JP2008255024A - Biarylamine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having DGAT1 (Diacylglycerol O-acyltransferase type 1) inhibitory actions. <P>SOLUTION: A biarylamine derivative is represented by formula (I) [wherein, ring A is a bivalent group or the like after removing two hydrogen atoms from a benzene ring; ring B is a bivalent group or the like after removing two hydrogen atoms from a benzene ring; R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each a hydrogen atom, a halogen atom, a lower alkyl group or the like; ring C is a group after removing two hydrogen atoms from a benzene ring; Y is an oxygen atom, a sulfur atom or the like; and D is a carboxy group-substituted cyclic hydrocarbon group]. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to a biarylamine derivative useful in the field of medicine. This compound has a diacylglycerol O-acyltransferase type 1 (hereinafter referred to as “DGAT1”) inhibitory action and is useful as a therapeutic and / or prophylactic agent for hyperlipidemia, diabetes and obesity.

Obesity is caused by a lack of exercise, excessive energy intake, aging, etc., resulting in a loss of energy balance, and excess energy is mainly accumulated in adipose tissue as neutral fat (triacylglycerol, TG). , Weight and body fat mass increased. In recent years, the concept of metabolic syndrome, in which multiple risk factors such as diabetes, dyslipidemia, and hypertension accumulate, has been established, with obesity associated with visceral fat accumulation being upstream, and diagnostic criteria and treatment guidelines have been formulated ( Non-patent document 1). Metabolic syndrome increases the risk of arteriosclerosis, cardiovascular and cerebrovascular disorders, and the importance of obesity treatment is recognized in preventing these diseases.
However, while the need for the treatment of obesity is regarded as important, the current drug treatment for obesity is very limited, and the emergence of new anti-obesity drugs with clearer action and fewer side effects is expected. It is rare.
In vivo, there are two types of TG synthesis pathways, glycerol phosphate pathway, which exists in almost all organs and performs de novo GT synthesis, and monoacylglycerol pathway mainly involved in fatty acid absorption from the small intestine. Exists. Diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) is a membrane-bound enzyme present in the endoplasmic reticulum, and is the final step of TG synthesis common to the two pathways of TG synthesis, namely acyl coenzyme A acyl. The group is transferred to the 3-position of 1,2-diacylglycerol to catalyze the reaction of generating TG (Non-patent Documents 2 and 3). It has been clarified that DGAT has two subtypes, DGAT1 and DGAT2. DGAT1 and 2 are encoded by different genes, and there is no significant homology at the gene level or amino acid level between them (Non-patent Documents 4 and 5). DGAT1 is present in the small intestine, adipose tissue, liver, etc. In the small intestine, it absorbs lipids, in fat cells it accumulates lipids in fat cells, and in the liver it secretes VLDL and lipids into the liver. It is considered to be involved in accumulation (Non-Patent Document 3, Non-Patent Document 6). From these functions of DGAT1, DGAT1 inhibitors are expected to improve metabolic syndrome by inhibiting fat absorption in the small intestine, adipose tissue, accumulation of fat in the liver, and inhibition of lipid secretion from the liver. .
In order to examine the physiological action of DGAT1 and the effect of DGAT1 inhibition in vivo, a DGAT1 knockout mouse in which DGAT1 is deleted at the gene level has been prepared and analyzed. As a result, it has been clarified that DGAT1 knockout mice have lower body fat mass than wild-type mice and are resistant to obesity, impaired glucose tolerance, insulin resistance, and fatty liver due to a high-fat diet load (non-) Patent Document 7, Non-Patent Document 8). In addition, it has been reported that DGAT1 knockout mice have increased energy consumption, and that fat tissue of DGAT1 knockout mice is transplanted into wild-type mice and becomes resistant to high fat diet-induced obesity and impaired glucose tolerance. (Non-patent document 9, Non-patent document 10). In contrast, it has been reported that obesity and diabetes due to high-fat diet load worsen in mice in which DGAT1 is overexpressed in adipose tissue (Non-patent Documents 11 and 12).
From these results, it is considered that DGAT1 inhibitor is effective as a therapeutic agent for obesity and type 2 diabetes associated with obesity, lipid metabolism abnormality, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and the like. .
To date, several compounds have been known as compounds having a DGAT1 inhibitory action, but all have structures different from the compounds of the present invention (see, for example, Patent Documents 1 to 3).
The compound of the present invention introduces a nitrogen atom into the biphenyl moiety of the compounds described in Patent Document 1 and Patent Document 2 to moderately reduce the fat solubility and provide good membrane permeability. is there.

Journal of Japanese Society of Obesity, 12, Extra Special Issue, 2006 Prog. Lipid Res. 43, 134-176.2004. Ann. Med. , 36, 252-261, 2004 Proc. Natl. Acad. Sci. USA. , 95, 13018-13023, 1998 JBC, 276, 38870-38876, 2001 JBC, 280, 21506-21514, 2005 Nature Genetics, 25, 87-90, 2000 JCI, 109, 1049-1055, 2002 JCI, 111, 1715-1722, 2003 Diabetes, 53, 1445-1451, 2004 Diabetes, 51, 3189-3195, 2002 Diabetes, 54, 3379-3386 WO2004 / 100801 gazette WO2006 / 044775 WO2006 / 113919

An object of the present invention is to provide a novel biarylamine derivative having a DGAT1 inhibitory action.

The present inventors have intensively studied to develop a compound having a DGAT1 inhibitory action, found that the compound according to the present invention is effective as a compound having a DGAT1 inhibitory action, and completed the present invention based on such knowledge. It came to do.
That is, the present invention
Formula (I)

[Where:
Ring A is a divalent group formed by removing two hydrogen atoms from a benzene ring or a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring constituent atoms in the ring, or
Formula (T-1)

Formula (T-2)

And the formula (T-3)

A divalent group selected from the group consisting of:
Ring B is a divalent group formed by removing two hydrogen atoms from a benzene ring or a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring-constituting atoms in the ring,
R ¹ is a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, or a lower alkoxy group,
R ² is a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, or a lower alkoxy group,
Ring C is a group formed by removing two hydrogen atoms from a benzene ring or a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring-constituting atoms in the ring,
R ³ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, or a lower alkoxy group,
Y is an oxygen atom, a sulfur atom or NR;
R is a hydrogen atom or a lower alkyl group,
D represents the formula (II-1)

式（ＩＩ−２）

Formula (II-2)

Formula (II-3)

及び式（ＩＩ−４）

から選択される基であり、
ここで、Ａ_１は、式（ＩＩＩ−１）

And formula (II-4)

A group selected from
Here, A ₁ represents the formula (III-1)

（式中、Ｒ^４は、水素原子又は、場合によりハロゲン原子、低級アルコキシ基若しくはジ低級アルキルアミノ基で置換された低級アルキル基であり、
Ｒ^５は、水素原子又は、場合によりハロゲン原子、低級アルコキシ基若しくはジ低級アル
キルアミノ基で置換された低級アルキル基であり、
Ｒ^６は、水素原子又は、場合によりハロゲン原子、低級アルコキシ基若しくはジ低級アル
キルアミノ基で置換された低級アルキル基であるか、或いは
Ｒ^５とＲ^６が互いに結合する炭素原子と一緒になって形成する３乃至５員の脂肪族環であるか、或いは、Ｒ^５とＲ^６一緒になって形成する式（ＩＶ）

(Wherein R ⁴ is a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group,
R ⁵ is a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group,
R ⁶ is a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group, or together with a carbon atom to which R ⁵ and R ⁶ are bonded. A 3 to 5 membered aliphatic ring that is formed, or a compound of formula (IV) that is formed together with R ⁵ and R ⁶

Wherein G is CH ₂ , C (CH ₃ ) ₂ , O, NR ⁷ , S or SO ₂ , R ⁷ is a hydrogen atom or a lower alkyl group,
p is 0 to 2 and q is 0 or 1 (provided that p and q are not 0 at the same time), or
Formula (III-2)

(Where
X is a nitrogen atom or CH,
CH ₂ may be substituted with a lower alkyl group (the lower alkyl group may be substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group),
m and n are groups in which m is 0 and n is 1, 2, 3 or 4, or m is 1 and n is 1, 2 or 3. However, however,
When A ₁ is a group represented by the formula (III-1) and q is 1, R ² and R ⁴ are combined to form the formula (V) in the formula (I).

Is the formula (V-1)

(Wherein r is 1 or 2, and other symbols are the same as above),
E is OH or NH ₂ ;
A ₂ represents the formula (III-3)

(Where p ₁ is 1 or 2, and R ⁵ and R ⁶ are the same as above),
Or formula (III-4)

(Wherein each symbol is the same as above),
A ₃ is synonymous with A ₂ ,
g represents an integer of 1 or 2, wherein ring A and ring B are both divalent groups formed by removing two hydrogen atoms from a benzene ring, and D is (II- 1), (II-2) or (II-3), or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition comprising the compound represented by the formula (I) and a pharmaceutically acceptable carrier.
The present invention also relates to a DGAT1 inhibitor comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

  The present invention also relates to a therapeutic and / or prophylactic agent for hyperlipidemia, diabetes and obesity comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

  Compound (I) or a pharmaceutically acceptable salt thereof according to the present invention has a strong DGAT1 inhibitory action and is useful for the treatment and / or prevention of hyperlipidemia, diabetes and obesity.

The meanings of terms used in the present specification will be described below, and the compounds according to the present invention will be described in more detail.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
“Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group. Tert-butyl group, pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethyl group Propyl group, a 1-ethyl-2-methylpropyl group.
The “lower alkoxy group” means a group in which a hydrogen atom of a hydroxy group is substituted with the lower alkyl group. For example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, Examples thereof include a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, and an isohexyloxy group.
The “di-lower alkylamino group” means a group in which two hydrogen atoms in an amino group are substituted with the same or different lower alkyl groups as defined above, or the same or different lower alkyl groups. Means a 5- to 7-membered ring formed by bonding to each other, and specific examples include a dimethylamino group, diethylamino group, ethylmethylamino group, pyrrolidinyl group, piperidinyl group or homopiperidinyl group.
Formula (I) according to the present invention

In order to further disclose the compound represented by [in the formula, each symbol is the same as described above], various symbols used in formula (I) will be described with specific examples.

  Ring A means a divalent group obtained by removing two hydrogen atoms from a benzene ring, or a hydrogen atom from a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms in the ring as ring constituent atoms. It means a divalent group formed by removing two or the formula (T-1)

Formula (T-2)

And the formula (T-3)

Means a divalent group selected from the group consisting of

Among the “groups formed by removing two hydrogen atoms from a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring constituent atoms” represented by ring A, “1 or 2 nitrogen atoms as ring constituent atoms” Specific examples of the “6-membered heteroaryl ring having” include a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring. Among these, a pyridine ring or a pyrimidine ring is preferable, and a pyridine ring is more preferable. preferable.
Of the groups represented by the formula (T-1), (T-2) or (T-3), the group represented by (T-1) is preferable.

R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.

The “lower alkyl group” represented by R ¹ may be substituted by 1 to 3 with a halogen atom or a lower alkoxy group.
Specific examples of the lower alkyl group substituted with a halogen atom include a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group.
Specific examples of the lower alkyl group substituted with a lower alkoxy group include a methoxymethyl group, an ethoxymethyl group, and an ethoxyethyl group.

  Ring B means a divalent group formed by removing two hydrogen atoms from a benzene ring, or two hydrogen atoms from a heteroaryl ring having 1 or 2 nitrogen atoms in the ring as ring constituent atoms. It means a divalent group that is excluded.

  Among the “groups formed by removing two hydrogen atoms from a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring constituent atoms” represented by ring B, “1 or 2 nitrogen atoms as ring constituent atoms” Examples of the “6-membered heteroaryl ring having” include the same groups as ring A, and among them, a pyridine ring or a pyrimidine ring is preferable.

R ² represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.

Further, the “lower alkyl group” represented by R ² may be substituted by 1 to 3 with a halogen atom or a lower alkoxy group.

Examples of the lower alkyl group substituted with a halogen atom and the lower alkyl group substituted with a lower alkoxy group include the same groups as in R ¹ .

  Ring C means a phenyl group or a 6-membered heteroaryl group having 1 or 2 nitrogen atoms in the ring.

  Examples of the “6-membered heteroaryl group having 1 or 2 nitrogen atoms in the ring” represented by ring C include a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group, and among these, a pyridinyl group is preferable. .

R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.

The “lower alkyl group” represented by R ³ may be substituted by 1 to 3 with a halogen atom or a lower alkoxy group.

Examples of the lower alkyl group substituted with a halogen atom and the lower alkyl group substituted with a lower alkoxy group include the same groups as in R ¹ .

  Y represents an oxygen atom, a sulfur atom or NR, wherein R represents a hydrogen atom or a lower alkyl group.

  Specific examples of “NR” represented by Y include an amino group, a methylamino group, an ethylamino group, an isopropylamino group, and an n-propylamino group.

  Y is preferably an oxygen atom or a sulfur atom.

  D represents the formula (II-1)

Formula (II-2)

And formula (III-3)

The group selected from is shown.
A _{1 in} formula (II-1) represents formula (III-1)

Or a group represented by formula (III-2)

The group represented by these is shown.

R ⁴ represents a hydrogen atom or a lower alkyl group.

  The lower alkyl group means the same group as the lower alkyl group defined above.

  The lower alkyl group may be substituted by 1 to 3 with a halogen atom, a lower alkoxy group or a di-lower alkylamino group.

Examples of the lower alkyl group substituted with a halogen atom and the lower alkyl group substituted with a lower alkoxy group include the same groups as in R ¹ .

  Specific examples of the lower alkyl group substituted with a di-lower alkylamino group include a dimethylaminomethyl group, a dimethylaminoethyl group, and a dimethylaminoisopropyl group.

  When the lower alkyl group is substituted two or more with a halogen atom, a lower alkoxy group or a di-lower alkylamino group, these may be the same or different.

R ⁵ represents a hydrogen atom or a lower alkyl group.

  The lower alkyl group means the same group as the lower alkyl group defined above.

  The lower alkyl group may be substituted by 1 to 3 with a halogen atom, a lower alkoxy group or a di-lower alkylamino group.

Examples of the lower alkyl group substituted with a halogen atom and the lower alkyl group substituted with a lower alkoxy group include the same groups as in R ¹ .

Examples of the lower alkyl group substituted with a di-lower alkylamino group include the same groups as in R ⁴ .

R ⁶ represents a hydrogen atom or a lower alkyl group.

  The lower alkyl group means the same group as the lower alkyl group defined above.

  The lower alkyl group may be substituted by 1 to 3 with a halogen atom, a lower alkoxy group or a di-lower alkylamino group.

Examples of the lower alkyl group substituted with a halogen atom and the lower alkyl group substituted with a lower alkoxy group include the same groups as in R ¹ .

Examples of the lower alkyl group substituted with a di-lower alkylamino group include the same groups as in R ⁴ .

R ⁵ and R ⁶ may form a 3- to 5-membered aliphatic ring together with the carbon atoms to which they are bonded.

  Specific examples of the aliphatic ring include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group.

R ⁵ and R ⁶ together with the carbon atoms to which they are bonded to each other form formula (IV)

The group represented by these may be formed.
G means CH ₂ , C (CH ₃ ) ₂ , O, NR ⁷ , S or SO ₂ .

R ⁷ represents a hydrogen atom or a lower alkyl group.

  p represents 0 to 2;

  q represents 0 or 1;

  However, p and q are not 0 at the same time.

A ¹ represents formula (III-2)

The group represented by these may be sufficient.

  X in Formula (III-2) means a nitrogen atom or CH.

CH _{2 in} formula (III-2) may be substituted with a lower alkyl group (the lower alkyl group may be substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group).

  In m and n, m is 0 and n is 1, 2, 3 or 4, or m is 1 and n is 1, 2 or 3.

  Specific examples of the group represented by the formula (III-2) include, for example, the formula (III-20)

(Wherein q ₁ 1 represents an integer of 1 to 4), and more specifically, for example, the formula (III-21)

The group etc. which are represented by these are mentioned.

When A ₁ is a group represented by the formula (III-1) and q is 1, R ² and R ⁴ in the formula (I) are combined to form the formula Formula (V) in (I)

Is the formula (V-1)

The group represented by these may be formed.

  In formula (V-1), each symbol has the same meaning as described above.

  Specific examples of the group represented by the formula (V-1) include, for example, the following formula (V-2):

The group represented by these is mentioned.
E represents OH or NH ₂ and is preferably OH.
A ₂ and A ₃ each independently represent formula (III-3)

Or formula (III-4)

The group represented by these is shown.
P _{1 in} Formula (III-3) represents 1 or 2.
R ₅ and R _{6 in} formula (III-3) have the same meaning as described above.
m and n mean the same groups as described above.
Among the compounds represented by formula (I), both ring A and ring B are divalent groups formed by removing two hydrogen atoms from a benzene ring, and D is (II-1), (II- In the case of 2) or (II-3), it is excluded from the present invention.
As a preferred embodiment of the compound according to the present invention, among the compounds represented by the formula (I), a ring A is a ring constituent atom, and a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms in the ring to a hydrogen atom. Or a divalent group formed by removing two of the formula (T-1)

[Wherein each symbol is the same as described above], and ring B is a divalent group formed by removing two hydrogen atoms from a benzene ring.

In another preferred embodiment of the compound according to the present invention, among the compounds represented by the formula (I), ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or a pyrimidine ring. Or the formula (T-1)

[Wherein each symbol is the same as above], and ring B is a divalent group formed by removing two hydrogen atoms from a benzene ring.

  In another preferred embodiment of the compound according to the present invention, among the compounds represented by formula (I), ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or a pyrimidine ring. Or the formula (T-1)

[Wherein each symbol is the same as defined above], ring B is a divalent group formed by removing two hydrogen atoms from a benzene ring, and D is a group represented by formula (II-11)

[Wherein each symbol is the same as defined above].

  In another preferred embodiment of the compound according to the present invention, among the compounds represented by formula (I), ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or a pyrimidine ring. Or the formula (T-1)

[Wherein each symbol is the same as defined above],
Ring B is a divalent group formed by removing two hydrogen atoms from benzene,
D is the formula (II-11)

[Wherein each symbol is the same as defined above],
A ₁ is the formula (III-1)

[Wherein each symbol is the same as defined above] or a group represented by formula (III-2)

[Wherein each symbol is the same as defined above].

  In another preferred embodiment of the compound according to the present invention, among the compounds represented by formula (I), ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or a pyrimidine ring. Or the formula (T-1)

[Wherein each symbol is the same as defined above],
Formula (V) in Formula (I)

Is the formula (V-1)

[Wherein each symbol is the same as defined above].

  In another preferred embodiment of the compound according to the present invention, among the compounds represented by formula (I), ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or a pyrimidine ring. Or the formula (T-1)

[Wherein each symbol is the same as defined above],
Ring B is a divalent group formed by removing two hydrogen atoms from benzene,
D is the formula (II-11)

[Wherein each symbol is the same as defined above],
A ₁ is

as well as

And a group selected from the group consisting of (in the formula, each symbol is the same as above).

In another preferred embodiment of the compound according to the present invention, among the compounds represented by formula (I), ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or a pyrimidine ring. ,
Ring B is a divalent group formed by removing two hydrogen atoms from a benzene ring,
D is the formula (II-11)

[Wherein each symbol is the same as defined above],
A ₁ is

as well as

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a group selected from the group consisting of: wherein each symbol is the same as defined above.

  In another preferred embodiment of the compound according to the present invention, among the compounds represented by formula (I), ring A is represented by formula (T-1).

[Wherein each symbol is the same as defined above],
Ring B is a divalent group formed by removing two hydrogen atoms from benzene,
D is the formula (II-11)

[Wherein each symbol is the same as defined above],
A ₁ is

as well as

And a group selected from the group consisting of (in the formula, each symbol is the same as above).

Specific examples of the compound represented by the formula (I) include 4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrimidin-5-yl] phenyl} -2. , 2-dimethyl-4-oxobutanoic acid,
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyridin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrazin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
2- {5- [4- (1,3-benzothiazol-2-ylamino) phenyl] -1-oxo-isoindoline-2-yl} -2,2-dimethylacetic acid,
4- {4- [5- (1,3-benzothiazol-2-ylamino) -pyrimidin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [6- (1,3-benzothiazol-2-ylamino) -pyridazin-3-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [4- (1,3-benzothiazol-2-ylamino) -pyridin-4-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [5- (oxazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
2-[(4-{[5- (oxazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid,
2- [4- [5- (1,3-benzothiazol-2-ylamino) -2-pyridinyl] phenyl] carbonyl) cyclopentanecarboxylic acid,
2-[(4-{[5- (thiazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid,
2-({4 ′-[(oxazolo [4,5-b] pyridin-2-yl) amino] -1,1′-biphenyl-4-yl} carbonyl) cyclopentanecarboxylic acid,
4- (4- {5-[(1,3-benzoxazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
2-({4- [5- (1,3-benzoxazol-2-ylamino) -2-pyridinyl] phenyl} carbonyl) cyclopentanecarboxylic acid,
4- (4- [5- (1-Isopropyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (4- [5- (1-ethyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (4- [5- (1-Methyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
N-[(4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -carbonyl] -L-proline,
4- (4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (5- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -2-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (6- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -3-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid, or 4- [4- [ 5- (thiazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl] -2,2-dimethyl-4-oxobutanoic acid and the like.

Ring A, ring B, ring C, A ₁ , A ₂ , A ₃ , D, E, G, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{80 described above} , R ⁸¹ , R ⁹ , R ¹⁰ , X, Y, p, p ₁ , q, q ₁ , r, m, n may be any combination.

  Next, the manufacturing method of the compound based on this invention is demonstrated.

Wherein, R ⁷ is a lower alkyl group, a benzyl group, R ⁸ is a hydrogen atom, a lower alkyl group, or two R ⁸ together may form a ring, X ₁ represents a halogen atom, and other symbols are the same as above]
(Process 1)
This step is a method for producing compound (3) by reacting compound (1) with compound (2) in the presence of a base and a palladium compound.

Examples of the base used in this step include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine and the like.
The amount of the base used in this step is usually 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to 1 equivalent of compound (1).
Examples of the palladium compound used in this step include PdCl ₂ (dppf) · CH ₂ Cl ₂ .
The amount of the palladium compound used in this step is usually 0.05 to 0.5 equivalent, preferably 0.2 to 0.4 equivalent, relative to 1 equivalent of compound (1).
The amount of compound (2) used in this step is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (1).

  The reaction time in this step is usually 5 to 48 hours, preferably 10 to 24 hours.

The reaction temperature in this step is usually 60 to 100 degrees, preferably 80 to 90 degrees.
The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include dimethylacetamide, water, or a mixed solvent thereof.

The compound (3) thus obtained can be isolated and purified by known separation and purification means such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like, or without isolation and purification. It can be attached to the next process.
(Step 1-2)
This step is a method for producing the compound (I-1) according to the present invention by removing a protecting group for a carboxyl group.

  The removal of the protecting group of the carboxyl group in this step is performed by a method described in the literature (for example, Protective Groups in Organic Synthesis, TW Green, 2nd edition, John Wiley & Sons, 1991). Etc.), a method according to this, or a combination thereof with a conventional method.

The compound (I-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
In addition, the compound (2) used in this step can be carried out by the method described in US 2004/0224997, a method according to this, or a combination thereof with a conventional method. For example, the following step 2- 1 or step 2-2.

[Wherein, X1 and X2 each represent a halogen atom, and other symbols are the same as above]
(Step 2-1)
This step is a method for producing compound (2) by reacting compound (3-1) with compound (4-1) in the presence of a base.

  Examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate and the like.

  The amount of the base used in this step is usually 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to 1 equivalent of compound (3-1).

  The reaction time in this step is usually 5 to 48 hours, preferably 10 to 24 hours.

The reaction temperature in this step is usually 50 to 120 ° C, preferably 80 to 100 ° C.
The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrohydrofuran, dimethylformamide, dioxane and the like.

The amount of (4-1) used in this step is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (3-1).
(Process 2-2)

[Wherein each symbol is the same as above]
This step is a method for producing compound (2) by reacting compound (3-2) with compound (4-2) in the presence of a base.

  Examples of the base used in this step include sodium hydride and the like.

  The amount of the base used in this step is usually 1 to 5 equivalents, preferably 2 to 3 equivalents, relative to 1 equivalent of compound (3-2).

  The amount of compound (4-2) used in this step is usually 0.5 to 2 equivalents, preferably 0.5 to 1 equivalent, relative to 1 equivalent of compound (3-2).

  The reaction time in this step is usually 1 to 24 hours, preferably 2 to 5 hours.

  The reaction temperature in this step is usually room temperature to 80 ° C, preferably 50 to 90 ° C.

  The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.

The compound (2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or without isolation and purification. It can be subjected to other processes.
Compound (3) can also be produced, for example, by the following method.

[Wherein X ¹¹ represents a halogen atom, and other symbols are the same as above]
(Step 1-3)
This step is a method for producing compound (3) by reacting compound (2-1) with compound (1-1) in the presence of a base and a palladium compound.

Examples of the base used in this step include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine and the like.
The amount of the base used in this step is usually 0.5 to 10 equivalents, preferably 0.75 to 3 equivalents, relative to 1 equivalent of compound (2-1).
Examples of the palladium compound used in this step include PdCl ₂ (dppf) · CH ₂ Cl ₂ .
The amount of the palladium compound used in this step is usually 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (2-1).
The amount of compound (1-1) used in this step is usually 0.5 to 5 equivalents, preferably 0.75 to 2 equivalents, relative to 1 equivalent of compound (2-1).

  The reaction time in this step is usually 1 to 48 hours, preferably 6 to 24 hours.

The reaction temperature in this step is usually 60 to 150 degrees, preferably 80 to 100 degrees.
The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like.
Compound (2-1) used in this step can be carried out, for example, by the method described in WO2001 / 019829, a method analogous thereto, or a combination of these with a conventional method.
The compound (1-1) used in this step is described in WO97 / 17317, Bioorganic & Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters), 1998, Vol. 8, No. 20, 2907-2912. Or a method according to this method or a combination thereof with a conventional method.

  In addition, the compound (1) is represented by the formula (1-A)

[Wherein each symbol is the same as defined above], the compound (1-A1) contained in the compound (1-A) can be produced, for example, by the following method.

[Wherein, p1 represents an integer of 1 or 2, R ⁷¹ represents a lower alkyl group, a benzyl group or the like, and other symbols are the same as above]
(Process 3)
This step is a method for producing compound (7) by reacting compound (5) and compound (6) in the presence of an acid and aluminum chloride.

  Examples of the acid used in this step include hydrochloric acid.

The amount of aluminum chloride used in this step is usually 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of compound (5).
In addition to aluminum chloride, for example, tin chloride, titanium tetrachloride, zinc chloride or the like can be used.

  The amount of (6) used in this step is usually 0.5 to 2 equivalents, preferably 0.8 to 1.5 equivalents, relative to 1 equivalent of compound (5).

  The reaction time in this step is usually 5 to 48 hours, preferably 10 to 24 hours.

  The reaction temperature in this step is usually 0 to 70 degrees, preferably room temperature to 50 degrees.

  The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloroethane.

  Compound (7) can also be produced by reacting compound (5) with compound (6) in the presence of a base.

  Examples of the base used in this step include isopropyl magnesium chloride, n-butyl lithium, methyl lithium, methyl magnesium bromide and the like.

The amount of the base used in this step is usually 0.5 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents, relative to 1 equivalent of compound (5).
The reaction temperature in this step is usually −78 ° C. to 35 ° C., preferably −78 ° C. to 10 ° C.

  The reaction time in this step is usually 0.5 to 48 hours, preferably 0.5 to 6 hours.

  The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include diethyl ether and tetrahydrofuran.

The compound (7) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or without isolation and purification. It can be attached to the next process.
(Process 4)
This step is a method for converting the compound (7) into an alkyl ester or a benzyl ester.

  The reaction in this step can be carried out by the above-described Protective Groups in Organic Synthesis, a method according to this, or a combination of these with conventional methods.

The compound (7-1) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or is isolated and purified. It can attach to the next process without it.
In addition, a compound (7-1) is a compound contained in the said (1-1).
(Step 4-1)
In this step, the compound (7-1) is reacted with the compound (R ⁸ O) B—B (OR ⁸ ) in the presence of potassium acetate, PdCl ₂ (dppf) · CHCl ₂ and dppf. This is a method for producing 1-A1).

  The amount of potassium acetate used in this step is usually 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to 1 equivalent of compound (7-1).

The amount of PdCl ₂ (dppf) · CHCl ₂ used in this step is usually 0.05 to 0.2 equivalents, preferably 0.1 to 0.15 equivalents, relative to 1 equivalent of compound (7-1). It is.

  The amount of dppf used in this step is generally 0.05 to 0.2 equivalents, preferably 0.1 to 0.15 equivalents, relative to 1 equivalent of compound (7-1).

The amount of compound (R ⁸ O) BB (OR ⁸ ) used in this step is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7-1).

Examples of the compound (R ⁸ O) BB (OR ⁸ ) used in this step include bis (pinacolato) diboron.

  The compound (1-A1) thus obtained is isolated or purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or is isolated and purified. The compound (I-11) according to the present invention, which is included in the formula (I), is obtained by performing the reaction in the step 1 and the step 1-2 without performing the reaction.

[Wherein each symbol is the same as defined above] can be produced.

  Further, the formula (I-2) included in the formula (I)

The compound according to the present invention represented by [wherein each symbol is the same as described above] can be produced, for example, by the following method.

[Wherein each symbol is the same as above]
(Process 5)
This step is a method for producing compound (9) by reacting compound (2) with compound (8) in the presence of a base and a palladium compound.

  The reaction in this step can be carried out by the method described in Step 1 or a method analogous thereto.

The compound (9) thus obtained can be isolated and purified by known separation and purification means such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like, or without isolation and purification. It can be attached to the next process.
(Step 6)
This step is a method for producing the compound (10) by removing the protecting group for the carboxyl group of the compound (9).

  The reaction in this step can be carried out by the same method as in Step 1-2 or a method analogous thereto.

The compound (10) thus obtained can be isolated and purified by known separation and purification means such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like, or without isolation and purification. It can be attached to the next process.
(Step 7)
This step is a method for producing compound (12) by reacting compound (10) with compound (11).

This reaction is performed according to literature methods (for example, peptide synthesis basics and experiments, Nobuo Izumiya et al., Maruzen, 1983, Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991, etc. ), A method according to the above, or a combination of these and a conventional method may be used to carry out a normal amide formation reaction, that is, using a condensing agent well known to those skilled in the art or available to those skilled in the art It can be performed by an ester activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method, or the like. Examples of such amide-forming reagents include thionyl chloride, oxalyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carbonyldiimidazole, diphenylphosphoryl chloride. , Diphenylphosphoryl azide, N, N′-disuccinimidyl carbonate, N, N′-disuccinimidyl oxalate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salts, ethyl chloroformate, isobutyl chloroformate or benzotriazo-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, and the like. Among them, for example, thionyl chloride, 1-ethyl-3- (3-dimethyl). Aminopropyl) carbodiimide hydrochloride, N, N-di Black dicyclohexylcarbodiimide or benzotriazol-1-yl - oxy - tris (dimethylamino) phosphonium hexafluorophosphate and the like. In the amide forming reaction, a base and a condensation aid may be used together with the amide forming reagent.
Examples of the base used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4. 0] tertiary aliphatic amines such as undec-7-ene (DBU), 1,5-azabicyclo [4.3.0] non-5-ene (DBN); for example, pyridine, 4-dimethylaminopyridine, picoline And aromatic amines such as lutidine, quinoline or isoquinoline, among which tertiary aliphatic amines are preferred, and triethylamine or N, N-diisopropylethylamine is particularly preferred.
Examples of the condensation aid used include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide or 3-hydroxy-3,4- Examples thereof include dihydro-4-oxo-1,2,3-benzotriazole, among which N-hydroxybenzotriazole and the like are preferable.
The amount of compound (11) used varies depending on the type of compound and solvent used and other reaction conditions, but is usually 1 to 10 equivalents, preferably 1 to 10 equivalents, preferably 1 equivalent of compound (10) or a reactive derivative thereof. 1 to 3 equivalents.
The amount of the base used varies depending on the compound used, the type of solvent, and other reaction conditions, but is usually 1 to 10 equivalents, preferably 1 to 5 equivalents.
The reaction solvent used in this step includes, for example, an inert solvent, and is not particularly limited as long as the reaction is not hindered. Specific examples include methylene chloride, chloroform, 1,2-dichloroethane, dimethylformamide, Examples include acetic acid ethyl ester, acetic acid methyl ester, acetonitrile, benzene, xylene, toluene, 1,4-dioxane, tetrahydrofuran, dimethoxyethane or a mixed solvent thereof. From the viewpoint of securing a suitable reaction temperature, for example, methylene chloride, chloroform, etc. 1,2-dichloroethane, acetonitrile or N, N-dimethylformamide is preferred.
The reaction time is usually 0.5 to 96 hours, preferably 3 to 24 hours.
The reaction temperature is usually 0 ° C. to the boiling point of the solvent, preferably room temperature to 80 ° C.
The base, amide forming reagent, and condensation aid used in this step can be used alone or in combination.
The compound (12) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. or without isolation and purification. It can be attached to the process.
(Process 8)
This step is a method for producing the compound (I-2) according to the present invention by removing the protecting group for the carboxyl group of the compound (12).

  The reaction in this step can be produced by the same method as in Step 1-2 or a method analogous thereto.

  The compound (I-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

  In addition, compound (I-3) according to the present invention

[Wherein each symbol is the same as described above] can be produced, for example, by the following method.

[Wherein each symbol is the same as above]
(Step 9)
This step is a method for producing compound (15) by reacting compound (13) with compound (14) in the presence of a base.

  Examples of the base used in this step include triethylamine, diisopropylethylamine and the like.

  The amount of the base used in this step is usually 1 to 10 equivalents, preferably 1.5 to 5 equivalents, relative to 1 equivalent of compound (13).

  The amount of compound (14) used in this step is usually 1 to 10 equivalents, preferably 1.5 to 5 equivalents, relative to 1 equivalent of compound (13).

  The reaction time in this step is usually 1 to 64 hours, preferably 6 to 48 hours.

  The reaction temperature in this step is usually 0 to 120 ° C, preferably 25 to 100 ° C.

  The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, dimethylformamide, tetrahydrofuran and the like.

The compound (15) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or without isolation and purification. It can be attached to the next process.
(Process 10)
This step is a method for producing the compound (16) by removing the protecting group for the carboxyl group of the compound (15).

The reaction in this step can be carried out by the same method as in Step 1-2, a method analogous thereto or a combination thereof with a conventional method. Compound (16) thus obtained can be obtained by known separation. It can be isolated and purified by purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or can be subjected to the next step without isolation and purification.
(Step 11)
This step is a method for producing compound (I-3) according to the present invention by reacting compound (16) with compound (17) in the presence of a base and a palladium compound.

  The reaction in this step can be carried out by the same method as in Step 1, a method according to this, or a combination of these with conventional methods.

  Compound (13) can be produced by the method described in EP 26749 or the like, a method analogous thereto, or a combination of these with a conventional method.

  Compound (17) can be produced by the method described in WO2001 / 019829 or the like, a method analogous thereto, or a combination of these with a conventional method.

  In addition, compound (I-4) according to the present invention

[Wherein each symbol is the same as described above] can be produced, for example, by the following method.

[Wherein each symbol is the same as above]
(Step 12)
This step is a method for producing compound (19) by reacting compound (18) with compound (7-1) described above in the presence of a base.

  Examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate and the like.

  The amount of the base used in this step is usually 1 to 50 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (18).

  The amount of compound (7-1) used in this step is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (18).

The compound (19) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or without isolation and purification. It can be attached to the next process.
(Step 13)
This step is a method for producing a compound (20) by removing a protecting group for a hydroxy group. The reaction in this step can be carried out by the method described in Protective Groups in Organic Synthesis, a method according to this, or a combination of these with a conventional method.

The compound (20) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or without isolation and purification. It can be attached to the next process.
(Step 14)
This step is a method for producing a compound (21) by converting a hydroxy group of the compound (20) into a leaving group (OR ¹⁰ ).

The reaction in this step can be performed, for example, by reacting the compound (20) with an acid anhydride (R ¹⁰ O) ₂ O.

  Examples of the acid anhydride used in this step include (bis) trifluoromethanesulfonic acid anhydride.

  The amount of the acid anhydride to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (20).

  The reaction temperature in this step is usually −20 to 50 ° C., preferably −10 to 20 ° C.

  The reaction time in this step is usually 0.5 to 48 hours, preferably 0.5 to 12 hours.

  The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, tetrahydrofuran, dichloroethane, and mixed solvents thereof.

  In this step, a base may be added to the reaction system, and examples of the base include triethylamine.

The compound (21) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or without isolation and purification. It can be attached to the next process.
(Step 15)
This step is a method for producing compound (22) by reacting compound (21) with compound (4-1) in the presence of Xantphos and a palladium catalyst.

  The amount of compound (4-1) used in this step is usually 0.5 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (21).

  The amount of XAntphos used in this step is usually 0.01 to 5 equivalents, preferably 0.1 to 0.5 equivalents, relative to 1 equivalent of compound (21).

Examples of the palladium catalyst used in this step include Pd ₂ (dba) ₃ CHCl _{3 and the} like.

  The amount of the palladium catalyst used in this step is usually 0.01 to 5 equivalents, preferably 0.1 to 0.5 equivalents, relative to 1 equivalent of compound (21).

  The reaction temperature in this step is usually 20 to 200 degrees, preferably 80 to 150 degrees.

  The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 12 hours.

  The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include 1,4-dioxane, tetrahydrofuran, dimethylformamide and the like.

The compound (22) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or without isolation and purification. It can be attached to the next process.
(Step 16)
This step is a method for producing the compound (I-4) according to the present invention by removing the protecting group for the carboxyl group of the compound (22).

  The reaction in this step can be carried out by the method described in Protective Groups in Organic Synthesis, a method according to this, or a combination of these with a conventional method.

Thus obtained compound (I-4) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

The biarylamine derivative according to the present invention can exist as a pharmaceutically acceptable salt, and the salt can be produced according to a conventional method using the compound represented by (I).
Examples of the acid addition salt include hydrohalides such as hydrochloride, hydrofluoride, hydrobromide and hydroiodide; nitrates, perchlorates, sulfates, phosphates, carbonates Inorganic acid salts such as salts; lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; Organic acid salts such as acid salts, succinates, citrates, tartrates, oxalates and maleates; and acid addition salts which are organic acids such as amino acids such as glutamates and aspartates it can.
In addition, when the compound of the present invention has an acidic group in the group, for example, when it has a carboxyl group or the like, the corresponding pharmaceutically acceptable can also be obtained by treating the compound with a base. Can be converted into a salt. Examples of the base addition salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts with organic bases such as ammonium salts, guanidine, triethylamine and dicyclohexylamine.
Furthermore, the compounds of the present invention may exist as any hydrate or solvate of the free compound or salt thereof.
Conversely, conversion from a salt or ester to a free compound can also be carried out according to a conventional method.

In addition, the compound according to the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers, geometric isomers and the like depending on the mode of the substituent. Needless to say, all of these isomers are included in the compounds of the present invention. Furthermore, it goes without saying that any mixture of these isomers is also encompassed by the compounds according to the invention.
In the compound according to the present invention, the aromatic hydrogen in the compound is tritium, the methyl group is ³ H ₃ C, ¹⁴ CH ₃ , ¹¹ CH ₃ , the fluorine is ¹⁸ F, and the carbon of the carbonyl group is ¹¹ C. It can also be used as a radiolabel by converting it to an isotope such as
The compound represented by the general formula (I) can be administered orally or parenterally, and by formulating it into a form suitable for such administration, hyperlipidemia, diabetes, An agent for treating and / or preventing obesity is provided.
When the compound of the present invention is used clinically, it can be administered after various preparations by adding pharmaceutically acceptable additives according to the administration form. Various additives that are usually used in the pharmaceutical field can be used as the additive at that time, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, Crystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, Polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glyco Le, cyclodextrin or hydroxypropyl cyclodextrin and the like.

  Examples of dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections, etc. These can be prepared according to conventional methods in the pharmaceutical field. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. In particular, in the case of injections, they may be dissolved or suspended in physiological saline or glucose solution as necessary, and buffering agents and preservatives may be added.

These preparations can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.
The compound of the present invention can be used in combination with a drug effective for hyperlipidemia, diabetes, obesity and the like (hereinafter referred to as “combination drug”). Such agents can be administered simultaneously, separately or sequentially in the prevention or treatment of the disease. When the compound of the present invention is used at the same time as one or more concomitant drugs, it can be a pharmaceutical composition in a single dosage form. However, in combination therapy, the composition containing the compound of the present invention and the concomitant drug may be administered to the subject of administration in different packages, simultaneously, separately or sequentially. They may be administered at a time lag.

  The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration form of the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) separate preparation of the compound of the present invention and the concomitant drug. 3) Simultaneous administration of the two preparations obtained by the same administration route by the same administration route, 3) There is a time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug. 4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, 5) Formulating the compound of the present invention and the concomitant drug separately Administration of the two types of preparations obtained by the formation of the two preparations at different time intervals (for example, the compound of the present invention; administration in the order of the concomitant drugs, or administration in the reverse order) and the like. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.

When the compound of the present invention is used, for example, in a clinical setting, the dose and frequency of administration vary depending on the patient's sex, age, weight, degree of symptom and the type and range of the desired treatment effect, but generally administered orally. In this case, 0.01-100 mg / kg per day for an adult, preferably 0.03-1 mg / kg divided into 1 to several times, and in the case of parenteral administration, 0.001-10 mg / kg, Preferably, 0.001 to 0.1 mg / kg is administered in 1 to several divided doses.
Any suitable route of administration may be employed for administering an effective amount of a compound of the present invention to a mammal, particularly a human. For example, oral, rectal, topical, vein, eye, lung, nose and the like can be used. Examples of dosage forms include tablets, troches, powders, suspensions, solutions, capsules, creams, aerosols and the like, and oral tablets are preferred.

  In preparing an oral composition, any conventional pharmaceutical medium can be used. Examples thereof include water, glycols, oils, alcohols, fragrance additives, and storage. In the case of preparing a liquid composition for oral use, examples include suspensions, elixirs and solutions, and examples of carriers include starch, sugar, microcrystalline cellulose, Diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be mentioned. When preparing an oral solid composition, for example, powders, capsules, tablets and the like can be mentioned. A solid composition is preferred.

  Because of ease of administration, tablets and capsules are the most advantageous oral dosage forms. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

  In addition to the usual dosage forms described above, the compounds according to formula (I) are described, for example, in U.S. Pat. S. Also by the release control means and / or delivery device described in Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 3,630,200 and 4,008,719 Can be administered.

  The pharmaceutical composition according to the present invention suitable for oral administration is preliminarily determined as a powder or granule, or as a water-soluble liquid, water-insoluble liquid, oil-in-water emulsion or water-in-oil emulsion. Mention may be made of capsules, cashews or tablets containing a certain amount of active ingredient. Such compositions can be prepared using any pharmacological method, but all methods also include a method of combining the active ingredient with a carrier comprising one or more necessary ingredients. .

In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or well-separated solid carriers or both and then, if necessary, shaping the product into a suitable form. . For example, a tablet is prepared by compression and molding, optionally with one or more accessory ingredients. Compressed tablets can be mixed with binders, lubricants, inert excipients, surfactants or dispersants as appropriate, in any suitable machine, and the active ingredient can be freely formed into powders, granules, etc. Prepared by compression.
Molded tablets are prepared by molding in a suitable machine a mixture of the powdered moist compound and an inert liquid diluent.
Preferably, each tablet contains about 1 mg to 1 g of the active ingredient and each cashew or capsule contains about 1 mg to 500 mg of the active ingredient.
Examples of pharmaceutical dosage forms for the compounds of formula (I) are as follows.

  The compound of formula (I) is not only a disease or symptom associated with hyperlipidemia, diabetes or obesity, but also other drugs used for the treatment / prevention / delay of the onset of hyperlipidemia, diabetes or obesity Can be used in combination. The other agent can be administered simultaneously or separately with the compound of formula (I), using the administration route or dose normally used.

When the compound of formula (I) is used simultaneously with one or more drugs, a pharmaceutical composition comprising the compound of formula (I) and these other drugs is preferred.
Accordingly, the pharmaceutical compositions according to the invention also contain one or more other active ingredients, in addition to the compound of formula (I). Examples of active ingredients used in combination with a compound of formula (I) include the following (a) to (i), which may be administered separately or in the same pharmaceutical composition: However, it is not limited to the following.
(A) other DGAT1 inhibitors (b) glucokinase activators (c) biguanides (eg, buformin, metformin, phenformin)
(D) PPAR agonist (eg, troglitazone, pioglitazone, nosiglitazone)
(E) insulin (f) somatostatin (g) α-glucosidase inhibitor (eg, voglibose, miglitol, acarbose),
(H) an insulin secretagogue (e.g., acetohexamide, carbutamide, chlorpropamide, glybomlide, gliclazide, glimelpide, glipizide, glyxidine, glyoxepide, glyburide, glyhexamide, glipinamide, fenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide, Repaglinide), and (i) DPP-IV (dipeptidyl peptidase IV inhibitor)
The weight ratio of the compound of formula (I) to the second active ingredient will vary within wide limits and will further depend on the effective dose of each active ingredient. Thus, for example, when the compound of formula (I) is used in combination with a PPAR agonist, the weight ratio of the compound of formula (I) to the PPAR agonist is generally about 1000: 1 to 1: 1000, Preferably, it is about 200: 1 to 1: 200. Combinations of a compound of formula (I) and other active ingredients are within the aforementioned ranges, but in each case, an effective amount of each active ingredient should be used.

Hereinafter, the present invention will be described more specifically with reference to formulation examples, examples and reference examples, but the present invention is not limited thereto.
Formulation Example 1
10 parts of the compound of Example 1, 15 parts of heavy magnesium oxide and 75 parts of lactose are uniformly mixed to obtain a powdery or fine powder powder of 350 μm or less. This powder is put into a capsule container to form a capsule.
Formulation Example 2
After uniformly mixing 45 parts of the compound of Example 1, 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water, the mixture was crushed and granulated and dried, and then sieved to obtain a diameter. Granules having a size of 1410 to 177 μm are used.
Formulation Example 3
A granule is prepared in the same manner as in Formulation Example 2, and then 3 parts of calcium stearate is added to 96 parts of this granule and compression-molded to prepare a tablet having a diameter of 10 mm.
Formulation Example 4
10 parts of crystalline cellulose and 3 parts of calcium stearate are added to 90 parts of the granules obtained by the method of Formulation Example 2 and compression-molded to form tablets with a diameter of 8 mm, followed by syrup gelatin and precipitated calcium carbonate Drag suspension to make dragees.
For the silica gel column chromatography of Examples, Wakogel (registered trademark) C-300 manufactured by Wako Pure Chemical Industries, Ltd. or KP-Sil (registered trademark) Silica prepacked column manufactured by Biotage Corporation was used. Preparative thin layer chromatography was performed by Kieselgel ^™ 60F ₂₅₄ , Art. 5744 was used. Chromatorex (registered trademark) NH (100-250 mesh or 200-350 mesh) manufactured by Fuji Silysia Chemical Ltd. was used for basic silica gel column chromatography.
¹ H-NMR was measured using Gemini (200 MHz, 300 MHz), Mercury (400 MHz), and Inova (400 MHz) manufactured by Varian, using tetramethylsilane as a standard substance. The mass spectrum was measured by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) using a Micromass ZQ manufactured by Waters.

The meanings of the abbreviations in the following examples are shown below.
i-Bu: isobutyl group n-Bu: n-butyl group t-Bu: tert-butyl group Boc: tert-butoxycarbonyl group Me: methyl group Et: ethyl group Ph: phenyl group i-Pr: isopropyl group n-Pr : N-propyl group CDCl ₃ : deuterated chloroform CD ₃ OD: deuterated methanol DMSO-d ₆ : deuterated dimethyl sulfoxide The meanings of the abbreviations in the nuclear magnetic resonance spectrum are shown below.
s: singlet d: doublet dd: double doublet dt: double triplet ddd: double double doublet Sept: septet t: triplet m: multiplet br: broad brs: broad singlet q: quartet J: coupling constant Hz: Hertz Example 1
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrimidin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 4- (4-bromophenyl) -2,2-dimethyl-4-oxobutanoic acid

Aluminum chloride was added to a dichloroethane solution (125 ml) of 3,3-dimethyldihydrofuran-2,5-dinone (5.00 g, 39.0 mmol) and bromobenzene (4.31 g, 40.9 mmol) under ice-cooling in a nitrogen atmosphere. (10.9 g, 81.9 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. The mixture was cooled again to ice cooling, 1N hydrochloric acid (82.0 ml, 82.0 mmol) and water (62.0 ml) were slowly added. After separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate. After filtration, the resulting solution was concentrated under reduced pressure, and the resulting residue was roughly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-50 / 50) to give 4- (4-bromophenyl) -2. , 2-Dimethyl-4-oxobutanoic acid-containing mixture (10.0 g) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (6H, s), 3.26 (2H, s), 7.59 (2H, d, J = 8.53 Hz), 7.80 (2H , D, J = 8.53 Hz)
2) Synthesis of methyl 4- (4-bromophenyl) -2,2-dimethyl-4-oxobutanoate

Acetone dimethyl acetal (5.61 ml, 56.7 mmol) was added to a methanol solution (125 ml) of the mixture (10.0 g) containing 4- (4-bromophenyl) -2,2-dimethyl-4-oxobutanoic acid obtained above. Then, 4N hydrochloric acid-dioxane solution (0.878 ml, 3.51 mmol) was added, and the mixture was heated to 50 ° C. and stirred at the same temperature overnight. The residue obtained after distilling off the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15) to give 4- (4-bromophenyl) -2,2- Methyl dimethyl-4-oxobutanoate (5.60 g, over 2 steps) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (6H, s), 3.25 (2H, s), 3.68 (3H, s), 7.59 (2H, d, J = 8 .29Hz)
7.80 (2H, d, J = 8.29Hz)
3) Synthesis of methyl 2,2-dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate

To the dioxane solution (40.0 ml) of methyl 4- (4-bromophenyl) -2,2-dimethyl-4-oxobutanoate (2.19 g, 7.32 mmol) obtained above was added bis (pinacolate) diboron (1. 95 g, 7.69 mmol), potassium acetate (2.16 g, 22.0 mmol), PdCl ₂ (dppf) · CH ₂ Cl ₂ (598 mg, 0.732 mmol), dppf (406 mg, 0.732 mmol) were added, and 90 ° C. The mixture was warmed to 1 and stirred overnight. The reaction mixture was diluted with ethyl acetate, insoluble materials were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 10-70 / 30) to give 2,2-dimethyl-4-oxo-4- [4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoic acid methyl ester (2.15 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (6H, s), 1.36 (12H, s), 3.30 (2H, s), 3.68 (3H, s), 7. 87 (2H, d, J = 8.54hz), 7.90 (2H, d, J = 8.54Hz)
4) Synthesis of N- (5-bromopyrimidin-2-yl) -1,3-benzothiazol-2-amine

To a solution of 5-bromo-2-chloropyrimidine (200 mg, 1.03 mmol) in DMF (4.00 ml) was added 2-aminobenzothiazole (171 mg, 1.13 mmol) and potassium carbonate (427 mg, 3.09 mmol), and 100 The temperature was raised to ° C. and stirred for 1 night. Water and ethyl acetate were added to this reaction mixture, and the resulting solid was collected by filtration, washed with water and methanol, and then dried under reduced pressure to give N- (5-bromopyrimidin-2-yl) -1,3-benzothiazole- 2-Amine (272 mg) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.23 (1H, t, J = 7.32 Hz), 7.39 (1H, t, J = 7.32 Hz), 7.66 (1H, d, J = 7.32 Hz), 7.92 (1H, d, J = 7.32 Hz), 8.81 (2H, s)
5) Synthesis of methyl 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyrimidin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoate

2,2-Dimethyl-4-synthesized in Step 3 from the N- (5-bromopyrimidin-2-yl) -1,3-benzothiazol-2-amine (27.9 mg, 0.0909 mmol) obtained above. Methyl oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (30.0 mg, 0.0866 mmol), potassium carbonate (35 .9 mg, 0.260 mmol) and PdCl ₂ (dppf) .CH ₂ Cl ₂ (21.2 mg, 0.0260 mmol) are added and to this mixture is poured DMA (0.800 ml) and purified water (0.200 ml), After raising the temperature to 85 ° C., the mixture was stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (chloroform / methanol = 39/1) to give 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyrimidin-5-yl] phenyl. } -Methyl-2,2-dimethyl-4-oxobutanoate (7.8 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (6H, s), 3.35 (2H, s), 3.72 (3H, s), 7.32 (1H, t, J = 8 .05 Hz), 7.44 (1H, t, J = 8.05 Hz), 7.66 (2H, d, J = 7.81 Hz), 7.79 (1H, d, J = 8.05 Hz), 7 .97 (1H, d, J = 8.05 Hz), 8.06 (2H, d, J = 7.81 Hz), 8.98 (2H, s)
6) Synthesis of 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyrimidin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid obtained above 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyrimidin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoate (7.8 mg, 0.0175 mmol) Was dissolved in dioxane (0.500 ml), THF (0.500 ml) and purified water (0.500 ml), 1N aqueous sodium hydroxide solution (0.0873 ml, 0.0873 mmol) was added to the reaction solution, The mixture was heated up to 1 hour and stirred overnight. 1N Hydrochloric acid (0.0873 ml, 0.0873 mmol) was added, and the resulting solid was collected by filtration, washed with water and acetone, and dried under reduced pressure to give the title compound (4.8 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.22 (6H, s), 3.34 (2H, s), 7.25 (1H, t, J = 8.05 Hz), 7.40 (1H, t, J = 8.05 Hz), 7.68 (1H, d, J = 8.05 Hz), 7.94 (1H, d, J = 8.05 Hz), 7.95 (2H, d, J = 8.54 Hz), 8.06 (2H, d, J = 8.54 Hz), 9.12 (2H, s)
ESI-MS (m / e): 433.1 [M + H] +
Example 2
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyridin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 2-bromobenzothiazole

Acetonitrile (20.0 ml) was poured into copper (II) bromide (2.98 g, 13.3 mmol), and t-butyl nitrite was added thereto under ice cooling, followed by stirring for 30 minutes. 2-Aminobenzothiazole (1.00 g, 6.66 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A mixed solution (20.0 ml) of 28% aqueous ammonia / saturated aqueous ammonium chloride (9/1) was added, and the mixture was stirred overnight. After liquid separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 90/10) to give 2-bromobenzothiazole (1.12 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.41 (1H, t, J = 7.81 Hz), 7.47 (1H, t, J = 7.81 Hz), 7.80 (1H, d, J = 7.81 Hz), 7.98 (1H, d, J = 7.81 Hz)
2) Synthesis of N- (5-bromopyridin-2-yl) -1,3-benzothiazol-2-amine

To the THF solution (4.00 ml) of 2-bromobenzothiazole (200 mg, 0.934 mmol) obtained above, 2-amino-5-bromopyridine (323 mg, 1.87 mmol) and then sodium hydride (60% in oil, 149 mg, 3.74 mmol) was added. The reaction mixture was stirred at 60 ° C. for 3 hours, 5N hydrochloric acid (0.747 ml, 3.74 mmol) was added under ice cooling, and the resulting solid was collected by filtration and washed with water and acetone. The obtained solid was dried under reduced pressure to obtain N- (5-bromopyridin-2-yl) -1,3-benzothiazol-2-amine (135 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.17 (1H, d, J = 8.78 Hz), 7.19 (1H, t, J = 7.81 Hz), 7.36 (1H, t, J = 7.81 Hz), 7.62 (1H, d, J = 7.81 Hz), 7.89 (1H, d, J = 7.81 Hz), 7.96 (1H, d, J = 8) .78 Hz), 8.44 (1 H, s)
3) Synthesis of methyl 4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyridin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoate

2,2-synthesized in 3) of Example 1 to N- (5-bromopyridin-2-yl) -1,3-benzothiazol-2-amine (27.8 mg, 0.0909 mmol) obtained above. Methyl dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (30.0 mg, 0.0866 mmol), Potassium carbonate (35.9 mg, 0.260 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (21.2 mg, 0.0260 mmol) were added and to this mixture DMA (0.800 ml) and purified water (0.200 ml). ), And the mixture was heated to 85 ° C. and stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by thin layer chromatography (chloroform / methanol = 39/1) to give 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyridin-5-yl] phenyl. } -2,2-dimethyl-4-oxobutanoic acid methyl ester (15.5 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (6H, s), 3.34 (2H, s), 3.70 (3H, s), 6.99 (1H, brs), 7. 22 (1H, t, J = 7.81 Hz), 7.39 (1H, t, J = 7.81 Hz), 7.62 (1H, d, J = 7.81 Hz), 7.63 (2H, d , J = 8.29 Hz), 7.68 (1H, d, J = 7.81 Hz), 7.74 (1H, brs), 8.03 (2H, d, J = 8.29 Hz), 8.69 (1H, s)
4) Synthesis of 4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyridin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid Obtained methyl 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyridin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoate (15.5 mg, 0.0348 mmol) ) Is dissolved in dioxane (0.500 ml), THF (0.500 ml) and purified water (0.500 ml), and 1N aqueous sodium hydroxide solution (0.174 ml, 0.174 mmol) is added to the reaction solution. After heating up to 0 ° C., the mixture was stirred overnight. 1N Hydrochloric acid (0.174 ml, 0.174 mmol) was added, and the resulting solid was collected by filtration, washed with water and acetone, and dried under reduced pressure to give the title compound (11.1 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.22 (6H, s), 3.35 (2H, s), 7.21 (1H, t, J = 8.05 Hz), 7.29 (1H, d, J = 8.54 Hz), 7.38 (1H, t, J = 8.05 Hz), 7.63 (1H, d, J = 8.05 Hz), 7.87 (2H, d, J = 8.29 Hz), 7.91 (1H, d, J = 8.05 Hz), 8.03 (2H, d, J = 8.29 Hz), 8.19 (1H, d, J = 8.54 Hz) ), 8.78 (1H, s)
ESI-MS (m / e): 432.1 [M + H] +
Example 3
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrazin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 2-amino-5-bromopyrazine

Pyridine (5.11 ml, 63.1 mmol) was added to a chloroform solution (400 ml) of 2-aminopyrazine (5.00 g, 52.6 mmol), and then a chloroform solution (100 ml of bromine (3.23 ml, 63.1 mmol)). ) Was added dropwise over 2.5 hours. After completion of the dropwise addition, the mixture was further stirred for 1 hour, water (100 ml) was added to the reaction solution, and the mixture was vigorously stirred for 30 minutes. After liquid separation, the aqueous phase was extracted with chloroform, and the combined organic phases were washed with water and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-50 / 50) to give 2-amino-5-bromopyrazine (2. 78 g) was obtained. In addition, 2-amino-3,5-dibromopyrazine (1.61 g) was obtained as a by-product.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 6.65 (2H, brs), 7.66 (1H, s), 8.01 (1H, s)
2) Synthesis of N- (5-bromopyrazin-2-yl) -1,3-benzothiazol-2-amine

To a THF solution (4.00 ml) of 2-bromobenzothiazole (200 mg, 0.934 mmol) synthesized in 1) of Example 2 was added 2-amino-5-bromopyrazine (325 mg, 1.87 mmol) and then sodium hydride ( 60% in oil, 149 mg, 3.74 mmol) was added. The reaction mixture was stirred at 60 ° C. for 3 hours, 5N hydrochloric acid (0.747 ml, 3.74 mmol) was added under ice cooling, and the resulting solid was collected by filtration and washed with water and acetone. The obtained solid was dried under reduced pressure to obtain N- (5-bromopyrazin-2-yl) -1,3-benzothiazol-2-amine (255 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.23 (1H, t, J = 7.80 Hz), 7.39 (1H, t, J = 7.80 Hz), 7.65 (1H, d, J = 7.80 Hz), 7.91 (1H, d, J = 7.80 Hz), 8.49 (1H, s), 8.55 (1H, s)
3) Synthesis of methyl 4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrazin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoate

2,2- synthesized in 3) of Example 1 to N- (5-bromopyrazin-2-yl) -1,3-benzothiazol-2-amine (27.9 mg, 0.0909 mmol) obtained above. Methyl dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (30.0 mg, 0.0866 mmol), Potassium carbonate (35.9 mg, 0.260 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (21.2 mg, 0.0260 mmol) were added and to this mixture DMA (0.800 ml) and purified water (0.200 ml). ), And the mixture was heated to 85 ° C. and stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by thin layer chromatography (chloroform / methanol = 39/1) to give 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyrazin-5-yl] phenyl. } -Methyl-2,2-dimethyl-4-oxobutanoate (9.5 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (6H, s), 3.34 (2H, s), 3.70 (3H, s), 7.32 (1H, t, J = 7 .32 Hz), 7.47 (1H, t, J = 7.32 Hz), 7.74 (1H, d, J = 7.32 Hz), 7.83 (1H, d, J = 7.32 Hz), 8 .06 (1H, d, J = 8.78 Hz), 8.08 (1 H, d, J = 8.78 Hz), 8.58 (1 H, s), 8.85 (1 H, s)
4) Synthesis of 4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrazin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

Methyl 4- {4- [2- (1,3-benzothiazol-2-ylamino) pyrazin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoate (9.5 mg, 0 0.0213 mmol) was dissolved in dioxane (0.500 ml), THF (0.500 ml) and purified water (0.500 ml), and 1N aqueous sodium hydroxide solution (0.106 ml, 0.106 mmol) was added to the reaction solution. The mixture was heated to 50 ° C. and stirred overnight. 1N Hydrochloric acid (0.106 ml, 0.106 mmol) was added, water and ethyl acetate were further added, the resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (chloroform / methanol = 9/1) to give the title compound (8.6 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.23 (6H, s), 3.35 (2H, s), 7.24 (1H, t, J = 8.05 Hz), 7.40 (1H, t, J = 8.05 Hz), 7.67 (1H, d, J = 8.05 Hz), 7.94 (1H, d, J = 8.05 Hz), 8.06 (2H, d, J = 8.54 Hz), 8.23 (2H, d, J = 8.54 Hz), 8.69 (1H, s), 9.08 (1H, s)
ESI-MS (m / e): 433.1 [M + H] +
Example 4
2- {5- [4- (1,3-benzothiazol-2-ylamino) phenyl] -1-oxo-isoindoline-2-yl} -2,2-dimethylacetic acid

1) Synthesis of 2- (5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl) -2-methylpropanoic acid

To 1.03 g of 2-aminoisobutyric acid and 1.54 g of methyl 4-bromo-2- (bromomethyl) benzoate were added 30 ml of methanol and 2.78 ml of triethylamine, and the mixture was stirred for 24 hours while heating under reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with 2M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to obtain 124 mg of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.53 (6H, s), 4.61 (2H, s), 7.56 (1H, d = 8.3 Hz), 7.66 (1H , J = 8.3 Hz), 7.85 (1H, s)
2) Synthesis of 2- {5- [4- (1,3-benzothiazol-2-ylamino) phenyl] -1-oxo-isoindoline-2-yl} -2,2-dimethylacetic acid 1) 2- (5-Bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl) -2-methylpropanoic acid 29.8 mg, the method described in WO2001019829, or a method analogous thereto Prepared N- [4- (4,4,5,5, -tetramethyl-1,3,2-dioxoborolan-2-yl) phenyl] -1,3-benzothiazol-2-amine 39 mg, PdCl2 (dppf ) 16.3 mg of methylene chloride complex and 45.6 mg of potassium carbonate were suspended in 1.6 ml of dimethylacetamide and 400 μl of water, and stirred overnight at 85 ° C. in a nitrogen atmosphere. After the resulting mixture was cooled to room temperature, the mixture was diluted with ethyl acetate and washed with 2M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by reverse phase preparative HPLC (YMC HPLC COLUMN CombiPrep Pro C18; 0.1% trifluoroacetic acid, water / acetonitrile = 90/10 to 5/95) to obtain 12.4 mg of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.57 (6H, s), 4.66 (2H, s), 7.17 (1H, t, J = 7.6 Hz), 7.34 (1H, t, J = 7.1 Hz), 7.60-7.75 (2H, m), 7.77-7.85 (5H, m), 7.92 (2H, d, J = 8. 8Hz)
ESI-MS (m / e): 444.1 [M + H] +
Example 5
4- {4- [5- (1,3-benzothiazol-2-ylamino) -pyrimidin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of methyl 4- [4- (5-bromopyrimidin-2-yl) phenyl] -2,2-dimethyl-4-oxobutanoate

2,2-Dimethyl-4-oxo-4- [4- (4,4,5,5) synthesized in 3) of Example 1 to 5-bromo-2-iodopyrimidine (29.6 mg, 0.104 mmol) -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoic acid methyl (30.0 mg, 0.0866 mmol), cesium carbonate (84.6 mg, 0.260 mmol) and Pd (PPh ₃ ) ₄ ( 10.0 mg, 0.00866 mmol) was added, DMF (1.00 ml) was poured into the mixture, and the mixture was heated to 85 ° C. and stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (chloroform / methanol = 39/1) to give 4- [4- (5-bromopyrimidin-2-yl) phenyl] -2,2-dimethyl-4-oxobutane. Methyl acid (22.6 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (6H, s), 3.35 (2H, s), 3.69 (3H, s), 8.04 (2H, d, J = 8) .78 Hz), 8.49 (2H, d, J = 8.78 Hz), 8.88 (2H, s)
2) Synthesis of methyl 4- {4- [5- (1,3-benzothiazol-2-ylamino) -pyrimidin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoate

4- [4- (5-Bromopyrimidin-2-yl) phenyl] -2,2-dimethyl-4-oxobutanoate (22.6 mg, 0.0599 mmol) obtained above was added to 2-aminobenzothiazole (13 0.5 mg, 0.0899 mmol), sodium t-butoxide (23.0 mg, 0.240 mmol), Xantphos (10.4 mg, 0.0180 mmol) and Pd ₂ (dba) ₃ .CHCl ₃ (6.2 mg, 0.00599 mmol) ) Was added, and toluene (1.00 ml) was poured into the mixture, followed by stirring at 100 ° C. for 1 night. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (chloroform / methanol = 39/1) to give 4- {4- [5- (1,3-benzothiazol-2-ylamino) -pyrimidin-2-yl] Phenyl} -2,2-dimethyl-4-oxobutanoic acid methyl ester (6.0 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (6H, s), 3.36 (2H, s), 3.71 (3H, s), 7.25 (1H, t, J = 8 .05 Hz), 7.41 (1H, t, J = 8.05 Hz), 7.68 (1H, d, J = 8.05 Hz), 7.72 (1H, d, J = 8.05 Hz), 8 .03 (2H, d, J = 8.54 Hz), 8.48 (2H, d, J = 8.54 Hz), 9.28 (2H, s)
3) Synthesis of 4- {4- [5- (1,3-benzothiazol-2-ylamino) -pyrimidin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid Obtained methyl 4- {4- [5- (1,3-benzothiazol-2-ylamino) -pyrimidin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoate (6.0 mg, 0.0. 0134 mmol) was dissolved in dioxane (0.500 ml), THF (0.500 ml) and purified water (0.500 ml), 1N aqueous sodium hydroxide solution (0.0672 ml, 0.0672 mmol) was added to the reaction solution, After raising the temperature to 50 ° C., the mixture was stirred overnight. 1N Hydrochloric acid (0.0672 ml, 0.0672 mmol) was added, and the insoluble material produced by dilution with excess acetone was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (chloroform / methanol = 9/1) to give the title compound (6.0 mg, quant.).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.23 (6H, s), 3.34 (2H, s), 7.22 (1H, t, J = 7.81 Hz), 7.39 (1H, t, J = 7.81 Hz), 7.70 (1H, d, J = 7.81 Hz), 7.86 (1H, d, J = 7.81 Hz), 8.08 (2H, d, J = 8.54 Hz), 8.45 (2H, d, J = 8.54 Hz), 9.39 (2H, s)
ESI-MS (m / e): 433.1 [M + H] +
Example 6
4- {4- [6- (1,3-benzothiazol-2-ylamino) -pyridazin-3-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of N- (6-chloropyridazin-3-yl) -1,3-benzothiazol-2-amine

2-bromobenzothiazole (268 mg, 1.25 mmol) synthesized in Example 1 1) in THF (5.00 ml) was added to 3-amino-6-chloropyridazine (130 mg, 1.00 mmol) and then sodium hydride ( 60% in oil, 80.0 mg, 2.00 mmol) was added. The reaction mixture was stirred at 60 ° C. for 3 hours, 4M-hydrochloric acid-dioxane solution (0.500 ml, 2.00 mmol) was added under ice cooling, and the resulting solid was collected by filtration and washed with water and methanol. The obtained solid was dried under reduced pressure to obtain N- (6-chloropyridazin-3-yl) -1,3-benzothiazol-2-amine (178 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.24 (1H, t, J = 7.32 Hz), 7.40 (1H, t, J = 7.32 Hz), 7.59 (1H, d, J = 9.27 Hz), 7.67 (1H, d, J = 7.32), 7.81 (1H, d, J = 9.27 Hz), 7.95 (1H, d, 7.32 Hz) )
2) Synthesis of methyl 4- {4- [6- (1,3-benzothiazol-2-ylamino) -pyridazin-3-yl] phenyl} -2,2-dimethyl-4-oxobutanoate

2,2-synthesized in 3) of Example 1 to N- (6-chloropyridazin-3-yl) -1,3-benzothiazol-2-amine (23.9 mg, 0.0909 mmol) obtained above Methyl dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (30.0 mg, 0.0866 mmol), Potassium carbonate (35.9 mg, 0.260 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (21.2 mg, 0.0260 mmol) were added and to this mixture DMA (0.800 ml) and purified water (0.200 ml). ), And the mixture was heated to 85 ° C. and stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (chloroform / methanol = 39/1) to give 4- {4- [6- (1,3-benzothiazol-2-ylamino) -pyridazin-3-yl] Phenyl} -2,2-dimethyl-4-oxobutanoic acid methyl ester (8.2 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (6H, s), 3.36 (2H, s), 3.71 (3H, s), 7.27 (1H, t, J = 7 .56 Hz), 7.42 (1H, t, J = 7.56 Hz), 7.67-7.86 (3H, m), 7.99-8.25 (5H, m)
3) Synthesis of 4- {4- [6- (1,3-benzothiazol-2-ylamino) -pyridazin-3-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid Obtained methyl 4- {4- [6- (1,3-benzothiazol-2-ylamino) -pyridazin-3-yl] phenyl} -2,2-dimethyl-4-oxobutanoate (8.2 mg, .0. 0184 mmol) was dissolved in dioxane (0.500 ml), THF (0.500 ml) and purified water (0.500 ml), 1N aqueous sodium hydroxide solution (0.0918 ml, 0.0918 mmol) was added to the reaction solution, After raising the temperature to 50 ° C., the mixture was stirred overnight. 1N Hydrochloric acid (0.0918 ml, 0.0918 mmol) was added, and the resulting solid was collected by filtration, washed with water and methanol, and dried under reduced pressure to give the title compound (3.5 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.24 (6H, s), 3.36 (2H, s), 7.25 (1H, t, J = 7.81 Hz), 7.41 (1H, t, J = 7.81 Hz), 7.62 (1H, d, J = 9.02 Hz), 7.68 (1H, d, J = 7.81 Hz), 7.95 (1H, d, J = 7.81 Hz), 8.10 (2H, d, J = 8.29 Hz), 8.26 (2H, d, J = 8.28 Hz), 8.32 (1H, d, J = 9.02 Hz) )
ESI-MS (m / e): 433.1 [M + H] +
Example 7
4- {4- [4- (1,3-Benzothiazol-2-ylamino) -pyridin-4-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 4- {4- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid methyl ester

4- (Benzyloxy) pyridin-2 (1H) -one 503 mg, 4- (4-Bromophenyl) -2,2-dimethyl-4-oxobutanoic acid methyl ester 375 mg, CuI 238 mg, potassium carbonate 259 mg in dimethylformamide 10 ml The suspension was suspended and stirred overnight at 150 ° C. under a nitrogen stream. The reaction mixture was cooled to room temperature, filtered through celite, and diluted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and 0.5N HCl aqueous solution and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 118 mg of the title compound.
¹ H-NMR (400 MHz, CDCL3) δ: 1.33 (6H, s), 3.30 (2H, s), 3.68 (3H, s), 5.05 (2H, s), 6.08 −6.13 (2H, m), 7.22 to 7.30 (1H), 7.35 to 7.52 (7H, m), 8.05 (2H, d, J = 8.8 Hz)
2) 2,2-Dimethyl-4-oxo-4- {4- [2-oxo-4-{[(trifluoromethyl) sulfonyl] oxy} pyridin-1 (2H) -yl] phenyl} butanoic acid methyl ester Synthesis of

115 mg of 4- {4- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid methyl ester obtained in 1) was added to 5 ml of methanol. -It melt | dissolved in the mixed solvent of 5 ml of tetrahydrofuran, 20% of 10% Pd-C was added, and it stirred at normal pressure under hydrogen atmosphere for 2 hours. The catalyst was removed with celite, and the solvent was removed under reduced pressure. After the obtained residue was dissolved in chloroform, 57 μl of bis (trifluoromethanesulfonic acid) anhydride and 47 μl of triethylamine were added at 0 ° C. and stirred overnight at room temperature. Further, 57 μl of additional trifluoroacetic anhydride and 47 μl of triethylamine were added and stirred at room temperature for 1 hour. Water was added to stop the reaction, the product was extracted with ethyl acetate, insoluble matters were filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 45.6 mg of the title compound.
¹ H-NMR (400 MHz, CDCl 3) δ: 1.26 (6H, s), 3.31 (2H, s), 3.69 (3H, s), 6.32 (1H, dd, J = 2. 4, 7.8 Hz), 6.60 (1 H, d, J = 2.4 Hz), 7.44-7.52 (3 H, m), 8.09 (2 H, d, J = 8.8 Hz)
3) Synthesis of 4- {4- [4- (1,3-benzothiazol-2-ylamino) -2-oxopyridin-1 (2H) -yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid 2,2-Dimethyl-4-oxo-4- {4- [2-oxo-4-{[(trifluoromethyl) sulfonyl] oxy} pyridin-1 (2H) -yl] phenyl} obtained in 2) Butanoic acid methyl ester 43.3 mg, 2-aminobenzthiazole 21 mg, tert-BuONa 35.7 mg, Xantphos 17.4 mg, Pd2 (dba) 3 CHCl3 20.7 mg were suspended in 3 ml of toluene at 100 ° C. for 3 hours. Stir. The reaction solution was cooled to room temperature, diluted with chloroform, and washed with water. The organic layer was dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 29.5 mg of a corresponding crude product of methyl ester. The obtained crude product was dissolved in 2 ml of 1,4-dioxane, 0.5 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was stirred at 50 ° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with water and washed with ethyl acetate. After adding 0.75 ml of 2N hydrochloric acid water, the insoluble product was recovered by filtration. The obtained product was subjected to thin layer silica gel column chromatography (chloroform: methanol = 9: 1), followed by reverse phase preparative HPLC (YMC HPLC COLUMN CombiPrep Pro C18; 0.1% trifluoroacetic acid, water / acetonitrile = 90 / 10 to 5/95) to obtain 2.03 mg of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.23 (6H, s), 6.44 (1H, dd, J = 2.4, 7.8 Hz), 7.20-7.31 ( 2H, m), 7.40 (1H, t, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.66 (1H, d, J = 7.8 Hz), 7.75 (1H, d, J = 7.3 Hz), 7.91 (1H, d, J = 7.8 Hz), 8.06 (2H, d, J = 8.8 Hz), 10.89 (1H , Brs), 12.01 (1H, brs)
ESI-MS (m / e): 448.2 [M + H] +
Example 8
4- {4- [5- (Oxazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of methyl 4- [4- (5-nitropyridin-2-yl) phenyl] -2,2-dimethyl-4-oxobutanoate

2,2-Dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl obtained in 3) of Example 1 ] To a solution of 50 mg of methyl butanoate in 2 ml of dimethylformamide, 35 mg of 2-bromo-5-nitropyridine, 91 mg of cesium carbonate and 16 mg of tetrakis (triphenylphosphine) palladium were sequentially added and stirred at 85 ° C. for 24 hours. After returning the reaction solution to room temperature, water was added and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform / methanol = 1/0 to 100/1) to obtain 53 mg of the title compound as a pale yellow solid.
ESI-MS (m / e): 343.1 [M + H] +
2) Synthesis of methyl 4- [4- (5-aminopyridin-2-yl) phenyl] -2,2-dimethyl-4-oxobutanoate

1) 84 mg of iron powder and 40 mg of ammonium chloride were added to a 5 ml solution of 53 mg of the compound (tetrahydrofuran / methanol / water = 3/1/1), and the mixture was stirred at 90 ° C. for 3 hours. After returning the reaction solution to room temperature, insolubles were filtered and the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform / methanol = 10/1) to obtain 36 mg of the title compound as a pale yellow solid.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 1.34 (6H, s), 3.32 (2H, s), 3.69 (3H, s), 7.06 (1H, dd, J = 3.0) , 8.3 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.99 (4H, s), 8.20 (1H, d, J = 2.4 Hz)
ESI-MS Found: m / z 312.3 [M + H] +
3) Synthesis of 4- {4- [5- (oxazolo [4,5-b] pyridin-2-ylamino) -pyridin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid <br / > 2) 27 mg of 2-chloro [1,3] oxazolo [4,5-b] pyridine, which is known in the synthesis method, was added to a solution of 18 mg of the above compound in 1 ml of 1,2-dichloroethane, and the mixture was stirred at 85 ° C. for 1 hour. After returning the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform / methanol = 10/1) to obtain 26 mg of the corresponding methyl ester as a crude product.
The obtained methyl ester was dissolved in 2 ml of 1,4-dioxane, 1 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was returned to room temperature, neutralized with 0.5 ml of 2N aqueous hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in (chloroform / methanol = 3/1), insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol, diethyl ether was added for precipitation, and the residue was collected by filtration and dried to obtain 15 mg of the title compound as a pale yellow solid.
¹ HNMR (400 MHz, DMSO) δ: 1.23 (6H, s), 3.35 (2H, s), 7.14 (1H, dd, J = 8.0, 5.1 Hz), 7.88 ( 1H, d, J = 7.8 Hz), 8.05 (2H, d, J = 8.3 Hz), 8.16 (1H, d, J = 8.8 Hz), 8.27-8.19 (3H M), 8.43 (1H, dd, J = 8.8, 2.4 Hz), 8.94 (1H, d, J = 2.9 Hz)
ESI-MS (m / e): 417.3 [M + H] +
Example 9
2-[(4-{[5- (Oxazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid

1) Synthesis of methyl (1,2-trans) -2- [4- (5-aminopyridin-2-yl) benzoyl] cyclopentanecarboxylate

Example 10 instead of methyl 2,2-dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (1,2-trans) -2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] cyclopentanecarboxylic acid obtained in 3) The same operation as 1) of Example 8 was performed using methyl to obtain the corresponding nitropyridine as a crude product.
Using the obtained nitropyridine, the title compound was obtained as a yellow oil by the same operation as 2) of Example 8.
ESI-MS Found: m / z 324.2 [M + H] +
2) (1,2-trans) -2-[(4-{[5- (oxazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid Synthesis of 4- {4- [5- (oxazolo [4,5-b] pyridin-2-ylamino) -pyridin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid ) Was used in the same manner as in Example 8 3) to give the title compound as a light brown solid.
¹ HNMR (400 MHz, DMSO) δ: 1.53 to 2.08 (6H, m), 2.94 to 3.04 (1H, m), 4.02 to 4.13 (1H, m), 6. 76 (1H, brs), 7.39 (1H, brs), 7.92 (2H, d, J = 9.8 Hz), 8.03 (2H, d, J = 8.8 Hz), 8.12 ( 2H, d, J = 8.5 Hz), 8.31 (1H, dd, J = 8.9, 2.3 Hz), 8.62 (1H, brs)
ESI-MS (m / e): 429.2 [M + H] +
Example 10
(1,2-trans) -2- [4- [5- (1,3-Benzothiazol-2-ylamino) -2-pyridinyl] phenyl] carbonyl) cyclopentanecarboxylic acid

1) Synthesis of methyl (1,2-trans) -2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] cyclopentanecarboxylate

Synthesis of known (1,2-trans) -2- (4-bromobenzoyl) cyclopentanecarboxylate (2.00 g, 6.43 mmol) in dioxane (30.0 ml) with bis (pinacolate) diboron ( 1.71 g, 6.75 mmol), potassium acetate (1.89 g, 19.3 mmol), PdCl ₂ (dppf) · CH ₂ Cl ₂ (525 mg, 0.643 mmol), dppf (356 mg, 0.643 mmol) were added, The temperature was raised to 90 ° C. and stirred for 1 night. The reaction mixture was diluted with ethyl acetate, insoluble materials were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-60 / 40) to obtain (1,2-trans) -2- [4- (4,4,5,5). -Tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] methyl cyclopentanecarboxylate (2.17 g) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (12H, s), 1.71-1.96 (4H, m), 2.05-2.22 (2H, m), 3.45 (1H, dt, J = 8.05, 7.56 Hz), 3.65 (3H, s), 4.11 (1H, dt, J = 8.05, 6.83 Hz), 7.89 (2H, d, J = 8.53 Hz), 7.95 (2H, d, J = 8.53 Hz)
2) Synthesis of N- (6-bromopyridin-3-yl) -1,3-benzothiazol-2-amine

2-Amino-6-bromopyridine (1.62 g, 9.34 mmol) was added to a THF solution (20.0 ml) of 2-bromobenzothiazole (1.00 g, 4.67 mmol) synthesized in 1) of Example 2. Sodium hydride (60% in oil, 747 mg, 18.7 mmol) was added. The reaction mixture was stirred at 60 ° C. for 1 hour, 1N hydrochloric acid (50.0 ml, 50.0 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes. The resulting solid was collected by filtration, washed with water, methanol and chloroform, and then the obtained solid was dried under reduced pressure to give N- (6-bromopyridin-3-yl) -1,3-benzothiazol-2-amine. (727 mg) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.20 (1H, t, J = 7.32 Hz), 7.35 (1H, t, J = 7.32 Hz), 7.63 (1H, d, J = 8.78 Hz), 7.64 (1H, d, J = 7.32 Hz), 7.84 (1H, d, J = 7.32 Hz), 8.29 (1H, dd, J = 8) .78, 2.93 Hz), 8.72 (1 H, d, J = 2.93 Hz), 10.87 (1 H, s)
3) Synthesis of methyl (1,2-trans) -2- [4- [5- [1,3-benzothiazol-2-ylamino) -2-pyridinyl] phenyl] carbonyl) cyclopentanecarboxylate

The N- (6-bromopyridin-3-yl) -1,3-benzothiazol-2-amine (46.5 mg, 0.152 mmol) obtained above was synthesized in 1) of Example 10 (1,2 -Trans) -2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] methyl cyclopentanecarboxylate (51.8 mg, 0.145 mmol), Potassium carbonate (60.1 mg, 0.435 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (35.5 mg, 0.0435 mmol) were added and to this mixture DMA (1.20 ml) and purified water (0.300 ml). ), And the mixture was heated to 85 ° C. and stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (chloroform / methanol = 39/1) to give (1,2-trans) -2- [4- [5- (1,3-benzothiazol-2-ylamino). ) -2-Pyridinyl] phenyl] carbonyl) cyclopentanecarboxylate methyl ester (27.1 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.73-1.98 (4H, m), 2.12-2.23 (2H, m), 3.49 (1H, dt, J = 8. 29, 7.32 Hz), 3.68 (3H, s), 4.10-4.17 (1 H, m), 7.21 (1 H, t, J = 8.05 Hz), 7.38 (1 H, t, J = 8.05 Hz), 7.66 (1H, d, J = 8.05 Hz), 7.70 (1H, d, J = 8.05 Hz), 7.80 (1H, d, J = 8) .78 Hz), 8.06 (2H, s), 8.45 (1 H, dd, J = 8.78, 2.68 Hz), 8.82 (1 H, d, J = 2.68 Hz)
4) Synthesis of (1,2-trans) -2- [4- [5- (1,3-benzothiazol-2-ylamino) -2-pyridinyl] phenyl] carbonyl) cyclopentanecarboxylic acid (1,2-trans) -2- [4- [5- (1,3-benzothiazol-2-ylamino) -2-pyridinyl] phenyl] carbonyl) cyclopentanecarboxylate (27.1 mg) obtained in 0.0592 mmol) was dissolved in dioxane (0.500 ml), THF (0.500 ml) and purified water (0.500 ml), and 1N aqueous sodium hydroxide solution (0.296 ml, 0.296 mmol) was added to the reaction solution. In addition, the mixture was heated to 50 ° C. and stirred overnight. 1N hydrochloric acid (0.296 ml, 0.296 mmol) was added, followed by extraction with a mixed solvent of chloroform / methanol (4/1), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by thin layer chromatography (chloroform / methanol = 9/1) to obtain the title compound (26.0 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.56-1.86 (4H, m), 1.95-2.18 (2H, m), 3.17 (1H, dt, J = 8.29, 7.80 Hz), 4.10 (1H, dt, J = 8.05, 7.80 Hz), 7.20 (1H, t, J = 7.81 Hz), 7.37 (1H, t , J = 7.81 Hz), 7.67 (1H, d, J = 7.81 Hz), 7.85 (1H, d, J = 7.81 Hz), 8.10 (2H, d, J = 8. 29 Hz), 8.12 (1H, d, J = 8.78 Hz), 8.21 (2H, d, J = 8.29 Hz), 8.51 (1H, dd, J = 8.78, 2.20 Hz) ), 8.99 (1H, d, J = 2.20 Hz), 11.01 (1H, brs)
ESI-MS (m / e): 444.1 [M + H] +
Example 11
(1,2-trans) -2-[(4-{[5- (thiazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid

1) Synthesis of N- (3-bromopyridin-2-yl) -N ′-(6-bromopyridin-3-yl) thiourea

To a chloroform solution (20.0 ml) of thiophosgene (1.33 ml, 17.4 mmol) was added a chloroform solution (20.0 ml) of 3-amino-6-bromopyridine (3.00 g, 17.4 mmol) under ice cooling. Then, it heated up to room temperature and stirred for 1 hour. To this reaction solution, 2-amino-3-bromopyridine (2.00 g, 11.6 mmol) and then triethylamine (7.30 ml, 52.2 mmol) were added, and the mixture was stirred under reflux conditions (75 ° C.) for 3 hours. Water was added to stop the reaction, the aqueous phase was extracted with chloroform, and the combined organic phase was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, the resulting residue was roughly purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3), and the resulting solid was washed with isopropyl ether to give N- (3-Bromopyridin-2-yl) -N ′-(6-bromopyridin-3-yl) thiourea (2.13 g) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.18 (1H, dd, J = 7.81, 3.90 Hz), 7.66 (1H, d, J = 8.29 Hz), 8. 12 (1H, dd, J = 8.29, 2.68 Hz), 8.22 (1H, d, J = 7.81 Hz), 8.38 (1H, d, J = 3.90 Hz), 8.58 (1H, d, J = 2.68 Hz), 9.23 (1H, brs)
2) Synthesis of N- (6-bromopyridin-3-yl) thiazolo [4,5-b] pyridin-2-amine

N- (3-bromopyridin-2-yl) -N ′-(6-bromopyridin-3-yl) thiourea (2.13 g, 5.49 mmol) obtained above was added to cesium carbonate (5.81 g, 16. 5 mmol), o-phenanthroline monohydrate (218 mg, 1.10 mmol) and copper iodide (209 mg, 1.10 mmol) were added, and dimethoxyethane (100 ml) was poured into the mixture and stirred at 85 ° C. for 4 hours. A mixed solution (200 ml) of 28% aqueous ammonia / saturated aqueous ammonium chloride (9/1) was added and stirred overnight, and then the resulting solid was collected by filtration and washed with water and a small amount of methanol. The obtained solid mixture was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to give N- (6-bromopyridin-3-yl) thiazolo [4,5-b]. Pyridin-2-amine (420 mg) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.18 (1H, dd, J = 7.80, 4.63 Hz), 7.67 (1H, d, J = 8.53 Hz), 8. 27 (1H, d, J = 7.80 Hz), 8.32 (1H, dd, J = 8.53, 2.44 Hz), 8.39 (1H, d, J = 4.63 Hz), 8.71 (1H, d, 2.44 Hz), 11.15 (1H, brs)
3) (1,2-trans) -2-[(4-{[5- (thiazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid Synthesis of methyl

The N- (6-bromopyridin-3-yl) thiazolo [4,5-b] pyridin-2-amine (47.8 mg, 0.155 mmol) obtained above was synthesized in 1 of Example 10) (1 , 2-trans) -2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] methyl cyclopentanecarboxylate (53.1 mg, 0.148 mmol) ), Potassium carbonate (61.4 mg, 0.444 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (36.3 mg, 0.0444 mmol) were added to this mixture and DMA (1.20 ml) and purified water (0 300 ml), and the mixture was heated to 85 ° C. and stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (chloroform / methanol = 19/1) to give (1,2-trans) -2-[(4-{[5- (thiazolo [4,5-b] Pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylate methyl (21.8 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.70-1.96 (4H, m), 2.10-2.20 (2H, m), 3.46 (1H, dt, J = 8. 29, 7.81 Hz), 3.65 (3H, s), 4.11 (1H, dt, J = 7.81, 6.34 Hz), 7.08 (1H, dd, J = 6.34, 4) .39 Hz), 7.66 (1H, d, J = 8.78 Hz), 7.87 (1H, d, J = 6.34 Hz), 7.94 (2H, d, J = 8.29 Hz), 8 0.00 (2H, d, J = 8.29 Hz), 8.51 (1H, d, J = 4.39 Hz), 8.67 (1H, dd, J = 8.78, 2.44 Hz), 8. 86 (1H, d, J = 2.44Hz)
4) (1,2-trans) -2-[(4-{[5- (thiazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid Synthesis of (1,2-trans) -2-[(4-{[5- (thiazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} obtained above Phenyl) carbonyl] cyclopentanecarboxylate methyl (21.8 mg, 0.476 mmol) was dissolved in dioxane (0.500 ml), THF (0.500 ml) and purified water (0.500 ml). A sodium hydroxide aqueous solution (0.238 ml, 0.238 mmol) was added, and the mixture was heated to 50 ° C. and stirred for 2 hours. 1N Hydrochloric acid (0.238 ml, 0.238 mmol) was added, and the mixture was extracted with a mixed solvent of chloroform / methanol (4/1), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by thin layer chromatography (chloroform / methanol = 9/1) to give the title compound (18.1 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.57-1.86 (4H, m), 1.95-2.20 (2H, m), 3.18 (1H, dt, J = 8.05, 7.81 Hz), 4.11 (1H, dt, J = 8.78, 7.81 Hz), 7.18 (1H, dd, J = 7.81, 4.88 Hz), 8.10 (2H, d, J = 8.29 Hz), 8.16 (1H, d, J = 8.78 Hz), 8.23 (2H, d, J = 8.29 Hz), 8.28 (1H, dd, J = 7.81, 1.71 Hz), 8.41 (1H, dd, J = 4.88, 1.71 Hz), 8.55 (1H, dd, J = 8.78, 2.68 Hz), 8 .96 (1H, d, J = 2.68 Hz)
ESI-MS (m / e): 445.0 [M + H] +
Example 12
4- (4- {5-[(1,3-Benzoxazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of N- (6-bromopyridin-3-yl) -1,3-benzoxazol-2-amine

To a solution of 2-chloro-1,3-benzoxazole (335 mg) in 1,4-dioxane (2 ml), 6-bromopyridin-3-amine (0.69 ml) and 4N hydrochloric acid dioxane solution (0.1 ml) were sequentially added, followed by stirring at 100 ° C. for 2 hours. did. After returning the reaction solution to room temperature, water was added and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform / methanol = 1/0 to 25/1) to obtain 300 mg of the title compound as a white solid.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.16 (1H, q, J = 8.0 Hz), 7.24 (1H, t, J = 7.3 Hz), 7.53-7.46 (2H, m), 7.65 (1H, d, J = 8.5 Hz), 8.25 (1H, dd, J = 8.8, 2.9 Hz), 8.66 (1H, d, J = 2.2 Hz) )
ESI-MS (m / e): 291.0 [M + H] +
2) Preparation of 4- (4- {5-[(1,3-benzooxazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid 1) 2,2-dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1, obtained in 3) of Example 1 in a solution of 50 mg of the compound in 2 ml of dimethylformamide [3,2-dioxaborolan-2-yl) phenyl] butanoic acid 59 mg, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium methylene chloride 41 mg, potassium carbonate 47 mg and purified water 0.2 ml were sequentially added. And stirred at 85 ° C. overnight. After returning the reaction solution to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform / methanol = 20/1) to obtain 30 mg of the corresponding methyl ester as a crude product.
The obtained methyl ester was dissolved in 2 ml of 1,4-dioxane, 1 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was returned to room temperature, neutralized with 0.5 ml of 2N aqueous hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in (chloroform / methanol = 10/1), insolubles were filtered, and the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform / methanol = 5/1) to obtain 18 mg of the title compound as a pale yellow solid.
¹ HNMR (400 MHz, DMSO) δ: 1.23 (6H, s), 3.34 (2H, s), 7.17 (1H, td, J = 7.7, 1.3 Hz), 7.25 ( 1H, td, J = 7.7, 1.1 Hz), 7.56-7.49 (2H, m), 8.05 (2H, d, J = 8.3 Hz), 8.14 (1H, d , J = 8.8 Hz), 8.20 (2H, d, J = 8.8 Hz), 8.43 (1H, dd, J = 8.8, 2.7 Hz), 8.95 (1H, d, J = 2.7Hz)
ESI-MS (m / e): 416.3 [M + H] +
Example 13
2-({4- [5- (1,3-Benzoxazol-2-ylamino) -2-pyridinyl] phenyl} carbonyl) cyclopentanecarboxylic acid

２，２−ジメチル−４−オキソ−４−［４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル］ブタン酸メチルの代わりに実施例１０の１）で得られた（１，２−ｔｒａｎｓ）−２−[４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾイル]シクロペンタンカルボン酸メチルを用い、実施例１２の２）と同様の操作を行い表題化合物を淡黄色固体として得た。
^１ＨＮＭＲ（４００ＭＨｚ、ＤＭＳＯ） δ：１．５５−１．８６（４Ｈ，ｍ），１．９４−２．０３（１Ｈ，ｍ），２．１１−２．１９（１Ｈ，ｍ），３．１９（１Ｈ，ｑ，Ｊ＝８．０Ｈｚ），４．１１（１Ｈ，ｄｄ，Ｊ＝１６．７，７．７Ｈｚ），７．１７（１Ｈ，ｔｄ，Ｊ＝７．７，１．２Ｈｚ），７．２６（１Ｈ，ｔｄ，Ｊ＝７．６，１．１Ｈｚ），７．５０−７．５６（２Ｈ，ｍ），８．１６−８．０８（３Ｈ，ｍ），８．２１（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．４３（１Ｈ，ｄｄ，Ｊ＝８．７，２．８Ｈｚ），８．９６（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）
ＥＳＩ−ＭＳ（ｍ／ｅ）：ｍ／ｚ ４２８．３［Ｍ＋Ｈ］＋
実施例１４
４−（４−［５−（１−イソプロピル−１Ｈ−ベンゾイミダゾール−２−イルアミノ）−２−ピリジニル］−フェニル）−２，２−ジメチル−４−オキソブタン酸

Example 10 instead of methyl 2,2-dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (1,2-trans) -2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] cyclopentanecarboxylic acid obtained in 1) The same operation as in Example 12, 2) was performed using methyl to obtain the title compound as a pale yellow solid.
¹ HNMR (400 MHz, DMSO) δ: 1.55-1.86 (4H, m), 1.94-2.03 (1H, m), 2.11-2.19 (1H, m), 3. 19 (1H, q, J = 8.0 Hz), 4.11 (1H, dd, J = 16.7, 7.7 Hz), 7.17 (1H, td, J = 7.7, 1.2 Hz) 7.26 (1H, td, J = 7.6, 1.1 Hz), 7.50-7.56 (2H, m), 8.16-8.08 (3H, m), 8.21 ( 2H, d, J = 8.5 Hz), 8.43 (1H, dd, J = 8.7, 2.8 Hz), 8.96 (1H, d, J = 2.4 Hz)
ESI-MS (m / e): m / z 428.3 [M + H] +
Example 14
4- (4- [5- (1-Isopropyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid

１）２−クロロ−１−イソプロピル−１Ｈ−ベンゾイミダゾールの合成

1) Synthesis of 2-chloro-1-isopropyl-1H-benzimidazole

To a solution of 500 mg of 2-chloro-1H-benzimidazole in 10 ml of dimethylformamide were added 0.66 ml of 2-iodopropane, sodium hydride and 264 mg of an oil (60%) successively, and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 98/2 to 3/1) to obtain 527 mg of the title compound as a white solid.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 1.66 (6H, d, J = 6.8 Hz), 4.89-4.97 (1H, m), 7.23-7.28 (2H, m) 7.47-7.52 (1H, m), 7.72-7.67 (1H, m)
ESI-MS (m / e): 195.1 [M + H] +
2) Synthesis of N- (6-bromopyridin-3-yl) -1-isopropyl-1H-benzimidazol-2-amine

Using the compound of 1) above in place of 2-chloro-1,3-benzoxazole, the same operation as in 1) of Example 12 was performed to obtain the title compound as a light brown solid.
¹ HNMR (400 MHz, DMSO) δ: 1.57 (6H, d, J = 6.8 Hz), 4.86-4.95 (1H, m), 7.01-7.09 (2H, m), 7.41 (1H, dd, J = 7.6, 1.2 Hz), 7.52-7.59 (2H, m), 8.34 (1H, dd, J = 8.8, 2.9 Hz) , 8.74 (1H, d, J = 2.9 Hz), 9.21 (1H, s)
ESI-MS (m / e): 333.0 [M + H] +
3) Synthesis of 4- (4- [5- (1-Isopropyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid N- (6- Using the compound of 2) above in place of bromopyridin-3-yl) -1,3-benzoxazol-2-amine, the same operation as in 2) of Example 12 was performed to obtain the title compound as a light brown solid. It was.
¹ HNMR (400 MHz, DMSO) δ: 1.22 (6H, s), 1.59 (6H, d, J = 6.8 Hz), 3.34 (2H, s), 4.93-4.99 ( 1H, m), 7.02-7.10 (2H, m), 7.43 (1H, d, J = 6.8 Hz), 7.56 (1H, d, J = 7.3 Hz), 8. 9-8.01 (3H, m), 8.19 (2H, d, J = 8.3 Hz), 8.50 (1H, dd, J = 9.0, 2.7 Hz), 9.02 (1H , D, J = 2.4 Hz), 9.30 (1H, s), 11.99 (1H, s)
ESI-MS (m / e): 457.3 [M + H] +
Example 15
4- (4- [5- (1-Ethyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 2-chloro-1-ethyl-1H-benzimidazole

The title compound was obtained as a white solid in the same manner as in Example 14, 1) except that ethane iodide was used in place of 2-iodopropane.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 1.44 (3H, t, J = 7.3 Hz), 4.26 (2H, q, J = 7.2 Hz), 7.25-7.34 (3H, m), 7.68-7.72 (1H, m)
ESI-MS (m / e): 181.1 [M + H] +
2) Synthesis of N- (6-bromopyridin-3-yl) -1-ethyl-1H-benzimidazol-2-amine

Using the compound of 1) above instead of 2-chloro-1,3-benzoxazole, the same operation as in 1) of Example 12 was performed to obtain the title compound as a crude product.
3) Synthesis of 4- (4- [5- (1-ethyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid N- (6- Using the compound of 2) above in place of bromopyridin-3-yl) -1,3-benzoxazol-2-amine, the same operation as in 2) of Example 12 was performed to obtain the title compound as a light brown solid. It was.
¹ HNMR (400 MHz, DMSO) δ: 1.23 (6H, s), 1.31 (3H, t, J = 7.1 Hz), 3.35 (2H, s), 4.31 (2H, d, J = 7.1 Hz), 7.09 (2H, dd, J = 5.6, 3.4 Hz), 7.35-7.46 (2H, m), 8.11-8.02 (3H, m ), 8.20 (2H, d, J = 8.5 Hz), 8.61 (1H, d, J = 6.3 Hz), 9.09 (1H, d, J = 2.2 Hz), 9.36 (1H, s), 11.93 (1H, s)
ESI-MS (m / e): 443.0 [M + H] +
Example 16
4- (4- [5- (1-Methyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 2-chloro-1-methyl-1H-benzimidazole

The title compound was obtained as a white solid by performing the same operation as 1) in Example 14 using iodomethane instead of 2-iodopropane.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 3.79 (3H, s), 7.26-7.33 (3H, m), 7.67-7.71 (1H, m)
ESI-MS (m / e): 167.0 [M + H] +
2) Synthesis of N- (6-bromopyridin-3-yl) -1-methyl-1H-benzimidazol-2-amine

Using the compound of 1) above in place of 2-chloro-1,3-benzoxazole, the same operation as in 1) of Example 12 was performed to obtain the title compound as a light brown solid.
¹ HNMR (400 MHz, DMSO) δ: 3.72 (3H, s), 7.11-7.06 (2H, m), 7.43-7.31 (2H, m), 7.59 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 7.8 Hz), 8.80 (1H, s), 9.36 (1H, s)
ESI-MS (m / e): 305.0 [M + H] +
3) Synthesis of 4- (4- [5- (1-Methyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid N- (6- Using the compound of 2) above in place of bromopyridin-3-yl) -1,3-benzoxazol-2-amine, the same operation as in 2) of Example 12 was performed to obtain the title compound as a light brown solid. It was.
¹ HNMR (400 MHz, DMSO) δ: 1.23 (6H, s), 3.34 (2H, s), 3.76 (3H, s), 7.06-7.12 (2H, m), 7 .35 (1H, dd, J = 5.9, 2.9 Hz), 7.43 (1H, dd, J = 5.9, 2.9 Hz), 8.11-8.02 (3H, m), 8.19 (2H, d, J = 8.8 Hz), 8.60 (1H, dd, J = 9.0, 2.7 Hz), 9.08 (1H, d, J = 2.4 Hz), 9 .44 (1H, s)
ESI-MS (m / e): 429.3 [M + H] +
Example 17
N-[(4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -carbonyl] -L-proline

1) Synthesis of {4- [5- (1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -ethyl benzoate

N- (6-Bromopyridin-3-yl) -1,3-benzothiazol-2-amine (30 mg, 0.10 mmol), 4-ethoxycarbonylphenylboric acid (25 mg, 0.2 mg) obtained in Example 10 13 mmol) was added DMA (2 ml) and water (0.5 ml) under a nitrogen atmosphere. Potassium carbonate (41 mg, 0.3 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (8 mg, 0.01 mmol) were added thereto, and deaeration was performed. The reaction solution was stirred at 100 ° C. overnight, then the reaction solution was cooled to room temperature, water was added thereto, and the mixture was filtered through celite. The filtrate was extracted with chloroform, and the extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer silica gel chromatography to obtain the title compound (13 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43 (3H, t, J = 6.0 Hz), 4.39 (2H, d, J = 6.0 Hz), 7.19-7.29 ( 1H, m), 7.36-7.44 (1H, m), 7.66-7.75 (2H, m), 7.85 (1H, d, J = 8.0 Hz), 8.07 ( 2H, d, J = 8.0 Hz), 8.15 (2H, d, J = 8.0 Hz), 8.39-8.40 (1H, m), 8.80 (1H, s)
2) Synthesis of methyl (S) -1- {4- [5- (1,3-benzothiazol-2-ylamino) -2-pyridinyl] -benzoyl} -pyrrolidine-2-carboxylate

{4- [5- (1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -ethyl benzoate (13 mg, 0.034 mmol) obtained above was added to MeOH-water (2 mL, 1: 1). ) 1M NaOH aqueous solution (204 μL) was added to the mixed solvent, and the mixture was stirred at 60 ° C. for 8 hours. The reaction solution was cooled to room temperature, 1M hydrochloric acid (300 μL) was added thereto, and the solvent was removed under reduced pressure. DMF (2 mL) was added to the obtained residue, and L-proline methyl ester (8.4 mg, 0.05 mmol), triethylamine (14 μL, 0.1 mmol), HOBt (8 mg, 0.050 mmol), WSC ( 10 mg, 0.05 mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was poured into sodium bicarbonate water and extracted with chloroform. The extract was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography to obtain the title compound (16 mg).
¹ H-NMR (400 MHz, CDCl ₃ ), δ 1.87-2.40 (4H, m), 3.54-3.88 (2H, m), 3.81 (3H, s), 4.70- 4.73 (1H, m), 7.19-7.29 (1H, m), 7.36-7.44 (1H, m), 7.70-7.78 (5H, m), 7. 95-8.01 (2H, m), 8.30-8.40 (1H, m), 8.80 (1H, s).
3) Synthesis of N-[(4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -carbonyl] -L-proline obtained above. Of (S) -1- {4- [5- (1,3-benzothiazol-2-ylamino) -2-pyridinyl] -benzoyl} -pyrrolidine-2-carboxylate (16 mg, 0.034 mmol) 1M NaOH aqueous solution (111 μL) was added to THF (1 mL) and water (1 mL), and the mixture was stirred at 60 ° C. overnight. The reaction mixture was cooled to room temperature, 1M hydrochloric acid (170 μL) was added thereto, and the solvent was concentrated under reduced pressure. The obtained residue was diluted with water and extracted with a chloroform-methanol (10: 1) mixed solvent. The extract was dried over sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure to give the title compound (15 mg).
¹ H-NMR (400 MHz, DMSO-d6), δ 1.78-2.34 (4H, m), 3.50-3.65 (2H, m), 4.40-4.45 (1H, m) 7.19-7.29 (1H, m), 7.36-7.38 (1H, m), 7.47-7.66 (3H, m), 7.85 (1H, d, J = 4.0 Hz), 8.06-8.15 (3H, m), 8.48-8.51 (1H, m), 8.98 (1H, s), 10.91 (1H, s).
ESI-MS Found m / z: 445.1 [M + H] +
Example 18
4- (4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of methyl 4- (4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoate

Example 10 Step 2 synthesized in Example 1 Step 3 to N- (6-Bromopyridin-3-yl) -1,3-benzothiazol-2-amine (46.3 mg, 0.151 mmol) synthesized in Step 2 , 2-dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (50.0 mg, 0. 144 mmol), potassium carbonate (59.7 mg, 0.432 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (35.3 mg, 0.0432 mmol) were added to this mixture and DMA (1.20 ml) and purified water ( 0.300 ml) was poured, the temperature was raised to 85 ° C., and the mixture was stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (chloroform / methanol = 39/1) to give 4- (4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl } -Phenyl) -2,2-dimethyl-4-oxobutanoate (41.8 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (6H, s), 3.32 (2H, s), 3.71 (3H, s), 7.21 (1H, t, J = 7 .80 Hz), 7.38 (1H, t, J = 7.80 Hz), 7.65 (1H, d, J = 7.80 Hz), 7.69 (1H, d, J = 7.80 Hz), 7 .77 (1H, d, J = 8.78 Hz), 7.98 (2H, d, J = 8.54 Hz), 8.03 (2H, d, J = 8.54 Hz), 8.36 (1H, dd, J = 8.78, 2.45 Hz), 8.79 (1H, d, J = 2.45 Hz)
2) Synthesis of 4- (4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid 4- (4- {5-[(1,3-Benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoate (41. 8 mg, 0.0938 mmol) was dissolved in dioxane (0.800 ml), THF (0.800 ml) and purified water (0.800 ml), and 1N aqueous sodium hydroxide solution (0.469 ml, 0.469 mmol) was added to the reaction solution. ) Was added and the temperature was raised to 50 ° C., followed by stirring overnight. 1N Hydrochloric acid (0.469 ml, 0.469 mmol) was added, and the resulting solid was collected by filtration, washed with water and methanol, and dried under reduced pressure to give the title compound (28.9 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.23 (6H, s), 3.33 (2H, s), 7.20 (1H, t, J = 7.81 Hz), 7.37 (1H, t, J = 7.81 Hz), 7.67 (1H, d, J = 7.81 Hz), 7.85 (1H, d, J = 7.81 Hz), 8.04 (2H, d, J = 8.54 Hz), 8.12 (1H, d, J = 8.78 Hz), 8.20 (2H, d, J = 8.54 Hz), 8.51 (1H, dd, J = 8.78) , 2.44 Hz), 8.99 (1H, d, J = 2.44 Hz), 10.98 (1H, brs)
ESI-MS (m / e): 432.0 [M + H] +
Example 19
4- (5- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -2-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 4- (5-bromopyridin-2-yl) -2,2-dimethyl-4-oxobutanoic acid methyl ester

Under a nitrogen atmosphere, 284 mg of 5-bromo-2-iodopyridine was dissolved in 2 ml of tetrahydrofuran, and 1.1 ml of an isopropyl magnesium chloride 2.0 M tetrahydrofuran solution was added dropwise at -5 ° C. After stirring for 30 minutes, a solution of 2,2-dimethylsuccinic anhydride 128 mg in tetrahydrofuran 1 ml was added dropwise. After stirring at 0 ° C. for 20 minutes, a saturated aqueous ammonium chloride solution was added to stop the reaction, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, insoluble matters were filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by thin layer silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 40.1 mg of the corresponding carboxylic acid as a crude product. After the obtained carboxylic acid was dissolved in 4.0 ml of diethyl ether, 0.5 ml of a 2.0M TMS diazomethane hexane solution was added and stirred for 20 minutes. The solvent was removed under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, insoluble matters were filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 10.2 mg of the title compound.
¹ H-NMR (400 MHz, CDCL3) δ: 1.44 (6H, s), 3.26 (2H, s), 3.54 (3H, s), 7.90-7.95 (2H, m) , 8.62 (1H, s)
ESI-MS (m / e): 300.0, 302.0 [M + H] +
2) Synthesis of 4- (6- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -3-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid 1) Of the resulting 4- (5-bromopyridin-2-yl) -2,2-dimethyl-4-oxobutanoic acid methyl ester 10.0 mg, N- [4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) phenyl] -1,3-benzothiazol-2-amine 14.1 mg, potassium carbonate 11.0 mg, PdCl 2 (dppf) methylene chloride complex 5.0 mg dimethylformamide The 0 ml suspension was stirred at 90 ° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The organic layer was washed with water, dried over anhydrous sodium sulfate, insolubles were filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 8.2 mg of the corresponding methyl ester as a crude product. The obtained methyl ester was dissolved in 0.5 ml of 1,4-dioxane, 0.5N-aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. overnight. The mixture was acidified with 2N-hydrochloric acid, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by thin layer silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 2.39 mg of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.24 (6H, s), 3.48 (2H, brs), 7.12-7.15 (2H, m), 7.32-7 .69 (6H, m), 7.94 (1H, d, J = 8.0 Hz), 8.14 (1H, brs), 8.76 (1H, s)
ESI-MS (m / e): 432.2 [M + H] +
Example 20
4- (6- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -3-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of 4- (6-chloropyridin-2-yl) -2,2-dimethyl-4-oxobutanoic acid methyl ester

Under a nitrogen atmosphere, 431 mg of 2-chloro-5-iodopyridine was dissolved in 3 ml of tetrahydrofuran, and 0.66 ml of a 2.71 M hexane solution of n-butyllithium was added dropwise at −78 ° C. After stirring for 5 minutes, a solution of 2,2-dimethylsuccinic anhydride (256 mg) in tetrahydrofuran (2 ml) was added dropwise. The temperature of the reaction solution was raised to 0 ° C., saturated aqueous ammonium chloride solution was added to stop the reaction, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, insoluble matters were filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by thin layer silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 71.0 mg of the corresponding carboxylic acid as a crude product. After the obtained carboxylic acid was dissolved in 4.0 ml of diethyl ether, 0.5 ml of a 2.0M TMS diazomethane hexane solution was added and stirred for 10 minutes. The solvent was removed under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, insoluble matters were filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 33.4 mg of the title compound.
¹ H-NMR (400 MHz, CDCL3) δ: 1.21 (6H, s), 2.80 (2H, s), 3.63 (3H, s), 7.38 (1H, dd, J = 1. 0, 8.3 Hz), 7.94 (1H, dd, J = 2.9, 8.3 Hz), 8.66 (1H, d, J = 1.0 Hz)
2) Synthesis of 4- (6- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -3-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid 1) The obtained 4- (5-bromopyridin-2-yl) -2,2-dimethyl-4-oxobutanoic acid methyl ester was treated in the same manner as in Example 19 to obtain 2.91 mg of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.23 (6H, s), 2.80 (2H, brs), 7.16-7.20 (1H, m), 7.33-7 .37 (1H, m), 7.65 (1H, d, J = 8.0 Hz), 7.84 (1H, d, J = 8.0 Hz), 7.90-8.15 (4H, m) , 8.16 (2H, d, J = 8.0 Hz), 8.95 (1H, brs), 10.73 (1H, brs)
ESI-MS (m / e): 432.1 [M + H] +
Example 21
4- [4- [5- (Thiazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl] -2,2-dimethyl-4-oxobutanoic acid

1) Synthesis of methyl [4- [5- (thiazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl] -2,2-dimethyl-4-oxobutanoate

Synthesis of N- (6-bromopyridin-3-yl) thiazolo [4,5-b] pyridin-2-amine (100 mg, 0.325 mmol) synthesized in Example 11 2) in Example 1 3) 2,2-dimethyl-4-oxo-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] butanoate (124 mg, 0. 358 mmol), potassium carbonate (135 mg, 0.975 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (79.6 mg, 0.0975 mmol) were added to this mixture and DMA (2.40 ml) and purified water (0. 600 ml) was poured, and the mixture was heated to 85 ° C. and stirred overnight. The reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (chloroform / methanol = 9/1) to give 4- [4- [5- (thiazolo [4,5-b] pyridin-2-yl) -pyridine-2. -Iyl] phenyl] -2,2-dimethyl-4-oxobutanoic acid methyl ester (38.7 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (6H, s), 3.27 (2H, s), 3.68 (3H, s), 7.05 (1H, dd, J = 8 .29, 4.15 Hz), 7.54 (1H, d, J = 8.54 Hz), 7.83 (1H, d, J = 8.29 Hz), 7.84 (2H, d, J = 8. 54 Hz), 7.88 (2H, d, J = 8.54 Hz), 8.49 (1H, d, J = 4.15 Hz), 8.64 (1H, dd, J = 8.54, 2.20 Hz) ), 8.87 (1H, d, J = 2.20 Hz)
2) Synthesis of 4- [4- [5- (thiazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl] -2,2-dimethyl-4-oxobutanoic acid > Methyl 4- [4- [5- (thiazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl] -2,2-dimethyl-4-oxobutanoate obtained above ( 38.7 mg, 0.0867 mmol) was dissolved in dioxane (0.600 ml), THF (0.600 ml) and purified water (0.600 ml), and 1N aqueous sodium hydroxide solution (0.433 ml, 0 .433 mmol) was added, the temperature was raised to 50 ° C., and the mixture was stirred for 2 hours. 1N Hydrochloric acid (0.433 ml, 0.433 mmol) was added, followed by extraction with a mixed solvent of chloroform / methanol (4/1), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by thin layer chromatography (chloroform / methanol = 9/1) to give the title compound (34.8 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.23 (6H, s), 3.34 (2H, s), 7.18 (1H, dd, J = 7.80, 4.63 Hz) , 8.05 (2H, d, J = 8.54 Hz), 8.16 (1H, d, J = 8.78 Hz), 8.21 (2H, d, J = 8.54 Hz), 8.28 ( 1H, dd, J = 7.80, 1.46 Hz), 8.41 (1H, dd, J = 4.63, 1.46 Hz), 8.56 (1H, dd, J = 8.78, 2. 44 Hz), 8.95 (1H, d, J = 2.44 Hz)
ESI-MS (m / e): 433.2.0 [M + H] +
Example 22
{Trans-4- [4 '-(1,3-benzothiazol-2-ylamino) biphenyl-4-yl] cyclohexyl} acetic acid

1) Synthesis of [4- (methoxymethylene) cyclohexyl] benzene

To a 60 ml tetrahydrofuran solution of 12.2 g of (methoxymethyl) triphenylphosphonium chloride, 40 ml of a tetrahydrofuran solution of 0.99 N hexamethyldisilazane sodium and a tetrahydrofuran 20 ml solution of 3.11 g of 4-phenylcyclohexanone were sequentially added under ice cooling. Stir at room temperature overnight. To this reaction mixture was added 10 ml of water and 1 ml of hydrogen peroxide, and the mixture was stirred for 30 minutes. Water was added, the organic layer was distilled under reduced pressure, extracted with chloroform, the chloroform layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform / methanol = 1/0 to 99/1) and (hexane / ethyl acetate = 98/2 to 80/20) to give 3.24 g of the title compound as a colorless liquid. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.39-1.52 (2H, m), 1.74-1.84 (1H, m), 1.89-1.98 (2H, m) , 2.01-2.11 (1H, m), 2.14-2.21 (1H, m), 2.58-2.67 (1H, m), 2.86-2.95 (1H, m), 3.57 (3H, s), 5.82 (1H, t, J = 1.7 Hz), 7.15-7.23 (3H, m), 7.26-7.32 (2H, m)
2) Synthesis of trans-4-phenylcyclohexanecarbaldehyde

1) 2N hydrochloric acid was added to a solution of the compound 1.74 g in tetrahydrofuran 40 ml, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 99/1 to 90/10) to obtain 1.03 g of the title compound and 0.39 g of a cis isomer as a stereoisomer.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.38-1.58 (4H, m), 2.00-2.08 (2H, m), 2.09-2.17 (2H, m) 2.27-2.35 (1H, m), 2.45-2.55 (1H, m), 7.23-7.17 (3H, m), 7.33-7.28 (2H, m), 9.68 (1H, d, J = 1.5 Hz)
3) Synthesis of [trans-4- (2-methoxyvinyl) cyclohexyl] benzene

Using the compound obtained in 2) above in place of 4-phenylcyclohexanone, the title compound was obtained as a colorless liquid in the same manner as in Example 22 1).
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.33 (2H, m), 1.43-1.55 (2H, m), 1.79-2.01 (5H, m), 2 .41-2.52 (1H, m), 3.51 (2.25H, s), 3.60 (0.75H, s), 4.25 (0.25H, dd, J = 8.8, 6.3 Hz), 4.72 (0.75 H, dd, J = 12.7, 7.8 Hz), 5.83 (0.25 H, d, J = 6.3 Hz), 6.33 (0.75 H) , D, J = 12.7 Hz), 7.15-7.23 (3H, m), 7.26-7.32 (2H, m)
4) Synthesis of (trans-4-phenylcyclohexyl) acetic acid

Using 758 mg of the compound obtained in 3) above instead of [4- (methoxymethylene) cyclohexyl] benzene, the same operation as in 2) of Example 22 was performed to obtain the corresponding aldehyde as a crude product.
The obtained aldehyde was dissolved in 30 ml of t-butyl alcohol, and 10 ml of water, 1.32 ml of 2-methyl-2-butene, 420 mg of sodium dihydrogen phosphate and 1.11 g of sodium chlorite were sequentially added for 1 hour at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with 2N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane / chloroform / ethyl acetate = 45/45/10 to 0/0/100) to give 712 mg of the title compound as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 1.13-1.25 (2H, m), 1.47-1.59 (2H, m), 1.82-1.98 (5H, m), 2 .31 (2H, d, J = 6.8 Hz), 2.48 (1H, tt, J = 12.2, 3.3 Hz), 7.16-7.22 (3H, m), 7.32- 7.27 (2H, m)
5) Synthesis of methyl [trans-4- (4-iodophenyl) cyclohexyl] acetate

4) Periodic acid dihydrate (262 mg), iodine (582 mg), water (2.5 ml) and 9 N sulfuric acid (0.3 ml) were sequentially added to a solution of compound (1.25 g) in acetic acid (10 ml), and the mixture was stirred overnight at 75 ° C. The reaction solution was returned to room temperature, water was added, and the resulting precipitate was collected by filtration, dissolved in chloroform, and washed with water and saturated brine. This solution was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a corresponding iodine product as a crude product.
The obtained iodine body was dissolved in a 10% hydrochloric acid-methanol solution and stirred at 60 ° C. for 3 hours. After returning the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, followed by washing with aqueous sodium bicarbonate and saturated brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by (hexane / ethyl acetate = 98/2 to 80/20) to obtain 1.93 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 1.07-1.22 (2H, m), 1.39-1.51 (2H, m), 1.79-1.94 (5H, m), 2 .25 (2H, d, J = 6.8 Hz), 2.37-2.46 (1H, m), 3.68 (3H, s), 6.95 (2H, d, J = 8.3 Hz) , 7.60 (2H, d, J = 8.3 Hz)
6) Synthesis of [trans-4- (4′-aminobiphenyl-4-yl) cyclohexyl] methyl acetate

5) To a solution of 1.93 g of compound in 25 ml of 1,4-dioxane, 1.54 g of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, PdCl ₂ ( dppf) · CH ₂ Cl _{2 (} 1.76 g) and 2N aqueous sodium carbonate solution (6.5 ml) were sequentially added, and the mixture was stirred at 80 ° C for 10 hours. After returning this reaction liquid to room temperature, it is separated and purified directly by silica gel column chromatography (chloroform / methanol = 99.8 / 0.2 to 98/2) and (hexane / ethyl acetate = 95/5 to 50/50). This gave 0.44 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 1.09-1.25 (2H, m), 1.45-1.61 (2H, m), 1.79-1.99 (5H, m), 2 .26 (2H, d, J = 6.8 Hz), 2.43-2.54 (1H, m), 3.69 (3H, s), 6.75 (2H, d, J = 8.8 Hz) , 7.23 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.3 Hz)
ESI-MS (m / e): 323.2 [M + H] +
7) Synthesis of {trans-4- [4 ′-(1,3-benzothiazol-2-ylamino) biphenyl-4-yl] cyclohexyl} acetic acid 4- [4- (5-aminopyridin-2-yl) phenyl ] -2,2-dimethyl-4-oxobutanoic acid methyl and 2-chloro [1,3] oxazolo [4,5-b] pyridine, and the compound obtained in 6) above and 2-chloro-1,3 Using benzothiazole, the same operation as in Example 8 3) was performed to obtain the title compound as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.9-1.18 (2H, m), 1.43-1.56 (2H, m), 1.69-1.89 (5H, m) , 2.13 (2H, d, J = 6.1 Hz), 2.51-2.53 (1H, m), 7.14-7.19 (1H, m), 7.28-7.36 ( 3H, m), 7.57 (2H, d, J = 8.5 Hz), 7.61-7.67 (3H, m), 7.88-7.80 (3H, m), 10.58 ( 1H, s)
ESI-MS (m / e): 442.2 [M + H] +

The usefulness of the compound represented by the formula (I) as a pharmaceutical is proved, for example, in the following test examples.
<Cloning of human DGAT1 gene and expression in yeast>
The human DGAT1 gene was amplified from a human cDNA library (Clontech) by the PCR method using the following primers.
DGAT1F: 5′-ATGGGCGACCGCGGCAGCTC-3 ′
DGAT1R: 5′-CAGGCCTCTCGCCGCTGGGGCCTC-3 ′
The amplified human DGAT1 gene was introduced into a yeast expression vector, pPICZA (Invitrogen). The obtained expression plasmid was introduced into yeast (Pichia pastris) by electroporation to prepare a recombinant yeast. The recombinant yeast is cultured for 72 hours in the presence of 0.5% methanol, and the cells are disrupted with glass beads in 10 mM Tris pH 7.5, 250 mM sucrose, 1 mM EDTA, and then the membrane fraction is obtained by centrifugation. Prepared and used as enzyme source.
<DGAT1 inhibitory activity test>
0.25 μg of yeast membrane fraction expressing test substance DGAT1 was added to a reaction solution (100 mM Tris pH 7.5, 100 mM MgCl ₂ , 100 mM Sucrose, 40 μM Dioelin, 15 μM [ ¹⁴ C] -oleoyl-CoA) having the following composition: Incubated in a volume of 100 μl for 30 minutes at room temperature. To the reaction solution, 100 μl of 2-propanol / heptan / H ₂ O (80/20/2) was added and stirred well, and then 200 μl of heptan was added and further stirred. After centrifugation, the heptane layer was taken, ethanol / 0.1N NaOH / H ₂ O (50: 5: 45) was added and stirred, and then centrifuged again to recover the heptane layer. After the resulting heptan layer was dried, 100 μl of Microscint 0 (PerkinElmer) was added, and the radioactivity was measured with a liquid scintillation counter. Inhibitory activity was calculated by the following formula. The radioactivity without addition of membrane fraction was used as the background.
Inhibition rate = 100− (radioactivity with addition of test compound−background) / (radioactivity without addition of test compound−background) × 100
The DGAT1 inhibitory activity of the compound according to the present invention is shown below by the method described above.

  The compound according to the present invention or a pharmaceutically acceptable salt thereof has a potent DGAT1 inhibitory action and is useful for the treatment and / or prevention of hyperlipidemia, diabetes and obesity.

Claims (15)

Formula (I)

[Where:
Ring A is a divalent group formed by removing two hydrogen atoms from a benzene ring or a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring constituent atoms in the ring, or
Formula (T-1)

Formula (T-2)

And the formula (T-3)

A divalent group selected from the group consisting of:
Ring B is a divalent group formed by removing two hydrogen atoms from a benzene ring or a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring-constituting atoms in the ring,
R ¹ is a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, or a lower alkoxy group,
R ² is a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, or a lower alkoxy group,
Ring C is a group formed by removing two hydrogen atoms from a benzene ring or a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms as ring-constituting atoms in the ring,
R ³ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, or a lower alkoxy group,
Y is an oxygen atom, a sulfur atom or NR;
R is a hydrogen atom or a lower alkyl group,
D represents the formula (II-1)

Formula (II-2)

Formula (II-3)

And formula (II-4)

A group selected from
Here, A ₁ represents the formula (III-1)

(Wherein R ⁴ is a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group,
R ⁵ is a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group,
R ⁶ is a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group, or together with a carbon atom to which R ⁵ and R ⁶ are bonded. A 3- to 5-membered aliphatic ring to form,
Or R ⁵ and R ⁶ together form (IV)

(Wherein G is CH ₂ , C (CH ₃ ) ₂ , O, NR ⁷ , S or SO ₂ , R ⁷ is a hydrogen atom or a lower alkyl group),
p is 0 to 2 and q is 0 or 1 (provided that p and q are not 0 at the same time), or
Formula (III-2)

(Where
X is a nitrogen atom or CH,
CH ₂ may be substituted with a lower alkyl group (the lower alkyl group may be substituted with a halogen atom, a lower alkoxy group or a di-lower alkylamino group),
m and n are groups in which m is 0 and n is 1, 2, 3 or 4, or m is 1 and n is 1, 2 or 3. However, however,
When A ₁ is a group represented by the formula (III-1) and q is 1, R ² and R ⁴ are combined to form the formula (V) in the formula (I).

Is the formula (V-1)

(Wherein r is 1 or 2, and other symbols are the same as above),
E is OH or NH ₂ ;
A ₂ represents the formula (III-3)

(Where p ₁ is 1 or 2, and R ⁵ and R ⁶ are the same as above),
Or formula (III-4)

(Wherein each symbol is the same as above),
A ₃ is synonymous with A ₂ ,
g represents an integer of 1 to 3], wherein both ring A and ring B are divalent groups formed by removing two hydrogen atoms from a benzene ring, and D is (II- 1), (II-2) or (II-3), or a pharmaceutically acceptable salt thereof. Ring A is a divalent group formed by removing two hydrogen atoms from a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms in the ring as a ring-constituting atom, or a compound represented by formula (T-1)

[Wherein each symbol is the same as defined above],
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is a divalent group obtained by removing two hydrogen atoms from a benzene ring. Ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or pyrimidine ring, or the formula (T-1)

[Wherein each symbol is the same as defined above],
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is a divalent group obtained by removing two hydrogen atoms from a benzene ring. Ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or pyrimidine ring, or the formula (T-1)

[Wherein each symbol is the same as defined above],
Ring B is a divalent group formed by removing two hydrogen atoms from benzene,
D is the formula (II-11)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each symbol is a group represented by the same formula as above. Ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or pyrimidine ring, or the formula (T-1)

[Wherein each symbol is the same as defined above],
Ring B is a divalent group formed by removing two hydrogen atoms from benzene,
D is the formula (II-11)

[Wherein each symbol is the same as defined above],
A ₁ is the formula (III-1)

[Wherein each symbol is the same as defined above] or a group represented by formula (III-2)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each symbol is a group represented by the same formula as above. Ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or pyrimidine ring, or the formula (T-1)

[Wherein each symbol is the same as defined above],
Formula (V) in Formula (I)

Is the formula (V-1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each symbol is a group represented by the same formula as above. Ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or pyrimidine ring, or the formula (T-1)

[Wherein each symbol is the same as defined above],
Ring B is a divalent group formed by removing two hydrogen atoms from benzene,
D is the formula (II-11)

[Wherein each symbol is the same as defined above],
A ₁ is

as well as

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a group selected from the group consisting of: wherein each symbol is the same as defined above. Ring A is a divalent group formed by removing two hydrogen atoms from a pyridine ring or pyrimidine ring,
Ring B is a divalent group formed by removing two hydrogen atoms from a benzene ring,
A ₁ is

as well as

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a group selected from the group consisting of: wherein each symbol is the same as defined above. Ring A is represented by formula (T-1)

[Wherein each symbol is the same as defined above],
Ring B is a divalent group formed by removing two hydrogen atoms from benzene,
D is the formula (II-11)

[Wherein each symbol is the same as defined above],
A ₁ is

as well as

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a group selected from the group consisting of: wherein each symbol is the same as defined above. Y is an oxygen atom, The compound or its pharmaceutically acceptable salt as described in any one of Claims 1 thru | or 9. Y is a sulfur atom, The compound or its pharmaceutically acceptable salt as described in any one of Claims 1 thru | or 9. The compound represented by formula (I) is:
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrimidin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyridin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [2- (1,3-benzothiazol-2-ylamino) -pyrazin-5-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
2- {5- [4- (1,3-benzothiazol-2-ylamino) phenyl] -1-oxo-isoindoline-2-yl} -2,2-dimethylacetic acid,
4- {4- [5- (1,3-benzothiazol-2-ylamino) -pyrimidin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [6- (1,3-benzothiazol-2-ylamino) -pyridazin-3-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [4- (1,3-benzothiazol-2-ylamino) -pyridin-4-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
4- {4- [5- (oxazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl} -2,2-dimethyl-4-oxobutanoic acid,
2-[(4-{[5- (oxazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid,
2- [4- [5- (1,3-benzothiazol-2-ylamino) -2-pyridinyl] phenyl] carbonyl) cyclopentanecarboxylic acid,
2-[(4-{[5- (thiazolo [4,5-b] pyridin-2-yl) amino] -2-pyridinyl} phenyl) carbonyl] cyclopentanecarboxylic acid,
4- (4- {5-[(1,3-benzoxazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
2-({4- [5- (1,3-benzoxazol-2-ylamino) -2-pyridinyl] phenyl} carbonyl) cyclopentanecarboxylic acid,
4- (4- [5- (1-Isopropyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (4- [5- (1-ethyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (4- [5- (1-Methyl-1H-benzimidazol-2-ylamino) -2-pyridinyl] -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
N-[(4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -carbonyl] -L-proline,
4- (4- {5-[(1,3-benzothiazol-2-yl) amino] -2-pyridinyl} -phenyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (5- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -2-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid,
4- (6- {4-[(1,3-benzothiazol-2-yl) amino] -phenyl} -3-pyridinyl) -2,2-dimethyl-4-oxobutanoic acid, or 4- [4- [ 5. The compound according to claim 1, which is 5- (thiazolo [4,5-b] pyridin-2-yl) -pyridin-2-yl] phenyl] -2,2-dimethyl-4-oxobutanoic acid or a pharmaceutically acceptable salt thereof. Acceptable salt. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. A DGAT1 inhibitor comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for hyperlipidemia, diabetes and obesity comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.