JP2010222298A - Pyrrolidone derivative having npyy5 receptor antagonism - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having NPYY5 receptor antagonism. <P>SOLUTION: The compound is represented by formula (I) (wherein R<SP>1</SP>is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl or substituted or unsubstituted heteroarylalkyl; and R<SP>2</SP>is substituted or unsubstituted morpholino-substituted aryl or substituted or unsubstituted heterocyclyl with the proviso that a case in which R<SP>2</SP>is substituted or unsubstituted carbazol-3-yl is omitted), and a pharmaceutically acceptable salt thereof or their solvates are provided. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel pyrrolidone derivative 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 feeding promoting action, anticonvulsant action, learning promoting action, anti-anxiety action, anti-stress 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 prophylactic 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 Document 1 describes a pyrrolidone derivative having an NPY Y5 receptor antagonistic action. Further, pyridine derivatives having a pyrrolidine ring having an NPY Y5 receptor antagonistic action are described in Patent Document 2, and thiazole derivatives are described in Patent Document 3.
In addition, compounds having an NPY Y5 antagonistic activity although having a structure different from that of the compound according to the present invention are disclosed in Patent Documents 4 to 7 and the like.

International Publication No. 2003/059905 Pamphlet International Publication No. 98/40356 Pamphlet International Publication No. 2005/014593 Pamphlet International Publication No. 01/037826 Pamphlet International Publication No. 2006/001318 Pamphlet International Publication No. 2003/104255 Pamphlet International Publication No. 97/20823 Pamphlet

Trends in Pharmacological Sciences, 1994, Vol. 15, p. 153 Trends in Pharmacological Sciences, 1997, Vol. 18, p. 372 Peptides, 1997, Vol. 18, p. 445 Obesity, 2006, Vol. 14, p. A235 Obesity, 2007, Vol. 15, p. A57

  An object of the present invention is to provide a novel 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. In Patent Document 1, as a compound having an NPY Y5 receptor antagonistic activity, a compound in which the R ² moiety in the following formula (I) is 9-ethyl-9H-carbazol-3-yl or 4-substituted aminophenyl is disclosed. It is disclosed. The present inventors have found that the compounds of the present invention not only have NPY Y5 receptor antagonistic activity, but also have little inhibition on drug-metabolizing enzymes, good metabolic stability and water solubility.

（式中、Ｒ^１ は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、置換若しくは非置換のヘテロアリール、置換若しくは非置換のアラルキルまたは置換若しくは非置換のヘテロアリールアルキルであり、
Ｒ^２ は置換若しくは非置換のモルホリノで置換されたアリールまたは置換若しくは非置換のヘテロサイクリルである。
ただし、Ｒ^２ が置換若しくは非置換のカルバゾール−３−イルである場合を除く。）
で示される化合物、その製薬上許容される塩またはそれらの溶媒和物。
（２）Ｒ^１ が置換若しくは非置換のフェニルまたは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またはそれらの溶媒和物。
（３）Ｒ^１ がハロゲン、アルキル、ハロアルキル、アルコキシ、ハロアルコキシまたはシアノから選択される１以上の置換基で置換されたフェニルまたは炭素数５〜８の非置換シクロアルキルである、（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（４）Ｒ^１ がフルオロ、メチル、エチル、イソプロピル、ジフルオロメトキシまたはシアノから選択される１以上の置換基で置換されたフェニル、非置換シクロペンチルまたは非置換シクロオクチルである、
（３）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（５）Ｒ^２ が置換若しくは非置換のヘテロサイクリルである、（１）〜（４）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（６）Ｒ^２ が式：

（式中、環Ａはヘテロサイクルであり、
Ｒ^３ およびＲ^４ はそれぞれ独立してハロゲン、シアノ、オキソ、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シクロアルキル、置換若しくは非置換のヘテロサイクリルまたは置換若しくは非置換のアリールであり、
ｍおよびｎはそれぞれ独立して０〜２の整数。）で示される基である、
（５）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（７）環Ａがピラゾール、イミダゾール、ピリジン、ピリダジン、ピリミジン、ピラジン、ベンズオキサゾール、２，３−ジヒドロベンズオキサゾール、ベンズチアゾール、２，３−ジヒドロベンズチアゾール、ベンズイミダゾールまたは２，３−ジヒドロベンズイミダゾールである、（６）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（８）環Ａがピラゾールまたは２，３−ジヒドロベンズオキサゾールである、（７）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（９）環Ａがピラゾールである、（８）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１０）環Ａが２，３−ジヒドロベンズオキサゾールである、（８）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１１）Ｒ^３ がハロゲン置換フェニルまたは非置換アルキルであり、
Ｒ^４ がオキソであり、
ｍが１であり、
ｎが０または１の整数である、
（９）または（１０）に記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１２）Ｒ^３ がフルオロフェニルまたはイソプロピルであり、
Ｒ^４ がオキソであり、
ｍが１であり、
ｎが０または１の整数である、
（１１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１３）（１）〜（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を有効成分とする医薬組成物。
（１４）（１）〜（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を有効成分とするＮＰＹ Ｙ５受容体拮抗作用を有する医薬組成物。 (1) Formula (I):

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted hetero Arylalkyl,
R ² is aryl substituted with substituted or unsubstituted morpholino or substituted or unsubstituted heterocyclyl.
Except when R ² is a substituted or unsubstituted carbazole-3-yl. )
Or a pharmaceutically acceptable salt or solvate thereof.
(2) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein R ¹ is substituted or unsubstituted phenyl or substituted or unsubstituted cycloalkyl.
(3) The description of (2), wherein R ¹ is phenyl substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano, or unsubstituted cycloalkyl having 5 to 8 carbon atoms Or a pharmaceutically acceptable salt or solvate thereof.
(4) R ¹ is phenyl, unsubstituted cyclopentyl or unsubstituted cyclooctyl substituted with one or more substituents selected from fluoro, methyl, ethyl, isopropyl, difluoromethoxy or cyano.
(3) The compound according to the above, a pharmaceutically acceptable salt thereof or a solvate thereof.
(5) The compound according to any one of (1) to (4), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ² is substituted or unsubstituted heterocyclyl.
(6) R ² is the formula:

(Wherein ring A is a heterocycle,
R ³ and R ⁴ are each independently halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclyl or substituted or unsubstituted aryl;
m and n are each independently an integer of 0-2. Is a group represented by
(5) The compound, pharmaceutically acceptable salt or solvate thereof according to the above.
(7) Ring A is pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, benzoxazole, 2,3-dihydrobenzoxazole, benzthiazole, 2,3-dihydrobenzthiazole, benzimidazole or 2,3-dihydrobenzimidazole The compound according to (6), a pharmaceutically acceptable salt thereof or a solvate thereof.
(8) The compound according to (7), a pharmaceutically acceptable salt or a solvate thereof, wherein ring A is pyrazole or 2,3-dihydrobenzoxazole.
(9) The compound according to (8), wherein ring A is pyrazole, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(10) The compound according to (8), ring A is a pharmaceutically acceptable salt or solvate thereof, wherein ring A is 2,3-dihydrobenzoxazole.
(11) R ³ is halogen-substituted phenyl or unsubstituted alkyl;
R ⁴ is oxo,
m is 1,
n is an integer of 0 or 1,
(9) or the compound according to (10), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(12) R ³ is fluorophenyl or isopropyl;
R ⁴ is oxo,
m is 1,
n is an integer of 0 or 1,
(11) The compound, its pharmaceutically acceptable salt or solvate thereof according to (11).
(13) A pharmaceutical composition comprising the compound according to any one of (1) to (12), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
(14) A pharmaceutical composition having an NPY Y5 receptor antagonistic activity comprising the compound according to any one of (1) to (12), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

  The compound of the present invention exhibits NPY Y5 receptor antagonistic activity, and the compound of the present invention is used for diseases involving pharmaceuticals, particularly NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, It is very useful as a medicament for the treatment and / or prevention of depression, epileptic seizures, hypertension, cerebral overflow, congestive heart failure or sleep disorders.

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

  “Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine is preferred.

“Alkyl” includes linear or branched alkyl having 1 to 10 carbon atoms, such as 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.
“Alkyl” in R ³ is preferably 1 to 6 carbon atoms, more preferably isopropyl.
“Alkyl” in other cases preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms.

  “Haloalkyl” means a group in which one or more, preferably 1 to 5, more preferably 1 to 3, of the above “halogen” is substituted with an alkyl group.

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

  “Alkynyl” means linear or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms. Specific examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These have one or more triple bonds at arbitrary positions, and 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.

“Haloalkoxy” means a group in which one or more of the above “halogens” is substituted with an alkoxy group.
“Haloalkoxy” as a substituent of “phenyl” in R ¹ is preferably difluoromethoxy.

“Cycloalkyl” means cyclic alkyl having 3 to 8 carbon atoms, preferably 5 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
“Cycloalkyl” in R ¹ is particularly preferably cycloheptyl or cyclooctyl.

  The “cycloalkenyl” means one having one or more double bonds at any position in the ring of the “cycloalkyl”. Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl and the like.

  “Aryl” means a monocyclic or polycyclic aromatic carbocyclic group. Specific examples include phenyl, naphthyl, anthryl, phenanthryl and the like.

“Monocyclic aromatic heterocycle” means a 4- to 8-membered monocyclic aromatic heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring, specifically Pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, thiophene and the like. In particular, a 5-membered or 6-membered monocyclic aromatic heterocycle is preferable.
The “bicyclic aromatic heterocycle” means an aromatic carbocycle (aromatic carbocycle derived from the above “aryl”) or an aromatic heterocycle (O, S) to the above “monocyclic aromatic heterocycle”. And a condensed aromatic heterocycle in which a 4- to 8-membered aromatic heterocycle having one or more heteroatoms arbitrarily selected from N is condensed. For example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo Examples include thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine and the like.

  “Heteroaryl” refers to a monocyclic or polycyclic aromatic heterocyclic group. For example, a group derived from the above “monocyclic aromatic heterocycle”, a group derived from the above “bicyclic aromatic heterocycle”, and a polyaryl having 3 or more rings are also included. Examples of the group derived from “monocyclic aromatic heterocycle” include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl , Furyl, thienyl and the like. Examples of the group derived from the “bicyclic aromatic heterocycle” include, for example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, prill, pteridinyl, benzimidazolyl, benzil. Isoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothia Examples include zolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl and the like. Examples of the polycyclic heteroaryl having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, dibenzofuryl and the like. In the case of “polycyclic heteroaryl”, any ring may have a bond.

“Heterocyclyl” refers to the above “heteroaryl”, a 4- to 8-membered monocyclic non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, Or “monocyclic non-aromatic heterocyclic group” to aromatic carbocyclic ring (ring derived from the above “aryl”), aromatic heterocyclic ring (ring derived from the above “heteroaryl”), monocyclic non-cyclic It means a condensed heterocycle in which an aromatic heterocycle (ring derived from a “monocyclic non-aromatic heterocyclic group”) and a cycloalkane (ring derived from the above “cycloalkyl”) are condensed. Specific examples of monocyclic heterocyclyls that are “monocyclic non-aromatic heterocyclic groups” include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl , Piperidino, piperazinyl, piperazino, morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl and the like. Specific examples of the condensed heterocyclyl include indolinyl, isoindolinyl, chromanyl, isochromanyl, 2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzthiazolyl, 2,3-dihydrobenzimidazolyl and the like.
“Heterocycle” means a cyclic structure forming the above “heterocyclyl” group.
“Heterocycle” in ring A includes pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, benzoxazole, 2,3-dihydrobenzoxazole, benzthiazole, 2,3-dihydrobenzthiazole, benzimidazole or 2,3- Dihydrobenzimidazole is preferred, and pyrazole or 2,3-dihydrobenzoxazole is more preferred.

  “Aralkyl” means a group in which one or more of the above “aryl” is substituted with an alkyl group.

  “Heteroarylalkyl” means a group in which one or more of the above “heteroaryl” is substituted with an alkyl group.

"Substituted or unsubstituted alkyl", "substituted or unsubstituted alkenyl", "substituted or unsubstituted alkynyl", "substituted or unsubstituted aralkyl" alkyl group or "substituted or unsubstituted heteroarylalkyl" Alkyl group substituents include halogen, cyano, nitro, nitroso, azide, acyl, acyloxy, imino, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or Non Conversion heteroaryloxy, substituted or unsubstituted heterocycle, substituted or unsubstituted heterocycle-oxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclethio, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or Unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocycleoxycarbonyl, substituted or unsubstituted carbamoyl , Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted Heteroarylcarbonyl, substituted or unsubstituted heterocyclecarbonyl, sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl Substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted Sulfamoyl, substituted or unsubstituted amino, oxo, and the like. Any position may be substituted with one or more groups selected from these.

Aryl of "substituted or unsubstituted cycloalkyl", "substituted or unsubstituted aryl", "substituted or unsubstituted heteroaryl", "substituted or unsubstituted heterocyclyl", "substituted or unsubstituted aralkyl" As the substituent of the heteroaryl group of the group or “substituted or unsubstituted heteroarylalkyl”, lower alkyl which may be substituted, lower alkenyl which may be substituted, lower alkynyl which may be substituted, halogen , Cyano, nitro, nitroso, azide, acyl, acyloxy, imino, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, substituted Or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heterocycle, substituted Or unsubstituted heterocycleoxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted Or unsubstituted heteroarylthio, substituted or unsubstituted heterocyclethio, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted Cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocycleoxycarbonyl, substituted or unsubstituted carbamoyl , Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted Heteroarylcarbonyl, substituted or unsubstituted heterocyclecarbonyl, sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or Unsubstituted sulfamoyl, substituted or unsubstituted amino, oxo, substituted or unsubstituted alkylene, substituted or unsubstituted alkylenedioxy, represented by the formula: —N (R ⁵ ) -substituted or unsubstituted alkylene-O— A group represented by the formula: —N (R ⁵ ) -substituted or unsubstituted alkylene-N (R ⁵ ) — (wherein R ⁵ is independently hydrogen or alkyl), and the like. When substituted with a divalent group, the divalent group may be substituted with the same or different atoms. Not only when substituting with an adjacent atom, but may be substituted to form a bicyclo ring or a spiro ring. Any position may be substituted with one or more groups selected from these.

For example, when the substituent of “substituted or unsubstituted cycloalkyl (eg, cyclohexyl)” is substituted or unsubstituted alkylene (eg, —CH ₂ —CH ₂ —), it may be substituted as follows. .

For example, when the substituted or unsubstituted aryl substituent is substituted or unsubstituted alkylenedioxy, the following groups are exemplified.

他の二価の基の場合も、同様である。
For example, when the substituted or unsubstituted aryl substituent is a group represented by the formula: —N (R ⁵ ) -substituted or unsubstituted alkylene-O—, the following groups are exemplified.

The same applies to other divalent groups.

  Hereinafter, preferred embodiments of the compound represented by the formula (I) will be described.

R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroarylalkyl . Preferably it is selected from substituted or unsubstituted phenyl or substituted or unsubstituted cycloalkyl, more preferably halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano, particularly preferably fluoro, methyl, ethyl, isopropyl, difluoro Phenyl substituted with one or more substituents selected from methoxy or cyano or unsubstituted cycloalkyl having 5 to 8 carbon atoms, particularly preferably 5 or 8 carbon atoms.

（式中、環Ａはヘテロサイクルであり、
Ｒ^３ およびＲ^４ はそれぞれ独立してハロゲン、シアノ、オキソ、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シクロアルキル、置換若しくは非置換のヘテロサイクリルまたは置換若しくは非置換のアリールであり、
ｍおよびｎはそれぞれ独立して０〜２の整数。）で示される。
環Ａは好ましくはピラゾール、イミダゾール、ピリジン、ピリダジン、ピリミジン、ピラジン、ベンズオキサゾール、２，３−ジヒドロベンズオキサゾール、ベンズチアゾール、２，３−ジヒドロベンズチアゾール、ベンズイミダゾールまたは２，３−ジヒドロベンズイミダゾールであり、さらに好ましくはピラゾールまたは２，３−ジヒドロベンズオキサゾールである。
Ｒ^３は好ましくはハロゲン置換フェニルまたは非置換アルキルであり、さらに好ましくはフルオロフェニルまたはイソプロピルである。
Ｒ^４は好ましくはオキソである。
ｍは０〜２の整数である。好ましくは１である。
ｎは０〜２の整数である。好ましくは０または１である。 R ² is substituted aryl (the substituent is substituted or unsubstituted morpholino) or substituted or unsubstituted heterocyclyl. Except when R ² is a substituted or unsubstituted carbazole-3-yl. Preferably the formula:

(Wherein ring A is a heterocycle,
R ³ and R ⁴ are each independently halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclyl or substituted or unsubstituted aryl;
m and n are each independently an integer of 0-2. ).
Ring A is preferably pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, benzoxazole, 2,3-dihydrobenzoxazole, benzthiazole, 2,3-dihydrobenzthiazole, benzimidazole or 2,3-dihydrobenzimidazole. More preferably pyrazole or 2,3-dihydrobenzoxazole.
R ³ is preferably halogen-substituted phenyl or unsubstituted alkyl, more preferably fluorophenyl or isopropyl.
R ⁴ is preferably oxo.
m is an integer of 0-2. Preferably it is 1.
n is an integer of 0-2. Preferably 0 or 1.

  The compound according to the present invention includes a pharmaceutically acceptable salt capable of producing each compound. “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 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 compound according to the present invention includes its solvate and is directed to compound (I). Preferably, it is a hydrate, and one molecule of the compound according to the present invention may be coordinated with an arbitrary number of water molecules.

  When the compound (I) according to the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). In addition, when the compound (I) according to the present invention has a double bond, both of the E-form and the Z-form can be present.

  The compound represented by the formula (I) according to the present invention can be synthesized, for example, by the following method.

第１工程
式：Ｒ^１ＮＨ_２（式中、Ｒ^１は式（Ｉ）と同意義。）で示される化合物とイタコン酸を酢酸存在下で適当な溶媒中、８０℃〜２００℃、好ましくは１００℃〜１５０℃で、１５分〜５時間、好ましくは３０分〜２．５時間反応させ、式（ＩＩ）で示される化合物を得る。場合によっては、反応にマイクロウェーブ照射装置を用いてもよい。
反応溶媒としては、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、アセトニトリルおよびそれらの混合溶媒等を用いることができる。好ましくはトルエンである。
第２工程
式（ＩＩ）で示される化合物と式：Ｒ^２ＮＨ_２（式中、Ｒ^２は式（Ｉ）と同意義。）で示される化合物を塩基存在下で適当な溶媒中、０℃〜５０℃、好ましくは室温で、３０分〜２４時間、好ましくは１時間〜１６時間反応させ、式（Ｉ）で示される化合物を得る。
上記反応の際、必要に応じて、脱水縮合剤を入れて反応させることができる。また、必要に応じて、反応前に式（ＩＩ）で示される化合物を適当な溶媒中でハロゲン化剤を用いて対応する酸塩化物に変換させてから反応させることもできる。
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、水酸化カリウム等を使用することができる。好ましくはトリエチルアミンである。
反応溶媒としては、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、アセトニトリルおよびそれらの混合溶媒等を用いることができる。好ましくはジメチルホルムアミドである。
脱水縮合剤としては、DCC（Ｎ，Ｎ’-ジシクロヘキシルカルボジイミド）、ジフェニルリン酸アジド、BOP（ヘキサフルオロリン酸（ベンゾトリアゾール−１−イルオキシ）トリ（ジメチルアミノ）ホスホニウム）、PyBOP（ヘキサフルオロリン酸（ベンゾトリアゾール−１−イルオキシ）トリピロリジノホスホニウム）、HATU（ヘキサフルオロリン酸Ｏ−（７−アザベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ’,Ｎ’−テトラメチルウロニウム）等を用いることができる。好ましくはHATUである。
ハロゲン化剤としては、チオニルクロリド、塩化スルフリル、ホスゲン、オキザリルクロリド等を用いることができる。好ましくはオキザリルクロリドである。

First Step: A compound represented by the formula: R ¹ NH ₂ (wherein R ¹ is as defined in formula (I)) and itaconic acid in the presence of acetic acid in a suitable solvent, preferably at 80 ° C. to 200 ° C., preferably The reaction is carried out at 100 ° C. to 150 ° C. for 15 minutes to 5 hours, preferably 30 minutes to 2.5 hours to obtain the compound represented by the formula (II). In some cases, a microwave irradiation apparatus may be used for the reaction.
As the reaction solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof are used. be able to. Preferably it is toluene.
Second Step A compound represented by the formula (II) and a compound represented by the formula: R ² NH ₂ (wherein R ² is as defined in the formula (I)) in a suitable solvent in the presence of a base at 0 ° C. The reaction is carried out at ˜50 ° C., preferably at room temperature, for 30 minutes to 24 hours, preferably 1 hour to 16 hours to obtain the compound represented by the formula (I).
In the case of the above reaction, a dehydration condensing agent can be added and reacted as necessary. In addition, if necessary, the compound represented by the formula (II) may be converted to the corresponding acid chloride using a halogenating agent in an appropriate solvent before the reaction.
As the base, pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred.
As the reaction solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof are used. be able to. Preferred is dimethylformamide.
Examples of the dehydrating condensing agent include DCC (N, N′-dicyclohexylcarbodiimide), diphenylphosphoric acid azide, BOP (hexafluorophosphoric acid (benzotriazol-1-yloxy) tri (dimethylamino) phosphonium), PyBOP (hexafluorophosphoric acid). (Benzotriazol-1-yloxy) tripyrrolidinophosphonium), HATU (hexafluorophosphate O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium), etc. Can be used. HATU is preferred.
As the halogenating agent, thionyl chloride, sulfuryl chloride, phosgene, oxalyl chloride and the like can be used. Oxalyl chloride is preferred.

The pharmaceutical composition having an NPY Y5 receptor antagonistic activity of the present invention is used for all diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension It effectively acts on cerebral overflow, congestive heart failure or sleep disorder, but is particularly useful for the prevention and / or treatment of obesity and suppression of eating. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, 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) Among CYP enzymes, the inhibitory action against CYP1A2, CYP2C19, and CYP2D6 is weak.
b) High metabolic stability.
c) High water solubility.

  A pharmaceutical composition having an NPY Y5 receptor antagonistic action 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 to do is one of the features of this drug.

  When the compound according to the present invention is administered as an antiobesity agent or an antifeedant, 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 according to the present invention as necessary to produce a pharmaceutical preparation It can be. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.

  Specifically, the excipients are lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose, and the binders are methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin or polyvinyl. Examples of disintegrants include pyrrolidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, agar powder or sodium lauryl sulfate, and lubricants include talc, magnesium stearate, or macrogol. It is done. 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. In the case of oral administration, a flavoring agent, a fragrance or the like may be added.

  The dose of the compound according to the present invention as an anti-obesity agent or an antifeedant is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. When administered, the dose is usually 0.05 to 100 mg / kg / day, preferably 0.1 to 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 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
Pr: Propyl
iPr: Isopropyl
DMF: Dimethylformamide
HATU: hexafluorophosphoric acid O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium

４−フルオロアニリン(１)(1.1 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、100℃で２．５時間攪拌した。反応液を室温まで冷却して析出した粗結晶をろ取し、再結晶させることにより化合物２(1.18 g, 収率53%)を白色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 2.65-2.81 (m, 3H), 3.92-4.10 (m, 2H), 7.21 (m, 2H), 7.68 (m, 2H,)
第２工程

化合物２(220 mg, 1 mmol)のジクロロメタン混濁液に、DMFを一滴加え、次に氷冷下でオキザリルクロライド(96 μl, 1.1 mmol)を加え、室温で３０分攪拌した。反応液に、氷冷下1-(2-フルオロフェニル)-1H-ピラゾール-3-アミン(159 mg, 0.9 mmol)、トリエチルアミン(418 μl, 3 mmol)のジクロロメタン溶液を加え、室温で１時間攪拌した。反応液よりクロロホルムを用いて抽出し、２Ｎ塩酸、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。得られた粗結晶を酢酸エチルーヘキサンで再結晶させることにより、化合物Ｉ−１(156 mg, 収率41%)を得た。
¹H-NMR (DMSO-d₆) δ: 2.69-2.87 (m, 2H), 3.51 (m, 1H), 3.93-4.12 (m, 2H), 6.85 (s, 1H), 7.22 (t, 2H, J = 9.0 Hz), 7.32-7.53 (m, 3H), 7.65-7.78 (m, 3H), 8.12 (s, 1H) Example 1 Synthesis of Compound (I-1)
First step

To a solution of 4-fluoroaniline (1) (1.1 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was stirred at 100 ° C. for 2.5 hours. The reaction solution was cooled to room temperature, and the precipitated crude crystals were collected by filtration and recrystallized to obtain Compound 2 (1.18 g, yield 53%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.65-2.81 (m, 3H), 3.92-4.10 (m, 2H), 7.21 (m, 2H), 7.68 (m, 2H,)
Second step

One drop of DMF was added to a dichloromethane suspension of compound 2 (220 mg, 1 mmol), then oxalyl chloride (96 μl, 1.1 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 1- (2-fluorophenyl) -1H-pyrazol-3-amine (159 mg, 0.9 mmol) and triethylamine (418 μl, 3 mmol) in dichloromethane under ice-cooling, and the mixture was stirred at room temperature for 1 hour. did. The reaction solution was extracted with chloroform, washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate-hexane to obtain Compound I-1 (156 mg, yield 41%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.69-2.87 (m, 2H), 3.51 (m, 1H), 3.93-4.12 (m, 2H), 6.85 (s, 1H), 7.22 (t, 2H, J = 9.0 Hz), 7.32-7.53 (m, 3H), 7.65-7.78 (m, 3H), 8.12 (s, 1H)

３−フルオロアニリン(３)(1.1 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、100℃で２．５時間攪拌した。反応液を室温まで冷却して析出した粗結晶をろ取し、再結晶させることにより化合物４(1.35 g, 収率60%)を白色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 2.65-2.86 (m, 3H), 3.94-4.10 (m, 2H), 4.10-4.31 (m, 2H), 6.98 (m, 1H,), 7.41 (m, 2H), 7.65(d, 1H, J = 12.3Hz)
第２工程

化合物４(150 mg, 0.67 mmol)のジクロロメタン混濁液に、DMFを一滴加え、次に氷冷下でオキザリルクロライド(63 μl, 0.73 mmol)を加え、室温で３０分攪拌した。反応液に、氷冷下1-(2-フルオロフェニル)-1H-ピラゾール-3-アミン(107 mg, 0.64 mmol)、トリエチルアミン(281 μl, 2 mmol)のジクロロメタン溶液を加え、室温で１時間攪拌した。反応液よりクロロホルムを用いて抽出し、２Ｎ塩酸、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製し、得られた粗結晶を酢酸エチルーヘキサンで再結晶させることにより、化合物Ｉ−２(113 mg)を得た。
¹H-NMR (DMSO-d₆) δ: 2.70-2.91 (m, 2H), 3.50 (q, 1H, J = 6.9 Hz), 3.93-4.20 (m, 2H), 6.83 (s, 1H), 6.97 (m, 1H), 7.30-7.49 (m, 5H), 7.62-7.76 (m, 2H), 8.10 (s, 1H), 11.05 (s, 1H) Example 2 Synthesis of Compound (I-2)
First step

To a solution of 3-fluoroaniline (3) (1.1 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was stirred at 100 ° C. for 2.5 hours. The reaction solution was cooled to room temperature, and the precipitated crude crystals were collected by filtration and recrystallized to obtain Compound 4 (1.35 g, yield 60%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.65-2.86 (m, 3H), 3.94-4.10 (m, 2H), 4.10-4.31 (m, 2H), 6.98 (m, 1H,), 7.41 (m , 2H), 7.65 (d, 1H, J = 12.3Hz)
Second step

A drop of DMF was added to a dichloromethane suspension of compound 4 (150 mg, 0.67 mmol), then oxalyl chloride (63 μl, 0.73 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 1- (2-fluorophenyl) -1H-pyrazol-3-amine (107 mg, 0.64 mmol) and triethylamine (281 μl, 2 mmol) in dichloromethane under ice-cooling, and the mixture was stirred at room temperature for 1 hour. did. The reaction solution was extracted with chloroform, washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, and the resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain Compound I-2 (113 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 2.70-2.91 (m, 2H), 3.50 (q, 1H, J = 6.9 Hz), 3.93-4.20 (m, 2H), 6.83 (s, 1H), 6.97 (m, 1H), 7.30-7.49 (m, 5H), 7.62-7.76 (m, 2H), 8.10 (s, 1H), 11.05 (s, 1H)

２−メチルアニリン(５)(1.1 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、100℃で２．５時間攪拌した。室温まで冷却して析出した粗結晶をろ取し、再結晶させることにより化合物６(1.35 g, 収率62%)を白色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 2.13 (s, 3H), 2.58-2.80 (m, 2H), 3.78 (m, 1H), 3.91 (t, 1H, J = 8.7Hz), 7.18-7.29(m, 4H), 12.5 (br-s, 1H)
第２工程

化合物６(120 mg, 0.55 mmol)のジクロロメタン混濁液に、DMFを一滴加え、次に氷冷下でオキザリルクロライド(52 μl, 0.61 mmol)を加え、室温で３０分攪拌した。反応液に、氷冷下1-(2-フルオロフェニル)-1H-ピラゾール-3-アミン(92 mg, 0.52 mmol)、トリエチルアミン(228 μl, 1.8 mmol)のジクロロメタン溶液を加え、室温で1時間攪拌した。反応液よりクロロホルムを用いて抽出し、２Ｎ塩酸、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製し、化合物Ｉ−３(78 mg)をアモルファスとして得た。
¹H-NMR (CDCl3) δ: 2.70-3.00 (m, 2H), 3.03 (m, 1H), 3.78 (t, 1H, J = 8.7 Hz), 4.04 (t, 1H, J = 6.9 Hz), 7.00 (d, 1H, J = 2.4 Hz), 7.12-7.28 (m, 7H), 7.75 (t, 1H, J = 7.8 Hz), 7.93 (s, 1H), 8.68 (br-s, 1H) Example 3 Synthesis of Compound (I-3)
First step

To a solution of 2-methylaniline (5) (1.1 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was stirred at 100 ° C. for 2.5 hours. The crude crystals precipitated upon cooling to room temperature were collected by filtration and recrystallized to obtain Compound 6 (1.35 g, yield 62%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.13 (s, 3H), 2.58-2.80 (m, 2H), 3.78 (m, 1H), 3.91 (t, 1H, J = 8.7Hz), 7.18-7.29 (m, 4H), 12.5 (br-s, 1H)
Second step

One drop of DMF was added to a dichloromethane suspension of compound 6 (120 mg, 0.55 mmol), and then oxalyl chloride (52 μl, 0.61 mmol) was added under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a solution of 1- (2-fluorophenyl) -1H-pyrazol-3-amine (92 mg, 0.52 mmol) and triethylamine (228 μl, 1.8 mmol) in ice-cooled solution and stirred at room temperature for 1 hour. did. The reaction solution was extracted with chloroform, washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain compound I-3 (78 mg) as an amorphous substance.
¹ H-NMR (CDCl3) δ: 2.70-3.00 (m, 2H), 3.03 (m, 1H), 3.78 (t, 1H, J = 8.7 Hz), 4.04 (t, 1H, J = 6.9 Hz), 7.00 (d, 1H, J = 2.4 Hz), 7.12-7.28 (m, 7H), 7.75 (t, 1H, J = 7.8 Hz), 7.93 (s, 1H), 8.68 (br-s, 1H)

２−フルオロアニリン(７)(1.4 g)とイタコン酸1.4 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で１．５時間照射した。溶媒を留去したのち反応器に析出した粗結晶を酢酸エチル−ヘキサンで再結晶させることにより化合物８(1.35 g, 収率62%)を白色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 2.84-3.05 (m, 2H), 3.46 (q, 1H, J = 8.1Hz), 4.00-4.10 (m, 2H), 7.12-7.45 (m, 4H)
第２工程

化合物８(140 mg, 0.63 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(133 mg, 0.69 mmol)のDMF溶液に、トリエチルアミン(0.44 ml, 3.14 mmol)、HATU(242 mg, 0.75 mmol)を順次加え、室温で３時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製して得られた粗結晶を再結晶させることにより、化合物Ｉ−６(52 mg, 収率62%)を得た。
¹H-NMR (DMSO-d6) δ: 1.45 (d, 6H, J = 6.9Hz), 2.69-2.82 (m, 2H), 3.49 (m, 1H), 3.82-4.04 (m, 2H), 4.46 (q, 1H, J = 6.6Hz), 7.23-7.40 (m, 6H), 7.75 (s, 1H), 10.27 (s, 1H) Example 4 Synthesis of Compound (I-6)
First step

To a solution of 2-fluoroaniline (7) (1.4 g) and itaconic acid 1.4 g in toluene (8 ml) was added 2 ml of acetic acid, and irradiated with a microwave irradiation apparatus at 150 ° C. for 1.5 hours. After distilling off the solvent, the crude crystals precipitated in the reactor were recrystallized from ethyl acetate-hexane to obtain Compound 8 (1.35 g, yield 62%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 2.84-3.05 (m, 2H), 3.46 (q, 1H, J = 8.1Hz), 4.00-4.10 (m, 2H), 7.12-7.45 (m, 4H)
Second step

To a DMF solution of compound 8 (140 mg, 0.63 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (133 mg, 0.69 mmol), triethylamine (0.44 ml, 3.14 mmol), HATU (242 mg, 0.75 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The crude crystals obtained by purifying the residue by silica gel chromatography were recrystallized to obtain Compound I-6 (52 mg, 62% yield).
¹ H-NMR (DMSO-d6) δ: 1.45 (d, 6H, J = 6.9Hz), 2.69-2.82 (m, 2H), 3.49 (m, 1H), 3.82-4.04 (m, 2H), 4.46 ( q, 1H, J = 6.6Hz), 7.23-7.40 (m, 6H), 7.75 (s, 1H), 10.27 (s, 1H)

２−イソプロピルアニリン(９)(1.49 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で３０分照射した。溶媒を留去することにより化合物１０(1.68 g, 収率62%)を黄色油状物として得た。
第２工程

化合物１０(200 mg, 0.81 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(187 mg, 0.97 mmol)のDMF溶液に、トリエチルアミン(0.56 ml, 4.1 mmol)、HATU(338 mg, 1.05 mmol)を順次加え、室温で１６時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製して得られた粗結晶を酢酸エチル−ヘキサンで再結晶させることにより、化合物Ｉ−７(55 mg, 収率16%)を得た。
¹H-NMR (CDCl3) δ: 1.23 (d, 6H, J = 6.9 Hz), 1.53 (d, 6H, J = 6.9 Hz), 2.83-3.10 (m, 3H), 3.45 (m, 1H), 3.39 (m, 1H), 4.01 (t, 1H, J = 9.6 Hz), 4.27 (t, 1H, J = 8.4 Hz), 4.53(m, 1H), 7.03 (t, 2H, J = 9.0 Hz), 7.27-7.38 (m, 3H), 7.42 (s, 1H), 7.58 (d, 1H, J = 1.8 Hz), 7.39 (br-s, 1H) Example 5 Synthesis of Compound (I-7)
First step

To a solution of 2-isopropylaniline (9) (1.49 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was irradiated with a microwave irradiation apparatus at 150 ° C. for 30 minutes. The solvent was distilled off to give compound 10 (1.68 g, yield 62%) as a yellow oil.
Second step

To a DMF solution of compound 10 (200 mg, 0.81 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (187 mg, 0.97 mmol), triethylamine (0.56 ml, 4.1 mmol), HATU (338 mg, 1.05 mmol) was sequentially added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, and the crude crystals obtained were recrystallized from ethyl acetate-hexane to obtain Compound I-7 (55 mg, 16% yield).
¹ H-NMR (CDCl3) δ: 1.23 (d, 6H, J = 6.9 Hz), 1.53 (d, 6H, J = 6.9 Hz), 2.83-3.10 (m, 3H), 3.45 (m, 1H), 3.39 (m, 1H), 4.01 (t, 1H, J = 9.6 Hz), 4.27 (t, 1H, J = 8.4 Hz), 4.53 (m, 1H), 7.03 (t, 2H, J = 9.0 Hz), 7.27 -7.38 (m, 3H), 7.42 (s, 1H), 7.58 (d, 1H, J = 1.8 Hz), 7.39 (br-s, 1H)

２−エチルアニリン(１１)(1.3 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で３０分照射した。溶媒を留去することにより化合物１２(1.6 g, 収率69%)を黄色油状物として得た。
¹H-NMR (DMSO-d₆) δ: 1.10 (t, 3H), 2.48-2.80 (m, 3H), 3.78 (m, 1H), 3.89 (dd, 1H, J = 8.7Hz), 7.15-7.32(m, 4H), 12.6 (br-s, 1H)
第２工程

化合物１２(200 mg, 0.86 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(165 mg, 0.86 mmol)のDMF溶液に、トリエチルアミン(0.24 ml, 1.7 mmol)、HATU(336 mg, 1.06 mmol)を順次加え、室温で１時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製することにより、化合物Ｉ−８(202 mg, 収率58%)を微黄色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 1.13 (t, 3H, J = 7.2 Hz), 1.44 (s, 3H), 1.46 (s, 3H), 2.61-2.80 (m, 2H), 3.50 (m, 1H), 3.78 (m, 1H), 3.94 (t, 1H, J = 8.4 Hz), 4.46 (q, 1H, J = 6.9 Hz), 7.18-7.41 (m, 7H), 7.76 (s, 1H), 10.26 (s, 1H) Example 6 Synthesis of Compound (I-8)
First step

To a solution of 2-ethylaniline (11) (1.3 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was irradiated with a microwave irradiation apparatus at 150 ° C. for 30 minutes. The solvent was distilled off to obtain Compound 12 (1.6 g, yield 69%) as a yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.10 (t, 3H), 2.48-2.80 (m, 3H), 3.78 (m, 1H), 3.89 (dd, 1H, J = 8.7Hz), 7.15-7.32 (m, 4H), 12.6 (br-s, 1H)
Second step

To a DMF solution of compound 12 (200 mg, 0.86 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (165 mg, 0.86 mmol), triethylamine (0.24 ml, 1.7 mmol), HATU (336 mg, 1.06 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give compound I-8 (202 mg, yield 58%) as slightly yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.13 (t, 3H, J = 7.2 Hz), 1.44 (s, 3H), 1.46 (s, 3H), 2.61-2.80 (m, 2H), 3.50 (m , 1H), 3.78 (m, 1H), 3.94 (t, 1H, J = 8.4 Hz), 4.46 (q, 1H, J = 6.9 Hz), 7.18-7.41 (m, 7H), 7.76 (s, 1H) , 10.26 (s, 1H)

３−アミノベンゾニトリル(１３)(1.1 g)とイタコン酸1.2 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で１．５時間照射した。溶媒を留去したのち反応器に析出した粗結晶を酢酸エチル−ヘキサンで再結晶させることにより化合物１４(0.52 g, 収率24%)を白色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 2.68-2.90 (m, 2H), 3.97-4.21 (m, 2H), 7.58-7.62(m, 2H), 8.01(m, 1H), 8.13 (m, 1H), 12.6 (br-s, 1H)
第２工程

化合物１４(140 mg, 0.61 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(123 mg, 0.64 mmol)のDMF溶液に、トリエチルアミン(0.25 ml, 1.83 mmol)、HATU(234 mg, 0.73 mmol)を順次加え、室温で３時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製して得られた粗結晶を酢酸エチル−ヘキサンで再結晶することにより、化合物Ｉ−１０(85 mg, 収率35%)を得た。
¹H-NMR (CDCl3) δ: 1.53 (d, 6H, J = 6.9 Hz), 2.89-3.14 (m, 2H), 3.43 (q, 1H, J = 7.5 Hz), 4.08 (t, 1H, J = 9.0 Hz), 4.25 (t, 1H, J = 7.8 Hz), 4.54(q, 1H, J =6.9 Hz), 7.05 (d, 1H, J = 8.4 Hz), 7.32-7.56 (m, 3H), 7.56 (s, 1H), 7.90 (d, 1H, J = 8.1 Hz), 7.98 (s, 1H), 8.12 (s, 1H) Example 7 Synthesis of Compound (I-10)
First step

To a solution of 3-aminobenzonitrile (13) (1.1 g) and 1.2 g of itaconic acid in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was irradiated with a microwave irradiation apparatus at 150 ° C. for 1.5 hours. After distilling off the solvent, the crude crystals precipitated in the reactor were recrystallized from ethyl acetate-hexane to obtain Compound 14 (0.52 g, yield 24%) as white crystals.
^{1 H-NMR (DMSO-d} 6) δ: 2.68-2.90 (m, 2H), 3.97-4.21 (m, 2H), 7.58-7.62 (m, 2H), 8.01 (m, 1H), 8.13 (m, 1H), 12.6 (br-s, 1H)
Second step

To a DMF solution of compound 14 (140 mg, 0.61 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (123 mg, 0.64 mmol), triethylamine (0.25 ml, 1.83 mmol), HATU (234 mg, 0.73 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, and the crude crystals obtained were recrystallized from ethyl acetate-hexane to obtain Compound I-10 (85 mg, 35% yield).
¹ H-NMR (CDCl3) δ: 1.53 (d, 6H, J = 6.9 Hz), 2.89-3.14 (m, 2H), 3.43 (q, 1H, J = 7.5 Hz), 4.08 (t, 1H, J = 9.0 Hz), 4.25 (t, 1H, J = 7.8 Hz), 4.54 (q, 1H, J = 6.9 Hz), 7.05 (d, 1H, J = 8.4 Hz), 7.32-7.56 (m, 3H), 7.56 (s, 1H), 7.90 (d, 1H, J = 8.1 Hz), 7.98 (s, 1H), 8.12 (s, 1H)

３−イソプロピルアニリン(１５)(1.49 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で１時間照射した。溶媒を留去したのち化合物１６(1.1 g, 収率39%)を黄色油状物として得た。
¹H-NMR (DMSO-d₆) δ: 1.24 (s, 3H), 1.27 (s, 3H), 2.87-2.96 (m, 3H), 3.39 (m, 1H), 4.04-4.19 (m, 2H), 7.06 (d, 1H, J = 8.7Hz), 7.24-7.45 (m, 3H)
第２工程

化合物１６(150 mg, 0.61 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(117 mg, 0.61 mmol)のDMF溶液に、トリエチルアミン(0.17 ml, 1.2 mmol)、HATU(234 mg, 0.73 mmol)を順次加え、室温で１時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製することにより、化合物Ｉ−１１(181 mg, 収率71%)を黄色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 1.20 (d, 6H, J = 7.2 Hz), 1.50 (d, 6H, J = 6.9 Hz), 2.74-2.89 (m, 3H), 3.44 (m, 1H), 3.98-4.10 (m, 2H), 4.46 (m, 1H), 7.03 (d, 1H J =7.5 Hz), 7.26-7.49 (m, 4H), 7.55 (s, 1H), 7.75 (s, 1H), 10.29 (br-s, 1H) Example 8 Synthesis of Compound (I-11)
First step

To a solution of 3-isopropylaniline (15) (1.49 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was irradiated with a microwave irradiation apparatus at 150 ° C. for 1 hour. After the solvent was distilled off, Compound 16 (1.1 g, yield 39%) was obtained as a yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (s, 3H), 1.27 (s, 3H), 2.87-2.96 (m, 3H), 3.39 (m, 1H), 4.04-4.19 (m, 2H) , 7.06 (d, 1H, J = 8.7Hz), 7.24-7.45 (m, 3H)
Second step

To a DMF solution of compound 16 (150 mg, 0.61 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (117 mg, 0.61 mmol), triethylamine (0.17 ml, 1.2 mmol), HATU (234 mg, 0.73 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give compound I-11 (181 mg, 71% yield) as yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (d, 6H, J = 7.2 Hz), 1.50 (d, 6H, J = 6.9 Hz), 2.74-2.89 (m, 3H), 3.44 (m, 1H ), 3.98-4.10 (m, 2H), 4.46 (m, 1H), 7.03 (d, 1H J = 7.5 Hz), 7.26-7.49 (m, 4H), 7.55 (s, 1H), 7.75 (s, 1H ), 10.29 (br-s, 1H)

３−ジフルオロメトキシアニリン(１７)(1.6 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で３０分照射した。溶媒を留去したのち粗結晶をジエチルエーテル−トルエンで再結晶することにより化合物１８(1.68 g, 収率62%)を白色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 3.04-3.11 (m, 2H), 3.52 (q, 1H, J = 7.2Hz), 4.10-4.31 (m, 2H), 7.04 (d, 1H, J = 7.2Hz), 7.40-7.59(m, 3H)
第２工程

化合物１８(150 mg, 0.55 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(106 mg, 0.55 mmol)のDMF溶液に、トリエチルアミン(0.16 ml, 1.1 mmol)、HATU(213 mg, 0.66 mmol)を順次加え、室温で１時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製して得られた粗結晶を酢酸エチル−ヘキサンで再結晶することにより、化合物Ｉ−１２(141 mg, 収率57%)を黄色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 1.31 (d, 6H, J = 6.9 Hz), 2.68-2.90 (m, 3H), 3.26 (q, 1H, J = 7.8 Hz), 3.83 (t, 1H, J = 9.6 Hz), 4.05 (t, 1H, J = 7.8 Hz), 4.31(q, 1H, J =6.9 Hz), 6.31 (s, 1H), 6.71 (d, 1H, J = 7.5 Hz), 6.81 (d, 1H, J = 8.4 Hz), 7.05-7.20 (m, 2H), 7.29 (m, 1H), 7.37 (m, 1H), 7.61 (m, 1H), 8.43 (br-s, 1H) Example 9 Synthesis of Compound (I-12)
First step

To a solution of 3-difluoromethoxyaniline (17) (1.6 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was irradiated with a microwave irradiation apparatus at 150 ° C. for 30 minutes. After the solvent was distilled off, the crude crystals were recrystallized from diethyl ether-toluene to obtain Compound 18 (1.68 g, yield 62%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 3.04-3.11 (m, 2H), 3.52 (q, 1H, J = 7.2Hz), 4.10-4.31 (m, 2H), 7.04 (d, 1H, J = 7.2Hz), 7.40-7.59 (m, 3H)
Second step

To a DMF solution of compound 18 (150 mg, 0.55 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (106 mg, 0.55 mmol), triethylamine (0.16 ml, 1.1 mmol), HATU (213 mg, 0.66 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, and the crude crystals obtained were recrystallized from ethyl acetate-hexane to give compound I-12 (141 mg, yield 57%) as yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.31 (d, 6H, J = 6.9 Hz), 2.68-2.90 (m, 3H), 3.26 (q, 1H, J = 7.8 Hz), 3.83 (t, 1H , J = 9.6 Hz), 4.05 (t, 1H, J = 7.8 Hz), 4.31 (q, 1H, J = 6.9 Hz), 6.31 (s, 1H), 6.71 (d, 1H, J = 7.5 Hz), 6.81 (d, 1H, J = 8.4 Hz), 7.05-7.20 (m, 2H), 7.29 (m, 1H), 7.37 (m, 1H), 7.61 (m, 1H), 8.43 (br-s, 1H)

４−イソプロピルアニリン(１９)(1.49 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で３０分照射した。溶媒を留去することにより化合物２０(1.94 g, 収率79%)を黄色油状物として得た。
第２工程

化合物２０(140 mg, 0.57 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(109 mg, 0.57 mmol)のDMF溶液に、トリエチルアミン(0.16 ml, 1.1 mmol)、HATU(218 mg, 0.68 mmol)を順次加え、室温で１時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製して得られた粗結晶を酢酸エチル−ヘキサンで再結晶することにより、化合物Ｉ−１３(120 mg, 収率50%)を黄色結晶として得た。
¹H-NMR (CDCl3) δ: 1.21 (d, 6H, J = 6.9 Hz), 1.52 (d, 6H, J = 6.9 Hz), 2.87 (m, 1H), 2.94-3.03 (m, 2H), 3.49 (m, 1H), 4.00 (t, 1H, J =9.6 Hz), 4.28(t, 1H, J =6.9 Hz), 4.52 (m, 1H), 7.01 (d, 1H, J = 8.4 Hz), 7.20-7.27 (m, 2H), 7.36 (m, 1H), 7.43-7.49 (m, 2H), 7.62 (m, 1H), 7.81 (m, 1H), 8.88 (m, 1H) Example 10 Synthesis of Compound (I-13)
First step

To a solution of 4-isopropylaniline (19) (1.49 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was irradiated with a microwave irradiation apparatus at 150 ° C. for 30 minutes. The solvent was distilled off to obtain Compound 20 (1.94 g, yield 79%) as a yellow oil.
Second step

To a DMF solution of compound 20 (140 mg, 0.57 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (109 mg, 0.57 mmol), triethylamine (0.16 ml, 1.1 mmol), HATU (218 mg, 0.68 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, and the crude crystals obtained were recrystallized from ethyl acetate-hexane to give compound I-13 (120 mg, yield 50%) as yellow crystals.
¹ H-NMR (CDCl3) δ: 1.21 (d, 6H, J = 6.9 Hz), 1.52 (d, 6H, J = 6.9 Hz), 2.87 (m, 1H), 2.94-3.03 (m, 2H), 3.49 (m, 1H), 4.00 (t, 1H, J = 9.6 Hz), 4.28 (t, 1H, J = 6.9 Hz), 4.52 (m, 1H), 7.01 (d, 1H, J = 8.4 Hz), 7.20 -7.27 (m, 2H), 7.36 (m, 1H), 7.43-7.49 (m, 2H), 7.62 (m, 1H), 7.81 (m, 1H), 8.88 (m, 1H)

４−ジフルオロメトキシアニリン(２１)(1.59 g)とイタコン酸1.3 gのトルエン(8 ml)溶液に、酢酸2 mlを加え、マイクロウェーブ照射装置により150℃で１時間照射した。溶媒を留去することにより化合物２２(505 mg, 収率19%)をアモルファスとして得た。
第２工程

化合物２２(150 mg, 0.55 mmol)と6-アミノ-3-イソプロピルベンゾ[d]オキサゾール-2(3H)-オン(106 mg, 0.55 mmol)のDMF溶液に、トリエチルアミン(0.15 ml, 1.1 mmol)、HATU(213 mg, 0.66 mmol)を順次加え、室温で１時間攪拌した。反応液を２Ｎ塩酸にあけ酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製することにより、化合物Ｉ−１４(145 mg, 収率59%)を黄色結晶として得た。
¹H-NMR (DMSO-d₆) δ: 1.45 (d, 6H, J = 7.5 Hz), 2.68-2.90 (m, 2H), 3.45 (m, 1H), 3.96-4.10 (m, 2H), 4.46(q, 1H, J =6.9 Hz), 7.20-7.25 (m, 2H), 7.32-7.45 (m, 3H), 7.71-7.80 (m, 3H), 10.3 (s, 1H)
実施例１２ 化合物（Ｉ−１７）の合成

化合物１４(150 mg, 0.65 mmol)のジクロロメタン混濁液に、DMFを一滴加え、次に氷冷下でオキザリルクロライド(68 μl, 0.77 mmol)を加え、室温で３０分攪拌した。反応液に、氷冷下4-((2S,6R)-2,6-ジメチルモルホリノ)アニリン(150 mg, 0.62 mmol)、トリエチルアミン(272 μl, 1.96 mmol)のジクロロメタン溶液に加え、室温で１６時間攪拌した。反応液をクロロホルムで抽出し、２Ｎ塩酸、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し溶媒を減圧留去した。残渣をシリカゲルクロマトグラフィーで精製し、得られた粗結晶を酢酸エチル−ヘキサンで再結晶することにより、化合物Ｉ−１７(85 mg, 収率31%)を得た。
¹H-NMR (CDCl3) δ: 1.24 (s, 3H), 1.27 (s, 3H), 2.33-2.43 (m, 2H), 2.85-3.11 (m, 2H), 3.29-3.78 (m, 3H), 3.75-3.84 (m, 2H), 4.01 (t, 1H, J =9.0 Hz), 6.84-6.90 (m, 2H), 7.39-7.54 (m, 4H), 7.87 (d, 1H, J =7.5 Hz), 7.97 (s, 1H) Example 11 Synthesis of Compound (I-14)
First step

To a solution of 4-difluoromethoxyaniline (21) (1.59 g) and itaconic acid 1.3 g in toluene (8 ml) was added 2 ml of acetic acid, and the mixture was irradiated with a microwave irradiation apparatus at 150 ° C. for 1 hour. The solvent was distilled off to obtain Compound 22 (505 mg, 19% yield) as amorphous.
Second step

To a DMF solution of compound 22 (150 mg, 0.55 mmol) and 6-amino-3-isopropylbenzo [d] oxazol-2 (3H) -one (106 mg, 0.55 mmol), triethylamine (0.15 ml, 1.1 mmol), HATU (213 mg, 0.66 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give compound I-14 (145 mg, yield 59%) as yellow crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.45 (d, 6H, J = 7.5 Hz), 2.68-2.90 (m, 2H), 3.45 (m, 1H), 3.96-4.10 (m, 2H), 4.46 (q, 1H, J = 6.9 Hz), 7.20-7.25 (m, 2H), 7.32-7.45 (m, 3H), 7.71-7.80 (m, 3H), 10.3 (s, 1H)
Example 12 Synthesis of Compound (I-17)

One drop of DMF was added to a dichloromethane suspension of compound 14 (150 mg, 0.65 mmol), and then oxalyl chloride (68 μl, 0.77 mmol) was added under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction solution was added 4-((2S, 6R) -2,6-dimethylmorpholino) aniline (150 mg, 0.62 mmol) and triethylamine (272 μl, 1.96 mmol) in dichloromethane under ice-cooling and at room temperature for 16 hours. Stir. The reaction mixture was extracted with chloroform, washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, and the resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain Compound I-17 (85 mg, yield 31%).
¹ H-NMR (CDCl3) δ: 1.24 (s, 3H), 1.27 (s, 3H), 2.33-2.43 (m, 2H), 2.85-3.11 (m, 2H), 3.29-3.78 (m, 3H), 3.75-3.84 (m, 2H), 4.01 (t, 1H, J = 9.0 Hz), 6.84-6.90 (m, 2H), 7.39-7.54 (m, 4H), 7.87 (d, 1H, J = 7.5 Hz) , 7.97 (s, 1H)

¹H-NMR (DMSO-d₆) δ: 1.45-1.77 (m, 8H), 2.49 (m, 2H), 3.40 (m, 2H), 3.68 (t, 1H, J = 9.0 Hz), 4.30 (m, 1H), 6.83 (d, 1H, J = 2.6 Hz), 7.31-7.50 (m, 3H), 7.72 (m, 1H), 8.10 (t, 1H, J = 2.6 Hz), 10.93 (s, 1H).
化合物Ｉ−５

¹H-NMR (DMSO-d₆) δ: 1.45 (d, 6H, J = 6.9 Hz), 2.18 (s, 3H), 2.67-2.77 (m, 2H), 3.49 (m, 1H), 3.80 (m, 1H), 3.96 (t, 1H, J = 9.6 Hz), 4.46 (q, 1H, J = 6.6 Hz), 7.23-7.40 (m, 5H), 7.75 (s, 1H), 10.25 (s, 1H)
化合物Ｉ−９

¹H-NMR (DMSO-d₆) δ: 1.46 (d, 6H, J = 6.9 Hz), 2.12 (s, 3H), 2.27 (s, 3H), 2.67-2.76 (m, 2H), 3.49 (m, 1H), 3.76 (m, 1H), 3.93 (m, 1H), 4.46 (q, 1H, J = 6.9 Hz), 7.04-7.07 (m, 2H), 7.16 (d, 1H, J = 8.1 Hz), 7.29-7.40 (m, 2H), 7.76 (s, 1H), 10.25 (br-s, 1H)
化合物Ｉ−１５

¹H-NMR (DMSO-d₆) δ: 1.44 (d, 6H, J = 8.0 Hz), 1.45-1.70 (m, 14H), 2.48 (m, 2H), 3.38 (m, 2H), 3.58 (t, 1H, J = 9.0), 4.01 (m, 1H), 4.44 (m, 1H), 7.27 (dd, 1H, J = 1.8, 8.7 Hz), 7.35 (d, 1H, J = 8.7 Hz), 7.71 (d, 1H, J = 1.8 Hz), 10.2 (s, 1H).
化合物Ｉ−１６

¹H-NMR (CDCl3) δ: 1.25 (s, 3H), 1.27 (s, 3H), 2.26 (s, 3H), 2.31-2.50 (m, 2H), 2.74-3.30 (m, 2H), 3.28-3.42 (m, 3H), 3.78-3.85 (m, 3H), 4.05 (m, 1H), 6.78-6.92 (m, 2H), 7.13-7.27 (m, 4H), 7.38-7.42 (m, 2H), 7.81 (br-s, 1H) The following compounds synthesized in the same manner are also included in the present invention.
Compound I-4

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.77 (m, 8H), 2.49 (m, 2H), 3.40 (m, 2H), 3.68 (t, 1H, J = 9.0 Hz), 4.30 (m , 1H), 6.83 (d, 1H, J = 2.6 Hz), 7.31-7.50 (m, 3H), 7.72 (m, 1H), 8.10 (t, 1H, J = 2.6 Hz), 10.93 (s, 1H) .
Compound I-5

¹ H-NMR (DMSO-d ₆ ) δ: 1.45 (d, 6H, J = 6.9 Hz), 2.18 (s, 3H), 2.67-2.77 (m, 2H), 3.49 (m, 1H), 3.80 (m , 1H), 3.96 (t, 1H, J = 9.6 Hz), 4.46 (q, 1H, J = 6.6 Hz), 7.23-7.40 (m, 5H), 7.75 (s, 1H), 10.25 (s, 1H)
Compound I-9

¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (d, 6H, J = 6.9 Hz), 2.12 (s, 3H), 2.27 (s, 3H), 2.67-2.76 (m, 2H), 3.49 (m , 1H), 3.76 (m, 1H), 3.93 (m, 1H), 4.46 (q, 1H, J = 6.9 Hz), 7.04-7.07 (m, 2H), 7.16 (d, 1H, J = 8.1 Hz) , 7.29-7.40 (m, 2H), 7.76 (s, 1H), 10.25 (br-s, 1H)
Compound I-15

¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (d, 6H, J = 8.0 Hz), 1.45-1.70 (m, 14H), 2.48 (m, 2H), 3.38 (m, 2H), 3.58 (t , 1H, J = 9.0), 4.01 (m, 1H), 4.44 (m, 1H), 7.27 (dd, 1H, J = 1.8, 8.7 Hz), 7.35 (d, 1H, J = 8.7 Hz), 7.71 ( d, 1H, J = 1.8 Hz), 10.2 (s, 1H).
Compound I-16

¹ H-NMR (CDCl3) δ: 1.25 (s, 3H), 1.27 (s, 3H), 2.26 (s, 3H), 2.31-2.50 (m, 2H), 2.74-3.30 (m, 2H), 3.28- 3.42 (m, 3H), 3.78-3.85 (m, 3H), 4.05 (m, 1H), 6.78-6.92 (m, 2H), 7.13-7.27 (m, 4H), 7.38-7.42 (m, 2H), 7.81 (br-s, 1H)

Test Example 1 Affinity for NPY Y5 receptor The cDNA sequence encoding human NPY Y5 receptor (see WO96 / 16542) was cloned into the expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 8957). . The obtained expression vector was transfected into host cells CHO using LipofectAMINE reagent (trademark, Gibco BRL) according to the instruction manual to obtain NPY Y5 receptor stably expressing cells.
Membrane preparations prepared from CHO cells expressing the NPY Y5 receptor were combined with the compounds of the present invention and 30,000 cpm [ ¹²⁵ I] peptide YY (final concentration 60 pM: Amersham) with an assay buffer (0.1 After incubating in 20 mM HEPES-Hanks buffer solution (pH 7.4) containing 2% bovine serum albumin at 25 ° C. for 2 hours, the solution was 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. Nonspecific 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. 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 NPY Y5 receptor. That is, this compound showed affinity for the NPY Y5 receptor.

Test Example 2 CYP Inhibition Test Using a commercially available pooled human liver microsome, O-deethylase activity of ethoxyresorufin (CYP1A2), tolbutamide as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C19, 2D6) Metabolites produced using 4-hydroxylation activity (CYP2C9), mephenytoin 4'-hydroxylation activity (CYP2C19), dextromethorphan O-demethylation activity (CYP2D6), and terfenadine hydroxylation activity (CYP3A4) as indices. The extent to which the amount was inhibited by the test compound was evaluated.
The reaction conditions were as follows: substrate, 0.5 μM ethoxyresorufin (CYP1A2), 100 μM tolbutamide (CYP2C9), 50 μM S-mephenytoin (CYP2C19), 5 μM dextromethorphan (CYP2D6), 1 μM terfenadine (CYP3A4) ); Reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg / mL; test drug concentration, 1, 5, 10, 20 μM (4 points).
As a reaction solution in a 96-well plate, add 5 types of each substrate, human liver microsome, and test drug in 50 mM Hepes buffer with the above composition, and add NADPH, a coenzyme, to start a metabolic reaction as an indicator. Then, after reacting at 37 ° C. for 15 minutes, 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 supernatant is collected using a fluorescent multilabel counter, hydroxytolbutamide (CYP2C9 metabolite), 4'-hydroxymephenytoin (CYP2C19 metabolite), (CYP2D6 metabolite) and terfenadine alcohol metabolite (CYP3A4 metabolite) were quantified by LC / MS / MS.
The control (100%) was obtained by adding only 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. IC50 value was calculated from the formula of (BA) / (1 + ((C / x) ^ D))) to evaluate inhibition. The results are shown in Table 2.
Based on the above, it was confirmed that the compounds according to the present invention have a weak inhibitory effect on CYP1A2, CYP2C19, and CYP2D6.

Test example 3
Metabolic stability Evaluation of metabolic stability by liver microsomes: NADPH (final concentration 1 mM, in the case of oxidative metabolism), human liver microsomes (final concentration 0.5 mg protein / ml) and each compound in Tris-HCl buffer (pH 7.4) (Final concentration 2 μM) was 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 twice the amount of the reaction solution acetonitrile / methanol = 1/1 (v / v), the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from a comparison of the values of 0 and 30 minutes. The results are shown in Table 3.
From the above, it was confirmed that the compound of the present invention has high metabolic stability.

Test example 4
Solubility The compound of the present invention and the measurement solvent (JP-2 solution, 20 mM sodium taurocholate-containing JP-2 solution) were stirred at 37 ° C for 3 hours, filtered through a 0.45 µm filter, and the concentration of the filtrate was measured by the HPLC method. did. The results are shown in Table 4.
From the above, it was confirmed that the compound of the present invention was excellent in solubility.

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 were uniformly mixed, crushed and granulated, and dried to give granules of an appropriate size. Next, calcium stearate was added and compression molded to obtain tablets.

Formulation Example 2 Capsule Compound (I) 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to make a powder as a fine powder or powder. This was filled into a capsule container to obtain a capsule.

Formulation Example 3 Granules Compound (I) 30 g
Lactose 265g
Magnesium stearate 5g
After thoroughly mixing and compression molding, the mixture was pulverized, sized and sieved to give granules of an appropriate size.

  As is clear from the above test examples, the compound according to the present invention exhibits NPY Y5 receptor antagonistic action. Therefore, the compound according to the present invention is very useful as an antiobesity agent and an antifeedant.

Claims (14)

Formula (I):

(In the formula, R ¹ represents a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl or substituted or unsubstituted heteroaryl Arylalkyl,
R ² is aryl substituted with substituted or unsubstituted morpholino or substituted or unsubstituted heterocyclyl.
Except when R ² is a substituted or unsubstituted carbazole-3-yl. )
Or a pharmaceutically acceptable salt or solvate thereof. 2. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ¹ is substituted or unsubstituted phenyl or substituted or unsubstituted cycloalkyl. The compound according to claim 2, wherein R ¹ is phenyl substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano, or unsubstituted cycloalkyl having 5 to 8 carbon atoms, The pharmaceutically acceptable salt or solvate thereof. R ¹ is phenyl, unsubstituted cyclopentyl or unsubstituted cyclooctyl substituted with one or more substituents selected from fluoro, methyl, ethyl, isopropyl, difluoromethoxy or cyano.
The compound according to claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 4, wherein R ² is substituted or unsubstituted heterocyclyl, a pharmaceutically acceptable salt thereof, or a solvate thereof. R ² is the formula:

(Wherein ring A is a heterocycle,
R ³ and R ⁴ are each independently halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclyl or substituted or unsubstituted aryl;
m and n are each independently an integer of 0-2. Is a group represented by
6. The compound according to claim 5, a pharmaceutically acceptable salt thereof or a solvate thereof. Ring A is pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, benzoxazole, 2,3-dihydrobenzoxazole, benzthiazole, 2,3-dihydrobenzthiazole, benzimidazole or 2,3-dihydrobenzimidazole, The compound according to claim 6, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to claim 7, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Ring A is pyrazole or 2,3-dihydrobenzoxazole. 9. The compound according to claim 8, wherein ring A is pyrazole, a pharmaceutically acceptable salt thereof, or a solvate thereof. 9. The compound according to claim 8, a pharmaceutically acceptable salt or a solvate thereof, wherein Ring A is 2,3-dihydrobenzoxazole. R ³ is halogen-substituted phenyl or unsubstituted alkyl;
R ⁴ is oxo,
m is 1,
n is an integer of 0 or 1,
The compound according to claim 9 or 10, a pharmaceutically acceptable salt thereof, or a solvate thereof. R ³ is fluorophenyl or isopropyl;
R ⁴ is oxo,
m is 1,
n is an integer of 0 or 1,
The compound according to claim 11, a pharmaceutically acceptable salt thereof, or a solvate thereof. Pharmaceutical composition which uses the compound in any one of Claims 1-12, its pharmaceutically acceptable salt, or those solvates as an active ingredient. A pharmaceutical composition having an NPY Y5 receptor antagonistic activity comprising the compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.