JP2010138073A - Picolinic acid amide compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having GK-activating activity and useful as a medicine. <P>SOLUTION: The picolinic acid amide compound is represented by formula (1) (wherein, R<SP>1</SP>is 1-8C alkyl, 1-9C heteroaryl, 2-9C heterocyclyl or the like; R<SP>2</SP>is hydrogen, 1-8C alkyl, phenyl, 7-14C arylalkyl or the like; Ar is 1-9C heteroaryl having a C=N bond and bonded to nitrogen of amide neighboring to Ar in formula (1) through carbon forming a C=N bond in the Ar). <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to novel picolinic acid amide compounds having a glucokinase activating action and pharmaceuticals containing them as active ingredients.

Glucokinase (hereinafter referred to as GK) belongs to the hexokinase family, and catalyzes phosphorylation of glucose taken into cells in pancreatic beta cells and hepatocytes. The GK of liver and pancreatic beta cells are identical enzymatically, although the N-terminal 15 amino acid sequences differ due to splicing differences. GK has a high affinity S _0.5 is a longitudinal 10mM for glucose and for glucose 6 inhibition of phosphate free from the product, the reaction rate is sensitive to physiological variation range of the blood glucose level To do. Pancreatic beta cells regulate glucose-dependent insulin secretion, while the liver regulates glycolysis or glycogen synthesis to maintain and regulate blood glucose levels. For this reason, GK is considered to function as a glucose sensor for maintaining blood glucose level homeostasis (see Non-Patent Document 1).
The hypothesis that GK functions as an in vivo glucose sensor is supported by the discovery of genetically engineered mice and human genetic mutations. GK homo-deficient mice exhibit hyperglycemia soon after birth and die, and in hetero-deficient mice, hyperglycemia and impaired glucose tolerance have been observed (see Non-Patent Document 2). On the other hand, a decrease in blood glucose has been confirmed in GK overexpressing mice (see Non-Patent Document 3). Furthermore, diabetes occurs from a young age in human MODY2 (maturity onset diabetics of the young) in which a GK gene mutation is observed (see Non-Patent Document 4). This gene mutation has been confirmed to reduce GK activity. On the other hand, a family having a gene mutation that enhances GK activity has also been reported (see Non-Patent Document 5). In this gene mutation, the affinity of GK for glucose is enhanced, and a fasting hypoglycemia symptom accompanied by an increase in blood insulin concentration is observed.
Thus, GK has been shown to function as a glucose sensor in mammals including humans.

  Substances that increase GK activity (hereinafter referred to as GK activators) can correct hyperglycemia by increasing glucose metabolism in the liver, glycogen synthesis, and glucose-induced insulin secretion from pancreatic beta cells. It seems possible. Treatment and prevention of diabetic chronic complications such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis, and obesity, hyperlipidemia, hypertension, metabolic syndrome, etc. It can also be expected to lead to the treatment and prevention of diabetes related diseases. Therefore, a compound that enhances GK function is expected to be an effective therapeutic agent for diabetes.

On the other hand, it has been reported that GK is expressed not only in the pancreas and liver but also in the feeding center and has an important function in the feeding-suppressing action by glucose (see Non-Patent Document 6). Therefore, it is considered that the GK activator acts on the feeding center and has a feeding-suppressing action, and can be expected not only as a treatment for diabetes but also as a therapeutic agent for obesity.
Conventionally, certain propionamide compounds, picolinic acid amide compounds, benzamide compounds, and benzimidazole compounds have been reported as GK activators, but there is no disclosure of the compounds of the present invention (Patent Documents 1, 2, 3 and 4). Also, structurally similar picolinic acid amide compounds have been reported, but there is no disclosure of the compounds of the present invention, which are different from the uses of the compounds of the present invention in that they are used as rheumatic drugs and central disease drugs, respectively. (See Patent Documents 5 and 6).

Matschinsky F.M. M.M. and Magnnuson M. et al. A. , Frontiers in Diabetes, 16, 2004 Group A. et al. Cell, 83, 1, 69-78, 1995 Ferre T. et al. Proc. Natl. Acad. Sci. , 93, 14, 7225-7230, 1996 Vionet N.E. et al. Nature, 356, 6371, 721-722, 1992 Glaser B. et al. N. Engl. J. et al. Med. 338, 4, 226-230, 1998 Kang L. et al, Diabetes, 55, 2, 412-420, 2006 WO01 / 085707 WO04 / 081001 WO05 / 044801 WO07 / 007910 WO06 / 061715 WO05 / 079782

  An object of the present invention is to provide a compound having an excellent GK activation action and useful as a pharmaceutical product.

  As a result of diligent research to find a compound having a GK activation action, the present inventors have achieved this object by a picolinic acid amide compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof. The present invention has been completed.

（式（１）中、
Ｒ¹はＣ_１−８アルキル基（該Ｃ_１−８アルキル基は置換されていないか、又はヒドロキシ基、カルボキシ基、カルバモイル基、Ｃ_１−６アルコキシ基、Ｃ_２−６アルコキシカルボニル基、Ｃ_２−８アルカノイルアミノ基、ジ（Ｃ_１−８アルキル）アミノ基、及びシアノ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）、Ｃ_３−８シクロアルキル基、Ｃ_１−６アルコキシ基（該Ｃ_１−６アルコキシ基は置換されていないか、又はヒドロキシ基で置換されている。）、Ｃ_２−６アルコキシカルボニル基、Ｃ_１−６アルキルチオ基、Ｃ_２−８アルカノイルアミノ基、Ｃ_１−８アルキルスルホニルアミノ基、Ｃ_２−９ヘテロシクリル基（該Ｃ_２−９ヘテロシクリル基は置換されていないか、又はハロゲン原子、ヒドロキシ基、オキソ基、Ｃ_１−８アルキル基、（Ｃ_１−８アルキル）アミノ基（該（Ｃ_１−８アルキル）アミノ基は置換されていないか、又はヒドロキシ基で置換されている。）、ジ（Ｃ_１−８アルキル）アミノ基、カルボキシ基、シアノ基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から４個の基で置換されている。）、（Ｃ_１−８アルキル）アミノ基、ジ（Ｃ_１−８アルキル）アミノ基、ヒドロキシ基、フェニル基、フェノキシ基、フェニルチオ基、Ｎ−（Ｃ_１−８アルキル）アニリノ基、Ｃ_１−９ヘテロアリール基、Ｃ_１−９ヘテロアリールチオ基、又はＣ_７−１４アリールアルキル基（該フェニル基、フェノキシ基、フェニルチオ基、Ｎ−（Ｃ_１−８アルキル）アニリノ基、Ｃ_１−９ヘテロアリール基、Ｃ_１−９ヘテロアリールチオ基、及びＣ_７−１４アリールアルキル基は置換されていないか、又はＣ_１−８アルキル基、ヒドロキシ基、アミノ基、（Ｃ_１−８アルキル）アミノ基、ジ（Ｃ_１−８アルキル）アミノ基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）を示し、
Ｒ²は水素原子、Ｃ_１−８アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−９ヘテロシクリル基、フェニル基、Ｃ_１−９ヘテロアリール基、Ｃ_７−１４アリールアルキル基、又はＣ_１−９ヘテロアリールＣ_１−６アルキル基（該フェニル基、Ｃ_１−９ヘテロアリール基、Ｃ_７−１４アリールアルキル基、及びＣ_１−９ヘテロアリールＣ_１−６アルキル基は置換されていないか、又はハロゲン原子、ヒドロキシ基、Ｃ_１−８アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルチオ基、Ｃ_１−８アルキルスルホニル基、カルボキシ基、Ｃ_２−６アルコキシカルボニル基、及びＣ_２−８アルカノイル基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）を示し、
Ａｒは、式（２）

で示される単環系又は縮合多環系Ｃ_１−９ヘテロアリール基（該式（２）中、環Ａは置換されていないか、又はハロゲン原子、Ｃ_１−８アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_１−６アルコキシ基、カルボキシ基、カルボキシＣ_１−８アルキル基、Ｃ_２−６アルコキシカルボニル基、Ｃ_２−６アルコキシカルボニルＣ_１−８アルキル基、カルバモイル基、カルバモイルＣ_１−８アルキル基、ヒドロキシ基、ヒドロキシＣ_１−８アルキル基、アミノＣ_１−８アルキル基、（Ｃ_１−８アルキル）アミノＣ_１−８アルキル基、ジ（Ｃ_１−８アルキル）アミノＣ_１−８アルキル基、Ｃ_２−６アルカノイル基、及びＣ_２−９ヘテロシクリル基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）を示し、
Ｘは−ＣＲ^３Ｒ^４−、又は−Ｓ−を示し、
Ｙは単結合、−Ｏ−、−ＮＲ^５−、又は−Ｓ−を示し、
Ｒ^３、Ｒ^４、及びＲ^５は同一又は異なって水素原子、若しくはＣ_１−６アルキル基を示す。）
で表されるピコリン酸アミド化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
本発明の他の態様としては、式（１）において、

（式（１）中、
Ｒ¹はＣ_１−８アルキル基（該Ｃ_１−８アルキル基は置換されていないか、又はヒドロキシ基、カルボキシ基、カルバモイル基、Ｃ_１−６アルコキシ基、Ｃ_２−６アルコキシカルボニル基、Ｃ_２−８アルカノイルアミノ基、ジ（Ｃ_１−８アルキル）アミノ基、及びシアノ基からなる群より選ばれる１個の基で置換されている。）、Ｃ_３−８シクロアルキル基、Ｃ_１−６アルコキシ基（該Ｃ_１−６アルコキシ基は置換されていないか、又はヒドロキシ基で置換されている。）、Ｃ_１−６アルキルチオ基、Ｃ_２−８アルカノイルアミノ基、Ｃ_１−８アルキルスルホニルアミノ基、Ｃ_２−９ヘテロシクリル基（該Ｃ_２−９ヘテロシクリル基は置換されていないか、又はハロゲン原子、オキソ基、Ｃ_１−８アルキル基、ジ（Ｃ_１−８アルキル）アミノ基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から４個の基で置換されている。）、（Ｃ_１−８アルキル）アミノ基、ジ（Ｃ_１−８アルキル）アミノ基、ヒドロキシ基、フェニル基、フェノキシ基、フェニルチオ基、Ｎ−（Ｃ_１−８アルキル）アニリノ基、Ｃ_１−９ヘテロアリール基、又はＣ_１−９ヘテロアリールチオ基（該フェニル基、フェノキシ基、フェニルチオ基、Ｎ−（Ｃ_１−８アルキル）アニリノ基、Ｃ_１−９ヘテロアリール基、及びＣ_１−９ヘテロアリールチオ基は置換されていないか、又はＣ_１−８アルキル基、及びヒドロキシ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）を示し、
Ｒ²は水素原子、Ｃ_１−８アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−９ヘテロシクリル基、フェニル基、Ｃ_１−９ヘテロアリール基、又はＣ_７−１４アリールアルキル基（該フェニル基、Ｃ_１−９ヘテロアリール基、及びＣ_７−１４アリールアルキル基は置換されていないか、又はハロゲン原子、ヒドロキシ基、Ｃ_１−８アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルチオ基、及びＣ_１−８アルキルスルホニル基からなる群より同一若しくは異なって選ばれる１から２個の基で置換されている。）を示し、
Ａｒは、式（２）

で示される単環系又は縮合多環系Ｃ_１−９ヘテロアリール基（該式（２）中、環Ａは置換されていないか、又はハロゲン原子、Ｃ_１−８アルキル基、カルボキシ基、カルボキシＣ_１−８アルキル基、Ｃ_２−６アルコキシカルボニル基、Ｃ_２−６アルコキシカルボニルＣ_１−８アルキル基、及びヒドロキシＣ_１−８アルキル基からなる群より選ばれる１個の基で置換されている。）を示し、
Ｘは−ＣＲ^３Ｒ^４−、又は−Ｓ−を示し、
Ｙは単結合、−Ｏ−、又は−Ｓ−を示し、
Ｒ^３、及びＲ^４は同一又は異なって水素原子、若しくはＣ_１−６アルキル基を示す。）
で表されるピコリン酸アミド化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。 That is, the present invention provides the formula (1)

(In the formula (1),
R ¹ represents a C _1-8 alkyl group (the C _1-8 alkyl group is not substituted, or a hydroxy group, a carboxy group, a carbamoyl group, a C _1-6 alkoxy group, a C _2-6 alkoxycarbonyl group, a C Substituted with 1 to 3 groups selected from the group consisting of _2-8 alkanoylamino group, di (C _1-8 alkyl) amino group, and cyano group, the same or different.), C _3-8 cyclo An alkyl group, a C _1-6 alkoxy group (the C _1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), a C _2-6 alkoxycarbonyl group, a C _1-6 alkylthio group, C _2-8 alkanoylamino _group, or _{C 1-8} alkylsulfonylamino _{group, C 2-9} heterocyclyl group (the _{C 2-9} heterocyclyl group is unsubstituted or halo Emissions atom, hydroxy group, oxo _{group, C 1-8} alkyl _group, optionally substituted with _{(C 1-8} alkyl) amino group (or not the _{(C 1-8} alkyl) amino group is substituted, or hydroxy group And 1 to 4 groups selected from the group consisting of a di (C _1-8 alkyl) amino group, a carboxy group, a cyano group, and a C _1-6 alkoxy group. ), (C _1-8 alkyl) amino group, di (C _1-8 alkyl) amino group, hydroxy group, phenyl group, phenoxy group, phenylthio group, N- (C _1-8 alkyl) anilino group, C _{1- 9} heteroaryl _{groups, C 1-9} heteroarylthio group, or a _{C 7-14} arylalkyl group (the phenyl group, a phenoxy group, a phenylthio group, _{N-(C 1-8} alkyl) anilino groups, C _-9 heteroaryl _{group, C 1-9} heteroarylthio group, and _{C 7-14} arylalkyl group is unsubstituted, or _{C 1-8} alkyl group, hydroxy group, an amino _{group, (C 1-8} alkyl And 1 to 3 groups selected from the same or different groups from the group consisting of an amino group, a di (C _1-8 alkyl) amino group, and a C _1-6 alkoxy group.
R ² is a hydrogen atom, a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _2-9 heterocyclyl group, a phenyl group, a C _1-9 heteroaryl group, a C _7-14 arylalkyl group, or C _{1. -9} heteroaryl C _1-6 alkyl group (the phenyl group, C _1-9 heteroaryl group, C _7-14 arylalkyl group, and C _1-9 heteroaryl C _1-6 alkyl group are not substituted) Or a halogen atom, a hydroxy group, a C _1-8 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a C _1-8 alkylsulfonyl group, a carboxy group, a C _2-6 alkoxycarbonyl group, and C Substituted with 1 to 3 groups selected from the group consisting of _2-8 alkanoyl groups, which are the same or different.
Ar is the formula (2)

A monocyclic or condensed polycyclic C _1-9 heteroaryl group represented by (in the formula (2), ring A is not substituted or is a halogen atom, a C _1-8 alkyl group, C _3-8 Cycloalkyl group, C _1-6 alkoxy group, carboxy group, carboxy C _1-8 alkyl group, C _2-6 alkoxycarbonyl group, C _2-6 alkoxycarbonyl C _1-8 alkyl group, carbamoyl group, carbamoyl C _{1- 8} alkyl group, hydroxy group, hydroxy C _1-8 alkyl group, amino C _1-8 alkyl group, (C _1-8 alkyl) amino C _1-8 alkyl group, di (C _1-8 alkyl) amino C _1- Substituted with 1 to 3 groups selected from the group consisting of ₈ alkyl groups, C _2-6 alkanoyl groups, and C _2-9 heterocyclyl groups, which are the same or different.
X represents —CR ³ R ⁴ —, or —S—,
Y represents a single bond, —O—, —NR ⁵ —, or —S—,
R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group. )
And a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound or a solvate thereof.
As another aspect of the present invention, in the formula (1),

(In the formula (1),
R ¹ represents a C _1-8 alkyl group (the C _1-8 alkyl group is not substituted, or a hydroxy group, a carboxy group, a carbamoyl group, a C _1-6 alkoxy group, a C _2-6 alkoxycarbonyl group, a C Substituted with one group selected from the group consisting of a _2-8 alkanoylamino group, a di (C _1-8 alkyl) amino group, and a cyano group), a C _3-8 cycloalkyl group, a C _{1- 6} alkoxy group (the C _1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), C _1-6 alkylthio group, C _2-8 alkanoylamino group, C _1-8 alkylsulfonyl amino _{group, C 2-9} heterocyclyl group (or not the _{C 2-9} heterocyclyl group is substituted, or a halogen atom, an oxo _{group, C 1-8} alkyl groups, di _{(C 1-8} alkyl ) Amino group, and _{C 1-6} is substituted the same or different from 1 selected by the four groups from the group consisting of alkoxy _{group.), (C 1-8} alkyl) amino group, di _{(C 1- 8} alkyl) amino group, hydroxy group, phenyl group, phenoxy group, phenylthio group, N- (C _1-8 alkyl) anilino group, C _1-9 heteroaryl group, or C _1-9 heteroarylthio group (this phenyl Group, phenoxy group, phenylthio group, N- (C _1-8 alkyl) anilino group, C _1-9 heteroaryl group, and C _1-9 heteroarylthio group are unsubstituted or C _1-8 alkyl Substituted with 1 to 3 groups selected from the group consisting of a group and a hydroxy group, the same or different.
R ² represents a hydrogen atom, a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _2-9 heterocyclyl group, a phenyl group, a C _1-9 heteroaryl group, or a C _7-14 arylalkyl group (the phenyl Group, C _1-9 heteroaryl group, and C _7-14 arylalkyl group are not substituted, or are a halogen atom, a hydroxy group, a C _1-8 alkyl group, a C _1-6 alkoxy group, a C _1-6. Substituted with 1 to 2 groups selected from the group consisting of an alkylthio group and a C _1-8 alkylsulfonyl group, which are the same or different.
Ar is the formula (2)

A monocyclic or condensed polycyclic C _1-9 heteroaryl group represented by the formula (In the formula (2), ring A is not substituted or is a halogen atom, a C _1-8 alkyl group, a carboxy group, a carboxy group, Substituted with one group selected from the group consisting of a C _1-8 alkyl group, a C _2-6 alkoxycarbonyl group, a C _2-6 alkoxycarbonyl C _1-8 alkyl group, and a hydroxy C _1-8 alkyl group. )
X represents —CR ³ R ⁴ —, or —S—,
Y represents a single bond, —O—, or —S—;
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group. )
And a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound or a solvate thereof.

  According to the present invention, a compound having an excellent GK activation action could be provided.

Hereinafter, the present invention will be described in detail, but the present invention is not particularly limited thereto.
In the present invention, “n” is normal, “i” is iso, “s” is secondary, “t” is tertiary, “c” is cyclo, “o” is ortho, “m” Indicates meta, and “p” indicates para.
The “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n— Examples include pentyl group, n-hexyl group, i-propyl group, i-butyl group, t-butyl group, s-butyl group, i-pentyl group, neopentyl group, t-pentyl group, methyl group, ethyl group Group, i-propyl group is more preferable.
The “C _1-8 alkyl group” refers to a linear or branched alkyl group having 1 to 8 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n— Pentyl group, n-hexyl group, n-heptyl group, n-octyl group, i-propyl group, i-butyl group, t-butyl group, s-butyl group, i-pentyl group, neopentyl group, t-pentyl group And a methyl group, an ethyl group, and an i-propyl group are more preferable.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, more preferably a fluorine atom or a chlorine atom.
“C _3-8 cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms, for example, c-propyl group, c-butyl group, c-pentyl group, c-hexyl group, c-heptyl group. Group, c-octyl group, and c-pentyl group and c-hexyl group are more preferable.
The “C _1-6 alkoxy group” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, n -Butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyloxy group, n-hexyloxy group can be mentioned, and methoxy group and ethoxy group are more preferable .
The “C _2-6 alkoxycarbonyl group” refers to a carbonyl group having a linear or branched alkoxy group having 1 to 5 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, i-propoxycarbonyl. A methoxycarbonyl group and an ethoxycarbonyl group are more preferable.

The “(C _1-8 alkyl) amino group” refers to an amino group having one “C _1-8 alkyl group” as a substituent, and includes linear, branched and C _3-8 cycloalkylamino. Group, for example, methylamino group, ethylamino group, n-propylamino group, i-propylamino group, c-propylamino group, n-butylamino group, i-butylamino group, s-butyl. An amino group, a t-butylamino group, a c-butylamino group, and a c-hexylamino group can be exemplified, and a methylamino group, an ethylamino group, and an i-propylamino group are more preferable.
“Di (C _1-8 alkyl) amino group” refers to an amino group having two identical or different “C _1-8 alkyl groups” as substituents, such as dimethylamino group, diethylamino group, di-n. -Propylamino group, di-i-propylamino group, di-i-butylamino group, di-s-butylamino group, di-t-butylamino group, ethyl (methyl) amino group, methyl (n-propyl) An amino group can be mentioned, and a dimethylamino group and a diethylamino group are more preferable.
The “C _1-6 alkylthio group” refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, such as a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, n -Butylthio group, i-butylthio group, s-butylthio group, t-butylthio group can be mentioned, and methylthio group and ethylthio group are more preferable.
The “C _1-8 alkylsulfonyl group” refers to a linear or branched alkylsulfonyl group having 1 to 8 carbon atoms, such as a methylsulfonyl group, an n-propylsulfonyl group, or an i-butylsulfonyl group. , N-hexylsulfonyl group can be mentioned, and methylsulfonyl group is more preferable.
The “C _2-6 alkanoyl group” refers to a carbonyl group having a linear or branched alkyl group having 1 to 5 carbon atoms, such as acetyl group, propionyl group, n-butyryl group, i-butyryl group. Group, n-valeryl group, i-valeryl group and pivaloyl group can be mentioned, and acetyl group is more preferable.
The “C _2-8 alkanoyl group” refers to a carbonyl group having a linear or branched alkyl group having 1 to 7 carbon atoms, such as acetyl group, propionyl group, n-butyryl group, i-butyryl group. Group, n-valeryl group, i-valeryl group, pivaloyl group and n-octanoyl group can be mentioned, and acetyl group is more preferable.
The “C _2-8 alkanoylamino group” refers to an amino group having a “C _2-8 alkanoyl group” as a substituent, for example, an acetylamino group, an n-propionylamino group, an n-butyrylamino group, an i-butyrylamino group. , A valerylamino group and an n-octanoylamino group, and an acetylamino group is more preferable.
“C _1-8 alkylsulfonylamino group” means an amino group having “C _1-8 alkylsulfonyl group” as a substituent, for example, methylsulfonylamino group, n-propylsulfonylamino group, n-butylsulfonylamino group. Group, i-butylsulfonylamino group, t-butylsulfonylamino group and n-octylsulfonylamino group, and methylsulfonylamino group is more preferable.
The “C _2-9 heterocyclyl group” means a 5- to 7-membered monocyclic system composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 2 to 9 carbon atoms. A heterocyclic group or a condensed polycyclic heterocyclic group composed of 10 to 14 atoms, such as tetrahydrofuranyl group, tetrahydropyranyl group, isothiazolidinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolinyl group, piperidyl group Piperazinyl group, morpholinyl group, 1,3-oxazolidinyl group, 1,6-dihydropyridazinyl group, thiazolidinyl group, indolinyl group, 1,6-dihydropyrimidinyl group, 1,2,3,4-tetrahydropyrimidinyl group Tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl group, piperidyl group, Zorijiniru group, 1,6-dihydro-pyridazinyl group, 1,6-dihydro-pyrimidinyl group, 1,3-oxazolidinyl group, 1,2,3,4-tetrahydronaphthalene-pyrimidinyl group is more preferable.

で示される単環系又は縮合多環系Ｃ_１−９ヘテロアリール基とは、式（１）中で該基と隣接するアミド基の窒素原子と、該基が有する

結合を形成する炭素原子とが結合する、酸素原子、硫黄原子及び窒素原子からなる群から選ばれる１つ以上の原子と１から９個の炭素原子からなる、５から７員環の単環系芳香族複素環基又は１０から１４の原子から構成される縮合多環系芳香族複素環基を示し、例えばピラゾリル基、チアゾリル基、ピリジル基、チアジアゾリル基、ピリドチアゾリル基、イソキサゾリル基を挙げることができる。
式（３）

で示されるＣ_２−９ヘテロシクリル基とは、酸素原子、窒素原子からなる群から選ばれる１つ以上の原子と２から９個の炭素原子からなる、５から７員環の単環系複素環基又は１０から１４の原子から構成される縮合多環系複素環基を示し、例えば２−オキソピロリジニル基、２−オキソイミダゾリジニル基、２−オキソピペリジル基、２−オキソ−１，３−オキサゾリジニル基、６−オキソ−１，６−ジヒドロピリダジニル基、６−オキソ−１，６−ジヒドロピリミジニル基、２−オキソ−１，２，３，４−テトラヒドロピリミジニル基、２，５−ジオキソピロリジニル基、２，４−ジオキソ−１，２，３，４−テトラヒドロピリミジニル基を挙げることができ、２−オキソピロリジン−１−イル基、６−オキソ−１，６−ジヒドロピリダジン−１−イル基、２，５−ジオキソピロリジン−１−イル基、２，４−ジオキソ−１，２，３，４−テトラヒドロピリミジン−３−イル基がより好ましい。 The “C _1-9 heteroaryl group” is a 5- to 7-membered monocyclic ring composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 1 to 9 carbon atoms. An aromatic heterocyclic group or a condensed polycyclic aromatic heterocyclic group composed of 10 to 14 atoms, such as an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, a pyrrolyl group, a triazolyl group, a pyridyl group, Examples thereof include a pyrimidinyl group, a pyrazinyl group, an indolyl group, and a quinolyl group, and a pyrazolyl group, a thiazolyl group, a triazolyl group, and a pyridyl group are more preferable.
The “C _1-9 heteroarylthio group” refers to a group in which a “C _1-9 heteroaryl group” and a sulfur atom are bonded, and examples thereof include an imidazolylthio group and a triazolylthio group, and a triazolylthio group is more preferable. .
The “C _7-14 arylalkyl group” means a linear or branched alkyl group having a monocyclic or polycyclic aromatic hydrocarbon group as a substituent, or a monocyclic or polycyclic aromatic group. A group having 7 to 14 carbon atoms in which an aromatic hydrocarbon group and a linear or branched alkyl group are condensed, such as benzyl group, phenethyl group, phenylpropyl group, naphthylmethyl group, indanyl Group, (2H) -indenyl group and tetrahydronaphthyl group can be mentioned, and benzyl group, phenethyl group and indanyl group are more preferable.
The _{"C 1-9} heteroaryl _{C 1-6} alkyl group" refers to _{"C 1-6} alkyl group" having as a substituent _{"C 1-9} heteroaryl group" such as 2-pyridylmethyl group, 3 -Pyridylmethyl group, 4-pyridylmethyl group, 2- (2-pyridyl) ethyl group, 2- (3-pyridyl group) ethyl group and 2- (4-pyridyl) ethyl group can be mentioned.
“N- (C _1-8 alkyl) anilino group” refers to an anilino group in which a nitrogen atom is substituted with one “C _1-8 alkyl group”. For example, N-methylanilino group, N-ethylanilino group, N An -n-propylanilino group and a Ni-propylanilino group can be mentioned, and an N-methylanilino group is more preferable.
The “carboxy C _1-8 alkyl group” refers to a “C _1-8 alkyl group” having a carboxy group as a substituent, such as a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxy-n-propyl group, A 2-carboxy-n-propyl group, a 2-carboxy-i-propyl group, and a 4-carboxy-n-butyl group can be exemplified, and a carboxymethyl group and a 2-carboxyethyl group are more preferable.
The _{"C 2-6} alkoxycarbonyl _{C 1-8} alkyl group" refers to _{"C 1-8} alkyl group" having as a substituent _{"C 2-6} alkoxycarbonyl group", for example, methoxycarbonylmethyl group, 2- (Methoxycarbonyl) ethyl group, 3- (methoxycarbonyl) -n-propyl group, 2- (methoxycarbonyl) -n-propyl group, 2- (methoxycarbonyl) -i-propyl group, ethoxycarbonylmethyl group, 2- (Ethoxycarbonyl) ethyl group can be mentioned, and a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a 2- (ethoxycarbonyl) ethyl group, and a 2- (methoxycarbonyl) ethyl group are more preferable.
The “carbamoyl C _1-8 alkyl group” refers to a “C _1-8 alkyl group” having a carbamoyl group as a substituent, such as a carbamoylmethyl group, a 2-carbamoylethyl group, a 3-carbamoyl-n-propyl group, A 2-carbamoyl-n-propyl group, a 2-carbamoyl-i-propyl group, and a 4-carbamoyl-n-butyl group can be exemplified, and a carbamoylmethyl group and a 2-carbamoylethyl group are more preferable.
“Hydroxy C _1-8 alkyl group” means a “C _1-8 alkyl group” having a hydroxy group as a substituent, such as a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxy-n-propyl group, 2-hydroxy-n-propyl group, 4-hydroxy-n-butyl group, 2-hydroxy-i-propyl group can be mentioned, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxy-n-propyl group Is more preferable.
The “amino C _1-8 alkyl group” refers to a “C _1-8 alkyl group” having an amino group as a substituent, such as an aminomethyl group, a 2-aminoethyl group, a 3-amino-n-propyl group, Examples include 2-amino-n-propyl group, 2-amino-i-propyl group, and 4-amino-n-butyl group.
“(C _1-8 alkyl) amino C _1-8 alkyl group” means “C _1-8 alkyl group” having “(C _1-8 alkyl) amino group” as a substituent, for example, methylaminomethyl Group, ethylaminomethyl group, n-propylaminomethyl group, i-propylaminomethyl group, 2- (methylamino) ethyl group, 2- (ethylamino) ethyl group, 2- (n-propylamino) ethyl group, Examples include 2- (i-propylamino) ethyl group, 3- (methylamino) -n-propyl group, 2- (methylamino) -n-propyl group, and 3- (ethylamino) -n-propyl group. it can.
“Di (C _1-8 alkyl) amino C _1-8 alkyl group” refers to a “C _1-8 alkyl group” having “di (C _1-8 alkyl) amino group” as a substituent. Dimethylamino) methyl group, 2- (dimethylamino) ethyl group, 2- {di (n-propyl) amino} ethyl group, di- (i-propyl) aminomethyl group, 2- (ethylmethylamino) ethyl group, A (methyl) (n-propyl) aminoethyl group can be mentioned.
Formula (2)

The monocyclic or condensed polycyclic C _1-9 heteroaryl group represented by the formula (1) includes a nitrogen atom of an amide group adjacent to the group and the group

5- to 7-membered monocyclic system consisting of one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms and 1 to 9 carbon atoms, which are bonded to carbon atoms forming the bond An aromatic heterocyclic group or a condensed polycyclic aromatic heterocyclic group composed of 10 to 14 atoms is shown, and examples thereof include a pyrazolyl group, a thiazolyl group, a pyridyl group, a thiadiazolyl group, a pyridothiazolyl group, and an isoxazolyl group. .
Formula (3)

The C _2-9 heterocyclyl group represented by the above is a 5- to 7-membered monocyclic heterocyclic ring composed of one or more atoms selected from the group consisting of an oxygen atom and a nitrogen atom and 2 to 9 carbon atoms. A fused polycyclic heterocyclic group composed of a group or 10 to 14 atoms, such as 2-oxopyrrolidinyl group, 2-oxoimidazolidinyl group, 2-oxopiperidyl group, 2-oxo-1, 3-oxazolidinyl group, 6-oxo-1,6-dihydropyridazinyl group, 6-oxo-1,6-dihydropyrimidinyl group, 2-oxo-1,2,3,4-tetrahydropyrimidinyl group, 2, Examples include 5-dioxopyrrolidinyl group and 2,4-dioxo-1,2,3,4-tetrahydropyrimidinyl group, 2-oxopyrrolidin-1-yl group, 6-oxo-1,6- Dihydropyrida More preferred are a din-1-yl group, a 2,5-dioxopyrrolidin-1-yl group, and a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl group.

（式（３）中、環Ｂは置換されていないか、又はハロゲン原子、ヒドロキシ基、オキソ基、Ｃ_１−８アルキル基、Ｃ_１−８アルキルアミノ基、ジ（Ｃ_１−８アルキル）アミノ基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されており、好ましくは、置換されていないか、又はハロゲン原子、オキソ基、Ｃ_１−８アルキル基、ジ（Ｃ_１−８アルキル）アミノ基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）で表されるＣ_２−９ヘテロシクリル基である。
他の好ましいＲ^１はＣ_１−９ヘテロアリール基（該Ｃ_１−９ヘテロアリール基は置換されていないか、又はＣ_１−８アルキル基、ヒドロキシ基、アミノ基、（Ｃ_１−８アルキル）アミノ基、ジ（Ｃ_１−８アルキル）アミノ基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されており、好ましくは、置換されていないか、又はＣ_１−８アルキル基、及びヒドロキシ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）であり、さらに好ましいＲ^１はトリアゾリル基（該トリアゾリル基は置換されていないか、又はＣ_１−８アルキル基、ヒドロキシ基、アミノ基、（Ｃ_１−８アルキル）アミノ基、ジ（Ｃ_１−８アルキル）アミノ基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されており、好ましくは、置換されていないか、又は１から２個のＣ_１−８アルキル基で置換されている。）である。
好ましいＲ^２は水素原子、Ｃ_１−８アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−９ヘテロシクリル基、フェニル基、Ｃ_１−９ヘテロアリール基、又はＣ_７−１４アリールアルキル基（該フェニル基、Ｃ_１−９ヘテロアリール基、及びＣ_７−１４アリールアルキル基は置換されていないか、又はハロゲン原子、ヒドロキシ基、Ｃ_１−８アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルチオ基、及びＣ_１−８アルキルスルホニル基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されており、好ましくは、置換されていないか、又はハロゲン原子、ヒドロキシ基、Ｃ_１−８アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルチオ基、及びＣ_１−８アルキルスルホニル基からなる群より同一若しくは異なって選ばれる１から２個の基で置換されている。）である。
好ましいＲ^２はＣ_７−１４アリールアルキル基（該Ｃ_７−１４アリールアルキル基は置換されていないか、又はハロゲン原子、ヒドロキシ基、Ｃ_１−８アルキル基、及びＣ_１−６アルコキシ基からなる群より同一若しくは異なって選ばれる１から２個の基で置換されている。）である。
好ましいＡｒは、式（２）で表されるチアゾリル基、ピリジル基、又はピラゾリル基であり、チアゾリル基、ピラゾリル基が好ましく、Ｘが−Ｓ−の場合はピラゾリル基がさらに好ましい。
これらの好ましいＡｒは、置換されていないか、又はハロゲン原子、Ｃ_１−８アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_１−６アルコキシ基、カルボキシ基、カルボキシＣ_１−８アルキル基、Ｃ_２−６アルコキシカルボニル基、Ｃ_２−６アルコキシカルボニルＣ_１−８アルキル基、カルバモイル基、カルバモイルＣ_１−８アルキル基、ヒドロキシ基、ヒドロキシＣ_１−８アルキル基、アミノＣ_１−８アルキル基、（Ｃ_１−８アルキル）アミノＣ_１−８アルキル基、ジ（Ｃ_１−８アルキル）アミノＣ_１−８アルキル基、Ｃ_２−６アルカノイル基、及びＣ_２−９ヘテロシクリル基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されており、より好ましくは、置換されていないか、又はハロゲン原子、Ｃ_１−８アルキル基、カルボキシ基、カルボキシＣ_１−８アルキル基、Ｃ_２−６アルコキシカルボニル基、Ｃ_２−６アルコキシカルボニルＣ_１−８アルキル基、及びヒドロキシＣ_１−８アルキル基からなる群より選ばれる１個の基で置換されている。
Ａｒが置換されている場合の好ましい置換基の具体例としては、塩素原子、メチル基、エチル基、ｉ−プロピル基、カルボキシ基、カルボキシメチル基、メトキシカルボニル基、エトキシカルボニルメチル基、２−ヒドロキシエチル基を挙げることができ、メチル基、エチル基がさらに好ましい。
好ましいＸは−ＣＲ^３Ｒ^４−、又は−Ｓ−であり、さらに好ましくは−ＣＨ_２−、又は−Ｓ−であり
好ましいＹは単結合又は−Ｏ−であり、さらに好ましいＹは−Ｏ−であり、
好ましいＲ^３は水素原子であり、
好ましいＲ^４は水素原子であり、
好ましいＲ^５は水素原子である。 Preferred forms of the compound of the present invention are as follows.
That is, preferred R ¹ is a C _1-8 alkyl group (the C _1-8 alkyl group is not substituted, or a hydroxy group, a carboxy group, a carbamoyl group, a C _1-6 alkoxy group, a C _2-6 alkoxy group). Substituted with 1 to 3 groups selected from the group consisting of carbonyl group, C _2-8 alkanoylamino group, di (C _1-8 alkyl) amino group, and cyano group, preferably, Unsubstituted or hydroxy group, carboxy group, carbamoyl group, C _1-6 alkoxy group, C _2-6 alkoxycarbonyl group, C _2-8 alkanoylamino group, di (C _1-8 alkyl) amino group, and it is substituted with one group selected from the group consisting of cyano group.), and more preferably R ¹ is an ethyl group or an isopropyl group (diether Do not Le group and isopropyl group are substituted or substituted with a hydroxy group.) It is.
Other preferable R ¹ is a C _2-9 heterocyclyl group (the C _2-9 heterocyclyl group is unsubstituted or is a halogen atom, a hydroxy group, an oxo group, a C _1-8 alkyl group, (C _1-8 alkyl group). ) Amino group (the (C _1-8 alkyl) amino group is unsubstituted or substituted with a hydroxy group), a di (C _1-8 alkyl) amino group, a carboxy group, a cyano group, and It is substituted with 1 to 4 groups selected from the group consisting of C _1-6 alkoxy groups, which are the same or different, and is preferably not substituted or a halogen atom, an oxo group, a C _1-8 alkyl group a di (C _1-8 alkyl) are substituted amino groups, and C _1-6 1 the same or different and are selected from the group consisting of alkoxy groups with four groups.), further preferred There ^{R 1} has the formula (3)

(In Formula (3), Ring B is not substituted, or is a halogen atom, a hydroxy group, an oxo group, a C _1-8 alkyl group, a C _1-8 alkylamino group, or di (C _1-8 alkyl) amino. Substituted with 1 to 3 groups selected from the group consisting of a group and a C _1-6 alkoxy group, which are the same or different, and are preferably unsubstituted or substituted with a halogen atom, an oxo group, C _1- Substituted with 1 to 3 groups selected from the group consisting of ₈ alkyl groups, di (C _1-8 alkyl) amino groups, and C _1-6 alkoxy groups. _2-9 heterocyclyl group.
Other preferable R ¹ is a C _1-9 heteroaryl group (the C _1-9 heteroaryl group is unsubstituted or is a C _1-8 alkyl group, a hydroxy group, an amino group, (C _1-8 alkyl)). Substituted with 1 to 3 groups selected from the group consisting of amino group, di (C _1-8 alkyl) amino group, and C _1-6 alkoxy group, which are the same or different, preferably not substituted Or a C _1-8 alkyl group and a 1 to 3 group selected from the same or different group selected from the group consisting of a hydroxy group, and more preferably R ¹ is a triazolyl group (the triazolyl group). Is unsubstituted or C _1-8 alkyl, hydroxy, amino, (C _1-8 alkyl) amino, di (C _1-8 alkyl) amino, and C _1-6 alcohol Substituted with 1 to 3 groups selected from the group consisting of xy groups, the same or different, preferably unsubstituted or substituted with 1 to 2 C _1-8 alkyl groups .)
Preferred R ² is a hydrogen atom, a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _2-9 heterocyclyl group, a phenyl group, a C _1-9 heteroaryl group, or a C _7-14 arylalkyl group ( The phenyl group, C _1-9 heteroaryl group, and C _7-14 arylalkyl group are not substituted, or are a halogen atom, a hydroxy group, a C _1-8 alkyl group, a C _1-6 alkoxy group, a C _1- Substituted with 1 to 3 groups selected from the group consisting of a ₆ alkylthio group and a C _1-8 alkylsulfonyl group, which are the same or different, and are preferably unsubstituted or substituted with a halogen atom, a hydroxy group, The same or different from the group consisting of a C _1-8 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, and a C _1-8 alkylsulfonyl group. And is substituted with 1 to 2 groups selected.
Preferred R ² is a C _7-14 arylalkyl group (the C _7-14 arylalkyl group is unsubstituted or consists of a halogen atom, a hydroxy group, a C _1-8 alkyl group, and a C _1-6 alkoxy group) Substituted with 1 to 2 groups selected identically or differently from the group).
Preferred Ar is a thiazolyl group, pyridyl group or pyrazolyl group represented by the formula (2), preferably a thiazolyl group or a pyrazolyl group, and more preferably a pyrazolyl group when X is —S—.
These preferred Ar are unsubstituted or substituted with a halogen atom, a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, a carboxy group, a carboxy C _1-8 alkyl group, C _2-6 alkoxycarbonyl group, C _2-6 alkoxycarbonyl C _1-8 alkyl group, carbamoyl group, carbamoyl C _1-8 alkyl group, hydroxy group, hydroxy C _1-8 alkyl group, amino C _1-8 alkyl group, Same from the group consisting of (C _1-8 alkyl) amino C _1-8 alkyl group, di (C _1-8 alkyl) amino C _1-8 alkyl group, C _2-6 alkanoyl group, and C _2-9 heterocyclyl group. or different 1 is substituted with three groups from selected, more preferably, unsubstituted or substituted, or a halogen atom, C _1-8 Alkyl group, a carboxy group, a carboxy _{C 1-8} alkyl _{group, C 2-6} alkoxycarbonyl _{group, C 2-6} alkoxycarbonyl _{C 1-8} alkyl group, and 1 is selected from the group consisting of hydroxy _{C 1-8} alkyl group Substituted with 1 group.
Specific examples of preferable substituents when Ar is substituted include chlorine atom, methyl group, ethyl group, i-propyl group, carboxy group, carboxymethyl group, methoxycarbonyl group, ethoxycarbonylmethyl group, 2-hydroxy An ethyl group can be mentioned, and a methyl group and an ethyl group are more preferable.
Preferred X is —CR ³ R ⁴ —, or —S—, more preferably —CH ₂ —, or —S—. Preferred Y is a single bond or —O—, and more preferred Y is —O—. And
Preferred R ³ is a hydrogen atom,
Preferred R ⁴ is a hydrogen atom,
Preferred R ⁵ is a hydrogen atom.

In the present invention, the pharmaceutically acceptable salt is, for example, a mineral salt such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonate Sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, Carboxylates such as mandelate, ascorbate, lactate, gluconate, malate; amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, aspartate, or Inorganic or ammonium salts such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, triethylamine salt, diisopropylamine salt, cyclohexyl Salts with organic bases such as amine salts, preferably hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate Citrate, acetate, lactate, glutamate, aspartate, sodium salt, potassium salt, ammonium salt or triethylamine salt.
The solvate in the present invention is a pharmaceutically acceptable solvate of the compound of the present invention or a salt thereof. The compound of the present invention and its salt may absorb moisture or be adsorbed water or become a hydrate by exposure to the atmosphere or recrystallization. The compound in the present invention includes such a hydrate.
The compounds of the present invention may have asymmetric centers, in which case various optical isomers exist. Therefore, the compound of the present invention may exist as a (+) isomer (single), a (-) isomer (single), a racemate, or a (±) mixture containing both optically active substances in an arbitrary ratio. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can. Further, the compound of the present invention may have geometric isomers such as cis isomer and trans isomer. The compound of the present invention includes those isomers and those containing these isomers in an arbitrary ratio.
The picolinic acid amide compound of the present invention may be a pharmaceutically acceptable salt thereof or a solvate thereof. Hereinafter, the picolinic acid amide compound of the present invention, a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound or a solvate thereof will be referred to as “the compound of the present invention”.
Also, a compound that has a group that can be chemically or metabolically decomposed and forms a pharmacologically active compound of the present invention by solvolysis or in vivo under physiological conditions, usually a compound called a prodrug It is included in “the present compound”.

The compound of the present invention has a GK activation action. Therefore, the compound of the present invention can correct hyperglycemia by increasing glucose metabolism in the liver, glycogen synthesis, and glucose-induced insulin secretion from pancreatic beta cells. Therefore, it can be used as a new drug therapy having a different mechanism of action from existing anti-diabetic drugs. Diabetes includes type I diabetes, type II diabetes, and other diabetes due to specific causes. Furthermore, the compound of the present invention can be used for ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, peripheral arterial occlusion, etc.), neuropathy (sensory nerve, motor Nerves, autonomic nerves, etc.), foot gangrene, infection and other diabetic complications.
Furthermore, it can also be used for the treatment and prevention of diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia, and gout.
The compound of the present invention can also be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension and the like having a different mechanism of action other than GK activation. . By combining the compound of the present invention with other drugs, an additive effect can be expected when used in combination with the above diseases, rather than the effect obtained with a single agent.
Examples of antidiabetics and diabetic complications that can be used in combination include insulin preparations, insulin sensitizers (PPARγ agonists, PPARα / γ agonists, PPARδ agonists, PPARα / γ / δ agonists, etc.) (eg, pioglitazone, rosi Glitazone, GW-501516, GW-590735, ABT-335, AZD-6610, AVE-8133), α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol), biguanide drug (eg, metformin, buformin, phenformin), Insulin secretion promoter (eg, glibenclamide, glimepiride, repaglinide, nateglinide, mitiglinide), insulin preparation, glucagon receptor antagonist, insulin receptor kinase promoter, dipeptidyl peptidase V inhibitor (eg, vildagliptin, TS-021, sitagliptin, BMS-477118), SGLT inhibitor (eg, sagliflozin, dapagliflozin, KGT-1681, YM543, TS-033, AVE-2268), PTP1b inhibitor (Eg, sodium vanadate), glucose 6 phosphatase inhibitor, glycogen phosphorylase inhibitor (eg, PSN-357, FR-258900), FBPase inhibitor (eg, MB-07803), PEPCK inhibitor, pyruvate dehydrogenase kinase inhibitor Drugs, D-chileunositol, GSK3 inhibitors, GLP-1 agonists (eg, liraglutide), amylin agonists (eg, pramlintide), glucocorticoid receptor antagonists, 11 beta HSD1 inhibitors (eg, AM) -221, INCB-13739), protein kinase C inhibitors (eg, ruboxistaurin), beta 3 adrenergic receptor agonists (eg, AJ-9777), phosphatidylinositol kinase inhibitors, phosphatidylinositol phosphatase inhibitors Drugs, ACC inhibitors, GPR40 receptor agonists, GPR119 receptor agonists (eg, APD-668), TGR5 receptor agonists, AMPK activators (eg, DRL-16536), aldose reductase inhibitors, AGE inhibitors, etc. Is mentioned.
Examples of the drugs for diabetes-related diseases that can be used in combination include HMG-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid adsorbents, IBAT inhibitors, CETP inhibitors, CPT inhibitors, fibrate drugs, ACAT inhibitors MGAT inhibitor, DGAT inhibitor, cholesterol absorption inhibitor, pancreatic lipase inhibitor, MTP inhibitor, nicotinic acid derivative, LXR agonist, LDL receptor promoter, angiotensin converting enzyme inhibitor, angiotensin II antagonist, diuretic, calcium Examples include antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, appetite suppressants, uric acid production inhibitors, uric acid excretion promoters, and the like.
The compound of the present invention can be administered alone or in combination with a pharmaceutically or pharmaceutically acceptable carrier or diluent. When the compound of the present invention is used as a GK activator, the compound of the present invention may be administered orally or parenterally as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. For example, when administered orally to an adult diabetic patient, the dose is usually about 0.01 to 100 mg / kg body weight. It is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

  The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

（スキーム中Ｒ¹、Ｒ^２、及びＡｒは前記と同意義である。）
工程（１−１）：溶媒中、化合物（１−ａ）と、トリフェニルホスフィン、トリブチルホスフィンなどのホスフィン試薬、及びジエチルアゾジカルボキシレートなどのアゾ試薬を反応させ、続いて式Ｒ^２−ＯＨで表される化合物を用いて光延反応を行うことにより化合物（１−ｂ）を製造することができる。
あるいは、溶媒中、化合物（１−ａ）と、式Ｒ^２−ＨＡＬ（式中、ＨＡＬは塩素原子、臭素原子又はヨウ素原子を示す）で表される化合物を、塩基存在下反応させることにより化合物（１−ｂ）を製造することができる。
工程（１−２）：溶媒中、化合物（１−ｂ）と酸化剤を反応させることにより化合物（１−ｃ）を製造することができる。
工程（１−３）：化合物（１−ｃ）と無水酢酸を反応させ、続いて塩酸を用いて反応させることにより化合物（１−ｄ）を製造することができる。
工程（１−４）：化合物（１−ｄ）とオキシ塩化リンなどのクロロ化試薬を反応させることにより化合物（１−ｅ）を製造することができる。
工程（１−５）：溶媒中、化合物（１−ｅ）を水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより化合物（１−ｆ）を製造することができる。
工程（１−６）：溶媒中、化合物（１−ｆ）と式Ａｒ−ＮＨ_２で表される化合物を、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミドハイドロクロライド、１−ヒドロキシベンゾトリアゾールなどの縮合剤存在下反応させることにより化合物（１−ｇ）を製造することができる。あるいは化合物（１−ｆ）を溶媒中、塩化チオニル、塩化オキザリル、オキシ塩化リン、五塩化リンなどと反応させ、酸クロライドとした後、塩基存在下、式Ａｒ−ＮＨ_２で表される化合物を反応させることにより化合物（１−ｇ）を製造することができる。
工程（１−７）：溶媒中、化合物（１−ｉ）（特開平１０−５９９４２）と式Ａｒ−ＮＨ_２で表される化合物を、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミドハイドロクロライド、１−ヒドロキシベンゾトリアゾールなどの縮合剤存在下反応させることにより化合物（１−ｊ）を製造することができる。あるいは化合物（１−ｉ）を溶媒中、塩化チオニル、塩化オキザリル、オキシ塩化リン、五塩化リンなどと反応させ、酸クロライドとした後、塩基存在下、式Ａｒ−ＮＨ_２で表される化合物を反応させることにより化合物（１−ｊ）を製造することができる。
工程（１−８）：溶媒中、化合物（１−ｊ）と式Ｒ^２−ＯＨで表される化合物を塩基存在下反応させ、生成する異性体をシリカゲルカラムクロマトグラフィーなどを用いて分離することにより化合物（１−ｇ）を製造することができる。
工程（１−９）：溶媒中、化合物（１−ｇ）と式Ｒ^１−ＳＨで表される化合物を、塩基存在下反応させることにより本発明化合物（１−ｈ）を製造することができる。
ここで、本発明化合物（１−ｈ）中のＲ^２にＣ_１−６アルキルチオ基が存在する場合、オキソン（商標登録）等の酸化剤を用いて酸化することにより、対応するアルキルスルホニル基に変換することができる。
工程（１−１０）：溶媒中、化合物（１−ｊ）と式Ｒ^２−ＳＨで表される化合物を塩基存在下反応させ、生成する異性体をシリカゲルカラムクロマトグラフィーなどを用いて分離することにより化合物（１−ｋ）を製造することができる。
工程（１−１１）：溶媒中、化合物（１−ｋ）と式Ｒ^１−ＳＨで表される化合物を、塩基存在下反応させることにより本発明化合物（１−ｌ）を製造することができる。 Scheme 1: Compound (1-a) to Compound (1-h), and Compound (1-i) to Compound (1-h) and (1-l) Production Method

(In the scheme, R ¹ , R ² and Ar are as defined above.)
Step (1-1): In a solvent, the compound (1-a) is reacted with a phosphine reagent such as triphenylphosphine and tributylphosphine and an azo reagent such as diethyl azodicarboxylate, followed by the formula R ² —OH. A compound (1-b) can be manufactured by performing a Mitsunobu reaction using the compound represented by these.
Alternatively, the compound (1-a) and a compound represented by the formula R ² -HAL (wherein HAL represents a chlorine atom, a bromine atom or an iodine atom) are reacted in the presence of a base in a solvent. (1-b) can be produced.
Step (1-2): Compound (1-c) can be produced by reacting compound (1-b) with an oxidizing agent in a solvent.
Step (1-3): Compound (1-d) can be produced by reacting compound (1-c) with acetic anhydride, followed by reaction with hydrochloric acid.
Step (1-4): Compound (1-e) can be produced by reacting compound (1-d) with a chlorinating reagent such as phosphorus oxychloride.
Step (1-5): Compound (1-f) can be produced by hydrolyzing compound (1-e) in a solvent using a base such as an aqueous sodium hydroxide solution.
Step (1-6): In a solvent, compound (1-f) and a compound represented by the formula Ar—NH ₂ are mixed with dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1 -Compound (1-g) can be produced by reacting in the presence of a condensing agent such as hydroxybenzotriazole. Alternatively, the compound (1-f) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then the compound represented by the formula Ar—NH ₂ is present in the presence of a base. A compound (1-g) can be manufactured by making it react.
Step (1-7): In a solvent, compound (1-i) (Japanese Patent Laid-Open No. 10-59942) and a compound represented by the formula Ar—NH ₂ are converted into dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3. -Compound (1-j) can be produced by reacting in the presence of a condensing agent such as ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. Alternatively, the compound (1-i) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then the compound represented by the formula Ar—NH ₂ is present in the presence of a base. Compound (1-j) can be produced by reacting.
Step (1-8): The compound (1-j) and the compound represented by the formula R ² —OH are reacted in a solvent in the presence of a base, and the resulting isomer is separated using silica gel column chromatography or the like. Can produce the compound (1-g).
Step (1-9): The compound (1-h) of the present invention can be produced by reacting the compound (1-g) with a compound represented by the formula R ¹ -SH in the presence of a base in a solvent. .
Here, when a C _1-6 alkylthio group is present in R ² of the compound (1-h) of the present invention, the corresponding alkylsulfonyl group can be converted to a corresponding alkylsulfonyl group by oxidation using an oxidizing agent such as Oxone (registered trademark). Can be converted.
Step (1-10): The compound (1-j) and the compound represented by the formula R ² —SH are reacted in the presence of a base in a solvent, and the resulting isomer is separated using silica gel column chromatography or the like. Can produce the compound (1-k).
Step (1-11): The compound (1-l) of the present invention can be produced by reacting the compound (1-k) with the compound represented by the formula R ¹ -SH in a solvent in the presence of a base. .

（スキーム中Ｒ¹、Ｒ^２、及びＡｒは前記と同意義である。）
工程（２−１）：溶媒中、スキーム１の化合物（１−ｆ）とジメチルアミン塩酸塩とを、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミドハイドロクロライド、１−ヒドロキシベンゾトリアゾールなどの縮合剤存在下反応させることにより化合物（２−ａ）を製造することができる。あるいは化合物（１−ｆ）を溶媒中、塩化チオニル、塩化オギザリル、オキシ塩化リン、五塩化リンなどと反応させ、酸クロライドとした後、塩基存在下、ジメチルアミン塩酸塩を反応させることにより化合物（２−ａ）を製造することができる。
工程（２−２）：溶媒中、化合物（２−ａ）と式Ｒ^１−ＳＨで表される化合物を、塩基存在下反応させることにより化合物（２−ｂ）を製造することができる。
工程（２−３）：溶媒中、化合物（２−ｂ）を、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより化合物（２−ｃ）を製造することができる。
工程（２−４）：溶媒中、化合物（２−ｃ）と式Ａｒ−ＮＨ_２で表される化合物を、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミドハイドロクロライド、１−ヒドロキシベンゾトリアゾールなどの縮合剤存在下反応させることにより本発明化合物（２−ｄ）を製造することができる。あるいは化合物（２−ｃ）を溶媒中、塩化チオニル、塩化オキザリル、オキシ塩化リン、五塩化リンなどと反応させ、酸クロライドとした後、塩基存在下、式Ａｒ−ＮＨ_２で表される化合物を反応させることにより本発明化合物（２−ｄ）を製造することができる。
ここで、Ａｒ部分にＣ_２−６アルコキシカルボニル基が存在する場合は、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより、カルボキシ基へと変換することができる。 Scheme 2: Method for producing compound (2-d) from compound (1-f)

(In the scheme, R ¹ , R ² and Ar are as defined above.)
Step (2-1): In a solvent, the compound (1-f) of Scheme 1 and dimethylamine hydrochloride are mixed with dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxy. Compound (2-a) can be produced by reacting in the presence of a condensing agent such as benzotriazole. Alternatively, compound (1-f) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then reacted with dimethylamine hydrochloride in the presence of a base. 2-a) can be produced.
Step (2-2): Compound (2-b) can be produced by reacting compound (2-a) with a compound represented by formula R ¹ -SH in the presence of a base in a solvent.
Step (2-3): Compound (2-c) can be produced by hydrolyzing compound (2-b) in a solvent using a base such as an aqueous sodium hydroxide solution.
Step (2-4): Compound (2-c) and a compound represented by the formula Ar—NH ₂ are mixed with dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1 The compound (2-d) of the present invention can be produced by reacting in the presence of a condensing agent such as -hydroxybenzotriazole. Alternatively, the compound (2-c) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then the compound represented by the formula Ar—NH ₂ is present in the presence of a base. The compound (2-d) of the present invention can be produced by reacting.
Here, if there is C _2-6 alkoxycarbonyl group Ar moiety, by hydrolysis with a base such as sodium hydroxide solution, it can be converted into a carboxy group.

（スキーム中Ａｒ、及びＲ^１は前記と同意義である。）
工程（３−１）：溶媒中、化合物（３−ａ）と式Ａｒ−ＮＨ_２で表される化合物を、ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミドハイドロクロライド、１−ヒドロキシベンゾトリアゾールなどの縮合剤存在下反応させることにより化合物（３−ｂ）を製造することができる。あるいは化合物（３−ａ）を溶媒中、塩化チオニル、塩化オギザリル、オキシ塩化リン、五塩化リンなどと反応させ、酸クロライドとした後、塩基存在下、式Ａｒ−ＮＨ_２で表される化合物を反応させることにより化合物（３−ｂ）を製造することができる。
工程（３−２）：溶媒中、化合物（３−ｂ）と式Ｒ^１−ＳＨで表される化合物を、塩基存在下反応させることにより本発明化合物（３−ｃ）を製造することができる。 Scheme 3: Method for producing compound (3-c) from compound (3-a)

(In the scheme, Ar and R ¹ are as defined above.)
Step (3-1): In a solvent, compound (3-a) and a compound represented by the formula Ar—NH ₂ are mixed with dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1 -Compound (3-b) can be produced by reacting in the presence of a condensing agent such as hydroxybenzotriazole. Alternatively, the compound (3-a) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then the compound represented by the formula Ar—NH ₂ is present in the presence of a base. Compound (3-b) can be produced by reacting.
Step (3-2): The compound (3-c) of the present invention can be produced by reacting the compound (3-b) with a compound represented by the formula R ¹ -SH in a solvent in the presence of a base. .

（スキーム中Ｒ^２及びＡｒは前記と同意義であり、Ｒ^１１はフェニル基、アルキル基、ヒドロキシＣ_１−６アルキル基、又はＣ_１−９ヘテロアリール基を示し、ＤはＯ、ＮＲ^５(該Ｒ^５は前記と同意義である。)又はＳを示し、Ｅは下記式（４）

（該式（４）は、Ｃ_２−９ヘテロシクリル基又はＣ_１−９ヘテロアリール基を示す。）で表される基を示す。） Scheme 4: Method for producing compounds (4-i) and (4-j) from compound (4-a)

(In the scheme, R ² and Ar are as defined above, R ¹¹ represents a phenyl group, an alkyl group, a hydroxy C _1-6 alkyl group, or a C _1-9 heteroaryl group, D represents O, NR ⁵ ( R ⁵ is as defined above.) Or S, E represents the following formula (4)

(The formula (4) represents a C _2-9 heterocyclyl group or a C _1-9 heteroaryl group.). )

Step (4-1): Compound (4-a) is reacted in methanol in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole. Thus, compound (4-b) can be produced. Alternatively, compound (4-b) can be produced by reacting compound (4-a) in methanol under an acid catalyst such as sulfuric acid.
Step (4-2): The compound (4-b) is reacted with a phosphine reagent such as triphenylphosphine and tributylphosphine and an azo reagent such as diethyl azodicarboxylate in a solvent, and is represented by the formula R ² —OH. A compound (4-d) can be manufactured by performing a Mitsunobu reaction using the compound made.
Step (4-3): Compound (4-c) can be produced by reacting compound (4-a) with phosphorus oxychloride, followed by treatment with methanol.
Step (4-4): Compound (4-d) can be produced by reacting compound (4-c) with a compound represented by formula R ² —OH in the presence of a base in a solvent.
Step (4-5): Compound (4-e) can be produced by reacting compound (4-d) with a reducing agent in a solvent.
Step (4-6): Compound (4-f) can be produced by hydrolyzing compound (4-e) with a base such as an aqueous sodium hydroxide solution in a solvent.
Step (4-7): In a solvent, compound (4-f) and a compound represented by the formula Ar—NH ₂ are mixed with dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1 -Compound (4-g) can be produced by reacting in the presence of a condensing agent such as hydroxybenzotriazole. Alternatively, the compound (4-f) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then the compound represented by the formula Ar—NH ₂ is present in the presence of a base. A compound (4-g) can be manufactured by making it react.
Step (4-8): Compound (4-h) can be produced by reacting compound (4-g) with triphenylphosphine and carbon tetrachloride in a solvent.
Step (4-9): The compound (4-i) of the present invention is produced by reacting the compound (4-h) with a compound represented by the formula R ¹¹ -DH in a solvent in the presence of a base. Can do.
Step (4-10): Compound (4-j) of the present invention can be produced by reacting compound (4-h) with a compound represented by formula EH in the presence of a base in a solvent.
Here, when R ² in the compound (4-j) of the present invention has a methoxy group, it can be converted to a hydroxy group by reacting with a Lewis acid such as boron tribromide.
In addition, when a halogen atom is present in the moiety represented by the formula (3) in the compound (4-j) of the present invention, a method using 10% palladium carbon in a solvent under a hydrogen stream or palladium acetate, triphenyl A hydrogenation reaction can be performed by a method using phosphine or sodium formate to convert the halogen atom into a hydrogen atom.
When a halogen atom is present in E in the compound (4-j) of the present invention, the halogen atom is reacted with an amine in the presence or absence of a base to give a (C _1-8 alkyl) amino group, It can also be substituted with a di (C _1-8 alkyl) amino group.
Step (4-11): Compound (4-g) and a compound represented by the formula EH in a solvent with a phosphine reagent such as triphenylphosphine and tributylphosphine, and an azo reagent such as diethylazodicarboxylate. The compound (4-j) of the present invention can be produced by carrying out Mitsunobu reaction using the compound.
Step (4-12): Compound (4-k) can be produced by reacting compound (4-e) with triphenylphosphine and carbon tetrachloride in a solvent.
Here, when a C _1-6 alkylthio group is present in R ² in the compound (4-k), it is converted to a corresponding alkylsulfonyl group by oxidation using an oxidizing agent such as Oxone (registered trademark). be able to.
Step (4-13): The compound (4-1) can be produced by reacting the compound (4-k) with the compound represented by the formula R ¹¹ -DH in a solvent in the presence of a base. .
Step (4-14): Compound (4-m) can be produced by hydrolyzing compound (4-1) in a solvent using a base such as an aqueous sodium hydroxide solution.
Step (4-15): In a solvent, compound (4-m) and a compound represented by the formula Ar—NH ₂ are mixed with dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1 The compound (4-i) of the present invention can be produced by reacting in the presence of a condensing agent such as -hydroxybenzotriazole. Alternatively, the compound (4-m) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then the compound represented by the formula Ar—NH ₂ is present in the presence of a base. The compound (4-i) of the present invention can be produced by reacting.
Step (4-16): Compound (4-n) can be produced by reacting compound (4-k) with a compound represented by formula EH in the presence of a base in a solvent.
Step (4-17): Compound (4-o) can be produced by hydrolyzing compound (4-n) in a solvent using a base such as an aqueous sodium hydroxide solution.
Step (4-18): In a solvent, compound (4-o) and a compound represented by the formula Ar—NH ₂ are mixed with dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1 The compound (4-j) of the present invention can be produced by reacting in the presence of a condensing agent such as -hydroxybenzotriazole. Alternatively, the compound (4-o) is reacted with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent to form an acid chloride, and then the compound represented by the formula Ar—NH ₂ is present in the presence of a base. The compound (4-j) of the present invention can be produced by reacting.

（スキーム中Ｒ^２及びＡｒは前記と同意義であり、Ｒ^１２はＣ_２−８アルカノイル基又はＣ_１−８アルキルスルホニル基を示す。）
工程（５−１）：溶媒中、スキーム４の化合物（４−ｈ）とアジ化ナトリウムを反応させることにより化合物（５−ａ）を製造することができる。
工程（５−２）：溶媒中、化合物（５−ａ）を、１０％パラジウムカーボン存在下、水素気流下反応させることにより化合物（５−ｂ）を製造することができる。
工程（５−３）：溶媒中、化合物（５−ｂ）と式Ｒ^１２−ＨＡＬ（式中、ＨＡＬは塩素原子、臭素原子又はヨウ素原子を示す）又は式（Ｒ^１２）_２Ｏで表される化合物を、塩基存在下反応させることにより本発明化合物（５−ｃ）を製造することができる。 Scheme 5: Method for producing compound (5-c) from compound (4-h)

(In the scheme, R ² and Ar are as defined above, and R ¹² represents a C _2-8 alkanoyl group or a C _1-8 alkylsulfonyl group.)
Step (5-1): The compound (5-a) can be produced by reacting the compound (4-h) of Scheme 4 with sodium azide in a solvent.
Step (5-2): Compound (5-b) can be produced by reacting compound (5-a) in a solvent in the presence of 10% palladium carbon in a hydrogen stream.
Step (5-3): In a solvent, the compound (5-b) and the formula R ¹² -HAL (wherein HAL represents a chlorine atom, a bromine atom or an iodine atom) or a formula (R ¹² ) ₂ O The compound of the present invention (5-c) can be produced by reacting the compound in the presence of a base.

（スキーム中Ｒ^２及びＡｒは前記と同意義である。）
工程（６−１）：溶媒中、スキーム４の化合物（４−ｇ）に１，１，１−トリスアセトキシ−１，１−ジヒドロ−１，２−ベンズヨードキソル−３（１Ｈ）−オン（デスマーチン試薬）などの酸化剤を作用させることにより化合物（６−ａ）を製造することができる。
工程（６−２）：溶媒中、化合物（６−ａ）に２−ブロモピリジンとノルマルブチルリチウムより調製した２−リチオピリジンを作用させることにより化合物（６−ｂ）を製造することができる。
工程（６−３）：溶媒中、化合物（６−ｂ）にトリフェニルホスフィン、四臭化炭素を作用させ、続いて１０％パラジウムカーボン存在下、水素気流下にて反応させることにより本発明化合物（６−ｃ）を製造することができる。
工程（６−４）：溶媒中、化合物（６−ａ）にベンジルホスホノアセテート及び塩基を作用させることにより化合物（６−ｄ）を製造することができる。
工程（６−５）：溶媒中、化合物（６−ｄ）を１０％パラジウムカーボン存在下、水素気流下、反応させることにより化合物（６−ｅ）を製造することができる。
工程（６−６）：溶媒中、化合物（６−ｅ）を水酸化ナトリウム水溶液などの塩基を作用させることにより本発明化合物（６−ｆ）を製造することができる。
工程（６−７）：溶媒中、本発明化合物（６−ｆ）に水素化ホウ素ナトリウム及び１Ｈ−ベンゾトリアゾール−１−イルオキシトリス（ジメチルアミノ）ホスホニウム ヘキサフルオロホスフェート（ボップ試薬）を作用させることにより本発明化合物（６−ｇ）を製造することができる。 Scheme 6: Method for producing compounds (6-c), (6-f) and (6-g) from compound (4-g)

(In the scheme, R ² and Ar are as defined above.)
Step (6-1): 1,1,1-Trisacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one in the compound (4-g) of Scheme 4 in a solvent Compound (6-a) can be produced by reacting an oxidizing agent such as (Dessmartin reagent).
Step (6-2): Compound (6-b) can be produced by reacting compound (6-a) with 2-lithiopyridine prepared from 2-bromopyridine and normal butyllithium in a solvent.
Step (6-3): Compound of the present invention by reacting compound (6-b) with triphenylphosphine and carbon tetrabromide in a solvent, followed by reaction in the presence of 10% palladium carbon in a hydrogen stream. (6-c) can be produced.
Step (6-4): Compound (6-d) can be produced by reacting compound (6-a) with benzylphosphonoacetate and a base in a solvent.
Step (6-5): Compound (6-e) can be produced by reacting compound (6-d) in a solvent in the presence of 10% palladium carbon in a hydrogen stream.
Step (6-6): The compound (6-f) of the present invention can be produced by reacting the compound (6-e) with a base such as an aqueous sodium hydroxide solution in a solvent.
Step (6-7): reacting the compound (6-f) of the present invention with sodium borohydride and 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (Bopp reagent) in a solvent The compound of the present invention (6-g) can be produced by

（スキーム中、Ｒ^２及びＡｒは前記と同意義であり、Ｅは前記式（４）で表されるＣ_２−９ヘテロシクリル基を示す。）
工程（７−１）：溶媒中、スキーム６の化合物（６−ａ）にメチルマグネシウムブロマイドを作用させることにより本発明化合物（７−ａ）を製造することができる。
工程（７−２）：溶媒中、本発明化合物（７−ａ）をトリフェニルホスフィン、トリブチルホスフィンなどのホスフィン試薬、及びジエチルアゾジカルボキシレートなどのアゾ試薬を反応させ、続いて式Ｅ−Ｈで表される化合物を用いて光延反応を行うことにより、本発明化合物（７−ｂ）を製造することができる。 Scheme 7: Method for producing compounds (7-a) and (7-b) from compound (6-a)

(In the scheme, R ² and Ar are as defined above, and E represents a C _2-9 heterocyclyl group represented by the formula (4).)
Step (7-1): The compound (7-a) of the present invention can be produced by allowing methylmagnesium bromide to act on the compound (6-a) of Scheme 6 in a solvent.
Step (7-2): The present compound (7-a) is reacted with a phosphine reagent such as triphenylphosphine and tributylphosphine and an azo reagent such as diethyl azodicarboxylate in a solvent, followed by formula EH. This invention compound (7-b) can be manufactured by performing Mitsunobu reaction using the compound represented by these.

Examples of the base in the description of the general production method of the compound of the present invention include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, sodium hydride, lithium hydride, sodium amide, Examples include alkali metal salts such as t-butoxypotassium, n-butyllithium and lithium diisopropylamide, amines such as triethylamine, diisopropylethylamine, pyrrolidine and piperidine, sodium acetate and potassium acetate.
Examples of the oxidizing agent in the description of the general production method of the compound of the present invention include m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, organic peracids such as peracetic acid and excessive acid, hydrogen peroxide, Urea hydrogen peroxide adduct / inorganic and organic peroxides such as phthalic anhydride, t-butyl hydroperoxide, cumene hydroperoxide, sodium periodate, oxone (registered trademark), N-bromosuccinimide, N-chloro Examples include succinimide, chloramine-T, t-butyl hypochlorite, iodobenzene diacetate, and a bromine-1,4-diazabicyclo [2,2,2] octane addition complex.
Examples of the reducing agent in the description of the general production method of the compound of the present invention include sodium borohydride and lithium borohydride.
The solvent in the description of the general production method of the compound of the present invention is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction. For example, water, methanol, Alcohols such as ethanol, i-propyl alcohol, n-butanol and t-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, pyridine, ethyl acetate, methylene chloride, chloroform, acetone, acetic acid , Benzene, toluene, and a mixed solvent thereof.
The reaction temperature in the general production method of the compound of the present invention can be selected from an appropriate temperature in the range of −78 ° C. to the boiling point of the solvent used in the reaction. This production method is conducted under atmospheric pressure, under pressure, and microwave irradiation. It can be carried out under the following conditions.

  In order to show the compound of the present invention in more detail below, examples and test examples are shown, but the examples are not limited.

Example 1
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6-[(4-methyl-4H-1,2,4-triazol-3-yl) thio] pyridine Preparation of 2-carboxyamide (Compound No. 1) (1) To a solution of 4-hydroxypyridine-2-carboxylic acid ethyl ester (50.0 g, 299 mmol) in dimethylformamide (50 ml), cyclopentyl bromide (51 ml, 358 mmol), Potassium carbonate (82 g, 598 mmol) was added, and the mixture was stirred at an external temperature of 80 ° C. for 4 hours. The reaction mixture is cooled, poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue is subjected to silica gel column chromatography [developing solvent; By purification with hexane: ethyl acetate = 1: 1], a colorless gel-like substance 4-cyclopentyloxypyridine-2-carboxylic acid ethyl ester (41.5 g) was obtained.
MS (ESI): 258 (M + Na)
¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.45 (t, J = 7.2 Hz, 3 H) 1.54-2.27 (m, 8 H) 4.47 (q, J = 7.2 Hz, 2 H) 4.77-5.11 (m , 1 H) 6.92 (dd, J = 5.6, 2.5 Hz, 1 H) 7.63 (d, J = 2.5 Hz, 1 H) 8.52 (d, J = 5.6 Hz, 1 H)
(2) To a solution of 4-cyclopentyloxypyridine-2-carboxylic acid ethyl ester (41.5 g, 176 mmol) in chloroform (300 ml) was added m-chloroperbenzoic acid (60 g, 352 mmol), and the mixture was stirred at room temperature for 15 hours. . The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue was subjected to silica gel column chromatography [development]. By purifying with a solvent: chloroform: methanol = 9: 1], 4-cyclopentyloxypyridine-2-carboxylic acid ethyl ester 1-oxide (34.7 g) was obtained as a pale yellow powdery substance.
MS (ESI): 274 (M + Na)
1H NMR (300 MHz, CDCl3) δ ppm 1.42 (t, J = 7.2 Hz, 3 H) 1.56-2.14 (m, 8 H) 4.48 (q, J = 7.2 Hz, 2 H) 4.66-4.88 (m, 1 H) 6.82 (dd, J = 7.2, 3.5 Hz, 1 H) 7.00 (d, J = 3.5 Hz, 1 H) 8.13 (d, J = 7.2 Hz, 1 H)
(3) A solution of 4-cyclopentyloxypyridine-2-carboxylic acid ethyl ester 1-oxide (34.7 g, 98 mmol) in acetic anhydride (150 ml) was stirred at an external temperature of 160 ° C. for 2 hours. The reaction mixture was allowed to cool and concentrated. A 10% aqueous hydrochloric acid solution (80 ml) was added to the residue, and the mixture was stirred at an external temperature of 80 ° C. for 1 hr. The reaction solution is allowed to cool and basified with an aqueous potassium carbonate solution, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. Purification by chromatography [developing solvent; ethyl acetate] gave 4-cyclopentyloxy-6-hydroxypyridine-2-carboxylic acid ethyl ester (17.7 g) as a pale yellow powdery substance.
MS (ESI): 252 (M + 1), 250 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.38 (t, J = 7.2 Hz, 3 H) 1.52-2.04 (m, 8 H) 4.39 (q, J = 7.2 Hz, 2 H) 4.64-4.79 (m, 1 H) 6.00 (d, J = 2.3 Hz, 1 H) 6.65 (d, J = 2.3 Hz, 1 H) 9.14-9.49 (br, 1 H)
(4) A solution of 4-cyclopentyloxy-6-hydroxypyridine-2-carboxylic acid ethyl ester (4.0 g, 15.9 mmol) in phosphorus oxychloride (10 ml) was stirred at an external temperature of 110 ° C. for 2 hours. The reaction solution is cooled, poured into an aqueous potassium carbonate solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue is subjected to silica gel column chromatography. By purifying with [developing solvent; hexane: ethyl acetate = 4: 1 to 1: 1], a light brown powdery substance 6-chloro-4-cyclopentyloxypyridine-2-carboxylic acid ethyl ester (4.2 g) Got.
MS (ESI): 270 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.42 (t, J = 7.1 Hz, 3 H) 1.57-2.19 (m, 8 H) 4.46 (q, J = 7.1 Hz, 2 H) 4.77-5.00 (m, 1 H) 6.94 (d, J = 2.2 Hz, 1 H) 7.55 (d, J = 2.2 Hz, 1 H)
(5) To a solution of 6-chloro-4-cyclopentyloxypyridine-2-carboxylic acid ethyl ester (4.2 g, 15.6 mmol) in methanol (10 ml) and tetrahydrofuran (3 ml), potassium hydroxide (1.68 g, 30 mmol). ) Solution (10 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was acidified with 10% aqueous hydrochloric acid under ice-cooling, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to give a colorless oily substance. Chloro-4-cyclopentyloxypyridine-2-carboxylic acid (4.1 g) was obtained.
MS (ESI): 242 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.52-2.19 (m, 8 H) 4.72-5.00 (m, 1 H) 7.01 (d, J = 2.2 Hz, 1 H) 7.63 (d, J = 2.2 Hz, 1 H)
(6) To a solution of 6-chloro-4-cyclopentyloxypyridine-2-carboxylic acid (4.1 g, 17 mmol) and 2-amino-5-methylthiazole (2.17 g, 19 mmol) in dimethylformamide (30 ml), 1 -(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.64 g, 19 mmol) and 1-hydroxybenzotriazole (2.62 g, 19 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is purified by silica gel column chromatography [developing solvent; hexane: 6-Chloro-4-cyclopentyloxy-N- (5-methyl-1,3-thiazol-2-yl) pyridine--a colorless powdery substance by purifying with ethyl acetate = 4: 1 to 1: 1] 2-Carboxamide (3.5 g) was obtained.
MS (ESI): 338 (M + 1), 336 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.48-2.17 (m, 8 H) 2.45 (d, J = 1.2 Hz, 3 H) 4.73-5.07 (m, 1 H) 6.96 (d, J = 2.2 Hz, 1 H) 7.18 (d, J = 1.2 Hz, 1 H) 7.69 (d, J = 2.2 Hz, 1 H) 10.68-11.02 (br, 1 H)
(7) To a solution of 6-chloro-4-cyclopentyloxy-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (220 mg, 0.65 mmol) in dimethylformamide (4 ml) 3-mercapto-4-methyl-1,2,4-triazole (112 mg, 0.975 mmol) and potassium carbonate (90 mg, 0.65 mmol) were added, and the mixture was stirred at an external temperature of 180 ° C. for 8 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; chloroform: Methanol = 9: 1] Next, purification by NH-silica gel column chromatography [developing solvent; ethyl acetate] gave 4- (cyclopentyloxy) -N- (5-methyl-1,3- Thiazol-2-yl) -6-[(4-methyl-4H-1,2,4-triazol-3-yl) thio] pyridine-2-carboxamide (60 mg) was obtained.

Example 2
[(4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) thio] Preparation of acetic acid methyl ester (Compound No. 2) (1) 4-hydroxypyridine-2-carboxylic acid ethyl ester (20 g, 119 mmol), (R) -1-phenyl-2-propanol (26 g, 191 mmol), triphenylphosphine To a solution of (50 g, 191 mmol) in tetrahydrofuran (200 ml) was added diethyl azodicarboxylate 40% toluene solution (83 g, 191 mmol) under ice cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue was subjected to silica gel column chromatography [development]. Solvent; 4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid ethyl ester of colorless oily substance by purification with hexane: ethyl acetate = 5: 1 to 1: 1] 16.4 g) was obtained.
MS (ESI): 286 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.28 (t, J = 7.2 Hz, 3 H) 1.36 (d, J = 6.2 Hz, 3 H) 2.89 (dd, J = 13.9, 6.3 Hz, 1 H) 3.10 ( dd, J = 13.9, 6.3 Hz, 1 H) 4.47 (q, J = 7.2 Hz, 2 H) 4.65-4.84 (m, 1 H) 6.90 (dd, J = 5.6, 2.6 Hz, 1 H) 7.14-7.39 (m, 5 H) 7.63 (d, J = 2.6 Hz, 1 H) 8.51 (d, J = 5.6 Hz, 1 H)
(2) To a solution of 4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid ethyl ester (16.2 g, 56.8 mmol) in chloroform (130 ml), m-chloroperbenzoic acid ( 19.6 g, 114 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue was subjected to silica gel column chromatography [development]. 4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid ethyl ester 1-oxide (9) of pale yellow oily substance by purifying with solvent; chloroform: methanol = 9: 1] 0.1 g) was obtained.
MS (ESI): 302 (M + 1), 300 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J = 6.1 Hz, 3 H) 1.42 (t, J = 7.2 Hz, 3 H) 2.83-2.96 (m, 1 H) 3.01-3.11 (m, 1 H) 4.47 (q, J = 7.2 Hz, 2 H) 4.52-4.66 (m, 1 H) 6.76 (dd, J = 7.3, 3.4 Hz, 1 H) 6.96 (d, J = 3.4 Hz, 1 H) 7.13 -7.37 (m, 5 H) 8.08 (d, J = 7.3 Hz, 1 H)
(3) A solution of 4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid ethyl ester 1-oxide (9.1 g, 30 mmol) in acetic anhydride (35 ml) at an external temperature of 160 ° C. And stirred for 1 hour. The reaction mixture was allowed to cool and concentrated. A 10% aqueous hydrochloric acid solution (80 ml) was added to the residue, and the mixture was stirred at an external temperature of 80 ° C. for 1 hr. The reaction mixture is allowed to cool, basified with potassium carbonate, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue is subjected to silica gel column chromatography. 6-Hydroxy-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid ethyl ester (5) of a pale yellow powdery substance by purification with a chromatography [developing solvent; ethyl acetate]. 0.5 g) was obtained.
MS (ESI): 302 (M + 1), 300 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.33 (d, J = 6.1 Hz, 3 H) 1.39 (t, J = 7.2 Hz, 3 H) 2.86 (dd, J = 13.8, 6.2 Hz, 1 H) 3.07 ( dd, J = 13.8, 6.2 Hz, 1 H) 4.40 (q, J = 7.2 Hz, 2 H) 4.51-4.66 (m, 1 H) 6.02 (d, J = 2.5 Hz, 1 H) 6.65 (d, J = 2.5 Hz, 1 H) 7.13-7.38 (m, 5 H)
(4) A solution of 6-hydroxy-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid ethyl ester (5.3 g, 17.6 mmol) in phosphorus oxychloride (15 ml) The mixture was stirred at an external temperature of 110 ° C. for 2 hours. The reaction solution is cooled, poured into an aqueous potassium carbonate solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue is subjected to silica gel column chromatography. By purifying with [developing solvent; hexane: ethyl acetate = 4: 1 to 1: 1], colorless oily substance 6-chloro-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2 was obtained. -Carboxylic acid ethyl ester (4.58 g) was obtained.
MS (ESI): 320 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.37 (d, J = 6.1 Hz, 3 H) 1.40 (t, J = 7.2 Hz, 3 H) 2.82-2.97 (m, 1 H) 3.02-3.15 (m, 1 H) 4.45 (q, J = 7.2 Hz, 2 H) 4.64-4.88 (m, 1 H) 6.91 (d, J = 2.2 Hz, 1 H) 7.13-7.38 (m, 5 H) 7.53 (d, J = (2.2 Hz, 1 H)
(5) A solution of 6-chloro-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid ethyl ester (4.58 g, 14 mmol) in methanol (20 ml) and tetrahydrofuran (20 ml) To the mixture was added an aqueous solution (10 ml) of potassium hydroxide (1.57 g, 28 mmol), and the mixture was stirred for 2 hours under ice cooling. The reaction mixture was acidified with 10% aqueous hydrochloric acid under ice-cooling, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated to give a colorless oily substance. Chloro-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid (4.27 g) was obtained.
MS (ESI): 292 (M + 1), 290 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.39 (d, J = 6.1 Hz, 3 H) 2.83-3.00 (m, 1 H) 3.02-3.13 (m, 1 H) 4.61-4.88 (m, 1 H) 6.97 (d, J = 2.3 Hz, 1 H) 7.14-7.41 (m, 5 H) 7.59 (d, J = 2.3 Hz, 1 H)
(6) 6-chloro-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid (4.27 g, 14 mmol), 2-amino-5-methylthiazole (2.4 g, 21 mmol) in dimethylformamide (40 ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.1 g, 21 mmol), 1-hydroxybenzotriazole (2.96 g, 21 mmol), Stir at room temperature for 15 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is subjected to silica gel column chromatography [developing solvent; hexane: Purification by ethyl acetate = 2: 1] gave 6-chloro-4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3- Thiazol-2-yl) pyridine-2-carboxamide (4.8 g) was obtained.
MS (ESI): 388 (M + 1), 386 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.38 (d, J = 6.1 Hz, 3 H) 2.45 (d, J = 1.4 Hz, 3 H) 2.79-2.98 (m, 1 H) 3.01-3.14 (m, 1 H) 4.64-4.85 (m, 1 H) 6.92 (d, J = 2.2 Hz, 1 H) 7.12-7.40 (m, 6 H) 7.68 (d, J = 2.2 Hz, 1 H) 10.45-11.04 (br, 1 H)
(7) 6-chloro-4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (389 mg, Mercaptoacetic acid methyl ester (0.27 ml, 3.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added to a 1.0 mmol) dimethylformamide (3 ml) solution, and the mixture was stirred at an external temperature of 110 ° C. for 4 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is subjected to silica gel column chromatography [developing solvent; hexane: Purification by ethyl acetate = 4: 1 to 1: 1] gave [(4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl- 1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) thio] acetic acid methyl ester (157 mg) was obtained.

Example 3
According to the production method of Example 1 and Example 2, cyclopentyl bromide, (R) -1-phenyl-2-propanol is used, or isopropyl bromide, phenethyl alcohol, (S) -1-phenyl-2 is used instead. -Propanol, (R) -1- (4-fluorophenyl) -2-propanol, (R) -1- (2-methylphenyl) -2-propanol, (R) -1- (4-methylphenyl)- Use 2-propanol and 2-amino-5-methylthiazole, or alternatively 2-aminopyridine, 3-amino-1-methylpyrazole, 3-amino-1- (2-hydroxyethyl) pyrazole, 3 -Use amino-1-isopropylpyrazole and 3-mercapto-4-methyl-1,2,4-triazole or Instead, thiophenol, 2-mercaptopyridine, 4-mercaptopyridine, 1-methyl-1H-imidazole-2-thiol, 4H-1,2,4-triazole-3-thiol, 2-mercaptopyrimidine, 2-propanethiol , Cyclopentanethiol, 2-methyl-1-propanethiol, 3-methyl-1-butanethiol, 2-mercaptoethanol, 3-mercapto-1-propanol, (1S) -2-hydroxy-1-methylethanethiol, By using (3S) -tetrahydrofuran-3-thiol, 2-methoxy-ethanethiol, N- (2-mercaptoethyl) acetamide, 2- (dimethylamino) ethanethiol, mercaptoacetonitrile, the following compounds of the present invention are obtained. Obtained.
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (phenylthio) pyridine-2-carboxamide (Compound No. 3)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (pyridin-2-ylthio) pyridine-2-carboxamide (Compound No. 4)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (pyridin-4-ylthio) pyridine-2-carboxamide (Compound No. 5)
4- (cyclopentyloxy) -6-[(1-methyl-1H-imidazol-2-yl) thio] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide ( Compound No. 6)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (compound Number 7)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (pyrimidin-2-ylthio) pyridine-2-carboxamide (Compound No. 8)
4- (Cyclopentyloxy) -6- (isopropylthio) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 9)
4- (Cyclopentyloxy) -6- (cyclopentylthio) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 10)
4- (Cyclopentyloxy) -6- (isobutylthio) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 11)
4- (Cyclopentyloxy) -6-[(3-methylbutyl) thio] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 12)
4- (Cyclopentyloxy) -6-[(2-hydroxyethyl) thio] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 13)
4- (cyclopentyloxy) -6-[(3-hydroxypropyl) thio] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 14)
4- (Cyclopentyloxy) -N-pyridin-2-yl-6- (pyridin-2-ylthio) pyridine-2-carboxamide (Compound No. 15)
4- (Cyclopentyloxy) -N- (1-methyl-1H-pyrazol-3-yl) -6- (pyridin-2-ylthio) pyridine-2-carboxamide (Compound No. 16)
6-[(2-hydroxyethyl) thio] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridin-2- Carboxamide (Compound No. 17)
6-{[(1S) -2-hydroxy-1-methylethyl] thio} -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazole- 2-yl) pyridine-2-carboxamide (Compound No. 18)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6-[(3S) -tetrahydrofuran-3-ylthio] pyridine- 2-Carboxamide (Compound No. 19)
6-[(2-hydroxyethyl) thio] -N- (5-methyl-1,3-thiazol-2-yl) -4- (2-phenylethoxy) pyridine-2-carboxamide (Compound No. 20)
6-{[(1S) -2-hydroxy-1-methylethyl] thio} -N- (5-methyl-1,3-thiazol-2-yl) -4- (2-phenylethoxy) pyridine-2- Carboxamide (Compound No. 21)
4- (Cyclopentyloxy) -6-{[(1S) -2-hydroxy-1-methylethyl] thio} -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 22)
6-[(2-Methoxyethyl) thio] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridin-2- Carboxamide (Compound No. 23)
6-{[2- (acetylamino) ethyl] thio} -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine -2-Carboxamide (Compound No. 24)
6-{[2- (Dimethylamino) ethyl] thio} -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine -2-Carboxamide (Compound No. 25)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazole-3- (Ilthio) pyridine-2-carboxamide (Compound No. 26)
6-[(Cyanomethyl) thio] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide ( Compound No. 27)
N- (5-methyl-1,3-thiazol-2-yl) -4- (2-phenylethoxy) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 28)
4- (2-Phenylethoxy) -N-pyridin-2-yl-6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 29)
N- (1-Methyl-1H-pyrazol-3-yl) -4- (2-phenylethoxy) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (compound Number 30)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (1-methyl-1H-pyrazol-3-yl) -6- (4H-1,2,4-triazol-3-ylthio) Pyridine-2-carboxamide (Compound No. 31)
4-[(1S) -1-methyl-2-phenylethoxy] -N-pyridin-2-yl-6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (compound Number 32)
4-Isopropoxy-N- (1-methyl-1H-pyrazol-3-yl) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 33)
4-[(1R) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazole-3- (Ilthio) pyridine-2-carboxamide (Compound No. 34)
N- [1- (2-hydroxyethyl) -1H-pyrazol-3-yl] -4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazole -3-ylthio) pyridine-2-carboxamide (Compound No. 35)
N- (1-Isopropyl-1H-pyrazol-3-yl) -4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) Pyridine-2-carboxamide (Compound No. 36)
4-[(1S) -2- (4-Fluorophenyl) -1-methylethoxy] -N- (1-methyl-1H-pyrazol-3-yl) -6- (4H-1,2,4-triazole -3-ylthio) pyridine-2-carboxamide (Compound No. 37)
4-[(1S) -1-methyl-2- (2-methylphenyl) ethoxy] -N- (1-methyl-1H-pyrazol-3-yl) -6- (4H-1,2,4-triazole -3-ylthio) pyridine-2-carboxamide (Compound No. 38)
4-[(1S) -1-methyl-2- (4-methylphenyl) ethoxy] -N- (1-methyl-1H-pyrazol-3-yl) -6- (4H-1,2,4-triazole -3-ylthio) pyridine-2-carboxamide (Compound No. 39)

Example 4
[(4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) thio] Preparation of acetic acid (Compound No. 40) [(4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} To a solution of pyridin-2-yl) thio] acetic acid methyl ester (125 mg, 0.306 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml) was added 1M aqueous sodium hydroxide solution (1 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Stir. The reaction mixture is acidified with 1M aqueous hydrochloric acid, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to give a pale yellow powdery substance [(4 -[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) thio] acetic acid (102 mg )

Example 5
6-[(2-Amino-2-oxoethyl) thio] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine Preparation of 2-carboxyamide (Compound No. 41) [(4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) Amino] carbonyl} pyridin-2-yl) thio] acetic acid (92 mg, 0.207 mmol) in dimethylformamide (2 ml) was added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (47 mg,. 428 mmol), 1-hydroxybenzotriazole (34 mg, 0.428 mmol), 28% aqueous ammonia (0.056 ml), and at room temperature for 15:00 And the mixture was stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to preparative thin-layer silica gel chromatography [ By purifying with developing solvent; chloroform: ethyl acetate = 1: 1], colorless solid substance 6-[(2-amino-2-oxoethyl) thio] -4-[(1S) -1-methyl-2 -Phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (25 mg) was obtained.

Example 6
6-({[4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridin-2-yl] carbonyl} amino) nicotine Preparation of acid methyl ester (Compound No. 42) (1) 6-chloro-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid (6.0 g, 21.9 mmol) in chloroform (60 ml) Under cooling with ice, oxalyl chloride (5.63 ml, 65.7 mmol) and dimethylformamide (catalytic amount) were added and stirred for 20 minutes. Dimethylamine hydrochloride (2.62 g, 32.2 mmol) and triethylamine (9.14 ml, 65.7 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; hexane: 6-Chloro-N, N-dimethyl-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxamide (5) by purifying with ethyl acetate = 1: 1] 0.5 g) was obtained.
MS (ESI / APCI Dual): 319 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J = 6.2 Hz, 3 H) 2.81-2.95 (m, 1 H) 2.99-3.15 (m, 7 H) 4.57-4.83 (m, 1 H) 6.80 (d, J = 2.2 Hz, 1 H) 7.04 (d, J = 2.2 Hz, 1 H) 7.17-7.43 (m, 5 H)
(2) 6-chloro-N, N-dimethyl-4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxamide (1.1 g, 3.45 mmol) in dimethyl sulfoxide (6 ml) To the solution, 4H-1,2,4-triazole-3-thiol (1.05 g, 10.4 mmol) and cesium carbonate (2.2 g, 6.9 mmol) were added, and at 160 ° C. using a microwave reactor. Stir for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; chloroform. : Methanol = 20: 1] to give colorless gum N, N-dimethyl-4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2, 4-Triazol-3-ylthio) pyridine-2-carboxamide (1.53 g) was obtained.
MS (ESI / APCI Dual): 384 (M + 1), 382 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.34 (d, J = 6.1 Hz, 3 H) 2.88 (dd, J = 13.9, 5.8 Hz, 1 H) 2.99 (s, 3 H) 3.05 (dd, J = 13.9 , 6.9 Hz, 1 H) 3.13 (s, 3 H) 4.59-4.76 (m, 1 H) 6.80 (d, J = 2.2 Hz, 1 H) 6.92 (d, J = 2.2 Hz, 1 H) 7.09-7.36 (m, 5 H) 8.08 (s, 1 H)
(3) N, N-dimethyl-4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide ( To a mixed solution of 1.53 g, 3.99 mmol) in methanol (8 ml) and tetrahydrofuran (8 ml) were added potassium hydroxide (671 mg, 11.9 mmol) and water (4 ml), and the mixture was stirred at 60 ° C. for 6 hours. After allowing to cool, the reaction mixture is acidified with 1M aqueous hydrochloric acid, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to give a colorless gum-like substance. Of 4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxylic acid (1.10 g).
MS (ESI / APCI Dual): 357 (M + 1), 355 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.39 (d, J = 6.2 Hz, 3 H) 2.82-3.00 (m, 1 H) 3.03-3.20 (m, 1 H) 4.64-4.87 (m, 1 H) 6.94 (d, J = 2.2 Hz, 1 H) 7.11-7.36 (m, 5 H) 7.56 (d, J = 2.2 Hz, 1 H) 8.32 (s, 1 H)
(4) 4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxylic acid (187 mg, 0.524 mmol) To a chloroform (4 ml) solution of 6-aminonicotinic acid methyl ester (170 mg, 1.12 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (215 mg, 1.12 mmol), 1-hydroxy Benzotriazole (155 mg, 1.12 mmol) was added and stirred at room temperature for 15 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in that order, water, saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. Purification by methanol = 100: 1 to 20: 1] gave 6-({[4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1, 2,4-Triazol-3-ylthio) pyridin-2-yl] carbonyl} amino) -nicotinic acid methyl ester (45 mg) was obtained.

Example 7
According to the production method of Example 6, (2-amino-1,3-thiazol-4-yl) acetic acid ethyl ester and 3-amino-1-ethylpyrazole are used instead of 6-aminonicotinic acid methyl ester. As a result, the following compounds of the present invention were obtained.
[2-({[4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridin-2-yl] carbonyl} amino) -1,3-thiazol-4-yl] acetic acid methyl ester (Compound No. 43)
N- (1-ethyl-1H-pyrazol-3-yl) -4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) Pyridine-2-carboxamide (Compound No. 44)

Example 8
6-({[4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridin-2-yl] carbonyl} amino) nicotine Preparation of acid (Compound No. 45) 6-({[4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2 To a solution of -yl] carbonyl} amino) nicotinic acid methyl ester (32 mg, 0.065 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml), 1M aqueous sodium hydroxide solution (0.143 ml) and water (0.5 ml) were added, Stir at room temperature for 4 hours. Water was added to the reaction solution, and the unreacted ester was extracted and removed with ethyl acetate, acidified with 1M aqueous hydrochloric acid, extracted with chloroform, washed (in order of water and saturated brine), and dried (anhydrous magnesium sulfate). The residue obtained by filtration and concentration was purified by silica gel column chromatography [developing solvent; chloroform: methanol = 100: 1 to 20: 1] and recrystallized from methanol to give colorless powdery substance 6- ( {[4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridin-2-yl] carbonyl} amino) nicotinic acid (13 mg )

Example 9
According to the production method of Example 6 and Example 8, the following book was obtained by using (2-amino-1,3-thiazol-4-yl) acetic acid ethyl ester instead of 6-aminonicotinic acid methyl ester The inventive compound was obtained.
[2-({[4-[(1S) -1-methyl-2-phenylethoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridin-2-yl] carbonyl} amino) -1,3-thiazol-4-yl] acetic acid (Compound No. 46)

Example 10
Production of N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 47) (1 ) To a solution of 6-bromo-2-pyridinecarboxylic acid (1.20 g, 5.94 mmol), 2-amino-5-methylthiazole (1.00 g, 8.91 mmol) in dimethylformamide (20 ml), 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.27 g, 11.88 mmol) and 1-hydroxybenzotriazole (1.64 g, 11.88 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is purified by silica gel column chromatography [developing solvent; hexane: 6-Bromo-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (1.40 g) as a colorless powder by purifying with ethyl acetate = 1: 1] Got.
MS (ESI / APCI Dual): 299 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 2.46 (d, J = 1.2 Hz, 3 H) 7.19 (d, J = 1.2 Hz, 1 H) 7.61-7.74 (m, 1 H) 7.75-7.85 (m, 1 H) 8.24 (dd, J = 7.5, 0.93 Hz, 1 H) 10.68-10.95 (br, 1 H)
(2) To a solution of 6-bromo-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (400 mg, 1.34 mmol) in dimethyl sulfoxide (5 ml), 4H-1, 2,4-Triazole-3-thiol (406 mg, 4.02 mmol) and cesium carbonate (873 mg, 2.68 mmol) were added, and the mixture was stirred at 160 ° C. for 2 hours using a microwave reactor. The reaction solution is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue is subjected to NH-silica gel column chromatography (developing solvent). N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazole) as a colorless solid substance by purification with chloroform: methanol = 9: 1) -3-ylthio) pyridine-2-carboxamide (200 mg) was obtained.

Example 11
According to the production method of Example 10, the following compound of the present invention was obtained by using 3-amino-1-methylpyrazole instead of 2-amino-5-methylthiazole.
N- (1-Methyl-1H-pyrazol-3-yl) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 48)

Example 12
N- (5-methyl-1,3-thiazol-2-yl) -4- (tetrahydro-2H-pyran-4-yloxy) -6- (4H-1,2,4-triazol-3-ylthio) pyridine Preparation of 2-carboxamide (Compound No. 49) (1) To a solution of 4,6-dichloropyridine-2-carboxylic acid (880 mg, 4.58 mmol) in dimethylformamide (15 ml), 2-amino-5-methylthiazole (830 mg, 7.27 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.39 g, 7.27 mmol), 1-hydroxybenzotriazole (1.00 g, 7.27 mmol) were added. And stirred at room temperature for 4 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is subjected to silica gel column chromatography [developing solvent; chloroform]. To give 4,6-dichloro-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (1.12 g) as a pale yellow powder.
MS (ESI / APCI Dual): 288 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 2.46 (d, J = 1.2 Hz, 3 H) 7.19 (d, J = 1.2 Hz, 1 H) 7.57 (d, J = 1.7 Hz, 1 H) 8.20 (d, J = 1.7 Hz, 1 H) 10.62-10.85 (br, 1 H)
(2) To a suspension of sodium hydride (added 30% liquid paraffin) (382 mg, 9.57 mmol) in dimethylformamide (30 ml) under ice-cooling, 4-hydroxytetrahydropyran (977 mg, 9.57 mmol) in dimethylformamide ( 10 ml) solution was added and stirred at room temperature for 30 minutes. The reaction solution was ice-cooled and a suspension of 4,6-dichloro-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (720 mg, 2.50 mmol) in dimethylformamide (10 ml) was suspended. The solution was added and stirred for 3 hours under ice cooling. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; hexane. : Ethyl acetate = 1: 1 to 1: 2] to give 6-chloro-N- (5-methyl-1,3-thiazol-2-yl) -4- (tetrahydro- 2H-pyran-4-yloxy) pyridine-2-carboxamide (368 mg) was obtained.
MS (ESI / APCI Dual): 354 (M + 1), 352 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.74-1.92 (m, 2 H) 1.98-2.18 (m, 2 H) 2.45 (d, J = 1.2 Hz, 3 H) 3.55-3.69 (m, 2 H) 3.92 -4.07 (m, 2 H) 4.62-4.78 (m, 1 H) 7.01 (d, J = 2.2 Hz, 1 H) 7.18 (d, J = 1.2 Hz, 1 H) 7.72 (d, J = 2.2 Hz, 1 H)
(3) 6-chloro-4- (tetrahydro-2H-pyran-4-yloxy) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (368 mg, 1.04 mmol) 4H-1,2,4-triazole-3-thiol (420 mg, 4.16 mmol) and cesium carbonate (1.02 g, 3.12 mmol) were added to a dimethyl sulfoxide (3 ml) solution. Stir for hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. : 7M ammonia-containing methanol = 20: 1 to 10: 1] to give N- (5-methyl-1,3-thiazol-2-yl) -4- (tetrahydro-2H- Pyran-4-yloxy) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (65 mg) was obtained.

Example 13
According to the production method of Example 12, instead of 4-hydroxytetrahydropyran, 2-indanol, isopropanol, (S) -1- (4-chlorophenyl) -2-propanol, (S) -1-phenyl-2 -Use butanol, phenol, 4- (methylthio) phenol, 2-phenylethyl mercaptan, 3-hydroxypyridine, use 2-amino-5-methylthiazole, or use 3-amino-1-methylpyrazole instead As a result, the following compounds of the present invention were obtained.
4- (2,3-dihydro-1H-inden-2-yloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazole-3 -Ilthio) pyridine-2-carboxamide (Compound No. 50)
4-Isopropoxy-N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 51 )
4-[(1S) -2- (4-Chlorophenyl) -1-methylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4- Triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 52)
4-{[(1S) -1-benzylpropyl] oxy} -N- (5-methyl-1,3-thiazol-2-yl) -6- (4H-1,2,4-triazol-3-ylthio) ) Pyridine-2-carboxamide (Compound No. 53)
N- (5-methyl-1,3-thiazol-2-yl) -4-phenoxy-6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 54)
N- (5-methyl-1,3-thiazol-2-yl) -4- [4- (methylthio) phenoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2- Carboxamide (Compound No. 55)
N- (5-methyl-1,3-thiazol-2-yl) -4-[(2-phenylethyl) thio] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2 -Carboxamide (Compound No. 56)
N- (1-Methyl-1H-pyrazol-3-yl) -4-phenoxy-6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 57)
N- (1-methyl-1H-pyrazol-3-yl) -4- [4- (methylthio) phenoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide (Compound No. 58)
N- (1-methyl-1H-pyrazol-3-yl) -4- (pyridin-3-yloxy) -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxamide ( Compound No. 59)

Example 14
N- (5-methyl-1,3-thiazol-2-yl) -4- [4- (methylsulfonyl) phenoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2 -Preparation of Carboxamide (Compound No. 60) N- (5-Methyl-1,3-thiazol-2-yl) -4- [4- (methylthio) phenoxy] -6- (4H-1,2,4- To a mixed solution of triazol-3-ylthio) pyridine-2-carboxamide (155 mg, 0.339 mmol) in tetrahydrofuran (4 ml), methanol (4 ml) and water (2 ml) was added Oxone ™ (250 mg, 0.406 mmol). ) And stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue obtained is recrystallized from methanol. A colorless powder of N- (5-methyl-1,3-thiazol-2-yl) -4- [4- (methylsulfonyl) phenoxy] -6- (4H-1,2,4-triazole -3-ylthio) pyridine-2-carboxamide (51 mg) was obtained.

Example 15
The following compounds of the present invention were obtained by using 3-amino-1-methylpyrazole instead of 2-amino-5-methylthiazole according to the production methods of Example 13 and Example 14.
N- (1-methyl-1H-pyrazol-3-yl) -4- [4- (methylsulfonyl) phenoxy] -6- (4H-1,2,4-triazol-3-ylthio) pyridine-2-carboxy Amide (Compound No. 61)

Example 16
Preparation of 4- (cyclopentyloxy) -6- (hydroxymethyl) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 62) (1) 4-hydroxy To a dimethylformamide (300 ml) solution of pyridine-2,6-dicarboxylic acid dimethyl ester (21 g, 99 mmol), potassium carbonate (27 g, 119 mmol) and cyclopentyl bromide (17 ml, 198 mmol) were added, and the external temperature was 80 ° C. for 4 hours. Stir. The reaction solution is allowed to cool, poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated to give 4- ( Cyclopentyloxy) pyridine-2,6-dicarboxylic acid dimethyl ester (17 g) was obtained.
MS (ESI): 280 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.32-2.56 (m, 8 H) 4.01 (s, 6 H) 4.61-5.31 (m, 1 H) 7.77 (s, 2 H)
(2) Sodium borohydride (2.3 g, 61 mmol) was gradually added to a methanol (120 ml) solution of 4- (cyclopentyloxy) pyridine-2,6-dicarboxylic acid dimethyl ester (17 g, 61 mmol) under ice cooling. The mixture was stirred for 3 hours under ice cooling. The reaction solution was poured into saturated brine, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; Hexane: ethyl acetate = 1: 1 to ethyl acetate alone] to give 4- (cyclopentyloxy) -6- (hydroxymethyl) pyridine-2-carboxylic acid methyl ester (14 g) as a light brown powdery substance. Obtained.
MS (ESI): 252 (M + 1), 250 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.54-2.05 (m, 8 H) 3.98 (s, 3 H) 4.78 (s, 2 H) 4.84-5.00 (m, 1 H) 6.97 (d, J = 2.3 Hz , 1 H) 7.53 (d, J = 2.3 Hz, 1 H)
(3) To a solution of 4- (cyclopentyloxy) -6- (hydroxymethyl) pyridine-2-carboxylic acid methyl ester (1.9 g, 7.5 mmol) in methanol (10 ml), potassium hydroxide (1.2 g, 22 mmol) and water (0.2 ml) were added and stirred at room temperature for 2 hours. The reaction was acidified with 1M aqueous hydrochloric acid and concentrated. The obtained residue was suspended in a mixed solution of tetrahydrofuran and ethanol, filtered, and the filtrate was concentrated. 4- (Cyclopentyloxy) -6- (hydroxymethyl) pyridine-2-carboxylic acid obtained by dimethylformamide ( 20-ml), 2-amino-5-methylthiazole (856 mg, 7.5 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.44 g, 7.5 mmol), 1- Hydroxybenzotriazole (1.0 g, 7.5 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to NH-silica gel column chromatography [developing solvent; By purification with ethyl acetate], the colorless solid substance 4- (cyclopentyloxy) -6- (hydroxymethyl) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxyl Amide (995 mg) was obtained.

Example 17
6- (Hydroxymethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 63) Preparation (1) To a solution of 4-hydroxypyridine-2,6-dicarboxylic acid dimethyl ester (27.1 g, 100 mmol) in tetrahydrofuran (200 ml) was added (R) -1-phenyl-2-propanol (19 g, 139 mmol). ), Triphenylphosphine (36 g, 139 mmol) was added, and diethylazodicarboxylate 40% toluene solution (60 g, 139 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 15 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [development]. Solvent; hexane: ethyl acetate = 5: 1 to 1: 1] to give colorless oily substance dimethyl 4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2,6-dicarboxylate The ester (25 g) was obtained.
MS (ESI / APCI Dual): 330 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.39 (d, J = 6.1 Hz, 3 H) 2.85-3.03 (m, 1 H) 3.04-3.19 (m, 1 H) 4.00 (s, 6 H) 4.73-4.95 (m, 1 H) 7.11-7.43 (m, 5 H) 7.75 (s, 2 H)
(2) Boron hydride in a methanol (180 ml) solution of 4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2,6-dicarboxylic acid dimethyl ester (23 g, 69.8 mmol) under ice-cooling Sodium (2.64 g, 70 mmol) was added, and the mixture was stirred for 4 hours under ice cooling. The reaction mixture was poured into saturated brine, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent. Ethyl acetate] to give 6- (hydroxymethyl) -4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid methyl ester (15 g) as a colorless oily substance. It was.
MS (ESI): 302 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J = 6.1 Hz, 3 H) 2.79-2.97 (m, 1 H) 3.01-3.17 (m, 1 H) 3.29-3.41 (br, 1 H) 3.97 (s, 3 H) 4.66-4.86 (m, 3 H) 6.95 (d, J = 2.3 Hz, 1 H) 7.14-7.41 (m, 5 H) 7.52 (d, J = 2.3 Hz, 1 H)
(3) 6- (hydroxymethyl) -4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid methyl ester (2.00 g, 6.64 mmol) in methanol (10 ml) and tetrahydrofuran An aqueous solution (5 ml) of sodium hydroxide (0.53 g, 13.27 mmol) was added to a mixed solution of (10 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 10% aqueous hydrochloric acid solution, and the solvent was evaporated. Ethanol (40 ml) and tetrahydrofuran (40 ml) were added to the resulting residue and stirred, and then insoluble matter was removed. The filtrate was concentrated to give colorless solid substance 6- (hydroxymethyl) -4-[(1S). -1-Methyl-2-phenylethoxy] pyridine-2-carboxylic acid (1.79 g) was obtained.
MS (ESI): 288 (M + 1), 286 (M-1)
1H NMR (300 MHz, DMSO-D6) δ ppm 1.34 (d, J = 6.1 Hz, 3 H) 2.88-3.15 (m, 2 H) 4.70 (s, 2 H) 5.09-5.25 (m, 1 H) 7.13 -7.37 (m, 5 H) 7.48 (d, J = 2.5 Hz, 1 H) 7.60 (d, J = 2.5 Hz, 1 H)
(4) 6- (hydroxymethyl) -4-[(1S) -1-methyl-2-phenylethoxy] pyridine-2-carboxylic acid (1.79 g, 6.23 mmol), 2-amino-5-methylthiazole (0.78 g, 6.85 mmol), 1-hydroxybenzotriazole (1.43 g, 9.35 mmol) in dimethylformamide (30 ml) was added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 1.78 g, 9.35 mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in that order, water, saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; chloroform: By purifying with methanol = 9: 1], 6- (hydroxymethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1, 3-Thiazol-2-yl) pyridine-2-carboxamide (1.29 g) was obtained.

Example 18
Preparation of 4- (cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (pyridin-2-ylmethyl) pyridine-2-carboxamide (Compound No. 64) (1) To a solution of 4- (cyclopentyloxy) -6- (hydroxymethyl) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (995 mg) in chloroform (10 ml), 1,1-Trisacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (desmartin reagent) (1.9 g, 4.47 mmol) was added under ice cooling to room temperature. And stirred for 15 hours. A saturated aqueous sodium bicarbonate solution and a 1M aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: By purifying in 1), a colorless powdery substance 4- (cyclopentyloxy) -6-formyl-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (557 mg) Got.
MS (ESI): 330 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.85-2.80 (m, 8 H) 2.92-3.18 (br, 3 H) 5.32-5.72 (br, 1 H) 7.43-7.94 (br, 1 H) 8.04-8.25 ( br, 1 H) 8.42-8.71 (br, 1 H) 10.55-10.65 (br, 1 H)
(2) A normal butyl lithium (2.64 M) hexane solution (0.342 ml) was added to a tetrahydrofuran (2 ml) solution of 2-bromopyridine (0.087 ml, 0.904 mmol) at an external temperature of −78 ° C. For 10 minutes. Thereto was added a solution of 4- (cyclopentyloxy) -6-formyl-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (150 mg, 0.452 mmol) in tetrahydrofuran (2 ml). In addition, the mixture was stirred at the same temperature for 30 minutes. Saturated saline was added to the reaction solution, and the residue obtained after extraction with chloroform, washing (in order of water and saturated saline), drying (anhydrous magnesium sulfate), filtration and concentration was subjected to silica gel column chromatography [developing solvent; By purifying with ethyl], colorless powdery substance 4- (cyclopentyloxy) -6- [hydroxy (pyridin-2-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl ) Pyridine-2-carboxamide (55 mg) was obtained.
MS (ESI): 411 (M + 1), 409 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.64-2.08 (m, 8 H) 2.46 (d, J = 1.2 Hz, 3 H) 4.73-5.04 (m, 1 H) 5.56-5.76 (m, 1 H) 5.80 -5.97 (m, 1 H) 7.11-7.29 (m, 3 H) 7.47-7.60 (m, 1 H) 7.62-7.75 (m, 2 H) 8.49-8.65 (m, 1 H)
(3) 4- (Cyclopentyloxy) -6- [hydroxy (pyridin-2-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (55 mg, Triphenylphosphine (42 mg, 0.160 mmol) and carbon tetrabromide (53 mg, 0.160 mmol) were added to a chloroform (2 ml) solution of 0.134 mmol), and the mixture was stirred at room temperature for 15 hours. The residue obtained by concentrating the reaction solution was dissolved in a mixed solution of methanol (1 ml) and tetrahydrofuran (1 ml), 10% palladium carbon was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen gas stream. The reaction solution was filtered through Celite and concentrated, and the residue obtained was purified by NH-silica gel column chromatography [developing solvent; hexane: ethyl acetate = 1: 1] to give 4- (cyclopentyloxy) as a colorless oily substance. -N- (5-methyl-1,3-thiazol-2-yl) -6- (pyridin-2-ylmethyl) pyridine-2-carboxamide (10 mg) was obtained.

Example 19
3- (4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) propion Preparation of acid (Compound No. 65) (1) A suspension of sodium hydride (with 30% liquid paraffin added) (80 mg, 2.0 mmol) in tetrahydrofuran (2 ml) under cooling with benzyldimethylphosphonoacetate (516 mg, 2. 0 mmol) in tetrahydrofuran (3 ml) was added, and the mixture was stirred for 10 minutes under ice cooling. Thereto, 6-formyl-4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3) obtained according to the production methods of Examples 17 and 18 was obtained. -A solution of -thiazol-2-yl) pyridine-2-carboxamide (381 mg, 1.0 mmol) in tetrahydrofuran (3 ml) was added, and the mixture was stirred for 2 hours 30 minutes under ice cooling. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; hexane. : Ethyl acetate = 4: 1] to give (2E) -3- (4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl -1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) acrylic acid benzyl ester (434 mg) was obtained.
MS (ESI / APCI Dual): 514 (M + 1), 512 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.38 (d, J = 6.1 Hz, 3 H) 2.45 (d, J = 1.2 Hz, 3 H) 2.85-2.98 (m, 1 H) 3.03-3.19 (m, 1 H) 4.74-4.88 (m, 1 H) 5.29 (s, 2 H) 6.98-7.02 (m, 1 H) 7.04 (d, J = 15 Hz, 1 H) 7.17 (d, J = 1.2 Hz, 1 H ) 7.17-7.52 (m, 10 H) 7.62 (d, J = 15 Hz, 1 H) 7.73 (d, J = 2.5 Hz, 1 H) 10.89-11.02 (br, 1 H)
(2) (2E) -3- (4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} To a mixed solution of pyridine-2-yl) acrylic acid benzyl ester (434 mg, 0.846 mmol) in methanol (4 ml) and tetrahydrofuran (4 ml), 10% palladium carbon (40 mg) was added, and the mixture was stirred at room temperature under a hydrogen gas stream for 2 days. did. The reaction mixture was filtered through celite and the residue obtained by concentration was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 4: 1] to give 3- (4-[(1S ) -1-Methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) propionic acid benzyl ester (267 mg) It was.
1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J = 6.1 Hz, 3 H) 2.45 (d, J = 1.2 Hz, 3 H) 2.78-2.97 (m, 3 H) 3.01-3.25 (m, 3 H) 4.61-4.85 (m, 1 H) 5.15 (s, 2 H) 6.81 (d, J = 2.3 Hz, 1 H) 7.17 (d, J = 1.2 Hz, 1 H) 7.19-7.37 (m, 10 H ) 7.60 (d, J = 2.5 Hz, 1 H) 10.75-11.02 (br, 1 H)
(3) 3- (4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridine-2- Yl) 1M sodium hydroxide aqueous solution (0.136 ml) was added to a mixed solution of propionic acid benzyl ester (60 mg, 0.116 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution is acidified with 1M aqueous hydrochloric acid, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. Purification by plate silica gel chromatography [developing solvent; chloroform: methanol = 9: 1] gave 3- (4-[(1S) -1-methyl-2-phenylethoxy] -6- { [(5-Methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridin-2-yl) propionic acid (22 mg) was obtained.

Example 20
6- (3-hydroxypropyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide ( Preparation of Compound No. 66) 3- (4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(5-methyl-1,3-thiazol-2-yl) amino] carbonyl} pyridine To a solution of 2-yl) propionic acid (110 mg, 0.26 mmol) in tetrahydrofuran (5 ml), 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (Bopp reagent) (205 mg, 0.465 mmol) ), Sodium borohydride (22 mg, 0.585 mmol) was added, and the mixture was stirred for 1 hour under ice cooling. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [ By purifying with a developing solvent; hexane: ethyl acetate = 1: 1], a colorless oily substance 6- (3-hydroxypropyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- ( 5-Methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (17 mg) was obtained.

Example 21
In accordance with the production method of Example 19, the following compounds of the present invention were obtained by using cyclopentyltriphenylphosphonium bromide and isopropyltriphenylphosphonium iodide instead of benzyldimethylphosphonoacetate.
6- (Cyclopentylmethyl) -4-phenoxy-N-1,3-thiazol-2-ylpyridin-2-carboxamide (Compound No. 67)
6-isobutyl-N- (5-methyl-1,3-thiazol-2-yl) -4-phenoxypyridine-2-carboxamide (Compound No. 68)

Example 22
Preparation of 4- (cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (phenoxymethyl) pyridine-2-carboxamide (Compound No. 69) (1) 4- ( To a solution of cyclopentyloxy) -6- (hydroxymethyl) pyridine-2-carboxylic acid methyl ester (300 mg, 1.19 mmol) in tetrahydrofuran (5 ml) was added phenol (112 mg, 1.2 mmol), triphenylphosphine (314 mg, 1.2 mmol). ), Diethyl azodicarboxylate 40% toluene solution (522 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue was purified by silica gel column chromatography. A colorless oily substance 4- (cyclopentyloxy) -6- (phenoxymethyl) pyridine-2-carboxylic acid methyl ester (270 mg) was obtained.
MS (ESI): 328 (M + 1), 326 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.55-2.08 (m, 8 H) 4.01 (s, 3 H) 4.76-5.01 (m, 1 H) 5.25 (s, 2 H) 6.91-7.04 (m, 3 H ) 7.21 (d, J = 2.5 Hz, 1 H) 7.25-7.37 (m, 2 H) 7.56 (d, J = 2.5 Hz, 1 H)
(2) 4- (cyclopentyloxy) -6- (phenoxymethyl) pyridine-2-carboxylic acid methyl ester (270 mg, 0.827 mmol) in methanol (5 ml) solution in potassium hydroxide (140 mg, 2.48 mmol), water (1 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was acidified with 1M aqueous hydrochloric acid, extracted with ethyl acetate, washed (in that order, water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated to give 4- (cyclopentyloxy) as a colorless oily substance. ) -6- (phenoxymethyl) pyridine-2-carboxylic acid (260 mg) was obtained.
MS (ESI): 314 (M + 1), 312 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.55-2.10 (m, 8 H) 4.82-4.98 (m, 1 H) 5.17 (s, 2 H) 6.90-7.07 (m, 3 H) 7.19-7.39 (m, 3 H) 7.61 (d, J = 2.5 Hz, 1 H)
(3) 4- (cyclopentyloxy) -6- (phenoxymethyl) pyridine-2-carboxylic acid (260 mg, 0.83 mmol), 2-amino-5-methylthiazole (114 mg, 1.00 mmol) in dimethylformamide (5 ml) ) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole (136 mg, 1.00 mmol) were added to the solution and stirred at room temperature for 4 hours. . The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is subjected to silica gel column chromatography [developing solvent; hexane: By purifying with ethyl acetate = 4: 1 to 2: 1], 4- (cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (phenoxy) was obtained as a colorless oily substance. Methyl) pyridine-2-carboxamide (290 mg) was obtained.

Example 23
Based on the production methods of Example 17 and Example 22, the following compounds of the present invention were obtained by using succinimide instead of phenol.
6-[(2,5-Dioxopyrrolidin-1-yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazole-2 -Yl) pyridine-2-carboxamide (Compound No. 70)

Example 24
4- (cyclopentyloxy) -6- preparation of (methoxymethyl)-N-(5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 71) (1) Sodium hydride (Addition of 30% liquid paraffin) (132 mg, 3.3 mmol) in a suspension of dimethylformamide (5 ml) under ice-cooling, 4- (cyclopentyloxy) -6- (hydroxymethyl) pyridine-2-carboxylic acid methyl ester ( 251 mg, 1.0 mmol) in dimethylformamide (5 ml) was added and stirred for 5 minutes. A solution of methyl iodide (426 mg, 3.0 mmol) in dimethylformamide (5 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution is added to a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated to give 4- (cyclopentyloxy) as a yellow oily substance. -6- (methoxymethyl) pyridine-2-carboxylic acid methyl ester (210 mg) was obtained.
MS (ESI) 266 (M + 1), 264 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.45-2.21 (m, 8 H) 3.48 (s, 3 H) 3.98 (s, 3 H) 4.62 (s, 2 H) 4.79-5.04 (m, 1 H) 7.12 (d, J = 2.4 Hz, 1 H) 7.53 (d, J = 2.4 Hz, 1 H)
(2) To a solution of 4- (cyclopentyloxy) -6- (methoxymethyl) pyridine-2-carboxylic acid methyl ester (210 mg) in methanol (5 ml) was added 10% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 15 hours. . The reaction solution was added to a 10% aqueous citric acid solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to give 4- (cyclopentyloxy) as a colorless oily substance. ) -6- (methoxymethyl) pyridine-2-carboxylic acid (100 mg) was obtained.
MS (ESI) 252 (M + 1), 250 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.59-2.07 (m, 8 H) 3.50 (s, 3 H) 4.57 (s, 2 H) 7.15 (d, J = 2.4 Hz, 1 H) 7.61 (d, J = 2.4 Hz, 1 H)
(3) To a solution of 4- (cyclopentyloxy) -6- (methoxyxymethyl) pyridine-2-carboxylic acid (100 mg) and 2-amino-5-methylthiazole (137 mg, 1.2 mmol) in dimethylformamide (10 ml) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) and 1-hydroxybenzotriazole (270 mg, 2.00 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent. Hexane: ethyl acetate = 2: 3] to give colorless solid substance 4- (cyclopentyloxy) -6- (methoxymethyl) -N- (5-methyl-1,3-thiazole-2- Yl) pyridine-2-carboxamide (68 mg) was obtained.

Example 25
In accordance with the production method of Example 24, the following compound of the present invention was obtained by using ethyl iodide instead of methyl iodide.
4- (Cyclopentyloxy) -6- (ethoxymethyl) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 72)

Example 26
6-[(Acetylamino) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide Preparation of (Compound No. 73) (1) 6- (Hydroxymethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl ) Triphenylphosphine (609 mg, 2.33 mmol) was added to a mixed solution of pyridine-2-carboxamide (686 mg, 1.79 mmol) in chloroform (3.4 ml) and carbon tetrachloride (3.4 ml), and the external temperature was 90 ° C. And heated at reflux for 2 hours. The reaction mixture was allowed to cool and concentrated, and the residue obtained was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 3: 1] to give 6- (chloromethyl)- 4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (570 mg) was obtained.
MS (ESI): 402 (M + 1), 400 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.38 (d, J = 6.1 Hz, 3 H) 2.44 (d, J = 1.1 Hz, 3 H) 2.91 (dd, J = 13.9, 5.7 Hz, 1 H) 3.10 ( dd, J = 13.9, 6.5 Hz, 1 H) 4.60 (s, 2 H) 4.77-4.83 (m, 1 H) 7.11 (d, J = 2.5 Hz, 1 H) 7.16 (d, J = 1.2 Hz, 1 H) 7.19-7.32 (m, 5 H) 7.69 (d, J = 2.5 Hz, 1 H) 10.94 (s, 1 H)
(2) 6- (Chloromethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide To a solution of (1.0 g, 2.48 mmol) in dimethylformamide (10 ml) was added sodium azide (244 mg, 3.72 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; hexane. : Ethyl acetate = 2: 1 to 1: 1] to give 6- (azidomethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5- Methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (890 mg) was obtained.
MS (ESI): 409 (M + 1), 407 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.38 (d, J = 6.1 Hz, 3 H) 2.45 (d, J = 1.1 Hz, 3 H) 2.82-3.01 (m, 1 H) 3.05-3.22 (m, 1 H) 4.44 (s, 2 H) 4.55-4.95 (m, 1 H) 6.98 (d, J = 2.3 Hz, 1 H) 7.13-7.19 (m, 1 H) 7.19-7.39 (m, 5 H) 7.70 ( d, J = 2.3 Hz, 1 H) 10.88-11.02 (br, 1 H)
(3) 6- (azidomethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide ( To a solution of 890 mg, 2.17 mmol) in methanol (6 ml) and tetrahydrofuran (6 ml) was added 10% palladium carbon (100 mg), and the mixture was stirred at room temperature under a hydrogen gas stream for 15 hours. The filtrate obtained by diluting the reaction solution with chloroform and filtering through celite is concentrated and purified by NH-silica gel column chromatography [developing solvent; chloroform: methanol = 9: 1] to give colorless powdery substance 6- (Aminomethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (832 mg) was obtained. It was.
MS (ESI): 383 (M + 1), 381 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.37 (d, J = 6.1 Hz, 3 H) 2.45 (d, J = 1.2 Hz, 3 H) 2.90 (dd, J = 13.9, 6.0 Hz, 1 H) 3.09 ( dd, J = 13.9, 6.5 Hz, 1 H) 3.94 (s, 2 H) 4.67-4.91 (m, 1 H) 6.95 (d, J = 2.3 Hz, 1 H) 7.16 (d, J = 1.2 Hz, 1 H) 7.18-7.38 (m, 5 H) 7.65 (d, J = 2.3 Hz, 1 H)
(4) 6- (Aminomethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide Pyridine (0.126 ml, 1.566 mmol) and acetic anhydride (0.098 ml, 1.044 mmol) were added to a chloroform (2 ml) solution of (200 mg, 0.522 mmol) under ice cooling, and the mixture was stirred at room temperature for 15 hours. . The reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [development]. Solvent; ethyl acetate] to give a colorless powdery substance 6-[(acetylamino) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl- 1,3-thiazol-2-yl) pyridine-2-carboxamide (152 mg) was obtained.

Example 27
In accordance with the production method of Example 26, the following compound of the present invention was obtained by using methylsulfonyl chloride instead of acetic anhydride.
4-[(1S) -1-methyl-2-phenylethoxy] -6-{[(methylsulfonyl) amino] methyl} -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2 -Carboxamide (Compound No. 74)

Example 28
6- [1- (2,5-Dioxopyrrolidin-1-yl) ethyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazole 2-yl) Pyridine-2-carboxyamide (Compound No. 75) (1) 6-Formyl-4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1 , 3-thiazol-2-yl) pyridine-2-carboxamide (381 mg, 1.0 mmol) in tetrahydrofuran (5 ml) at an external temperature of −78 ° C. in 3M methylmagnesium bromide in tetrahydrofuran (0.7 ml, 2 ml). 0.1 mmol) and stirred at -30 ° C for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to NH-silica gel column chromatography. [Developing solvent; hexane: ethyl acetate = 1: 1 to ethyl acetate alone] to give 4-[(1S) -1-methyl-2-phenylethoxy] -6- (1- Hydroxyethyl) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (220 mg) was obtained.
MS (ESI / APCI Dual): 398 (M + 1), 396 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.33-1.42 (m, 3 H) 1.50-1.58 (m, 3 H) 2.42-2.47 (m, 3 H) 2.83-2.96 (m, 1 H) 2.95-3.05 ( m, 1 H) 3.04-3.15 (m, 1 H) 4.65-5.01 (m, 2 H) 6.94-7.08 (m, 1 H) 7.13-7.19 (m, 1 H) 7.19-7.37 (m, 5 H) 7.66-7.69 (m, 1 H) 10.85-11.02 (br, 1 H)
(2) 4-[(1S) -1-methyl-2-phenylethoxy] -6- (1-hydroxyethyl) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2- A solution of carboxamide (220 mg, 0.553 mmol), succinimide (60 mg, 0.608 mmol), triphenylphosphine (159 mg, 0.608 mmol) in tetrahydrofuran (5 ml) was added to a solution of 40% toluene in diethyl azodicarboxylate under ice-cooling. 105 mg, 0.608 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The residue obtained by concentrating the reaction solution was subjected to silica gel column chromatography [developing solvent; hexane: ethyl acetate = 1: 1] and preparative thin layer silica gel chromatography [developing solvent; hexane: ethyl acetate = 2: 1. ] To give 6- [1- (2,5-dioxopyrrolidin-1-yl) ethyl] -4-[(1S) -1-methyl-2-phenylethoxy]- N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (35 mg) was obtained.

Example 29
4- (cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N-1,3-thiazol-2-ylpyridin-2-carboxamide (Compound No. 76) Preparation (1) Triphenylphosphine (9.40 g, 35) was added to a solution of 4- (cyclopentyloxy) -6- (hydroxymethyl) pyridine-2-carboxylic acid methyl ester (6 g, 23.88 mmol) in carbon tetrachloride (180 ml). .82 mmol) was added, and the mixture was stirred at an external temperature of 100 ° C. for 6 hours. The reaction mixture is allowed to cool, poured into water, extracted with chloroform, washed (in that order, water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue is subjected to silica gel column chromatography [developing solvent. Hexane: ethyl acetate = 1: 1] to give 4- (cyclopentyloxy) -6- (chloromethyl) pyridine-2-carboxylic acid methyl ester (6.13 g) as a pale yellow oily substance. .
MS (ESI): 270 (M + 1), 268 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.50-1.93 (m, 8 H) 2.25 (s, 3 H) 2.28 (s, 3 H) 4.00 (s, 3 H) 4.68-4.82 (m, 1 H) 5.39 (s, 2 H) 5.90 (s, 1 H) 6.22 (d, J = 2.5 Hz, 1 H) 7.50 (d, J = 2.5 Hz, 1 H)
(2) A suspension of sodium hydride (added 30% liquid paraffin) (356 mg, 8.90 mmol) in dimethylformamide (20 ml) at room temperature with 3,5-dimethylpyrazole (855 mg, 8.90 mmol) in dimethylformamide (5 ml) solution was added and stirred for 10 minutes. 4- (cyclopentyloxy) -6- (chloromethyl) pyridine-2-carboxylic acid methyl ester (2.0 g, 7.42 mmol), triethylamine (1.24 ml, 8.90 mmol) in dimethylformamide (12 ml) And stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed (in that order, water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. : Methanol = 18: 1] to give a colorless oily substance 4- (cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2 -Carboxylic acid methyl ester was dissolved in methanol (24 ml), 6M aqueous sodium hydroxide solution (12 ml) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture is allowed to cool, acidified with concentrated hydrochloric acid, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to give a colorless powdery substance Of 4- (cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxylic acid (1.14 g).
MS (ESI / APCI Dual): 316 (M + 1), 314 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.52-2.05 (m, 8 H) 2.22 (s, 3 H) 2.26 (s, 3 H) 4.68-4.87 (m, 1 H) 5.30 (s, 2 H) 5.92 (s, 1 H) 6.49 (d, J = 2.3 Hz, 1 H) 7.57 (d, J = 2.3 Hz, 1 H)
(3) 4- (Cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxylic acid (100 mg, 0.32 mmol), 2-aminothiazole (38 mg , 0.38 mmol) in dimethylformamide (2 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (73 mg, 0.38 mmol), 1-hydroxybenzotriazole (51 mg, 0.38 mmol) And stirred at room temperature for 15 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is purified by silica gel column chromatography [developing solvent; hexane: By purifying with ethyl acetate = 1: 1 to 1: 2], 4- (cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl]- N-1,3-thiazol-2-ylpyridin-2-carboxamide (65 mg) was obtained.

Example 30
6-[(3,5-Dimethyl-1H-pyrazol-1-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) -4-phenoxypyridine-2-carboxamide (compound Preparation of No. 77) (1) A solution of 4-hydroxypyridine-2,6-dicarboxylic acid (9.0 g, 49 mmol) in phosphorus oxychloride (18 ml) was stirred at an external temperature of 90 ° C. for 3 hours. The reaction solution was ice-cooled, diluted with chloroform, and gradually poured into methanol. Water was added thereto, and the mixture was extracted with chloroform, washed (in that order, water, saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; hexane. : Ethyl acetate = 1: 1] to give 4-chloropyridine-2,6-dicarboxylic acid dimethyl ester (9.5 g) as a colorless powdery substance.
MS (ESI): 230 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 4.04 (s, 6 H) 8.30 (s, 2 H)
(2) Potassium carbonate (9.95 g, 72 mmol) was added to a solution of 4-chloropyridine-2,6-dicarboxylic acid dimethyl ester (4.1 g, 18 mmol) and phenol (3.38 g, 36 mmol) in dimethylformamide (20 ml). In addition, the mixture was stirred at an external temperature of 80 ° C. for 5 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the residue obtained was subjected to silica gel column chromatography [developing solvent; Purification by hexane: ethyl acetate = 2: 1 to 1: 1] gave colorless powdery material 4-phenoxypyridine-2,6-dicarboxylic acid dimethyl ester (1.16 g).
MS (ESI): 288 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 4.00 (s, 6 H) 6.94-7.16 (m, 2 H) 7.28-7.41 (m, 1 H) 7.43-7.55 (m, 2 H) 7.81 (s, 2 H )
(3) Sodium borohydride (152 mg, 4.04 mmol) was gradually added to a methanol (15 ml) solution of 4-phenoxypyridine-2,6-dicarboxylic acid dimethyl ester (1.16 g, 4.04 mmol) under ice cooling. The mixture was stirred for 3 hours under ice cooling. The reaction solution is poured into a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. Solvent; ethyl acetate] to give 6- (hydroxymethyl) -4-phenoxypyridine-2-carboxylic acid methyl ester (610 mg) as a colorless powdery substance.
MS (ESI): 260 (M + 1), 258 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 3.97 (s, 3 H) 4.78 (s, 2 H) 7.03 (d, J = 2.3 Hz, 1 H) 7.08-7.19 (m, 2 H) 7.25-7.37 (m , 1 H) 7.40-7.50 (m, 2 H) 7.58 (d, J = 2.3 Hz, 1 H)
(4) 4-phenyloxy-6- (hydroxymethyl) pyridine-2-carboxylic acid methyl ester (610 mg, 2.35 mmol) in chloroform (10 ml) and carbon tetrachloride (10 ml) in a mixed solution of triphenylphosphine (680 mg, 2 .59 mmol) was added, and the mixture was heated to reflux for 1 hour at an external temperature of 100 ° C. The reaction solution was poured into water, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the residue obtained was subjected to silica gel column chromatography [developing solvent; hexane: Purification by ethyl acetate = 1: 1] gave 4-phenoxy-6- (chloromethyl) pyridine-2-carboxylic acid methyl ester (510 mg) as a colorless powdery substance.
MS (ESI): 278 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 3.98 (s, 3 H) 4.71 (s, 2 H) 7.06-7.16 (m, 2 H) 7.21-7.41 (m, 2 H) 7.42-7.54 (m, 2 H ) 7.59 (d, J = 2.33 Hz, 1 H)
(5) To a solution of 4-phenoxy-6- (chloromethyl) pyridine-2-carboxylic acid methyl ester (510 mg, 1.83 mmol) and 3,5-dimethylpyrazole (192 mg, 2.00 mmol) in dimethylformamide (5 ml) Potassium carbonate (506 mg, 3.66 mmol) was added, and the mixture was stirred at an external temperature of 80 ° C. for 8 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the residue obtained was purified by silica gel column chromatography [developing solvent; acetic acid. By purifying with ethyl], 4-phenoxy-6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxylic acid methyl ester (320 mg) was obtained as a colorless oily substance. .
MS (ESI): 338 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 2.16 (s, 3 H) 2.20 (s, 3 H) 3.97 (s, 3 H) 5.40 (s, 2 H) 5.85 (s, 1 H) 6.32 (d, J = 2.3 Hz, 1 H) 6.92-7.09 (m, 2 H) 7.20-7.33 (m, 1 H) 7.35-7.49 (m, 3 H)
(6) 4-phenoxy-6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxylic acid methyl ester (320 mg, 0.95 mmol) in methanol (8 ml) in water An aqueous solution (1 ml) of potassium oxide (160 mg, 2.85 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with diethyl ether, the aqueous layer was acidified with 1M aqueous hydrochloric acid solution, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to give a colorless powder. The material 4-phenoxy-6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxylic acid (220 mg) was obtained.
MS (ESI): 324 (M + 1), 322 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 2.22 (s, 6 H) 5.32 (s, 2 H) 5.89 (s, 1 H) 6.61 (d, J = 2.1 Hz, 1 H) 6.93-7.10 (m, 2 H) 7.21-7.37 (m, 1 H) 7.38-7.48 (m, 2 H) 7.51 (d, J = 2.1 Hz, 1 H)
(7) 4-Phenoxy-6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxylic acid (220 mg, 0.68 mmol) in dimethylformamide (5 ml) was added 2 -Amino-5-methylthiazole (94 mg, 0.82 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol), 1-hydroxybenzotriazole (113 mg, 0.82 mmol) ) And stirred at room temperature for 15 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained is washed with a mixture of ethyl acetate and hexane. To 6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) -4-phenoxypyridine as a light brown powder -2-Carboxamide (140 mg) was obtained.

Example 31
6-[(3,5-Dimethyl-1H-pyrazol-1-yl) methyl] -4- [4- (methylsulfonyl) phenoxy] -N- (5-methyl-1,3-thiazol-2-yl) Production of Pyridine-2-Carboxamide (Compound No. 78) (1) 6- (Hydroxymethyl) -4- [4- (methylthio) phenoxy] pyridine-2- obtained according to the production method of Example 30 Oxone (registered trademark) (1.8 g, 3.0 mmol) was added to a solution of carboxylic acid methyl ester (303 mg, 1.0 mmol) in acetone (10 ml) and water (0.5 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; ethyl acetate. In this way, 6- (hydroxymethyl) -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid methyl ester (220 mg) was obtained as a colorless powdery substance.
MS (ESI): 338 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 3.12 (s, 3 H) 3.99 (s, 3 H) 4.82 (s, 2 H) 7.18 (d, J = 2.3 Hz, 1 H) 7.27 (d, J = 8.9 Hz, 2 H) 7.63 (d, J = 2.3 Hz, 1 H) 8.03 (d, J = 8.9 Hz, 2 H)
(2) 6- (hydroxymethyl) -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid methyl ester (220 mg, 0.65) mixed with chloroform (3 ml) and carbon tetrachloride (3 ml) Triphenylphosphine (204 mg, 0.78 mmol) was added to the solution, and the mixture was heated to reflux at an external temperature of 100 ° C. for 1 hour. The reaction solution was poured into water, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the residue obtained was subjected to silica gel column chromatography [developing solvent; hexane: Purification with ethyl acetate = 1: 1] gave 6- (chloromethyl) -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid methyl ester (160 mg) as a colorless powdery substance. .
MS (ESI): 356 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 3.13 (s, 3 H) 4.00 (s, 3 H) 4.75 (s, 2 H) 7.29 (d, J = 8.7 Hz, 2 H) 7.37 (d, J = 2.3 Hz, 1 H) 7.65 (d, J = 2.3 Hz, 1 H) 8.05 (d, J = 8.7 Hz, 2 H)
(3) 6- (Chloromethyl) -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid methyl ester (160 mg, 0.45 mmol), 3,5-dimethylpyrazole (48 mg, 0.50 mmol) To a dimethylformamide (1.5 ml) solution was added potassium carbonate (124 mg, 0.90 mmol), and the mixture was stirred at an external temperature of 80 ° C. for 8 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated, and the residue obtained was purified by silica gel column chromatography [developing solvent; acetic acid. By purifying with ethyl], colorless oily substance 6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid The methyl ester (81 mg) was obtained.
MS (ESI): 416 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 2.19 (s, 3 H) 2.22 (s, 3 H) 3.10 (s, 3 H) 4.00 (s, 3 H) 5.43 (s, 2 H) 5.88 (s, 1 H) 6.45 (d, J = 2.3 Hz, 1 H) 7.19 (d, J = 8.9 Hz, 2 H) 7.54 (d, J = 2.3 Hz, 1 H) 8.00 (d, J = 8.9 Hz, 2 H)
(4) 6-[(3,5-Dimethyl-1H-pyrazol-1-yl) methyl] -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid methyl ester (500 mg, 1.20 mmol) An aqueous solution (2 ml) of potassium hydroxide (201 mg, 3.60 mmol) was added to a methanol (10 ml) solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with diethyl ether, the aqueous layer was acidified with 1M aqueous hydrochloric acid, extracted with chloroform, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to give a colorless powder. 6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid (300 mg) was obtained.
1H NMR (300 MHz, CDCl3) δ ppm 2.34 (s, 3 H) 2.35 (s, 3 H) 3.13 (s, 3 H) 5.36 (s, 2 H) 5.91 (s, 1 H) 6.72 (d, J = 2.2 Hz, 1 H) 7.11-7.30 (m, 2 H) 7.59 (d, J = 2.2 Hz, 1 H) 8.03 (d, J = 9.0 Hz, 2 H)
(5) 6-[(3,5-Dimethyl-1H-pyrazol-1-yl) methyl] -4- [4- (methylsulfonyl) phenoxy] pyridine-2-carboxylic acid (300 mg, 0.75 mmol) in dimethyl To a formamide (5 ml) solution was added 2-amino-5-methylthiazole (102 mg, 0.90 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (172 mg, 0.90 mmol), 1-hydroxy. Benzotriazole (124 mg, 0.90 mmol) was added and stirred at room temperature for 15 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; hexane. : Ethyl acetate = 1: 1] to give a colorless powdery substance 6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -4- [4- (methylsulfonyl) phenoxy ] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (250 mg) was obtained.

Example 32
According to the production methods of Example 16, Example 17, and Example 29, cyclopentyl bromide, (R) -1-phenyl-2-propanol was used, or instead of 1-bromo-2-methylpropane, 2 -Phenylethanol, 2- (4-fluoro) phenylethanol, benzyl bromide, cyclohexanol, (R) -1- (4-fluoro) phenyl-2-propanol, (R) -1- (4-methoxy) phenyl- Use 2-propanol, use 3,5-dimethylpyrazole, or alternatively 3,5-diethylpyrazole, 3,5-diisopropylpyrazole, 3-methylpyrrole, 3,4,5-trimethylpyrazole, pyrrolidine, 3 -Mercapto-4-methyl-4H-1,2,4-triazole, thiophenol, N-methyl Aniline, methyl mercaptan sodium salt, pyrazole, imidazole, ethyl mercaptan sodium salt, dimethylamine hydrochloride, pyrrole, 1,2,4-1H-triazole, methylamine hydrochloride, ethylene glycol, 2-pyrrolidone, 2-oxazolidone, 2 , 6-piperidinedione, 1-methyl-2-imidazolidinone, 1-methyl-2,5-dioxoimidazolidine, 3 (2H) -pyridazinone, 1,1-dioxoisothiazolidine, 4 (3H)- Pyrimidinone, 4,5-dichloro-6-methoxy-3 (2H) -pyridazinone, 5-hydroxy-3-methylpyrazole, 1-methyl-1H, 3H-pyrimidine-2,4-dione, 4,5-dichloro- 3 (2H) -pyridazinone and 6-methyl-3 (2H) -pyridazinone 2-amino-5-methylthiazole or 2-amino-5-chlorothiazole, thiazolo [5,4-B] pyridin-2-amine, 1-methyl-1H-pyrazole-3- The following compounds of the present invention were obtained by using amines.
N- (5-chloro-1,3-thiazol-2-yl) -4- (cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxy Amide (Compound No. 79)
N- (5-chloro-1,3-thiazol-2-yl) -4- (cyclopentyloxy) -6-[(3,5-diethyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxy Amide (Compound No. 80)
N- (5-chloro-1,3-thiazol-2-yl) -4- (cyclopentyloxy) -6-[(3,5-diisopropyl-1H-pyrazol-1-yl) methyl] pyridine-2-carboxy Amide (Compound No. 81)
4- (Cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxy Amide (Compound No. 82)
4- (Cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- [1,3] thiazolo [5,4-b] pyridin-2-ylpyridin-2 -Carboxamide (Compound No. 83)
4- (cyclopentyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- (1-methyl-1H-pyrazol-3-yl) pyridine-2-carboxamide ( Compound No. 84)
4- (cyclopentyloxy) -6-[(3-methyl-1H-pyrrol-1-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide ( Compound No. 85)
N- (5-chloro-1,3-thiazol-2-yl) -4- (cyclopentyloxy) -6-[(3,4,5-trimethyl-1H-pyrazol-1-yl) methyl] pyridine-2 -Carboxamide (Compound No. 86)
6-[(3,5-Dimethyl-1H-pyrazol-1-yl) methyl] -4-isobutoxy-N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (compound Number 87)
6-[(3,5-Dimethyl-1H-pyrazol-1-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) -4- (2-phenylethoxy) pyridine-2 Carboxamide (Compound No. 88)
4- (Benzyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxy Amide (Compound No. 89)
4- (Cyclohexyloxy) -6-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxy Amide (Compound No. 90)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (pyrrolidin-1-ylmethyl) pyridine-2-carboxamide (Compound No. 91)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6-{[(4-methyl-4H-1,2,4-triazol-3-yl) thio] Methyl} pyridine-2-carboxamide (Compound No. 92)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6-[(phenylthio) methyl] pyridine-2-carboxamide (Compound No. 93)
4- (Cyclopentyloxy) -6-{[methyl (phenyl) amino] methyl} -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 94)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6-[(methylthio) methyl] pyridine-2-carboxamide (Compound No. 95)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (1H-pyrazol-1-ylmethyl) pyridine-2-carboxamide (Compound No. 96)
4- (Cyclopentyloxy) -6- (1H-imidazol-1-ylmethyl) -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 97)
4- (Cyclopentyloxy) -6-[(ethylthio) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 98)
4- (Cyclopentyloxy) -6-[(dimethylamino) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 99)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (1H-pyrrol-1-ylmethyl) pyridine-2-carboxamide (Compound No. 100)
4- (Cyclopentyloxy) -N- (5-methyl-1,3-thiazol-2-yl) -6- (1H-1,2,4-triazol-1-ylmethyl) pyridine-2-carboxamide (compound Number 101)
4- (Cyclopentyloxy) -6-[(methylamino) methyl] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 102)
6-[(2-hydroxyethoxy) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridin-2- Carboxamide (Compound No. 103)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6-[(2-oxopyrrolidin-1-yl) methyl] Pyridine-2-carboxamide (Compound No. 104)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6-[(2-oxo-1,3-oxazolidine-3 -Yl) methyl] pyridine-2-carboxamide (Compound No. 105)
6-[(2,6-Dioxopiperidin-1-yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazole-2 -Yl) pyridine-2-carboxamide (Compound No. 106)
6-[(3-Methyl-2-oxoimidazolidin-1-yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazole -2-yl) pyridine-2-carboxamide (Compound No. 107)
6-[(3-Methyl-2,4-dioxoimidazolidin-1-yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1, 3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 108)
6-[(2,5-Dioxopyrrolidin-1-yl) methyl] -4- [2- (4-fluorophenyl) ethoxy] -N- (5-methyl-1,3-thiazol-2-yl) Pyridine-2-carboxamide (Compound No. 109)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6-[(6-oxopyridazin-1 (6H) -yl ) Methyl] pyridine-2-carboxamide (Compound No. 110)
6-[(1,1-Dioxoisothiazolidin-2-yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazole- 2-yl) pyridine-2-carboxamide (Compound No. 111)
6-[(2,5-Dioxopyrrolidin-1-yl) methyl] -4-[(1S) -2- (4-methoxyphenyl) -1-methylethoxy] -N- (5-methyl-1, 3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 112)
4-[(1S) -2- (4-Fluorophenyl) -1-methylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6-[(6-oxopyridazine-1 (6H) -yl) methyl] pyridine-2-carboxamide (Compound No. 113)
6-[(2,5-Dioxopyrrolidin-1-yl) methyl] -4-[(1S) -2- (4-fluorophenyl) -1-methylethoxy] -N- (5-methyl-1, 3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 114)
4-[(1S) -2- (4-Fluorophenyl) -1-methylethoxy] -N- (1-methyl-1H-pyrazol-3-yl) -6-[(6-oxopyridazine-1 (6H ) -Yl) methyl] pyridine-2-carboxamide (Compound No. 115)
6-[(2,5-Dioxopyrrolidin-1-yl) methyl] -4-[(1S) -2- (4-fluorophenyl) -1-methylethoxy] -N- (1-methyl-1H- Pyrazol-3-yl) pyridine-2-carboxamide (Compound No. 116)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (1-methyl-1H-pyrazol-3-yl) -6-[(6-oxopyrimidin-1 (6H) -yl) methyl Pyridine-2-carboxamide (Compound No. 117)
4-[(1S) -1-methyl-2-phenylethoxy] -N- (1-methyl-1H-pyrazol-3-yl) -6-[(6-oxopyridazin-1 (6H) -yl) methyl Pyridine-2-carboxamide (Compound No. 118)
6-[(4,5-Dichloro-3-methoxy-6-oxopyridazin-1 (6H) -yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5 -Methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 119)
6- [5-Hydroxy-3-methyl-1H-pyrazol-1-ylmethyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (1-methyl-1H-pyrazole-3- Yl) pyridine-2-carboxamide (Compound No. 120)
6-[(3-Methyl-2,6-dioxo-3,6-dihydropyrimidin-1 (2H) -yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N— (1-Methyl-1H-pyrazol-3-yl) pyridine-2-carboxamide (Compound No. 121)
6-[(3-Methyl-6-oxopyridazin-1 (6H) -yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3 -Thiazol-2-yl) pyridine-2-carboxamide (Compound No. 122)
6-[(4,5-Dichloro-6-oxopyridazin-1 (6H) -yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1 , 3-Thiazol-2-yl) pyridine-2-carboxamide (Compound No. 123)

Example 33
According to the preparation method of Example 31, 3 (2H) -pyridazinone is used instead of 3,5-dimethylpyrazole, 2-amino-5-methylthiazole is used, or 3-amino-1-methyl is used instead. The following compounds of the present invention were obtained by using pyrazole.
N- (1-methyl-1H-pyrazol-3-yl) -4- [4- (methylsulfonyl) phenoxy] -6-[(6-oxopyridazin-1 (6H) -yl) methyl] -pyridine-2 Carboxamide (Compound No. 124)
4- [4- (Methylsulfonyl) phenoxy] -N- (5-methyl-1,3-thiazol-2-yl) -6-[(6-oxopyridazin-1 (6H) -yl) methyl] pyridine- 2-Carboxamide (Compound No. 125)

Example 34
6-[(2,5-Dioxopyrrolidin-1-yl) methyl] -4-[(1S) -2- (4-hydroxyphenyl) -1-methylethoxy] -N- (5-methyl-1, Preparation of 3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 126) 6-[(2,5-Dioxopyrrolidin-1-yl) methyl] -4-[(1S) -2- ( To a solution of 4-methoxyphenyl) -1-methylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (80 mg, 0.16 mmol) in methylene chloride (2 ml). 1M Boron tribromide methylene chloride solution (2 ml) was added at an external temperature of −78 ° C., and the mixture was stirred overnight at the same temperature. Methanol (10 mL) was added to the reaction mixture, the solvent was distilled off, the resulting residue was dissolved in water, extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated to obtain a residue. Purification by column chromatography [developing solvent; ethyl acetate] gave colorless amorphous substance 6-[(2,5-dioxopyrrolidin-1-yl) methyl] -4-[(1S) -2- ( 4-Hydroxyphenyl) -1-methylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (68 mg) was obtained.

Example 35
6-{[4- (Dimethylamino) -6-oxopyridazin-1 (6H) -yl] methyl} -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl- Preparation of 1,3-thiazol-2-yl) pyridine-2-carboxamide (Compound No. 127) (1) Sodium hydride (45% liquid paraffin added) (104 mg, 2.39 mmol) in dimethylformamide (8 ml) To the suspension, 4,5-dibromo-3 (2H) -pyridazinone (505 mg, 1.99 mmol) was added and stirred for 30 minutes. There, 6- (chloromethyl) -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide ( A solution of 400 mg, 1.00 mmol) in dimethylformamide (8 ml) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed (saturated aqueous ammonium chloride solution), dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was obtained by silica gel column chromatography [developing solvent; = 4: 1 to 1: 1], the colorless amorphous material 6-[(4,5-dibromo-6-oxopyridazin-1 (6H) -yl) methyl] -4-[(1S ) -1-Methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (520 mg).
MS (ESI): 618 (M + 1), 616 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.34 (d, J = 6.1Hz, 3H), 2.45 (d, J = 1.1Hz, 3H), 2.87 (dd, J = 13.8, 6.3Hz, 1H), 3.08 ( dd, J = 13.8, 6.3Hz, 1H), 4.73-4.83 (m, 1H), 5.41 (d, J = 3.0Hz, 2H), 6.94 (d, J = 2.5Hz, 1H), 7.16-7.32 (m , 6H), 7.70 (d, J = 2.5Hz, 1H), 7.88 (s, 1H), 10.79-11.02 (br, 1H)
(2) 6-[(4,5-Dibromo-6-oxopyridazin-1 (6H) -yl) methyl] -4-[(1S) -1-methyl-2-phenylethoxy] -N- (5- To a mixed solution of methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (200 mg, 0.32 mmol) in 1,4-dioxane (2 ml) and water (2 ml), a 50% aqueous solution of dimethylamine (0. 01 ml, 0.97 mmol) was added and the mixture was stirred at an external temperature of 100 ° C. for 4 hours. The reaction mixture is allowed to cool, poured into water, extracted with chloroform, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue obtained is NH-silica gel column chromatography [developing solvent; hexane: ethyl acetate = 1: 2. ] To give colorless oily substance 6-{[5-bromo-4- (dimethylamino) -6-oxopyridazin-1 (6H) -yl] methyl} -4-[(1S) -1- Methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (143 mg) was obtained.
MS (ESI): 583 (M + 1), 581 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.32 (d, J = 6.1Hz, 3H), 2.44 (d, J = 1.0Hz, 3H), 2.85 (dd, J = 13.6, 6.5Hz, 1H), 3.05- 3.16 (m, 7H), 4.72-4.82 (m, 1H), 5.39 (d, J = 4.4Hz, 2H), 6.94 (d, J = 2.4Hz, 1H), 7.15-7.32 (m, 6H), 7.60 (s, 1H), 7.67 (d, J = 2.4Hz, 1H), 10.86-11.03 (br, 1H)
(3) 6-{[5-Bromo-4- (dimethylamino) -6-oxopyridazin-1 (6H) -yl] methyl} -4-[(1S) -1-methyl-2-phenylethoxy]- To a solution of N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (134 mg, 0.23 mmol) in dimethylformamide (3 ml) was added sodium formate (23 mg, 0.35 mmol), Phenylphosphine (24 mg, 0.09 mmol) and palladium acetate (5 mg, 0.02 mmol) were added, and the mixture was stirred at an external temperature of 100 ° C. for 4 hours. Further, sodium formate (23 mg, 0.35 mmol), triphenylphosphine (24 mg, 0.09 mmol) and palladium acetate (5 mg, 0.02 mmol) were added, and the mixture was stirred at an external temperature of 100 ° C. for 4 hours. The reaction mixture is allowed to cool, poured into water, extracted with ethyl acetate, washed (saturated aqueous ammonium chloride solution), dried (anhydrous sodium sulfate), filtered and concentrated. The residue obtained is subjected to NH-silica gel column chromatography [developing solvent Ethyl acetate] to give a pale yellow amorphous substance of 6-{[4- (dimethylamino) -6-oxopyridazin-1 (6H) -yl] methyl} -4-[(1S) -1 -Methyl-2-phenylethoxy] -N- (5-methyl-1,3-thiazol-2-yl) pyridine-2-carboxamide (27 mg) was obtained.
Tables 1-1 to 1-16 show the structures, NMR data, and MS data of the compounds obtained in the examples.

  The GK activation action of the compound of the present invention can be evaluated according to a known method such as the method described in Test Examples.

  The GK activation action of the compound of the present invention was measured using the method described in the following test examples.

(Test Example 1.) -GK activation test-
The GK activation test of the test compound is performed by Irwin A. et al. The method of Rose et al. (J. Biol. Chem. 1964 Jan; 239: 12-7) was implemented with some modifications.
The enzyme source human liver type GK used in this assay was expressed in E. coli as a fusion protein with GST (Glutathione S-transferase) added to the amino terminus, and purified using Glutathione Sepharose 4B (Amersham Bioscience).
The plate was a flat bottom 96 well plate (Sumitomo Bakelite). A dimethyl sulfoxide (DMSO) solution of the test compound and DMSO as a control were added to the plate to a final DMSO concentration of 1%. Further, final concentrations of 25 mM Hepes-KOH (pH = 7.1), 25 mM KCl, 2 mM MgCl ₂ , 2 mM ATP, 4 mM ¹⁴ C-labeled glucose (Amersham Pharmacia), and 1 mM DTT (dithiothreitol) were added. Finally, human liver type GK was added at 0.24 microgram per well to initiate the reaction. This system was carried out in a 100 μl system. The reaction was performed at room temperature.
After 20 minutes, 66% AG1-X4 (BioRad) suspended in 25 mM Hepes-KOH (pH = 7.1) was added to bind labeled glucose 6-phosphate. The whole amount was transferred to a multiscreen plate (Millipore), washed with water, and labeled glucose 6-phosphate was eluted with a 0.5 M NaCl solution. By measuring the labeling activity of labeled glucose 6-phosphate, it was used as an index of GK activity.
GK activity of the wells to which only DMSO was added (control group) was defined as 100%, and GK activity that was maximized by the test compound was expressed as the maximum activation ability Emax value. Furthermore, the test compound concentration required to activate 50% of the maximum activation ability was expressed as an EC ₅₀ value.
The results are shown in Table 1-17 below.

(Test Example 2.)-Blood glucose lowering action-
The hypoglycemic effect of the compound of the present invention was carried out using SD rats.
Body weights of 8 week old SD rats reared by free feeding were measured, and groups of 6 rats were grouped so that there was no difference in the average value of body weight. A compound suspended in a 0.5% methylcellulose aqueous solution was orally administered to the drug administration group, while a 0.5% methylcellulose aqueous solution was orally administered to the control group. At 10 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 360 minutes, and 480 minutes after administration, blood was collected from the orbital vein under ether anesthesia.
Plasma was collected from the obtained blood by centrifugation, and blood glucose was measured with a glucose CII test Wako. Plasma insulin was measured with an ultrasensitive rat insulin measurement kit (Morinaga Biochemical Research Institute). The blood glucose transition was graphed from the blood glucose level at each time, and the blood glucose lowering effect was evaluated by the area under the blood glucose curve. The obtained numerical values were subjected to T test or Dunnett test, and their statistical significance was calculated.
The compound of the present invention subjected to this test showed a blood glucose lowering effect.
Formulation examples of the compound of the present invention are shown below.
Formulation Example 1
A granule containing the following ingredients is produced.
Component Compound represented by formula (1) 10mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
1000mg
The compound represented by formula (1) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer. Add low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution to the mixed powder, knead and granulate (extruded granulation pore size 0.5-1mm), then dry. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.
Formulation Example 2
A powder for capsule filling containing the following components is produced.
Component Compound represented by formula (1) 10mg
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
100mg
The compound represented by formula (1) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. Fill 100 mg of 10 times powder into a No. 5 hard gelatin capsule.
Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Ingredients Compound represented by formula (1) 15mg
Lactose 90mg
Cornstarch 42mg
HPC-L 3mg
150mg
The compound represented by formula (1) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg is filled into a No. 4 hard gelatin capsule.
Formulation Example 4
A tablet containing the following ingredients is produced.
Component Compound represented by formula (1) 10mg
Lactose 90mg
Microcrystalline cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
150mg
The compound represented by the formula (1), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly pressed to obtain a 150 mg tablet.
Formulation Example 5
The intravenous formulation is produced as follows.
100 mg of the compound represented by the formula (1)
Saturated fatty acid glyceride 1000ml
The solution of the above components is usually administered intravenously to the patient at a rate of 1 ml per minute.

  The compound of the present invention has an excellent GK activating action, and not only diabetes treatment but also diabetes-related diseases such as obesity treatment and hyperlipidemia, or diabetic chronic complications such as retinopathy, nephropathy and arteriosclerosis Can be provided.

Claims (12)

Formula (1)

(In the formula (1),
R ¹ represents a C _1-8 alkyl group (the C _1-8 alkyl group is not substituted, or a hydroxy group, a carboxy group, a carbamoyl group, a C _1-6 alkoxy group, a C _2-6 alkoxycarbonyl group, a C Substituted with 1 to 3 groups selected from the group consisting of _2-8 alkanoylamino group, di (C _1-8 alkyl) amino group, and cyano group, the same or different.), C _3-8 cyclo An alkyl group, a C _1-6 alkoxy group (the C _1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), a C _2-6 alkoxycarbonyl group, a C _1-6 alkylthio group, C _2-8 alkanoylamino _group, or _{C 1-8} alkylsulfonylamino _{group, C 2-9} heterocyclyl group (the _{C 2-9} heterocyclyl group is unsubstituted or halo Emissions atom, hydroxy group, oxo _{group, C 1-8} alkyl _group, optionally substituted with _{(C 1-8} alkyl) amino group (or not the _{(C 1-8} alkyl) amino group is substituted, or hydroxy group And 1 to 4 groups selected from the group consisting of a di (C _1-8 alkyl) amino group, a carboxy group, a cyano group, and a C _1-6 alkoxy group. ), (C _1-8 alkyl) amino group, di (C _1-8 alkyl) amino group, hydroxy group, phenyl group, phenoxy group, phenylthio group, N- (C _1-8 alkyl) anilino group, C _{1- 9} heteroaryl _{groups, C 1-9} heteroarylthio group, or a _{C 7-14} arylalkyl group (the phenyl group, a phenoxy group, a phenylthio group, _{N-(C 1-8} alkyl) anilino groups, C _-9 heteroaryl _{group, C 1-9} heteroarylthio group, and _{C 7-14} arylalkyl group is unsubstituted, or _{C 1-8} alkyl group, hydroxy group, an amino _{group, (C 1-8} alkyl And 1 to 3 groups selected from the same or different groups from the group consisting of an amino group, a di (C _1-8 alkyl) amino group, and a C _1-6 alkoxy group.
R ² is a hydrogen atom, a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _2-9 heterocyclyl group, a phenyl group, a C _1-9 heteroaryl group, a C _7-14 arylalkyl group, or C _{1. -9} heteroaryl C _1-6 alkyl group (the phenyl group, C _1-9 heteroaryl group, C _7-14 arylalkyl group, and C _1-9 heteroaryl C _1-6 alkyl group are not substituted) Or a halogen atom, a hydroxy group, a C _1-8 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a C _1-8 alkylsulfonyl group, a carboxy group, a C _2-6 alkoxycarbonyl group, and C Substituted with 1 to 3 groups selected from the group consisting of _2-8 alkanoyl groups, which are the same or different.
Ar is the formula (2)

A monocyclic or condensed polycyclic C _1-9 heteroaryl group represented by (in the formula (2), ring A is not substituted or is a halogen atom, a C _1-8 alkyl group, C _3-8 Cycloalkyl group, C _1-6 alkoxy group, carboxy group, carboxy C _1-8 alkyl group, C _2-6 alkoxycarbonyl group, C _2-6 alkoxycarbonyl C _1-8 alkyl group, carbamoyl group, carbamoyl C _{1- 8} alkyl group, hydroxy group, hydroxy C _1-8 alkyl group, amino C _1-8 alkyl group, (C _1-8 alkyl) amino C _1-8 alkyl group, di (C _1-8 alkyl) amino C _1- Substituted with 1 to 3 groups selected from the group consisting of ₈ alkyl groups, C _2-6 alkanoyl groups, and C _2-9 heterocyclyl groups, which are the same or different.
X represents —CR ³ R ⁴ —, or —S—,
Y represents a single bond, —O—, —NR ⁵ —, or —S—,
R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group. )
Or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof. Formula (1)

(In the formula (1),
R ¹ represents a C _1-8 alkyl group (the C _1-8 alkyl group is not substituted, or a hydroxy group, a carboxy group, a carbamoyl group, a C _1-6 alkoxy group, a C _2-6 alkoxycarbonyl group, a C Substituted with one group selected from the group consisting of a _2-8 alkanoylamino group, a di (C _1-8 alkyl) amino group, and a cyano group), a C _3-8 cycloalkyl group, a C _{1- 6} alkoxy group (the C _1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), C _1-6 alkylthio group, C _2-8 alkanoylamino group, C _1-8 alkylsulfonyl amino _{group, C 2-9} heterocyclyl group (or not the _{C 2-9} heterocyclyl group is substituted, or a halogen atom, an oxo _{group, C 1-8} alkyl groups, di _{(C 1-8} alkyl ) Amino group, and _{C 1-6} is substituted the same or different from 1 selected by the four groups from the group consisting of alkoxy _{group.), (C 1-8} alkyl) amino group, di _{(C 1- 8} alkyl) amino group, hydroxy group, phenyl group, phenoxy group, phenylthio group, N- (C _1-8 alkyl) anilino group, C _1-9 heteroaryl group, or C _1-9 heteroarylthio group (this phenyl Group, phenoxy group, phenylthio group, N- (C _1-8 alkyl) anilino group, C _1-9 heteroaryl group, and C _1-9 heteroarylthio group are unsubstituted or C _1-8 alkyl Substituted with 1 to 3 groups selected from the group consisting of a group and a hydroxy group, the same or different.
R ² represents a hydrogen atom, a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a C _2-9 heterocyclyl group, a phenyl group, a C _1-9 heteroaryl group, or a C _7-14 arylalkyl group (the phenyl Group, C _1-9 heteroaryl group, and C _7-14 arylalkyl group are not substituted, or are a halogen atom, a hydroxy group, a C _1-8 alkyl group, a C _1-6 alkoxy group, a C _1-6. Substituted with 1 to 2 groups selected from the group consisting of an alkylthio group and a C _1-8 alkylsulfonyl group, which are the same or different.
Ar is the formula (2)

A monocyclic or condensed polycyclic C _1-9 heteroaryl group represented by the formula (In the formula (2), ring A is not substituted or is a halogen atom, a C _1-8 alkyl group, a carboxy group, a carboxy group, Substituted with one group selected from the group consisting of a C _1-8 alkyl group, a C _2-6 alkoxycarbonyl group, a C _2-6 alkoxycarbonyl C _1-8 alkyl group, and a hydroxy C _1-8 alkyl group. )
X represents —CR ³ R ⁴ —, or —S—,
Y represents a single bond, —O—, or —S—;
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group. )
Or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof. R ¹ is a C _1-9 heteroaryl group (the C _1-9 heteroaryl group is unsubstituted or selected from the same or different from the group consisting of a C _1-8 alkyl group and a hydroxy group; Substituted with a group of
The picolinic acid amide compound according to claim 1 or 2, wherein X is -S-, a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or a solvate thereof. The picolinic acid amide compound according to claim 3, wherein R ¹ is a triazolyl group (the triazolyl group is unsubstituted or substituted with 1 to 2 C _1-8 alkyl groups). Tautomers, stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof. Ar is a 3-pyrazolyl group (the pyrazolyl group is unsubstituted or a halogen atom, a C _1-8 alkyl group, a carboxy group, a carboxy C _1-8 alkyl group, a C _2-6 alkoxycarbonyl group, C _{2 A -6} alkoxycarbonyl C _1-8 alkyl group, and a group selected from the group consisting of hydroxy C _1-8 alkyl groups). A tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof. R ² is a C _7-14 arylalkyl group (the C _7-14 arylalkyl group is unsubstituted or a group consisting of a halogen atom, a hydroxy group, a C _1-8 alkyl group, and a C _1-6 alkoxy group) 6) The picolinic acid amide compound according to claim 5, a tautomer, a steric form of the compound, wherein Y is —O—. An isomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. R ¹ is a C _2-9 heterocyclyl group (the C _2-9 heterocyclyl group is unsubstituted or a halogen atom, an oxo group, a C _1-8 alkyl group, a di (C _1-8 alkyl) amino group, and Substituted with 1 to 4 groups selected from the same or different from the group consisting of C _1-6 alkoxy groups), or a C _1-9 heteroaryl group (the C _1-9 heteroaryl group is substituted). Or is substituted with 1 to 3 groups selected from the group consisting of C _1-8 alkyl groups and hydroxy groups, which are the same or different.
X is ^-CR 3 ^{R 4} - (. The ^{R 3} and ^{R 4} are the same or different and each represents a hydrogen atom, the or _{C 1-6} alkyl group), in claim 1 or 2 Y is -O- The described picolinic acid amide compound, a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof. R ¹ is a C _2-9 heterocyclyl group (the C _2-9 heterocyclyl group is unsubstituted or a halogen atom, an oxo group, a C _1-8 alkyl group, a di (C _1-8 alkyl) amino group, and A picolinic acid amide compound according to claim 7, a tautomer of the compound, which is substituted with 1 to 4 groups selected from the group consisting of C _1-6 alkoxy groups, which are the same or different from each other. A stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. R ¹ is the formula (3)

A C _2-9 heterocyclyl group represented by the formula (In the formula (3), ring B is not substituted or is a halogen atom, an oxo group, a C _1-8 alkyl group, a di (C _1-8 alkyl) amino group; , And 1 to 3 groups selected from the same or different groups selected from the group consisting of C _1-6 alkoxy groups), and X is —CH ₂ —. Amide compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds, or solvates thereof.   The picolinic acid amide compound according to any one of claims 1 to 9, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient Medicine to do.   The medicament according to claim 10, for preventing or treating a disease or condition that can be improved by activating action of glucokinase.   The medicament according to claim 11, which is a prophylactic / therapeutic agent for diabetes or obesity.