JP2011231050A - Heterocyclic compound having npyy5 receptor antagonism - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide novel compounds having an NPY Y5 receptor antagonism.SOLUTION: The compounds shown by Formula (I), pharmaceutically permitted salts thereof, or those solvates are disclosed (wherein R, Rand Rare each independently hydrogen, (un)substituted alkyl, (un)substituted alkoxy, (un)substituted cycloalkyl, (un)substituted cycloalkenyl, (un)substituted aryl, (un)substituted heteroaryl, (un)substituted heterocyclyl or the like; Rand Rmay join together with an adjoining nitrogen atom to form (un)substituted nitrogen-containing aromatic heterocyclic ring or (un)substituted nitrogen-containing non-aromatic heterocyclic ring; X is S(O), S(O)or C(O); m is an integer of 0-2; Y is S or O; Rs are each independently halogen or the like; and n is an integer of 0-2).

Description

  The present invention relates to a novel heterocyclic compound having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.

  Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.

  In previous reports, NPY has been found to have a feeding promoting action, an anticonvulsant action, a learning promoting action, an anxiolytic action, an antistress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease. In peripheral tissues, NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders. Furthermore, it is known to be involved in metabolic diseases such as obesity, diabetes, and hormonal abnormalities (see Non-Patent Document 1). Therefore, a pharmaceutical composition having an NPY receptor antagonistic action may be a preventive or therapeutic agent for various diseases involving the NPY receptor as described above.

  To date, subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered for NPY receptors (see Non-Patent Document 2). The Y5 receptor is involved in at least the feeding function, and it has been suggested that the antagonist is an anti-obesity drug (see Non-Patent Documents 3 to 5).

  Patent Documents 1 to 3 describe amine derivatives having NPY Y5 receptor antagonistic activity. Patent Documents 4 to 6 describe derivatives having a sulfamide side chain having an NPY Y5 receptor antagonistic action. These compounds differ in structure from the compounds of the present invention.

  Derivatives having a similar structure to the compound of the present application are described in Patents 7 and 8, but their actions are completely different and do not suggest the present invention.

International Publication No. 2007/1255952 International Publication No. 2009/054434 International Publication No. 2008/134228 International Publication No. 00/64880 International Publication No. 01/02379 International Publication No. 97/20823 International Publication No. 2008/028860 International Publication No. 2005/097738

Trends in Pharmacological Sciences, Vol. 15, 153 (1994) Trends in Pharmacological Sciences, Vol. 18, 372 (1997) Peptides, Vol. 18, 445 (1997) Obesity, Vol. 14, no. 9, A235 (2006) Obesity, Vol. 15, no. 9, A57 (2007)

  An object of the present invention is to provide a novel heterocyclic compound having an excellent NPY Y5 receptor antagonistic action.

  As a result of intensive studies, the present inventors have succeeded in synthesizing a novel compound having an excellent NPY Y5 receptor antagonistic action. Moreover, it discovered that this compound showed the strong eating suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.

（式中、
Ｒ^１、Ｒ^２及びＲ^３はそれぞれ独立して水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール又は置換若しくは非置換のヘテロサイクリルであり、
Ｒ^１及びＲ^２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環又は置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、又は
Ｒ^２及びＲ^３は一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環を形成してもよく、
ＸはＳ（Ｏ）、Ｓ（Ｏ）_２又はＣ（Ｏ）であり、
Ｒ^４及びＲ^５はそれぞれ独立して水素又は置換若しくは非置換のアルキルであり、又は
Ｒ^４及びＲ^５は一緒になってオキソを形成してもよく、
Ｒ^６は水素又は置換若しくは非置換のアルキルであり、
Ｒはそれぞれ独立してハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル又は置換若しくは非置換のアルキニルであり、
ｍは０〜２の整数であり、
ＹはＳ又はＯであり、
Ｒ^７はそれぞれ独立してハロゲン、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル又は置換若しくは非置換のアルコキシであり、
ｎは０〜２の整数である）で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（２）Ｒ^１及びＲ^２がそれぞれ独立して水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアリール又は置換若しくは非置換のヘテロアリールである、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（３）Ｒ^１及びＲ^２がそれぞれ独立して置換若しくは非置換のアルキルである、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（４）Ｒ^１が置換若しくは非置換のアルキルであり、Ｒ^２が置換若しくは非置換のシクロアルキルである、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（５）Ｒ^１が置換若しくは非置換のアルキルであり、Ｒ^２が置換若しくは非置換のアルコキシである、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（６）Ｒ^１及びＲ^２が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している、（１）に記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（７）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のアルキルである、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（８）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のシクロアルキルである、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（９）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のアルコキシである、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（１０）ＸがＳ（Ｏ）_２である、（１）〜（９）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（１１）ＹがＯである、（１）〜（１０）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（１２）Ｒ^３が水素、置換若しくは非置換のアルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアリール又は置換若しくは非置換のヘテロアリールである、（１）〜（１１）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（１３）Ｒ^２及びＲ^３が一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環を形成している、（１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（１４）Ｒ^７がハロゲンである、（１）〜（１３）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（１５）Ｒ^３が水素、置換若しくは非置換のアルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のアリール又は置換若しくは非置換のヘテロアリールであり、
ＸがＳ（Ｏ）_２又はＣ（Ｏ）であり、
Ｒ^４及びＲ^５が水素であり、又は
Ｒ^４及びＲ^５が一緒になってオキソを形成してもよく、
Ｒ^６が水素であり、
ｍは０であり、
ＹはＳ又はＯであり、
Ｒ^７はそれぞれ独立してハロゲンであり、
ｎは０〜２の整数である（１）〜（９）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。
（１６）（１）〜（１５）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を有効成分とする医薬組成物。
（１７）ＮＰＹ Ｙ５受容体拮抗作用を有する、（１６）記載の医薬組成物。
（１８）（１）〜（１５）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（１９）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（１）〜（１５）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（２０）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（１）〜（１５）のいずれかに記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 That is, the present invention relates to the following.
(1) Formula (I):

(Where
R ¹ , R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R ¹ and R ² may form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring together with the adjacent nitrogen atom, or R ² and R ³ together may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle,
X is S (O), S (O) ₂ or C (O);
R ⁴ and R ⁵ are each independently hydrogen or substituted or unsubstituted alkyl, or R ⁴ and R ⁵ together may form an oxo;
R ⁶ is hydrogen or substituted or unsubstituted alkyl;
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
m is an integer from 0 to 2,
Y is S or O;
Each R ⁷ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted alkoxy;
n is an integer of 0 to 2, and a pharmaceutically acceptable salt or solvate thereof.
(2) R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted hetero The compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is aryl.
(3) The compound according to (1), pharmaceutically acceptable salt or solvate thereof, wherein R ¹ and R ² are each independently substituted or unsubstituted alkyl.
(4) The compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ is substituted or unsubstituted alkyl, and R ² is substituted or unsubstituted cycloalkyl.
(5) The compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ is substituted or unsubstituted alkyl and R ² is substituted or unsubstituted alkoxy.
(6) The compound according to (1), wherein R ¹ and R ² together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, and its pharmaceutically acceptable Salts or solvates thereof.
(7) The compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R ¹ is hydrogen and R ² is substituted or unsubstituted alkyl.
(8) The compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R ¹ is hydrogen and R ² is substituted or unsubstituted cycloalkyl.
(9) The compound according to (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R ¹ is hydrogen and R ² is substituted or unsubstituted alkoxy.
(10) The compound according to any one of (1) to (9), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is S (O) ₂ .
(11) The compound according to any one of (1) to (10), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Y is O.
(12) Any of (1) to (11), wherein R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl Or a pharmaceutically acceptable salt or solvate thereof.
(13) The compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ² and R ³ are combined to form a substituted or unsubstituted nitrogen-containing aromatic heterocycle. .
(14) The compound according to any one of (1) to (13), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ⁷ is halogen.
(15) R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
X is S (O) ₂ or C (O);
R ⁴ and R ⁵ are hydrogen, or R ⁴ and R ⁵ together may form oxo,
R ⁶ is hydrogen;
m is 0,
Y is S or O;
Each R ⁷ is independently halogen;
n is an integer of 0-2, The compound in any one of (1)-(9), its pharmaceutically acceptable salt, or those solvates.
(16) A pharmaceutical composition comprising the compound according to any one of (1) to (15), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
(17) The pharmaceutical composition according to (16), which has an NPY Y5 receptor antagonistic action.
(18) Treatment or prevention of a disease involving NPY Y5, comprising administering the compound according to any one of (1) to (15), a pharmaceutically acceptable salt thereof, or a solvate thereof. Method.
(19) Use of the compound according to any one of (1) to (15), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5. .
(20) The compound according to any one of (1) to (15), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（２２）（２１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（２３）ＮＰＹ Ｙ５受容体拮抗作用を有する、（２２）記載の医薬組成物。
（２４）（２１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（２５）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（２１）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（２６）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（２１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (21) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(22) A pharmaceutical composition comprising the compound according to (21), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(23) The pharmaceutical composition according to (22), which has an NPY Y5 receptor antagonistic action.
(24) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (21), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(25) Use of the compound according to (21), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(26) The compound according to (21), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（２８）（２７）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（２９）ＮＰＹ Ｙ５受容体拮抗作用を有する、（２８）記載の医薬組成物。
（３０）（２７）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（３１）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（２７）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（３２）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（２７）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (27) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(28) A pharmaceutical composition comprising the compound according to (27), a pharmaceutically acceptable salt thereof or a solvate thereof.
(29) The pharmaceutical composition according to (28), which has an NPY Y5 receptor antagonistic action.
(30) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (27), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(31) Use of the compound according to (27), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(32) The compound according to (27), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（３４）（３３）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（３５）ＮＰＹ Ｙ５受容体拮抗作用を有する、（３４）記載の医薬組成物。
（３６）（３３）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（３７）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（３３）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（３８）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（３３）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (33) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(34) A pharmaceutical composition comprising the compound according to (33), a pharmaceutically acceptable salt thereof or a solvate thereof.
(35) The pharmaceutical composition according to (34), which has an NPY Y5 receptor antagonistic action.
(36) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (33), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(37) Use of the compound according to (33), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(38) The compound according to (33), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（４０）（３９）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（４１）ＮＰＹ Ｙ５受容体拮抗作用を有する、（４０）記載の医薬組成物。
（４２）（３９）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（４３）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（３９）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（４４）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（３９）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (39) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(40) A pharmaceutical composition comprising the compound according to (39), a pharmaceutically acceptable salt thereof or a solvate thereof.
(41) The pharmaceutical composition according to (40), which has an NPY Y5 receptor antagonistic action.
(42) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (39), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(43) Use of the compound according to (39), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(44) The compound according to (39), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（４６）（４５）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（４７）ＮＰＹ Ｙ５受容体拮抗作用を有する、（４６）記載の医薬組成物。
（４８）（４５）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（４９）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（４５）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（５０）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（４５）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (45) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(46) A pharmaceutical composition comprising the compound according to (45), a pharmaceutically acceptable salt thereof or a solvate thereof.
(47) The pharmaceutical composition according to (46), which has an NPY Y5 receptor antagonistic action.
(48) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (45), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(49) Use of the compound according to (45), a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(50) The compound according to (45), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（５２）（５１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（５３）ＮＰＹ Ｙ５受容体拮抗作用を有する、（５２）記載の医薬組成物。
（５４）（５１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（５５）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（５１）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（５６）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（５１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (51) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(52) A pharmaceutical composition comprising the compound according to (51), a pharmaceutically acceptable salt thereof or a solvate thereof.
(53) The pharmaceutical composition according to (52), which has an NPY Y5 receptor antagonistic action.
(54) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (51), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(55) Use of the compound according to (51), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(56) The compound according to (51), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（５８）（５７）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（５９）ＮＰＹ Ｙ５受容体拮抗作用を有する、（５８）記載の医薬組成物。
（６０）（５７）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（６１）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（５７）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（６２）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（５７）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (57) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(58) A pharmaceutical composition comprising the compound according to (57), a pharmaceutically acceptable salt thereof or a solvate thereof.
(59) The pharmaceutical composition according to (58), which has an NPY Y5 receptor antagonistic action.
(60) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (57), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(61) Use of the compound according to (57), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(62) The compound according to (57), a pharmaceutically acceptable salt or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（６４）（６３）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（６５）ＮＰＹ Ｙ５受容体拮抗作用を有する、（６４）記載の医薬組成物。
（６６）（６３）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（６７）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（６３）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（６８）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（６３）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (63) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(64) A pharmaceutical composition comprising the compound according to (63), a pharmaceutically acceptable salt thereof or a solvate thereof.
(65) The pharmaceutical composition according to (64), which has an NPY Y5 receptor antagonistic action.
(66) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (63), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(67) Use of the compound according to (63), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(68) The compound according to (63), a pharmaceutically acceptable salt or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（７０）（６９）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（７１）ＮＰＹ Ｙ５受容体拮抗作用を有する、（７０）記載の医薬組成物。
（７２）（６９）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（７３）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（６９）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（７４）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（６９）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (69) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(70) A pharmaceutical composition comprising the compound according to (69), a pharmaceutically acceptable salt thereof or a solvate thereof.
(71) The pharmaceutical composition according to (70), which has an NPY Y5 receptor antagonistic action.
(72) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (69), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(73) Use of the compound according to (69), a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing an agent for treating or preventing a disease involving NPY Y5.
(74) The compound according to (69), a pharmaceutically acceptable salt or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（７６）（７５）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（７７）ＮＰＹ Ｙ５受容体拮抗作用を有する、（７６）記載の医薬組成物。
（７８）（７５）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（７９）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（７５）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（８０）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（７５）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 Formula (75):

Or a pharmaceutically acceptable salt or solvate thereof.
(76) A pharmaceutical composition comprising the compound according to (75), a pharmaceutically acceptable salt thereof or a solvate thereof.
(77) The pharmaceutical composition according to (76), which has an NPY Y5 receptor antagonistic action.
(78) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (75), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(79) Use of the compound according to (75), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(80) The compound according to (75), a pharmaceutically acceptable salt or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.

で示される化合物、その製薬上許容される塩又はそれらの溶媒和物。
（８２）（８１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を含有する医薬組成物。
（８３）ＮＰＹ Ｙ５受容体拮抗作用を有する、（８２）記載の医薬組成物。
（８４）（８１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療又は予防方法。
（８５）ＮＰＹ Ｙ５の関与する疾患の治療又は予防剤を製造するための、（８１）の記載の化合物、その製薬上許容される塩又はそれらの溶媒和物の使用。
（８６）ＮＰＹ Ｙ５受容体の関与する疾患を治療又は予防するための、（８１）記載の化合物、その製薬上許容される塩又はそれらの溶媒和物。 (81) Formula:

Or a pharmaceutically acceptable salt or solvate thereof.
(82) A pharmaceutical composition comprising the compound according to (81), a pharmaceutically acceptable salt thereof or a solvate thereof.
(83) The pharmaceutical composition according to (82), which has an NPY Y5 receptor antagonistic action.
(84) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (81), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(85) Use of the compound according to (81), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
(86) The compound according to (81), a pharmaceutically acceptable salt thereof or a solvate thereof, for treating or preventing a disease involving NPY Y5 receptor.

  The compound of the present invention exhibits NPY Y5 receptor antagonistic action, and is associated with drugs, particularly diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral hyperemia, congestive heart failure, sleep disorder and the like. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for the treatment or prevention of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndromes.

  The terms used in this specification will be described below. In addition, in this specification, each term has the same meaning, whether used alone or in combination with other terms, unless otherwise specified.

  Each atom in the compound of the present invention may be an isotope. For example, hydrogen may be any of the hydrogen isotopes, ie light hydrogen (H), deuterium (D) and tritium (T).

  “Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.

  “Alkyl” means a straight or branched hydrocarbon group having 1 to 10 carbon atoms. C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc. are included. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like.

  “Alkenyl” means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any position. Including alkenyl having 2 to 8 carbon atoms, alkenyl having 3 to 6 carbon atoms and the like. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.

  “Alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. C2-C6 alkynyl, C2-C4 alkynyl, etc. are included. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.

  “Alkoxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.

  “Cycloalkyl” means a C3-C8 cyclic saturated hydrocarbon group. Examples include cycloalkyl having 3 to 6 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, and the like. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.

  “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Cycloalkenyl also includes bridged cyclic unsaturated aliphatic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.

  “Aryl” means a monocyclic or polycyclic aromatic carbocyclic group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. Further, a condensed aromatic hydrocarbon cyclic group in which a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed is also included. For example, indanyl, indenyl, biphenylenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.

“Aromatic heterocycle” means an aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic aromatic heterocycles.
The “monocyclic aromatic heterocycle” means a 4- to 8-membered monocyclic aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Examples thereof include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, and thiophene. In particular, a 5-membered or 6-membered monocyclic aromatic heterocycle is preferable.
The term “polycyclic aromatic heterocycle” refers to the above “monocyclic aromatic heterocycle”, an aromatic carbocycle (ring derived from the above “aryl”), an aromatic heterocycle, a cycloalkane (above “cyclohexane”). A ring derived from “alkyl” or a ring fused with cycloalkene (ring derived from “cycloalkenyl” above). For example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo A bicyclic aromatic heterocycle such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine; carbazole, Examples include tricyclic aromatic heterocycles such as acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, and dibenzofuran. It is.

The “nitrogen-containing aromatic heterocycle” means a monocyclic or polycyclic aromatic heterocycle having at least one nitrogen atom in the ring.
Examples of the “monocyclic nitrogen-containing aromatic heterocycle” include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, and thiazole. , Thiadiazole and the like.
Examples of the `` polycyclic nitrogen-containing aromatic heterocycle '' include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benziso Two-ring nitrogen-containing compounds such as oxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzothiazole, benzothiadiazole, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine Aromatic heterocycles: 3-ring nitrogen-containing aromatic heterocycles such as carbazole, acridine, phenothiazine, phenoxazine and the like.

“Heteroaryl” means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. For example, it includes a group derived from the above “monocyclic aromatic heterocycle” and a group derived from the above “polycyclic aromatic heterocycle”.
Examples of the `` monocyclic aromatic heterocyclic group '' include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, Examples include thienyl and the like.
Examples of the “polycyclic aromatic heterocyclic group” include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl , Benzoxazolyl, benzoxiadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra Bicyclic aromatic heterocyclic groups such as dinopyridazinyl, oxazolopyridyl, thiazolopyridyl; carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathi Le, phenoxazinyl, heterocyclic groups such as the aromatic tricyclic dibenzofuryl and the like. In the case of a polycyclic aromatic heterocyclic group, any ring may have a bond.

“Non-aromatic heterocycle” means a non-aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic non-aromatic heterocycles.
The “monocyclic non-aromatic heterocycle” means a 4- to 8-membered monocyclic non-aromatic ring having one or more hetero atoms arbitrarily selected from O, S and N in the ring. For example, dioxane, thiirane, oxirane, oxathiolane, azetidine, thiane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroiso Examples include thiazole, oxazolidine, thiazolidine and the like. In particular, a 5-membered or 6-membered monocyclic non-aromatic heterocycle is preferable.
“Polycyclic non-aromatic heterocycle” refers to the above “monocyclic non-aromatic heterocycle”, aromatic carbocycle (ring derived from the above “aryl”), aromatic heterocycle, monocyclic A non-aromatic heterocycle, a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed. For example, indoline, isoindoline, chroman, isochroman and the like can be mentioned.

The “nitrogen-containing non-aromatic heterocycle” means a monocyclic or polycyclic non-aromatic heterocycle having at least one nitrogen atom in the ring.
`` Monocyclic nitrogen-containing non-aromatic heterocycle '' includes, for example, azetidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrothiazole, tetrahydro Examples include isothiazole, oxazolidine, thiazolidine and the like.
Examples of the “polycyclic nitrogen-containing non-aromatic heterocycle” include indoline, isoindoline, dihydrobenzothiadiazole and the like.

“Heterocyclyl” means a non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. A monocyclic non-aromatic heterocyclic group (a group derived from the above-mentioned “monocyclic non-aromatic heterocyclic ring”) or a polycyclic non-aromatic heterocyclic group (the above “polycyclic non-aromatic heterocyclic group”); Group derived from “aromatic heterocycle”.
Specific examples of `` monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.

Substituents of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl” or “substituted or unsubstituted alkoxy” include halogen, cyano, nitro, nitroso, azide Acyl, acyloxy, imino, hydroxy, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, Heterocyclyloxy,
Mercapto, alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, heteroarylthio, heterocyclylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heteroaryloxy Carbonyl, heterocyclyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, cycloalkyl Sulfonyl, cycloalkenylsulfoni , Arylsulfonyl, heteroarylsulfonyl, heterocyclyl sulfonyl, sulfamoyl, amino, oxo and the like. Arbitrary positions may have a substituent by one or more groups selected from these.

  “Substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted heteroaryl”, “substituted or unsubstituted heterocyclyl”, Examples of the substituent of “substituted or unsubstituted nitrogen-containing aromatic heterocycle” or “substituted or unsubstituted nitrogen-containing nonaromatic heterocycle” include alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, nitroso, Azide, acyl, acyloxy, imino, hydroxy, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl , Heterocyclyloxy, mercapto, alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, heteroarylthio, heterocyclylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryl Oxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, sulfino, sulfo, alkylsulfonyl , Alkenylsulfonyl, cycloalkylsulfoni , Cycloalkenyl sulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclyl sulfonyl, sulfamoyl, amino, oxo and the like. Any position may be substituted with one or more groups selected from these.

“Acyl” means (1) a linear or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms,
(2) cycloalkylcarbonyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms and (3) arylcarbonyl having 7 to 11 carbon atoms are included. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.

  “Acyloxy” means a group in which the above “acyl” is bonded to an oxygen atom.

  “Haloalkyl” and “haloalkoxy” mean a group in which the “halogen” is bonded to the “alkyl” and “alkoxy”.

  "Alkenyloxy", "alkynyloxy", "cycloalkyloxy", "cycloalkenyloxy", "heteroaryloxy" and "heterocyclyloxy" are the above "alkenyl", "alkynyl", "cycloalkyl" , "Cycloalkenyl", "heteroaryl" and "heterocyclyl" mean a group bonded to an oxygen atom.

  “Aryloxy” means a group in which the above “aryl” is bonded to an oxygen atom. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy, indanyloxy, indenyloxy, biphenylyloxy, acenaphthyloxy, tetrahydronaphthyloxy, fluorenyloxy and the like.

  “Alkylthio”, “alkenylthio”, “cycloalkylthio”, “cycloalkenylthio”, “arylthio”, “heteroarylthio” and “heterocyclylthio” are the above-mentioned “alkyl”, “alkenyl”, “cycloalkyl” ”,“ Cycloalkenyl ”,“ aryl ”,“ heteroaryl ”and“ heterocyclyl ”mean a group bonded to a sulfur atom.

  “Alkoxycarbonyl”, “alkenyloxycarbonyl”, “cycloalkyloxycarbonyl”, “cycloalkenyloxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl” and “heterocyclyloxycarbonyl” It means a group in which an oxygen atom of “alkoxy”, “alkenyloxy”, “cycloalkyloxy”, “cycloalkenyloxy”, “aryloxy”, “heteroaryloxy” and “heterocyclyloxy” is bonded to a carbonyl group. .

  "Alkylcarbonyl", "alkenylcarbonyl", "cycloalkylcarbonyl", "cycloalkenylcarbonyl", "arylcarbonyl", "heteroarylcarbonyl" and "heterocyclylcarbonyl" are the above "alkyl", "alkenyl" , “Cycloalkyl”, “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a carbonyl group.

  "Alkylsulfonyl", "alkenylsulfonyl", "cycloalkylsulfonyl", "cycloalkenylsulfonyl", "arylsulfonyl", "heteroarylsulfonyl" and "heterocyclylsulfonyl" are the above "alkyl", "alkenyl" , “Cycloalkyl”, “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a sulfonyl group.

  All of the compounds of the present invention have NPY Y5 receptor antagonistic action, and particularly preferred compounds include the following compounds in the formula (I).

（Ｒ１，Ｒ２−６）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のアルキルである化合物。Ｒ^２の置換基の例としては、ハロゲン等が挙げられる。

（Ｒ１，Ｒ２−７）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のシクロアルキルである化合物。Ｒ^２として好ましくは、非置換のシクロアルキルである。

（Ｒ１，Ｒ２−８）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のアルコキシである化合物。Ｒ^２として好ましくは、非置換のアルコキシである。

（Ｒ１，Ｒ２−９）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のアリールである化合物。Ｒ^２の置換基の例としては、ハロゲン等が挙げられる。

（Ｒ１，Ｒ２−１０）Ｒ^１が水素であり、Ｒ^２が置換若しくは非置換のヘテロアリール化合物。Ｒ^２として好ましくは、非置換のピリミジンである。

（Ｒ１,Ｒ２−１１）Ｒ^１及びＲ^２が水素である化合物。 (R1, R2-1) R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or A compound that is unsubstituted heteroaryl. Examples of the substituent for R ¹ and R ² include one or more groups selected from cyano, alkoxy, halogen, and hydroxy.

(R1, R2-2) The compound wherein R ¹ and R ² are each independently substituted or unsubstituted alkyl. Examples of the substituent for R ¹ and R ² include one or more groups selected from cyano, alkoxy, halogen, and hydroxy.

(R1, R2-3) A compound wherein R ¹ is substituted or unsubstituted alkyl and R ² is substituted or unsubstituted cycloalkyl. R ¹ is preferably unsubstituted alkyl, and R ² is preferably unsubstituted cycloalkyl.

(R1, R2-4) A compound wherein R ¹ is substituted or unsubstituted alkyl and R ² is substituted or unsubstituted alkoxy. R ¹ is preferably unsubstituted alkyl, and R ² is preferably unsubstituted alkoxy.

(R1, R2-5) A compound in which R ¹ and R ² together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle. Examples of the nitrogen-containing non-aromatic heterocycle include morpholine, piperidine, pyrrolidine, oxazolidine and the like. Examples of the substituent of the nitrogen-containing non-aromatic heterocycle include one or more groups selected from halogen, alkyl and oxo. For example, the following compounds are mentioned.

(R1, R2-6) A compound wherein R ¹ is hydrogen and R ² is substituted or unsubstituted alkyl. Examples of the substituent for R ² include halogen.

(R1, R2-7) A compound wherein R ¹ is hydrogen and R ² is substituted or unsubstituted cycloalkyl. R ² is preferably unsubstituted cycloalkyl.

(R1, R2-8) A compound wherein R ¹ is hydrogen and R ² is substituted or unsubstituted alkoxy. R ² is preferably unsubstituted alkoxy.

(R1, R2-9) The compound wherein R ¹ is hydrogen and R ² is substituted or unsubstituted aryl. Examples of the substituent for R ² include halogen.

(R1, R2-10) A heteroaryl compound in which R ¹ is hydrogen and R ² is substituted or unsubstituted. R ² is preferably unsubstituted pyrimidine.

(R1, R2-11) A compound in which R ¹ and R ² are hydrogen.

(R3-1) R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A compound that is cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl. Examples of the substituent include one or more groups selected from phenyl, cyano and halogen.

(R3-2) The compound, wherein R ³ is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted cycloalkyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl. Examples of the substituent include one or more groups selected from phenyl, cyano and halogen.

(R3-3) The compound wherein R ³ is hydrogen; alkyl optionally substituted with phenyl; cycloalkyl optionally substituted with cyano; aryl optionally substituted with halogen or cyano; or heteroaryl.

（式中、Ｒ^１は式（Ｉ）で示される化合物における記号と同意義である。）等が挙げられる。 R ² and R ³ may be combined to form a substituted or unsubstituted nitrogen-containing aromatic heterocycle. For example, the formula:

(Wherein R ¹ has the same meaning as the symbol in the compound represented by formula (I)).

  Below, the preferable aspect in the compound shown by Formula (I) is demonstrated about substituents other than R1-R3.

X is S (O), S (O) ₂ or C (O).

R ⁴ and R ⁵ are each independently hydrogen or substituted or unsubstituted alkyl. Or, R ⁴ and R ⁵ together may form an oxo.

R ⁶ is hydrogen or substituted or unsubstituted alkyl.

Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
m is an integer of 0-2.

  Y is S or O.

Each R ⁷ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkoxy. Particularly preferred is halogen.
n is an integer of 0-2.

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物、及び／又は
式：

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物を意味する。特に好ましくは、
式：

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物である。 The compound represented by the formula (I) is
formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by the formula (I).)
And / or the formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by the formula (I).)
Means a compound represented by Particularly preferably,
formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by the formula (I).)
It is a compound shown by these.

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。） The above compounds can also be described as follows.

(In the formula, each symbol has the same meaning as each symbol in the compound represented by the formula (I).)

  The compound of the present invention can produce each compound, and includes pharmaceutically acceptable salts. “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples thereof include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.

  The compounds of the present invention include solvates thereof. Preferable examples include hydrates and alcohol hydrates. For example, monohydrate, dihydrate, monoalcohol hydrate, dialcohol solvate and the like.

  When the compound of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). Moreover, when this invention compound has a double bond, when both E body and Z body may exist, both are included.

  Prodrugs of the compounds of the invention are within the scope of the invention. Prodrugs of the compounds of the present invention are functional derivatives of the compounds of the present invention and are easily converted into the compounds of the present invention in vivo. Therefore, the compound of the present invention is a specifically disclosed compound or a compound that is not specifically disclosed in some cases, but is administered in vivo to a patient with a disease involving NPY Y5. Including compounds that convert to Conventional procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｒはアルキルである。） The compound represented by the formula (I) which is the compound of the present invention can be synthesized, for example, by the following method.
Method A

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and R is alkyl.)

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される基を導入する。例えば、式：

(式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｈａｌはハロゲンである。)
で示される基を塩基存在下で反応させることにより、化合物（ｃ）を得ることができる。溶媒としては、メタノール、エタノール、イソプロパノール、ジメチルホルムアミド等を用いることができる。反応は、室温下又は加温下で行うことができる。例えば、封管し、マイクロウェ−ブ反応装置を用いて行うこともできる。塩基としては、Ｎ,Ｎ-ジイソプロピルエチルアミン等を用いることができる。

工程Ｃ
化合物（ｃ）を還元し、化合物（ｄ）を得る。還元剤として、水素化リチウムアルミニウム等を用いることができる。溶媒としては、テトラヒロドフラン等を用いることができる。反応は、室温で行うことができる。 Process A
The substituent R ⁶ is introduced into the compound (a). For example, compound (b) can be obtained by reacting R ⁶ -Hal (Hal is halogen) in the presence of a base. As the solvent, tetrahydrofuran, dimethylformamide, or the like can be used. The reaction can be carried out at room temperature. As the base, triethylamine, pyridine, dimethylaminopyridine and the like can be used.
Note that, in the compound represented by the formula (I), the compound in which R ⁶ is hydrogen does not perform this step.

Process B
Compound (b) is represented by the formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by the formula (I).)
A group represented by is introduced. For example, the formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Hal is halogen.)
The compound (c) can be obtained by reacting the group represented by the above in the presence of a base. As the solvent, methanol, ethanol, isopropanol, dimethylformamide, or the like can be used. The reaction can be carried out at room temperature or under heating. For example, it can be sealed and sealed using a microwave reactor. As the base, N, N-diisopropylethylamine or the like can be used.

Process C
Compound (c) is reduced to obtain compound (d). As the reducing agent, lithium aluminum hydride or the like can be used. Tetrahydrofuran or the like can be used as the solvent. The reaction can be carried out at room temperature.

(式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｈａｌはハロゲンである。)
で示される化合物を反応させ、化合物（Ｉ−Ａ）を得る。式（ＩＩ）で示される化合物として、各種のスルホニルクロライド、アシルクロライド等を用いることができる。溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、ヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等を用いることができる。反応は、室温下又は加温下で行うことができる。塩基の存在下で行うのが好ましい。塩基としては、ピリジン、トリエチルアミン、Ｎ‐メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等を使用することができる。
なお、式（Ｉ）で示される化合物において、Ｒ^３、Ｒ^４及びＲ^５が水素である化合物は、以降の工程Ｇを行わず、化合物（Ｉ−Ａ）が最終目的化合物となる。
式（Ｉ）で示される化合物において、置換基Ｒ^４及びＲ^５が水素以外である化合物については、適宜方法により、化合物（Ｉ−Ａ）に置換基Ｒ^４及びＲ^５を導入する工程を経て得ることができる。
また、Ｘ＝Ｓ又はＳＯである式（ＩＩ）で示される化合物を用いて反応させ、化合物（Ｉ−Ａ）を得て、その後に酸化して、ＸがＳＯ_２である化合物に変換し、次の工程に用いても良い。酸化工程は、酸化剤を用いて行うことができる。酸化剤としては、ｍ−クロロ過安息香酸、過酢酸、過酸化水素、過トリフルオロ酢酸、過ヨウ素酸ナトリウム、次亜塩素酸ナトリウム、過マンガン酸カリウム、タングステン酸ナトリウム等が挙げられる。 Process D
Compound (d) is azidated to give compound (e). For example, compound (d) is reacted with mesyl chloride using triethylamine as a base to induce compound (d) to mesylate. As a solvent for the mesylation, chloroform or the like can be used. The compound obtained can be reacted with sodium azide and azidated in dimethylformamide or the like at room temperature or under heating to obtain compound (e).

Process E
Compound (e) is reduced to obtain compound (f). It can be carried out by catalytic reduction. As the catalyst, 10% palladium carbon or the like can be used. As the solvent, ethanol or the like can be used.

Process F
Compound (f) is converted to formula (II):

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Hal is halogen.)
The compound shown by these is made to react, and a compound (IA) is obtained. As the compound represented by the formula (II), various sulfonyl chlorides, acyl chlorides and the like can be used. Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do. The reaction can be carried out at room temperature or under heating. It is preferably carried out in the presence of a base. As the base, pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used.
In the compound represented by the formula (I), a compound in which R ³ , R ⁴ and R ⁵ are hydrogen does not perform the subsequent step G, and the compound (IA) becomes the final target compound.
In the compound represented by the formula (I), the compound in which the substituents R ⁴ and R ⁵ are other than hydrogen is appropriately subjected to a step of introducing the substituents R ⁴ and R ⁵ into the compound (IA) by an appropriate method. Obtainable.
Further, X = is reacted with a compound represented by S or SO Formula (II), to give compound (I-A), it is oxidized thereafter, converted to compounds wherein X is SO _2, You may use for the next process. The oxidation step can be performed using an oxidizing agent. Examples of the oxidizing agent include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, and sodium tungstate.

(式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。)
で示される化合物を反応させ、化合物（Ｉ−Ａ）を得ることもできる。
例えば、化合物（ｄ）に、塩基としてトリエチルアミン、ピリジン等を用い、メシルクロライドを反応させて、化合物（ｄ）をメシレートに誘導する。メシル化する際の溶媒としては、クロロホルム、塩化メチレン等を用いることができる。得られた化合物に、式（ＩＩＩ）で示される化合物を反応させ、化合物（Ｉ−Ａ）を得る。塩基としては、カリウムｔｅｒｔ−ブトキシド、ナトリウムｔｅｒｔ−ブトキシド、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムペントキシド、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウム等を用いることができる。溶媒としては、メタノール、エタノール、イソプロパノール、ｎ−プロパノール、ｔｅｒｔ−ブタノール、ｎ−ブタノール、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドン、１，３−ジメチル−２−イミダゾリジノン、酢酸エチル、酢酸プロピル、テトラヒドロフラン、２−メチルテトラヒドロフラン、ジメチルスルホキシド、アセトニトリル、プロピオニトリル、アセトン、メチルエチルケトン、それらの混合溶媒等を使用することができる。式（ＩＩＩ）で示される化合物中のＮＨ_２のうち１つの水素を保護して上記反応を行い、反応後に脱保護してもよい。
また、化合物（ｄ）と式（ＩＩＩ）で示される化合物を、トリフェニルホスフィン、アゾジカルボン酸ジイソプロピルエステル（ＤＩＡＤ）やアゾジカルボン酸ジエチルエステル（ＤＥＡＤ）存在下で反応させ、化合物（Ｉ−Ａ）を得ることもできる。式（ＩＩＩ）で示される化合物については、その保護体（例えば、Ｂｏｃ保護体）を使用し、上記反応後に脱保護してもよい。 In addition, compound (d) is represented by formula (III):

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
Compound (IA) can also be obtained by reacting the compound represented by formula (I).
For example, mesyl chloride is reacted with compound (d) using triethylamine, pyridine or the like as a base to induce compound (d) to mesylate. As the solvent for the mesylation, chloroform, methylene chloride or the like can be used. The obtained compound is reacted with a compound represented by the formula (III) to obtain a compound (IA). As the base, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium pentoxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like can be used. As the solvent, methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazo Lidinone, ethyl acetate, propyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, a mixed solvent thereof and the like can be used. The above reaction may be carried out while protecting one hydrogen of NH _{2 in} the compound represented by the formula (III), followed by deprotection after the reaction.
Further, the compound (d) and the compound represented by the formula (III) are reacted in the presence of triphenylphosphine, azodicarboxylic acid diisopropyl ester (DIAD), or azodicarboxylic acid diethyl ester (DEAD) to obtain the compound (IA). You can also get About the compound shown by Formula (III), you may deprotect after the said reaction using the protector (for example, Boc protector).

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｒはアルキル、Ｐｒｏは保護基である。） Method B

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), R is alkyl, and Pro is a protecting group.)

Process H
A protecting group is introduced into the compound (b). As the protecting group, the protecting groups described in Protective Groups in Organic Synthesis (by Theodora W. Greene) and the like can be widely used. Amino protecting groups that can be removed under acidic conditions are preferred. Examples thereof include a benzyloxycarbonyl group and a tert-butyloxycarbonyl group. For example, compound (h) can be obtained by reacting ProHal (Hal is halogen, Pro is a protecting group), Pro-O-Pro (Pro is a protecting group) in the presence of a base. As the solvent, tetrahydrofuran, dimethylformamide, or the like can be used. The reaction can be carried out at room temperature. As the base, triethylamine, pyridine, dimethylaminopyridine and the like can be used.
It is to be noted that the reaction can be similarly performed even when R ⁶ is a hydrogen compound.

Process I
Compound (h) is reduced to obtain compound (i). As the reducing agent, lithium aluminum hydride or the like can be used. Tetrahydrofuran or the like can be used as the solvent. The reaction can be carried out at room temperature.

Process J
Compound (i) is azidated to give compound (j). For example, compound (i) is converted to mesylate by reacting mesyl chloride with triethylamine as a base. As a solvent for the mesylation, chloroform can be used. The obtained compound is reacted with sodium azide, and azidated in dimethylformamide or the like at room temperature or under heating to obtain compound (j).

(式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｈａｌはハロゲンである。)
で示される化合物を反応させ、化合物（ｍ）を得る。式（ＩＩ）で示される化合物として、各種のスルホニルクロライド、アシルクロライド等を用いることができる。溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、ヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等を用いることができる。反応は、室温下又は加温下で行うことができる。塩基の存在下で行うのが好ましい。塩基としては、ピリジン、トリエチルアミン、Ｎ‐メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等を使用することができる。
また、Ｘ＝Ｓ又はＳＯである式（ＩＩ）で示される化合物を用いて反応させ、化合物（ｍ）を得て、その後に酸化して、ＸがＳＯ_２である化合物に変換し、次の工程に用いても良い。酸化工程は、酸化剤を用いて行うことができる。酸化剤としては、ｍ−クロロ過安息香酸、過酢酸、過酸化水素、過トリフルオロ酢酸、過ヨウ素酸ナトリウム、次亜塩素酸ナトリウム、過マンガン酸カリウム、タングステン酸ナトリウム等が挙げられる。 Process K
Compound (j) is reduced to obtain compound (k). Compound (j) is obtained by reducing compound (j) with triphenylphosphine and water. The reaction can be carried out under warming. Tetrahydrofuran or the like can be used as the solvent. In addition to the reduction method using triphenylphosphine, it can be carried out by catalytic reduction. In the case of catalytic reduction, 10% palladium carbon or the like can be used as the catalyst. As the solvent, ethanol or the like can be used. Which reduction method is used can be appropriately selected depending on the protecting group to be used.

Process L
Compound (k) is converted to formula (II):

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Hal is halogen.)
The compound shown by these is made to react, and a compound (m) is obtained. As the compound represented by the formula (II), various sulfonyl chlorides, acyl chlorides and the like can be used. Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do. The reaction can be carried out at room temperature or under heating. It is preferably carried out in the presence of a base. As the base, pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used.
Alternatively, the compound represented by the formula (II) in which X = S or SO is reacted to obtain a compound (m), which is then oxidized to be converted into a compound in which X is SO ₂ . You may use for a process. The oxidation step can be performed using an oxidizing agent. Examples of the oxidizing agent include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, and sodium tungstate.

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される基を導入する。例えば、式：

(式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｈａｌはハロゲンである。)
で示される基を塩基存在下で反応させることにより、化合物（Ｉ−Ｂ）を得ることができる。溶媒としては、メタノール、エタノール、イソプロパノール、ジメチルホルムアミド等を用いることができる。反応は、室温下又は加温下で行うことができる。例えば、封管し、マイクロウェ−ブ反応装置を用いて行うこともできる。塩基としては、Ｎ,Ｎ-ジイソプロピルエチルアミン等を用いることができる。
式（Ｉ）で示される化合物において、置換基Ｒ^４及びＲ^５が水素以外である化合物については、適宜方法により、化合物（Ｉ−Ｂ）に置換基Ｒ^４及びＲ^５を導入する工程を経て得ることができる。 Process M
The protecting group of compound (m) is removed. The removal of the protecting group can be used by selecting various conditions depending on the protecting group. For example, a tert-butyloxycarbonyl group can be removed with an acid. The benzyloxycarbonyl group can be removed by catalytic reduction or the like.

Process N
Compound (n) is represented by the formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by the formula (I).)
A group represented by is introduced. For example, the formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Hal is halogen.)
The compound (IB) can be obtained by reacting the group represented by the above in the presence of a base. As the solvent, methanol, ethanol, isopropanol, dimethylformamide, or the like can be used. The reaction can be carried out at room temperature or under heating. For example, it can be sealed and sealed using a microwave reactor. As the base, N, N-diisopropylethylamine or the like can be used.
In the compound represented by the formula (I), the compound in which the substituents R ⁴ and R ⁵ are other than hydrogen is appropriately subjected to a step of introducing the substituents R ⁴ and R ⁵ into the compound (IB) by an appropriate method. Obtainable.

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。式中のベンゼン環は置換基を有していてもよいし、ベンゼン環の代わりに他の環であってもよい。）
工程Ｏ
化合物（ｏ）とＨ_２ＮＳＯ_２ＮＨ_２を塩基の存在下で反応させ、化合物（Ｉ−Ｃ）を得る。塩基としては、ピリジン等を用いることができる。 Method C
A compound in which R ² and R ³ are combined to form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle can also be synthesized as follows.

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I). The benzene ring in the formula may have a substituent, or another ring instead of the benzene ring. It may be.)
Process O
Compound (o) is reacted with H ₂ NSO ₂ NH ₂ in the presence of a base to obtain compound (IC). As the base, pyridine or the like can be used.

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、ＸはＳＯ^２である。） Method D

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and X is SO ^2. )

Process P
2-chloroethanol and chlorosulfonyl isocyanate are reacted, and the reaction solution is reacted with compound (f) to obtain compound (ID). In this case, it is preferable to use a base. As the base, for example, 1-methylmorpholine or the like can be used. As the solvent, acetonitrile or the like can be used.

Process Q
Compound (ID) is reacted with an amine represented by the formula: NH (R ¹ ) (R ² ) to obtain compound (IA). This step can be performed in the presence of a base and TMSOTf (trimethylsilyl triflate). Examples of the base include triethylamine, pyridine and the like.
In addition, in the compound represented by the formula (I), for the compounds in which the substituents R ⁴ and R ⁵ are other than hydrogen, the step of introducing the substituents R ⁴ and R ⁵ into the compound (IA) by an appropriate method Can be obtained through

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。） Method E

(In the formula, each symbol has the same meaning as each symbol in the compound represented by the formula (I).)

Process R
Compound (d) is oxidized to give compound (q). As the oxidizing agent, for example, 2-iodoxybenzoic acid (IBX) can be used. As the solvent, dimethyl sulfoxide or the like can be used.

Process S
Compound (r) is obtained by reacting compound (q) with a compound represented by the formula: R ³ —NH ₂ . This step can be performed in the presence of a reducing agent. As the reducing agent, sodium triacetoxyborohydride or the like can be used. As the solvent, methylene chloride or the like can be used.

Process T
Chlorosulfonyl isocyanate and t-butanol are reacted, and the reaction solution is reacted with compound (r) to obtain compound (s). In this case, it is preferable to use a base, and as the base, for example, triethylamine or the like can be used. As the solvent, methylene chloride or the like can be used.

Process U
The compound (s) may be reacted with the formula: R ¹ —OH in the presence of triphenylphosphine, azodicarboxylic acid diisopropyl ester (DIAD) or azodicarboxylic acid diethyl ester (DEAD) to obtain compound (IE). it can. Tetrahydrofuran or the like can be used as the solvent.
In addition, in the compound represented by the formula (I), for the compounds in which the substituents R ² , R ⁴ and R ⁵ are other than hydrogen, the substituents R ² , R ⁴ and It can be obtained through the step of introducing R ⁵ .

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｒはアルキルであり、Ｐｒｏは保護基である。） Method F

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), R is alkyl, and Pro is a protecting group.)

(式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義であり、Ｐｒｏは保護基である。)
で示される化合物を反応させ、化合物（ｕ）を得る。この際、縮合剤と塩基の存在下で反応させることが好ましい。縮合剤としては、ＨＡＴＵ等を用いることができる。塩基としては、トリエチルアミン等を用いることができる。溶媒としては、ジメチルホルムアミド等を用いることができる。

工程Ｘ
化合物（ｕ）を強酸性条件下で脱保護させることにより化合物（Ｉ−Ｆ）を得る。強酸としては、トリフルオロ酢酸等を用いることができる。溶媒としては、塩化メチレン等を用いることができる。
なお、式（Ｉ）で示される化合物において、Ｒ^１及びＲ^２が水素である化合物は、以降の工程Ｙを行わず、化合物（Ｉ−Ｆ）が最終目的化合物となる。また、Ｘ＝Ｓ又はＳＯである式（ＩＩ）で示される化合物を用いて反応させ、化合物（Ｉ−Ｆ）を得て、その後に酸化して、ＸがＳＯ_２である化合物に変換し、次の工程に用いても良い。酸化工程は、酸化剤を用いて行うことができる。酸化剤としては、ｍ−クロロ過安息香酸、過酢酸、過酸化水素、過トリフルオロ酢酸、過ヨウ素酸ナトリウム、次亜塩素酸ナトリウム、過マンガン酸カリウム、タングステン酸ナトリウム等が挙げられる。

工程Ｙ
化合物（Ｉ−Ｆ）と式：Ｒ^１−ＯＨを、トリフェニルホスフィン、アゾジカルボン酸ジイソプロピルエステル（ＤＩＡＤ）やアゾジカルボン酸ジエチルエステル（ＤＥＡＤ）存在下で反応させ、化合物（Ｉ−Ｇ）を得ることもできる。溶媒としては、テトラヒドロフラン等を用いることができる。
なお、式（Ｉ）で示される化合物において、置換基Ｒ^２が水素以外である化合物については、適宜方法により、化合物（Ｉ−Ｇ）に置換基Ｒ^２を導入する工程を経て得ることができる。 Process V
Compound (c) is hydrolyzed to obtain compound (t). At this time, it is preferable to use a base, and as the base, for example, sodium hydroxide or the like can be used. Tetrahydrofuran or the like can be used as the solvent.

Process W
Compound (t) is represented by formula (IV):

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Pro is a protecting group.)
The compound shown by these is made to react, and a compound (u) is obtained. At this time, it is preferable to react in the presence of a condensing agent and a base. As the condensing agent, HATU or the like can be used. As the base, triethylamine or the like can be used. As the solvent, dimethylformamide or the like can be used.

Process X
Compound (IF) is obtained by deprotecting compound (u) under strongly acidic conditions. As the strong acid, trifluoroacetic acid or the like can be used. As the solvent, methylene chloride or the like can be used.
In the compound represented by the formula (I), the compound in which R ¹ and R ² are hydrogen does not perform the subsequent step Y, and the compound (IF) becomes the final target compound. Further, X = is reacted with a compound represented by S or SO Formula (II), to give compound (I-F), it is oxidized thereafter, converted to compounds wherein X is SO _2, You may use for the next process. The oxidation step can be performed using an oxidizing agent. Examples of the oxidizing agent include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, and sodium tungstate.

Process Y
Compound (IF) is reacted with the formula: R ¹ —OH in the presence of triphenylphosphine, azodicarboxylic acid diisopropyl ester (DIAD) or azodicarboxylic acid diethyl ester (DEAD) to obtain compound (IG). You can also. Tetrahydrofuran or the like can be used as the solvent.
In the compound represented by the formula (I), the compound in which the substituent R ² is other than hydrogen can be obtained through a step of introducing the substituent R ² into the compound (IG) by an appropriate method. .

The compounds of the present invention are effective for all diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders It is particularly useful for the prevention and / or treatment of obesity and weight management in obesity. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndrome.
Furthermore, the compound of the present invention has not only an NPY Y5 receptor antagonistic action but also a usefulness as a medicine, and has any or all of the following excellent features.
a) The inhibitory action against CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak.
b) It is difficult to induce drug metabolizing enzymes.
c) Good pharmacokinetics such as high bioavailability and moderate clearance.
d) Low toxicity such as anemia-inducing action.
e) High metabolic stability.
f) High Y5 receptor selectivity.
g) High water solubility.
h) High brain transferability.
i) Does not cause reproductive toxicity (eg teratogenicity).
j) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).

  Furthermore, the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and high Y5 receptor selectivity. NPY induces a sustained vasoconstrictive action in the periphery, but this action is mainly mediated by the Y1 receptor. Since the Y5 receptor is not involved in such an action at all, the possibility of inducing side effects based on peripheral vasoconstriction is low, and a pharmaceutical composition containing the compound of the present invention as an active ingredient can be preferably used as a safe medicine. It is considered possible.

  A pharmaceutical composition comprising the compound of the present invention as an active ingredient suppresses food intake and exhibits an anti-obesity effect. Therefore, side effects such as indigestion as seen in drugs that exhibit anti-obesity effects by inhibiting digestion and absorption, and central side effects such as antidepressant effects such as serotonin transporter inhibitors that exhibit anti-obesity effects Not doing so is one of the features of the pharmaceutical composition.

  When the pharmaceutical composition of the present invention is administered, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.

  Various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.

  Examples of the excipient include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like. Examples of the binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate. Examples of the lubricant include talc, magnesium stearate or macrogol. As a suppository base, cacao butter, macrogol, methyl cellulose or the like can be used. In addition, when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.

  The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc. 100 mg / kg / day, preferably in the range of 0.1-10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

  The pharmaceutical composition of the present invention can also be used in combination with other anti-obesity agents (agents that can be used for weight management in obesity or obesity). Moreover, the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.

The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.
Moreover, the symbol used in this specification represents the following meaning.
Me: methyl Et: ethyl Bu: butyl Ph: phenyl Boc: tert-butoxycarbonyl Ph3P: triphenylphosphine DME: dimethoxyethane DMF: N, N-dimethylformamide TMSOTf: trimethylsilyl triflate DIAD: azodicarboxylic acid diisopropyl ester TFA: trifluoro DMSO acetate: Dimethyl sulfoxide IBX: 2-iodoxybenzoic acid THF: Tetrahydrofuran HATU: 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphoric acid Methaneami Ni-LC / MS: Liquid Chromatography / Mass Spectrometry

化合物１（５ｇ， ５２．０ｍｍｏｌ）をＤＭＥ（３０ｍｌ）に溶解後、室温でピペリジン（３．９１ｍｌ， ４６．８ｍｍｏｌ）を加え、１００℃で６時間攪拌した。溶媒を減圧下留去した後、得られた固体をクロロホルム−ヘキサン（１：１、５ｍＬ）で洗い、化合物２（７．０５ｇ， ９０％）を得た。

第２工程

化合物３（１ｇ， ３．７８ｍｍｏｌ）を塩化メチレン（１０ｍＬ）に溶解後、室温にて撹拌しながらトリエチルアミン（１．０５ｍＬ， ７．５７ｍｍｏｌ）、続けてメシルクロライド（０．３２４ｍＬ， ４．１６ｍｍｏｌ）を加えた。室温で５時間撹拌後、水を加え、塩化メチレンで抽出した。有機層を水洗いした後、無水硫酸マグネシウムで乾燥させ、減圧下溶媒を留去した。そのまま精製なしで次の反応に用いた。
得られたメシレート（３００ｍｇ， ０．８７６ｍｍｏｌ）と第１工程で得られた化合物２（１５８ｍｇ， １．０５１ｍｍｏｌ）と炭酸セシウム（４２８ｍｇ， １．３１４ｍｍｏｌ）をＤＭＦ（８ｍＬ）溶媒中１００℃で４時間加熱した。その後、化合物２（１５８ｍｇ， １．０５１ｍｍｏｌ）と炭酸セシウム（４２８ｍｇ， １．３１４ｍｍｏｌ）を再び加え、７５℃で５時間加熱した。溶媒を減圧下留去後、シリカゲルカラムクロマトグラフィーにより精製し、化合物Ｉｄ−１（１１５ｍｇ， ３３％）を得た。
¹H-NMR (DMSO-d₆) δ: 0.90-1.07 (m, 2H), 1.17-1.31 (m, 2H), 1.33-1.47 (m, 1H), 1.72-1.90 (m, 6H), 1.99-2.09 (m, 2H), 2.77 (t, 2H, J = 6.34 Hz), 3.05-3.19 (m, 4H), 3.40-3.53 (m, 1H), 6.90-6.98 (m, 1H), 7.06 (t, 1H, J = 5.83 Hz), 7.15-7.25 (m, 1H), 7.27-7.37 (m, 1H), 7.86 (d, 1H, J = 8.00 Hz). Example 1 First Step of Synthesis of Compound Id-1

Compound 1 (5 g, 52.0 mmol) was dissolved in DME (30 ml), piperidine (3.91 ml, 46.8 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 6 hours. After the solvent was distilled off under reduced pressure, the obtained solid was washed with chloroform-hexane (1: 1, 5 mL) to obtain Compound 2 (7.05 g, 90%).

Second step

Compound 3 (1 g, 3.78 mmol) was dissolved in methylene chloride (10 mL), and then triethylamine (1.05 mL, 7.57 mmol) was added with stirring at room temperature, followed by mesyl chloride (0.324 mL, 4.16 mmol). added. After stirring at room temperature for 5 hours, water was added and extracted with methylene chloride. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The product was used in the next reaction without purification.
The obtained mesylate (300 mg, 0.876 mmol), the compound 2 (158 mg, 1.051 mmol) obtained in the first step, and cesium carbonate (428 mg, 1.314 mmol) were mixed in DMF (8 mL) solvent at 100 ° C. for 4 hours. Heated. Thereafter, Compound 2 (158 mg, 1.051 mmol) and cesium carbonate (428 mg, 1.314 mmol) were added again, and the mixture was heated at 75 ° C. for 5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain compound Id-1 (115 mg, 33%).
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.07 (m, 2H), 1.17-1.31 (m, 2H), 1.33-1.47 (m, 1H), 1.72-1.90 (m, 6H), 1.99- 2.09 (m, 2H), 2.77 (t, 2H, J = 6.34 Hz), 3.05-3.19 (m, 4H), 3.40-3.53 (m, 1H), 6.90-6.98 (m, 1H), 7.06 (t, 1H, J = 5.83 Hz), 7.15-7.25 (m, 1H), 7.27-7.37 (m, 1H), 7.86 (d, 1H, J = 8.00 Hz).

２−クロロエタノール（０．１２３ｍＬ， １．８３５ｍｍｏｌ）のアセトニトリル （１５ｍＬ）溶液に０℃でクロロスルホニルイソシアネート（０．１５９ｍＬ， １．８３５ｍｍｏｌ）を滴下し０℃で３０分撹拌した（反応液Ａ）。化合物５（５００ ｍｇ， １．６６８ ｍｍｏｌ）をアセトニトリル（１０ｍＬ）に懸濁させ、０℃で１−メチルモルホリン（０．９７２ｍＬ， ８．８４ｍｍｏｌ）を加えた。先に調製した反応液Ａを０℃で滴下し、室温で一晩撹拌した。減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィーにより精製し、化合物Ｉｄ−２（４７７ｍｇ， ６９％）を得た。
¹H-NMR (DMSO-d₆) δ: 0.90-1.10 (m, 2H), 1.18-1.32 (m, 2H), 1.33-1.50 (m, 1H), 1.73-1.87 (m, 2H), 1.97-2.10 (m, 2H), 2.88 (s, 2H), 3.40-3.53 (m, 1H), 3.95 (t, 2H, J = 7.86 Hz), 4.39 (t, 2H, J = 7.86 Hz), 6.90-7.00 (m, 1H), 7.15-7.21 (m, 1H), 7.29-7.37 (m, 1H), 7.86 (d, 1H J = 7.60 Hz), 8.36 (s, 1H).

第２工程

化合物Ｉｄ−２（２００ｍｇ， ０．４８５ｍｍｏｌ）をジオキサン（６ｍＬ）に溶解し室温で撹拌しながらジエチルアミン（０．１００ｍＬ， ０．９７０ｍｍｏｌ）、トリエチルアミン（０．１３４ｍＬ， ０．９７０ｍｍｏｌ）、ＴＭＳＯＴｆ（０．０８８ｍＬ， ０．４８５ｍｍｏｌ）を加えて１００℃で８時間撹拌した。溶媒を減圧下留去後、シリカゲルカラムクロマトグラフィーにより精製し、化合物Ｉａ−１（１８５ｍｇ， ９６％）を得た。
¹H-NMR (DMSO-d₆) δ: 0.90-1.05 (m, 2H), 1.08 (t, 6H, J = 7.10 Hz), 1.19-1.31 (m, 2H), 1.32-1.47 (m, 1H), 1.75-1.87 (m, 2H), 1.97-2.08 (m, 2H), 2.65 (t, 2H, J = 6.34 Hz), 3.07-3.20 (m, 2H), 3.40-3.52 (m, 1H), 6.87-7.05 (m, 2H), 7.15-7.21 (m, 1H), 7.29-7.37 (m, 1H), 7.86 (d, 1H J = 7.60 Hz). Example 2 First Step of Synthesis of Compound Id-2 and Compound Ia-1

Chlorosulfonyl isocyanate (0.159 mL, 1.835 mmol) was added dropwise at 0 ° C. to a solution of 2-chloroethanol (0.123 mL, 1.835 mmol) in acetonitrile (15 mL), and the mixture was stirred at 0 ° C. for 30 minutes (reaction solution A). . Compound 5 (500 mg, 1.668 mmol) was suspended in acetonitrile (10 mL), and 1-methylmorpholine (0.972 mL, 8.84 mmol) was added at 0 ° C. The previously prepared reaction solution A was added dropwise at 0 ° C. and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound Id-2 (477 mg, 69%).
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.10 (m, 2H), 1.18-1.32 (m, 2H), 1.33-1.50 (m, 1H), 1.73-1.87 (m, 2H), 1.97- 2.10 (m, 2H), 2.88 (s, 2H), 3.40-3.53 (m, 1H), 3.95 (t, 2H, J = 7.86 Hz), 4.39 (t, 2H, J = 7.86 Hz), 6.90-7.00 (m, 1H), 7.15-7.21 (m, 1H), 7.29-7.37 (m, 1H), 7.86 (d, 1H J = 7.60 Hz), 8.36 (s, 1H).

Second step

Compound Id-2 (200 mg, 0.485 mmol) was dissolved in dioxane (6 mL) and stirred at room temperature with diethylamine (0.100 mL, 0.970 mmol), triethylamine (0.134 mL, 0.970 mmol), TMSOTf (0. 088 mL, 0.485 mmol) was added, and the mixture was stirred at 100 ° C. for 8 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain Compound Ia-1 (185 mg, 96%).
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.05 (m, 2H), 1.08 (t, 6H, J = 7.10 Hz), 1.19-1.31 (m, 2H), 1.32-1.47 (m, 1H) , 1.75-1.87 (m, 2H), 1.97-2.08 (m, 2H), 2.65 (t, 2H, J = 6.34 Hz), 3.07-3.20 (m, 2H), 3.40-3.52 (m, 1H), 6.87 -7.05 (m, 2H), 7.15-7.21 (m, 1H), 7.29-7.37 (m, 1H), 7.86 (d, 1H J = 7.60 Hz).

化合物８（３．０７ｍＬ， ３５．３ｍｍｏｌ）をトルエン（５０ｍＬ）に溶解し、０℃でｔ−ＢｕＯＨ（３．３６ｍＬ， ３５．３ｍｍｏｌ）を加え、同温で１０分間撹拌した。ピリジン（６．２７ｍＬ， ７８．０ｍｍｏｌ）を滴下し、０℃で３０分間撹拌した。４０％メチルアミン水溶液（１６．４６ｍＬ， ２１２ｍｍｏｌ）を滴下し、０℃で１．５時間撹拌した。トルエン層を分離した後、水層をｐＨ２にまで酸性にした後、クロロホルムで抽出を行なった。無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去し、化合物９（６．０２ｇ， ８１％）を得た。
¹H-NMR (DMSO-d₆) δ: 1.43 (9.5H, s), 2.49 (3H, d, J = 1.52 Hz), 7.33 (1.0H, d, J = 4.56 Hz), 10.76 (1.0H, s).

第２工程

化合物１０（３ｇ， １１．３５ｍｍｏｌ）、化合物９（３．５８ｇ， １７．０３ｍｍｏｌ）、トリフェニルホスフィン（３．５７ｇ， １３．６２ｍｍｏｌ）を塩化メチレン（４０ｍＬ）に溶解し、室温でＤＩＡＤ（２．７９ｍＬ， １３．６２ｍｍｏｌ）を滴下した。室温で１時間撹拌し、ＬＣ／ＭＳにて、原料である化合物１０の消失を確認した。

第３工程

第２工程の反応液にトリフルオロ酢酸（１５．７２ｍＬ， ２０４ｍｍｏｌ）を室温で加え、一晩撹拌した。０℃に冷却した後に２規定水酸化ナトリウム水溶液で塩基性にした後、塩化メチレンで抽出した。減圧下溶媒を半分量留去したところで結晶が析出した。これをろ取し、塩化メチレンで洗浄後、化合物Ｉｅ−１（３．６２ｇ， ９０％）を得た。
¹H-NMR (DMSO-d₆) δ: 0.90-1.10 (m, 2H), 1.12-1.28 (m, 2H), 1.36-1.50 (m, 1H), 1.77-1.87 (m, 2H), 2.01-2.12 (m, 2H), 2.45 (d, 3H, J = 5.07 Hz), 2.61-2.70 (m, 2H), 3.55-3.68 (m, 1H), 6.60-6.67 (m, 1H), 6.79-6.86 (m, 1H), 6.98-7.07 (m, 1H), 7.30-7.49 (m, 1H), 7.54-7.60 (m, 1H), 7.91 (d, 1H, J = 7.60 Hz). Example 3 First Step of Synthesis of Compound Ie-1

Compound 8 (3.07 mL, 35.3 mmol) was dissolved in toluene (50 mL), t-BuOH (3.36 mL, 35.3 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 10 min. Pyridine (6.27 mL, 78.0 mmol) was added dropwise and stirred at 0 ° C. for 30 minutes. A 40% methylamine aqueous solution (16.46 mL, 212 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 1.5 hours. After separating the toluene layer, the aqueous layer was acidified to pH 2 and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 9 (6.02 g, 81%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.43 (9.5H, s), 2.49 (3H, d, J = 1.52 Hz), 7.33 (1.0H, d, J = 4.56 Hz), 10.76 (1.0H, s).

Second step

Compound 10 (3 g, 11.35 mmol), compound 9 (3.58 g, 17.03 mmol) and triphenylphosphine (3.57 g, 13.62 mmol) were dissolved in methylene chloride (40 mL), and DIAD (2. 79 mL, 13.62 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour, and disappearance of compound 10 as a raw material was confirmed by LC / MS.

Third step

To the reaction solution of the second step, trifluoroacetic acid (15.72 mL, 204 mmol) was added at room temperature and stirred overnight. After cooling to 0 ° C., the solution was basified with 2N aqueous sodium hydroxide solution and extracted with methylene chloride. When half of the solvent was distilled off under reduced pressure, crystals were precipitated. This was collected by filtration and washed with methylene chloride to obtain Compound Ie-1 (3.62 g, 90%).
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.10 (m, 2H), 1.12-1.28 (m, 2H), 1.36-1.50 (m, 1H), 1.77-1.87 (m, 2H), 2.01- 2.12 (m, 2H), 2.45 (d, 3H, J = 5.07 Hz), 2.61-2.70 (m, 2H), 3.55-3.68 (m, 1H), 6.60-6.67 (m, 1H), 6.79-6.86 ( m, 1H), 6.98-7.07 (m, 1H), 7.30-7.49 (m, 1H), 7.54-7.60 (m, 1H), 7.91 (d, 1H, J = 7.60 Hz).

ＩＢＸ（５．００ｇ， １６．７７ｍｍｏｌ）をジメチルスルホキシド（１０ｍＬ） に溶解し、化合物３（３．００ｇ， １１．３５ｍｍｏｌ）のジメチルスルホキシド（９．０ｍＬ）溶液を加え、室温で２４時間攪拌した。反応液中の不溶物をセライトでろ過して取り除き、水へあけ、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた粗生成物をカラムクロマトグラフィ−（クロロホルム／メタノール）にて精製後、得られた固体をクロロホルム／ヘキサンにて再結晶化し、化合物１３（２．７６ｇ， ６３％）を得た。
¹H-NMR (CDCl₃) δ: 1.21-1.43 (m, 4H), 1.94-2.02 (m, 2H), 2.05-2.14 (m, 2H), 2.22-2.34 (m, 1H), 3.39-3.53 (m, 1H), 6.91-7.00 (m, 1H), 7.18-7.23 (m, 1H), 7.32-7.7.36 (m, 1H), 7.94 (d, 1H, J = 7.8 Hz), 9.59 (s, 1H)

第２工程

化合物１３（１５０ｍｇ， ０．５７２ｍｍｏｌ）を塩化メチレン（５．０ｍＬ）に溶解させた。そこへ、シクロヘキシルアミン（０．０７２ｍｌ， ０．６２９ｍｍｏｌ）を加えて室温で４０分間攪拌させた後、水素化トリアセトキシホウ素ナトリウム（１８２ｍｇ， ０．８５８ｍｍｏｌ）を加え、そのまま２０時間攪拌した。ＬＣ／ＭＳで化合物１３が消失したのを確認し、反応液に飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、化合物１４（１５７ｍｇ， ７９％）を得た。 Example 4 First Step of Synthesis of Compound Ie-2

IBX (5.00 g, 16.77 mmol) was dissolved in dimethyl sulfoxide (10 mL), a solution of compound 3 (3.00 g, 11.35 mmol) in dimethyl sulfoxide (9.0 mL) was added, and the mixture was stirred at room temperature for 24 hours. Insolubles in the reaction solution were removed by filtration through celite, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (chloroform / methanol), and then the obtained solid was recrystallized from chloroform / hexane to obtain Compound 13 (2.76 g, 63%).
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.43 (m, 4H), 1.94-2.02 (m, 2H), 2.05-2.14 (m, 2H), 2.22-2.34 (m, 1H), 3.39-3.53 ( m, 1H), 6.91-7.00 (m, 1H), 7.18-7.23 (m, 1H), 7.32-7.7.36 (m, 1H), 7.94 (d, 1H, J = 7.8 Hz), 9.59 (s, 1H)

Second step

Compound 13 (150 mg, 0.572 mmol) was dissolved in methylene chloride (5.0 mL). Thereto, cyclohexylamine (0.072 ml, 0.629 mmol) was added and stirred at room temperature for 40 minutes, then sodium triacetoxyborohydride (182 mg, 0.858 mmol) was added, and the mixture was stirred as it was for 20 hours. After confirming disappearance of Compound 13 by LC / MS, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 14 (157 mg, 79%).

氷冷下、塩化メチレン（３．０ｍＬ）にクロロスルホニルイソシアネート（０．０４４ｍｌ， ０．５０９ｍｍｏｌ）を加え、そこへｔ−ＢｕＯＨ（０．０４８ｍｌ， ０．５００ｍｍｏｌ）を滴下し、そのまま４０分間攪拌させた。そこへ、塩化メチレン（３．０ｍＬ）に化合物１４（１５７ｍｇ， ０．４５４ｍｍｏｌ）とトリエチルアミン（０．１２６ｍｌ， ０．９０９ｍｍｏｌ）を溶解させた反応液を滴下し、室温に上げて２時間攪拌した。ＬＣ／ＭＳで化合物１４が消失したのを確認し、反応液に飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた固体をクロロホルム／ヘキサンにて再結晶化し、化合物１５（１９７ｍｇ， ７４％）を得た。

第４工程

化合物１５（１００ｍｇ， ０．１９１ｍｍｏｌ）をテトラヒドロフラン（３ｍｌ）に溶解させ、そこへ室温下にてメタノール（０．０７７ｍＬ， １．９０６ｍｍｏｌ）とＰＰｈ_３−ｐｏｌｙｍｅｒ（１５０ｍｇ， ０．５７２ｍｍｏｌ）を加え、最後にＤＩＡＤ（０．０７８ｍＬ， ０．３８１ｍｍｏｌ）を滴下し、１７時間攪拌した。ＬＣ／ＭＳで化合物１５が消失したのを確認し、反応液中の不溶物をセライトでろ過して取り除き、溶媒を減圧下留去した。得られた粗生成物を、塩化メチレン（２．０ｍＬ）に溶解させ、トリフルオロ酢酸（０．２５０ｍｌ， ３．２４ｍｍｏｌ）を滴下し、室温で１９時間攪拌した。ＬＣ／ＭＳで反応が終了したのを確認し、反応液に２Ｎ水酸化ナトリウム水溶液（２．０ｍＬ）を加え、室温で１時間攪拌し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた粗生成物をカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、化合物Ｉｅ−２（６３ｍｇ， ７５％）を得た。
¹H-NMR (CDCl₃) δ:1.01-1.18 (m, 4H), 1.34-1..51 (m, 4H), 1.62-2.00 (m. 9H), 2.22-2.32 (m, 2H), 2.69 (d, 3H, J = 5.4 Hz), 3.04 (d, 2H, J = 7.7Hz), 3.40-3.52 (m, 1H), 3.61-3.72 (m, 1H), 3.94-4.00 (m, 1H), 4.66 (d, 1H, J = 8.0 Hz), 6.86-6.94 (m, 1H), 6.98-6.02 (dd, 1H, J = 2.4 Hz, 8.1 Hz), 7.23-7.28 (m, 1H) Third step

Under ice-cooling, chlorosulfonyl isocyanate (0.044 ml, 0.509 mmol) was added to methylene chloride (3.0 mL), t-BuOH (0.048 ml, 0.500 mmol) was added dropwise thereto, and the mixture was allowed to stir for 40 minutes. It was. Thereto was added dropwise a reaction solution in which compound 14 (157 mg, 0.454 mmol) and triethylamine (0.126 ml, 0.909 mmol) were dissolved in methylene chloride (3.0 mL), and the mixture was warmed to room temperature and stirred for 2 hours. After confirming disappearance of Compound 14 by LC / MS, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from chloroform / hexane to obtain Compound 15 (197 mg, 74%).

Fourth step

Compound 15 (100 mg, 0.191 mmol) was dissolved in tetrahydrofuran (3 ml), methanol (0.077 mL, 1.906 mmol) and PPh ₃ -polymer (150 mg, 0.572 mmol) were added thereto at room temperature, and finally DIAD (0.078 mL, 0.381 mmol) was added dropwise thereto, and the mixture was stirred for 17 hours. After confirming disappearance of Compound 15 by LC / MS, insoluble matters in the reaction solution were removed by filtration through Celite, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in methylene chloride (2.0 mL), trifluoroacetic acid (0.250 ml, 3.24 mmol) was added dropwise, and the mixture was stirred at room temperature for 19 hours. After confirming the completion of the reaction by LC / MS, 2N aqueous sodium hydroxide solution (2.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (chloroform / methanol) to obtain Compound Ie-2 (63 mg, 75%).
¹ H-NMR (CDCl ₃ ) δ: 1.01-1.18 (m, 4H), 1.34-1..51 (m, 4H), 1.62-2.00 (m. 9H), 2.22-2.32 (m, 2H), 2.69 (d, 3H, J = 5.4 Hz), 3.04 (d, 2H, J = 7.7 Hz), 3.40-3.52 (m, 1H), 3.61-3.72 (m, 1H), 3.94-4.00 (m, 1H), 4.66 (d, 1H, J = 8.0 Hz), 6.86-6.94 (m, 1H), 6.98-6.02 (dd, 1H, J = 2.4 Hz, 8.1 Hz), 7.23-7.28 (m, 1H)

化合物１７（１０．２ｇ， ３３．４ｍｍｏｌ）をテトラヒドロフラン（１００ｍｌ）中で攪拌し、２Ｎ水酸化ナトリウム水溶液を加えて３時間加熱還流した。反応液に２Ｎ塩酸水溶液を加え、ｐＨを３．５とした。析出した結晶をろ取し、減圧乾燥することで化合物１８（７１９０ｍｇ， 収率７７％）を得た。

第２工程

化合物１８（５００ｍｇ， １．７９７ｍｍｏｌ）をジメチルホルムアミド（３ｍｌ）に溶解し、ＨＡＴＵ（８２０ｍｇ， ２．１５６ｍｍｏｌ）とトリエチルアミン（０．５４８ｍｌ， ３．９５ｍｍｏｌ）を加え、室温で１分間攪拌した。反応液に化合物９（４５３ｍｇ， ２．１５６ｍｍｏｌ）を加え、室温で一晩攪拌した。トリエチルアミン（０．５４８ｍｌ， ３．９５ｍｍｏｌ）を追加し、さらに室温で３時間攪拌した後、１０％クエン酸水溶液で酸性にし、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、酢酸エチルとジイソプロピルエーテルで結晶化した。析出した結晶をろ取し、乾燥させることで化合物１９（５２４ｍｇ， 収率６２％）を得た。 Example 5 First Step of Synthesis of Compounds Ij-1 and Ie-3

Compound 17 (10.2 g, 33.4 mmol) was stirred in tetrahydrofuran (100 ml), 2N aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 3 hours. A 2N aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 3.5. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain Compound 18 (7190 mg, yield 77%).

Second step

Compound 18 (500 mg, 1.797 mmol) was dissolved in dimethylformamide (3 ml), HATU (820 mg, 2.156 mmol) and triethylamine (0.548 ml, 3.95 mmol) were added, and the mixture was stirred at room temperature for 1 minute. Compound 9 (453 mg, 2.156 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Triethylamine (0.548 ml, 3.95 mmol) was added, and the mixture was further stirred at room temperature for 3 hours, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and crystallized with ethyl acetate and diisopropyl ether. The precipitated crystals were collected by filtration and dried to obtain Compound 19 (524 mg, yield 62%).

化合物１９（２００ｍｇ， ０．４２５ｍｍｏｌ）を塩化メチレン（３ｍｌ）に溶解し、ＴＦＡ（１０００μｌ， １２．９８ｍｍｏｌ）を加え、０℃で３時間攪拌した。冷凍室で一晩保存した後、飽和炭酸水素ナトリウム水溶液でｐＨを８．６に調製した。水層を酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製した後、酢酸エチルとジイソプロピルエーテルで結晶化した。析出した結晶をろ取し、乾燥させることで化合物Ｉｊ−１（７０ｍｇ， 収率４５％）を得た。
¹H-NMR (DMSO-d₆) δ: 1.34-1.49 (m, 4H), 1.86-1.90 (m, 2H), 2.05-2.09 (m, 2H), 3.12-3.16 (m, 4H), 3.49-3.51 (m, 1H), 6.92-6.97 (m, 1H), 7.19-7.22 (m, 1H), 7.32-7.34 (m, 1H), 7.82 (s, 2H), 7.94 (d, J = 7.6 Hz, 1H).

第４工程

化合物Ｉｊ−１（５６ｍｇ， ０．１５１ｍｍｏｌ）をテトラヒドロフラン（３ｍｌ）に溶解し、トリフェニルホスフィン（４７．６ｍｇ， ０．１８１ｍｍｏｌ）とメタノール （０．０６１ｍｌ， １．５１２ｍｍｏｌ）を加えた後、０℃でＤＩＡＤ（０．０３７ｍｌ， ０．１８１ｍｍｏｌ）を滴下し、室温で２時間攪拌した。水を加え、水層を酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製した後、酢酸エチルとジイソプロピルエーテルで結晶化した。析出した結晶をろ取し、乾燥させることで化合物Ｉｅ−３（１５ｍｇ， 収率２６％）を得た。
¹H-NMR (DMSO-d₆) δ: 1.39-1.45 (m, 4H), 1.87-1.89 (m, 2H), 2.06-2.10 (m, 2H), 2.52 (s, 3H), 3.03-3.04 (m, 1H), 3.18 (s, 3H), 3.49-3.51 (m, 1H), 6.94-6.96 (m, 1H), 7.19-7.22 (m, 1H), 7.34 (dd, J = 8.6, 4.3 Hz, 1H), 7.93-7.95 (m, 2H). Third step

Compound 19 (200 mg, 0.425 mmol) was dissolved in methylene chloride (3 ml), TFA (1000 μl, 12.98 mmol) was added, and the mixture was stirred at 0 ° C. for 3 hours. After storing overnight in the freezer, the pH was adjusted to 8.6 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and then crystallized with ethyl acetate and diisopropyl ether. The precipitated crystals were collected by filtration and dried to obtain Compound Ij-1 (70 mg, yield 45%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.34-1.49 (m, 4H), 1.86-1.90 (m, 2H), 2.05-2.09 (m, 2H), 3.12-3.16 (m, 4H), 3.49- 3.51 (m, 1H), 6.92-6.97 (m, 1H), 7.19-7.22 (m, 1H), 7.32-7.34 (m, 1H), 7.82 (s, 2H), 7.94 (d, J = 7.6 Hz, 1H).

Fourth step

Compound Ij-1 (56 mg, 0.151 mmol) was dissolved in tetrahydrofuran (3 ml), triphenylphosphine (47.6 mg, 0.181 mmol) and methanol (0.061 ml, 1.512 mmol) were added, and then 0 ° C. DIAD (0.037 ml, 0.181 mmol) was added dropwise and stirred at room temperature for 2 hours. Water was added, and the aqueous layer was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and then crystallized with ethyl acetate and diisopropyl ether. The precipitated crystals were collected by filtration and dried to obtain Compound Ie-3 (15 mg, yield 26%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.39-1.45 (m, 4H), 1.87-1.89 (m, 2H), 2.06-2.10 (m, 2H), 2.52 (s, 3H), 3.03-3.04 ( m, 1H), 3.18 (s, 3H), 3.49-3.51 (m, 1H), 6.94-6.96 (m, 1H), 7.19-7.22 (m, 1H), 7.34 (dd, J = 8.6, 4.3 Hz, 1H), 7.93-7.95 (m, 2H).

Thereafter, the compound represented by the formula (I) can be synthesized in the same manner.

Ia-2
¹ H-NMR (DMSO-d ₆ ) δ: 0.98-1.03 (m, 2H), 1.21-1.27 (m, 2H), 1.38-1.39 (m, 1H), 1.80-1.83 (m, 2H), 2.01- 2.05 (m, 2H), 2.65 (s, 6H), 2.76 (t, J = 6.3 Hz, 2H), 3.44-3.46 (m, 1H), 6.92-6.97 (m, 1H), 7.12-7.20 (m, 2H), 7.33 (dd, J = 8.6, 2.5 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H).

Ia-3
¹ H-NMR (DMSO-d ₆ ) δ: 0.94-1.04 (m, 2H), 1.08 (s, 3H), 1.10 (s, 3H), 1.20-1.30 (m, 2H), 1.36-1.41 (m, 1H), 1.76-1.87 (m, 2H), 1.97-2.07 (m, 2H), 2.56 (s, 3H), 2.64 (t, 2H, J = 6.34 Hz), 3.44-3.48 (m, 1H), 3.88 -3.95 (m, 1H), 6.91-6.97 (m, 1H), 6.99-7.07 (m, 1H), 7.15-7.22 (m, 1H), 7.29-7.37 (m, 1H), 7.86 (d, 1H J = 7.60 Hz).

Ia-4
¹ H-NMR (DMSO-d ₆ ) δ: 0.91-1.08 (m, 2H), 1.18-1.32 (m, 2H), 1.38-1.43 (m, 1H), 1.73-1.87 (m, 2H), 1.98- 2.08 (m, 2H), 2.70-2.77 (m, 2H), 2.78 (s, 3H), 3.40-3.55 (m, 1H), 4.27 (s, 2H), 6.88-7.00 (m, 1H), 7.15- 7.23 (m, 1H), 7.29-7.39 (m, 1H), 7.55-7.67 (m, 1H), 7.87 (d, 1H J = 7.60 Hz).

Ia-5
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.06 (m, 2H), 1.08 (t, 3H, J = 7.10 Hz), 1.17-1.31 (m, 2H), 1.32-1.46 (m, 1H) , 1.75-1.87 (m, 2H), 1.99-2.07 (m, 2H), 2.66 (s, 3H), 2.67-2.83 (m, 2H), 3.04-3.12 (m, 2H), 3.40-3.52 (m, 1H), 6.90-7.00 (m, 1H), 7.02-7.10 (m, 1H), 7.15-7.22 (m, 1H), 7.29-7.36 (m, 1H), 7.86 (d, 1H J = 7.60 Hz).

Ia-6
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.08 (m, 2H), 1.18-1.32 (m, 2H), 1.32-1.47 (m, 1H), 1.74-1.89 (m, 2H), 1.98- 2.09 (m, 2H), 2.65-2.72 (m, 2H), 2.73 (s, 3H), 3.15-3.21 (m, 2H), 3.26 (s, 3H), 3.40-3.53 (m, 3H), 6.89- 7.00 (m, 1H), 7.03-7.12 (m, 1H), 7.14-7.22 (m, 1H), 7.28-7.38 (m, 1H), 7.86 (d, 1H, J = 8.11 Hz).

Ia-7
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.07 (m, 2H), 1.07-1.18 (m, 9H), 1.19-1.31 (m, 2H), 1.32-1.48 (m, 1H), 1.76- 1.86 (m, 2H), 1.98-2.08 (m, 2H), 2.60-2.69 (m, 2H), 3.03-3.18 (m, 2H), 3.40-3.52 (m, 1H), 3.77-3.88 (m, 1H ), 6.88-7.00 (m, 2H), 7.15-7.22 (m, 1H), 7.29-7.36 (m, 1H), 7.86 (d, 1H J = 7.60 Hz).

Ia-8
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.08 (m, 2H), 1.18-1.31 (m, 2H), 1.32-1.48 (m, 1H), 1.76-1.87 (m, 2H), 1.97- 2.07 (m, 2H), 2.74 (s, 3H), 2.75-2.82 (m, 4H), 3.40-3.52 (m, 1H), 6.90-7.00 (m, 1H), 7.15-7.23 (m, 1H), 7.25-7.37 (m, 2H), 7.86 (d, 1H, J = 7.60 Hz).

Ia-9
¹ H-NMR (DMSO-d ₆ ) δ: 0.92-1.10 (m, 2H), 1.20-1.33 (m, 2H), 1.34-1.49 (m, 1H), 1.77-1.87 (m, 2H), 2.00- 2.10 (m, 2H), 2.68-2.77 (m, 2H), 2.85 (s, 3H), 3.41-3.54 (m, 1H), 3.90-4.01 (m, 2H), 6.90-6.98 (m, 1H), 7.17-7.23 (m, 1H), 7.30-7.37 (m, 1H), 7.45-7.52 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz).

Ia-10
¹ H-NMR (DMSO-d ₆ ) δ: 0.91-1.09 (m, 2H), 1.19-1.32 (m, 2H), 1.34-1.48 (m, 1H), 1.75-1.88 (m, 2H), 1.97- 2.09 (m, 2H), 2.65-2.73 (m, 2H), 2.74 (s, 3H), 3.05-3.14 (m, 2H), 3.40-3.50 (m, 1H), 3.51-3.59 (m, 2H), 4.69-4.75 (m, 1H), 6.88-6.99 (m, 1H), 7.00-7.08 (m, 1H), 7.15-7.23 (m, 1H), 7.28-7.36 (m, 1H), 7.86 (d, 1H , J = 7.60 Hz).

Ia-11
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.05 (m, 2H), 1.19-1.31 (m, 2H), 1.32-1.47 (m, 1H), 1.75-1.88 (m, 2H), 1.99- 2.10 (m, 2H), 2.64 (s, 3H), 2.66 (s, 3H), 2.71-2.80 (m, 2H), 3.41-3.55 (m, 1H), 6.91-6.98 (m, 1H), 7.05- 7.11 (m, 1H), 7.12-7.18 (m, 1H), 7.22 (d, 1H, J = 7.60 Hz), 7.31 (d, 1H, J = 8.11 Hz), 7.81 (d, 1H, J = 7.60 Hz ).

Ia-12
¹ H-NMR (DMSO-d ₆ ) δ: 0.92-1.06 (m, 2H), 1.19-1.32 (m, 2H), 1.33-1.48 (m, 1H), 1.78-1.87 (m, 2H), 1.99- 2.07 (m, 2H), 2.64 (s, 3H), 2.66 (s, 3H), 2.72-2.80 (m, 2H), 3.42-3.55 (m, 1H), 7.12-7.17 (m, 2H), 7.19- 7.22 (m, 1H), 7.49-7.50 (m, 1H), 8.01 (d, 1H, J = 7.60 Hz).

Ia-13
¹ H-NMR (DMSO-d ₆ ) δ: 0.97-1.11 (m, 2H), 1.16-1.30 (m, 2H), 1.35-1.47 (m, 1H), 1.78-1.88 (m, 2H), 2.03- 2.12 (m, 2H), 2.66 (s, 6H), 2.74-2.80 (m, 2H), 3.58-3.70 (m, 1H), 7.03-7.10 (m, 1H), 7.12-7.18 (m, 1H), 7.24-7.28 (m, 1H), 7.40 (d, 1H, J = 7.60 Hz), 7.70 (d, 1H, J = 7.60 Hz).

Ia-14
H-NMR (DMSO-d ₆ ) δ: 1.33-1.50 (m, 4H), 1.87-1.90 (m, 2H), 2.08-2.11 (m, 2H), 2.82 (s, 6H), 2.87-2.93 (m , 1H), 3.23 (s, 3H), 3.49-3.53 (m, 1H), 6.92-6.98 (m, 1H), 7.20-7.22 (m, 1H), 7.34 (dd, J = 8.6, 2.5 Hz, 1H ), 7.93 (d, J = 7.6 Hz, 1H).

Ib-1
¹H-NMR (DMSO-d₆) δ: 0.58-0.68 (m, 4H), 0.90-1.08 (m, 2H), 1.21-1.29 (m, 2H), 1.31-1.46 (m, 1H), 1.78-1.88 (m, 2H), 1.98-2.10 (m, 2H), 2.26-2.29 (m, 1H), 2.68 (s, 3H), 2.72-2.80 (m, 2H), 3.44-3.48 (m, 1H), 6.91-6.97 (m, 1H), 7.15-7.27 (m, 2H), 7.30-7.36 (m, 1H), 7.86 (d, 1H J = 7.60 Hz).

Ib-1
¹ H-NMR (DMSO-d ₆ ) δ: 0.58-0.68 (m, 4H), 0.90-1.08 (m, 2H), 1.21-1.29 (m, 2H), 1.31-1.46 (m, 1H), 1.78- 1.88 (m, 2H), 1.98-2.10 (m, 2H), 2.26-2.29 (m, 1H), 2.68 (s, 3H), 2.72-2.80 (m, 2H), 3.44-3.48 (m, 1H), 6.91-6.97 (m, 1H), 7.15-7.27 (m, 2H), 7.30-7.36 (m, 1H), 7.86 (d, 1H J = 7.60 Hz).

Ic-1
¹H-NMR (DMSO-d₆) δ: 0.90-1.10 (m, 2H), 1.17-1.31 (m, 2H), 1.32-1.48 (m, 1H), 1.75-1.88 (m, 2H), 1.97-2.08 (m, 2H), 2.83 (s, 3H), 2.90-2.98 (m, 2H), 3.40-3.53 (m, 1H), 3.62 (s, 3H), 6.90-7.00 (m, 1H), 7.15-7.25 (m, 1H), 7.30-7.39 (m, 1H), 7.72-7.82 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz).

Ic-1
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.10 (m, 2H), 1.17-1.31 (m, 2H), 1.32-1.48 (m, 1H), 1.75-1.88 (m, 2H), 1.97- 2.08 (m, 2H), 2.83 (s, 3H), 2.90-2.98 (m, 2H), 3.40-3.53 (m, 1H), 3.62 (s, 3H), 6.90-7.00 (m, 1H), 7.15- 7.25 (m, 1H), 7.30-7.39 (m, 1H), 7.72-7.82 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz).

Id-3
¹ H-NMR (DMSO-d ₆ ) δ: 0.99-1.03 (m, 2H), 1.23-1.27 (m, 2H), 1.35-1.45 (m, 1H), 1.76-1.86 (m, 2H), 1.99- 2.08 (m, 2H), 2.78 (t, 2H, J = 6.34 Hz), 2.88-3.10 (m, 4H), 3.40-3.52 (m, 1H), 3.57-3.66 (m, 4H), 6.92-6.97 ( m, 1H), 7.15-7.21 (m, 1H), 7.24-7.34 (m, 2H), 7.86 (d, 1H, J = 7.60 Hz).

Id-4
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.03 (m, 2H), 1.18-1.31 (m, 2H), 1.33-1.58 (m, 7H), 1.77-1.87 (m, 2H), 1.99- 2.10 (m, 2H), 2.74 (t, 2H, J = 6.34 Hz), 2.99-3.10 (m, 4H), 3.40-3.54 (m, 1H), 6.90-6.97 (m, 1H), 7.09-7.14 ( m, 1H), 7.17-7.22 (m, 1H), 7.30-7.35 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz).

Id-5
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.11 (m, 2H), 1.18-1.32 (m, 2H), 1.33-1.48 (m, 1H), 1.75-1.87 (m, 2H), 1.99- 2.11 (m, 2H), 2.37-2.50 (m, 2H), 2.77-2.89 (m, 2H), 3.35-3.40 (m, 2H), 3.40-3.51 (m, 1H), 3.53 (t, 2H, J = 13.18 Hz), 6.90-6.99 (m, 1H), 7.15-7.22 (m, 1H), 7.27-7.37 (m, 1H), 7.43 (s, 1H), 7.87 (d, 1H, J = 8.00 Hz) .

Id-6
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.06 (m, 2H), 1.09 (s, 3H), 1.11 (s, 3H), 1.19-1.32 (m, 2H), 1.33-1.48 (m, 1H), 1.73-1.87 (m, 2H), 1.98-2.10 (m, 2H), 2.29 (t, 2H, J = 12.00 Hz), 2.40-2.51 (m, 2H), 2.72-2.83 (m, 2H) , 3.40-3.51 (m, 1H), 3.53-3.63 (m, 2H), 6.90-6.99 (m, 1H), 7.15-7.22 (m, 1H), 7.30-7.39 (m, 2H), 7.86 (d, 1H, J = 7.60 Hz).

Ie-4
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.08 (m, 2H), 1.19-1.32 (m, 2H), 1.35-1.49 (m, 1H), 1.78-1.90 (m, 2H), 1.98- 2.08 (m, 2H), 2.44 (d, 3H, J = 5.07 Hz), 2.60-2.73 (m, 2H), 3.40-3.53 (m, 1H), 6.58-6.68 (m, 1H), 6.78-6.85 ( m, 1H), 6.90-6.99 (m, 1H), 7.15-7.22 (m, 1H), 7.29-7.37 (m, 1H), 7.87 (d, 1H, J = 8.11 Hz).

Ie-5
¹ H-NMR (DMSO-d ₆ ) δ: 0.91-1.03 (m, 2H), 1.07 (t, 3H, J = 7.10 Hz), 1.19-1.32 (m, 2H), 1.35-1.50 (m, 1H) , 1.75-1.90 (m, 2H), 1.97-2.10 (m, 2H), 2.60-2.73 (m, 2H), 2.79-2.90 (m, 2H), 3.40-3.53 (m, 1H), 6.66-6.73 ( m, 1H), 6.74-6.81 (m, 1H), 6.90-7.00 (m, 1H), 7.14-7.23 (m, 1H), 7.29-7.38 (m, 1H), 7.86 (d, 1H, J = 7.60 Hz).

Ie-6
¹ H-NMR (DMSO-d ₆ ) δ: 0.91-1.10 (m, 2H), 1.18-1.32 (m, 2H), 1.35-1.50 (m, 1H), 1.75-1.88 (m, 2H), 1.98- 2.10 (m, 2H), 2.63-2.75 (m, 2H), 3.40-3.52 (m, 1H), 3.53-3.60 (m, 2H), 6.89-7.00 (m, 1H), 7.05-7.14 (m, 1H ), 7.15-7.23 (m, 1H), 7.28-7.37 (m, 1H), 7.87 (d, 1H, J = 8.11 Hz).

Ie-7
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.05 (m, 2H), 1.09 (s, 3H,), 1.11 (s, 3H), 0.90-1.05 (m, 2H), 1.35-1.50 (m , 1H), 1.75-1.90 (m, 2H), 1.98-2.10 (m, 2H), 2.60-2.74 (m, 2H), 3.21-3.32 (m, 1H), 3.40-3.52 (m, 1H), 6.61 -6.79 (m, 2H), 6.90-6.99 (m, 1H), 7.15-7.23 (m, 1H), 7.28-7.37 (m, 1H), 7.87 (d, 1H, J = 8.11 Hz).

Ie-8
¹ H-NMR (DMSO-d ₆ ) δ: 0.77-0.90 (m, 6H), 0.90-1.10 (m, 2H), 1.19-1.32 (m, 2H), 1.33-1.53 (m, 5H), 1.77- 1.88 (m, 2H), 1.98-2.09 (m, 2H), 2.63-2.73 (m, 2H), 2.90-3.00 (m, 1H), 3.40-3.52 (m, 1H), 6.52-6.63 (m, 1H ), 6.64-6.73 (m, 1H), 6.90-7.01 (m, 1H), 7.15-7.23 (m, 1H), 7.28-7.37 (m, 1H), 7.86 (d, 1H, J = 7.60 Hz).

Ie-9
¹ H-NMR (DMSO-d ₆ ) δ: 0.80-0.90 (m, 3H), 0.90-1.06 (m, 2H), 1.17-1.31 (m, 2H), 1.32-1.52 (m, 3H), 1.77- 1.88 (m, 2H), 1.96-2.09 (m, 2H), 2.60-2.70 (m, 2H), 2.71-2.80 (m, 2H), 3.40-3.52 (m, 1H), 6.69-6.82 (m, 2H ), 6.90-6.99 (m, 1H), 7.15-7.25 (m, 1H), 7.30-7.38 (m, 1H), 7.86 (d, 1H, J = 7.60 Hz).

Ie-10
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.08 (m, 2H), 1.19-1.31 (m, 2H), 1.32-1.50 (m, 1H), 1.77-1.90 (m, 2H), 1.98- 2.10 (m, 2H), 2.44 (d, 3H, J = 4.00 Hz), 2.60-2.71 (m, 2H), 3.40-3.56 (m, 1H), 6.59-6.69 (m, 1H), 6.78-6.87 ( m, 1H), 6.90-7.00 (m, 1H), 7.05-7.14 (m, 1H), 7.19-7.25 (m, 1H), 7.31 (d, 1H, J = 8.11 Hz), 7.82 (d, 1H, J = 8.11 Hz).

Ie-11
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.07 (m, 2H), 1.19-1.32 (m, 2H), 1.33-1.48 (m, 1H), 1.77-1.88 (m, 2H), 1.97- 2.08 (m, 2H), 2.44 (d, 3H, J = 5.07 Hz), 2.71-2.80 (m, 2H), 3.40-3.55 (m, 1H), 6.50-6.69 (m, 1H), 6.77-6.88 ( m, 1H), 7.10-7.19 (m, 1H), 7.19-7.24 (m, 1H), 7.49 (d, 1H, J = 1.52 Hz), 8.01 (d, 1H, J = 8.11 Hz).

Ie-12
¹ H-NMR (DMSO-d ₆ ) δ: 0.92-1.04 (m, 2H), 1.12-1.28 (m, 2H), 1.33-1.50 (m, 1H), 1.78-1.88 (m, 2H), 2.03- 2.12 (m, 2H), 2.44 (d, 3H, J = 4.56 Hz), 2.63-2.70 (m, 2H), 3.55-3.68 (m, 1H), 6.66-6.68 (m, 1H), 6.79-6.86 ( m, 1H), 6.96-7.01 (m, 1H), 7.17-7.22 (m, 1H), 7.36-7.39 (m, 1H), 7.60-7.67 (m, 1H), 7.91 (d, 1H, J = 7.60 Hz).

Ie-13
¹ H-NMR (DMSO-d ₆ ) δ: 1.89-1.05 (m, 2H), 1.16-1.38 (m, 3H), 1.68-1.79 (m, 2H), 1.98-1.27 (m, 2H), 2.53 ( d, 3H, J = 4.8 Hz), 2.85 (t, 2H, J = 6.1 Hz), 3.37-3.52 (m, 1H), 5.58-5.64 (m, 1H), 5.86-5.95 (m, 1H), 6.70 -6.98 (m, 1H), 7.16-7.21 (m, 1H), 7.31-7.36 (m, 1H), 7.86 (d, 1H, J = 4.8 Hz)

Ie-14
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.05 (m, 2H), 1.18-1.31 (m, 2H), 1.33-1.48 (m, 1H), 1.78-1.88 (m, 2H), 1.97- 2.07 (m, 2H), 2.44 (d, 3H, J = 5.07 Hz), 2.60-2.70 (m, 2H), 3.40-3.51 (m, 1H), 6.58-6.68 (m, 1H), 6.79-6.88 ( m, 1H), 7.26-7.35 (m, 1H), 7.58-7.66 (m, 1H), 8.06 (d, 1H, J = 7.60 Hz).

Ie-15
¹ H-NMR (DMSO-d ₆ ) δ: 0.91-1.21 (m, 5H), 1.74-1.83 (m, 2H), 1.93-2.02 (m, 2H), 2.53 (d, 3H, J = 4.8 Hz) , 3.42 (d, 2H, J = 7.8 Hz), 6.88-6.96 (m, 1H), 7.13-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.36-7.40 (m, 4H), 7.78 (d, 1H, J = 7.8 Hz)

Ie-16
¹ H-NMR (CDCl ₃ ) δ: 0.99-1.28 (m, 4H), 1.51-1.67 (m, 1H), 1.82-1.91 (m, 2H), 2.16-2.25 (m, 2H), 2.72 (d. 3H, J = 4.6 Hz), 3.57-3.69 (m, 3H), 4.10-4.28 (m, 1H), 4.72 (d. 1H, J = 7.5 Hz) 6.84-6.92 (m, 1H), 6.96-7.00 ( m, 1H), 7.20-7.31 (m, 3H), 7.32-7.36 (m, 1H), 7.40-7.48 (m, 2H)

Ie-17
¹ H-NMR (CDCl ₃ ) δ 1.10-1.31 (m, 4H), 1.66-1.80 (m, 1H), 1.82-1.91 (m, 2H), 2.21-2.30 (m, 2H), 2.77 (d, 3H , J = 4.8 Hz), 3.19 (d, 2H, J = 7.2 Hz), 3.50-3.61 (m, 1H), 4.22-4.28 (m, 1H), 4.48 (s, 2H), 4.66-4.71 (m, 1H), 6.85-6.92 (m, 1H), 6.97-7.01 (m, 1H), 7.18-7.38 (m, 6H)

Ie-18
¹ H-NMR (DMSO-d ₆ ) δ: 0.92-1.10 (m, 2H), 1.14-1.30 (m, 2H), 1.36-1.50 (m, 1H), 1.78-1.88 (m, 2H), 2.00- 2.11 (m, 2H), 2.44 (d, 3H, J = 5.07 Hz), 2.60-2.70 (m, 2H), 3.57-3.68 (m, 1H), 6.59-6.68 (m, 1H), 6.78-6.90 ( m, 2H), 7.13-7.20 (m, 1H), 7.60-7.68 (m, 1H), 8.10 (d, 1H, J = 7.60 Hz).

Ie-19
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.06 (m, 2H), 1.18-1.32 (m, 2H), 1.34-1.48 (m, 1H), 1.77-1.89 (m, 2H), 1.96- 2.08 (m, 2H), 2.44 (d, 3H, J = 4.56 Hz), 2.60-2.70 (m, 2H), 3.42-3.55 (m, 1H), 6.60-6.68 (m, 1H), 6.70-6.79 ( m, 1H), 6.80-6.86 (m, 1H), 7.02-7.09 (m, 1H), 7.27-7.33 (m, 1H), 8.02 (d, 1H, J = 7.60 Hz).

Ie-20
¹ H-NMR (CDCl3) δ: 1.08-1.25 (m, 4H), 1.57-1.67 (m, 1H), 1.87-1.96 (m, 2H), 2.24-2.33 (m, 2H), 2.71 (d, 3H , J = 5.4 Hz), 2.84 (m, 3H), 3.04 (d, 2H, J = 7.2 Hz), 3.61-3.78 (m, 1H), 3.98-4.07 (m, 1H), 4.66-4.71 (m, 1H), 6.85-6.92 (m, 1H), 6.98-7.01 (m, 1H), 7.23-7.28 (m, 2H)

Ie-21
¹ H-NMR (CDCl3) δ: 1.16-1.37 (m, 4H), 1.49-1.62 (m, 1H), 1.77-1.86 (m, 2H), 2.16-2.27 (m, 2H), 2.67 (d, 3H , J = 5.4 Hz), 3.06 (d, 2H, J = 7.2 Hz), 3.56-3.68 (m, 1H), 3.94-4.00 (m, 1H), 4.39 (s, 2H), 4.68-4.75 (m, 1H), 6.85-6.93 (m, 1H), 6.96-7.01 (m, 1H), 7.21-7.26 (m, 1H), 7.32-7.39 (m, 5H)

Ie-22
¹ H-NMR (CDCl3) δ: 1.14-1.30 (m, 4H), 1.60-1.75 (m, 1H), 1.91-1.98 (m, 2H), 2.20-2.28 (m, 2H), 2.66 (d, 3H , J = 5.4 Hz), 3.59-3.72 (m, 1H), 3.85 (d, 2H, J = 7.2 Hz), 4.62-4.70 (m, 1H), 5.25-5.32 (m, 1H), 6.84-6.92 ( m, 1H), 6.96-7.00 (m, 1H), 7.06-7.26 (m, 2H), 7.67-7.74 (m, 1H), 8.36-8.40 (m, 1H)

Ie-23
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.22 (m, 4H), 1.33-1.47 (m, 1H), 1.86-1.95 (m, 2H), 2.18-2.26 (m, 2H), 2.77 (d. 3H, J = 5.4 Hz), 3.57-3.69 (3H, m), 4.28-4.37 (m, 1H), 4.66-4.74 (m, 1H), 6.84-6.94 (m, 1H), 6.96-7.01 (m, 1H), 7.20-7.26 (m, 1H), 7.34-7.41 (m, 1H), 7.76-7.82 (m, 1H), 8.54-8.58 (m, 1H), 8.62-8.67 (m, 1H)

Ie-24
¹ H-NMR (CDCl3) δ: 0.77-0.80 (m, 4H), 1.14-1.18 (m, 2H), 1.50-1.64 (m, 2H), 1.90-2.02 (m, 3H), 2.13-2.23 (m , 2H), 2.44-2.52 (m, 1H), 2.67 (s, 3H), 3.16 (d, 2H, J = 6.0 Hz), 3.65-3.78 (m, 1H), 4.06-4.17 (m, 1H), 7.04-7.12 (m, 1H), 7.16-7.20 (m, 1H, 7.30-7.35 (m, 1H)

Ie-25
¹ H-NMR (CDCl3) δ: 0.99-1.19 (m, 9H), 1.34-1.45 (m, 1H), 1.87-1.95 (m, 2H), 3.45-3.56 (m, 3H), 3.47-3.71 (m , 1H), 3.89 (d, 1H, J = 7.2 Hz), 4.60 (d, 1H, J = 8.1 Hz), 6.84-6.92 (m, 1H), 6.95-7.00 (m, 1H), 7.21-7.26 ( m. 1H), 7.28-7.35 (m, 1H), 7.37-7.43 (m, 4H)

Ie-26
¹ H-NMR (CDCl3) δ: 0.91 (t, 3H, J = 7.2 Hz), 1.06-1.21 (m, 2H), 1.34-1.59 (m, 5H), 1.92-2.01 (m, 2H), 2.08- 2.18 (m, 2H), 2.96-3.06 (m, 2H), 3.56 (d, 2H, J = 7.2 Hz), 3.60-3.76 (m, 1H), 4.03-4.10 (m, 1H), 7.02-7.10 ( m, 1H), 7.14-7.18 (m, 1H), 7.26-7.47 (m, 6H)

Ie-27
¹ H-NMR (CDCl3) δ: 1.1.15-1.33 (m, 4H), 1.77-1.97 (m, 3H), 2.21-2.32 (m, 2H), 2.68 (d, 3H, J = 5.4 Hz), 3.61-3.75 (m, 2H), 3.79 (d, 2H, J = 7.2 Hz), 4.75-4.82 (m, 1H), 4.82-4.90 (m, 1H), 6.56 (d, 1H, J = 1.8 Hz) , 6.85-6.91 (m, 1H), 6.97-6.71 (m, 1H), 7.21-7.26 (m, 1H), 8.29 (d, 1H, J = 1.8 Hz)

Ie-28
¹ H-NMR (CDCl ₃ ) δ: 1.22-1.36 (m, 4H), 1.89-2.04 (m, 3H), 2.18-2.28 (m, 2H), 3.61-3.74 (m, 1H), 4.05 (d, 2H, J = 6.6 Hz), 4.73-4.84 (m, 1H), 6.09-6.18 (m, 1H), 6.84-7.02 (m, 3H), 7.21-7.27 (m, 1H), 8.53 (d, 2H, (J = 4.2 Hz)

Ie-29
¹ H-NMR (CDCl ₃ ) δ: 1.05-1.23 (m, 2H), 1.30-1.53 (m, 3H), 1.95-2.06 (m, 2H), 2.08-2.19 (m, 2H), 2.79 (d, 3H, J = 4.6 Hz), 3.55 (d, 2H, J = 7.2 Hz), 3.62-3.75 (m, 1H), 4.06-4.14 (m, 1H), 7.02-7.10 (m, 1H), 7.13-7.24 (m, 4H), 7.28-7.42 (m. 2H), 7.44-7.52 (m, 1H)

Ie-30
¹ H-NMR (CDCl3) δ: 1.10-1.26 (4H, m), 1.81-1.88 (1H, m), 2.18-2.29 (3H, m), 2.83 (3H, d, J = 5.4 Hz), 3.41- 3.51 (1H, m), 3.53-3.58 (1H, m), 3.62-3.72 (1H, m), 4.17-4.27 (1H, m), 4.64 (1H, d, J = 7.8 Hz), 6.85-6.94 ( 1H, m), 6.96-7.01 (1H, m), 7.03-7.11 (1H, m), 7.21-7.26 (1H, m), 7.38-7.45 (1H, m), 7.54-7.59 (1H, m), 7.93-7.97 (1H, m)

Ie-31
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.22 (m, 4H), 1.28-1.43 (m, 1H), 1.94-2.06 (m, 2H), 2.21-2.29 (m, 2H), 2.92 (brs, 3H), 3.36 (d, 2H, J = 6.6 Hz), 3.59-3.70 (m, 1H), 4.28-4.36 (m, 1H), 4.65 (d, 1H, J = 8.1 Hz), 6.85-6.92 (m , 1H), 6.98 (dd, 1H, J = 2.4 Hz, 7.7 Hz), 7.23 (dd, 1H, J = 4.8 Hz, 8.7 Hz), 7.45-7.7.50 (m, 1H)), 7.63-7.68 ( m, 2H), 7.72-7.76 (m, 1H)

Ie-32
¹ H-NMR (DMSO-d ₆ ) δ: 1.09 (d, J = 6.6 Hz, 6H), 1.37-1.49 (m, 4H), 1.86-1.87 (m, 2H), 2.06-2.10 (m, 2H) , 3.16 (s, 3H), 6.92-6.98 (m, 1H), 7.19-7.21 (m, 1H), 7.34 (dd, J = 8.6, 2.5 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H ), 8.11 (s, 1H).

Ie-33
¹ H-NMR (CDCl ₃ ) δ: 1.01-1.16 (m, 2H), 1.18-1.33 (8H, m), 1.67-1.82 (m, 1H), 1.89-1.20 (m, 2H), 2.21-2.31 ( m, 2H), 2.69 (d, 3H. J = 5.4 Hz), 2.97 (d, 2H, J = 7.3 Hz), 3.60-3.74 (m, 1H), 3.86-4.02 (m, 2H), 4.68 (d , 1H, J = 8.0 Hz), 6.84-6.93 (m, 1H), 6.96-7.01 (m, 1H), 7.21-7.27 (m, 1H)

Ie-34
¹ H-NMR (CDCl ₃ ) δ 1.08-1.20 (m, 2H), 1.22-1.35 (4H, m), 1.60-1.68 (m, 2H), 1.78-1.95 (m, 3H), 2.24-2.32 (m , 2H), 2.89 (d, 3H, J = 5.6 Hz), 3.25 (d, 2H, J = 7.8 Hz), 3.53-3.76 (m, 1H), 4.34-4.40 (m, 1H), 4.67 (d, 1H, J = 8.1 Hz), 6.86-6.94 (m, 1H), 6.97-7.02 (m, 1H), 7.22-7.28 (m, 1H)

Ie-35
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.35 (m, 4H), 1.79-1.96 (m, 3H), 2.23-2.32 (m, 2H), 2.70 (d, 3H, J = 8.1 Hz), 3.63 -3.74 (m, 1H), 3.77 (d, 2H, J = 6.9 Hz), 4.73 (d, 1H, J = 8.1 Hz), 5.71-5.81 (m, 1H), 6.85-6.94 (m, 1H), 6.96-7.03 (m, 2H), 7.22-7.26 (m, 1H), 7.41 (d, 1H, J = 0.91 Hz)

If-1
¹H-NMR (DMSO-d₆) δ: 0.43-0.59 (m, 4H), 0.90-1.09 (m, 2H), 1.16-1.32 (m, 2H), 1.35-1.50 (m, 1H), 1.78-1.90 (m, 2H), 1.98-2.10 (m, 2H), 2.22-2.32 (m, 1H), 2.63-2.73 (m, 2H), 3.40-3.52 (m, 1H), 6.88-6.99 (m, 2H), 7.12-7.22 (m, 2H), 7.30-7.36 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz).

If-2
¹H-NMR (DMSO-d₆) δ: 0.90-1.06 (m, 2H), 1.19-1.32 (m, 2H), 1.35-1.52 (m, 5H), 1.56-1.68 (m, 2H), 1.75-1.90 (m, 4H), 2.00-2.08 (m, 2H), 2.63-2.70 (m, 2H), 3.40-3.52 (m, 2H), 6.69-6.80 (m, 2H), 6.90-6.99 (m, 1H), 7.15-7.22 (m, 1H), 7.30-7.36 (m, 1H), 7.86 (d, 1H, J = 7.60 Hz).

If-1
¹ H-NMR (DMSO-d ₆ ) δ: 0.43-0.59 (m, 4H), 0.90-1.09 (m, 2H), 1.16-1.32 (m, 2H), 1.35-1.50 (m, 1H), 1.78- 1.90 (m, 2H), 1.98-2.10 (m, 2H), 2.22-2.32 (m, 1H), 2.63-2.73 (m, 2H), 3.40-3.52 (m, 1H), 6.88-6.99 (m, 2H ), 7.12-7.22 (m, 2H), 7.30-7.36 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz).

If-2
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.06 (m, 2H), 1.19-1.32 (m, 2H), 1.35-1.52 (m, 5H), 1.56-1.68 (m, 2H), 1.75- 1.90 (m, 4H), 2.00-2.08 (m, 2H), 2.63-2.70 (m, 2H), 3.40-3.52 (m, 2H), 6.69-6.80 (m, 2H), 6.90-6.99 (m, 1H ), 7.15-7.22 (m, 1H), 7.30-7.36 (m, 1H), 7.86 (d, 1H, J = 7.60 Hz).

Ig-1
¹H-NMR (DMSO-d₆) δ: 0.90-1.06 (m, 2H), 1.13 (s, 3H), 1.14 (s, 3H), 1.19-1.31 (m, 2H), 1.33-1.50 (m, 1H), 1.75-1.89 (m, 2H), 1.98-2.08 (m, 2H), 2.70-2.80 (m, 2H), 3.40-3.52 (m, 1H), 3.95-4.03 (m, 1H), 6.90-6.99 (m, 1H), 7.16-7.22 (m, 1H), 7.30-7.35 (m, 1H), 7.35-7.45 (m, 1H), 7.86 (d, 1H, J = 8.11 Hz), 9.36 (s, 1H).

Ig-2
¹H-NMR (DMSO-d₆) δ: 0.90-1.06 (m, 2H), 1.25-1.31 (m, 2H), 1.35-1.49 (m, 1H), 1.75-1.89 (m, 2H), 1.98-2.08 (m, 2H), 2.70-2.80 (m, 2H), 3.40-3.53 (m, 1H), 3.63 (s, 3H), 6.90-7.00 (m, 1H), 7.15-7.22 (m, 1H), 7.30-7.37 (m, 1H), 7.50-7.58 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz), 9.68 (s, 1H).

Ig-1
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.06 (m, 2H), 1.13 (s, 3H), 1.14 (s, 3H), 1.19-1.31 (m, 2H), 1.33-1.50 (m, 1H), 1.75-1.89 (m, 2H), 1.98-2.08 (m, 2H), 2.70-2.80 (m, 2H), 3.40-3.52 (m, 1H), 3.95-4.03 (m, 1H), 6.90- 6.99 (m, 1H), 7.16-7.22 (m, 1H), 7.30-7.35 (m, 1H), 7.35-7.45 (m, 1H), 7.86 (d, 1H, J = 8.11 Hz), 9.36 (s, 1H).

Ig-2
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.06 (m, 2H), 1.25-1.31 (m, 2H), 1.35-1.49 (m, 1H), 1.75-1.89 (m, 2H), 1.98- 2.08 (m, 2H), 2.70-2.80 (m, 2H), 3.40-3.53 (m, 1H), 3.63 (s, 3H), 6.90-7.00 (m, 1H), 7.15-7.22 (m, 1H), 7.30-7.37 (m, 1H), 7.50-7.58 (m, 1H), 7.87 (d, 1H, J = 7.60 Hz), 9.68 (s, 1H).

Ih-1
¹H-NMR (DMSO-d₆) δ: 0.90-1.00 (m, 2H), 1.25-1.29 (m, 2H), 1.30-1.43 (m, 1H), 1.61-1.77 (m, 2H), 1.90-2.02 (m, 2H), 2.65-2.78 (m, 2H), 3.38-3.50 (m, 1H), 6.89-7.02 (m, 2H), 7.12-7.21 (m, 3H), 7.23-7.38 (m, 3H), 7.40-7.56 (brs, 1H）, 7.83 (d, 1H, J = 7.60 Hz), 9.54 (s, 1H).

Ih-2
¹H-NMR (DMSO-d₆) δ: 0.88-1.00 (m, 2H), 1.25-1.30 (m, 2H), 1.30-1.44 (m, 1H), 1.68-1.78 (m, 2H), 1.92-2.04 (m, 2H), 2.70-2.80 (m, 2H), 3.38-3.50 (m, 1H), 6.90-7.00 (m, 1H), 7.08-7.25 (m, 4H), 7.28-7.35 (m, 1H), 7.42-7.50 (m, 1H), 7.84 (d, 1H, J = 8.11 Hz), 8.32 (s, 1H), 8.85 (s, 1H).

Ih-1
¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.00 (m, 2H), 1.25-1.29 (m, 2H), 1.30-1.43 (m, 1H), 1.61-1.77 (m, 2H), 1.90- 2.02 (m, 2H), 2.65-2.78 (m, 2H), 3.38-3.50 (m, 1H), 6.89-7.02 (m, 2H), 7.12-7.21 (m, 3H), 7.23-7.38 (m, 3H ), 7.40-7.56 (brs, 1H), 7.83 (d, 1H, J = 7.60 Hz), 9.54 (s, 1H).

Ih-2
¹ H-NMR (DMSO-d ₆ ) δ: 0.88-1.00 (m, 2H), 1.25-1.30 (m, 2H), 1.30-1.44 (m, 1H), 1.68-1.78 (m, 2H), 1.92- 2.04 (m, 2H), 2.70-2.80 (m, 2H), 3.38-3.50 (m, 1H), 6.90-7.00 (m, 1H), 7.08-7.25 (m, 4H), 7.28-7.35 (m, 1H ), 7.42-7.50 (m, 1H), 7.84 (d, 1H, J = 8.11 Hz), 8.32 (s, 1H), 8.85 (s, 1H).

Ii-1
¹H-NMR (DMSO-d₆) δ: 0.80-0.97 (m, 2H), 1.09-1.22 (m, 2H), 1.30-1.45 (m, 1H), 1.65-1.74 (m, 2H), 1.90-2.00 (m, 2H), 2.67-2.75 (m, 2H), 3.36-3.45 (m, 1H), 6.89-7.00 (m, 2H), 7.05 (d, 1H, J = 8.62 Hz), 7.14-7.21 (m, 1H), 7.28-7.40 (m, 2H), 7.68-7.73 (m, 1H), 7.80-7.86 (m, 1H), 8.22 (d, 1H, J = 4.06 Hz), 10.20-10-50 (brs, 1H).

Ii-1
¹ H-NMR (DMSO-d ₆ ) δ: 0.80-0.97 (m, 2H), 1.09-1.22 (m, 2H), 1.30-1.45 (m, 1H), 1.65-1.74 (m, 2H), 1.90- 2.00 (m, 2H), 2.67-2.75 (m, 2H), 3.36-3.45 (m, 1H), 6.89-7.00 (m, 2H), 7.05 (d, 1H, J = 8.62 Hz), 7.14-7.21 ( m, 1H), 7.28-7.40 (m, 2H), 7.68-7.73 (m, 1H), 7.80-7.86 (m, 1H), 8.22 (d, 1H, J = 4.06 Hz), 10.20-10-50 ( brs, 1H).

Ij-2
¹ H-NMR (DMSO-d ₆ ) δ: 0.89-1.06 (m, 2H), 1.17-1.32 (m, 2H), 1.36-1.50 (m, 1H), 1.77-1.89 (m, 2H), 1.97- 2.10 (m, 2H), 2.70-2.79 (m, 2H), 3.40-3.53 (m, 1H), 6.48-6.55 (brs, 2H), 6.49-6.53 (m, 1H), 6.90-7.00 (m, 1H ), 7.15-7.22 (m, 1H), 7.29-7.37 (m, 1H), 7.86 (d, 1H, J = 7.60 Hz).

Ij-3
¹ H-NMR (DMSO-d ₆ ) δ: 0.81-1.26 (m, 5H), 1.74-1.84 (m, 2H), 1.91-2.02 (m, 2H), 3.30-3.48 (m, 3H), 6.90 ( brs, 2H), 7.13-7.18 (m, 1H), 7.24-7.42 (m, 5H), 7.78 (d, 1H, J = 8.4 Hz)

Ij-4
¹ H-NMR (DMSO-d ₆ ) δ: 0.79-0.85 (m, 2H), 0.94-1.08 (m, 2H), 1.21-1.34 (m, 1H), 1.59-1.60 (m, 2H), 1.86- 1.95 (m, 2H), 2.84 (d, 2H, J = 7.8 Hz), 3.20 (s, 2H), 6.82 (s, 2H), 6.87-6.96 (m, 1H), 7.12-7.17 (m, 1H) , 7.26-7.41 (m, 6H), 7.76 (d, 1H, J = 0.9 Hz)

Ij-5
¹ H-NMR (CDCl ₃ ) δ: 1.17-1.37 (m, 4H), 1.71-1,83 (m, 1H), 1.85-1.95 (m, 2H), 2.24-2.33 (m, 2H), 3.22 ( d, 2H, J = 7.5 Hz), 3.62-3.77 (m, 1H), 4.36 (s, 2H), 4.52 (s, 2H), 4.66-4.74 (m, 1H), 6.87-6.95 (m, 1H) , 6.98-7.06 (m, 1H), 7.23-7.41 (m, 6 H)

Ij-6
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.26 (m, 4H), 1.82-1.91 (m, 2H), 2.18-2.28 (m, 2H), 3.59 (d, 2H, J = 7.5 Hz), 3.59 -3.68 (m, 1H), 4.29 (s, 2H), 4.67 (d, 1H, J = 7.4 Hz), 6.85-6.92 (m, 1H), 6.96-7.00 (m, 1H), 7.21-7.26 (m , 1H), 7.26-7.30 (m, 2H), 7.34-7.38 (m, 1H), 7.41-7.48 (m, 2H)

Ij-7
¹ H-NMR (CDCl ₃ ) δ 1.09-1.33 (m, 4H), 1.62-1.75 (m, 1H), 1.78-1.88 (m, 2H), 2.21-2.30 (m, 2H), 2.93 (s, 3H ), 3.14 (d, 2H, J = 7.2 Hz), 3.60-3.73 (m, 1H), 4.41 (s, 2H)), 4.83 (d, 1H, J = 7.4 Hz), 6.85-6.92 (m, 1H ), 6.99 (dd, 1H, J = 8.1 Hz, 2.4 Hz), 7.24 (dd, 1H, J = 4.6 Hz, 8.4 Hz)

Ij-8
¹ H-NMR (CDCl ₃ ) δ 1.07-1.36 (m, 4H), 1.6-1.68 (m, 1H), 1,86-1.96 (m, 2H), 2.22-2.31 (m, 2H), 2.83 (s , 3H), 2.94 (d, 2H, 7.2 Hz), 3.60-3.74 (m, 1H), 4.53 (s, 2H), 4.90 (d, 1H, J = 7.6 Hz), 6.85-6.93 (m, 1H) , 6.97-6.02 (dd, 1H, J = 2.4 Hz, 8.1 Hz), 7.22-.7.26 (dd, 1H, J = 4.7 Hz, 8.4 Hz)

Ij-9
¹ H-NMR (CDCl3) δ: 1.22-1.30 (m, 4H), 1.56-1.74 (m, 1H), 1.88-1.97 (m, 2H), 2.11-2.30 (m, 2H), 3.62-3.76 (m , 3H), 4.62-4.68 (m, 1H), 5.20 (brs, 2H), 6.85-6.91 (m, 1H), 6.96-6.99 (m, 1H), 7.00-7.26 (m, 3H), 7.72-7.78 (m, 1H), 8.40-8.44 (m, 1H)

Ij-10
¹ H-NMR (CDCl3) δ: 1.15-1.32 (m, 4H), 1.65-1.69 (m, 1H), 1.82-1.90 (m, 2H), 2.17-2.26 (m, 2H), 3.61-4.74 (m , 1H), 3.91 (d, 2H, J = 7.2 Hz), 4.69 (d, 1H, J = 8.4 Hz), 6.85-6.92 (m, 1H), 6.97-7.00 (m, 2H), 7.01-7.03 ( m, 1H), 7.09-7.26 (m, 1H), 7.69-7.75 (m, 1H), 8.31-8.34 (m, 1H)

Ik-1
¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.37 (m, 4H), 1.76-1.93 (m, 3H), 2.03-2.11 (m, 2H), 3.45-3.53 (m, 3H), 6.83- 7.00 (m ,, 5H), 7.17-7.23 (m, 1H), 7.32-7.35 (m, 1H), 7.87-7.93 (m, 1H), 11.3 (brs, 1H)

Ik-2
¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.31 (m, 4H), 1.64-1.72 (m, 2H), 1.72-1.84 (m, 1H), 1.99-2.08 (m, 2H), 3.41- 3.54 (m, 1H), 3.65 (d, 2H, J = 6.6 Hz), 6.90-7.03 (m, 4H), 7.13-7.21 (m, 2H), 7.30-7.34 (m, 1H), 7.85-7.89 ( d, 1H, J = 7.8 Hz), 10.8 (s, 1H)

Ik-3
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.37 (m, 4H), 1.56-1.72 (m, 1H), 1.95-2.04 (m, 2H), 2.24-2.33 (m, 2H), 2.87 (s, 2.25H), 2.00 (d, 1.5H, J = 6.4 Hz), 3.35 (s, 0.75H), 3.60 (d, 0.5H, J = 6.6 Hz), 3.66-3.77 (m, 1H), 4.64-4.72 (m, 1H), 6.65-6.71 (m, 1.5H), 6.80-6.84 (m, 2H), 6.86-6.93 (m, 1H), 6.97-7.03 (m. 1.5H), 7.22-7.28 (m, 1H)

Ik-4
¹ H-NMR (CDCl ₃ ) δ: 1.16-1.38 (m, 4H), 1.82-1.98 (m, 3H), 2.18-2.26 (m, 2H), 3.43 (s, 3H), 3.63-3.73 (m, 1H), 3.76 (d, 2H, J = 6.6 Hz), 4.68-4.75 (m, 1H), 6.85-6.2 (m, 1H), 6.96-7.01 (m, 3H), 7.08-7.13 (m, 2H) , 7.22-7.26 (dd, 1H, J = 5.1 Hz, 8.4 Hz)

Ik-5
¹ H-NMR (CDCl3) δ: 1.24-1.36 (m, 4H), 1.92-2.08 (m, 3H), 2.27-2.36 (m, 2H), 3.28 (s, 3H), 3.67 (d, 2H, J = 7.2 Hz), 3.65-3.80 (m, 1H), 4.64-4.69 (m, 1H), 6.72-6.76 (m, 2H), 6.86-6.94 (m, 1H), 6.96-7.01 (m, 3H), 7.23-7.28 (m, 1H)

Test Example 1-1 Affinity for Mouse NPY Y5 Receptor A cDNA sequence encoding the mouse NPY Y5 receptor (see Biochim. Biophys. Acta 1328: 83-89, 1997) was expressed in the expression vector pME18S (Takebe et al. Mol. Cell.Biol.8, 466-472). The obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
Membrane preparations prepared from CHO cells expressing mouse NPY Y5 receptor were assay buffer together with the compounds of the present invention and 30,000 cpm [ ¹²⁵ I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). The solution was incubated in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter. Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC ₅₀ value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)]. The results are shown in Table 1.
The compound according to the present invention inhibited the binding of peptide YY (NPY and homologous substances) to the mouse NPY Y5 receptor. That is, this compound showed affinity for the mouse NPY Y5 receptor.

Test Example 1-2 Affinity for Human NPY Y5 Receptor A cDNA sequence encoding the human NPY Y5 receptor (see WO96 / 16542) was synthesized from the expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-). 472). The obtained expression vector is transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual to obtain NPY Y5 receptor stably expressing cells.
Membrane preparation prepared from CHO cells expressing human NPY Y5 receptor was assay buffer together with the compound of the present invention and 30,000 cpm [ ¹²⁵ I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). Incubate in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filter through a glass filter GF / C treated with 1% polyethyleneimine. . After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter is determined with a gamma counter. Non-specific binding is measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC ₅₀ value) of the test compound for specific peptide YY binding is determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].

Test Example 2-1 Evaluation of Rat Brain Transferability Using a cassette dosing method (Drug. Metab. Dispos. (2001); 29, 957-966), rat (Crl; CD (SD), ♂, 8weeks) From the plasma and brain concentration 30 minutes after intravenous administration (0.5 mg / mL / kg), brain transferability (brain / plasma partition coefficient; Kp) was evaluated.
As a result, the compound of the present invention showed good brain migration. For example, Compound Ic-1 and Compound Ie-1 were brain Kp: 1.70 and 0.72, respectively.

Test Example 2-2 Evaluation of transferability to mouse brain Using cassette dosing method (Drug. Metab. Dispos. (2001); 29, 957-966) Brain transferability (brain / plasma partition coefficient; Kp) is evaluated from plasma and brain concentrations 3 hours or 5 hours after administration (2 mg / 10 mL / kg).

Test Example 3 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life was determined from the change in plasma concentration after intravenous administration (0.5 mg / mL / kg) of rats (Crl; CD (SD), ♂, 8 weeks). (T1 / 2) and systemic clearance (CLtot) were evaluated.

Test Example 4 cAMP Production Inhibitory Action in CHO Cells After CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), the compounds according to the present invention Was added and incubated for 5 minutes, after which 50 nMNPY and 10 μM forskolin (Sigma) were added and incubated for 30 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using EIA kit (manufactured by Amersham LIFE SIENCE). The inhibitory action of NPY on cAMP production by forskolin stimulation was taken as 100%, and the 50% inhibitory concentration (IC ₅₀ value) of the compound according to the present invention for this NPY action was determined.

Test Example 5 NPY Y5 Receptor Selectivity Test Examples 1-2 and Y1-expressing cells (human neuroblastoma, SK-N-MC) and Y2-expressing cells (human neuroblastoma, SMS-KAN) membrane samples were used. The test is performed in the same manner, and the affinity of the compound of the present invention for the NPY Y1 receptor and NPY Y2 receptor is measured. As a result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.

Test Example 6 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the outer occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 25-30 g) to expose the upper skull. . A hole having a diameter of about 1 mm was formed using an electric drill at a position about 1 mm rearward from the exposed part bregma toward lamda, about 1 mm from the midline to the left side. A 0.5% hydroxypropylmethylcellulose aqueous solution (manufactured by Shin-Etsu Chemical Co., Ltd.) or a test substance suspended in this aqueous solution is forcibly orally administered to mice after waking up from anesthesia, and NPY Y5 receptor-specific agonist 1 hour after administration ([CPP ^1-7 , NPY ^19-23 , Ala ³¹ , Aib ³² , Gln ³⁴ ] -hPanalytic Polypeptide: manufactured by Tocris Co.) 0.1 nmol was injected from the head opening provided previously using a cannula. The food intake of the mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the 0.5% hydroxypropylmethylcellulose solution administration group and the test substance administration group was investigated. As a result, when the compound of the present invention was administered at a dose of 12.5 mg / kg, the amount of food intake was significantly suppressed as compared with the case where 0.5% hydroxypropylmethylcellulose was administered.
For example, in the group administered with the compound Ic-1 at a dose of 12.5 mg / kg (group A), the food intake after 2 hours and 4 hours after injection was 0.27 ± 0.02 g and 0.50 ± 0.09 g, respectively. there were. On the other hand, the amount of food consumed 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.69 ± 0.06 g and 1.30 ± 0.12 g, respectively. The 0.5% hydroxypropylmethylcellulose solution administration group (Group C) to which no NPY Y5 receptor-specific agonist was injected was 0.12 ± 0.02 g, 0.25 ± 0.03 g, and Group C If the value of A is subtracted from the A and B groups and converted, the feeding inhibition rates for the B group at 2 hours and 4 hours after the injection in the A group are 74.2% and 75.3%, respectively.

Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.

  The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan ( CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 μmol / L (4 points).

  As a reaction solution in a 96-well plate, 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer, and NADPH as a coenzyme is added to start a metabolic reaction as an index. The mixture was reacted at 37 ° C. for 15 minutes, and then the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

The control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model.
The results are shown below.
Compound Ia-13: 5 species> 20 μM
Compound Ib-1: 4 types> 20 μM, 3A4 10 μM
Compound Ic-1: 5 types> 20 μM
Compound Id-1: 5 species> 20 μM
Compound Ie-7: 5 species> 20 μM
Compound If-1: 5 types> 20 μM
Compound Ig-2: 5 species> 20 μM
Compound Ii-1: 5 types> 20 μM
Compound Ij-8: 5 species> 20 μM

Test Example 8 Metabolic stability Metabolic stability evaluation by human liver microsomes: NADPH (final concentration 1 mM, in the case of oxidative metabolism), liver microsomes (final concentration 0.5 mg protein / in) in Tris-HCl buffer (pH 7.4) ml) and each compound (final concentration 2 μM) were added and reacted at 37 ° C. for 0 and 30 minutes. In the case of glucuronidation, UDPGA (final concentration 5 mM) was added instead of NADPH. After the reaction was stopped by adding acetonitrile / methanol = 1/1 (v / v) twice the amount of the reaction solution, the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from the comparison of values of 0 minute and 30 minutes, and the metabolic stability of the compound of the present invention was confirmed.
The remaining rate at a compound concentration of 0.5 μM is shown below.
Compound Ia-2: 92.1%
Compound Ib-1: 65.8%
Compound Ic-1: 94.3%
Compound Id-3: 89.1%
Compound Ie-5: 95.9%
Compound If-2: 84.1%
Compound Ig-2: 97.8%
Compound Ih-2: 72.9%
Compound Ii-1: 94.2%
Compound Ij-9: 95.2%
Compound Ik-1: 100%

Test Example 9 Powder Solubility Test An appropriate amount of specimen is put in a suitable container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to make 1000 mL), JP-2 solution (phosphorus of pH 6.8). 200 mL of water was added to 500 mL of an acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (water was added to 1.08 g of TCA to make 100 mL). When dissolved after adding the test solution, a bulk powder was added as appropriate. Sealed and shaken at 37 ° C. for 1 hour. After filtration, 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution factor was changed as necessary. After confirming that there were no bubbles and precipitates, the mixture was sealed and shaken. Quantification was performed using HPLC by the absolute calibration curve method.
For example, the results for Compound Ie-18 are as follows:
JP-1 solution;> 1000 μg / mL,
JP-2 solution: 7.59 μg / mL, 20 mmol / L
TCA / JP-2 solution: 40.4 μg / mL

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet Compound (I) 15 mg
Starch 15mg
Lactose 15mg
Crystalline cellulose 19mg
Polyvinyl alcohol 3mg
30ml distilled water
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

Formulation Example 2 Capsule Compound (I) 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.

Formulation Example 3 Granules Compound (I) 30 g
Lactose 265g
Magnesium stearate 5g
After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.

  As is clear from the above test examples, the compound of the present invention exhibits NPY Y5 receptor antagonistic action. Therefore, the compound of the present invention is used as a medicament for the prevention or treatment of eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure, sleep disorders, etc. Very useful. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for the treatment or prevention of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndromes.

Claims (17)

Formula (I):

(Where
R ¹ , R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R ¹ and R ² may form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring together with the adjacent nitrogen atom, or R ² and R ³ together may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle,
X is S (O), S (O) ₂ or C (O);
R ⁴ and R ⁵ are each independently hydrogen or substituted or unsubstituted alkyl, or R ⁴ and R ⁵ together may form an oxo;
R ⁶ is hydrogen or substituted or unsubstituted alkyl;
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
m is an integer from 0 to 2,
Y is S or O;
Each R ⁷ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted alkoxy;
n is an integer of 0 to 2, and a pharmaceutically acceptable salt or solvate thereof. R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The compound of Claim 1, its pharmaceutically acceptable salt, or those solvates. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ and R ² are each independently substituted or unsubstituted alkyl. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ is substituted or unsubstituted alkyl, and R ² is substituted or unsubstituted cycloalkyl. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ is substituted or unsubstituted alkyl, and R ² is substituted or unsubstituted alkoxy. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a compound thereof, wherein R ¹ and R ² together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle Solvates. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ is hydrogen and R ² is substituted or unsubstituted alkyl. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ is hydrogen and R ² is substituted or unsubstituted cycloalkyl. The compound according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R ¹ is hydrogen and R ² is substituted or unsubstituted alkoxy. The compound according to any one of claims 1 to 9, wherein X is S (O) ₂ , a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 10, wherein Y is O, a pharmaceutically acceptable salt thereof, or a solvate thereof. R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A compound according to any one of claims 1 to 11, The pharmaceutically acceptable salt or solvate thereof. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ² and R ³ are combined to form a substituted or unsubstituted nitrogen-containing aromatic heterocycle. The compound according to any one of claims 1 to 13, wherein R ⁷ is halogen, a pharmaceutically acceptable salt thereof, or a solvate thereof. R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
X is S (O) ₂ or C (O);
R ⁴ and R ⁵ are hydrogen, or R ⁴ and R ⁵ together may form oxo,
R ⁶ is hydrogen;
m is 0,
Y is S or O;
Each R ⁷ is independently halogen;
n is an integer of 0-2, The compound in any one of Claims 1-9, its pharmaceutically acceptable salt, or those solvates. Pharmaceutical composition which uses the compound in any one of Claims 1-15, its pharmaceutically acceptable salt, or those solvates as an active ingredient. The pharmaceutical composition according to claim 16, which has an NPY Y5 receptor antagonistic action.