (3-fluorobenzyloxy) -phenyl]-{6-methyl-5-[(E) -2- (4-morpholin-4-ylmethylphenyl) -vinyl]- Preparation of pyrimidin-4-yl} -amine hydrochloride (V-4)
4-((E) -2- {4- [3-Chloro-4- (3-fluorobenzyloxy) -phenylamino] -6-methylpyrimidin-5-yl} -vinyl) -benzaldehyde (V-3) 61 mg was dissolved in 2 ml of methylene chloride, 15 μl of morpholine and 41 mg of sodium triacetoxyborohydride were added, and the mixture was stirred for 12 hours at room temperature. Thereafter, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated with a solvent. After purification by silica gel column chromatography, an equivalent amount of HCl / AcOEt was added to obtain the monohydrochloride, and [[3-chloro-4- (3-fluorobenzyloxy) -phenyl]-{6-methyl-5-[( E) -2- (4-morpholin-4-ylmethylphenyl) -vinyl] -pyrimidin-4-yl} -amine hydrochloride (V-4) 52 mg was obtained as a yellow solid.
¹ H NMR (DMSO-d6, δ): 11.60 (1H, br), 10.15 (1H, br), 8.74 (1H, s), 7.80 (2H, d, J = 8.4Hz), 7.70 (2H, d, J = 8.4Hz), 7.66 (1H, d, J = 2.4Hz), 7.52-7.40 (2H, m), 7.35-7.15 (4H, m), 7.18 (1H, d, J = 15.9Hz), 5.28 ( 2H, s), 4.35 (2H, s), 4.02-3.70 (4H, m), 3.30-3.00 (4H, m), 2.59 (3H, s).

The following compounds were synthesized by the same method as above.

Example 6

Of [3-chloro-4- (3-fluorobenzyloxy) -phenyl]-[6-methyl-5- (3-morpholin-4-ylmethylphenyl) -pyrimidin-4-yl] amine (VI-1) Preparation
[3-Chloro-4- (3-fluorobenzyloxy) -phenyl]-(5-iodo-6-methylpyrimidin-4-yl) -amine (3) 30 mg and 4- [3- (4,4,5 , 5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyl] -morpholine (14) 17 mg in dryDMF 1 ml, palladium acetate 1.5 mg, triphenylphosphine 5 mg, 2M aqueous potassium carbonate solution 0.1 After adding 3 ml, it was heated at 100 ° C. for 12 hours under nitrogen. The mixture was neutralized with 0.5M citric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated with solvent. Purified by silica gel column chromatography, [3-chloro-4- (3-fluorobenzyloxy) -phenyl]-[6-methyl-5- (3-morpholin-4-ylmethylphenyl) -pyrimidin-4-yl] 6 mg of amine (VI-1) was obtained as a yellow solid.
¹ H NMR (CDCl3, δ): 8.62 (1H, s), 7.60-7.10 (9H, m), 7.05-6.95 (1H, m), 6.87 (1H, d, J = 8.7Hz), 6.15 (1H, s), 5.14 (2H, s), 3.74 (4H, m), 3.58 (2H, s), 2.49 (2H, m), 2.19 (3H, s).

Test Example 1 Enzyme inhibitory activity of test compound against EGFR and HER2 384 wells with ATP added to EGFR, HER2 and biotinylated substrate (glutamic acid: tyrosine = 4: 1 synthetic peptide) purified from insect cell expression system In addition to the plate, the enzyme reaction was performed at room temperature. After the completion of the enzyme reaction, europium-labeled anti-phosphotyrosine antibody and alphycocyanin-labeled streptavidin were added, and phosphorylated tyrosine residues were quantified by time-resolved fluorescence.
(Preparation of test compound)
The test compound was adjusted to 10 mM using DMSO.
Furthermore, a 1 mM solution was prepared using a 10% DMSO solution, and this was taken as the maximum concentration point.
The dilution series was prepared as a 4-fold dilution series up to 10 stages.
(Reagent preparation)
Buffer preparation:
As the buffer, TBS containing 10 mM MgCl ₂ , 5 mM MnCl ₂ , 0.2 mM Na ₃ VO ₄ , and 0.1% BSA was used.
enzyme:
EGFR and HER2 enzymes were purchased from Carna Biosciences, purified from an insect cell expression system.
The EGFR enzyme solution was prepared at 250 ng / ml using a buffer.
HER2 kinase was prepared at 1000 ng / ml using a buffer.
Substrate solution:
Biotinylated poly-Glu-Tyr (4: 1, manufactured by CISbio) was used as the substrate. The concentration was 3.125 μg / ml using the above buffer.
ATP solution:
The ATP concentration in the examination of the EGFR enzyme was adjusted to 125 μM using the above buffer.
The ATP concentration in the study of the HER2 enzyme was adjusted to 290 μM.
Detection reagent:
For the preparation of the detection reagent, TBS containing 30 mM EDTA, 0.8 M KF, 0.1% BSA was used.
Europium-labeled anti-phosphotyrosine antibody PT-66K (CISbio) was prepared at 195 ng / ml, and phycocyanin-labeled streptavidin and SA-XL (CISbio) was prepared at 5 μg / ml.
(Assay method)
As the assay plate, a 384-well plate was used. After adding 1.1 μl of the test compound per well, 4 μl of the substrate solution, and 4 μl of the enzyme solution, 2 μl of the ATP solution was added to start the enzyme reaction. The enzyme reaction was performed at room temperature for 60 minutes, and 10 μl of a detection reagent was added to complete the reaction. One hour after completion of the reaction, time-resolved fluorescence measurement was performed.
(Evaluation method)
Using 10% DMSO instead of the test compound, the signal when ATP was added was 0% inhibition (enzyme activity 100%), and the signal in the absence of ATP was 100% inhibition (enzyme activity 0%). Inhibitory activity was calculated.
The inhibitory activity against EGFR and HER2 (IC ₅₀ value, nM) is shown below.

Test Example 2 In vitro cell growth inhibition test of test compound BT-474 and NCI N87 were used as human-derived cancer cell lines. All cells were cultured in Dulbecco's Modified Essential Medium (DMEM, Nacalai Tesque) supplemented with 10% fetal bovine serum (Fetal Bovine Serum, ICN) and 50 units / ml penicillin / 50 μg / ml streptomycin solution (GIBCO) at 37 ° C. The cells were cultured in a 5% CO ₂ incubator. Cells were seeded at 3000 cells / well in a 96-well plate (Sumitomo Bakelite), and the drug was added to the final concentration of 3 × ¹⁰ −10 −10 ⁻⁵ M the next day. After culturing for 3 days, a WST (water-soluble tetrazolium salt) assay was performed to calculate an IC ₅₀ value.
The inhibitory activity (IC ₅₀ value, nM) against BT-474 and NCI N87 is shown below.

Formulation Example Formulation Example 1
A granule containing the following ingredients is produced.
Ingredient Compound represented by formula (I) 10 mg
Lactose 700 mg
Corn starch 274 mg
HPC-L 16 mg
1000 mg
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. An HPC-L (low-viscosity hydroxypropylcellulose) aqueous solution is added to the mixed powder, kneaded and granulated (extruded granulation, pore diameter 0.5 to 1 mm), and then dried. The obtained dried granules are combed with a vibration sieve (12/60 mesh) to obtain granules.
Formulation Example 2
A powder for capsule filling containing the following components is produced.
Ingredient Compound represented by formula (I) 10 mg
Lactose 79 mg
Corn starch 10 mg
Magnesium stearate 1 mg
100 mg
The compound of formula (I), lactose, is passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh screen. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.
Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Ingredient Compound represented by formula (I) 15 mg
Lactose 90 mg
Corn starch 42 mg
HPC-L 3 mg
150 mg
The compound of formula (I), lactose, is passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed, the HPC-L solution is added to the mixed powder, kneaded, granulated and dried. After the resulting dried granules are sized, 150 mg thereof is filled into a No. 4 hard gelatin capsule.
Formulation Example 4
A tablet containing the following ingredients is produced.
Ingredient Compound represented by formula (I) 10 mg
Lactose 90 mg
Microcrystalline cellulose 30 mg
CMC-Na 15 mg
Magnesium stearate 5 mg
150 mg
A compound represented by the formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. The mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. The mixed powder is directly hit to obtain a 150 mg tablet.
Formulation Example 5
The intravenous formulation is manufactured as follows:
Compound represented by formula (I) 100 mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.

  The compound of the present invention has an excellent EGF receptor and HER2 inhibitory action and is highly safe, and thus is useful as a therapeutic agent for pharmaceuticals, particularly cancer.

Claims (8)

Formula (I):

[Wherein R ¹ represents C1-C3 alkyl, C1-C3 alkyloxy, C1-C3 alkylthio, or C1-C3 alkylamino;
R ² has the formula:

(Wherein R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ⁴⁴ , and R ⁴⁵ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, halogen, alkyloxy, substituted Optionally substituted aryl, or optionally substituted heteroaryl;
Ar ¹ , Ar ² and Ar ³ are allylene or heteroarylene;
R ⁶ and R ⁷ are optionally substituted alkyl, alkyloxy, alkoxycarbonyl, or formyl;
R ¹⁰ , R ¹¹ and R ¹⁴ are each a hydrogen atom, an optionally substituted amino group, an optionally substituted non-aromatic nitrogen-containing heterocyclic group, an optionally substituted aryl group, or an optionally substituted group. Heteroaryl, alkylsulfinyl, alkylsulfonyl, hydroxy, or alkyloxy;
X ¹ , X ² and X ^{4 each} represent —C (═O) —N (R ¹⁵ ) —, —N (R ¹⁶ ) —C (═O) —, or —C (═O) —N (R ¹⁵ )-, -N (R < ¹⁶ >)-C (= O)-, -N (R < ¹⁷ >)-, -O-, -S-, phenylene, or heteroarylene, or may be substituted. Alkylene; R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently a hydrogen atom, alkyl, or acyl;
R ¹² , R ⁴⁶ , and R ⁵⁰ are each a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, or a substituted Optionally substituted aryl, or optionally substituted heteroaryl;
X ³ , X ¹¹ and X ¹² are —O—, —N (R ¹⁸ ) —, or —O— or —N (R ¹⁹ ) — which may be interposed or substituted alkylene; R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl;
R ¹³ , R ⁴⁷ , and R ⁵¹ are each a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, or an optionally substituted non-aromatic nitrogen-containing And R each independently represents an optionally substituted alkyl, an alkyloxy, an alkyloxycarbonyl, an optionally substituted alkenyl, an alkenyloxy, an optionally substituted alkynyl, an alkynyloxy, A group represented by halogen, nitro, cyano, or optionally substituted amino; n is an integer of 0 to 2;
Y represents —NH— ; and R ³ represents the formula:

[Wherein R ²² represents a group represented by the formula: —Z—R ²⁵ (wherein Z represents an alkylene which may intervene —O—; R ²⁵ represents a substituent group E (substituent group E: halogen, carboxy A group represented by phenyl) which may be substituted with a substituent selected from alkyl, haloalkyl, hydroxyalkyl, alkyloxy, alkyloxycarbonyl, and optionally substituted amino); R ²³ is substituted An alkynyl which may be substituted, an alkyloxy which may be substituted, or a halogen; and a group wherein R ²⁴ is a hydrogen atom ]
Or a pharmaceutically acceptable salt or solvate thereof. R ² has the formula:

[Wherein, R ⁴ and R ⁵ each independently represents a hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, an optionally substituted aryl, or an optionally substituted heteroaryl; Ar ¹ , Ar ² and Ar ³ have the formula:

(In the formula, each R independently represents an optionally substituted alkyl, an alkyloxy, an alkyloxycarbonyl, an optionally substituted alkenyl, an alkenyloxy, an optionally substituted alkynyl, an alkynyloxy, or a halogen. , Nitro, cyano, or optionally substituted amino; n is an integer of 0 to 2);
R ⁶ and R ⁷ are selected from the substituent group A (substituent group A: optionally substituted amino, optionally substituted non-aromatic nitrogen-containing heterocyclic group, alkoxyimino, and hydroxy). Alkyl, alkyloxy, or alkoxycarbonyl optionally substituted with substituents;
X ⁴ is an alkylene which may be optionally substituted by —C (═O) —N (R ¹⁵ ) — or —N (R ¹⁶ ) —C (═O) —; R ¹⁵ and R ¹⁶ is each independently a hydrogen atom, alkyl, or acyl; and R ¹⁴ is an optionally substituted amino, an optionally substituted non-aromatic nitrogen-containing heterocyclic group, an alkylsulfinyl, an alkylsulfonyl, The compound of Claim 1, which is a group represented by hydroxy, or alkyloxy], or a pharmaceutically acceptable salt thereof, or a solvate thereof. R ⁶ and R ⁷ are substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted aminocarbonylalkyl. , Optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Or substituted group C (substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted alkyl, alkyloxyalkyl, cyano A The compound according to claim 2, which is an alkyl substituted with a non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent selected from alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl. Or a pharmaceutically acceptable salt thereof or a solvate thereof. R ² has the formula:

[Wherein R ⁸ , R ⁹ , R ¹² , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , and R ⁵⁰ are each independently a hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, substituted Optionally substituted aryl, or optionally substituted heteroaryl;
X ¹ and X ² are each an alkylene optionally intervening or substituted with —C (═O) —N (R ¹⁵ ) — or —N (R ¹⁶ ) —C (═O) —; R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, alkyl, or acyl;
X ³ , X ¹¹ , and X ¹² are —O— or —N (R ¹⁸ ) —; R ¹⁸ is a hydrogen atom, alkyl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, or aralkyloxycarbonyl;
R ¹⁰ and R ¹¹ are an optionally substituted amino, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted non-aromatic nitrogen-containing heterocyclic group;
R ¹³ , R ⁴⁷ , and R ⁵¹ are an alkyl substituted with an optionally substituted amino, or an alkyl substituted with an optionally substituted non-aromatic nitrogen-containing heterocyclic group. 1. The compound according to 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof. R ¹⁰ and R ¹¹ are substituent group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, optionally substituted aminocarbonylalkyl. Optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl), or optionally substituted amino, or Substituent group C (Substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted with alkyloxy, alkyloxyalkyl, cyano, alkylsulfonyl 5) a compound or a pharmaceutically acceptable salt thereof, which is a non-aromatic nitrogen-containing heterocyclic group optionally substituted with a substituent selected from alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl) Or a solvate thereof. R ¹³ , R ⁴⁷ , and R ⁵¹ are each substituted group B (substituent group B: alkyl, alkylsulfonylalkyl, alkylcarbonyl optionally substituted with halogen, alkyloxycarbonyl, cycloalkyl, substituted Good aminocarbonylalkyl, optionally substituted aminocarbonyloxyalkyl, alkyloxyalkyl, optionally substituted aminoalkylcarbonyl, arylalkyl, and heteroarylalkyl). Alkyl substituted with good amino, or Substituent group C (Substituent group C: oxo, hydroxy, optionally substituted aminocarbonyl, alkyloxycarbonyl, cyano or alkyloxy optionally substituted with alkyl, alkyl Oxya Alkyl substituted with a non-aromatic nitrogen-containing heterocyclic group which may be substituted with a substituent selected from a group selected from a group selected from the group consisting of alkyl, cyano, alkylsulfonyl, alkylcarbonyl, alkenylcarbonyl, and alkylsulfonylalkylcarbonyl]. Item 5. The compound according to Item 4, or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient. An anticancer agent comprising the compound according to claim 1 as an active ingredient.