JP2002322054A - Drug discharging pump inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine for prophylaxis and/or therapy of microbisms having removal actions on tolerance from a microoganism acquiring drug tolerance. SOLUTION: This medicine for prophylaxis and/or therapy of the microbisms comprises a compound represented by formula (I) [R<1> and R<2> denote each hydrogen atom, a halogen atom, carboxy group, or the like; J<1> denotes a five- or a six-membered aromatic heterocyclic ring; W<1> denotes CH=CH, CH≡CH, CH2 CH2 , or the like; A<1> denotes phenylene group, pyridinediyl group, furandiyl group, or the like; G<1> denotes oxygen atom, carbonyl group, ethynyl group, or the like; (p) denotes an integer of 0-3; G<2> denotes phenylene group, furandiyl group, tetrahydrofurandiyl group, or the like; G<3> denotes CH2 or a single bond; (m) and (n) denote each an integer of 0 or 1: and Q<1> denotes an acidic group] as an active ingredient and used for combined use with one or more kinds of antimicrobial agents.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a medicament useful for prevention and treatment of microbial infection.

[0002]

2. Description of the Related Art Many antibacterial agents have been developed so far for the prevention and treatment of infectious diseases caused by microorganisms. Drugs such as quinolone, macrolide, tetracycline, rifamycin, chloramphenicol and fosfomycin have been put to practical use. On the other hand, with the increasing use of antibacterial drugs in clinical practice, the emergence of resistant bacteria to these antibacterial drugs has become remarkable, which has become a serious problem in the treatment of infectious diseases.

[0003] Among the infections caused by resistant bacteria, bacterial strains that are particularly problematic in cases of intractable or severe infection include Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). Therapeutically effective antimicrobial agents for these bacterial species are currently limited, and it is uncertain whether current agents will have therapeutic effects in the future. In particular,
At present, there is no drug that can be expected to have a specific effect on drug-resistant Pseudomonas aeruginosa. With the aging of the population or the spread of advanced medical treatments such as organ transplantation and anticancer treatment, infectious diseases that frequently occur in patients with reduced immunity, so-called opportunistic infections, have become extremely serious problems in medical practice. Countermeasures against bacteria are urgently needed.

[0004] On the other hand, in recent years, the existence of a drug efflux pump as a drug efflux mechanism for bacteria has been recognized by analysis and research on the resistance mechanism of resistant bacteria. As early as 1980, a pump that specifically excretes tetracycline-based antibacterial drugs outside the cells was identified by the Levy group, and was noted as a major factor in tetracycline resistance (L. McMurry, Pr.
oc. Natl. Acad. Sci. USA, 77, 3974, 1980). More recent studies have reported the presence of multidrug efflux pumps in Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, staphylococci, pneumococci and gonococci. In particular, four types of multidrug efflux pumps have been reported to date as homologous Pseudomonas aeruginosa drug efflux pumps. (K. Poole et. Al, J. Bacteriol., 175,
7363, 1993; K. Poole et.al, M. Microbiol., 21, 71
3, 1996; T. Kohler et.al, M. Microbiol., 23, 345,
1997; T. Kohler et.al, M. Microbiol., 23, 345, 1
997; T. Mine et. Al, Antimicrob. Agents Chemothe
r., 43, 415, 1999).

The Pseudomonas aeruginosa drug efflux pump discharges a variety of drugs, such as β-lactam, tetracycline, chloramphenicol, and quinolone, out of the cells and contributes to drug resistance of Pseudomonas aeruginosa. ing. To overcome this problem, we need to develop an antibacterial drug with a new skeleton that can avoid resistance caused by the drug efflux pump, which is the cause of resistance, or to prevent the existing antibacterial drug by inhibiting the function of the drug efflux pump. Developing concomitant drugs that make the drug effective is considered an effective means.

[0006] In recent years, rational drug design has been recognized as an important approach in drug discovery. The method can be roughly classified into two categories.
One is a method applied when three-dimensional information such as a target protein is clarified, and a new compound is designed based on the data. In this case, if the crystal structure is solved in a state where the ligand is bound, the design becomes easier. Another method is applied when the coordinates of the target are not clear.
In this case, a method is employed in which modeling is performed based on the structure-activity relationship between a compound exhibiting activity and its peripheral compounds, and their three-dimensional structure, and utilized in a new design.

As a typical method of the latter, for example, a method using the following program can be mentioned:
CATALYST ^TM (Greene et al., J. Chem. Inf. Comp.Sc
i., 1994, 34, 1297-1308), DISCO (Martin YC, et.
al., J. Comp.Aided Mol. Design, 1993, 7, 83-102),
COMFA (Cramer RD, J. Am. Chem. Soc., 1988, 110,
5959-5967). By inputting and analyzing the structure-activity relationship information and structure using these programs, it is possible to obtain three-dimensional coordinates (pharmacophore) indicating conditions necessary for activity expression. Accurate pharmacophore use can greatly improve the accuracy of the design and contribute to efficient and effective drug acquisition. The activity of the compound can also be predicted using the obtained pharmacophore. Recently, such an approach has been actively carried out, for example, WO98 / 0
4913 describes the background and examples of implementation and practical application.

[0008]

DISCLOSURE OF THE INVENTION The present invention relates to a novel therapeutic agent for infectious diseases which improves the therapeutic effect of pathogenic microorganisms, and particularly to a microorganism which has acquired resistance to an antimicrobial agent to inhibit a drug efflux pump. It is an object of the present invention to provide a medicament for detolerating the microorganisms and enhancing the preventive and / or therapeutic effect of the antimicrobial agent.

[0009]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and using a Pseudomonas aeruginosa having acquired resistance, a novel and a novel method using the improvement of the action of overcoming drug resistance as an index. A group of compounds having a resistance overcoming effect was selected from the group of known compounds, their derivatives were produced, and their activities were intensively studied. Furthermore, by using a method for performing conformational analysis of derivatives and relating to the activity, a pharmacophore represented by specific coordinates was successfully constructed, and a compound satisfying the pharmacophore was used as a drug for Pseudomonas aeruginosa It was found to have efflux pump inhibitory activity. The present invention has been completed based on the above findings.

That is, the present invention provides the following general formula (I):

Embedded image[Wherein, R¹And R^TwoAre each independently a hydrogen atom, halogen
Atom, carboxyl group, alkoxycarbonyl group,
An amino group which may have a substituent,
Alkyl group which may be substituted, aryl which may have a substituent
Or a heterocyclic group which may have a substituent
Or R¹And R^TwoAre bonded to each other and they are replaced
J¹Formed with two adjacent ring-constituting atoms of
R 5 represents a 5- to 7-membered saturated or unsaturated ring;^ThreeIs hydrogen field
A hydroxyl group, a hydroxyl group or an alkoxy group;¹Is 5 members or
Represents a 6-membered aromatic heterocycle;¹Is -CH = CH-,
-C≡C-, -CH_TwoCH_Two-, -OCH_Two-, -SCH_Two
-, -OCH_TwoO-, -CH_TwoO-, -CH_Two-, -CO
-, -CH_TwoCH_TwoCH_Two-, -CH_TwoNH-, -NHCH
_Two-, -CH_TwoS-, -CONH-, -CH_TwoSCH _Two−,
-CH = CH-CONH- and -CH_TwoOCH_Two−
Group (the left side of the above group is J¹Ring element
A) or a single bond;¹Has a substituent
May have a phenylene group or a substituent
Pyridinediyl group, optionally substituted flange
Yl group, thiophenediyl optionally having substituent (s)
Group, a benzofurandiyl group which may have a substituent,
Benzo [b] thiophenedii which may have a substituent
Benzoxazoledi, which may have a substituent
Yl group, benzothiazole di which may have a substituent
Yl group, pyrido which may have a substituent [1,2-
a] a pyrimidinediyl group, an optionally substituted
Nazolinediyl group, benzoto which may have a substituent
Liazindiyl group, 2H-c which may have a substituent
Romenediyl group, quinoline optionally having substituent (s)
4-one-diyl group, Azaki optionally having substituent (s)
Norin-4-one-diyl group, which may have a substituent
Quinolinediyl group, thiazi optionally substituted
Azolo [3,2-a] pyrimidinediyl group or substituent
[3,2-a] pyrimidine optionally having
G represents a diyl group;¹Represents an oxygen atom, a carbonyl group,
Nyl group, -CH = N-, -N (R^Four) -CO-,-(C
H_Two) -N (R^Five) -CO-, -N (R⁶)-, -N
(R⁷) -SO_Two-, -SO_Two−N (R⁸)-, -CON
(R⁹)-, -C (= CHR^Ten)-, -C (R^{1 1}) = C
(R¹²)-, -NHCO-C (R¹³) (R¹⁴)-, -C
ONH-C (R^{1 Five}) (R¹⁶)-Or -CH_TwoO (C
H_Two)_q-(Where R^Four, R^Five, R⁶, R⁷, R⁸, And R⁹Is
Each independently having a hydrogen atom, a hydroxyl group, or a substituent
R represents an optionally substituted alkyl group;^TenIs a cyano group, carbo
Xyl group or alkoxyca which may have a substituent
R represents a carbonyl group;¹¹And R¹²Are each independently hydrogen
Atom, halogen atom, alkyl optionally having substituent (s)
Or an aryl group which may have a substituent
Or R¹¹And R¹²Is a ring formed by bonding
R;¹³And R¹⁴Are each independently a hydrogen atom or a
Represents a alkyl group, or R¹³And R¹⁴Are joined to each other
Represents an alkylene group formed by¹⁵And R ¹⁶Is it
Each independently represents a hydrogen atom or an alkyl group, or
R¹⁵And R¹⁶Are bonded to each other to form an alkylene group
And q is an integer of 0 to 5); p is 0 to 3
G;^TwoIs phenyl which may have a substituent
A len group, a frangiyl group which may have a substituent,
A tetrahydrofurandiyl group which may have a substituent,
A pyridinediyl group which may have a substituent,
With a thiazolinediyl group, which may have a substituent
Optionally having an isoxazolinediyl group, having a substituent
1,3-dioxolandiyl group which may have
Optionally having a thiophenediyl group or a substituent
A pyrimidinediyl group, -C (R¹⁷) = C
(R¹⁸)-[C (R¹⁹) = C (R²⁰)]_y-(Where R
¹⁷, R¹⁸, R¹⁹, And R²⁰Is independently a hydrogen atom,
A halogen atom, an alkyl group which may have a substituent,
Or an aryl group which may have a substituent,
Or R¹⁷And R¹⁸And a ring formed by bonding to each other; and
/ Or R¹⁹And R²⁰And a ring formed by bonding to each other,
y represents an integer of 0 to 3), or -C (R^{twenty one})
(R^{twenty two}) -C (R^{twenty three}) (R^{twenty four})-(Where R^{twenty one}, R^{twenty two},
R^{twenty three}, And R^{twenty four}Are each independently a hydrogen atom, phenyl
A group or an alkyl group having 1 to 6 carbon atoms,^{twenty one}And R
^{twenty two}And / or a ring formed by bonding to each other and / or R^{twenty three}And R
^{twenty four}And a ring formed by bonding to each other. Or R^{twenty one}
And R^{twenty three}Represents a ring formed by bonding to each other);
G^ThreeIs -CH_Two-Or a single bond; m and n are each
Independently represents an integer of 0 or 1;¹Indicates an acidic group
A compound represented by the formula:
And a substance selected from the group consisting of their hydrates
Contained as an ingredient and combined with one or more antimicrobial agents
Also used for the prevention and / or treatment of microbial infections
To provide medicines. According to a preferred embodiment
If used in combination with one antimicrobial agent, or
Can be used in combination with two antimicrobial agents
You. Can be used in combination with three or more antimicrobial agents
preferable. The same applies to other inventions described in this specification.
It is like.

From another viewpoint, a compound selected from the group consisting of the compound represented by the general formula (I), a physiologically acceptable salt thereof, and a hydrate thereof is contained as an active ingredient, A medicament for use in combination with one or more antimicrobial agents to detoxify a microorganism that has acquired drug resistance; and a compound represented by the above general formula (I), Containing, as an active ingredient, a substance selected from the group consisting of salts thereof and hydrates thereof, and used in combination with one or more antimicrobial agents to enhance the action of the antimicrobial agent Is provided. In these inventions, a medicament wherein the microorganism is Pseudomonas aeruginosa is a preferred embodiment of the present invention. Further, a compound selected from the group consisting of the compound represented by the above general formula (I), a physiologically acceptable salt thereof, and a hydrate thereof, and one or more antimicrobial agents are used. The present invention provides a pharmaceutical composition for prevention and / or treatment of a microbial infection comprising the same.

From another viewpoint, the present invention relates to a method for preventing and / or treating a microbial infectious disease, which comprises, together with one or more antimicrobial drugs, a compound represented by the above general formula (I), Administering to a mammal, including a human, a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of a pharmaceutically acceptable salt and a hydrate thereof;
A method for detolerating a microorganism that has acquired resistance to an antimicrobial agent, comprising, together with one or more antimicrobial agents, a compound represented by the above general formula (I); A method comprising contacting the microorganism with an effective amount of a substance selected from the group consisting of a salt thereof and a hydrate thereof; a method for inhibiting the acquisition of resistance of the microorganism to an antimicrobial drug, the method comprising: Or an effective amount of a compound selected from the group consisting of the compound represented by the above general formula (I), a physiologically acceptable salt thereof, and a hydrate thereof together with two or more antimicrobial agents. A method for increasing the sensitivity of a microorganism to an antimicrobial agent, the method comprising a step of bringing the compound represented by the above general formula (I) together with one or more antimicrobial agents; Is acceptable And a method comprising contacting the microorganism with an effective amount of a substance selected from the group consisting of hydrates thereof, and a method for enhancing the action of an antimicrobial drug, wherein one or more An effective amount of a compound selected from the group consisting of the compound represented by the above general formula (I), a physiologically acceptable salt thereof, and a hydrate thereof together with an antimicrobial agent is administered to mammals including humans. There is provided a method comprising the step of administering.

A substance selected from the group consisting of the compound represented by the general formula (I), a physiologically acceptable salt thereof, and a hydrate thereof is used in combination with one or more antimicrobial agents. They may be administered simultaneously, separately or sequentially. Also provided is the use of a compound represented by the above general formula (I), a physiologically acceptable salt thereof, or a hydrate thereof for the manufacture of the above medicament.

In addition to the above invention, the present invention provides the following general formula (II):

Embedded image[Wherein, R³¹And R³²Are each independently a hydrogen atom, halo
Gen atom, carboxyl group, alkoxycarbonyl
Group, an amino group which may have a substituent,
Alkyl group which may be substituted,
A reel group or a heterocyclic group which may have a substituent;
Show or R³¹And R³²Are joined to each other
Replaces J¹¹With two adjacent ring-constituting atoms of
Represents a 6-membered ring; J¹¹Is a 5- or 6-membered aromatic hete
Represents a ring; W¹¹Is -CH = CH-, -CH_TwoCH_Two−,
-OCH_Two-, -SCH_Two-, -OCH _TwoO-, -CH_TwoO
-, -CH_Two-, -CO-, -CH_TwoCH_TwoCH_Two-, -C
H_TwoNH-, -NHCH_Two-, -CH_TwoS-, -CONH
-, -CH_TwoSCH_Two-, -CH = CH-CONH-, and
And -CH_TwoOCH_Two-A group selected from the group consisting of
The left side of the group is J¹¹Or a single bond
A;¹¹Is pyridinediyl which may have a substituent
[1,2-a] pyrido which may have a group or a substituent
Limidinediyl group, quinoline optionally having substituent (s)
-4-one-diyl group, aza optionally having substituent (s)
Quinolin-4-one-diyl group, even if it has a substituent
Good quinolinediyl group, thia which may have a substituent
Diazolo [3,2-a] pyrimidinediyl group or substitution
Thiazolo [3,2-a] pyrimidi optionally having a group
G represents a diphenyl group;¹¹Represents an oxygen atom, a carbonyl group,
Tinyl group, -CH = N-, -N (R³³) CO-, -N
(R³⁴) -SO_Two-, -SO_Two−N (R³⁵)-, -CO-
N (R³⁶)-, -C (= CHR³⁷)-Or -C (R³⁸)
= C (R³⁹)-(Where R³³, R³⁴, R ³⁵, R³⁶,
R³⁷, R³⁸, And R³⁹Are each independently a hydrogen atom or
M represents an alkyl group which may have a substituent);
Represents an integer of 0 or 1;¹¹Represents an acidic group.)
The compound represented, a physiologically acceptable salt thereof, or a salt thereof.
Contains one or more of these hydrates as active ingredients
Prevention of microbial infections in combination with antimicrobial agents
Alternatively, a medicament for use in treatment is provided.

Further according to the invention, the following four sites are within the following tolerances:

[Table 2] A compound having a partial structure occupied by a compound having a Pseudomonas aeruginosa drug efflux pump inhibitory activity, a physiologically acceptable salt thereof, and a substance selected from the group consisting of hydrates thereof. There is provided a medicament for use in the prevention and / or treatment of a microbial infection, in combination with one or more antimicrobial agents.

According to a preferred embodiment of the present invention, the compound, a salt thereof, or a hydrate thereof has a Pseudomonas aeruginosa drug efflux pump inhibitory activity (MPC4; Means the lowest concentration of drug required to reduce the minimum inhibitory concentration by a factor of 4) to about 40 μg / mL or less, preferably 10 μg / mL or less,
More preferably, it is 1 μg / mL or less.

From another viewpoint, according to the present invention, one or more of the above compounds, physiologically acceptable salts thereof, and substances selected from the group consisting of hydrates thereof are included. Drug efflux pump inhibitors for use in combination with the antimicrobial agents of the present invention. As the compound having a partial structure occupying the above four sites within the above allowable range and having a drug efflux pump inhibitory action or a salt thereof, the compound of the above general formula (I) or the general formula (II) or Mention may be made of their salts.

[0018]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The terms used in the present specification have the following meanings. Unless otherwise specified, an alkyl group or an alkyl moiety in a substituent containing an alkyl moiety (such as an alkoxy group) may be linear, branched, cyclic, or a combination thereof. Unless otherwise specified, the alkyl group has 1 to 8 carbon atoms, preferably about 1 to 6 carbon atoms, and may be referred to as “lower”. More specifically, as the alkyl group, a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,
Cyclobutyl group, cyclopropylmethyl group, n-pentyl group, isopentyl group, neopentyl group, cyclopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, cyclohexyl group, n-heptyl group, n-
An octyl group and the like can be mentioned. The term “halogen atom” may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

As the aryl group, an aryl group having 5 to 14 carbon atoms, preferably an aryl group having 5 to 10 carbon atoms (for example, a benzene ring and a naphthalene ring) can be exemplified. The aryl ring may be a single ring or a condensed ring. As the heterocyclic group, a heterocyclic residue having 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom and having 3 to 10 total atoms constituting the ring can be used. Examples of the hetero ring constituting the heterocyclic group include, for example, a furan ring, a dihydrofuran ring, a tetrahydrofuran ring, a pyran ring, a dihydropyran ring, a tetrahydropyran ring, a benzofuran ring, an isobenzofuran ring, a chromene ring, a chroman ring, an isochroman ring, Thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring , Pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indolizine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring,
Purine ring, quinolidine ring, quinoline ring, phthalazine ring,
Naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, thiazole ring, benzothiazole ring, thiaziridine ring, isothiazole ring, isothiazolidine ring, dioxane ring, dithiane ring , A morpholine ring, a thiomorpholine ring, a phthalimide ring and the like.

In the present specification, the phrase "may have a substituent" with respect to a certain functional group means that the functional group may have one or more substituents. I do. The number, type, and substitution position of the substituents are not particularly limited, and when two or more types of substituents are present, they may be the same or different. Examples of the substituent include an alkyl group; an alkenyl group (preferably having 2 carbon atoms).
-8, more preferably 2-6 carbon atoms, particularly preferably 2-5 carbon atoms, for example, vinyl group, allyl group, 2-
A butenyl group, a 3-pentenyl group, etc., an alkynyl group (preferably having 2 to 8, more preferably 2 to 6, particularly preferably 2 to 5, for example, a propargyl group,
3-pentynyl group and the like, aryl group (preferably having 6 to 14 carbon atoms, more preferably having 6 to 12 carbon atoms, particularly preferably having 6 to 10 carbon atoms, for example, phenyl group, naphthyl group and the like), aralkyl group (Preferably having 7 to 7 carbon atoms)
15, preferably 7 to 13 carbon atoms, more preferably 7 to 11 carbon atoms, and still more preferably 7 to 9 carbon atoms, for example, benzyl group, α-methylbenzyl group, 2-phenylethyl group, naphthylmethyl group Etc.), an amino group, a substituted amino group (preferably having 0 to 16 carbon atoms, more preferably 0 to 12 carbon atoms, particularly preferably 0 to 8 carbon atoms,
For example, a methylamino group, a dimethylamino group, a diethylamino group, a dibenzylamino group, and the like, an alkoxy group (preferably having 1 to 8 carbon atoms, more preferably 1 to 1 carbon atoms)
6, particularly preferably having 1 to 4 carbon atoms, for example, a methoxy group, an ethoxy group, a butoxy group, etc., an aryloxy group (preferably having 6 to 14 carbon atoms, more preferably having 6 to 12 carbon atoms, particularly preferably It has 6 to 10 carbon atoms, for example, a phenyloxy group, a 2-naphthyloxy group, etc., an acyl group (preferably 1 to 14 carbon atoms, more preferably 1 to 12 carbon atoms, particularly preferably 1 to 10 carbon atoms).
For example, an acetyl group, a benzoyl group, a formyl group, a pivaloyl group, etc.), an alkoxycarbonyl group (preferably having 2 to 9 carbon atoms, more preferably 2 to 7 carbon atoms,
Particularly preferably, it has 2 to 5 carbon atoms, for example, a methoxycarbonyl group, an ethoxycarbonyl group and the like, and an aryloxycarbonyl group (preferably 7 to 15 carbon atoms, more preferably 7 to 13 carbon atoms, particularly preferably carbon number). 7 ~
11, for example, a phenyloxycarbonyl group), an acyloxy group (preferably having 2 to 15 carbon atoms, more preferably having 2 to 13 carbon atoms, particularly preferably having 2 carbon atoms).
To 11, for example, an acetoxy group, a benzoyloxy group and the like, an acylamino group (preferably having 2 to 1 carbon atoms).
5, more preferably 2 to 13 carbon atoms, particularly preferably 2 to 11 carbon atoms, for example, acetylamino group, benzoylamino group and the like, alkoxycarbonylamino group (preferably 2 to 9 carbon atoms, more preferably 2 carbon atoms
7, particularly preferably 2 to 5 carbon atoms, for example, a methoxycarbonylamino group and the like, and an aryloxycarbonylamino group (preferably 7 to 15 carbon atoms, more preferably 7 to 13 carbon atoms, particularly preferably carbon atoms) 7 to 11, for example, a phenyloxycarbonylamino group), a sulfonylamino group (preferably having 1 to 1 carbon atoms).
4, more preferably 1 to 12 carbon atoms, particularly preferably 1 to 10 carbon atoms, for example, methanesulfonylamino group, benzenesulfonylamino group and the like, sulfamoyl group (preferably 0 to 14 carbon atoms, more preferably It has 0 to 12 carbon atoms, particularly preferably 0 to 10 carbon atoms, for example, a sulfamoyl group, a methylsulfamoyl group, a dimethylsulfamoyl group, a phenylsulfamoyl group, etc., and a carbamoyl group (preferably 1 carbon atom). To 14, more preferably 1 to 12, particularly preferably 1 carbon atom
To 10, for example, a carbamoyl group, a methylcarbamoyl group, a diethylcarbamoyl group, a phenylcarbamoyl group and the like, an alkylthio group (preferably having 1 to 1 carbon atoms).
8, more preferably 1 to 6 carbon atoms, particularly preferably 1 to 4 carbon atoms, for example, a methylthio group, an ethylthio group, etc., an arylthio group (preferably 6 to 14 carbon atoms,
More preferably, it has 6 to 12 carbon atoms, particularly preferably 6 to 10 carbon atoms, for example, a phenylthio group and the like, and a sulfonyl group (preferably 1 to 14 carbon atoms, more preferably 1 to 12 carbon atoms, particularly preferably It has 1 to 10 carbon atoms, for example, a mesyl group, a tosyl group and the like, a sulfinyl group (preferably 1 to 14 carbon atoms, more preferably 1 to 12 carbon atoms, particularly preferably 1 to 10 carbon atoms, Methanesulfinyl group, benzenesulfinyl group, etc.), ureido group (preferably having 1 to 14 carbon atoms, more preferably 1 to 12 carbon atoms, particularly preferably 1 to 1 carbon atoms).
0, for example, a ureido group, a methylureide group, a phenylureide group, etc., a phosphoric acid amide group (preferably having 1 to 14 carbon atoms, more preferably 1 to 12 carbon atoms, particularly preferably 1 to 10 carbon atoms). Yes, for example, diethylphosphoramide, phenylphosphoramide, etc.), hydroxy group, mercapto group, halogen atom, cyano group, sulfo group, carboxyl group, nitro group, oxo group, hydroxamic acid group, sulfino group, hydrazino group, And a heterocyclic group. These substituents may further have one or more substituents exemplified above.

The alkyl group represented by R ¹ and R ² is a linear or branched alkyl group having 1 to 8 carbon atoms, preferably a linear or branched alkyl group having 1 to 5 carbon atoms. An alkyl group (eg, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or an n-pentyl group); And a cyclic alkyl group having 8 carbon atoms, preferably a cyclic alkyl group having 3 to 5 carbon atoms (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, etc.). On the ring of the cyclic alkyl group, for example, an alkyl group, a halogen atom or the like may be substituted.

The aryl group represented by R ¹ and R ² is an aryl group having 5 to 14 carbon atoms, preferably an aryl group having 5 to 10 carbon atoms (eg, a benzene ring and a naphthalene ring). . An alkyl group, a hydroxyl group, a halogen atom or the like may be substituted on the ring of the aryl group.

As the heterocyclic group represented by R ¹ and R ² , a heterocyclic group having 3 to 8, preferably 3 to 6, ring atoms can be used. Either may be used. Examples of the substituent bonded to the heterocyclic group include a tert-butoxycarbonyl group and a benzyloxycarbonyl group. The ring formed by the combination of R ¹ and R ² may be any of a saturated, partially saturated, or condensed aromatic ring, and is preferably a 6-membered ring,
One or more substituents may be present on the ring. For example, they combine to form a fused benzene ring, a fused pyridine ring, a fused tetrahydropyridine ring,
Alternatively, they are preferably combined to form a tetramethylene group, a butamonoenylene group, a butadienylene group, an azabutadienylene group, or the like, and a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group,
An alkyl group having 1 to 3 carbon atoms may be substituted.
R ³ is preferably hydrogen or a hydroxyl group.

The 5- or 6-membered aromatic heterocyclic ring represented by J ¹ is an aromatic heterocyclic ring containing at least one heteroatom selected from the group consisting of a sulfur atom, a nitrogen atom and an oxygen atom. The type is not limited, for example,
Formula (III) below:

Embedded image (In the formula, X, Y, and Z each independently represent a sulfur atom, a nitrogen atom, an oxygen atom, or a carbon atom, and at least one of X, Y, and Z represents a sulfur atom, a nitrogen atom, and an oxygen atom. A heteroatom selected from the group consisting of atoms; k
Represents 0 or 1), and is preferably an aromatic heterocyclic ring represented by the formula:

Embedded image The aromatic heterocyclic ring represented by

W ¹ is preferably -CH ₂ O-,-
CH = CH- or an ethynyl group can be used;
^{As 1} is a phenylene group which may have a substituent,
A pyridinediyl group which may have a substituent, a benzofurandyl group which may have a substituent, a benzo [b] thiophendiyl group which may have a substituent, Benzoxazoldiyl group, a benzothiazoldiyl group which may have a substituent, 4-oxo-pyrido [1,2-
a] A pyrimidinediyl group, a quinolin-4-one-diyl group which may have a substituent, or an azaquinolin-4-one-diyl group which may have a substituent are preferable.
The bonding position of these cyclic divalent groups is not particularly limited, and they can be bonded at any two of the ring-constituting carbon atoms. For example, the phenylene group may be any of a p-phenylene group, an m-phenylene group, and an o-phenylene group.

The type, number, and position of the substituents which can be present on the ring of the divalent cyclic group represented by A ¹ are not particularly limited, but may have, for example, a substituent. An alkyl group (for example, having 1 to 8 carbon atoms as described above);
, Preferably an alkyl group having 1 to 5 carbon atoms, and examples of the substituent include a halogen atom, a hydroxyl group, and an alkyloxy group.), And a phenyl which may have a substituent Group, an optionally substituted aralkylene phenyl group, an optionally substituted aralkylene pyridyl group, a hydroxyl group, or an amino group, more preferably a halogen atom, a substituent An alkyl group, a hydroxyl group, an amino group, or the like which may have a group may be used.

G ¹ is -N (R ⁴ ) -CO-, -C
O—N (R ⁹ ) — and —C (R ¹¹ ) ＝ C (R ¹² ) — are preferable. When A ¹ is a phenylene group having a substituent or a pyridinediyl group having a substituent, these groups are particularly preferable. preferable. A ¹ is a benzofurandiyl group which may have a substituent, and benzo [b] which may have a substituent.
Thiophenediyl group, benzoxazolediyl group which may have a substituent, benzothiazoldiyl group which may have a substituent, 4- which may have a substituent
Oxo-pyrido [1,2-a] pyrimidindiyl group, an optionally substituted quinolin-4-one-diyl group, or an optionally substituted azaquinoline-4-
In the case of an on-diyl group, G ¹ is —C (R ¹¹ ) ＝ C
It is preferred that (R ¹² ) — or m is 0.

P represents 0 to 3. When A ¹ is a phenylene group having a substituent or a pyridinediyl group having a substituent, p is preferably 0 or 1. A is a benzofurandiyl group which may have a substituent, a benzo [b] thiophendiyl group which may have a substituent,
Benzoxazoldiyl group which may have a substituent, benzothiazoldiyl group which may have a substituent, 4-oxo-pyrido [1,2-a] pyrimidine which may have a substituent In the case of a diyl group, a quinolin-4-one-diyl group which may have a substituent, or an azaquinolin-4-one-diyl group which may have a substituent, p may be 0. preferable.

A ¹ is a benzofurandiyl group which may have a substituent, a benzo [b] thiophendiyl group which may have a substituent, or a benzoxazolediyl which may have a substituent. Group, benzothiazolinediyl group optionally having substituent (s), 4-oxo-pyrido [1,2-a] pyrimidinediyl group optionally having substituent (s), optionally having substituent (s) A quinolin-4-one-diyl group or an azaquinoline which may have a substituent;
In the case of a 4-one-diyl group, p and n are preferably both 0.

When G ² represents a phenylene group which may have a substituent, preferred substituents on the benzene ring include, for example, —CH ₂ OH, —COR ^c [R ^c is —NH
(R ^d ) or -N (R ^e ) (R ^f ) (R ^d represents a hydrogen atom or an alkyl group, and ^Re and R ^f each independently represent a hydrogen atom or an alkyl group, or both are bonded to each other Represents an alkylene group)] or —CH ₂ COR ^g [R ^g
Is a hydroxyl group, an alkoxy group, -NH (R ^d ), or -N
(R ^e ) (R ^f ) (R ^d , R ^e and R ^f are as defined above)], or an aminoethoxy group, a hydroxyethoxy group, a halogen atom, an alkoxy group, an acyloxy group,
Examples include a hydroxyl group, an alkyl group, a nitro group, a trifluoromethyl group, and a cyano group.

G ² is -C (R ²¹ ) (R ²² ) -C (R ²³ )
When (R ²⁴ ) — represents a ring formed by R ²¹ and R ²² bonded to each other, a ring formed by R ²³ and R ²⁴ bonded to each other, or R ²¹ and R ²³ bonded to each other The ring formed may be either saturated or unsaturated, and includes a sulfur atom, a nitrogen atom,
And one or more heteroatoms selected from the group consisting of oxygen atoms and oxygen atoms. Also, 1 or 2 on the ring
It may have two or more substituents (for example, an alkyl group).

The type of the acidic group represented by Q ¹ is not particularly limited, and may be a cyclic or acyclic substituent, or a combination thereof. For example, a lower alkoxy group, a hydroxyl group, a carboxyl group, an N-cyanocarboxamide group,
A methanesulfonylamide group having 1 to 3 fluorine atoms, an alkoxycarbonyl group which may have a substituent, -CONH- (5-tetrazolyl) group, a 5-tetrazolyl group which may have a substituent, 1,2,3-triazolyl group which may have a substituent, 2,4-dioxothiazolidine-5-yridenyl group which may have a substituent, 4 which may have a substituent -Oxo-2-thioxothiazolidine-5-yridenyl group, an optionally substituted 5-oxo-4-tetrazolyl group, an optionally substituted 3- (5-oxo)-[ 1.2.4] Oxadiazolidinyl group, 2- which may have a substituent
(3,5-dioxo)-[1.2.4] oxadiazolidinyl group, 5- (3-oxo)-which may have a substituent
[1.2.4] oxadiazolidinyl group or 3- (5-oxo)-[1.2.4] isoxazolidyl group which may have a substituent, and the like. More preferably, a carboxyl group, an N-cyanocarboxamide group, a methanesulfonylamide group having 1 to 3 fluorine atoms, an alkoxycarbonyl group which may have a substituent, a -CONH- (5-tetrazolyl) group, or Examples thereof include a 5-tetrazolyl group which may have a substituent.

In the compound represented by the general formula (II),
R ³¹ , R ³² , J ¹¹ , m, and Q ¹¹ each represent the above R
Those described for ¹ , R ² , J ¹ , m, and Q ¹ can be suitably used. W ¹¹ is preferably —CH ₂ O
—, —CH ＝ CH—, or —CH ₂ CH ₂ can be used. As A ¹¹ , a pyridinediyl group optionally having a substituent, a 4-oxo optionally having a substituent -Pyrido [1,2-a] pyrimidindiyl group, an optionally substituted quinolin-4-one-diyl group, or an azaquinolin-4-one-diyl group is preferable, and the substituent on the ring is preferably , A halogen atom, an alkyl group which may have a substituent, a hydroxyl group, an alkoxy group, and an amino group. G ¹¹ includes -N (R ³³ ) -CO-,-
CO-N ( ^R36 )-or -C ( ^R38 ) = C ( ^R39 )-
(Wherein, R ³³ , R ³⁶ , R ³⁸ and R ³⁹ each independently represent a hydrogen atom or an alkyl group which may have a substituent), but the case where m is 0 is also preferable.

The compound represented by the general formula (I) or (II) may form a salt. Specific examples of the salt include, when an acidic group is present, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris Salts of amines such as (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine; or lysine , Δ-hydroxylysine, arginine and other basic amino acids. When a basic group is present, hydrochloric acid, hydrobromic acid, sulfuric acid,
Salts of mineral acids such as nitric acid and phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionate, tartaric acid, fumaric acid, maleic acid, malic acid,
Salts with organic acids such as oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid; or acidic acids such as aspartic acid and glutamic acid It can form salts with amino acids.

As the active ingredient of the medicament of the present invention, in addition to the compound represented by the above formula (I) or a salt thereof, a solvate or hydrate thereof can be used. Further, the compound represented by the above general formula (I) may have one or more asymmetric carbon atoms, and the stereochemistry of the asymmetric carbon is independently (R) or (S). )), And the compound may exist as a stereoisomer such as an optical isomer or a diastereoisomer. As the active ingredient of the medicament of the present invention, any of pure stereoisomers, arbitrary mixtures of stereoisomers, racemates and the like may be used. Further, when the compound represented by the general formula (I) has a double bond,
The configuration may be either the (E) configuration or the (Z) configuration, and the pure form of the geometric isomer or any mixture thereof may be used as the active ingredient of the medicament of the present invention. Also,
The compound represented by the general formula (I) may exist as a tautomer depending on the type of the substituent, and any of them may be used as an active ingredient of the medicament of the present invention.

The scope of the invention relating to the novel substance represented by the general formula (II) provided by the present invention includes a compound in a free form or a salt thereof, and a solvate or hydrate thereof. Is included. The compound represented by the general formula (II) may have one or more asymmetric carbon atoms, and the stereochemistry of the asymmetric carbon atoms is independently (R) or (S). ) Can take any of the body,
The compounds may exist as stereoisomers such as optical isomers or diastereoisomers. Any stereoisomers in pure form, any mixtures of stereoisomers, racemates and the like are all included in the scope of the present invention. Further, when the compound represented by the general formula (II) has a double bond, its configuration may be any of the (E) configuration and the (Z) configuration, and the pure geometric isomers or their geometric isomers may be used. Any mixture is included in the scope of the present invention. Further, the compound represented by the general formula (II) may have a tautomer depending on the type of the substituent, and these are all included in the scope of the present invention.

The compound represented by the above general formula (I) can be produced by a known method. Compound J ¹ is a thiazole derivative, for example, JP-62-14
2168, JP-A-6-80654, JP-A-10-195063, International Publication WO96 / 331
81, can be produced according to the method described in International Publication WO98 / 57935, etc., and the compound in which J ¹ is a quinoline derivative can be synthesized, for example, by the method described in JP-A-7-179426. . Further, other derivatives can be similarly produced.

For example, a compound in which the G ₁ moiety is —NHCO— can be produced according to the method shown in the following Scheme 1.

Embedded image

The carboxamide derivative is obtained by reacting a nitroaryl derivative having a carboxyl group with a chlorinating agent such as thionyl chloride and treating with ammonia water. Diethyl ether, tetrahydrofuran (TH
F), in an inert solvent such as toluene or benzene, a thioamide is prepared with Lawesson's reagent, and a commercial product is available.
Compound 5 can be obtained by condensation with a haloketone which is known per se or can be produced by a known method.
The amine obtained after producing an amine derivative by treating the nitro group with a known reducing agent, for example, tin chloride in an inert alcohol-based solvent such as ethanol, or treating under a reducing condition such as catalytic hydrogenation. The condensate can be obtained by reacting the derivative with the corresponding carboxylic acid derivative or carboxylic anhydride derivative. The reaction is carried out by reacting a condensing reagent of a carboxylic acid and an amine, for example, dicyclohexylcarbodiimide, N, N-bis (2-oxo-3
-Oxazolidinyl) phosphinic acid chloride, dimethylaminopyridine or the like. The compound in which the acidic group moiety of Q ¹ is protected can be deprotected using an appropriate reagent to obtain a compound represented by the formula 1A. Deprotection can be performed by, for example, hydrolysis or catalytic hydrogenation under alkaline or acidic conditions in the case of a carboxylic acid ester, and the presence of anisole or the like in the case of a tetrazole group protected by a paramethoxybenzyl group. It can be carried out by acting a strong acid such as trifluoroacetic acid under or in the absence.

The compound in which the W ¹ moiety is an ethynyl group can also be produced by the method shown in Scheme 2 below.

Embedded image 2-ethynylthiazole, which can be synthesized by a known method, and compound 10 (wherein L represents a leaving group such as a halogen atom or trifluoromethanesulfonate) are combined with an organic compound such as triethylamine or diisopropylamine according to a method known per se. Condensation by coupling in an amine solvent if necessary in the presence of an inert solvent (eg, tetrahydrofuran, 1,2-dimethoxyethane, diethylformamide, etc.) at a temperature in the range of 0 ° C. to the boiling point of the solvent. You can get the body. This reaction may be performed in the presence or absence of triphenylphosphine and cuprous iodide, and may include palladium [2] acetate, tetrakis (triphenylphosphine) palladium [0], or bis (triphenylphosphine) palladium [2] A catalytic amount of dichloride may be added. After the coupling, the compound represented by the formula 1B can be synthesized by removing the protecting group of the acidic group portion in Q as necessary.

The compound in which the W ¹ moiety is linked by an ether can also be produced by the method shown in the following scheme 3.

Embedded image A condensate can be obtained by subjecting an alcohol derivative and a phenol derivative to a Mitsunobu reaction, that is, a treatment in an inert solvent such as tetrahydrofuran in the presence of diethylazodicarboxylate and triphenylphosphine. The obtained condensate can be converted to a compound represented by the formula 1C using the same method as in Scheme 1.

The compound in which the W ¹ moiety is linked by an ethenyl group can also be synthesized by the method shown in Scheme 4.

Embedded image

Compound 13 and Compound 14, or Compound 15
And compound 16 are subjected to a Horner-Emmons reaction, and the nitro group of compound 17 obtained is reduced with stannous chloride and condensed with the corresponding carboxylic acid or carboxylic anhydride to obtain a compound represented by formula 1D be able to.

The compound of the present invention represented by the general formula (II) can be produced according to the following method, but the method of producing the compound of the present invention is not limited to the method described below. Further, in the examples of the present specification, a method for producing a representative compound of the present invention is specifically shown, with reference to the description of the following general production method and the specific description of the examples, By appropriately selecting reaction raw materials, reaction reagents, reaction conditions, and the like, and modifying or modifying these methods as necessary, it is possible to produce any of the compounds included in the general formula (II). .

The compound wherein J ¹¹ is an aromatic heterocyclic ring represented by the above formula (III) can be produced according to the method shown in the following scheme 5.

Embedded image

Compound 19, which is known or can be easily derived from known compounds, is prepared by combining diethyl ethoxymethylene malonate with Dowtherm A, propionic acid, PP
A, compound 21 by heating in a solvent such as PPE
Can be obtained. The carboxylic acid (compound 18A) can be obtained by treating the obtained compound 21 under ordinary hydrolysis conditions. Similarly, compound 23 can be synthesized by condensing compound 19 in the same manner as dimethylacetylenedicarboxylate. The carboxylic acid (compound 18B) can be obtained by treating the obtained compound 23 under ordinary hydrolysis conditions.

[0047]

Embedded image When the nitrogen atom in compound 21 or compound 23 has hydrogen, the compound is treated with a base such as sodium hydride or potassium carbonate in a solvent such as dimethylformamide (DMF) or THF to obtain a compound such as alkyl halide. Compounds having a substituent introduced on nitrogen by the same hydrolysis after the action of an electron agent (compound 18C and compound 1
8D) can be produced.

[0048]

Embedded image Known compound 24 (Chem. Pharm. Bull.
1991, 39, 1099) in place of diethyl ethoxymethylene malonate, followed by treatment with a strong acid such as trifluoroacetic acid to give a compound having tetrazole instead of carboxylic acid (compound 18E,
F) can be produced.

Compound 19A can be produced according to the method shown in the following scheme 8.

Embedded image

The condensate (compound 27) can be obtained by subjecting the 3-hydroxynitrobenzene derivative (compound 26) and compound 10 to a Mitsunobu reaction. Compound 19A can be obtained by treating the nitro group with stannous chloride in alcohol or subjecting it to catalytic reduction.

Compound 19B can be produced according to the method shown in the following scheme 9.

Embedded image

The 3-nitrobenzaldehyde derivative (compound 28) and compound 15 are treated with a base such as sodium methoxide in methanol, and then the nitro group is treated with stannous chloride in alcohol to reduce the nitro group. Thereby, compound 19B can be obtained.

Compound 19C can be produced by the method shown in the following Scheme 10.

Embedded image

N-acetyl (or pivaloyl) -2-pyridine-4-aldehyde 31 (International Publication WO 93/07)
Compound 19C can be obtained by heating 141) and compound 30 in acetic anhydride and then hydrolyzing in hydrochloric acid.

Compound 19D and compound 19E can be produced by the method shown in the following Scheme 11.

Embedded image

Tert-butyl N- (4-methyl-2
-Pyridyl) carbamate (Compound 33: J. Org.
Chem. 1996, 61, 4810) in THF
After treating with -butyllithium, the corresponding alkyl halide (compound 32) is allowed to act, and then treated with a strong acid such as trifluoroacetic acid to give compound 19D. Also, ethyl 4-hydroxypyridine-2-carboxylate (compound 34) (EP Publication 033
No. 0353) is treated with a base such as potassium carbonate in DMF and the corresponding alkyl halide (compound 32) is reacted to give compound 35. After hydrolyzing the ester moiety of compound 35, the hydrolyzate is subjected to a Curtius rearrangement reaction using diphenylphosphoric acid azide, t-butanol or the like, and the resulting t-butyl carbonate is treated with a strong acid such as trifluoroacetic acid. Thereby, compound 19E can be obtained.

Compound 18G can be produced by the method shown in the following Scheme 12.

Embedded image

The compound 10 was treated with a strong base such as sodium hydride in DMF or THF to form an alkoxide, and then the compound was treated with a known compound 36 (for example, JP-A-61-61).
246188, 62-12760, 6
0-197686) and then hydrolyze to convert to carboxylic acid (compound 18G).

The intermediates and target compounds in the above-mentioned production methods can be separated and purified by means of separation and purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, drying, concentration, recrystallization and various types of chromatography. It can be isolated and purified. In addition, the production intermediate can be subjected to the next reaction without purification. When it is desired to obtain a salt of the compound represented by the general formula (I) or (II), when the compound represented by the general formula (I) or (II) is obtained in the form of a salt, It may be purified, and when it is obtained in a free form, it may be dissolved or suspended in an appropriate organic solvent and a salt may be formed by a method of adding an acid or a base. Also, a compound of the general formula (I) obtained in the form of a salt
Alternatively, after converting the compound represented by (II) into a compound in a free form, it is also possible to convert it into an appropriate salt form.

Without wishing to be bound by any particular theory, the compounds of the general formula (I) have the effect of inhibiting the microbial drug efflux pump. More specifically, the compound represented by the general formula (I) can act on a microorganism that has acquired resistance to an antimicrobial agent, inhibit a drug efflux pump, and detolerize the microorganism. . Further, the compound represented by the general formula (I) can act on a microorganism to inhibit a drug efflux pump, thereby inhibiting the microorganism from becoming resistant to an antimicrobial agent. According to the present invention, prevention and / or prevention of microbial infectious diseases is achieved by using the medicament of the present invention containing the compound represented by the general formula (I) as an active ingredient in combination with one or more antimicrobial agents. Alternatively, treatment can be achieved very effectively. The medicament of the present invention is extremely useful as a medicament for preventing and / or treating infectious diseases caused by microorganisms that have acquired resistance to one or more antimicrobial agents.

[0061] The method of using the medicament of the present invention is not particularly limited. , Or over time, or 1
A method of producing and administering a pharmaceutical composition (a so-called combination drug) comprising one or more antimicrobial agents and the medicament of the present invention can be exemplified.

The type of microbial infectious disease to which the medicament of the present invention is applied is not particularly limited, but bacteria are suitable as microorganisms. Alternatively, the present invention can be applied to various microbial infections caused by aerobic or anaerobic bacteria. The medicament of the present invention can be particularly suitably applied to an infection caused by Pseudomonas aeruginosa having acquired resistance to an antimicrobial agent or Pseudomonas aeruginosa having low sensitivity to an antimicrobial agent. The medicament of the present invention is applicable to microbial infections of mammals including humans.

Drugs having various structures are known as antimicrobial drugs, and many drugs have been clinically used. The type of antimicrobial agent that can be administered together with the medicament of the present invention is not particularly limited. Carbapenem antibiotics, monobactam antibiotics, aminoglycoside antibiotics, macrolide antibiotics, chloramphenicol antibiotics, tetracycline antibiotics, glycopeptide antibiotics, fosfomycin antibiotics,
Examples include lincomycin antibiotics, sulfa drugs, paraaminosalicylic acid preparations, isonicotinic acid hydrazide preparations, and quinolone synthetic antibacterial agents. However, antimicrobial agents are not limited to these. According to the present invention, by using one or more of these antimicrobial agents in combination with the medicament of the present invention,
Extremely high therapeutic effects can be achieved. When producing a pharmaceutical composition containing one or more antimicrobial agents and the medicament of the present invention, the antimicrobial agents exemplified above can be used.

As the active ingredient of the medicament of the present invention, a substance selected from the group consisting of compound (I) and pharmacologically acceptable salts thereof, and hydrates and solvates thereof is used. Can be. Two or more of these substances may be used in appropriate combination. The substance itself selected from these groups may be administered as the medicament of the present invention, but usually, the form of a pharmaceutical composition comprising the above-mentioned substance as an active ingredient and a pharmaceutically acceptable additive for a pharmaceutical preparation It is desirable to administer in the. Such a pharmaceutical composition can be appropriately compounded with other pharmaceutical active ingredients, for example, the above-mentioned antimicrobial agents and β-lactamase inhibitors.

A pharmaceutical composition to be applied to a living body is prepared by mixing the above-mentioned substance, which is an active ingredient, with one or more pharmaceutically acceptable additives for pharmaceutical preparations, and Can be easily produced according to the formulation method described above. The route of administration of the medicament of the present invention is not particularly limited, but it is desirable to appropriately select the most effective route in preventing and / or treating infectious diseases. Pharmaceutical compositions suitable for oral administration include, for example, capsules, powders, tablets, granules, fine granules, emulsions, syrups, solutions, suspensions and the like, and pharmaceuticals suitable for parenteral administration. As the composition, for example, inhalants, sprays, rectal administration, injections, drops, ointments, creams, transdermal absorbents, transmucosal absorbents, eye drops, nasal drops, ear drops, Tapes, patches and the like can be mentioned, but the form of the medicament of the present invention is not limited to these.

Among the pharmaceutical compositions suitable for oral administration, liquid preparations such as emulsions and syrups include water; saccharides such as sucrose, sorbitol and fructose; glycols such as polyethylene glycol and propylene glycol; sesame oil, olive oil, It can be prepared using pharmaceutical additives such as oils such as bean oil; preservatives such as p-hydroxybenzoic acid esters; flavors such as strawberry flavor and peppermint. Solid preparations such as capsules, tablets, powders, and granules include excipients such as lactose, glucose, sucrose, mannitol; disintegrants such as starch and sodium alginate; lubricants such as magnesium stearate and talc; It can be produced using a binder such as polyvinyl alcohol, hydroxypropylcellulose, and gelatin; a surfactant such as a fatty acid ester; and a plasticizer such as glycerin.

Among the pharmaceutical compositions suitable for parenteral administration, liquid preparations such as injections, drops and eye drops can be prepared preferably as sterile isotonic liquid preparations. For example, an injection can be prepared using an aqueous medium consisting of a salt solution, a glucose solution, or a mixture of saline and a glucose solution. Rectal preparations can be prepared usually in the form of suppositories using carriers such as cocoa butter, hydrogenated fats and hydrogenated carboxylic acids. In preparing a spray, a non-irritating carrier which disperses the above-mentioned substance as an active ingredient as fine particles to facilitate absorption can be used. Such carriers include, for example, lactose, glycerin and the like, and the form of the preparation can be selected from aerosol, dry powder and the like. However, the pharmaceutical additives used in the production of the medicament of the present invention are not limited to those described above, and any additives that can be used by those skilled in the art may be used.

The dose and frequency of administration of the medicament of the present invention are not particularly limited. It is possible to select the amount.

From another viewpoint, the compound which is an active ingredient of the medicament provided by the present invention is characterized in that its partial structure occupies the following four sites within the following allowable range. That is, the compound which is an active ingredient of the medicament provided by the present invention has a pharmacophore consisting of the following four sites as a common pharmacophore for exhibiting a Pseudomonas aeruginosa drug efflux pump inhibitory activity. ing.
Sites 1 to 3 indicate hydrophobic features, and site 4 indicates negatively ionizable (acidic group) features. The definitions of these features are published in the following paper and the references cited in the paper (J. Chem. Inf., And Comp.
Sci., 34, 1297-1308).

[0070]

[Table 3]

In the above-mentioned pharmacophore, more specific
Typically, the hydrophobic feature is, in the partial structure of the compound,
Indicates the position occupied by the hydrophobic substituent. With a hydrophobic substituent
Is, for example, an alkyl group, a cycloalkyl group, an aryl
A functional group such as a group, a heterocyclic group, or a halogen atom
However, the present invention is not limited to these. Acid group site and
Indicates the position occupied by the acidic group in the partial structure of the compound.
You.

Examples of the substituent occupying site 1 include an alkyl group, an aryl group, a heterocyclic group and a halogen atom, and an alkyl group, an aryl group and a heterocyclic group are preferred. These groups may further have one or more substituents. Examples of the substituent occupying site 2 include an alkyl group, an aryl group, a heterocyclic group, and a halogen atom.
Aryl groups or heterocyclic groups are preferred. These groups may further have one or more substituents.

Examples of the substituent occupying site 3 include an alkyl group, an aryl group, a heterocyclic group, and a halogen atom, and an aryl group or a heterocyclic group is preferable. These groups may further have one or more substituents. The type of the acidic group occupying the site 4 is not particularly limited, and may be any of a cyclic or acyclic substituent or a combination thereof. The acidic group is one more
Alternatively, it may have two or more substituents.

The structure linking each site is
This linker is, for example, a carbon atom, water
Elemental elements such as elementary atom, oxygen atom, nitrogen atom, sulfur atom, etc.
And put the partial structure of the compound in each site
Have the necessary length, but the type is not particularly limited.
No. Specifically, -CH = CH-, -C≡C-, -CH
_TwoCH_Two-, -OCH_Two-, -SCH_Two-, -OCH_TwoO
-, -CH_TwoO-, -CH_Two-, -CO-, -CH_TwoCH_Two
CH_Two-, -CH_TwoNH-, -NHCH_Two-, -CH_TwoS
-, -CONH-, -CH_TwoSCH_Two-, -CH = CH-
CONH- and -CH_TwoOCH_Two-Selected from the group consisting of
Linkers or combinations of these linkers
Linkers. Note that the above linker
-Some of them are geometrically heterogeneous, but none of them
It may be one of these.

The compounds having the above-mentioned pharmacophore include the compounds represented by the above formula (I) or (II), but are not limited thereto. Here, R ¹ , R ² , R ³¹ , and R ³² are partial structures occupying site 1, J ¹ and J ¹¹ are partial structures occupying site 2, A ¹ and A ¹¹ are site 3 And Q ¹ and Q ¹¹ correspond to the partial structure occupying the site 4. Occupy means that the atoms constituting each structure itself or each structure (substituent) occupy an arbitrary position in the space within the sphere defined as a site.

By using the above-described pharmacophore, it can be determined whether or not any compound has Pseudomonas aeruginosa drug efflux pump inhibitory activity. In addition, a compound having a Pseudomonas aeruginosa drug efflux pump inhibitory action can be selected by performing screening using the above-described pharmacophore model using a compound library in which a conformation has been generated. Furthermore, a virtual compound can be created by performing a docking study with the above-described pharmacophore after similarly calculating the conformation using the fictitious compound group, and actually synthesizing the created compound. By assaying the Pseudomonas aeruginosa drug efflux pump inhibitory activity, useful drugs can be created. By appropriately combining two or more of these techniques, compounds having stronger Pseudomonas aeruginosa drug efflux pump inhibitory activity can also be found.

The superposition of the compounds is performed by CATALYST (Greene e
t al., J. Chem. Inf. Comp.Sci., 1994, 34, 1297-130
8; software is commercially available from Molecular Simulation Inc.), and can be efficiently performed by using software having a docking function.
It can also be done manually. Regarding the creation of pharmacophore using CATALYST, see, for example, International Publication WO
/ 04913 discloses a specific method in detail. A compound that is compatible with a pharmacophore generally means that, when the compound is optimally superimposed on the pharmacophore, the constituent atoms in the substructure that match the feature of that site are assigned to each site. From 0.5 to 3Å
It is a compound that falls within. A compound occupying the partial structure of the compound within the above permissible range at all four sites of the pharmacophore (2% for sites 1 and 4 and within 1.7% for sites 2 and 3) is a Pseudomonas aeruginosa drug Has the effect of inhibiting the discharge pump,
In the prevention and / or treatment of infectious diseases, a combined effect with an antibacterial agent can be expected. General formula (I) and general formula (II)
The compound represented by is used as a compound having an action of inhibiting a Pseudomonas aeruginosa drug efflux pump, in addition to a Pseudomonas aeruginosa drug efflux pump inhibitor, and as an active ingredient of a drug for preventing and / or treating infectious diseases According to the present invention, extremely high prophylactic and / or therapeutic effects can be achieved when used in combination with one or more antimicrobial agents.

[0078]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Example 1 2- (2-oxo-2--3-
[(E) -2- (4-phenyl-1,3-thiazole-
2-yl) -1-ethenyl] anilinoethyl) benzoic acid 3-[(E) -2- (4-phenyl-1,3-thiazol-2-yl) -1-ethenyl] aniline (Japanese Patent Laid-Open No. Sho 62)
-142168) (500 mg, 1.8 mmol) and homophthalic anhydride (440 mg, 2.7 mmol) were dissolved in toluene (10 mL) and heated under reflux for 30 minutes.
After cooling the reaction solution, the precipitated crystals were collected by filtration to give the title compound (720 mg, 91%) as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ: 4.11 (2H,
s), 7.30-7.54 (12H, m), 7.
89 (1H, d, J = 8.3 Hz), 7.96 (1H,
s), 7.99 (1H, d, J = 7.2 Hz), 8.0
9 (1H, s), 10.18 (1H, s). FAB-MS; m / z: 441 (MH ⁺ )

Example 2: 2- {2-oxo-2- [3-
(2-quinolylmethoxy) anilino] ethyl @ benzoic acid (A) 2-[(3-nitrophenyloxy) methyl] quinoline m-nitrophenol (500 mg, 3.59 mmol)
1), 2-chloromethylquinoline (846 mg, 3.9
5 mmol) was dissolved in DMF (10 ml), potassium carbonate (745 mg) was added, and the mixture was stirred at room temperature overnight. After concentrating the reaction solution, the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (n-hexane-ethyl acetate, 8: 1,
v / v) to give the title compound (245 mg, 24%)
I got ¹ H-NMR (CDCl ₃ ) δ: 5.45 (2H, s),
7.35 (1H, dd, J = 8.3, 2.4 Hz),
7.44 (1H, t, J = 8.3 Hz), 7.58 (1
H, t, J = 7.8 Hz), 7.65 (1H, d, J =
8.8 Hz), 7.76 (1H, t, J = 7.8H)
z), 7.84-7.86 (2H, m), 7.92 (1
H, d, J = 2.0 Hz), 8.10 (1H, d, J =
8.8 Hz), 8.23 (1H, d, J = 8.3H)
z).

(B) 2-[(3-nitrophenyloxy) obtained with 3- (2-quinolylmethoxy) aniline (A)
Methyl] quinoline (245 mg, 0.874 mmol)
Was dissolved in ethanol (10 ml), and stannous chloride (5
80 mg) and heated under reflux for 3 hours. After allowing the reaction solution to cool, a 5 M aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred for 15 minutes. Subsequently, extraction operation was performed with chloroform, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
The title compound (247 mg, quantitative) was obtained.

(C) 2- {2-oxo-2- [3- (2
-(Quinolylmethoxy) anilino] ethyl} benzoic acid 3- (2-quinolylmethoxy) aniline (219 mg, 0.875 mmol) obtained with (B) and homophthalic anhydride (213 mg, 0.131 mmol) were added to toluene ( 10 ml) and heated under reflux for 30 minutes. The precipitated solid was collected by filtration to give the title compound (223 m
g, 62%). ¹ H-NMR (DMSO-d ₆ ) δ: 4.06 (2H,
s), 5.32 (2H, s), 6.71 (1H, m),
7.14 (1H, m), 7.19 (1H, t, J = 7.
8Hz), 7.33-7.42 (3H, m), 7.50
(1H, t, J = 7.3 Hz), 7.63 (2H,
m), 7.78 (1H, m), 7.87 (1H, d, J
= 6.8 Hz), 8.00 (2H, t, J = 8.8H)
z), 8.40 (1H, d, J = 8.3 Hz), 10.
1 (1H, br). FAB-MS; m / z: 413 (MH ⁺ )

Example 3: 2- (2-3-[(E) -2-]
(4-Isopropyl-5-chloro-1,3-thiazol-2-yl) -1-ethenyl] anilino-2-oxoethyl) benzoic acid (A) 4-isopropyl-5-chloro-2-[(E) −
2- (3-nitrophenyl) -1-ethenyl] -1,3
-Thiazole hydrochloride 4-isopropyl-2-[(E) -2- (3-nitrophenyl) -1-ethenyl] -1,3-thiazole (JP-A-62-142168) (270 mg, 0.98 mmol)
l) was dissolved in carbon tetrachloride (5 mL), and N-chlorosuccinimide (160 mg, 1.2 mmol) was added.
The mixture was heated under reflux for 7 hours. The reaction solution was distributed between methylene chloride and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. After adding a small amount of hydrochloric acid / dioxane to the residue and evaporating the solvent again, the residue was purified by silica gel chromatography (hexane-ethyl acetate, 4: 1, v / v).
The title compound (236 mg, 69%) was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.8 Hz), 3.24 (1H, m), 7.30 (2
H, s), 7.56 (1H, t, J = 7.8 Hz),
7.81 (1H, d, J = 7.8 Hz), 8.16 (1
H, dd, J = 7.8, 2.0 Hz), 8.37 (1
H, t, J = 2.0 Hz).

(B) 2- (2-3-[(E) -2- (4
-Isopropyl-5-chloro-1,3-thiazole-2
-Yl) -1-ethenyl] anilino-2-oxoethyl) benzoic acid 4-isopropyl-5-chloro-2- obtained with (A)
[(E) -2- (3-nitrophenyl) -1-ethenyl] -1,3-thiazole hydrochloride (225 mg, 0.6
52 mmol) was dissolved in ethanol (10 mL), tin (II) chloride (590 mg, 3.11 mmol) was added, and the mixture was heated under reflux for 2 hours. A 4N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in toluene (10 mL) and homophthalic anhydride (126 mg, 0.78 mm
ol) Heated to reflux for 30 minutes. After cooling the reaction solution, the precipitated crystals were collected by filtration, and the title compound (88 mg, 30 mg) was obtained as a white solid.
%). ^{1 H-NMR (DMSO-d} 6) δ: 1.23 (6H,
d, J = 6.8 Hz), 3.15 (1H, m)
, 3.98 (2H, s), 7.25-7.50 (8
H, m), 7.80-7.90 (2H, m). FAB-MS; m / z: 441 (MH ⁺ )

Example 4: 2- [2-oxo-2- @ 3-
[(E)-(5-Phenyl-2-furyl) -1-ethenyl] anilinodidiethyl] benzoic acid (A) N-methyl-N-methoxy-5-bromo-2-furanamide 5-bromo-2- Furancarboxylic acid (3.00 g, 1
5.7 mmol) was dissolved in methylene chloride (60 ml) and N-methyl-N-methoxyamine hydrochloride (94 m
g), triethylamine (2.19 ml, 15.7 mm
ol) and HOBt (1.06 g, 7.85 mmol)
l), WSCD.HCl (3.31 g, 1
(7.3 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with methylene chloride, washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane-ethyl acetate, 4: 1, v / v) to give the title compound (3.18 g, 86%) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ; 3.33 (3H, s),
3.77 (3H, d, J = 2.0 Hz), 6.45 (1
H, dd, J = 3.9, 2.0 Hz), 7.10 (1
H, d, J = 3.9 Hz).

(B) N-methyl-N-methoxy-5-phenyl-2-furanamide N-methyl-N-methoxy-5-bromo-2-furanamide obtained in (A) (3.18 g, 13. 6 mmol)
Was dissolved in toluene-water (60 ml, 2: 1, v / v) and phenylboronic acid (1.74 g, 14.3 mmol) was dissolved.
l), tetrakis (triphenylphosphine) palladium (785 mg), sodium carbonate (4.32 g, 4
0.8 mmol) and heated to reflux overnight. After allowing the reaction solution to cool, an extraction operation was performed with ethyl acetate, and the mixture was dried over magnesium sulfate. The residue was purified by silica gel chromatography (n-hexane-ethyl acetate, 4:
1, v / v) to give the title compound (2.27 g, 72%) as white crystals. ¹ H-NMR (CDCl ₃ ) δ; 3.39 (3H, s),
3.84 (3H, s), 6.77 (1H, d, J = 3.
9Hz), 7.25 (1H, d, J = 3.9Hz),
7.34 (1H, m), 7.43 (2H, t, J = 7.
3 Hz), 7.80 (2H, d, J = 7.3 Hz).

(C) 5-phenyl-2-furaldehyde lithium aluminum hydride (410 mg, 10.8 m
mol) was suspended in THF (15 ml), and N-methyl-N-methoxy-5-phenyl-2-furanamide (500 mg, 2.16 mmol) obtained under ice cooling (B) was obtained.
l) was added and the mixture was stirred at 0 ° C for 30 minutes. After the reaction solution was poured into ice water, potassium hydrogen sulfate was added and the mixture was stirred for a while. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane-ethyl acetate, 20: 1, v / v) to give the title compound (289
mg, 78%). _{^{1 H-NMR (CDCl 3)}} δ; 6.83 (1H, d, J
= 3.9 Hz), 7.31 (1H, d, J = 3.9H)
z), 7.38-7.44 (3H, m), 7.82 (2
H, m), 9.64 (1H, s).

(D) Diethyl (3-nitrobenzyl)
Phosphonate 3-nitrobenzyl bromide (1.00 g, 4.63 m
mol) was dissolved in triethyl phosphite (15 ml) and stirred at 100 ° C. for 3 hours. After allowing the reaction solution to cool, ether was added, and the precipitated insoluble material was removed by filtration.
Purification with ethyl acetate (4: 1 → 1: 1, v / v) gave the title compound (1.14 g, 90%). ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, t, J
= 7.3 Hz), 3.21 (1H, s), 3.27 (1
H, s), 4.07 (4H, q, J = 7.3 Hz),
7.50 (1H, dd, J = 8.3, 7.8 Hz),
7.66 (1H, d, J = 7.8 Hz), 8.14 (1
H, d, J = 8.3 Hz), 8.16 (1H, d, J =
2.0 Hz).

(E) 2-[(E) -2- (3-nitrophenyl) -1-ethenyl] 5-phenylfuran 5-phenylfuranaldehyde (1) obtained from (C)
88 mg, 1.09 mmol) and the diethyl (3-nitrobenzyl) phosphonate obtained in (D) (597 m
g, 2.18 mmol) in DMF (3 ml),
Add sodium methoxide (118 mg) and add
Stirred for hours. Further, 5-phenyl-2-furaldehyde (191 mg) and sodium methoxide (118 mg)
, Followed by 60% sodium hydride (88.0 m
g) was added and stirred at room temperature overnight. After methanol was added to the reaction solution, the mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane-ethyl acetate, 2
0: 1, v / v) to give the title compound (288 mg, 45%) as yellow crystals. _{^{1 H-NMR (CDCl 3)}} δ; 6.54 (1H, d, J
= 3.4 Hz), 6.73 (1H, d, J = 3.4H)
z), 7.04 (1H, d, J = 16.1 Hz), 7.0.
15 (1H, d, J = 16.1 Hz), 7.30 (1
H, t, J = 7.8 Hz), 7.43 (1H, t, J =
7.8 Hz), 7.51 (1H, t, J = 7.8H)
z), 7.76 (3H, m), 8.07 (1H, m),
8.35 (1H, s).

(F) 3-[(E)-(5-phenyl-2)
-Furyl) -1-ethenyl] aniline 2-[(E) -2- (3-nitrophenyl) -1-ethenyl] -5-phenylfuran (288) obtained with (E).
mg, 0.989 mmol) in ethanol (15 ml)
And stannous chloride (656 mg) was added, followed by heating under reflux for 3 hours. After allowing the reaction solution to cool, a 5 M aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred for 15 minutes. Subsequently, an extraction operation was performed with chloroform, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure to give the title compound (259 mg,
Quantitative).

(G) 2- [2-oxo-2- @ 3-
[(E)-(5-phenyl-2-furyl) -1-ethenyl] anilinodiethyl] benzoic acid 3-[(E)-(5-phenylfuryl) -1-ethenyl obtained by (F) ] Aniline (259 mg, 0.98
7 mmol) and homophthalic anhydride (240 mg, 0.1
48 mmol) was dissolved in toluene (7 ml) and heated under reflux for 30 minutes. The precipitated solid was collected by filtration to give the title compound (302 mg, 72%) as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ: 4.11 (2H,
s), 6.69 (1H, d, J = 3.42), 7.02.
(1H, d, J = 16.2 Hz), 7.03 (1H,
d, J = 3.4 Hz), 7.09 (1H, d, J = 1)
6.2 Hz), 7.27-7.46 (8H, m), 7.
53 (1H, t, J = 7.3 Hz), 7.79 (2H,
d, J = 7.8 Hz), 7.89 (2H, d, J = 7.
3Hz), 7.92 (1H, s), 10.1 (1H,
s). FAB-MS; m / z: 423 (M ⁺ )

Example 5: 2- {2- [3-((E) -2]
-{5-amino-4-isopropyl-1,3-thiazol-2-yl} -1-ethenyl) amino] -2-oxoethyl} benzoic acid (A) ethyl 4-isopropyl-2-[(E)- 2-
(3-Nitrophenyl) -1-ethenyl] -1,3-thiazole-5-carboxylate (E) -3- (3-nitrophenyl) -2-propenethioamide (2.07 g, 9.99 mmol), ethyl
2-Chloro-4-methyl-3-oxopentanoate (1.92 g, 9.99 mmol) was added to ethanol (10
0 ml) and heated under reflux for 26 hours. The reaction solution was allowed to cool and then concentrated. The residue was purified by silica gel chromatography (n-hexane-ethyl acetate, 20: 1, v / v) to obtain the title compound (812 mg, 24%). ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 9.8 Hz), 1.39 (3H, t, J = 7.3H)
z), 3.99 (1H, m), 4.36 (2H, q, J
= 7.3 Hz), 7.36 (1H, d, J = 16.1H)
z), 7.56 (1H, d, J = 16.1 Hz), 7.
58 (1H, t, J = 8.3 Hz), 7.85 (1H,
d, J = 8.3 Hz), 8.19 (1H, dd, J =
8.3, 2.0 Hz), 8.41 (1H, brs).

(B) 4-isopropyl-2-[(E)-
2- (3-nitrophenyl) -1-ethenyl] -1,3
-Thiazole-5-carboxylic acid ethyl 4-isopropyl-2- obtained with (A)
[(E) -2- (3-nitrophenyl) -1-ethenyl] -1,3-thiazole-5-carboxylate (2
50 mg, 0.722 mmol) was dissolved in a mixed solvent of THF-methanol-water (6 ml, 3: 2: 1, v / v), and lithium hydroxide monohydrate (60.6 mg) was added thereto. Stir for 3 hours. The reaction solution was neutralized with 1 M hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (247 mg,
Quantitative).

(C) tert-butyl N- {4-isopropyl-2-[(E) -2- (3-nitrophenyl)
-1-ethenyl] -1,3-thiazol-5-yl} carbamate 4-isopropyl-2-[(E) -2 obtained from (B)
-(3-nitrophenyl) -1-ethenyl] -1,3-
Thiazole-5-carboxylic acid (230m
g, 0.722 mmol) with tert-butanol (8
ml) and triethylamine (0.121 m
1) and diphenyl phosphoric acid azide (0.187 ml) were added, and the mixture was heated under reflux for 6 hours. After allowing the reaction solution to cool, it was diluted with ethyl acetate and washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (n-hexane-ethyl acetate, 8: 1,
v / v) to give the title compound (272 mg, 97%).
I got _{^{1 H-NMR (CDCl 3)}} δ; 1.32 (6H, d, J
= 6.8 Hz), 1.54 (9H, s), 2.93 (1
H, m), 6.66 (1H, br), 7.23 (1H,
d, J = 16.1 Hz), 7.33 (1H, d, J = 1)
6.1 Hz), 7.52 (1H, dd, J = 8.3)
7.8 Hz), 7.76 (1H, d, J = 7.8H)
z), 8.10 (1H, dd, J = 8.3, 1.5H
z), 8.33 (s, 1H).

(D) tert-butyl N- {4-isopropyl-2-[(E) -2- (3-aminophenyl)
-1-Ethenyl] -1,3-thiazol-5-yl} carbamate tert-butyl N- {4-isopropyl-2-[(E) -2- (3-nitrophenyl)-obtained by (C)
1-ethenyl] -1,3-thiazol-5-yl} carbamate (272 mg, 0.698 mmol) was dissolved in ethanol (10 ml), and stannous chloride (463 m
g) was added and the mixture was heated under reflux for 3 hours. After allowing the reaction solution to cool, a 5 M aqueous sodium hydroxide solution (20 ml) was added,
Stir for 15 minutes. Subsequently, extraction operation is performed with ethyl acetate,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (241 mg, 96%).

(E) 2- {2- [3-((E) -2-)
{5-[(tert-butoxycarbonyl) amino]-
4-isopropyl-1,3-thiazol-2-yl}-
1-ethenyl) amino] -2-oxoethyl benzoic acid tert-butyl N- {4-isopropyl-2-[(E) -2- (3-aminophenyl)-obtained by (D)
[1-Ethenyl] -1,3-thiazol-5-yl} carbamate (241 mg, 0.670 mmol) and homophthalic anhydride (163 mg, 1.01 mmol) were dissolved in toluene (8 ml), and the mixture was heated under reflux for 1 hour. The precipitated solid was collected by filtration, and the title compound (244 m
g, 70%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (6H,
d, J = 6.8 Hz), 1.46 (9H, s), 2.4
9 (1H, m), 4.09 (2H, s), 7.28-
7.44 (6H, m), 7.82-7.88 (2H,
m), 9.65 (1H, br), 10.3 (1H, b
r). FAB-MS; m / z: 522 (MH ⁺ )

(F) 2- {2- [3-((E) -2-)
{5-amino-4-isopropyl-1,3-thiazol-2-yl} -1-ethenyl) amino] -2-oxoethyl {benzoic acid 2- {2- [3- ( (E) -2- ｛5
-[(Tert-butoxycarbonyl) amino] -4-
Isopropyl-1,3-thiazol-2-yl} -1-
[Ethenyl) amino] -2-oxoethyl} benzoic acid (150 mg, 0.288 mmol) was dissolved in 4N hydrochloric acid-dioxane (3 ml) and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, diethyl ether was added to the residue. The precipitated crystals were collected by filtration and dried to give the title compound (148 mg, quantitative) as a dihydrochloride as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (6H,
d, J = 6.8 Hz), 3.39 (1H, m), 4.1
1 (2H, s), 7.11 (1H, d, J = 16.1H
z), 7.24-7.42 (7H, m), 7.52 (1
H, t, J = 7.8 Hz), 7.89 (1H, d, J =
7.8 Hz), 7.96 (1H, s), 10.1 (1
H, s). FAB-MS; m / z: 422 (MH ⁺ )

Example 6: 2- (2-oxo-2- @ 3-
((E) -2- (pyrido [3,2-d] [1,3] thiazol-2-yl) -1-ethenyl] anilinodiethyl) benzoic acid (A) N ^1- (2-chloro- 3-pyridyl)-(E)-
3- (3-nitrophenyl) -2-propenamide (E) -3- (3-nitrophenyl) -2-propenoic acid (6.02 g, 31.2 mmol) was suspended in toluene (250 ml), Thionyl chloride (2.7m
1, 37.4 mmol) was added dropwise, and the mixture was heated under reflux for 1.5 hours. After cooling, the solvent and excess reagent were distilled off and azeotroped with toluene to obtain (E) -3- (3-nitrophenyl) -2-propenoyl chloride as a white solid. This was suspended in THF (100 ml), and 3-amino-2 was added under ice-cooling.
-Chloropyridine (4.01 g, 31.2 mmol) was added, and the mixture was stirred at the same temperature for 5 minutes and then at room temperature for 19 hours.
A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the insoluble matter was collected by filtration.
0: 1, v / v), washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound (1.00 g) as a white solid. , 10.6%). ¹ H-NMR (CDCl ₃ ) δ: 6.97 (1H, d, J
= 15.6 Hz), 7.36 (1H, t, J = 4.9H)
z), 7.64 (1H, t, J = 7.8 Hz), 7.8
3 (1H, d, J = 15.6 Hz), 7.92 (1H,
d, J = 8.3 Hz), 8.16 (1H, d, J = 4.
9 Hz), 8.26 (1H, dd, J = 8.3, 1.0
Hz), 8.49 (1H, m), 8.75 (1H, d,
J = 6.8 Hz).

(B) 2-[(E) -2- (3-nitrophenyl) -1-ethenyl] pyrido [3,2-d] [1,
3] N ^1- (2-chloro-3-pyridyl) obtained with thiazole (A)
-(E) -3- (3-Nitrophenyl) -2-propenamide (0.69 g, 2.27 mmol) was suspended in pyridine (20 ml), and phosphorus pentasulfide (0.51 g, 2.
27 mmol), and the mixture was heated and stirred at about 100 ° C. for 5 hours, and then heated under reflux for 30 minutes. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, extracted with chloroform-methanol (10: 1, v / v), washed with saturated saline, and then washed.
After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform) and (hexane: ethyl acetate = 1: 1 → 1: 4,
(v / v → chloroform) to give the title compound (0.17 g, 26.4%) as a pale orange solid. ¹ H-NMR (CDCl ₃ ) δ: 7.46 (1H, dd,
J = 7.8, 4.4 Hz), 7.50 (1H, d, J =
15.6 Hz), 7.62 (1H, t, J = 7.8H)
z), 7.65 (1H, d, J = 15.6 Hz), 7.
91 (1H, d, J = 7.8 Hz), 8.21-8.4
0 (1H, m), 8.26 (1H, dd, J = 8.3,
1.5 Hz), 8.45-8.48 (1H, m), 8.
59 (1H, dd, J = 4.4, 1.5 Hz).

(C) 3-[(E) -2- (pyrido [3,
2-d] [1,3] thiazol-2-yl) -1-ethenyl] aniline 2-[(E) -2- (3-nitrophenyl) -1-ethenyl] pyrido obtained from (B). 3,2-d] [1,
3] Thiazole (0.10 g, 0.35 mmol) was suspended in ethanol (15 ml), tin (II) chloride monohydrate (278 mg, 1.24 mmol) was added, and the mixture was heated under reflux for 3.5 hours. Under ice-cooling, a 1.5 N aqueous sodium hydroxide solution was added to the reaction mixture, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as a yellow solid ( 92 mg, quantitative)
I got ¹ H-NMR (CDCl ₃ ) δ: 3.80 (2H, b
r), 6.72 (1H, dd, J = 7.8, 2.4H
z), 6.91 (1H, m), 7.01 (1H, d, J
= 7.3 Hz), 7.21 (1H, t, J = 7.8H)
z), 7.32 (1H, d, J = 16.1 Hz), 7.
40 (1H, dd, J = 8.3, 4.4 Hz), 7.4
9 (1H, d, J = 16.1 Hz), 8.19 (1H,
dd, J = 8.3, 1.5 Hz), 8.54 (1H, d
d, J = 4.4, 1.5 Hz).

(D) 2- (2-oxo-2- ｛3-
[(E) -2- (pyrido [3,2-d] [1,3] thiazol-2-yl) -1-ethenyl] anilinodiethyl) benzoic acid 3-[( E) -2- (pyrido [3,2
-D] [1,3] thiazol-2-yl) -1-ethenyl] aniline (90 mg, 0.36 mmol) was dissolved in toluene (2 ml) and homophthalic anhydride (about 75%, 86 mg, 0.1 mg) was added. 53 mmol)
The mixture was heated under reflux for 30 minutes. After cooling, the precipitate was collected by filtration and washed with ether to give the title compound (12) as a pale orange powder.
(1 mg, 82.0%). ¹ H-NMR (DMSO-d ₆ ) δ: 4.12 (2H,
s), 7.36-7.42 (3H, m), 7.48 (1
H, d, J = 16.1 Hz), 7.46-7.61 (4
H, m), 7.69 (1H, d, J = 16.1 Hz),
7.90 (1H, d, J = 7.3 Hz), 7.99 (1
H, br), 8.35 (1H, d, J = 8.3 Hz),
8.60 (1H, dd, J = 4.4, 1.0 Hz), 1
0.25 (1H, br), 12.80 (1H, br). EI / MS; m / z: 415 (M ⁺ ). FAB / MS; m / z: 416 (MH ^<+> ).

Example 7: 2- (2-3-[(E) -2-]
(1,3-benzoxazol-2-yl) -1-ethenyl] anilino-2-oxoethyl) benzoic acid 2-[(diethoxyphosphinyl) methyl] benzoxazole (J. Org. Chem. 1993, 58) ,
7009) and 3-nitrobenzaldehyde in Example 15
(F) and then treated as in Example 3 (B) to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 4.12 (2H,
s), 7.18 (1H, d), 7.38 (7H, m),
7.51 (1H, m), 7.61 (1H, d), 7.7
2 (3H, m), 7.91 (2H, m). MS (ES-); m / z: 397 (M ^<+> -l).

Example 8: 2- [2-oxo-2- (3-
(E) -2- [4- (4-Pyridyl) -1,3-thiazol-2-yl] -1-ethylanilino) ethyl] benzoic acid (A) 4-bromoacetylpyridine 4-acetylpyridine (1 g) Was dissolved in acetic acid (5 mL), and pyridinium hydrobromide perbromide (2.64 g) was added, followed by stirring at 50 ° C. for 3 hours. After the reaction solution was cooled with ice, the precipitated crystals were collected by filtration, washed with toluene and dried,
The title compound (0.934 g) was obtained as a white powder. ¹ H-NMR (CD ₃ OD) δ: 3.70 (1 H, d, J
= 11.1 Hz), 3.80 (1H, d, J = 10.8)
Hz), 8.25 (2H, d, J = 6.0 Hz), 8.
90 (2H, d, J = 6.0 Hz).

(B) 2-[(E) -2- (3-nitrophenyl) -1-ethenyl] -4- (4-pyridyl)-
4-Bromoacetylpyridine obtained with 1,3-thiazole (A) was treated according to the method described in JP-A-6-80654 to obtain the title compound. ¹ H-NMR (CD ₃ OD) δ: 7.68 (1 H, d, J
= 15.9 Hz), 7.70 (1H, d, J = 7.5H)
z), 7.81 (1H, d, J = 16.2 Hz), 8.
09 (1H, d, J = 7.8 Hz), 8.23 (1H,
d, J = 8.4 Hz), 8.53 (1H, t, J = 1.
8 Hz), 6.66 (2H, d, J = 6.9 Hz),
8.76 (1H, s), 8.87 (2H, d, J = 6.
9 Hz).

(C) 2- [2-oxo-2- (3-
(E) -2- [4- (4-Pyridyl) -1,3-thiazol-2-yl] -1-ethylanilino) ethyl] benzoic acid 2-[(E) -2 obtained by (B) -(3-nitrophenyl) -1-ethenyl] -4- (4-pyridyl) -1,
The 3-thiazole was treated as in Example 3 (B) to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 4.12 (2H,
s), 7.35-7.56 (5H, m), 7.90 (1
H, d, J = 8.1 Hz), 7.96 (2H, m),
8.44 (1H, s), 8.65 (2H, m), 10.
18 (1H, s). MS (ES-); m / z: 440 (M ⁺ -1).

Example 9: 2- (2-3-[(6-isopropyl-2-pyridyl) methoxy] anilino-2-oxoethyl) benzoic acid (A) 2-isopropylpyridine-N-oxide 2-isopropylpyridine (5 g) in acetic acid (27 mL)
, And peracetic acid (9.2 mL, 37% solution) was added dropwise, followed by stirring at 70 ° C. for 16 hours. The solvent was carefully distilled off under reduced pressure, toluene was added to the residue, and residual acetic acid was azeotropically distilled off under reduced pressure. The residue was purified by distillation, 127 ° C
The title compound (4.9 g) was obtained from a / 1 mmHg fraction. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (6H, d, J
= 6.9 Hz), 3.91 (1H, Heptule)
t, J = 6.9 Hz), 7.28 (1H, m), 7.3
8-7.47 (2H, m), 8.50 (1H, d, J =
6.3 Hz).

(B) 6-Isopropyl-2-cyanopyridine 2-isopropylpyridine-N-oxide (4.9 g) obtained in (A) was treated with dimethylformamide (25 mL).
And sodium cyanide (5.26 g) and triethylamine (20 mL) were added. After chlorotrimethylsilane (13.6 mL) was added dropwise to the solution, 120
Stirred at C for 16 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure. The residue was partitioned between ethyl acetate and 7% aqueous lithium chloride solution, washed with brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate, 85:15, v
/ V), and the title compound (978m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, d, J
= 7.2 Hz), 3.22 (1H, Heptule)
t, J = 7.2 Hz), 7.50 (1H, dd, J =
7.9, 1.2 Hz), 7.62 (1H, dd, J =
7.6, 1.0 Hz), 7.83 (1H, t, J = 8.
1 Hz).

(C) 6-Isopropylpicolinic acid 5N hydrochloric acid (13.5 mL) was added to 6-isopropyl-2-cyanopyridine (978 mg) obtained in (B), and the mixture was stirred at 110 ° C for 16 hours. After cooling the reaction solution, the pH was adjusted to 5.5 with 1N sodium hydroxide, and the precipitate was collected by filtration.
Drying afforded the title compound (534 mg). The pH of the mother liquor was adjusted to 5.5 with 1N hydrochloric acid and extracted five times with methylene chloride.
After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 324 mg. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (6H, d, J
= 6.9 Hz), 3.23 (1H, heterogeneous)
t, J = 6.9 Hz), 7.55 (1H, d, J = 8.
1 Hz), 7.96 (1H, t, J = 7.8 Hz),
8.14 (1H, d, J = 7.5 Hz).

(D) 6-isopropylpicolinic acid (200 mg) obtained with 6-isopropyl-2-hydroxymethylpyridine (C) was dissolved in tetrahydrofuran (6 mL), and borane tetrahydrofuran was added at 0 ° C. under a nitrogen atmosphere. Complex (1M, 6 mL) was added dropwise. After stirring at the same temperature for 3.5 hours, methanol was added, and the solvent was distilled off under reduced pressure. 1N hydrochloric acid was added to the residue, and the mixture was stirred for 20 minutes. The pH was adjusted to 11 with 5N sodium hydroxide, extracted four times with methylene chloride, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride: methanol, 99: 1, v / v) to give the title compound (145 mg) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (d, J = 6.
9, 6H), 3.18 (heptuplet, J = 6.
9, 1H), 4.84 (s, 2H), 7.12 (d, J
= 7.8, 1H), 7.18 (d, J = 7.5, 1
H), 7.71 (d, J = 7.8, 1H).

(E) 3-Nitro-1-[(6-isopropyl-2-pyridyl) methoxy] benzene 6-isopropyl-2-hydroxymethylpyridine (118 mg) obtained from (D), triphenylphosphine ( 248 mg), 3-nitrophenol (132 m
g) was dissolved in anhydrous tetrahydrofuran (7 mL), diethyl azodicarboxylate (150 μL) was added at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate, 1: 1:
1, v / v) to give the title compound (202 mg) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, d, J
= 6.9 Hz), 3.19 (1H, heterogeneous)
t, J = 6.9 Hz), 5.37 (1H, s), 7.2
4 (1H, d, J = 7.5 Hz), 7.42 (1H,
d, J = 7.8 Hz), 7.44 (1H, ddd, J =
8.4, 2.7, 1.2 Hz), 7.54 (1H, t,
J = 8.4), 7.76 (1H, t, J = 7.5H)
z), 7.94 (1H, ddd, J = 8.1, 2.4,
1.2Hz), 8.00 (1H, t, J = 2.4H)
z).

(F) 2- [2-oxo-2- (3-
(E) -2- [4- (4-Pyridyl) -1,3-thiazol-2-yl] -1-ethylanilino) ethyl] benzoic acid 3-Nitro-1-[(obtained by (E) 6-Isopropyl-2-pyridyl) methoxy] benzene in Example 3
The same treatment as in (B) was performed to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, d, J
= 6.9 Hz), 3.32 (1H, heterogeneous)
t, J = 6.9 Hz), 4.08 (1H, s), 5.3
2 (1H, s), 6.34 (1H, broads),
7.15 (2H, m), 7.29 (2H, m), 7.4
0-7.63 (3H, m), 7.57 (2H, m),
7.82 (1H, td, J = 7.5, 2.4 Hz),
8.11 (1H, d, J = 8.1 Hz). MS (ES-); m / z: 403 (M ⁺ -1).

Example 10: 2- (2-oxo-2- ｛3
-[2- (4-phenyl-1,3-thiazol-2-yl) ethyl] anilinodiethyl) benzoic acid (A) methyl (E) -3- (3-nitrophenyl)-
2-propenate 3-nitrocinamic acid (10.00 g, 5
(1.8 mmol) was suspended in methanol (300 ml), concentrated sulfuric acid (10 ml) was added dropwise, and the mixture was heated and refluxed for 6 hours while dehydrating with a dropping funnel containing molecular sieves. After evaporating the solvent, water was added to the residue, and the mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as a white solid. (10.72 g, quantitative). ¹ H-NMR (CDCl ₃ ) δ: 3.84 (3H, s),
6.59 (1H, d, J = 16.1 Hz), 7.59
(1H, t, J = 7.8 Hz), 7.73 (1H, d,
J = 16.1 Hz), 7.83 (1H, d, J = 7.8)
Hz), 8.24 (1H, td, J = 7.3, 1.5H)
z), 8.38 (1H, t, J = 1.5 Hz).

(B) Methyl 3- (3-aminophenyl) propanate Methyl (E) -3- (3-nitrophenyl) -2-propenate obtained in (A) (2.01 g, 9.70 m)
mol) in methanol-ethyl acetate (1: 1, v / v,
500%) and 10% palladium on carbon (0.2
g) was added and the mixture was stirred at room temperature under a hydrogen stream (1 atm) for 24 hours. After filtering off the catalyst, the solvent was distilled off to obtain the title compound (1.73 g, quantitative) as a pale orange oil. ¹ H-NMR (CDCl ₃ ) δ: 2.59 (2H, t, J
= 7.8 Hz), 2.84 (2H, t, J = 7.8H)
z), 3.66 (3H, s), 3.66 (2H, b
r), 6.47-6.53 (2H, m), 6.58 (1
H, d, J = 7.3 Hz), 7.06 (1H, td, J)
= 7.8, 2.9 Hz).

(C) Methyl 3- {3-[(N-ter
Methyl 3- (3-aminophenyl) obtained from (t-butoxycarbonyl) amino] phenyl} propanate (B)
Dissolve propanate (1.73 g, 9.65 mmol) in chloroform (80 ml) and di-tert-butyl dicarbonate (3.16 g, 14.5 mmol)
And triethylamine (336 μl, 2.41 mm
ol) was added dropwise and stirred at room temperature for 21 hours. TLC
Above, since the raw materials remained, di-tert-butyl
Dicarbonate (3.16 g, 14.5 mmol) and triethylamine (336 μl, 2.41 mmol)
Was added, and the mixture was stirred at room temperature for 5 hours. Since the raw material still remained, di-tert-butyl dicarbonate (3.16 g, 14.5 mmol) was added, and the mixture was stirred at room temperature for 17 hours. After evaporating the solvent, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
Purification was carried out using 1, v / v → chloroform to give the title compound (2.34 g, 86.8%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s),
2.62 (2H, t, J = 7.8 Hz), 2.92 (2
H, t, J = 7.8 Hz), 3.67 (3H, s),
6.46 (1H, br), 6.87 (1H, d, J =
7.3 Hz), 7.13-7.25 (2H, m), 7.
26 (1H, br).

(D) tert-butyl N- [3- (3
-Amino-3-oxopropyl) phenyl] carbamate Methyl 3- {3-[(N-tert) obtained with (C)
-Butoxycarbonyl) amino] phenyl} propanate (1.84 g, 6.59 mmol) in methanol (1
0 ml) and an ammonia-methanol solution (30 ml).
ml) was added dropwise and stirred at room temperature for 18 hours. On TLC,
Since many raw materials remained, an ammonia-methanol solution (100 ml) was added, and the mixture was stirred at room temperature for 6 hours. Since the raw materials still remained, concentrated ammonia water (28%,
50 ml), and the mixture was further stirred at room temperature for 17 hours. After the methanol was distilled off, the residue was extracted with ethyl acetate, washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The title compound (1.60 g, 91.
9%). ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s),
2.52 (2H, t, J = 7.8 Hz), 2.94 (2
H, t, J = 7.8 Hz), 5.44 (2H, br),
6.54 (1H, br), 6.89 (1H, d, J =
7.3 Hz), 7.10-7.22 (2H, m), 7.
31 (1H, br).

(E) tert-butyl N- [3- (3
-Amino-3-thioxopropyl) phenyl] carbamate tert-butyl N- [3- (3-
Amino-3-oxopropyl) phenyl] carbamate (1.58 g, 5.98 mmol) in THF (30 m
1) and the inside of the reaction system was replaced with nitrogen. Lawess
The ons' reagent (1.21 g, 2.99 mmol) was added, and the mixture was stirred at room temperature for 10 minutes and then heated at about 60 ° C. for 2.5 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 30: 1, v / v) to give the title compound (1.08 g, 64.7%) as a pale yellow oil. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s),
2.94 (2H, t, J = 7.3 Hz), 3.08 (2
H, t, J = 7.8 Hz), 6.51 (1H, br),
6.81 (1H, br), 6.92 (1H, d, J =
7.8 Hz), 7.11 (1H, d, J = 8.3H)
z), 7.21 (1H, t, J = 7.8 Hz), 7.3
5 (2H, br).

(F) 3- [2- (4-phenyl-1,3
-Thiazol-2-yl) ethyl] aniline tert-butyl N- [3- (3-
[Amino-3-thioxopropyl) phenyl] carbamate (200 mg, 0.72 mmol) in ethanol (5
phenacyl bromide (142 mg,
(0.72 mmol) and heated to reflux for 1 hour and 20 minutes. After evaporating the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
This was dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. After evaporating the solvent, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (chloroform) to give the title compound (19) as a yellow oil.
4 mg, 96.9%). ¹ H-NMR (CDCl ₃ ) δ: 3.06 (2H, t, J
= 7.8 Hz), 3.33 (2H, t, J = 7.8H)
z), 3.61 (2H, br), 6.52-6.58.
(2H, m), 6.65 (1H, d, J = 7.3H
z), 7.08 (1H, t, J = 7.3 Hz), 7.2
8-7.35 (2H, m), 7.41 (2H, t, J =
7.8 Hz), 7.89 (2H, d, J = 7.8H)
z).

(G) 2- (2-oxo-2- {3- [2
-(4-Phenyl-1,3-thiazol-2-yl) ethyl] anilinodiethyl) benzoic acid 3- [2- (4-phenyl-1,3-
Thiazol-2-yl) ethyl] aniline (194m
g, 0.69 mmol) was dissolved in toluene (5 ml) and homophthalic anhydride (about 75%, 16
8 mg, 1.04 mmol), and the mixture was heated under reflux for 30 minutes. After cooling, the insolubles were collected by filtration and washed with ether to give the title compound (187 mg, 61.0 mg) as a white powder.
%). ¹ H-NMR (DMSO-d ₆ ) δ: 3.05 (2H,
t, J = 7.8 Hz), 3.33 (2H, t, J = 7.
8 Hz), 4.08 (2H, s), 6.95 (1H,
d, J = 7.8 Hz), 7.20 (1H, t, J = 7.
8 Hz), 7.30-7.45 (7H, m), 7.51
(1H, td, J = 7.3, 1.5 Hz), 7.55
(1H, br), 7.88 (1H, dd, J = 7.8,
1.5Hz), 7.92-7.96 (2H, m), 1
0.04 (1H, br), 12.82 (1H, br). FAB / MS; m / z: 443 (MH ^<+> ).

Example 11: 2- (2-oxo-2- ｛3
-[2- (4-phenyl-1,3-thiazol-2-yl) cyclopropyl] anilinodiethyl) benzoic acid (A) methyl 2- (3-nitrophenyl) -1-cyclopropanecarboxylate ether ( 30 ml) and a 40% aqueous potassium hydroxide solution (10 ml) were vigorously stirred under ice-cooling to give N-methyl-
N′-nitro-N-nitrosoguanidine (3.55 g,
24.1 mmol) was added little by little, and the mixture was stirred at the same temperature for 30 minutes. The solution was allowed to stand, and a diazomethane-ether solution was prepared as an upper layer. On the other hand, methyl (E) -3- (3-nitrophenyl) -2-propenate (500 mg, 2.41 mmol) synthesized in Example 10 (A) was dissolved in ether (300 ml), and palladium acetate (5 mg,
0.024 mmol), and the atmosphere in the reaction system was replaced with nitrogen. Under ice cooling, the diazomethane-ether solution prepared above was slowly added thereto, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. Acetic acid was added to the reaction solution, and the solvent was distilled off, followed by azeotropic distillation with toluene. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1, v
/ V) to give the title compound (5) as a pale yellow oil.
04 mg, 94.4%). ¹ H-NMR (CDCl ₃ ) δ: 1.34-1.42 (1
H, m), 1.64-1.73 (1H, m), 1.93.
−2.01 (1H, m), 1.58-1.66 (1H,
m), 3.74 (3H, s), 7.46 (2H, d, J
= 5.4 Hz), 7.94 (1H, s), 8.03-
8.10 (1H, m).

(B) 2- (3-nitrophenyl) -1-
Methyl 2- (3-nitrophenyl) obtained with cyclopropane carboxylic acid (A)
-1-cyclopropanecarboxylate (497 mg,
2.25 mmol) in methanol (5 ml)
1N sodium hydroxide aqueous solution (5 ml, 5.0 mmol
After l) was added dropwise and the mixture was stirred at room temperature for 1 hour, the solvent was distilled off. A 1N aqueous hydrochloric acid solution was added to the residue to adjust the pH to about 1, and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The title compound (471 mg, quantitative ) Got. ¹ H-NMR (CD ₃ OD) δ: 1.30-1.39
(0.5H, m), 1.40-1.49 (0.5H,
m), 1.54-1.64 (1H, m), 1.92-
2.05 (1H, m), 2.50-2.56 (0.5
H, m), 2.58-2.64 (0.5H, m), 7.
48-7.58 (2H, m), 8.00 (1H, d, J
= 8.8 Hz), 8.02-8.10 (1H, m).

(C) 2- (3-nitrophenyl) -1-
2- (3-nitrophenyl) -1-cyclopropanecarboxylic acid obtained with cyclopropanecarboxamide (B) (460 mg,
Thionyl chloride (10 ml) was added to 2.22 mmol), and the mixture was heated under reflux for 30 minutes. After cooling, excess reagent was distilled off and azeotroped with toluene. Under ice-cooling, concentrated aqueous ammonia (28%, 20 ml) was added thereto, and the mixture was stirred at the same temperature for 2 hours.
Stirred at room temperature for 14 hours. The precipitate was collected by filtration, washed with water, and dried to give the title compound (398m) as a pale yellow powder.
g, 87.1%). ¹ H-NMR (CD ₃ OD) δ: 1.32-1.39
(0.5H, m), 1.52-1.62 (1H, m),
1.66-1.73 (0.5H, m), 1.95-2.
01 (1H, m), 1.48-1.55 (0.5H,
m), 2.78-2.87 (0.5H, m), 2.49
-2.64 (2H, m), 7.97-8.14 (2H,
m).

(D) 2- (3-nitrophenyl) -1-
Cyclopropanecarbothioamide 2- (3-Nitrophenyl) -1-cyclopropanecarboxamide obtained with (C) (183 mg, 0.89 m
mol) was suspended in THF (5 ml), and the inside of the reaction system was replaced with nitrogen. Here Lawesson's reagent (179m
g, 0.44 mmol) and stirred at about 70 ° C. for 1.5 hours. After cooling, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 30: 1, v / v) to give the title compound (122 mg, 62.0%) as a pale yellow oil.
I got ¹ H-NMR (CDCl ₃ ) δ: 1.50-1.62 (1
H, m), 1.97-2.08 (1H, m), 2.15
-2.24 (1H, m), 2.81-2.91 (1H,
m), 7.21 (1H, br), 7.46 (1H, t,
J = 7.8 Hz), 7.53 (1H, d, J = 7.8H)
z), 7.60 (1H, br), 7.92 (1H,
s), 8.05 (1H, d, J = 7.8 Hz).

(E) 2- [2- (3-nitrophenyl)
Cyclopropyl] -4-phenyl-1,3-thiazole 2- (3-nitrophenyl) -1-cyclopropanecarbothioamide obtained with (D) (122 mg, 0.55
was dissolved in ethanol (5 ml), 2-bromoacetophenone (109 mg, 0.55 mmol) was added, and the mixture was heated under reflux for 1 hour. After cooling, the solvent was distilled off, and the residue was powdered from ethanol and ether, collected by filtration, and washed with ether to give the title compound (158 mg, 89.0%) as a pale orange powder. _{^{1 H-NMR (CDCl 3)}} δ: 1.70-1.80 (1
H, m), 1.91-2.00 (1H, m), 2.09
−2.19 (1H, m), 2.85-2.96 (1H,
m), 7.47 (1H, s), 7.48-7.60 (4
H, m), 7.73 (1H, d, J = 7.3 Hz),
8.05-8.20 (4H, m).

(F) 3- [2- (4-phenyl-1,3
-Thiazol-2-yl) cyclopropyl] aniline 2- [2- (3-nitrophenyl) cyclopropyl] -4-phenyl-1,3-thiazole (151 mg, 0.47 mmol) obtained in (E) was used. Ethanol (10
ml), and tin (II) chloride monohydrate (372 m
g, 1.65 mmol) and heated to reflux for 5 hours.
Under ice-cooling, a 1.5 N aqueous sodium hydroxide solution was added to the reaction solution, extracted with chloroform, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as a pale orange oil. The compound (114 mg, 83.1%) was obtained.

(G) 2- (2-oxo-2- {3- [2
-(4-Phenyl-1,3-thiazol-2-yl) cyclopropyl] anilinodiethyl) benzoic acid 3- [2- (4-phenyl-1,3-
Thiazol-2-yl) cyclopropyl] aniline (1
14 mg, 0.39 mmol) was dissolved in toluene (3 ml) and homophthalic anhydride (about 75%,
95 mg, 0.59 mmol) and heated under reflux for 30 minutes. After cooling, the insolubles were collected by filtration and washed with ether to give the title compound (139 mg, 78.4) as a white powder.
%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.53-1.63
(1H, m), 1.70-1.80 (1H, m), 2.
47-2.57 (1H, m), 2.61-2.71 (1
H, m), 4.07 (2H, s), 6.90 (1H,
d, J = 7.8 Hz), 7.21 (1H, t, J = 7.
8Hz), 7.29-7.52 (8H, m), 7.84
−7.89 (2H, m), 7.89−8.50 (2H,
m), 10.05 (1H, s), 12.75 (1H, b
r). EI / MS; m / z: 454 (M ⁺ ). FAB / MS; m / z: 455 (MH ^<+> ).

Example 12: 2- (2-oxo-2- (3
-((4-phenyl-1,3-thiazol-2-yl)
Amino) carbonylanilino) ethyl) benzoic acid (A) 4-phenyl-1,3-thiazol-2-amine 2-bromoacetophenone (13.1 g, 65.7 mm)
ol) and thiourea (5.00 g, 65.7 mmol) were dissolved in ethanol (100 mL) and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give the title compound (16.5 g, 91
%). ¹ H-NMR (CDCl ₃ ) δ: 7.10 (1H, s),
7.48-7.54 (3H, m), 7.67 (2H, d
d, J = 1.5, 7.8 Hz).

(B) N ^1- (4-Phenyl-1,3-thiazol-2-yl) -3-nitrobenzamide 4-Phenyl-1,3-thiazole- obtained by (A)
2-amine (250 mg, 0.972 mmol), 3-
Dissolve nitrobenzoic acid (163 mg, 0.972 mmol) in methylene chloride (10 mL) and diisopropylamine (0.508 mL, 2.92 mmol) at 0 ° C.
N, N-bis (2-oxo-3-oxazolidinyl) phosphorodiamidic chloride (297 mg, 1.17 m)
mol), and DMF (5 mL) was further added. After stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (hexane-ethyl acetate,
5: 1, v / v) to give the title compound as a white solid (59.9 mg, 19%), a fraction of the mixture was recrystallized from hexane to give the title compound as a white solid (44.7 mg, 14%). ¹ H-NMR (CDCl ₃ ) δ: 7.14-7.23 (4
H, m), 7.45-7.49 (1H, m), 7.46.
(1H, t, J = 8.3 Hz), 7.48 (1H, t,
J = 7.8 Hz), 8.10 (1H, dd, J = 1.
0, 7.8 Hz), 8.22 (1H, dt, J = 8.
3,1.0 Hz), 8.51 (1H, t, J = 2.0H)
z), 12.09 (1H, br).

(C) N ^1- (4-Phenyl-1,3-thiazol-2-yl) -3-aminobenzamide N ^1- (4-phenyl-1,3-thiazole- obtained by (B) 2-yl) -3-nitrobenzamide (105
mg, 0.322 mmol) in ethanol (5 mL) and tin (II) chloride dihydrate (363 mg, 1.
61 mmol) and heated under reflux for 2 hours. A 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, hexane was added, and the precipitated solid was collected by filtration to give the title compound as a white solid (75.8 mg,
80%). ¹ H-NMR (CD ₃ OD) δ: 7.04-7.07 (1
H, m), 7.28-7.44 (7H, m), 7.93
-7.95 (2H, m).

(D) 2- (2-oxo-2- (3-
((4-phenyl-1,3-thiazol-2-yl) amino) carbonylanilino) ethyl) benzoic acid N ^1- (4-phenyl-1,3-thiazol-2- obtained by (C) Yl) -3-aminobenzamide (75.
8 mmol, 0.257 mmol) in toluene (5 m
L), and homophthalic anhydride (62.4 mg,
(0.385 mmol), and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, toluene was added, and the precipitated solid was collected by filtration to give the title compound as a white amorphous (105 m
g, 89%). ¹ H-NMR (DMSO-d ₆ ) δ: 4.14 (2H,
s), 7.32-7.48 (7H, m), 7.52-
7.56 (1H, m), 7.69 (1H, s), 7.82
(2H, d, J = 7.8 Hz), 7.90 (1H, d
d, J = 1.5, 6.8 Hz), 7.85 (2H, d,
J = 7.3 Hz), 8.28 (1H, br), 10.3
1 (1H, br), 12.75 (1H, br). FAB-MS; m / z: 458 (MH ^<+> ).

Example 13: 2- (2-2,4-difluoro-5-[(3-isopropyl-1,2,4-thiadiazol-5-yl) methoxy] anilino-2-oxoethyl) benzoic acid ( A) Ethyl 3-isopropyl-1,2,4-thiadiazole-5-carboxylate isobutyric acid amide (9.1 g, 0.104 mol) was suspended in toluene (300 mL), and chlorocarbonylsulfenyl chloride (15 g, 0.1 g) was added. 115 mol)
The mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and ethyl cyanoformate (50 mL) and xylene (40 m
L) was added and the mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure,
The residue was purified by silica gel chromatography (hexane-ethyl acetate, 4: 1, v / v) to give the title compound (14 g, 67%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (6H, d, J
= 7.2 Hz), 1.54 (3H, t, J = 7.2H)
z), 3.56 (1H, m), 4.60 (2H, q, J
= 7.2 Hz).

(B) (3-isopropyl-1,2,4-
Thiadiazol-5-yl) methanol Ethyl 3-isopropyl-1,2,2 obtained from (A)
4-thiadiazole-5-carboxylate (13.8
g, 68.9 mmol) in methanol (500 mL), and stirred under ice-cooling with sodium borohydride (4.4).
g) was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and water. After separating the organic layer, the aqueous layer was made weakly acidic and extracted again with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
The title compound (10.7 g, 98%) was obtained as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (6H, d, J
= 7.2 Hz), 3.41 (1H, m), 5.09 (2
H, s).

(C) 2,4-Difluoro-5-nitrophenyl [(3-isopropyl-1,2,4-thiadiazol-5-yl) methyl] ether (B) , 2,4-thiadiazol-5-yl) methanol (4.5 g, 2
8.4 mmol), 2,4-difluoro-5-nitrophenol (5.0 g, 28.6 mmol) and triphenylphosphine (10 g) were dissolved in THF (200 ml), and diethyl azodicarboxylate (6 ml) was dissolved under ice-cooling. )
Was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 19 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane-methylene chloride, 1: 2, v / v) to give the title compound (6.0 g, 67) as a pale yellow oil.
%). ¹ H-NMR (CDCl ₃ ) δ: 1.41 (6H, d, J
= 7.2 Hz), 3.35 (1H, m), 5.57 (2
H, s), 7.15 (1H, t, J = 10.0 Hz),
7.89 (1H, t, J = 6.8 Hz).

(D) 2- (2-2,4-difluoro-5)
-[(3-isopropyl-1,2,4-thiadiazol-5-yl) methoxy] anilino-2-oxoethyl)
2,4-Difluoro-5-nitrophenyl [(3-isopropyl-1,2,4-thiadiazol-5-yl) methyl] ether obtained with benzoic acid (C) (2.1 g, 6.66)
mmol) in ethyl acetate (50 ml) and 10%
Add palladium carbon (water 50%, 200 mg) and add 5
Catalytic reduction was performed at 0 ° C. for 4 hours. After removing the catalyst by filtration and evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane-ethyl acetate, 1: 2, v / v) to obtain a pale brown oil (510 mg, 27%). . 10 of these
0 mg was dissolved in toluene (3 ml), homophthalic anhydride (60 mg) was added, and the mixture was stirred at 80 ° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform-methanol, 20: 1, v / v) to give the title compound (136 mg, 86%) as a white powder.
%). ¹ H-NMR (CD ₃ OD) δ: 1.36 (6H, d, J
= 6.8 Hz), 3.28 (1H, m), 4.03 (2
H, s), 5.52 (2H, s), 7.08 (1H,
m), 7.30-7.45 (3H, m), 7.88 (1
H, d, J = 7.6 Hz), 7.96 (1H, t, J =
8.8 Hz). FAB-MS; m / z: 448 (MH ⁺ )

Example 14: 2- (3-amino-5-
((4-Isopropyl-1,3-thiazol-2-yl) methoxy) anilino-2-oxoethyl) benzoic acid (A) 2- (chloromethyl) -4-isopropyl-1,
3-thiazole (4-isopropyl-1,3-thiazol-2-yl)
Methanol (1.04 g, 6.59 mmol) was dissolved in methylene chloride (10 mL), thionyl chloride (721 μL, 9.88 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure and azeotroped with toluene.
The residue was diluted with diethyl ether, and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (982 mg, 85%) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.8 Hz), 3.09 (1H, septet, J =
6.8 Hz), 4.83 (2H, s), 6.91 (1
H, d, J = 1.0 Hz).

(B) 2-((3,5-dinitrophenoxy) methyl) -4-isopropyl-1,3-thiazole 3,5-dinitrophenol (686 mg, 3.37 m)
mol) in DMF (5 mL) at 0 ° C. in sodium hydride (60% in oil, 224 mg, 5.5).
9 mmol) and stirred at 0 ° C. for 10 minutes. 2- (chloromethyl) -4-isopropyl-1,3-thiazole obtained in (A) at 0 ° C. (982 mg, 5.59 m)
mol) in DMF (5 mL) was added dropwise at room temperature.
Stir for 6 hours. The reaction solution was diluted with a 1N aqueous hydrochloric acid solution at 0 ° C., and extracted with ethyl acetate. The organic layers were combined and washed with water and saturated saline. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate, 10:
1, v / v) to give the title compound (435 mg, 36%) as brown crystals. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.8 Hz, 3.12 (1H, septet, J =
6.8 Hz), 5.52 (2H, s), 6.98 (1
7. H, s, 8.26 (2H, d, J = 2.0 Hz);
68 (1H, t, J = 2.0 Hz).

(C) 5-((4-isopropyl-1,3
-Thiazol-2-yl) methoxy) -1,3-benzenediamine 2-((3,5-dinitrophenoxy) methyl) -4-isopropyl-1,3-thiazole obtained in (B) (435 mg, 1 .34 mmol) of ethanol (10
mL) solution, tin (II) chloride dihydrate (3.04
g, 13.5 mmol) and heated to reflux for 2 hours.
A 4N aqueous sodium hydroxide solution was added to the reaction solution at 0 ° C., and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (351 mg, 71%) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 7.3H), 1.61 (2H, br), 3.10 (1
H, septet, J = 7.3 Hz, 3.59 (2H,
br), 5.25 (2H, s), 5.70 (1H, t,
J = 2.0 Hz), 5.80 (2H, d, J = 2.0H)
z), 6.87 (1H, s).

(D) tert-butyl N-3-amino-5-((4-isopropyl-1,3-thiazole-2
-Yl) methoxy) phenylcarbamate 5-((4-isopropyl-1,3-
Thiazol-2-yl) methoxy) -1,3-benzenediamine (351 mg, 1.33 mmol) in THF
To the (10 mL) solution was added di-tert-butyl dicarbonate (291 mg, 1.33 mmol) at 0 ° C., and the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform (chloroform-methanol, 98: 2, v / v)) to give the title compound as a brown oil (238 mg, 49
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 1.50 (9H, s), 1.58 (2
H, br), 3.10 (1H, septet, J = 6.
8Hz), 5.26 (2H, s), 6.03 (1H,
t, J = 2.0 Hz), 6.36 (1H, t, J = 2.
0 Hz), 6.55 (1H, s), 6.88 (1H,
s).

(E) 2- (3- (tert-butoxycarbonyl) amino) -5-((4-isopropyl-1,
3-thiazol-2-yl) methoxy) anilino-2-
Oxoethyl) benzoic acid tert-butyl N-3-amino- obtained by (D)
5-((4-isopropyl-1,3-thiazole-2-
Yl) methoxy) phenyl carbamate in toluene (5
mL) and homophthalic anhydride (159 mg,
0.983 mmol) and heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform (chloroform-methanol, 98: 2 (96: 4, v / v)) to obtain the title compound as white crystals (292 mg, 85%). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J
= 6.8 Hz), 1.47 (9H, s), 3.12 (1
H, septetJ = 6.8 Hz), 3.99 (2H,
s), 5.26 (2H, s), 6.79 (1H, s),
6.87 (1H, s), 6.93 (1H, s), 7.1
2-7.58 (4H, m), 8.05 (1H, d, J =
7.8 Hz), 8.95 (1 H, s).

(F) 2- (3-amino-5-((4-isopropyl-1,3-thiazol-2-yl) methoxy) anilino-2-oxoethyl) benzoic acid (E) -(3- (tert-butoxycarbonyl) amino) -5-((4-isopropyl-1,3
-Thiazol-2-yl) methoxy) anilino-2-oxoethyl) benzoic acid (100 mg, 0.1 mg).
190 mmol), 4N hydrochloric acid-dioxane (2 mL) was added dropwise at 0 ° C. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure by azeotropic distillation with toluene and ether, and ether was added to the residue, followed by filtration to obtain the title compound as white crystals (78.8 mg, 83%) as dihydrochloride. Was. ^{1 H-NMR (DMSO-d} 6 -CDCl 3) δ: 1.3
5 (6H, d, J = 6.8 Hz), 3.18 (1H, s
eptet, J = 6.8 Hz), 3.92 (2H, b
r), 4.06 (2H, s), 5.41 (2H, s),
6.86 (1H, s), 7.11 (1H, s), 7.3
0-7.52 (6H, m), 7.99 (1H, d, J =
7.8 Hz), 10.18 (1H, s). FAB-MS; m / z: 426 (MH ⁺ )

Example 15: (4S, 5S) -5-[(5
-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3-pyridylamino) carbonyl] -2,2-dimethyl-1,3-dioxolan-4- Carboxylic acid (A) 5-[(tert-Butoxycarbonyl) amino] nicotinic acid 5-pyridinedicarboxylic acid (5.00 g, 29.9 mmol) was added to t-
Suspended in butanol (35 ml), triethylamine (8.34 ml, 59.8 mmol) and diphenylphosphoric azide (7.10 ml, 32.9 mmol) were added dropwise, and the mixture was heated under reflux for 3 hours. Under ice-cooling, a 1N aqueous solution of sodium hydroxide was added to the reaction solution to adjust the pH to> 10, followed by ether washing. Under ice cooling again, the pH was adjusted to about 4 with a 1N aqueous hydrochloric acid solution, and the precipitate was collected by filtration, washed with water and ether,
The title compound as a white powder (3.27 g, 45.9%)
I got ¹ H-NMR (DMSO-d ₆ ) δ: 1.49 (9H,
s), 8.45 (1H, s), 8.66 (1H, s),
8.75 (1H, s), 9.83 (1H, br).

(B) tert-butyl N- (5- [methoxy (methyl) amino] carbonyl-3-pyridyl)
Carbamate 5-[(tert-butoxycarbonyl) amino] nicotinic acid obtained in (A) (3.25 g, 1
3.6 mmol) were suspended in methylene chloride (100 ml) and N, O-dimethylhydroxylamine hydrochloride (2.
00 g, 20.5 mmol), and N, N-bis- (2-oxo-3-oxazolidinyl) phosphinic chloride (6.95 g, 27.3 mmol) under ice cooling.
Diisopropylethylamine (9.51 ml, 54.6
mmol) was added dropwise. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 24 hours, and the solvent was distilled off. Water was added to the residue, and the mixture was extracted with chloroform, washed sequentially with a 5% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then washed.
After drying over anhydrous sodium sulfate and evaporating the solvent, the title compound (1.
80 g, 46.9%). ¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s),
3.38 (3H, s), 3.59 (3H, s), 7.2
7 (1H, br), 8.24 (1H, br), 8.59
(1H, d, J = 1.9 Hz), 8.64 (1H, d,
J = 1.9 Hz).

(C) tert-Butyl N- (5-formyl-3-pyridyl) carbamate The tert-butyl N- (5- [methoxy (methyl) amino] carbonyl-3-pyridyl) carbamate obtained in (B) (1.80 g, 6.40 mmol) in THF
(20 ml), and the system was replaced with nitrogen. -78 ° C
After cooling, lithium aluminum hydride (291 mg,
7.68 mmol) in THF (10 ml).
The mixture was added little by little over a period of minutes, stirred at the same temperature for 2.5 hours, and then stirred under ice cooling for 20 minutes. After cooling again to -78 ° C, 5%
An aqueous solution of potassium hydrogen sulfate (20 ml) was added, and the temperature was raised to room temperature. After evaporating the solvent, the residue was extracted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
The title compound (1.42 g, quantitative) was obtained as a mixture of a yellow foxtail and an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s),
6.78 (1H, br), 8.44 (1H, br),
8.69 (1H, d, J = 1.9 Hz), 8.75 (1
H, d, J = 1.9 Hz), 10.10 (1H, s).

(D) 2- (bromomethyl) -4-isopropyl-1,3-thiazole (4-isopropyl-1,3-thiazol-2-yl)
Methanol (1.55 g, 9.86 mmol) was dissolved in methylene chloride (20 ml), triphenylphosphine (3.10 g, 11.8 mmol) was added, and carbon tetrabromide (3.92 g, 11.8 mmol) / chloride was added. Methylene (1
0 ml) solution was added dropwise and stirred at room temperature for 30 minutes. After evaporating the solvent, the residue was subjected to silica gel column chromatography (hexane → hexane: ethyl acetate = 10: 1, v / v
v) to give the title compound (1.3) as a yellow oil.
9g, 64.1%). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J
= 7.3 Hz), 3.01-3.15 (1H, m),
4.72 (2H, s), 6.92 (1H, s).

(E) Diethyl [(4-isopropyl-
1,3-thiazol-2-yl) methyl] phosphonate 2- (bromomethyl) -4-isopropyl-1,3-thiazole (1.39 g, 6.31 mm) obtained in (D).
ol) in toluene (30 ml) and triethyl phosphite (1.08 ml, 6.31 mmol) was added dropwise.
The mixture was refluxed for 21 hours. After evaporating the solvent once, the residue was dissolved again in toluene (30 ml), triethyl phosphite (1.08 ml, 6.31 mmol) was added dropwise, and the mixture was refluxed for 20 hours. Triethyl phosphite (1.08 ml,
(6.31 mmol), and the mixture was further heated under reflux for 10 hours. After evaporating the solvent, the residue was subjected to silica gel column chromatography (chloroform → chloroform: ethyl acetate =
(1: 1 → 1: 2, v / v) to give the title compound (1.92 g, quantitative) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J
= 6.8 Hz), 1.30 (6H, t, J = 6.8H)
z), 3.01-3.15 (1H, m), 3.61 (2
H, d, J = 21.5 Hz), 4.11 (2H, q, J
= 6.8 Hz), 4.13 (2H, q, J = 6.8H)
z), 6.81 (1H, s).

(F) tert-butyl N-5
[(E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3-pyridylcarbamate Diethyl obtained from (E) [(4-isopropyl-
1,3-thiazol-2-yl) methyl] phosphonate (0.87 g, 3.14 mmol) in methanol (30
tert-butyl obtained in (C)
N- (5-formyl-3-pyridyl) carbamate (0.70 g, 3.14 mmol) / methanol (10
ml) solution was added dropwise, and sodium methoxide (203 mg, 3.76 mmol) was added under ice cooling, followed by stirring at room temperature for 3 hours. Sodium methoxide (203 mg,
(3.76 mmol) was added thereto, followed by stirring at room temperature for 5 hours.
After evaporating the solvent, ethyl acetate was added to the residue, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform → chloroform: ethyl acetate = 3:
(1 → 2: 1, v / v) to give the title compound (0.82 g, 75.7%) as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (6H,
d, J = 6.8 Hz), 1.54 (9H, s), 3.0
7-3.20 (1H, m), 6.70 (1H, s),
6.85 (1H, s), 7.33 (1H, d, J = 1
6.1 Hz), 7.39 (1H, d, J = 16.1H)
z), 8.29 (2H, br), 8.41 (1H,
s).

(G) 5-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3-pyridineamine tert-butyl obtained from (F) N-5-[(E)
-2- (4-Isopropyl-1,3-thiazole-2-
Yl) -1-ethenyl] -3-pyridylcarbamate (153 mg, 0.45 mmol) in methylene chloride (5
trifluoroacetic acid (5 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 2.5 hours.
After evaporating the solvent, water was added to the residue, washed with ether, adjusted to pH about 8 with a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. This gave the title compound (72 mg, 66.7%) as a pale yellow solid. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 7.3 Hz), 3.06-3.18 (1H, m),
3.74 (2H, br), 6.84 (1H, s), 7.
09-7.12 (1H, m), 7.24-7.29 (2
H, m), 8.03 (1H, d, J = 2.9 Hz),
8.16 (1H, d, J = 1.5 Hz).

(H) Methyl (4S, 5S) -5
[(5-[(E) -2- (4-isopropyl-1,3-
Thiazol-2-yl) -1-ethenyl] -3-pyridylamino) carbonyl] -2,2-dimethyl-1,3-
Dioxolan-4-carboxylate 5-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] obtained with (G)
-3-Pyridineamine (72 mg, 0.30 mmol)
Was dissolved in methylene chloride (5 ml), and Example 28 (A)
(4S, 5S) -5- (methoxycarbonyl) -2,2-dimethyl-1,3-dioxolane-4-
Carboxylic acid (90mg, 0.44mmo
l) and diisopropylethylamine (12
3 μl, 0.71 mmol) was added dropwise, N, N-bis- (2-oxo-3-oxazolidinyl) phosphinic chloride (90 mg, 0.35 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 16 hours. . After the solvent was distilled off, water was added to the residue, extracted with chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 20: 1, v / v) to give the title compound as a pale yellow oil (78 mg, 61.
2%). ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.8 Hz), 1.55 (3H, s), 1.59 (3
H, s), 3.05-3.20 (1H, m), 3.89.
(3H, s), 4.87 (1H, d, J = 5.4H)
z), 4.94 (1H, d, J = 5.4 Hz), 6.8
8 (1H, s), 7.28 (1H, s), 7.35-
7.45 (2H, m), 8.42-8.65 (3H,
m).

(I) (4S, 5S) -5-[(5-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3-pyridylamino) carbonyl] -2,2-dimethyl-1,3-dioxolan-4-carboxy Methyl (4S, 5S) -5-[(5
-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3-pyridylamino) carbonyl] -2,2-dimethyl-1,3-dioxolan-4- Carboxylate (78mg, 0.18m
mol) in THF-methanol (3: 1, v / v, 4m
l) and lithium hydroxide monohydrate (8 m
g, 0.20 mmol) / water (1 ml) solution was added dropwise,
The mixture was stirred at room temperature for 3.5 hours. After distilling off the solvent, a small amount of water was added to the residue and the mixture was washed with ether and washed with 1N aqueous hydrochloric acid to a pH of about 7 to obtain a residue.
The mixture was extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. Hexane was added to the residue, and the mixture was collected by filtration as a powder and washed with hexane to give the title compound (75 mg, quantitative) as a pale yellow powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 6.8 Hz), 1.45 (6H, s), 2.9
9-3.10 (1H, m), 4.73-4.83 (2
H, m), 7.30 (1H, s), 7.46 (1H,
d, J = 16.1 Hz), 7.52 (1H, d, J = 1)
6.1 Hz), 8.39 (1H, s), 8.63 (1
H, s), 8.71 (1H, s), 10.64 (1H,
br). EI / MS; m / z: 417 (M ⁺ ). FAB / MS; m / z: 418 (MH ^<+> ).

Example 16: 2- (3-((4-isopropyl-1,3-thiazol-2-yl) methoxy) -5
-(Methoxycarbonyl) anilino) -2-oxoethylbenzoic acid (A) dimethyl 5-((4-isopropyl-1,3-thiazol-2-yl) methoxy) isophthalate dimethyl 5-hydroxyphthalate (1.34 g,
6.36 mmol), (4-isopropyl 1,3-thiazol-2-yl) methanol (1.00 g, 6.36).
mmol) and triphenylphosphine (1.67).
g, 6.36 mmol) in THF (20 mL).
At −15 ° C., diethyl azodicarboxylate (1.00 m
L, 6.36 mmol). After stirring at room temperature for 3 hours, the solvent was concentrated under reduced pressure by azeotropic distillation with methylene chloride.
Methylene chloride was added to the residue, and insolubles were filtered off and washed with methylene chloride. The filtrate and the washings are combined and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 5: 1, v / v) to give the title compound as a mixture of a colorless oil and crystals (2.20 g, 9
9%). _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.8 Hz), 3.12 (1H, septet, J =
6.8 Hz), 3.94 (6H, s), 5.42 (2
H, s), 6.92 (1H, s), 7.87 (2H,
s), 8.33 (1H, d, J = 1.2 Hz).

(B) 3-((4-isopropyl-1,3
-Thiazol-2-yl) methoxy) -5- (methoxycarbonyl) benzoic acid Dimethyl 5-((4-isopropyl-1,3-thiazol-2-yl) methoxy) isophthalate obtained in (A) ( To a solution of 1.99 g, 5.69 mmol) in methanol (40 mL) at 0 ° C. was added barium hydroxide octahydrate (897 mg, 2.84 mmol) in methanol (2
0 mL) solution and stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure, the residue was diluted with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform (chloroform-methanol, 10: 1 (5:
1, v / v) to give the title compound (496 mg).
As a result, a raw material (1.31 g) was recovered. However, both compounds were difficult to separate from the ethyl ester. ¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (6H,
d, J = 6.8 Hz), 3.04 (1H, septe)
t, J = 6.8 Hz), 3.87 (3H, s), 5.5
2 (2H, s), 7.31 (1H, s), 7.73 (1
H, s), 7.81 (1H, s), 8.13 (1H,
s).

(C) Methyl 3-((tert-butoxycarbonyl) amino) -5-((4-isopropyl-
1,3-thiazol-2-yl) methoxy) benzoate 3-((4-isopropyl-1,3-
Thiazol-2-yl) methoxy) -5- (methoxycarbonyl) benzoic acid (102 mg)
Triethylamine (51.0 μL, 0.365 mmol) and azide diphenylphosphate (72.2 μL, 0.335 mmol) were added to an rt-butanol (5 mL) solution, and the mixture was heated under reflux for 13.5 hours. The reaction solution was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform (chloroform - methanol, 99:. 1, v / v was purified by (methanol), the title compound as difficult to separate a mixture of ethyl ester (72.2 mg) ¹ H NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 1.52 (9H, s), 3.11 (1
H, septet, J = 6.8 Hz), 3.89 (3
H, s), 5.36 (2H, s), 6.61 (1H, b
r), 6.89 (1H, s), 7.35 (1H, s),
7.53-7.54 (2H, m).

(D) 3-((tert-butoxycarbonyl) amino) -5-((4-isopropyl-1,3-
Thiazol-2-yl) methoxy) benzoic acid 3-((tert-butoxycarbonyl) amino) -5-((4-isopropyl-1,3-thiazol-2-yl) methoxy) obtained in (C) To a solution of benzoic acid (72.2 mg) in dioxane (2 mL) was added a 1N aqueous sodium hydroxide solution (1 mL). Since they do not mix, methanol (1 mL) is added, and the mixture is added at room temperature for 18 minutes.
Stirred for hours. The solvent was concentrated under reduced pressure, the residue was diluted with a 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (60.3 mg) as a white solid. ¹ H-NMR (CD ₃ OD) δ: 1.31 (6H, d, J
= 6.8 Hz), 1.52 (9H, s), 3.09 (1
H, septet, J = 6.8 Hz), 5.36 (2
H, s), 7.14 (1H, d, J = 0.7 Hz),
7.31 (1H, d, J = 1.2, 2.4 Hz);
45 (1H, br), 7.64-7.65 (1H,
m).

(E) Methyl 3-((tert-butoxycarbonyl) amino) -5-((4-isopropyl-
1,3-thiazol-2-yl) methoxy) benzoate 3-((tert-butoxycarbonyl) amino) -5-((4-isopropyl-1,3-thiazol-2-yl) obtained with (D) (Methoxy) benzoic acid (60.3 mg) in THF (3 mL) -methanol (1
Trimethylsilyldiazomethane (2.0 M in hexane, 85.5 μL, 0.1 mL) at 0 ° C.
169 mmol) and stirred at room temperature for 15.5 hours. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate, 5: 1, v / v).
v) to give the title compound as a colorless oil (5)
(7.2 mg, 92%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 1.52 (9H, s), 3.11 (1
H, septet, J = 6.8 Hz), 3.89 (3
H, s), 5.36 (2H, s), 6.61 (1H, b
r), 6.89 (1H, s), 7.35 (1H, s),
7.53-7.54 (2H, m).

(F) Methyl 3-amino-5-((4-
Isopropyl-1,3-thiazol-2-yl) methoxy) benzoate Methyl 3-((tert-butoxycarbonyl) amino) -5-((4-isopropyl-) obtained with (E).
1,3-thiazol-2-yl) methoxy) benzoate (57.2 mg, 0.140 mmol) at 0 ° C.
Normal hydrochloric acid-dioxane (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure by chloroform azeotrope,
The residue was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (44.4 mg, quantitative) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 3.11 (1H, septet, J =
6.8 Hz), 3.88 (3H, s), 5.33 (2
H, s), 6.53 (1H, t, J = 1.8 Hz),
6.90 (1H, d, J = 1.0 Hz), 7.03 (1
H, t, J = 1.0 Hz), 7.08 (1H, d, J =
1.7 Hz).

(G) 2- (3-((4-isopropyl-
1,3-thiazol-2-yl) methoxy) -5- (methoxycarbonyl) anilino) -2-oxoethylbenzoic acid Methyl 3-amino-5-((4-isopropyl-1) obtained with (F) , 3-thiazol-2-yl) methoxy)
Benzoic acid (44.4 mg, 0.145 mm
ol) in toluene (2 mL) was added with homophthalic anhydride (23.5 mg, 0.145 mmol) and heated under reflux for 1 hour. The reaction solution was cooled to 0 ° C., and the solid was collected by filtration.
After washing with toluene, the title compound was obtained as white crystals ((4)
8.3 mg, 71%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (6H,
d, J = 6.8 Hz), 3.03 (1H, septe
t, J = 6.8 Hz), 3.83 (3H, s), 4.0
9 (2H, s), 5.42 (2H, s), 7.27 (1
H, s), 7.29 (1H, s), 7.35-7.40.
(2H, m), 7.51 (1H, t, J = 7.2H
z), 7.60 (1H, s), 7.86 (1H, s),
7.89 (1H, d, J = 7.6 Hz), 10.4 (1
H, s), 12.82 (1H, s). EI-MS; m / z: 468 (M ⁺ )

Example 17: 2- [2- (5-[(E)-
2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3-pyridylamino) -2-oxoethyl] benzoic acid 5-[(E) obtained in Example 15 (G). ) -2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
[Ethenyl] -3-pyridineamine was treated under the conditions described in Example 1 to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (6H,
d, J = 6.7 Hz), 3.14 (1H, heptup)
let), 4.24 (2H, s,), 7.38 (1H,
s), 7.50 (1H, t, J = 6.0 Hz), 7.5
3 (2H, s), 7.63 (1H, t, J = 6.0H)
z), 7.99 (1H, d, J <1 Hz), 8.01
(1H, d, J = 1.8 Hz), 8.42 (1H, d,
J = 2.1 Hz), 8.65 (1H, d, J = 1.5H)
z), 8.70 (1H, d, J = 2.1 Hz), 10.
48 (1H, s), 12.94 (1H, s). MS (ES-); m / z: 406 (M ⁺ -1).

Example 18: 2- [2- (6-[(E)-]
2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -2-pyridylamino) -2-oxoethyl] benzoic acid (A) 6-[(tert-butoxycarbonyl) amino] picoli Nick acid 2,6-pyridinedicarboxylic acid was treated in the same manner as in Example 15 (A) to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.56 (9H,
s), 7.76 (1H, d, J = 7.2 Hz), 7.9
9 (1H, t, J = 7.5 Hz), 8.09 (1H,
d, J = 7.5 Hz), 10.09 (1H, s), 1
3.18 (1H, s).

(B) tert-butyl N- (6- [methoxy (methyl) amino] carbonyl-2-pyridyl)
The carbamate 6-[(tert-butoxycarbonyl) amino] picolinic acid was treated as in Example 15 (B),
The title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.64 (9H, s),
3.48 (3H, s), 3.82 (3H, s), 7.3
9 (1H, d, J = 7.5 Hz), 7.86 (1H,
t, J = 8.0 Hz), 8.13 (1H, d, J = 8.
0 Hz).

(C) tert-Butyl N- (6-formyl-2-pyridyl) carbamate The tert-butyl N- (6- [methoxy (methyl) amino] carbonyl-2-pyridyl) carbamate obtained in (B) Was treated in the same manner as in Example 15 (C) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.64 (9H, s),
7.64 (1H, broads), 7.73 (1H,
d, J = 8.1 Hz), 7.95 (1H, t, J = 8.
1 Hz), 8.31 (1H, d, J = 8.1 Hz), 1
0.03 (1H, s).

(D) tert-butyl N-6
[(E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -2-pyridylcarbamate Diethyl obtained from (C) [(4-isopropyl-
1,3-thiazol-2-yl) methyl] phosphonate, diethyl [(4-isopropyl-1,3-thiazol-2-yl) methyl] obtained in Example 15 (E)
The phosphonate was treated as in Example 15 (F) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (6H, d, J
= 7.0 Hz), 1.65 (9H, s), 3.25 (1
H, couplet, J = 7.0 Hz), 6.98
(1H, s), 7.18 (1H, d, J = 7.5H
z), 7.23-7.42 (2H, m), 7.78 (2
H, m), 7.98 (1H, m). MS (ES +); m / z: 346 (MH ^<+> ).

(F) 2- [2- (6-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -2-pyridylamino) -2-oxoethyl] benzoic acid tert-butyl N-6-[(E) obtained with (D)
-2- (4-Isopropyl-1,3-thiazole-2-
Yl) -1-ethenyl] -2-pyridylcarbamate was treated as in Example 15 (G) and then as in Example 1 to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (6H,
d, J = 6.9 Hz), 3.18 (1H, heptup)
let, J = 6.9 Hz), 4.26 (2H, s),
7.50 (5H, m), 7.62 (1H, t, J = 7.
5Hz), 7.86 (2H, m), 8.01 (2H,
m), 10.67 (1H, s), 12.97 (1H, b
load s). MS (ES-); m / z: 406 (M ⁺ -1).

Example 19: 2- [2- (5-[(E)-]
2- (3-isopropyl-1,2,4-thiadiazol-5-yl) -1-ethenyl] -3-pyridylamino)
-2-oxoethyl] benzoic acid (A) 5-chloromethyl-3-isopropyl-1,2,2
4-thiadiazole 3-isopropyl-1, obtained in Example 13 (B)
2,4-thiadiazol-5-yl) methanol (0.
57 g) was dissolved in methylene chloride (4 mL), pyridine (0.87 mL) and methanesulfonyl chloride (0.84 mL) were added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was partitioned between ethyl acetate and water, 1N hydrochloric acid,
After washing with a saturated aqueous solution of copper sulfate and saturated saline and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane-methylene chloride, 1:
1, v / v) and the title compound (37
8 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.53 (6H, d, J
= 7.2 Hz), 3.40 (1H, m), 5.01 (2
H, s).

(B) Diethyl (3-isopropyl-
(1,2,4) -Thiadiazol-5-yl) methylphosphonate 5-chloromethyl-3-isopropyl-1,2,4-thiadiazole (378 mg) obtained in (A) was added to acetone (15 mL). ) And sodium iodide (640 m
g) / Acetone (2 mL) solution was added, and the mixture was stirred in a dark place for 2 hours. The reaction solution was partitioned between ethyl acetate and water, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Triethyl phosphite (6 mL) was added to the residue, and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated to obtain the title compound. This compound was used for the next reaction without purification. ¹ H-NMR (CDCl ₃ ) δ: 1.42-1.51 (1
2H, m), 3.42 (1H, m), 3.60 (2H,
d, J = 21.4 Hz), 4.15-4.28 (4H,
m).

(C) tert-butyl N-5
[(E) -2- (3-Isopropyl-1,2,4-thiadiazol-5-yl) -1-ethenyl] -3-pyridylcarbamate Diethyl (3-isopropyl-) obtained with (B)
(1,2,4) -Thiadiazol-5-yl) methylphosphonate was treated in the same manner as in Example 15 (F) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (6H, d, J
= 6.9 Hz), 1.66 (9H, s), 3.46 (1
H, hepplett, J = 6.9 Hz), 7.05
(1H, s), 7.55 (1H, d, J = 16.5H
z), 7.70 (1H, d, J = 16.2 Hz), 8.
54 (2H, m), 8.58 (1H, m).

(D) 2- [2- (5-[(E) -2-
(3-isopropyl-1,2,4-thiadiazole-5
-Yl) -1-ethenyl] -3-pyridylamino) -2
-Oxoethyl] benzoic acid tert-butyl N-5-[(E) obtained with (C)
-2- (3-Isopropyl-1,2,4-thiadiazol-5-yl) -1-ethenyl] -3-pyridylcarbamate was treated in the same manner as in Example 15 (G) and then in Example 1, to give the title compound I got ¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (6H,
d, J = 6.9 Hz), 3.39 (1H, heptup)
let, J = 6.9 Hz), 4.25 (2H, s),
7.50 (1H, t, J = 8.1 Hz), 7.67 (1
H, t, J = 7.5 Hz), 7.82 (2H, s),
8.00 (1H, d, J = 7.8 Hz), 8.82 (1
H, m), 8.70 (1H, d, J = 2.1 Hz),
8.74 (1H, d, J = 2.1 Hz). MS (ES-); m / z: 407 (M ⁺ -1).

Example 20: 4-[(5-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -3-pyridylamino) carbonyl]
Tetrahydro-3-furancarboxylic acid (A) 4- (ethoxycarbonyl) tetrahydro-3-
Furancarboxylic acid 3,4,4-tetraethoxycarbonyldihydrofuran (J. Org. Chem., 1963, 28, 802)
(2.12 g) was dissolved in dimethyl sulfoxide (5 mL), and lithium chloride (749 mg) and water (200 μl) were dissolved.
L) and stirred at 160 ° C. for 3 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure,
4-diethoxycarbonyltetrahydrofuran (642
mg) as an oil. 442 mg of this was dissolved in ethanol (3 mL) and potassium hydroxide (135 m
g) was added and stirred for 16 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed twice with ether. Water layer
H2, extracted with ethyl acetate, dried over sodium sulfate,
The solvent was distilled off under reduced pressure to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.49 (3H, t, J
= 7.8 Hz), 3.58-3.72 (3H, m),
4.07 (1H, dd, J = 8.4, 5.7 Hz),
4.16 (1H, dd, J = 8.6, 5.0), 4.2
3 (1H, dd, J = 8.0, 4.9 Hz), 4.31
(2H, q, J = 7.8). MS (ES-); m / z: 187 (M ⁺ -1).

(B) 4-[(5-[(E) -2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
Ethenyl] -3-pyridylamino) carbonyl] tetrahydro-3-furancarboxylic acid The 4- (ethoxycarbonyl) tetrahydro-3-furancarboxylic acid obtained in (A) was prepared in Example 1.
The same treatment as in 5 (H) and (I) was performed to obtain the title compound. ¹ H-NMR (CD ₃ OD) δ: 1.49 (6H, d, J
= 6.9 Hz), 3.25 (1H, heterogeneous)
t, J = 6.9 Hz), 3.38 (1H, dd, J =
7.9, 7.9 Hz), 3.58 (1H, dd, J =
7.5, 7.5 Hz), 4.07-4.24 (3H,
m), 7.29 (1H, s), 7.50 (1H, d, J
= 16.3), 7.55 (1H, m), 7.60 (1
H, d, J = 16.3), 7.74 (1H, m), 8.
04 (1H, m). MS (ES-); m / z: 385 (M ⁺ -1).

Example 21: 2- [2- (4-[(E)-
2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -2-pyridylamino) -2-oxoethyl] benzoic acid (A) 4-[(E) -2- (4- Isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl] -2-aminopyridine N- (4-formyl-2-pyridyl) -2,2-dimethylpropanamide (1.7 g, 8.2 mmol), 4-
Isopropyl-2-methyl-1,3-thiazole (1.
(2 g, 8.5 mmol) was dissolved in acetic anhydride (10 ml), and the mixture was heated under reflux at 100 ° C. for 15 hours and at 170 ° C. for 7 hours. The reaction solution was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 3N hydrochloric acid (50 mL) was added to the residue, and the mixture was heated under reflux at 100 ° C. for 1 hour. Made alkaline with 3N aqueous sodium hydroxide solution,
After extraction with ethyl acetate and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol, 20: 1, v / v) to give the title compound (480 mg, 24
%). ¹ H-NMR (CD ₃ OD) δ: 1.33 (6H, d, J
= 6.8 Hz), 3.10 (1H, m), 6.70 (1
H, s), 6.82 (1H, d, J = 5.6 Hz),
7.15 (1H, s), 7.27 (1H, d, J = 1
6.5Hz), 7.43 (1H, d, J = 16.5H)
z), 7.88 (1H, d, J = 5.4 Hz).

(B) 2- [2- (4-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -2-pyridylamino) -2-oxoethyl] benzoic acid 4-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) obtained by (A) ) -1-Ethenyl]
Treatment of -2-aminopyridine under the conditions described in Example 1 gave the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.26 (6H,
d, J = 6.8 Hz), 2.99-3.09 (1H,
m), 4.17 (2H, s), 7.32 (1H, s),
7.36 (1H, d, J = 16.3 Hz), 7.35−
7.42 (3H, m), 7.49-7.55 (1H,
m), 7.57 (1H, d, J = 16.3 Hz), 7.
89 (1H, dd, J = 5.4, 1.2 Hz), 8.1
9 (1H, s), 8.30 (1H, d, J = 5.4H)
z), 10.61 (1H, s). FAB-MS; m / z: 408 (MH ^<+> ).

Example 22 2- [2- (4-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -2-pyridinoamino) -2-oxoethyl] benzoic acid (A) ethyl 4-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -2-pyridinecarboxylate ethyl 4-hydroxy-2-pyridinecarboxylate (U.S. Patent, No. 5,260,28)
6) was treated under the conditions described in Example 34 to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.9 Hz), 1.44 (3H, t, J = 7.1H)
z), 3.07-3.17 (1H, m), 4.47 (2
H, q, J = 7.1 Hz), 5.44 (2H, s),
6.94 (1H, d, J = 1.0 Hz), 7.09 (1
H, dd, J = 5.6, 2.7 Hz), 7.79 (1
H, d, J = 2.7 Hz), 8.58 (1H, d, J =
5.6 Hz).

(B) N-tert-butyl N-4-
[(4-Isopropyl-1,3-thiazol-2-yl) methoxy] -2-pyridinecarbamate Ethyl 4-[(4-isopropyl-) obtained from (A)
1,3-thiazol-2-yl) methoxy] -2-pyridinecarboxylate (198 mg, 0.65 mmol
l) is dissolved in ethanol (10 ml), and 1N aqueous sodium hydroxide solution (0.71 ml, 0.71 mmol)
Was added dropwise and stirred at room temperature for 17 hours. After the solvent was distilled off, a 1 N aqueous hydrochloric acid solution was added to the residue to adjust the pH to about 2, and the mixture was washed with ethyl acetate. This was suspended in tert-butanol (10 ml), and diphenylphosphate azide (12
2 μl, 0.56 mmol) and triethylamine (85 μl, 0.61 mmol) were added dropwise, and the mixture was heated under reflux for 8 hours. Further, tert-butanol (10 ml) and azide diphenylphosphate (122 μl, 0.56 mmol)
l) and triethylamine (85 μl, 0.61 mm
ol), and the mixture was heated under reflux for 6 hours. After distilling off the solvent,
The residue is subjected to silica gel column chromatography (chloroform → chloroform: methanol = 10: 1, v / v).
And preparative silica gel thin layer chromatography (chloroform → chloroform: methanol = 20: 1, v / v
v) to give the title compound (91) as a pale yellow oil.
mg, 56.0%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 1.54 (9H, s), 3.08-
3.17 (1H, m), 5.34 (2H, s), 6.6
1 (1H, dd, J = 5.9, 2.2 Hz), 6.91
(1H, s), 7.26 (1H, d, J = 2.2H
z), 8.15 (1H, d, J = 5.9 Hz), 9.3
6 (1H, br).

(C) 4-[(4-isopropyl-1,3
-Thiazol-2-yl) methoxy] -2-pyridinamine N-tert-butyl N-4- obtained from (B)
[(4-Isopropyl-1,3-thiazol-2-yl) methoxy] -2-pyridinecarbamate (90 m
g, 0.26 mmol) in dichloromethane (2 ml), and trifluoroacetic acid (2 ml) was added dropwise under ice cooling.
Stirred at room temperature for 30 minutes. After distilling off the solvent and excess reagent,
Saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to about 8, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as a pale orange oil (79 mg, quantitative ) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 3.05-3.17 (1H, m),
4.65 (2H, br), 5.33 (2H, s), 6.
10 (1H, d, J = 1.7 Hz), 6.36 (1H,
dd, J = 5.9, 1.7 Hz), 6.92 (1H,
s), 7.90 (1H, d, J = 5.9 Hz).

(D) 2- [2- (4-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -2
-Pyridinoamino) -2-oxoethyl] benzoic acid 4-[(4-isopropyl-1,3-
Thiazol-2-yl) methoxy] -2-pyridineamine was treated under the conditions described in Example 1 to give the title compound. ^{1 H-NMR (DMSO-d} 6) δ: 1.23 (6H,
d, J = 6.7 Hz), 2.95-3.09 (1H,
m), 4.13 (2H, s), 5.42 (2H, s),
6.81 (1H, dd, J = 5.6, 2.2 Hz),
7.29 (1H, s), 7.32-7.40 (2H,
m), 7.48-7.64 (1H, m), 7.71 (1
H, d, J = 2.2 Hz), 7.87-7.92 (1
H, m), 8.15 (1H, d, J = 5.6 Hz), 1
0.53 (1H, s). FAB-MS; m / z: 412 (MH ^<+> ).

Example 23: N-cyano-2- (2-
((5-((E) -2- (4-isopropyl-1,3-
Thiazol-2-yl) -1-ethenyl) -3-pyridyl) amino) -2-oxoethyl) benzamide 2- [2- (5-[(E) -2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl] -3
-Pyridylamino) -2-oxoethyl] benzoic acid (49 mg) in tetrahydrofuran (2 mL)
And pentafluorophenol (22 mg) and dicyclohexylcarbodiimide (25 mg) were added.
Stir for 4 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. This was dissolved in dimethylformamide (3 ml), and cyanamide (24 mg) and sodium hexamethyldisilazide (0.58 mmol) were added, followed by stirring for 72 hours. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was washed with saturated saline and dried over sodium sulfate. , V / v) to give the title compound (11 mg) as a white powder. ¹ H-NMR (CD ₃ OD) δ: 1.30 (6H, d),
3.09 (1H, hepplet), 3.94 (2
H, s), 7.10 (1H, s), 7.28 (1H,
m), 7.39 (5H, m), 7.75 (1H, d, J
= 7.5), 8.29 (1H, s), 8.38 (1H,
s), 8.68 (1H, s). MS (ES-); m / z: 430 (MH ^<+> ).

Example 24: 3- (2- (tert-butoxycarbonylamino) ethoxy) -5-((3-
((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) benzoic acid (A) 5-hydroxyisophthalic acid dimethyl ester 5-hydroxyisophthalic acid ( 10.0 g, 54.9 m
mol) in toluene-methanol (300 ml-100)
(trimethylsilyl) diazomethane (50 ml, 2.0 M hexane solution, 100 mmol)
Was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as colorless crystals ( 6.2
g, 59%). ¹ H-NMR (CDCl ₃ ) δ: 3.95 (6H, s ×
2), 5.96 (1H, br), 7.74 (2H, d,
J = 1.0 Hz), 8.25 (1H, d, J = 1.0H)
z).

(B) 5- (2- (tert-butoxycarbonylamino) ethoxy) isophthalic acid dimethyl ester 5-hydroxyisophthalic acid dimethyl ester obtained in (A) (2.54 g, 12.1 mmol) and 2 −
(Tert-Butoxycarbonylamino) ethanol (1.95 g, 12.1 mmol) was added to THF (110 m
l) and dissolved in diethyl azodicarboxylate (2.11)
g, 12.1 mmol) and triphenylphosphine (3.17 g, 12.1 mmol).
Stirred for hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (hexane-ethyl acetate, 2: 1,
v / v) to give a white solid (3.428 g). Since this was a mixture of the title compound and starting material 5-hydroxyisophthalic acid dimethyl ester, the following reaction was carried out.

2.43 g of the obtained white solid was dissolved in methylene chloride (50 ml), and trifluoroacetic acid (30
ml) and stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and the residue was partitioned between ether-1N aqueous hydrochloric acid,
The aqueous layer was neutralized with saturated sodium hydrogen carbonate and extracted with chloroform. After the organic layer was dried over sodium sulfate, chloroform was distilled off under reduced pressure to obtain a white solid (330 mg).
The solid was further dissolved in THF (40 ml) and saturated sodium hydrogen carbonate (40 ml), di-tert-butyl dicarbonate (320 mg) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was distributed between ethyl acetate and 1N aqueous hydrochloric acid, and the organic layer was washed with saturated sodium hydrogen carbonate and saturated saline in this order, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (550 mg) as a colorless oil. ) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s),
3.57 (2H, brdd), 3.94 (6H, s ×
2), 4.11 (2H, t, J = 5.37 Hz);
98 (1H, br), 7.74 (2H, d, J = 1.4)
6 Hz), 8.29 (1H, t, J = 1.46 Hz). EI-MS; m / z: 353 (M ⁺ ), 322 (M ⁺ -O
Me), 88 (BP).

(C) 5- (2- (tert-butoxycarbonylamino) ethoxy) isophthalic acid monomethyl ester 5- (2- (tert-butoxycarbonylamino) ethoxy) isophthalic acid dimethyl ester obtained in (B) 540 mg, 1.53 mmol) in THF (20
ml), and lithium hydroxide monohydrate (75 mg,
1.79 mmol) and water (20 ml) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with a 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel chromatography (hexane-ethyl acetate, 1: 1, v / v) to obtain the title compound (180 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.46-1.52 (9
H, brs × 2), 3.60 (2H, brdd),
3.94 (3H, s), 4.13 (2H, t, J = 5.
0 Hz), 5.06 (1H, br), 7.79 (2H,
brs), 8.35 (1H, brs).

(D) 3- (2- (tert-butoxycarbonylamino) ethoxy) -5-((3-((E)-
2- (4-phenyl-1,3-thiazol-2-yl)
-1-Ethenyl) anilino) carbonyl) benzoic acid methyl ester 5- (2- (tert-butoxycarbonylamino) ethoxy) isophthalic acid monomethyl ester (122 mg, 0.360 mmol) obtained in (C),
((E) -2- (4-phenyl-1,3-thiazole-
2-yl) -1-ethenyl) aniline (100 mg,
0.360 mmol) was dissolved in methylene chloride (10 ml) and N, N-bis- (2-oxo-3-oxazolidinyl) phosphinic chloride (92 mg, 0.360
mmol), diisopropylethylamine (0.13 m
1, 0.360 mmol) and stirred at room temperature under a nitrogen atmosphere for 14 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate, and saturated saline in this order, dried over sodium sulfate, and evaporated under reduced pressure to give the title compound (199 mg, 92%) as a yellow powder. Obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (9H,
s), 3.34 (2H), 3.92 (3H, s), 4.
14 (2H, m), 7.07 (1H, m), 7.38-
7.65 (8H, m), 7.73-7.82 (2H,
m), 8.01 (1H, s), 8.03 (1H, s),
8.12 (2H, s × 2), 8.17 (1H, s),
10.49 (1H, s). IR (KBr); cm ^-1 : 3282,2981,261
5,2440,1745,1608,1421,125
2,1207,1136,1063,1011,83
9,688.

(E) 3- (2- (tert-butoxycarbonylamino) ethoxy) -5-((3-((E)-
2- (4-phenyl-1,3-thiazol-2-yl)
-1-Ethenyl) anilino) carbonyl) benzoic acid 3- (2- (tert-butoxycarbonylamino) ethoxy) -5-((3-((E) -2) obtained by (D).
-(4-phenyl-1,3-thiazol-2-yl)-
1-ethenyl) anilino) carbonyl) benzoic acid methyl ester (190 mg, 0.317 mmol
l) was dissolved in THF (20 ml), an aqueous solution of lithium hydroxide (20 ml, 0.238 M) was added, and 1
Stirred for hours. The reaction solution was acidified with a 1N aqueous hydrochloric acid solution,
Extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure, and the residue was washed with ether to give the title compound (110 mg, 59%) as a pale yellow powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (9H,
s), 3.35 (2H), 4.13 (2H, t, J =
5.5 Hz), 7.07 (1H, m), 7.36-7.
63 (8H, m), 7.74-7.78 (2H, m),
8.01 (1H, s), 8.03 (1H, s), 8.1
2 (2H, s × 2), 8.17 (1H, s), 10.
48 (1H, s). FAB-MS; m / z: 530 (MH + - t Bu). IR (KBr); cm ^-1 : 3298, 2976, 168
9,1252,1065,688.

Example 25: 3- (2-aminoethoxy)
-5-((3-((E) -2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) benzoic acid 3- (2- (tert-butoxycarbonylamino) ethoxy) -5-((3-((E) -2- (4-phenyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) benzoic acid (76 m
g, 0.13 mmol) in methylene chloride (20 ml)
And trifluoroacetic acid (10 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and the residue was washed with ether to give the title compound (58m) as yellow plate-like crystals.
g, 75%). ¹ H-NMR (DMSO-d ₆ ) δ: 3.36 (2H),
4.33 (2H, t, J = 4.9 Hz), 7.36−
7.59 (7H, m), 7.72-7.80 (3H,
m), 8.01 (1H, s), 8.03 (1H, s),
8.12 (2H, s × 2), 8.25 (1H, s),
10.54 (1H, s). EI-MS; m / z: 485 (M ^<+> ).

Example 26: 3- (2-hydroxyethoxy) -5-((3-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino ) Carbonyl) benzoic acid (A) 2- (tert-butyldiphenylsilyloxy) ethanol ethylene glycol (4.87 g, 78.5 mmol)
l), imidazole (5.34 g, 78.5 mmol)
Was dissolved in DMF (60 ml), tert-butyldiphenylsilyl chloride (21 ml) was added at room temperature, and the mixture was stirred at room temperature under a nitrogen atmosphere for 14.5 hours. The reaction solution was distributed between ethyl acetate and 1N aqueous hydrochloric acid, the organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate, 3: 1, v / v) to give the title compound (9.298 g, 39%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s),
2.13 (1H, br), 3.69 (2H, br),
3.77 (2H, t, J = 4.5 Hz), 7.37 −
7.46 (6H, m), 7.66-7.68 (4H,
m).

(B) 5-hydroxyisophthalic acid dimethyl ester 5-hydroxyisophthalic acid (10.0 g, 54.9 m
mol) in toluene-methanol (300 ml-100)
(trimethylsilyl) diazomethane (50 ml, 2.0 M hexane solution, 100 mmol)
Was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as colorless crystals ( 6.24
1 g, 59%). ¹ H-NMR (CDCl ₃ ) δ: 3.95 (6H, s ×
2), 5.96 (1H, br), 7.74 (2H, d,
J = 1.0 Hz), 8.25 (1H, d, J = 1.0)
Hz).

(C) 5- (2- (tert-butyldiphenylsilyloxy) ethoxy) isophthalic acid dimethyl ester 2- (tert-butyldiphenylsilyloxy) ethanol (6) obtained in (A) and (B), respectively. .90
g, 23.0 mmol) and dimethyl 5-hydroxyisophthalate (4.83 g, 23.0 mmol) were dissolved in THF (110 ml), and diethyl azodicarboxylate (4.00 g, 23.0 mmol), triphenylphosphine ( 6.03 g, 23.0 mmol),
Stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate, 4: 1, v / v) to obtain the title compound (9.752 g, 86%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.05 (9H, s),
3.94 (6H, s × 2), 4.02 (2H, t, J
= 4.88 Hz), 4.17 (2H, t, J = 4.88).
Hz), 7.36-7.45 (6H, m), 7.69-
7.74 (6H, m), 8.27 (1H, d, J = 1.
47 Hz). EI-MS; m / z: 461 (M ^<+>- OMe), 435
(M ⁺ -tBu, BP).

(D) 5- (2- (tert-butyldiphenylsilyloxy) ethoxy) isophthalic acid monomethyl ester Dimethyl 5- (2- (tert-butyldiphenylsilyloxy) ethoxy) isophthalate obtained from (C) The ester (1.00 g, 2.03 mmol) was added to THF (2
0 ml) and lithium hydroxide monohydrate (85 m
g, 2.03 mmol) and water (20 ml), and the mixture was stirred at room temperature for 20 hours. A 1N aqueous hydrochloric acid solution was added to the reaction solution to make it strongly acidic, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate, 2: 1, v / v) to give the title compound (241 mg, 25%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s),
3.97 (3H, s), 4.04 (2H, t, J = 4.
89Hz), 4.20 (2H, t, J = 4.89H)
z), 7.38-7.45 (6H, m), 7.70-
7.73 (4H, m), 7.80 (2H, d, J = 1.
46Hz), 8.37 (1H, d, J = 1.46H)
z).

(E) 3- (2- (tert-butyldiphenylsilyloxy) ethoxy) -5-((3-
((E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) benzoic acid methyl ester 5- (2- (tert) -Butyldiphenylsilyloxy) ethoxy) isophthalic acid monomethyl ester (590 mg, 1.24 mmol);
((E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) aniline (310 m
g, 1.27 mmol) in methylene chloride (30 ml)
And N, N-bis- (2-oxo-3-oxazolidinyl) phosphinic acid chloride (320 mg) and diisopropylethylamine (0.3 ml) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with a 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate, and saturated saline in this order, dried over sodium sulfate, and evaporated under reduced pressure to give the title compound (815 mg, 94% ) Got.

(F) 3- (2-hydroxyethoxy)-
5-((3-((E) -2- (4-isopropyl-1,
3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) benzoic acid methyl ester 3- (2- (tert-butyldiphenylsilyloxy) ethoxy) -5-((3 -((E)
-2- (4-Isopropyl-1,3-thiazole-2-
Yl) -1-ethenyl) anilino) carbonyl) benzoic acid methyl ester (785 mg, 1.12
mmol) in THF (20 ml) and tetrabutylammonium fluoride (3.0 ml, 1.0 MT
HF solution, 3.0 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction solution was partitioned between ether-1N aqueous hydrochloric acid, and the ether layer was dried over sodium sulfate.
Ether was distilled off under reduced pressure. Silica gel chromatography of the residue (hexane-ethyl acetate, 1: 1, v / v)
And purified as a colorless amorphous title compound (287)
mg, 55%). _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.84 Hz), 3.12 (1H, quintet,
J = 6.84 Hz), 3.92 (3H, s), 4.00
(2H, t, J = 4.0 Hz), 4.14 (2H, t,
J = 4.0 Hz), 6.82 (1H, s), 7.29-
7.37 (4H, m), 7.57 (1H, d, J = 7.
82Hz), 7.62-7.65 (2H, m), 7.8
8 (1H, s), 8.02 (1H, s), 8.35 (1
H, s). EI-MS; m / z: 466 (M +, BP), 436
(M ⁺ -tBu + 1), 435 (M ⁺ -tBu).

(G) 3- (2-hydroxyethoxy)-
5-((3-((E) -2- (4-isopropyl-1,
3- (2-Hydroxyethoxy) -5 obtained with 3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) benzoic acid (F)
-((3-((E) -2- (4-isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl) anilino)
Carbonyl) benzoic acid methyl ester (2
53 mg, 0.543 mmol) in THF (30 m
l) and dissolved in an aqueous solution of lithium hydroxide (30 ml, 0.1 mL).
238M) and stirred at room temperature for 2 hours. The reaction solution was acidified with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate.
The organic layer was dried over sodium sulfate and evaporated under reduced pressure, and the residue was washed with ether to give the title compound (110 mg, 45%) as a pale yellow powder. Anal. calcd for C ₂₄ H ₂₄ N ₂ O ₅ S.0.
_{5H 2 O: C, 62.46;} H, 5.46; N, 6.07; S,
6.95. found: C, 62.59; H, 5.48; N, 5.78; S,
6.59. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 6.83 Hz), 3.05 (1H, quint)
et, J = 6.83 Hz), 3.77 (2H, t, J =
4.88 Hz), 4.15 (2H, t, J = 4.88H)
z), 4.94 (1H, t, J = 5.37 Hz), 7.
25 (1H, s), 7.41 (3H, m), 7.47
(1H, d, J = 7.81 Hz), 7.65 (1H,
s), 7.73 (1H, d, J = 7.81 Hz), 7.
78 (1H, s), 8.08 (1H, s), 8.15
(1H, s), 10.45 (1H, s), 13.25
(1H, br). EI-MS; m / z: 452 (M ⁺ , BP) IR (KBr); cm ^-1 : 3311, 962, 170
1,1589,1545,1439,1302,121
5,1057,687.

Example 27: (4R, 5R) -5- (3-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl)
-2,2-Dimethyl-1,3-dioxolan-4-carboxylic acid (A) (4R, 5R) -5- (methoxycarbonyl)-
2,2-dimethyl-1,3-dioxolane-4-carboxylic acid dimethyl (4R, 5R) -2,2-dimethyl-1,3
Dioxolane-4,5-dicarboxylate (1.1
0 g, 5.04 mmol) in methanol (30 ml), and a 1N aqueous sodium hydroxide solution (5.0 ml,
5.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 minutes.
The mixture was refluxed for half an hour. After cooling, the solvent was distilled off, a small amount of water was added to the residue, and the mixture was washed with ether and washed with 1N aqueous hydrochloric acid.
H was about 1. After extraction with ethyl acetate, the extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
74 g) were obtained. The conversion yield of the target product was 0.5 based on NMR.
0 g, 48.6%, 0.24 g of dicarboxylic acid. ¹ H-NMR (CDCl ₃ ) δ: 1.53 (3H, s),
1.54 (3H, s), 3.85 (3H, s), 4.7
7-4.91 (2H, m), 5.99 (1H, br).

(B) Methyl (4R, 5R) -5- (3
-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl) -2,2-dimethyl-1,3-dioxolan-4-
Carboxylate 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] aniline (202
mg, 0.83 mmol) in methylene chloride (10 ml)
(4R, 5R) -5- (methoxycarbonyl) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (containing about 1/3 of dicarboxylic acid) obtained in (A). ) (338 mg, 1.66 mmol)
And diisopropylethylamine (433 μl) under ice-cooling.
1, 2.49 mmol) was added dropwise, and N, N-bis- (2
-Oxo-3-oxazolidinyl) phosphinic chloride (316 mg, 1.24 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 13 and a half hours. After evaporating the solvent, water was added to the residue, and the mixture was extracted with chloroform, washed successively with 1N aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. . The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 50: 1, v / v) to give the title compound (90 mg, 25.2%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 7.3 Hz), 1.52 (3H, s), 1.55 (3
H, s), 3.06-3.17 (1H, m), 3.87.
(3H, s), 4.73-4.81 (1H, m), 4.
84-4.92 (1H, m), 6.81 (1H, s),
7.23-7.41 (4H, m), 7.45-7.51
(1H, m), 7.80 (1H, s), 8.32 (1
H, s).

(C) (4R, 5R) -5- (3-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl)
-Methyl (4R, 5R) -5- (3-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl)
-2,2-Dimethyl-1,3-dioxolane-4-carboxylate (90 mg, 0.21 mmol) in THF
-Dissolved in methanol (3: 1, v / v, 4 ml), and lithium hydroxide monohydrate (9 mg, 0.23 mmol
l) / Water (1 ml) solution was added dropwise and stirred at room temperature for 2 hours. After evaporating the solvent, a small amount of water was added to the residue, and the mixture was washed with ether, adjusted to pH about 1 with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. Distilled. Hexane was added to the residue, the mixture was collected by filtration as a powder, and washed with hexane to give the title compound (58 mg, 67.4%) as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.8 Hz), 1.59 (3H, s), 1.61 (3
H, s), 3.08-3.20 (1H, m), 4.59
(1H, s), 4.75 (1H, s), 6.85 (1
H, s), 7.17 (1H, br), 7.32-7.4.
5 (3H, m), 7.48-7.58 (1H, m),
7.80 (1H, s), 8.45 (1H, s). EI / MS; m / z: 416 (M ^<+> ). FAB / MS; m / z: 417 (MH ^<+> ).

Example 28: (4S, 5S) -5- (3-
[(4-isopropyl-5-methyl-1,3-thiazol-2-yl) methoxy] anilinocarbonyl) -2,
2-dimethyl-1,3-dioxolan-4-carboxylic acid (A) ethyl 4-isopropyl-2-[(3-nitrophenoxyl) methyl] -1,3-thiazole-5-carboxylate 2- (3 -Nitrophenoxy) ethanethioamide (77
5 mg, 3.66 mmol), ethyl 2-chloro-4
-Methyl-3-oxopentanoate (624 mg,
3.24 mmol) was dissolved in ethanol (10 ml) and heated under reflux for 2 days. The reaction solution was allowed to cool and then concentrated.
The precipitated crystals were collected by filtration to give the title compound (519 mg, 4 mg).
1%). ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.8 Hz), 1.36 (3H, t, J = 7.3H)
z), 3.98 (1H, m), 4.33 (2H, q, J
= 7.3 Hz), 5.41 (2H, s), 7.34 (1
H, m), 7.47 (1H, m), 7.90 (2H,
m).

(B) {4-isopropyl-2-[(3-
Nitrophenoxy) methyl] -1,3-thiazole-5
-Ethyl 4-isopropyl-2- obtained from yl @ methanol (A)
[(3-Nitrophenoxyl) methyl] -1,3-thiazole-5-carboxylate (519 mg, 1.48)
mmol) in THF (10 ml), and cooled under ice-cooling.
A 02M diisobutylaluminum hydride toluene solution (2.96 ml) was added, and the mixture was stirred for 30 minutes under ice cooling.
Further, a 1.02 M solution of diisobutylaluminum hydride in toluene (5.92 ml) was added, and the mixture was stirred for 1 hour.
An aqueous solution of potassium hydrogen sulfate was added to the reaction solution, and extraction was performed with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (454 mg, 99%) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J
= 6.8 Hz), 3.12 (1H, m), 4.83 (2
H, d, J = 4.9 Hz), 5.38 (2H, s),
7.33 (1H, dd, J = 8.3, 2.5 Hz),
7.45 (1H, t, J = 8.3 Hz), 7.86-
7.90 (2H, m).

(C) [5- (chloromethyl) -4-isopropyl-1,3-thiazol-2-yl] methyl (3
-Nitrophenyl) ether {4-isopropyl-2-[(3-nitrophenoxy) methyl] -1,3-thiazole-5 obtained in (B)
Il @ methanol (454 mg, 1.47 mmol) was dissolved in methylene chloride (10 ml), and thionyl chloride (0.215 ml) was added, followed by stirring at room temperature for 1.5 hours. The reaction solution was concentrated, diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (473 mg, 98%).

(D) [4-isopropyl-5-methyl-
1,4-thiazol-2-yl] methyl (3-nitrophenyl) ether [4-isopropyl-5-methyl- obtained by (C)
1,3-thiazol-2-yl] methyl (3-nitrophenyl) ether (60.7 mg, 0.186 mmol
l) was dissolved in DMSO (1.5 ml), sodium borohydride (17.5 mg) was added at room temperature, and the mixture was stirred overnight. Water (20 ml) was added to the reaction solution, and extraction was performed with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (n-hexane-ethyl acetate, 4: 1, v / v) to give the title compound (44.0 mg, 81%). Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J
= 6.8 Hz), 2.37 (3H, s), 3.05 (1
H, m), 5.35 (2H, s), 7.33 (1H, d
d, J = 8.3, 2.0 Hz), 7.44 (1H, t,
J = 8.3 Hz), 7.84 (1H, m), 7.90
(1H, m).

(E) 3-[(4-isopropyl-5-methyl-1,3-thiazol-2-yl) methoxy] aniline [4-isopropyl-5-methyl- obtained by (D)
1,3-thiazol-2-yl] methyl (3-nitrophenyl) ether (258 mg, 0.882 mmol)
Was dissolved in ethanol (10 ml), and stannous chloride (5
85 mg) and heated under reflux for 5 hours. After allowing the reaction solution to cool, a 5 M aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred for 15 minutes. Subsequently, extraction operation was performed with ethyl acetate, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (311 mg, quantitative).

(F) (4S, 5S) -5- (methoxycarbonyl) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid dimethyl (4S, 5S) -2,2-dimethyl-1 , 3
Dioxolane-4,5-dicarboxylate (3.0
0 g, 13.7 mmol) in methanol (100 ml)
In 1N aqueous sodium hydroxide solution (13.7m
1, 13.7 mmol) was added dropwise and stirred at room temperature for 16 hours. After evaporating the solvent, a small amount of water was added to the residue, washed with ether, adjusted to pH about 1 with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. Was distilled off to give the title compound (2.63 g, 93.7%) containing a dicarboxylic acid compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (6H, d, J
= 8.3 Hz), 3.85 (3H, s), 4.83 (1
H, d, J = 5.4 Hz), 4.89 (1H, d, J =
5.4 Hz), 7.27 (1 H, br).

(G) Methyl (4S, 5S) -5- (3
-[(4-Isopropyl-5-methyl-1,3-thiazol-2-yl) methoxy] anilinocarbonyl)-
2,2-Dimethyl-1,3-dioxolan-4-carboxylate 3-[(4-isopropyl-5-methyl-1,3-thiazol-2-yl) methoxy] aniline obtained in (E) (159 mg) , 0.61 mmol) was dissolved in methylene chloride (10 ml) and obtained in (F) (4S, 5
S) -5- (Methoxycarbonyl) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (186 mg, 0.91 mmol) was added, and diisopropylethylamine (254 μl, 1.46 mm) was added under ice cooling.
ol) was added dropwise, and N, N-bis- (2-oxo-3-oxazolidinyl) phosphinic chloride (186 mg,
(0.73 mmol), and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 20 hours. After evaporating the solvent, water was added to the residue, extracted with chloroform, washed with a 1N aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then washed.
After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 5: 1 → 2: 1, v / v) to give the title compound (139 mg, 5%) as a pale orange oil.
1.2%). ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J
= 6.8 Hz), 1.54 (3H, s), 1.56 (3
H, s), 2.36 (3H, s), 2.99-3.10.
(1H, m), 3.87 (3H, s), 4.85 (1
H, d, J = 5.4 Hz), 4.88 (1H, d, J =
5.4 Hz), 5.27 (2H, s), 6.79 (1
H, dd, J = 7.8, 2.4 Hz), 7.15 (1
H, d, J = 7.8 Hz), 7.25 (1H, t, J =
7.8 Hz), 7.36 (1H, t, J = 2.4H)
z), 8.24 (1H, s).

(H) (4S, 5S) -5- (3-[(4
-Isopropyl-5-methyl-1,3-thiazole-2
-Yl) methoxy] anilinocarbonyl) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid Methyl (4S, 5S) -5- (3-
[(4-isopropyl-5-methyl-1,3-thiazol-2-yl) methoxy] anilinocarbonyl) -2,
2-Dimethyl-1,3-dioxolane-4-carboxylate (139 mg, 0.31 mmol) was dissolved in THF-methanol (3: 1, v / v, 4 ml), and lithium hydroxide monohydrate (ICL) was added under ice cooling. 14mg, 0.34mmo
l) / Water (1 ml) solution was added dropwise and stirred at room temperature for 16 hours. After evaporating the solvent, a small amount of water was added to the residue, and the mixture was washed with ether, adjusted to pH about 1 with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated. I left. Hexane was added to the residue, and the mixture was collected by filtration as a powder and washed with hexane to give the title compound (98 mg, 73.0%) as a pale orange powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.18 (6H,
d, J = 6.8 Hz), 1.42 (6H, s), 2.3
4 (3H, s), 2.99-3.10 (1H, m),
4.72 (1H, d, J = 5.4 Hz), 4.77 (1
H, d, J = 5.4 Hz), 5.28 (2H, s),
6.75-6.82 (1H, m), 7.20-7.30
(2H, m), 7.45 (1H, s), 10.21 (1
H, s), 13.20 (1H, br). EI / MS; m / z: 434 (M ⁺ ). FAB / MS; m / z: 435 (MH ^<+> ).

Example 29: (1R ^* , 2R ^* )-2- (3
-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilinocarbonyl) cyclohexane-1-carboxylic acid (A) trans-cyclohexane-1,2- Dicarboxylic anhydride Trans-cyclohexane-1,2-dicarboxylic acid (5.00 g, 29.0 mmol) was dissolved in acetic anhydride (10 mL) and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure by azeotropic distillation with toluene and ether, and ether was added to the residue, followed by filtration to obtain the title compound as colorless crystals (3.82 g, 85%). ¹ H-NMR (DMSO
−d ₆ ) δ: 1.22-1.34 (2H, m), 1.4
7-1.61 (2H, m), 1.90-2.00 (2
H, m), 2.28-2.32 (2H, m), 2.54
-2.63 (2H, m).

(B) (1R ^* , 2R ^* )-2- (3-
((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilinocarbonyl)
Cyclohexane-1-carboxylic acid 3-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) aniline (100
mg, 0.409 mmol) in toluene (5 mL).
2-dicarboxylic anhydride (63.1 mg, 0.409 m
mol), and the mixture was stirred at room temperature for 2.5 hours. The solvent was concentrated under reduced pressure by ether azeotrope, ether was added to the residue, and the mixture was collected by filtration to give the title compound as pale yellow crystals (127 mg,
78%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.39
(2H, m), 1.27 (6H, d, J = 6.8H
z), 1.76 (2H, br), 1.90-2.05
(2H, m), 2.46-2.61 (2H, m), 3.
04 (1 septet, J = 6.8 Hz), 7.24
(1H, s), 7.28-7.42 (4H, m), 7.
47 (1H, d, J = 7.3 Hz), 7.93 (1H,
s), 10.00 (1H, s), 12.06 (1H,
s). EI-MS; m / z: 398 (M ⁺ )

Example 30: (1S ^* , 2R ^* )-2- (3
-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilinocarbonyl) cyclohexane-1-carboxylic acid 3-((E) -2- (4 -Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) aniline (100
mg, 0.409 mmol) in toluene (5 mL) was added with cis-cyclohexane-1,2-dicarboxylic anhydride (63.1 mg, 0.409 mmol), and the mixture was stirred at room temperature for 2.5 hours. The solvent was concentrated under reduced pressure by azeotropic distillation with ether, ether was added to the residue, and the mixture was collected by filtration to give the title compound as pale yellow crystals (120 mg, 73%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.21-1.47
(3H, m), 1.27 (6H, d, J = 6.8H
z), 1.60-1.80 (3H, m), 1.97-
2.18 (2H, m), 2.57-2.65 (1H,
m), 2.93-3.00 (1H, m), 3.04 (1
H, septet, J = 6.8 Hz), 7.24 (1
H, s), 7.28-7.40 (4H, m), 7.46.
(1H, d, J = 8.3 Hz), 7.93 (1H,
s), 9.78 (1H, s), 11.97 (1H,
s). FAB-MS; m / z: 399 (MH +).

Example 31: (1S ^* , 2R ^* )-2- (3
((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilinocarbonyl)
Cyclopropane-1-carboxylic acid (A) Methyl (1S ^* , 2R ^* ) 2-chlorocarbonylcyclopropane-1-carboxylate (1R ^* , 2S ^* )-2- (methoxycarbonyl) cyclopropane-1-carboxy Rick Acid (215m
g, 1.49 mmol) in methylene chloride (5 mL) at 0 ° C. with DMF (1 drop), oxalyl chloride (143).
mL, 1.64 mmol) and stirred at 0 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure by chloroform azeotrope,
The crude title compound (241 mg) was obtained as a colorless oil.

(B) Methyl (1S ^* , 2R ^* )-2-
(3 ((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilinocarbonyl) cyclopropane-1-carboxylate 3-((E) -2- ( 4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] aniline (182
mg, 0.744 mmol) of methylene chloride (2 mL)
The solution was added to triethylamine (208 mL, 1.
49 mmol), methyl (1S ^* ,
2R ^* ) 2-chlorocarbonylcyclopropane-1-carboxylate (128 mg) in methylene chloride (2 m
L) The solution was added. After stirring at room temperature for 18 hours, a 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1: 1, v / v) to give the title compound (180 mg, 65%) as a pale yellow oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.8 Hz), 1.42-1.50 (1H, m),
1.73 (1H, dd, J = 6.8, 12.2 Hz),
2.10-2.22 (2H, m), 3.11 (1H, s
eptet, J = 6.8 Hz), 3.76 (3H,
s), 6.80 (1H, s), 7.25-7.31 (4
H, m), 7.47 (1H, d, J = 7.3 Hz),
7.70 (1H, s), 8.36 (1H, br).

(C) (1S ^* , 2R ^* )-2- (3
((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilinocarbonyl)
Methyl (1S ^* , 2R ^* )-2- (3) obtained with cyclopropane-1-carboxylic acid (B)
((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilinocarbonyl)
Cyclopropane-1-carboxylate (180 mg,
Lithium hydroxide monohydrate (20.3 mg, 0.485 mmol) was added to a solution of 0.485 mmol) in THF (3 mL) -methanol (1 mL) at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. . Again at 0 ° C lithium hydroxide
Monohydrate (10.2 mg, 0.242 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, the residue was diluted with water, and washed with ether. The aqueous layer was acidified with a 5% aqueous citric acid solution, extracted with ethyl acetate, and the organic layer was washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with saturated saline. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, ether was added to the residue, and the mixture was collected by filtration to give the title compound as a white solid (51.0 m
g, 30%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (1H, b
r), 1.26 (6H, d, J = 6.8 Hz), 1.4
1 (1H, br), 1.86 (2H, t, J = 7.3H)
z), 3.30 (1H, septet, J = 6.8H
z), 7.23 (1H, s), 7.27-7.34 (4
H, m), 7.46 (1H, d, J = 7.3 Hz),
7.82 (1H, br), 11.68 (1H, br). EI-MS; m / z: 356 (M ⁺ ).

Example 32: 2- (2- {2,4-Difluoro-5-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] anilino} -2-oxoethyl) benzoic acid ( A) 2-[(2,4-Difluoro-5-nitrophenoxy) methyl] -4-isopropyl-1,3-thiazole 2,4-difluoro-5-nitrophenol (Akam
a, etc., Synthesis, 1447, (1997))
(200 mg, 1.14 mmol) and 2-hydroxymethyl-4-isopropyl-1,3-thiazole (198
mg, 1.25 mmol) in THF (6 ml), and after adding triphenylphosphine (389 mg), diethyl azodicarboxylate (0.234 m
l) was added under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (n-hexane-ethyl acetate, 10: 1,
v / v) and purified as white crystals of the title compound (313).
mg, 87%). ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.8 Hz), 3.11 (1H, m), 5.44 (2
H, s), 6.96 (1H, s), 7.08 (1H,
t, J = 10.3 Hz), 7.98 (1H, t, J =
8.3 Hz).

(B) 2,4-difluoro-5-[(4-
Isopropyl-1,3-thiazol-2-yl) methoxy] aniline 2-[(2,4-difluoro-5-nitrophenoxy) methyl] -4-isopropyl-1,3 obtained from (A).
-Thiazole (500 mg, 1.59 mmol) was dissolved in ethyl acetate (20 ml), 10% palladium on carbon (100 mg) was added, and the mixture was stirred at 40 ° C under a hydrogen atmosphere overnight. The catalyst was filtered, the mother liquor was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate, 4: 1, v / v) to give the title compound (396 mg, 87%). Obtained.

(C) 2- (2- {2,4-difluoro-
5-[(4-isopropyl-1,3-thiazole-2-
Yl) methoxy] anilino-2-oxoethyl) benzoic acid 2,4-Difluoro-5-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] aniline obtained in (B) (396 mg) , 1.39 mmol) and homophthalic anhydride (225 mg) were dissolved in toluene (10 ml), and the mixture was heated under reflux for 1 hour. Homophthalic anhydride (90
mg), and the mixture was heated under reflux for 12 hours. The precipitated solid was collected by filtration, and the title compound (383 m
g, 62%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.21 (6H,
d, J = 6.8 Hz), 3.00 (1H, m), 4.1
2 (2H, s), 5.34 (2H, s), 7.30 (1
H, s), 7.35-7.44 (3H, m), 7.52.
(1H, t, J = 7.3 Hz), 7.88 (2H,
m), 9.89 (1H, s). EI-MS; m / z: 446 (M ⁺ )

Example 34 2- (2- {2-chloro-5)
-[(4-Isopropyl-1,3-thiazol-2-yl) methoxy] anilino {-2-oxoethyl) nicotinic acid (A) tert-butyl 2- (2-ethoxy-2-oxoethyl) nicotinate 2- ( 2-ethoxy-2-oxoethyl) nicotinic acid (Ames et al., J. Chem. Soc. Perk)
in1,705, (1972)) (800 mg, 3.8
2 mmol) in toluene (15 ml),
N, N-dimethylformamide di-ter
t-Butyl acetal (3.66 ml) was slowly added dropwise. After stirring at 80 ° C for 1.5 hours, N, N-
Dimethylformamide di-tert-butyl acetal (0.915 ml) was added and stirred for 30 minutes. After allowing the reaction mixture to cool, it was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (chloroform-methanol, 100:
1, v / v) to give the title compound (736 mg, 73
%). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J
= 7.3 Hz), 1.58 (9H, s), 4.18 (2
H, q, J = 7.3 Hz), 4.27 (2H, s),
7.30 (1H, dd, J = 7.8, 4.6 Hz),
8.22 (1H, dd, J = 7.8, 1.5 Hz),
8.64 (1H, dd, J = 4.6, 1.5 Hz).

(B) 2- [3- (tert-Butoxycarbonyl) -2-pyridyl] acetic acid tert-butyl 2- (2-ethoxy-2-oxoethyl) nicotinate obtained in (A) (736 mg,
2.77 mmol) was dissolved in a mixed solvent of THF-methanol-water (17 ml, 10: 5: 2, v / v), lithium hydroxide monohydrate (128 mg) was added, and the mixture was stirred at room temperature overnight. . Neutralize the reaction with 10% aqueous citric acid,
After performing an extraction operation with ethyl acetate and drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as white crystals (516 mg, 78%).

(C) 2-[(4-Chloro-3-nitrophenoxy) methyl] -4-isopropyl-1,3-thiazole 4-chloro-3-nitrophenol (500 mg, 2.
88 mmol) in DMF and potassium carbonate (79
6 mg), 2-chloromethyl-4-isopropyl-1,
3-Thiazole (557 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (n-hexane-ethyl acetate, 12:
1, v / v) to give the title compound (767 mg, 85
%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 3.10 (1H, m), 5.37 (2
H, s), 6.93 (1H, s), 7.17 (1H, d
d, J = 8.8, 2.9 Hz), 7.44 (1H, d,
J = 9.3 Hz), 7.57 (1H, d, J = 2.9H)
z).

(D) 2-chloro-5-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] aniline 2-[(4-chloro-3-nitrophenoxy) obtained with (C) ) Methyl] -4-isopropyl-1,3-thiazole (767 mg, 2.45 mmol) was dissolved in ethanol (15 ml) and stannous chloride (1628 mg)
Was added and the mixture was refluxed overnight. After allowing the reaction solution to cool, 5M
An aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred for 15 minutes. Subsequently, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (6
47 mg, 93%).

(E) tert-butyl 2- (2- {2
-Chloro-5-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] anilino {-2-oxoethyl) nicotinate 2-chloro-5-[(4-isopropyl-) obtained with (D) 1,3-thiazol-2-yl) methoxy] aniline (110 mg, 0.388 mmol) and 2- [3- (tert-butoxycarbonyl) -2 obtained in (B).
-Pyridyl] acetyl acid (101 mg, 0.4
26 mmol) in methylene chloride (3 ml), diisopropylethylamine (0.101 ml) and N, N
-Bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (128 mg) was added, and the mixture was stirred at room temperature overnight. Diisopropylethylamine (0.253m
l) and N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (320 mg) were further added, and the mixture was stirred overnight. The reaction solution was diluted with chloroform and washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline.
After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate, 5: 1, v / v) to give the title compound (7
1.5 mg, 37%). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J
= 6.8 Hz), 1.62 (9H, s), 3.10 (1
H, m), 4.36 (2H, s), 5.29 (2H,
s), 6.65 (1H, dd, J = 8.8, 2.9H
z), 6.88 (1H, s), 7.21 (1H, d, J
= 8.8 Hz), 7.32 (1H, dd, J = 7.8,
4.9 Hz), 8.20 (1H, dd, J = 7.8,
1.5Hz), 8.28 (1H, d, J = 2.9H)
z), 8.73 (1H, dd, J = 4.9, 1.5H
z), 9.51 (s, 1H).

(F) 2- (2- {2-chloro-5-
[(4-isopropyl-1,3-thiazol-2-yl) methoxy] anilino {-2-oxoethyl) nicotinic acid tert-butyl 2- (2- {2-
Chloro-5-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] anilino {-2-oxoethyl) nicotinate (71.5 mg, 0.142 mmol)
l) was dissolved in chloroform (1 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration and dried to give the title compound (4) as a white powder.
(6.3 mg, 48%) as the ditrifluoroacetate salt. ^{1 H-NMR (DMSO-d} 6) δ: 1.23 (6H,
d, J = 6.8 Hz), 3.02 (1H, m), 4.3
6 (2H, s), 5.35 (2H, s), 6.88 (1
H, dd, J = 8.8, 2.4 Hz), 7.29 (1
H, s), 7.41 (1H, d, J = 8.8 Hz),
7.46 (1H, dd, J = 7.8, 4.9 Hz),
7.62 (1H, br), 8.25 (1H, d, J =
7.8 Hz), 8.68 (1H, d, J = 4.9H)
z), 9.74 (1H, s).

Example 35: N ¹ -3-[(E) -2-]
(4-Isopropyl-1,3-thiazol-2-yl)
-1-Ethenyl] phenyl-2- (2-[(trifluoromethyl) sulfonyl] aminophenyl) acetamido (A) methyl 2- (2-nitrophenyl) acetate 2- (2-nitrophenyl) acetic acid (5 0.06 g, 27.9 mmol) in methanol (10
0 ml), concentrated sulfuric acid (5 ml) was added dropwise, and the mixture was heated under reflux for 16 hours. After evaporating the solvent, water was added to the residue, and the mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a pale orange oil. Title compound (5.3
7g, 99.0%). ¹ H-NMR (CDCl ₃ ) δ: 3.72 (3H, s),
4.03 (2H, s), 7.36 (1H, d, J = 7.
3 Hz), 7.44-7.51 (1H, m), 7.57
−7.63 (1H, m), 8.12 (1H, d, J =
7.8 Hz).

(B) Methyl 2- (2-aminophenyl) acetate Methyl 2- (2-nitrophenyl) obtained by (A)
Acetate (1.69 g, 8.66 mmol) was dissolved in methanol (20 ml), 10% palladium on carbon (0.17 g) was suspended, and under a hydrogen atmosphere (1 atm),
Stirred at room temperature for 19 hours. After removing the catalyst by filtration, the residue was washed with methanol, and the solvent was distilled off to obtain the title compound (1.33 g, 93.0%) as a pale orange oil. ¹ H-NMR (CDCl ₃ ) δ: 3.57 (2H, s),
3.68 (3H, s), 4.06 (2H, br),
67-6.79 (2H, m), 7.04-7.12 (2
H, m).

(C) Methyl 2- (2-[(trifluoromethyl) sulfonyl] aminophenyl) acetate Methyl 2- (2-aminophenyl) obtained from (B)
Acetate (1.32 g, 7.99 mmol) was dissolved in methylene chloride (50 ml), and triethylamine (1.23 ml, 8.79 mmol) was added dropwise under ice-cooling, and trifluoroacetic anhydride (1.34 ml, 7.99 mmol) was added. )
Was slowly added dropwise. After stirring at the same temperature for 15 minutes, water was added to the reaction solution, the organic layer was separated, washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. Distilling
The title compound (1.41 g, 59.4) as a pale orange oil.
%). ¹ H-NMR (CDCl ₃ ) δ: 3.75 (2H, s),
3.77 (3H, s), 7.17-7.45 (3H,
m), 7.48-7.65 (1H, m).

(D) 2- (2-[(trifluoromethyl) sulfonyl] aminophenyl) acetic acid Methyl 2- (2-[(trifluoromethyl) sulfonyl] aminophenyl) acetate obtained by (C) (1.41 g, 4.74 mmol) dissolved in THF-methanol (3: 1, v / v, 80 ml) and lithium hydroxide monohydrate (218 mg, 5.22 mmol) under ice-cooling.
/ Water (20 ml) solution was added dropwise and stirred at room temperature for 3 hours. Lithium hydroxide monohydrate (218 mg, 5.
(22 mmol) / water (20 ml) solution was added, and the mixture was stirred at room temperature for 17 hours. After evaporating the solvent, a small amount of water was added to the residue, and the mixture was washed with ether, adjusted to pH about 1 with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. Evaporation gave the title compound (1.35 g, quantitative) as a pale orange oil. ¹ H-NMR (CDCl ₃ ) δ: 3.79 (2H, s),
5.61 (1H, br), 7.23-7.46 (3H,
m), 7.51 (1H, d, J = 7.8 Hz), 8.5
0 (1H, br).

(E) N ^1-3 -[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] phenyl-2- (2-[(trifluoromethyl ) Sulfonyl] aminophenyl) acetamide 2- (2-[(trifluoromethyl)) obtained with (D)
Thionyl chloride (663 ml, 9.09 mmol) was added dropwise to ice-cooled [sulfonyl] aminophenyl) acetic acid (515 mg, 1.82 mmol), followed by stirring at the same temperature for 10 minutes and then at room temperature for 30 minutes. After evaporating the solvent, the residue was dissolved in methylene chloride (20 ml), and cooled with ice to give 3-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) aniline. (222
mg, 0.91 mmol) / methylene chloride (10 ml)
Solution and triethylamine (1.27 ml, 9.09
mmol) and dimethylaminopyridine (222
mg, 1.82 mmol). After stirring at the same temperature for 30 minutes, the mixture was stirred at room temperature for 20 hours, and the solvent was distilled off. Water was added to the residue, extracted with chloroform, 1N aqueous hydrochloric acid, water,
After sequentially washing with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, the solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform → chloroform: methanol = 50: 1, v
/ V), and after distilling off the solvent, hexane was added to the residue to obtain a powder, which was collected by filtration and washed with hexane to obtain the title compound (98 mg, 21.2%) as a pale orange powder. . ¹ H-NMR (DMSO-d ₆ ) δ: 1.26 (6H,
d, J = 6.8 Hz), 2.97-3.09 (1H,
m), 3.85 (2H, s), 7.23-7.44 (1
0H, m), 7.50 (1H, d, J = 7.8 Hz),
7.92 (1H, br), 10.41 (1H, br). EI / MS; m / z: 509 (M ⁺ ). FAB / MS; m / z: 510 (MH ⁺ ).

Example 36: 1-benzyl-4-((3-
((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -1H-3-pyrrolecarboxylic acid (A) dimethyl 1-benzyl-2, 5-dihydro-1
H-3,4-pyrrole dicarboxylate N-benzyl-N-butoxymethyl-N-[(1,1,
1-trimethylsilyl) methyl] amine (803.7 m
g) and a solution of dimethyl acetylenedicarboxylate (0.353 ml) in methylene chloride (10 ml)
To the mixture was added trifluoroacetic acid (22 μl) at room temperature, and the mixture was stirred at the same temperature overnight. Chloroform was added to the reaction solution, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (chloroform: methanol = 99.5: 0.5, v / v), and dimethyl 1-benzyl-2,5-dihydro-1H-
3,4-pyrrole dicarboxylate (536.9 m
g, 68%) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 3.77 (6H, s),
3.80 (2H, s), 3.83 (4H, s), 7.3
2-7.34 (5H, m).

(B) 1-benzyl-4- (methoxycarbonyl) -2,5-dihydro-1H-3-pyrrolecarboxylic acid dimethyl 1-benzyl-2,5-dihydro-1H-
To a methanol solution (3 ml) of 3,4-pyrrole dicarboxylate (148 mg) was added a 1N aqueous sodium hydroxide solution (0.539 ml) at room temperature.
Stir for 5 hours. 1N hydrochloric acid (0.539 ml) was added to the residue obtained by evaporating the solvent, then toluene was added and the mixture was evaporated under reduced pressure. Chloroform and anhydrous sodium sulfate were added to the obtained residue, and the insoluble matter was removed by filtration. The solvent is distilled off and 1-benzyl-4- (methoxycarbonyl)-
2,5-Dihydro-1H-3-pyrrolecarboxylic acid (119.5 mg, 85%) was obtained as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 3.79 (2H, s),
3.89 (3H, s), 3.85-3.92 (2H,
m), 3.95-4.00 (2H, m), 7.20-
7.40 (5H, m).

(C) Methyl 1-benzyl-4- (3-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl)
-2,5-dihydro-1H-3-pyrrolecarboxylate 1-benzyl-4- (methoxycarbonyl) -2,5-
Dihydro-1H-3-pyrrolecarboxylic acid (117.4 mg) and 3-[(E) -2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
To a solution of [ethenyl] aniline (120.8 mg) in methylene chloride (5 ml) were added dicyclohexylcarbodiimide (102.0 mg) and N, N-dimethylaminopyridine (60.4 mg) at room temperature, and the mixture was stirred at the same temperature overnight. did. After removing the insoluble matter by filtration, the residue obtained by evaporating the solvent was dissolved in ethyl acetate, and the insoluble matter was removed by filtration. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1, v / v),
Methyl 1-benzyl-4- (3-[(E) -2- (4
-Isopropyl-1,3-thiazol-2-yl) -1
-Ethenyl] anilinocarbonyl) -2,5-dihydro-1H-3-pyrrolecarboxylate (107.1 m
g, 49%) as a yellow oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.8 Hz), 3.05-3.20 (1H, m),
3.80 (2H, s), 3.86 (3H, s), 3.9
1 (2H, t, J = 4.9 Hz), 4.06 (2H,
t, J = 4.9 Hz), 7.20-7.40 (9H,
m), 7.67 (1H, d, J = 7.8 Hz), 7.8
5 (1H, s), 11.65 (1H, s).

(D) 1-benzyl-4-((3-
((E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -1H-3-pyrrolecarboxylic acid methyl 1-benzyl-4- (3- [(E) -2- (4
-Isopropyl-1,3-thiazol-2-yl) -1
-Ethenyl] anilinocarbonyl) -2,5-dihydro-1H-3-pyrrolecarboxylate (106.7 m
g) in a mixed solution of methanol (2 ml) and THF (1 ml) at room temperature in lithium hydroxide monohydrate (9.6 mg).
Aqueous solution (0.3 ml) was added, and the mixture was stirred at the same temperature for 7 hours. Further, an aqueous solution (0.5 ml) of lithium hydroxide monohydrate (9.2 mg) was added, and the mixture was stirred at the same temperature for 16 hours. 3 ml) and stirred overnight at the same temperature. The solvent was distilled off, and 1N hydrochloric acid (0.558 ml) was added to the residue obtained.
Was added, and the precipitated solid was subjected to silica gel chromatography (chloroform: methanol = 96: 4 → 92: 8,
v / v) and purified by 1-benzyl-4-((3-
((E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -1H-3-pyrrolecarboxylic acid (32.3 mg, 31%) was colorless. Obtained as a solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 6.8 Hz), 3.04 (1H, quint, J =
6.8 Hz), 5.23 (2H, s), 7.24 (1
H, s), 7.30-7.45 (9H, m), 7.58.
(1H, d, J = 7.8 Hz), 7.65-7.75
(2H, m), 7.92 (1H, s). FAB-MS; m / z: 472 (MH ^<+> ). Elemental analysis (as _{C 27 H 25 N 3 O 3} S · 0.4H 2 O): Calculated: C, 67.73; H, 5.43 ; N, 8.78. Found: C, 67.91; H, 5.49; N, 8.47.

Example 37: 4-((3-((E) -2-)
(4-Isopropyl-1,3-thiazol-2-yl)
-1-Ethenyl) anilino) carbonyl) -3-floic acid (A) 4- (methoxycarbonyl) -3-floic acid A methanol solution (3 ml) of commercially available dimethyl 3,4-furandicarboxylate (504.1 mg) ), A 1N aqueous sodium hydroxide solution (3.01 ml) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. Water was added to the residue obtained by evaporating the solvent, and the residue was washed with diethyl ether.
The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 4- (methoxycarbonyl) -3-floic acid (379.8 mg, 82%) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 4.01 (3H, s),
8.13 (1H, d, J = 2.0 Hz), 8.25 (1
H, d, J = 2.0 Hz).

(B) Methyl 4- (3-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-Ethenyl] anilinocarbonyl) -3-furoate 4- (methoxycarbonyl) -3-floic acid (101.1 mg) and 3-[(E) -2- (4-isopropyl-1,3-thiazole) -2-yl) -1-ethenyl] aniline (132.0 mg) in methylene chloride (5 ml) at room temperature was added with dicyclohexylcarbodiimide (122.6 mg) and N, N-dimethylaminopyridine (72.6 mg). The mixture was stirred at the same temperature for 18 hours. After removing the insoluble matter by filtration, the residue obtained by evaporating the solvent was dissolved in ethyl acetate, and the insoluble matter was removed by filtration. The residue obtained by distilling off the solvent was subjected to silica gel chromatography (chloroform → chloroform: methanol = 99: 99).
1, v / v) to give methyl 4- (3-[(E) -2].
-(4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl) -3-furoate (165.3 mg, 77%) was obtained as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.8 Hz), 3.12 (1H, quint, J = 6.8).
Hz), 3.99 (3H, s), 6.81 (1H,
s), 7.20-7.30 (1H, m), 7.30-
7.40 (3H, m), 7.77 (1H, d, J = 7.
8Hz), 7.91 (1H, s), 8.14 (1H,
d, J = 2.0 Hz), 8.28 (1H, d, J = 2.
0 Hz).

(C) 4-((3-((E) -2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
Ethenyl) anilino) carbonyl) -3-fluoroic acid methyl 4- (3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl)- 3-Floate (162.
1 mg) of methanol (2 ml) -THF (1.5 m
l) At room temperature, lithium hydroxide monohydrate (1
9.3 mg) (0.6 ml) and stirred at the same temperature for 2 hours. 1N was added to the residue obtained by evaporating the solvent.
Hydrochloric acid (0.46 ml) was added, neutralized with a 1N aqueous sodium hydroxide solution, and extracted with chloroform and ethyl acetate. After drying over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was collected by filtration using diethyl ether, and 4-((3-((E) -2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -3-floic acid (11
6.1 mg, 74%) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 6.8 Hz), 3.05 (1H, quint, J =
6.8 Hz), 7.25 (1 H, s), 7.35-7.
45 (4H, m), 7.62 (1H, d, J = 7.8H
z), 7.94 (1H, s), 8.20-8.35 (2
H, m). FAB-MS; m / z: 383 (MH ^<+> ). Elemental analysis (as _{C 20 H 18 N 2 O 4} S · H 2 O): Calculated: C, 59.99; H, 5.03 ; N, 7.00. Found: C, 60.26; H, 4.68; N, 6.88.

Example 38: 3-((3-((E) -2-)
(4-Isopropyl-1,3-thiazol-2-yl)
-1-Ethenyl) anilino) carbonyl) -5-methyl-4-isoxazolecarboxylic acid (A) 4- (tert-butyl) 3-ethyl 5-methyl-3,4-isoxazoledicarboxylate tert -Butyl acetoacetate (500.0m
g) and ethyl cyanoformate (0.375 m
1) methylene chloride solution (10 ml) in a nitrogen stream at room temperature with zinc acetylacetonate (16.7 mg)
Was added and stirred at the same temperature for 3 days. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the insolubles were filtered through celite. The residue obtained by distilling off the solvent was purified by silica gel chromatography (chloroform), and hydroxylamine hydrochloride (113.8 mg) and triethylamine (0.228 ml) were added to a chloroform solution of enamine (6 ml). In addition, the mixture was stirred for 15 hours under a nitrogen stream at room temperature. A 5% aqueous citric acid solution was added to the reaction solution, and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off, and 4- (tert-butyl) 3-ethyl was removed.
5-Methyl-3,4-isoxazoledicarboxylate (242.0 mg, 30%) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J
= 7.3 Hz), 1.54 (9H, s), 2.67 (3
H, s), 4.43 (2H, q, J = 7.3 Hz).

(B) 4- (tert-butoxycarbonyl) -5-methyl-3-isoxazolecarboxylic acid 4- (tert-butyl) 3-ethyl 5-methyl-
3,4-isoxazole dicarboxylate (125.
Aqueous solution (0.3 ml) of lithium hydroxide monohydrate (9.6 mg) in a THF solution (4 ml) of THF (3 ml) at room temperature.
Was added and stirred at the same temperature for 7 hours. Further, an aqueous solution (0.5 ml) of lithium hydroxide monohydrate (22.7 mg) was added, and the mixture was stirred at the same temperature for 1.5 hours. A 5% aqueous citric acid solution was added to the residue obtained by evaporating the solvent, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off to give 4- (tert-butoxycarbonyl) -5.
-Methyl-3-isoxazolecarboxylic acid (86.7 mg, 78%) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s),
2.31 (3H, s).

(C) tert-butyl 3- (3-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl)
-5-methyl-4-isoxazolecarboxylate 4- (tert-butoxycarbonyl) -5-methyl-
3-Isoxazole carboxylic acid (86.
7 mg) and 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] aniline (93.2 mg) in methylene chloride (5 ml) and DMF (0.3 ml) ) Was added at room temperature to dicyclohexylcarbodiimide (86.6 mg) and N,
N-dimethylaminopyridine (51.3 mg) was added,
The mixture was stirred at the same temperature for 2 days. The residue obtained by evaporating the solvent was dissolved in ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 85: 15, v / v).
tert-butyl 3- (3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl) -5-methyl-4-isoxazolecarboxy The rate (16.3 mg, 9%) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.8 Hz), 1.69 (9H, s), 2.52 (3
H, s), 3.13 (1H, dq, J = 6.8, 0.5
Hz), 6.82 (1H, s), 7.30-7.45
(4H, m), 7.77 (1H, br d, J = 7.6)
Hz), 7.91 (1H, d, J = 1.5 Hz), 1
2.05 (1H, s).

(D) 3-((3-((E) -2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
Ethenyl) anilino) carbonyl) -5-methyl-4-
Isoxazolecarboxylic tert-butyl 3- (3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinocarbonyl) -5-methyl- To a dioxane solution (0.5 ml) of 4-isoxazolecarboxylate (16.3 mg) was added a 4N hydrochloric acid-dioxane solution (1 ml) at room temperature, and the mixture was stirred at the same temperature for 4.5 hours. Dioxane was added to the residue obtained by distilling off the solvent, and the solvent was distilled off. Then, the residue was collected by filtration with diethyl ether to give 3-((3-((E) -2- (4-isopropyl-
1,3-Thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -5-methyl-4-isoxazolecarboxylic acid (7.6 mg, 49%) was obtained as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 6.8 Hz), 2.46 (3H, s), 3.0
5 (1H, quint, J = 6.8 Hz), 7.27 (1
H, s), 7.35-7.50 (3H, m), 7.50.
-7.60 (2H, m), 7.95 (1H, s), 1
1.44 (1H, s). FAB-MS; m / z: 398 (MH ^<+> ).

Example 39: 4-((3-((E) -2-)
(4-Isopropyl-1,3-thiazol-2-yl)
-1-Ethenyl) anilino) carbonyl) -5-methyl-3-isoxazolecarboxylic acid (A) 3- (ethoxycarbonyl) -5-methyl-4-
Isoxazole carboxylic acid 4- (tert-butyl) synthesized in Example 38 (A)
To a solution of 3-ethyl 5-methyl-3,4-isoxazoledicarboxylate (121.5 mg) in methylene chloride (1.5 ml) was added trifluoroacetic acid (1.5 ml) under ice-cooling.
ml) and stirred at the same temperature for 2 hours. Water was added to the residue obtained by evaporating the solvent, and the mixture was neutralized with a 1N aqueous sodium hydroxide solution. A 5% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate under salting out. After drying over anhydrous sodium sulfate, the solvent was distilled off to give 3- (ethoxycarbonyl) -5-
Methyl-4-isoxazolecarboxylic acid (74.0 mg, 78%) was obtained as a yellow amorphous. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.42
(3H, t, J = 7.1 Hz), 2.74 (3H, t, J = 7.1 Hz)
s), 4.48 (2H, q, J = 7.1 Hz).

(B) Ethyl 4-((3-((E) -2)
-(4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -5-methyl-3-isoxazolecarboxylate 3- (ethoxycarbonyl) -5-methyl-4- Isoxazolecarboxylic acid (74.0 mg) and 3-[(E) -2- (4-isopropyl-1,3-
Thiazol-2-yl) -1-ethenyl] aniline (9
0.8 mg) methylene chloride (5 ml) and DMF
(0.5 ml), dicyclohexylcarbodiimide (84.3 mg) and N, N-dimethylaminopyridine (49.9 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 days. The residue obtained by evaporating the solvent was dissolved in ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 85: 15, v / v) to give ethyl 4-
((3-((E) -2- (4-isopropyl-1,3-
Thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -5-methyl-3-isoxazolecarboxylate (76.0 mg, 48%) was obtained as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.8 Hz), 1.52 (3H, t, J = 7.1H)
z), 2.89 (3H, s), 3.12 (1H, quin
t, J = 6.8 Hz), 4.61 (2H, d, J = 7.
1Hz), 6.81 (1H, s), 7.25-7.40
(3H, m), 7.67 (1H, br d, J = 7.8
Hz), 7.90 (1H, d, J = 1.7 Hz), 1
1.15 (1H, s).

(C) 4-((3-((E) -2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
Ethenyl) anilino) carbonyl) -5-methyl-3-
Isoxazolecarboxylic acid ethyl 4-((3-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl)
Anilino) carbonyl) -5-methyl-3-isoxazolecarboxylate (76.0 mg) in a mixed solution of methanol (1 ml) and THF (1.5 ml) at room temperature was mixed with lithium hydroxide monohydrate (8. 3 mg) (0.5 ml) and stirred at the same temperature for 2 hours. 1N
After adding hydrochloric acid (0.1 ml), chloroform and anhydrous sodium sulfate were added to the residue obtained by evaporating the solvent, and the insoluble matter was collected by filtration. Water and 1N hydrochloric acid were added to the obtained insoluble matter, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was collected by filtration using diethyl ether, and 4-((3-((E) -2)
-(4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) anilino) carbonyl) -5-methyl-3-isoxazolecarboxylic acid (42.9 mg, 60%) as a yellow solid As obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 6.9 Hz), 2.70 (3H, s), 3.0
5 (1H, quint, J = 6.9 Hz), 7.25 (1
H, m), 7.30-7.50 (4H, m), 7.56
(1H, d, J = 7.3 Hz), 7.95 (1H,
s). FAB-MS; m / z: 398 (MH ^<+> ). Main remeasurement elemental analysis (as _{C 20 H 19 N 3 O 4} S · 0.5H 2 O · 1HCl): Calculated: C, 54.23; H, 4,78 ; N, 9.49. Found: C, 53.97; H, 4.71; N, 9.14.

Example 40: 2- (2- (3-((4-isopropyl-1,3-thiazol-2-yl) methoxy) benzylamino) -2-oxoethyl) benzoic acid (A) methyl 2- (3-Hydroxyphenyl) acetate 2- (3-hydroxyphenyl) acetic acid (2.50 g, 16.4 mmol) in toluene (30 m
L) -Methanol (10 mL) solution at 0 ° C. in trimethylsilyldiazomethane (2.0 M in hexane)
e, 8.22 mL, 16.4 mmol) and stirred at room temperature for 30 minutes. Further, at 0 ° C., trimethylsilyldiazomethane (2.0 M in hexane, 4.
11 mL, 8.22 mmol) and stirred at room temperature for 15 minutes. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform (chloroform-
Purification with methanol, 10: 1, v / v) and (hexane (hexane-ethyl acetate, 10: 1 (5: 1, v / v)) gave the title compound as a colorless oil (2.70 g,
99%). ¹ H-NMR (CDCl ₃ ) δ: 3.58 (2H, s),
3.70 (3H, s), 5.93 (1H, br), 6.
74 (1H, dd, J = 2.7, 8.1 Hz), 6.7
7 (1H, s), 6.81 (1H, d, J = 7.57H)
z), 7.17 (1H, t, J = 7.8 Hz).

(B) Methyl 3-((4-isopropyl-1,3-thiazol-2-yl) methoxy) phenyl acetate Methyl 2- (3-hydroxyphenyl) acetate obtained in (A) (2.70 g) , 16.3 mmol),
(4-Isopropyl-1,3-thiazol-2-yl)
Methanol (2.56 g, 16.3 mmol) and triphenylphosphine (4.27 g, 16.3 mmol)
l) in THF (50 mL) at −15 ° C. in diethyl azodicarboxylate (2.56 mL, 16.3 mmol)
l) was added. After stirring at room temperature for 3.5 hours, the solvent was concentrated under reduced pressure by toluene azeotropy. Toluene was added to the residue, and insolubles were filtered off and washed with toluene. The filtrate and the washings were combined, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane (hexane-ethyl acetate, 1
Purification by 0: 1 (4: 1, v / v) gave the title compound as a colorless oil (3.78 g, 76%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 3.11 (1H, septet, J =
6.8 Hz), 3.60 (2H, s), 3.69 (3
H, s), 5.33 (2H, s), 6.90-6.94.
(4H, m), 7.25 (1H, t, J = 7.8H
z).

(C) 3-((4-isopropyl-1,3
-Thiazol-2-yl) methoxy) phenylacetic acid The methyl 3-((4-isopropyl-) obtained in (B)
1,3-thiazol-2-yl) methoxy) phenylacetate (3.78 g, 12.4 mmol) in THF
(30 mL)-Lithium hydroxide monohydrate (520 mg, 12.4 m
mol) in water (20 mL) and added at room temperature for 1.5
Stirred for hours. Further, lithium hydroxide monohydrate (260 mg, 6.19 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, and the residue was diluted with a 1 N aqueous sodium hydroxide solution and washed with ether. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform, and the organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.34 g, 65%) as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (6H,
d, J = 6.8 Hz), 3.03 (1H, septe
t, J = 6.8 Hz), 3.54 (2H, s), 5.3
6 (2H, s), 6.88 (1H, d, J = 7.6H)
z), 6.93-6.96 (2H, m), 7.24 (1
H, t, J = 7.8 Hz), 7.29 (1H, s), 1
2.32 (1H, br).

(D) tert-butyl N-3-((4
-Isopropyl-1,3-thiazol-2-yl) methoxy) benzylcarbamate 3-((4-isopropyl-1,3-
Thiazol-2-yl) methoxy) phenylacetic acid (1.00 g, 3.43 mmol) ter
Triethylamine (574 mL, 4.12 mmol) and azide diphenylphosphate (814 mL, 3.78 mmol) were added to a t-butanol (20 mL) solution, and 1
The mixture was refluxed for 5.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform, chloroform).
(Chloroform-methanol, 99: 1, v / v) and (hexane-ethyl acetate, 6: 1 (5: 1, v / v)
The title compound was purified as a colorless oil (203 m
g, 16%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 1.46 (9H, s), 3.11 (1
H, septet, J = 6.8 Hz), 4.30 (2
H, d, J = 5.4 Hz), 4.85 (1H, br),
5.33 (2H, s), 6.88-6.94 (4H,
m), 7.25 (1H, t, J = 7.8 Hz).

(E) 3-((4-isopropyl-1,3
-Thiazol-2-yl) methoxy) benzylamine tert-butyl N-3-((4-
(Isopropyl-1,3-thiazol-2-yl) methoxy) benzylcarbamate (203 mg, 0.561 m)
mol) at 0 ° C and 4N hydrochloric acid-dioxane (5 mL)
Was added, and methanol (1 mL) was added thereto, and the mixture was stirred at room temperature for 15 minutes. The solvent was concentrated under reduced pressure by azeotropic distillation with chloroform, and the residue was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (152 mg, quantitative) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 1.66 (2H, br), 3.11
(1H, septet, J = 6.8 Hz), 3.84
(2H, s), 5.34 (2H, s), 6.86-6.
89 (2H, m), 6.94 (1H, d, J = 7.6H
z), 6.99 (1H, br), 7.26 (1H, t,
J = 7.8 Hz).

(F) 2- (2- (3-((4-isopropyl-1,3-thiazol-2-yl) methoxy) benzylamino) -2-oxoethyl) benzoic acid (E) 3-(( 4-isopropyl-1,3-thiazol-2-yl) methoxy) benzylamine (52.1 m
g, 0.199 mmol) in toluene (2 mL) was added to homophthalic anhydride (32.2 mg, 0.199 m
mol), and the mixture was heated under reflux for 5 hours. The precipitated solid was collected by filtration and washed with toluene to give the title compound (63.3 mg, 75%) as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (6H,
d, J = 6.8 Hz), 3.04 (1H, septe)
t, J = 6.8 Hz), 3.93 (2H, s), 4.2
5 (2H, d, J = 5.9 Hz), 5.35 (2H,
s), 6.88-6.94 (3H, m), 7.24 (1
H, t, J = 7.7 Hz), 7.30-7.38 (3
H, m), 7.47-7.50 (1H, m), 7.84.
(1H, d, J = 7.6 Hz), 8.37-8.40
(1H, m), 12.89 (1H, br). EI-MS; m / z: 424 (M ^<+> ).

Example 41: 3- (3-[(E) -2-]
(4-Isopropyl-1,3-thiazol-2-yl)
-Ethyl] phenoxymethyl) benzoic acid (A) 3-[(E) -2- (4-isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl] phenol Diethyl [(4-isopropyl-1,3-thiazol-2-yl) methyl] phosphonate obtained in Example 15 (E) and 3-hydroxybenzaldehyde were used. Example 1
The same treatment as in 5 (F) was performed to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.6 Hz), 3.13 (1H, heterogeneous)
t, J = 6.6 Hz), 6.79-6.82 (2H,
m), 6.99 (1H, m), 7.08 (1H, d, J
= 7.5 Hz), 7.22 (1H, d, J = 7.8H)
z), 7.27 (1H, d, J = 8.4 Hz), 7.2
9 (1H, s).

(B) 3- (3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] phenoxymethyl) benzonitrile (A) 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl]
Phenol (221 mg, 0.9 mmol) was dissolved in dimethylformamide (5 mL), cesium carbonate (588 mg) was added, and the mixture was stirred for 20 minutes. 2-Bromomethylbenzonitrile (195 mg) was added, and the mixture was stirred for 16 hours. The reaction solution was distributed between ethyl acetate and water, washed with saturated saline and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (320 mg) as an oil. This compound was used for the next reaction without purification. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.9 Hz), 3.12 (1H, heterogeneous)
t, J = 6.9 Hz), 5.12 (2H, s), 6.8
2 (1H, s), 6.92 (1H, d, J = 7.8H
z), 7.12 (1H, s), 7.17 (1H, d, J
= 7.8 Hz), 7.31 (3H, m), 7.51 (1
H, t, J = 8.1 Hz), 7.63 (1H, d, J =
8.1), 7.68 (1H, d, J = 8.1 Hz),
7.76 (1H, s). MS (ES +); m / z: 361 (MH ^<+> ).

(C) 3- (3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -ethyl] phenoxymethyl) benzoic acid (B) -(3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] phenoxymethyl) benzonitrile (50 mg)
Was dissolved in ethanol (1 mL) and a 2 N aqueous solution of sodium hydroxide (1 mL), and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, the reaction solution was acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (methylene chloride:
Purification with methanol, 99: 1, v / v) gave the title compound (14 mg) as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (6H,
d, J = 6.9 Hz), 3.13 (1H, heptup)
let, J = 6.9 Hz), 5.14 (2H, s),
6.18 (1H, s), 6.95 (1H, d, J = 7.
5 Hz), 7.15 (2H, m), 7.26-7.34
(3H, m), 7.51 (1H, t, J = 8.4H
z), 7.71 (1H, d, J = 7.0 Hz), 8.0
8 (1H, d, J = 7.5 Hz), 8.20 (1H,
s). MS (ES-); m / z: 378 (M ⁺ -1).

Example 42: 3-[(E) -2- (4-cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl] phenyl [3- (1H-1,2,3,4 -Tetrazol-5-yl) propyl] ether (A) 3-[(E) -2- (4-cyclobutyl-1,3
-Thiazol-2-yl) -1-ethenyl] phenol It was synthesized in the same manner as in Example 41 (A). ¹ H-NMR (CDCl ₃ ) δ: 1.83-2.16 (2
H, m), 2.21-2.40 (4H, m), 3.69
(1H, m), 6.80 (1H, d, J = 8.1H
z), 6.84 (1H, s), 7.00 (1H, m),
7.09 (1H, d, J = 8.1 Hz), 7.21-
7.30 (3H, m).

(B) 3-3-[(E) -2- (4-Cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl] phenoxypropylcyanide [(E) -2- (4-Cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl]
Phenol (141 mg) was added to dimethylformamide (5
cesium carbonate (358 mg)
Was added and stirred for 10 minutes. 4-Bromobutyronitrile (60 μL) and sodium iodide (177 mg) were added, and the mixture was stirred for 16 hours. The reaction was partitioned between ethyl acetate-water,
After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (119 mg) as an oil. This compound was used for the next reaction without purification. ¹ H-NMR (CDCl ₃ ) δ: 2.01-2.62 (8
H, m), 2.72 (2H, t, J = 7.2 Hz),
3.80 (1H, m), 4.22 (2H, t, J = 5.
7Hz), 6.95 (1H, s), 6.97 (1H,
d, J = 8.4 Hz), 7.17 (1H, m), 7.2
5 (1H, d, J = 7.5 Hz), 7.37-7.42
(3H, m). MS (ES +); m / z: 325 (MH ^<+> ).

(C) 3-[(E) -2- (4-Cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl] phenyl [3- (1H-1,2,3,4- Tetrazol-5-yl) propyl] ether Sodium azide (337 mg) was suspended in dimethylformamide (1.5 mL), aluminum chloride (243 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours.
3-3-[(E) -2- (4-Cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl] phenoxypropyl cyanide (118 mg) obtained in (B) was treated with dimethylformamide (1 .5 mL), added to the above reaction solution, and stirred at 90 ° C. for 16 hours. After cooling the reaction solution,
The reaction solution was acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride: methanol, 9: 1, v / v) to give the title compound (40 mg) as a yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.96-2.18 (4
H, m), 2.25-2.50 (4H, m), 3.22
(2H, t, J = 7.2 Hz), 3.77 (1H,
m), 4.15 (2H, t, J = 6.0 Hz), 6.8
6 (1H, d, J = 8.1 Hz), 6.92 (1H,
s), 7.05 (1H, d, J = 7.2 Hz), 7.3
6-7.38 (3H, m), 7.68 (1H, d, J =
15.9 Hz). MS (ES-); m / z: 366 (M ^<+> -1).

Example 43: 4- (3-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] benzoylamino) benzoic acid (A) 3-[(E) -2- (4-isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl] benzonitrile diethyl [(4-isopropyl-1,3-thiazol-2-yl) methyl] phosphonate, 3-cyanobenzaldehyde in the same manner as in Example 15 (F) To give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, d),
3.23 (1H, hepplet), 6.99 (1
H, s), 7.42 (2H, s), 7.58 (1H,
m), 7.68 (1H, m), 7.86 (2H, m).

(B) 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] benzoic acid ) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl]
Concentrated hydrochloric acid (20 mL) was added to benzonitrile (470 mg), and the mixture was heated under reflux for 1.5 hours. The reaction solution was ethyl acetate-
The organic layer was washed with saturated saline and the solvent was distilled off under reduced pressure to obtain the title compound (288 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.35 (6H,
d), 3.18 (1H, m), 7.38 (1H, s),
7.62 (3H, m), 7.99 (1H, d), 8.1
2 (1H, d), 8.29 (1H, s).

(C) Methyl 4- (3-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-Ethenyl] benzoylamino) benzoate 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] obtained with (B).
Dissolve benzoic acid (100 mg) in methylene chloride (2.5 mL) and thionyl chloride (2.5 mL)
Was added and heated under reflux for 0.5 hour. The solvent was distilled off under reduced pressure, methylene chloride was added to the residue, and the residue was again distilled and dissolved in methylene chloride (2 mL). This solution was added to a solution of methyl 4-aminobenzoate (190 mg) in pyridine (2 mL).
After adding at 0 ° C, the mixture was stirred at room temperature for 14 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water, 1N hydrochloric acid and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (90 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, d),
3.37 (1H, hepplet), 3.96 (3
H, s), 7.12 (1H, s), 7.61 (1H,
t), 7.70 (1H, m), 7.81 (1H, m),
7.95 (4H, m), 8.18 (2H, m), 8.2
8 (1H, m). MS (ES +); m / z: 407 (MH ^<+> ).

(D) 4- (3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] benzoylamino) benzoic acid (C) Methyl 4- (3-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
[-1-Ethenyl] benzoylamino) benzoate was treated in the same manner as in Example 15 (I) to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d), 3.05 (1H, heptuplet), 7.2
8 (1H, s), 7.57 (4H, m), 7.94 (5
H, m), 10.55 (1H). MS (ES-); m / z: 391 (M ⁺ -1).

Example 44: N- [4- (1H-1,2,2,
3,4-tetrazol-5-yl) phenyl] -5-
[(E) -2- (4-Cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl] -2-furanamide (A) N- (4-cyanophenyl) -5-formyl-
2-Furanamide 5-formylfuran-2-carboxylic acid (100 mg) was dissolved in methylene chloride (5 mL),
Ogilzyl chloride (0.2 mL) and dimethylformamide (several drops) were added at ° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure to obtain an acid chloride. This is 4
-Treatment with -aminobenznitrile in the same manner as in Example 43 (C) gave the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 6.92 (1H,
d, J = 3.9 Hz), 7.48 (1H, d, J = 3.
9), 7.67 (1H, s), 7.85 (2H, d, J
= 9), 7.92 (2H, d, J = 9), 10.67
(1H, s).

(B) N- (4-cyanophenyl) -5
[(E) -2- (4-Cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl] -2-furanamide N- (4-cyanophenyl) -5-formyl obtained from (A) -2-Furanamide was treated in the same manner as in Example 15 (F) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.91 (2H, m),
2.10 (1H, m), 2.31 (3H, m), 6.6
4 (1H, d, J = 3.6 Hz), 6.93 (1H,
s), 7.20 (1H, d, J = 16 Hz), 7.33
(1H, d, J = 3.3 Hz), 7.42 (1H, d,
J = 16 Hz), 7.68 (2H, d, J = 9 Hz),
7.85 (2H, d, J = 8.8 Hz), 8.29 (1
H, s).

(C) N- [4- (1H-1,2,3,4
-Tetrazol-5-yl) phenyl] -5-[(E)
-2- (4-cyclobutyl-1,3-thiazole-2-
Yl) -1-ethenyl] -2-furanamide N- (4-cyanophenyl) -5- obtained from (B)
[(E) -2- (4-Cyclobutyl-1,3-thiazol-2-yl) -1-ethenyl] -2-furanamide was treated in the same manner as in Example 42 (C) to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.92 (2H,
m), 2.25 (4H, m), 6.96 (1H, s),
7.37 (3H, m), 7.68 (1H, m), 8.0
4 (4H, m), 10.48 (1H, s). MS (ES-); m / z: 417 (M ⁺ -1).

Example 45: N-3-[(E) -2- (4
-Isopropyl-1,3-thiazol-2-yl) -1
-Ethenyl] phenyl-3-trifluoromethanesulfonylaminobenzamide (A) N-3-[(E) -2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl] phenyl-3-nitrobenzamide 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] Aniline (59m
g) was dissolved in methylene chloride, and 3-nitrobenzyl chloride (82 mg) and triethylamine (67 µm) were dissolved at 0 ° C.
L) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate,
After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (methylene chloride: methanol, 90: 1, v / v) to give the title compound (86 mg) as a white powder. ) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (6Hd, J
= 6.9 Hz), 3.22 (1H, heterogeneous)
t, J = 6.9 Hz), 6.96 (1H, s), 7.4
8 (3H, m), 7.66 (1H, s, J = 8.3),
7.82 (t, 1H, J = 8.0), 8.00 (1H,
s), 8.29 (1H, s), 8.38 (1H, d, J
= 7.5), 8.53 (1H, d, J = 7.5), 8.
82 (1H, s).

(B) 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] aniline N-3-[(E ) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl] phenyl-3-nitrobenzamide was prepared in Example 5.
The same treatment as in (D) was performed to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, d, J
= 6.9 Hz), 3.21 (1H, heterogeneous)
t, J = 6.9 Hz), 6.93 (1H, s), 6.9
7 (1H, d, J = 7.7 Hz), 7.24-7.49
(6H, m), 7.64 (1Hd ,, J = 8.1H)
z), 7.95 (1H, s), 8.06 (1H, s).

(C) N-3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] phenyl-3-trifluoromethanesulfonylaminobenzamide (B) The obtained 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl]
The aniline was treated as in Example 35 (C) to give the title compound. MS (ES-); m / z: 949 (M ⁺ -1).

Example 46: N-3-[(E) -2- (4
-Isopropyl-1,3-thiazol-2-yl) -1
-Ethenyl] phenyl-3-fluoromethanesulfonylaminobenzamide 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] obtained in Example 45 (B). Aniline (98 mg) was added to tetrahydrofuran (2
mL), triethylamine (50 μL) was added, and fluoromethylsulfonyl chloride (Chem. Ber. 1991, 124, 1879) was added at −78 ° C.
(50 μL), and the temperature was gradually raised to room temperature. The reaction solution was distributed between ethyl acetate and water, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (methylene chloride: methanol, 90: 1,
Purification by v / v) gave the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (6H, d, J
= 6.9 Hz), 3.16 (1H, chapter)
t, J = 6.9 Hz), 4.53 (1H, s), 5.1
0 (1H, d, J = 47.1 Hz), 6.78 (1H,
s), 7.22-7.40 (3H, m), 7.37 (1
H, m), 7.48 (2H, m), 7.64 (1H,
t, J = 7.7 Hz), 7.77 (2H, m), 8.3
0 (1H, s). MS (ES-); m / z: 468 (M ^<+> -1).

Example 47: 4-isopropyl-2-
(E) -2- [7- (1H-1,2,3,4-tetrazol-5-yl) -3-quinolyl] -1-ethenyl-
1,3-thiazole (A) 3-[(E) -2- (4-isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl] -7-quinolinecarbonitrile Example 1 was prepared using 3-formyl-7-quinolinecarbonitrile.
The same treatment as in 5 (F) was performed to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J
= 6.9 Hz), 3.14 (1H, heterogeneous)
t, J = 6.9 Hz), 6.93 (1H, s), 7.5
5 (2H, m), 7.80 (1H, d, J = 8.4H
z), 7.92 (1 Hd, J = 8.4 Hz), 8.2
3 (1H, s), 8.45 (1H, s), 9.23 (1
H, s).

(B) 4-isopropyl-2- (E) -2
-[7- (1H-1,2,3,4-tetrazole-5-
3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1 obtained with yl) -3-quinolyl] -1-ethenyl-1,3-thiazole (A). -Ethenyl] -7-quinolinecarbonitrile was prepared in Example 42.
The same treatment as in (C) was performed to obtain the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (6H,
d, J = 6.9 Hz), 3.13 (1H, heptup)
let, J = 6.9 Hz), 7.33 (1H, s),
7.69 (1H, d, J = 15.5 Hz), 7.85
(1H, d, J = 16 Hz), 8.15 (1H, d, J
= 8.4 Hz), 8.27 (1H, d, J = 8.7H)
z), 8.69 (2H, m), 9.40 (1H, s). MS (ES-); m / z: 347 (M ⁺ -1).

Example 48: 1-ethyl-7- (E) -2
-(4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (A) ethyl 7-[(E) -2 -(4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl]-
4-oxo-1,4-dihydro-3-quinolinecarboxylate 3-[(E) -2- (4-phenyl-1,3-thiazol-2-yl) -1-ethenyl] aniline (Japanese Patent Laid-Open No. Sho 62)
-142168) (650 mg, 2.7 mmol) and diethyl ethoxymethylenemalonate (610 mg) were dissolved in toluene (3 mL) and heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and Dowsome A (2 mL) was added to the residue.
The mixture was heated and stirred at 20 ° C. for 1 hour. After cooling the reaction solution, 2-propanol was added, and the precipitated crystals were collected by filtration and washed with 2-propanol to give the title compound (480 mg,
9%). ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.36
(6H, d, J = 6.8 Hz), 1.41 (3H, t,
J = 7.3 Hz), 3.15 (1H, m), 4.38
(2H, q, J = 7.3 Hz), 7.01 (1H,
s), 7.65 (2H, m), 8.39 (1H, d, J
= 9.3 Hz), 8.61 (1H, s).

(B) 1-ethyl-7- (E) -2- (4
-Isopropyl-1,3-thiazol-2-yl) -1
-Ethenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid Ethyl 7-[(E) -2- (4-isopropyl-1,3-thiazole-2-) obtained with (A) Yl) -1-ethenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylate (40 mg, 0.11 mmol) was dissolved in THF (1 mL) -DMF (1 mL) and sodium hydride (60% In oil, 5 mg) and ethyl iodide (500 μL) were added, and the mixture was heated and stirred at 80 ° C. for 1 hour. The solvent was distilled off under reduced pressure, the residue was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a light brown powder. This is THF (2 mL), methanol (1 mL)
In 1N aqueous sodium hydroxide solution (400μ
L) was added and the mixture was heated under reflux for 2 hours. The reaction solution was ethyl acetate-
The mixture was partitioned between 1N hydrochloric acid, the organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol, 10: 1, v / v) to give the title compound (15 mg, 38%) as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J
= 6.8 Hz), 1.64 (3H, t, J = 7.3H)
z), 3.16 (1H, m), 4.42 (2H, q, J
= 7.3 Hz), 6.95 (1H, s), 7.52 (2
H, s), 7.67 (1H, s), 7.77 (1H,
d, J = 8.3 Hz), 8.55 (1H, d, J = 8.
3Hz), 8.79 (1H, s). FAB-MS; m / z: 369 (MH ⁺ )

Example 49: 1-cyclopropyl-6,7
-Difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (A) ethyl 1-cyclopropyl-6-fluoro-7
-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -4-oxo-1,4-dihydro-3-
Quinoline carboxylate (4-isopropyl-1,3-thiazol-2-yl)
Methanol (JP-A-6-80654) (95 mg, 0.1%).
60 mmol) in DMF (1.5 ml) and 18
-Crown-6 (174 mg), sodium hydride (9
5%, 17 mg) and stirred for 10 minutes under a nitrogen atmosphere. Ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate (150 mg) was added, and the mixture was stirred at 80 ° C. for 2 hours. The mixture was partitioned between 1N hydrochloric acid, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
Ether was added to the residue, and the resulting powder was collected by filtration to give the title compound (175 mg, 80%) as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (4H, m),
1.31 (6H, d, J = 6.8 Hz), 1.40 (3
H, t, J = 7.3 Hz), 3.11 (1H, m),
3.36 (1H, m), 4.38 (2H, q, J = 7.
3Hz), 5.57 (2H, s), 6.91 (1H,
s), 7.58 (1H, t, J = 6.8 Hz), 8.1.
6 (1H, d, J = 10.2 Hz), 8.53 (1H,
s).

(B) 1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid Ethyl 1-cyclopropyl-6-fluoro- obtained by (A) 7-[(4-isopropyl-1,3-thiazo-
Ru-2-yl) methoxy] -4-oxo-1,4-dihydro-3-quinolinecarboxylate (40 mg, 0.1 mg).
09 mmol) was dissolved in acetic acid (1 ml) -sulfuric acid (1 ml) and stirred at 130 ° C. for 11 hours. The reaction solution was distributed between ethyl acetate and ice water, and the organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol, 10: 1, v / v) to give the title compound (37 mg, 99%) as a white powder. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.19
(2H, m), 1.34 (6H, d, J = 7.3H
z), 1.47 (2H, m), 3.14 (1H, m),
3.69 (1H, m), 5.63 (2H, s), 7.1
2 (1H, s), 7.86 (1H, t, J = 6.8H)
z), 8.10 (1H, d, J = 10.8 Hz), 8.
84 (1H, s). FAB-MS; m / z: 403 (MH ⁺ )

Example 50: 1-cyclopropyl-6-fluoro-7- (2-quinolylmethoxy) -4-oxo-
1,4-Dihydro-3-quinolinecarboxylic acid Using quinoline-2-methanol, it was treated in the same manner as in Example 49 to obtain the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (2H,
m), 1.29 (2H, m), 3.40 (1H, m),
5.70 (2H, s), 7.63 (1H, dd, J =
7.8, 7.1 Hz), 7.73 (2H, m), 7.8
1 (1H, dd, J = 8.3, 7.1 Hz), 7.88
(1H, d, J = 7.8 Hz), 8.09 (1H, d,
J = 8.3 Hz), 8.15 (1H, d, J = 10.8)
Hz), 8.28 (1H, d, J = 8.1 Hz), 8.
73 (1H, s). EI-MS; m / z: 404 (M ⁺ )

Example 51 7-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-1,4-dihydro-2-quinoline Carboxylic acid (A) methyl 7-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl)-
4-oxo-1,4-dihydro-2-quinolinecarboxylate 3-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] aniline (24
5.0 mg) in methanol (4 ml) at room temperature was added with dimethyl acetylenedicarboxylate (0.129).
ml) and stirred at the same temperature for 6 hours. Furthermore, dimethyl acetylene dicarboxylate (0.025 ml)
Was added and stirred overnight. The residue obtained by evaporating the solvent was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1, v / v), and the diester (362.
8 mg, 93.6%) as a yellow oil. Dowsome A (5 m) was added to the obtained diester (360.0 mg).
l) was added, and the mixture was heated and stirred at 210 ° C. for 3 hours. After cooling the reaction solution, hexane and diethyl ether were added, and the precipitated solid was collected by filtration and treated with methyl 7-((E) -2-).
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl) -4-oxo-1,4-dihydro-2
-Quinoline carboxylate (98.2 mg, 29.7
%) As a brown solid. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (6H, d, J
= 7.1 Hz), 3.14 (1H, quint, J = 7.1).
Hz), 4.04 (1H, s), 6.92 (1H,
s), 6.98 (1H, s), 7.43 (2H, s),
7.55 (1H, d, J = 8.6 Hz), 7.74 (1
H, s), 8.30 (1H, d, J = 8.6 Hz).

(B) 7-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-1,4-dihydro-2-quinolinecarboxy Rick acid methyl 7-((E) -2- (4-isopropyl-1,
3-thiazol-2-yl) -1-ethenyl) -4-oxo-1,4-dihydro-2-quinolinecarboxylate (36.4 mg) in methanol (1 ml) -THF
(2 ml) -water (0.5 ml) mixed solution at room temperature
N sodium hydroxide aqueous solution (0.123 ml) was added,
The mixture was stirred at the same temperature for 5 hours. Further, a 1N aqueous sodium hydroxide solution (0.205 ml) was added, and the mixture was stirred overnight at the same temperature. After evaporating the solvent, water and 1N hydrochloric acid (0.328 m
l) was added, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure.
7-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-
1,4-Dihydro-2-quinolinecarboxylic acid (29.1 mg, 83.2%) was obtained as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (6H,
d, J = 6.8 Hz), 3.07 (1H, quint, J =
6.8 Hz), 6.63 (1H, s), 7.33 (1
H, s), 7.47 (1H, d, J = 16.2 Hz),
7.57 (1H, d, J = 16.2 Hz), 7.77
(1H, d, J = 8.7HZ), 8.00-8.10.
(2H, m). FAB-MS; m / z: 341 (MH ^<+> ). Elemental analysis (as _{C 18 H 16 N 2 O 3} S · 0.75H 2 O): Calculated: C, 61.09; H, 4.98 ; N, 7.92. Found: C, 61.17; H, 4.91; N, 7.94.

Example 52: (3S) -9-fluoro-1
0-[(4-Isopropyl-1,3-thiazole-2-
Yl) methoxy] -3-methyl-7-oxo-2,3-
Dihydro-7H- [1,4] oxazino- [2,3,4
-Ij] quinoline-6-carboxylic acid ethyl (3R) -9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- [1,4] oxazino [2,3,4- ij] Quinoline-6-carboxylate was treated as in Example 49 to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (6H,
d, J = 6.8 Hz), 1.45 (3H, d, J = 6.
8Hz), 2.98 (1H, m), 4.40 (1H,
d, J = 10.5 Hz), 4.63 (1H, d, J = 1)
0.5 Hz), 4.94 (1H, m), 5.55 (2
H, s), 7.33 (1H, s), 7.66 (1H,
d, J = 10.5 Hz), 8.89 (1H, s). EI-MS; m / z: 418 (M ⁺ )

Example 53: 1-Cyclopropyl-6-fluoro-7-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -4-oxo-1,4-dihydro [1,8 Naphthyridine-3-carboxylic acid ethyl 1-cyclopropyl-6,7-difluoro-4
-Oxo-1,4-dihydro [1,8] naphthyridine-
The 3-carboxylate was treated as in Example 49 to give the title compound. _{^{1 H-NMR (CDCl 3)}} δ: 1.02-1.11 (2
H, m), 1.20-1.28 (2H, m), 1.32
(6H, d, J = 6.8 Hz), 3.05-3.18
(1H, m), 3.62-3.72 (1H, m), 5.
91 (2H, s), 6.95 (1H, s), 8.35
(1H, d, J = 8.8 Hz), 8.85 (1H,
s), 14.53 (1H, br). EI / MS; m / z: 403 (M ⁺ ). FAB / MS; m / z: 404 (MH ⁺ ).

Examples 54 and 55: 1-ethyl-
7-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-
1,4-dihydro-2-quinolinecarboxylic acid and 1-ethyl-5-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4- Oxo-1,4-dihydro-2-quinolinecarboxylic acid (A) tert-butyl N
-3-[(E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl] phenylcarbamate 3-[(E) -2- (4-isopropyl-1,3- Thiazol-2-yl) -1-ethenyl] aniline (98.
3 mg) in THF (3 ml) at room temperature.
rt-Butyl dicarbonate (100 mg) and a saturated aqueous sodium hydrogen carbonate solution (1 ml) were added, and the mixture was stirred for 1 hour. While stirring overnight, di-tert-butyl dicarbonate (300 mg) and a saturated aqueous sodium hydrogen carbonate solution (3 ml) were added. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the mixture was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1, v / v), and tert-butyl N-3-[( E) -2- (4
-Isopropyl-1,3-thiazol-2-yl) -1
-Ethenyl] phenyl carbamate (129.5 mg,
93.5%) as a colorless solid. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.8 Hz), 1.53 (9H, s), 3.13 (1
H, quint, J = 6.8 Hz), 6.50 (1H, br)
s), 6.80 (1H, s), 7.15-7.35 (5
H, m), 7.65 (1H, br s).

(B) tert-butyl N-ethyl-3
-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] phenylcarbamate tert-butyl N-3-[(E) -2- (4-isopropyl-1 , 3-Thiazol-2-yl) -1-ethenyl] phenylcarbamate (126.1 mg) in DM
F solution (2 ml) was added to sodium hydride (2
2.0 mg) and stirred at the same temperature for 30 minutes. Then, ethyl iodide (58.6 μl) was added, and the mixture was stirred at the same temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the mixture was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and tert-butyl N-
Ethyl-3-[(E) -2- (4-isopropyl-1,
3-Thiazol-2-yl) -1-ethenyl] phenylcarbamate (143.0 mg, quant.) Was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J
= 7.1 Hz), 1.33 (6H, d, J = 6.8H)
z), 1.45 (9H, s), 3.11 (1H, quin
t, J = 6.8 Hz), 3.68 (3H, q, J = 7.
1 Hz), 6.81 (1H, s), 7.14 (1H, b
rd, J = 7.3 Hz), 7.25-7.40 (5
H, m).

(C) N-ethyl-3-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] aniline tert-butyl N-ethyl-3-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] phenyl carbamate (143.0 m
To a methanol solution (1 ml) of g), a 4N hydrochloric acid-dioxane solution (1 ml) was added at room temperature, and the mixture was stirred at the same temperature for 40 minutes. The solvent was distilled off, and the obtained residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. After the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off,
N-ethyl-3-[(E) -2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl] aniline (101.4 mg, quant.) Was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J
= 7.1 Hz), 1.33 (6H, d, J = 6.8H)
z), 3.11 (1H, quint, J = 6.8 Hz),
3.19 (3H, q, J = 7.1 Hz), 6.57 (1
H, dd, J = 8.0, 2.2 Hz), 6.76 (1
H, s), 6.78 (1H, s), 6.87 (1H,
d, J = 7.6 Hz), 7.17 (1H, t, J = 8.
0 Hz), 7.26 (1H, s), 7.29 (1H,
s).

(D) Methyl 1-ethyl-7-((E)
-2- (4-Isopropyl-1,3-thiazole-2-
Yl) -1-ethenyl) -4-oxo-1,4-dihydro-2-quinolinecarboxylate and methyl 1
-Ethyl-5-((E) -2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl) -4
-Oxo-1,4-dihydro-2-quinolinecarboxylate N-ethyl-3-[(E) -2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl] aniline (186.0 mg) in methanol (4 ml)
To the mixture was added dimethyl acetylenedicarboxylate (92.3 μl) at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. The solvent was distilled off to obtain a diester. Pyrophosphoric acid (1 ml) was added to the obtained diester (92.5 mg),
The mixture was heated and stirred at 110 ° C. for 1 hour. After cooling the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel chromatography (chloroform → chloroform: methanol = 99: 1, v / v), and methyl 1-ethyl-5-((E) -2- (4 -Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-
1,4-dihydro-2-quinoline carboxylate (3
1.1 mg, 36.4%) as a yellow oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.8 Hz), 1.54 (3H, t, J = 7.1H)
z), 3.11 (1H, quint, J = 6.8 Hz),
3.99 (3H, s), 4.27 (2H, q, J = 7.
1Hz), 6.55 (1H, s), 6.80 (1H,
s), 7.10 (1H, dd, J = 16.1, 0.7H)
z), 7.50-7.55 (2H, m), 7.66 (1
H, dd, J = 8.8, 7.3 Hz), 8.84 (1
H, d, J = 16.1 Hz).

Next, methyl 1-ethyl-7-((E)
-2- (4-Isopropyl-1,3-thiazole-2-
Yl) -1-ethenyl) -4-oxo-1,4-dihydro-2-quinolinecarboxylate (18.7 mg, 2
1.9%) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J
= 6.8 Hz), 1.58 (3H, t, J = 7.1H)
z), 3.15 (1H, quint, J = 6.8 Hz),
4.00 (3H, s), 4.31 (2H, q, J = 7.
1Hz), 6.59 (1H, s), 6.89 (1H,
s), 7.45 (1H, d, J = 16.1 Hz), 7.
50 (1H, d, J = 16.1 Hz), 7.59 (1
H, br d, J = 8.3 Hz), 7.61 (1H, b
rs), 8.42 (1H, d, J = 8.3 Hz).

(E) 1-ethyl-7-((E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl) -4-oxo-1,4-dihydro-2
-Quinolinecarboxylic acid methyl 1-ethyl-7-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-1,4-dihydro- 2-quinolinecarboxylate (37.0 mg) in methanol (1 m
l) 1N sodium hydroxide aqueous solution (0.145
ml) and stirred at the same temperature for 1 hour. After evaporating the solvent, 1N hydrochloric acid (0.145 ml) was added, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure, and dried with 1-ethyl-7-((E)).
-2- (4-Isopropyl-1,3-thiazole-2-
Yl) -1-ethenyl) -4-oxo-1,4-dihydro-2-quinolinecarboxylic acid (24.9
mg, 69.9%) as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (6H,
d, J = 6.8 Hz), 1.42 (3H, t, J = 7.
1 Hz), 3.08 (1H, quint, J = 6.8H)
z), 4.40 (2H, q, J = 7.1 Hz), 6.2
7 (1H, s), 7.32 (1H, s), 7.67 (1
H, d, J = 16.4 Hz), 7.77 (1H, d, J)
= 16.4 Hz), 7.84 (1H, d, J = 8.3H)
z), 8.12 (1H, s), 8.15 (1H, d, J
= 8.3 Hz). FAB-MS; m / z: 369 (MH ^<+> ). Elemental analysis (as _{C 20 H 20 N 2 O 3} S · 1.33H 2 O): Calculated: C, 61.21; H, 5.82 ; N, 7.14. Found: C, 61.43; H, 5.86; N, 6.84.

(F) 1-ethyl-5-((E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl) -4-oxo-1,4-dihydro-2
-Quinolinecarboxylic acid methyl 1-ethyl-5-((E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-1,4-dihydro- 2-quinolinecarboxylate (64.4 mg) in methanol (2 m
l) A 1N sodium hydroxide aqueous solution (0.253) was added to a mixed solution of -THF (1 ml) -water (0.5 ml) at room temperature.
ml) and stirred at the same temperature for 1.5 hours. After evaporating the solvent, 1N hydrochloric acid (0.253 ml) was added, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 1-ethyl-5-ethyl acetate.
((E) -2- (4-Isopropyl-1,3-thiazol-2-yl) -1-ethenyl) -4-oxo-1,4
-Dihydro-2-quinolinecarboxylic acid (29.9 mg, 48.2%) was obtained as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 6.8 Hz), 1.39 (3H, t, J = 7.
1Hz), 3.05 (1H, quint, J = 6.8H)
z), 4.32 (2H, q, J = 7.1 Hz), 6.2
7 (1H, s), 7.13 (1H, d, J = 16.1H
z), 7.22 (1H, s), 7.65 (1H, d, J
= 7.6 Hz), 7.77 (1H, dd, J = 8.8,
7.6 Hz), 7.86 (1H, d, J = 8.8H)
z), 8.84 (1H, d, J = 16.1 Hz). FAB-MS; m / z: 369 (MH ^<+> ). Elemental analysis (as _{C 20 H 20 N 2 O 3} S · 0.75H 2 O): Calculated: C, 62.89; H, 5.67 ; N, 7.33. Found: C, 63.07; H, 5.68; N, 7.12.

Example 56: 1-ethyl-6-((4-isopropyl-1,3-thiazol-2-yl) methoxy) -4-oxo-1,4-dihydro-2-quinolinecarboxylic acid (A ) (4-Isopropyl-1,3-thiazole-2-
Yl) methyl (4-nitrophenyl) ether (4-isopropyl-1,3-thiazol-2-yl)
To a THF solution (25 ml) of methanol (473.3 mg), 4-nitrophenol (460.6 mg), and triphenylphosphine (945.7 mg) was added diethyl azodicarboxylate (0 .569 ml) and stirred at room temperature for 7 hours.
Triphenylphosphine (23
6.9 mg) and a solution of diethyl azodicarboxylate (0.142 ml) in THF (5 ml) were added, and the mixture was stirred at room temperature overnight. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1, v / v) to give (4-isopropyl-
1,3-Thiazol-2-yl) methyl (4-nitrophenyl) ether (785.8 mg, 93.8%) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 3.12 (1H, quint, J = 6.8).
Hz), 5.43 (2H, s), 6.94 (1H, d,
J = 1.0 Hz), 7.09 (1H, d, J = 9.0H)
z), 8.21 (1H, d, J = 9.0 Hz).

(B) 4-[(4-isopropyl-1,3
-Thiazol-2-yl) methoxy] aniline (4-isopropyl-1,3-thiazol-2-yl)
Methyl (4-nitrophenyl) ether (775.7 m
To a solution of g) in ethanol (25 ml) was added tin (II) chloride dihydrate (1.907 g), and the mixture was heated under reflux for 3.5 hours. The solvent was distilled off, and the residue obtained was adjusted to pH 9 to 10 with 1N aqueous sodium hydroxide solution and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 99: 1, v / v) to give 4-[(4-isopropyl-1, 3-thiazol-2-yl) methoxy] aniline (386.2 mg, 5
(5.8%) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.8 Hz), 3.10 (1H, quint, J = 6.8)
Hz), 5.26 (2H, s), 6.64 (1H, d,
J = 9.0 Hz), 6.83 (1H, d, J = 9.0H)
z), 6.87 (1H, d, J = 0.7 Hz).

(C) tert-butyl N-3-[(4
-Isopropyl-1,3-thiazol-2-yl) methoxy] phenylcarbamate 4-[(4-isopropyl-1,3-
Thiazol-2-yl) methoxy] aniline (149.
To a mixed solution of 0 mg) in dioxane (4 ml) -THF (3 ml) were added di-tert-butyl dicarbonate (261.9 mg) and a saturated aqueous solution of sodium hydrogen carbonate (4 ml) at room temperature, and the mixture was stirred for 3 hours. J-te
rt-Butyl dicarbonate (65.5 mg) was added, and the mixture was stirred for 2 hours. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the mixture was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 85: 15, v / v).
rt-butyl N-3-[(4-isopropyl-1,3
-Thiazol-2-yl) methoxy] phenylcarbamate (126.5 mg, 60.5%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.8H), 1.50 (9H, s), 3.10 (1
H, d quint, J = 6.8, 0.7 Hz), 5.29
(2H, s), 6.40-6.50 (1H, m), 6.
88 (1H, d, J = 0.7 Hz), 6.93 (2H,
d, J = 9.0 Hz), 7.27 (2H, br d, J
= 9.0 Hz).

(B) tert-butyl N-ethyl-4
-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] phenylcarbamate tert-butyl N-3-[(4-isopropyl-
1,3-thiazol-2-yl) methoxy] phenylcarbamate (124.3 mg) in DMF (2 ml)
To the mixture was added sodium hydride (21.4 mg) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Then, ethyl iodide (57.1 μl) was added, and the mixture was stirred at the same temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the mixture was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and tert-butyl N-ethyl-4-
[(4-Isopropyl-1,3-thiazol-2-yl) methoxy] phenylcarbamate (141.2 m
g, quant.) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J
= 7.1 Hz), 1.32 (6H, d, J = 6.8).
H), 1.42 (9H, brs), 3.11 (1H,
quint, J = 6.8 Hz), 3.61 (2H, q, J =
7.1 Hz), 5.32 (2H, s), 6.90 (1
H, s), 6.95 (2H, d, J = 8.8 Hz),
7.05-7.15 (2H, m).

(C) N-ethyl-4-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] aniline tert-butyl N-ethyl-4-[(4-isopropyl-1,3- Thiazol-2-yl) methoxy] phenylcarbamate (139.2 mg) in methanol (1 ml) was added at room temperature to a 4N hydrochloric acid-dioxane solution (1
ml) and stirred at the same temperature for 1 hour. The residue obtained by evaporating the solvent was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. After the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off and N-ethyl-4-[(4-
Isopropyl-1,3-thiazol-2-yl) methoxy] aniline (85.8 mg, 87.0%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J
= 7.1 Hz), 1.29 (6H, d, J = 6.8)
H), 3.05-3.15 (1H, m), 3.10 (2
H, q, J = 7.1 Hz), 5.25 (2H, s),
6.56 (2H, d, J = 8.8 Hz), 6.87 (1
H, s), 6.88 (2H, d, J = 8.8 Hz).

(D) Methyl 1-ethyl-6-((4-
Isopropyl-1,3-thiazol-2-yl) methoxy) -4-oxo-1,4-dihydro-2-quinolinecarboxylate N-ethyl-4-[(4-isopropyl-1,3-thiazol-2- Il) methoxy] aniline (84.3m
To a methanol solution of g) (2 ml) was added dimethyl acetylenedicarboxylate (41.2 μl) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Pyrophosphoric acid (2 ml) was added to the diester obtained by distilling off the solvent, and the mixture was heated and stirred at 110 ° C. for 1 hour. After cooling the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel chromatography (chloroform → chloroform: methanol = 98:
2, v / v) and purified with methyl 1-ethyl-6-((4
-Isopropyl-1,3-thiazol-2-yl) methoxy) -4-oxo-1,4-dihydro-2-quinolinecarboxylate (95.0 mg, 80.6%) was obtained as a pale yellow solid. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.8H), 1.54 (3H, t, J = 7.1H)
z), 3.11 (1H, d quint, J = 6.8, 1.
0 Hz), 3.99 (3H, s), 4.30 (2H,
q, J = 7.1 Hz), 5.44 (2H, s), 6.6
0 (1H, s), 6.91 (1H, d, J = 1.0H
z), 7.45 (1H, dd, J = 9.3, 3.2H
z), 7.56 (1H, d, J = 9.3 Hz), 7.9
7 (1H, d, J = 3.2 Hz).

(E) 1-ethyl-6-((4-isopropyl-1,3-thiazol-2-yl) methoxy) -4
-Oxo-1,4-dihydro-2-quinolinecarboxylic acid methyl 1-ethyl-6-((4-isopropyl-1,
3-thiazol-2-yl) methoxy) -4-oxo-
1,4-dihydro-2-quinoline carboxylate (9
3.1 mg) methanol (1 ml) -THF (1 m
l) To a mixed solution of water and 0.5 ml of water was added a 1N aqueous solution of sodium hydroxide (0.361 ml) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. After evaporating the solvent, 1N hydrochloric acid (0.
361 ml), and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 1-ethyl-6-((4-isopropyl-1,
3-thiazol-2-yl) methoxy) -4-oxo-
1,4-Dihydro-2-quinolinecarboxylic acid (64.2 mg, 71.6%) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.26 (6H,
d, J = 6.8H), 1.38 (3H, t, J = 7.1)
Hz), 3.05 (1H, quint, J = 6.8 Hz),
4.34 (2H, q, J = 7.1 Hz), 5.51 (2
H, s), 6.25 (1H, s), 7.31 (1H,
d, J = 1.0 Hz), 7.55 (1H, dd, J =
9.3, 3.2 Hz), 7.73 (1H, d, J = 3.
2 Hz), 7.88 (1H, d, J = 9.3 Hz). FAB-MS; m / z: 373 (MH ^<+> ). Elemental analysis (as _{C 19 H 20 N 2 O 4} S · 0.75H 2 O): Calculated: C, 59.13; H, 5.61 ; N, 7.26. Found: C, 58.86; H, 5.76; N, 6.99.

Example 57: 8-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-4H-pyrido [1,2 -A] pyrimidine-3-carboxylic acid (A) ethyl 8-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl]-
4-oxo-4H-pyrido [1,2-a] pyrimidine-
3-carboxylate 4-[(E) -2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
Ethenyl] -2-aminopyridine (100 mg, 0.4
1 mmol), diethyl ethoxymethylenemalonate (3 mmol)
(00 μL) was heated under reflux in toluene (3 ml) for 2 hours. The solvent was distilled off under reduced pressure, and propionic acid (5 m
l) was added and the mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure,
The residue was purified by silica gel chromatography (chloroform-acetone, 10: 1, v / v) to give the title compound (101 mg, 67%) as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J
= 7.0 Hz), 1.42 (3H, t, J = 7.3H)
z), 3.17 (1H, m), 4.43 (2H, q, J
= 7.3 Hz), 7.02 (1H, s), 7.45 (1
H, d, J = 15.1 Hz), 7.46 (1H, m),
7.59 (1H, d, J = 15.1 Hz), 7.73
(1H, s), 9.04 (1H, s), 9.20 (1
H, d, J = 7.3 Hz).

(B) 8-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-4H-pyrido [1,2- a] Pyrimidine-3-carboxylic acid Ethyl 8-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4 obtained in (A) -Oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylate (55 mg, 0.15
mmol), concentrated hydrochloric acid (3 mL) and acetic acid (5 mL) were added, and the mixture was heated with stirring at 100 ° C. for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform-methanol, 10: 1, v / v) to obtain the title compound (22 mg, 43%) as a pale yellow powder. ¹ H-NMR (CD ₃ OD) δ: 1.37 (6H, d, J
= 6.8 Hz), 3.18 (1H, m), 7.19 (1
H, s), 7.57 (2H, m), 7.78 (1H,
d, J = 16.1 Hz), 7.84 (1H, d, J =
6.6 Hz), 7.92 (1H, s), 9.14 (1
H, s), 9.23 (1H, d, J = 6.8 Hz). FAB-MS; m / z: 342 (MH ^<+> ).

Example 58: 9-[(4-isopropyl-
1,3-thiazol-2-yl) methoxy] -4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid (A) ethyl 9-[(4-isopropyl-1,3- Thiazol-2-yl) methoxy] -4-oxo-4H-
Pyrid [1,2-a] pyrimidine-3-carboxylate 2- (chloromethyl) -4-isopropyl-1,3-thiazole (323 mg, 1.84 mmol) in DMF
(10 ml) and dissolved in ethyl 9-hydroxy-4-.
Oxo-4H-pyrido [1,2-a] pyrimidine-3-
Carboxylates (Hermetz et al., Synthesis,
1984, 152) (391 mg, 1.67 mmol)
And further add potassium carbonate (346 mg, 2.51 mm
ol) and potassium iodide (277 mg, 1.57 m
mol), and the mixture was heated and stirred at about 110 ° C. for 6 hours. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with water, dissolved once in chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 50: 1, v / v) to obtain the title compound (43 mg, 7%) as a pale brown solid. On the other hand, the solvent of the filtrate was distilled off, chloroform was added to the residue, and the mixture was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is subjected to silica gel column chromatography (chloroform → chloroform: methanol = 5).
0: 1, v / v) and preparative silica gel thin layer chromatography (chloroform: methanol = 20: 1, v
/ V) to give the title compound (32
4 mg, 52%). The title compound (367)
mg, 59%). ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.8 Hz), 1.42 (3H, t, J = 7.1H)
z), 3.09-3.18 (1H, m), 4.43 (2
H, q, J = 7.1 Hz), 5.66 (2H, s),
6.96 (1H, s), 7.19 (1H, t, J = 7.
6Hz), 7.59 (1H, dd, J = 7.8, 1.2)
Hz), 8.91 (1H, dd, J = 7.1, 1.2H)
z), 9.08 (1H, s).

(B) 9-[(4-isopropyl-1,3
-Thiazol-2-yl) methoxy] -4-oxo-4
Ethyl 9-[(4-isopropyl-) obtained with H-pyrido [1,2-a] pyrimidine-3-carboxylic acid (A)
1,3-thiazol-2-yl) methoxy] -4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylate (63 mg, 0.17 mmol) in THF
(3 ml), a 1% aqueous solution of sodium hydroxide (2.7 ml, 0.68 mmol) was added dropwise, and the solution was added at room temperature for 1 hour.
Stirred for hours. 1N hydrochloric acid aqueous solution (0.7 ml, 0.7
0 mmol) and water were added, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. Hexane and ether were added to the residue, the mixture was collected by filtration as a powder, and washed with hexane to give the title compound (39 mg, 67%) as a pale orange powder. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J
= 6.9 Hz), 3.07-3.18 (1H, m),
5.70 (2H, s), 6.97 (1H, s), 7.3
7 (1H, t, J = 7.6 Hz), 7.76 (1H,
d, J = 7.8 Hz), 8.87 (1H, d, J = 7.
1Hz), 9.32 (1H, s). EI / MS; m / z: 345 (M ⁺ ). FAB / MS; m / z: 346 (MH ^<+> ).

Example 59: 8-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3- (1H-1,2,3,3 4-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one (A) 8-[(E) -2- (4-isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl] -3- (2
-(4-methoxybenzyl-1H-1,2,3,4-tetrazol-5-yl) -4H-pyrido [1,2-a]
Pyrimidin-4-one (4-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -2-aminopyridine (150 mg, 0.61 mmol), Ethyl 3
-Dimethylamino-2- (2- (4-methoxybenzyl) tetrazol-5-yl) acrylate (Sugano et al.
Chem. Pharm. Bull. 1991, 39, 1
099) (305 mg) in propionic acid (2 ml)
The mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (chloroform-acetone,
10: 1, v / v) to give the title compound (256 mg, 86%) as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J
= 6.8 Hz), 3.17 (1H, m), 3.79 (3
H, s), 5.81 (2H, s), 6.89 (2H,
d, J = 8.5 Hz), 7.00 (1H, s), 7.4
3 (4H, m), 7.58 (1H, d, J = 16.1H
z), 7.74 (1H, s), 9.21 (2H, m).

(B) 8-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3- (1H-1,2,3,4 -Tetrazole-5
-Yl) -4H-pyrido [1,2-a] pyrimidine-4
-One 8-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] obtained in (A)
-3- (2- (4-methoxybenzyl-1H-1,2,2,
3,4-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one (240 mg,
(0.49 mmol), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the solvent was distilled off again. Chloroform, methanol and ether were added to the residue, and the precipitated crystals were collected by filtration, dried, and the title compound (130 mg, 73 mg) was obtained as a pale yellow powder.
%). ¹ H-NMR (CD ₃ OD) δ: 1.37 (6H, d, J
= 7.1 Hz), 3.18 (1H, m), 7.16 (1
H, s), 7.58 (1H, m), 7.75 (1H,
d, J = 16.1 Hz), 7.77 (1H, m), 7.
89 (1H, d, J = 1.7 Hz), 9.26 (1H,
d, J = 7.6 Hz), 9.34 (1H, s). FAB-MS; m / z: 366 (MH ^<+> ).

Example 60: 8-[(4-isopropyl-
1,3-thiazol-2-yl) methoxy] -3- (2
H-1,2,3,4-tetrazol-5-yl) -4H
-Pyrido [1,2-a] pyrimidin-4-one (A) 8-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -3- [2- (4-methoxybenzyl)- 2H-1,2,3,4-tetrazole-5
Yl] -4H-pyrido [1,2-a] pyrimidine-4-
On The 4-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -2-pyridylamine obtained in Example 22 (C) was treated in the same manner as in Example 59 (A) to give the title The compound was obtained. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (6H, d, J
= 6.9 Hz), 3.10-3.18 (1H, m),
3.79 (3H, s), 5.50 (2H, s), 5.7
9 (2H, s), 6.88 (2H, d, J = 8.7H)
z), 6.97 (1H, d, J = 0.7 Hz), 7.0
2 (1H, dd, J = 7.8, 2.7 Hz), 7.18
(1H, d, J = 2.7 Hz), 7.40 (2H, d,
J = 8.7 Hz), 9.11 (1H, s), 9.17
(1H, d, J = 7.8 Hz).

(B) 8-[(4-isopropyl-1,3
-Thiazol-2-yl) methoxy] -3- (2H-
1,2,3,4-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one 8-[(4-isopropyl-1,3-
Thiazol-2-yl) methoxy] -3- [2- (4-
(Methoxybenzyl) -2H-1,2,3,4-tetrazol-5-yl] -4H-pyrido [1,2-a] pyrimidin-4-one was treated in the same manner as in Example 59 (B), and the title was obtained. The compound was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (6H,
d, J = 7.1 Hz), 3.02-3.12 (1H,
m), 5.74 (2H, s), 7.37 (1H, dd,
J = 7.8, 2.7 Hz), 7.41 (1H, d, J =
0.7Hz), 7.50 (1H, d, J = 2.7H)
z), 9.07 (1H, s), 9.12 (1H, d, J
= 7.8 Hz). EI-MS; m / z: 369 (M ^<+> ). FAB-MS; m / z: 370 (MH ^<+> ).

Example 61 8- [2- (4-isopropyl-1,3-thiazol-2-yl) ethyl] -3-
(2H-1,2,3,4-tetrazol-5-yl)-
4H-pyrido [1,2-a] pyrimidin-4-one (A) tert-butyl N-4- [2- (4-isopropyl-1,3-thiazol-2-yl) ethyl] -2
-Pyridyl carbamate tert-butyl N- (4-methyl-2-pyridyl)
Carbamate (J. Org. Chem., 1996, 6)
1,4810. ) (0.69 g, 1.99 mmol) was dissolved in THF (30 ml), and a 1.63 N n-butyllithium hexane solution (5.89 ml,
9.60 mmol) was added dropwise over 5 minutes. After heating to room temperature and stirring for 30 minutes, the mixture was cooled again to -78 ° C,
(Bromomethyl) -4-isopropyl-1,3-thiazole (1.27 g, 5.76 mmol) in THF (10
ml) solution was added dropwise over 10 minutes and stirred at the same temperature for 30 minutes. Water was added to the reaction solution, the mixture was heated to room temperature, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform) to give the title compound (0.69 g, 51.7%) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J
= 6.9 Hz), 1.53 (9H, s), 3.02-
3.20 (1H, m), 3.05-3.13 (2H,
m), 3.27-3.34 (2H, m), 6.70 (1
H, s), 6.78-6.82 (1H, m), 7.87
(1H, brs), 7.93 (1H, brs), 8.1
3 (1H, d, J = 5.1 Hz).

(B) 4- [2- (4-isopropyl-
1,3-thiazol-2-yl) ethyl] -2-pyridinamine tert-butyl N-4- [2-
(4-Isopropyl-1,3-thiazol-2-yl)
Ethyl] -2-pyridyl carbamate was prepared according to Example 22.
The same treatment as in (C) was performed to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J
= 6.8 Hz), 2.98-3.01 (2H, m),
3.01-3.07 (1H, m), 3.11-3.15
(2H, m), 4.40 (2H, brs), 6.36
(1H, s), 6.50-6.52 (1H, m), 6.
71 (1H, s), 7.96 (1H, d, J = 5.1H)
z).

(C) 8- [2- (4-isopropyl-
1,3-thiazol-2-yl) ethyl] -3- [2-
(4-methoxybenzyl) -2H-1,2,3,4-tetrazol-5-yl] -4H-pyrido [1,2-a]
Pyrimidin-4-one 4- [2- (4-isopropyl-1,4) obtained in (B)
3-Thiazol-2-yl) ethyl] -2-pyridinamine was treated in the same manner as in Example 59 (A) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J
= 6.8 Hz), 3.00-3.10 (1H, m),
3.26-3.35 (2H, m), 3.35-3.43
(2H, m), 3.79 (3H, s), 5.80 (2
H, s), 6.73 (1H, d, J = 1.0 Hz),
6.88 (2H, d, J = 8.8 Hz), 7.14 (1
H, dd, J = 7.3, 1.8 Hz), 7.41 (2
H, d, J = 8.8 Hz), 7.57 (1H, s),
8.11 (1H, d, J = 5.1 Hz), 9.18 (1
H, s).

(D) 8- [2- (4-isopropyl-
1,3-thiazol-2-yl) ethyl] -3- (2H
-1,2,3,4-tetrazol-5-yl) -4H-
Pyrid [1,2-a] pyrimidin-4-one 8- [2- (4-isopropyl-1, obtained from (C))
3-thiazol-2-yl) ethyl] -3- [2- (4
-Methoxybenzyl) -2H-1,2,3,4-tetrazol-5-yl] -4H-pyrido [1,2-a] pyrimidin-4-one, treated as in Example 59 (B).
The title compound was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (6H,
d, J = 6.9 Hz), 2.92-3.02 (1H,
m), 3.30 (2H, t, J = 7.1 Hz), 3.4
3 (2H, t, J = 7.1 Hz), 7.08 (1H,
d, J = 0.7 Hz), 7.57 (1H, dd, J =
6.9, 0.7 Hz), 7.77 (1H, s), 9.0
5-9.20 (2H, m). EI-MS; m / z: 367 (M ^<+> ). FAB-MS; m / z: 368 (MH ^<+> ).

Example 62: 8- [3- (4-Isopropyl-1,3-thiazol-2-yl) propyl] -3-
(2H-1,2,3,4-tetrazol-5-yl)-
4H-pyrido [1,2-a] pyrimidin-4-one (A) methyl 4- [2-((tert-butoxycarbonyl) amino] -4-pyridylbutanoate tert-butyl N- (4-methyl-2) -Pyridyl)
Carbamate (2.04 g, 9.80 mmol) was treated with TH
F (50 ml) and dissolved at -78 ° C under a nitrogen stream.
50N n-butyllithium hexane solution (16.3m
1, 24.5 mmol) was added dropwise over 5 minutes. After heating to room temperature and stirring for 30 minutes, it was cooled again to -78 ° C,
Methyl 3-bromopropionate (3.21 ml, 2
9.4 mmol) was added dropwise and stirred at the same temperature for 30 minutes.
Water was added to the reaction solution, and the temperature was raised to room temperature, followed by extraction with ethyl acetate.
After washing with a saturated saline solution, the solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform → chloroform: ethyl acetate) to give the title compound (1.10 g, 38.2%) as a mixture of a colorless oil and a solid. ¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s),
1.93-2.05 (2H, m), 2.34 (2H,
t, J = 7.5 Hz), 2.65 (2H, t, J = 7.
7Hz), 3.67 (3H, s), 6.79 (1H, d
d, J = 5.1, 1.2 Hz), 7.81 (1H, br)
s), 8.11 (1H, brs), 8.15 (1H,
d, J = 5.1 Hz).

(B) 4-2-[(tert-butoxycarbonyl) amino] -4-pyridylbutanoic acid Methyl 4--2-[(tert-butoxycarbonyl) amino] -4 obtained in (A) -Pyridylbutanoate was treated in the same manner as in Example 11 (B) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s),
1.97-2.06 (2H, m), 2.39 (2H,
t, J = 7.1 Hz), 2.70 (2H, t, J = 7.
6 Hz), 6.82 (1H, dd, J = 5.4, 1.5)
Hz), 7.87 (1H, brs), 8.00 (1H,
d, J = 5.4 Hz), 8.32 (1H, brs).

(C) tert-butyl N- [4- (4
-Amino-4-oxobutyl) -2-pyridyl] carbamate 4--2-[(tert-butoxycarbonyl) amino] -4-pyridylbutanoic acid obtained in (B) (0.38 g, 1.36 mmol) To THF (20m
l) and triethylamine (189.1 μl,
1.36 mmol) was added dropwise, and ethyl chloroformate (129.6 μl, 1.36 mmol) was added dropwise under ice-cooling, followed by stirring at the same temperature for 15 minutes. Concentrated ammonia water (28
%, 10 ml) in THF (10 ml) was added dropwise and stirred at the same temperature for 15 minutes. After distilling off THF, a small amount of water was added to the residue, extracted with chloroform, washed with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain the title compound (0.46 g, quantitative) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s),
1.97-2.07 (2H, m), 2.23 (2H,
t, J = 7.5 Hz), 2.67 (2H, t, J = 7.
5 Hz), 5.31-5.47 (1H, brs), 5.
47-5.60 (1H, brs), 6.81 (1H,
d, J = 5.1 Hz), 7.78 (1H, brs),
7.80 (1H, brs), 8.14 (1H, d, J =
5.1 Hz).

(D) tert-butyl N- [4- (4
-Amino-4-thioxobutyl) -2-pyridyl] carbamate tert-butyl N- [4- (4-
Amino-4-oxobutyl) -2-pyridyl] carbamate was treated in the same manner as in Example 11 (D) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s),
2.13-2.22 (2H, m), 2.62 (2H,
t, J = 7.3 Hz), 2.69 (2H, t, J = 7.
3Hz), 6.82 (1H, d, J = 5.1Hz),
6.25-7.47 (3H, m), 7.72 (1H, b
rs), 8.13 (1H, d, J = 5.1 Hz).

(E) tert-butyl N-4- [3-
(4-Isopropyl-1,3-thiazol-2-yl)
Propyl] -2-pyridylcarbamate tert-butyl N- [4- (4-
[Amino-4-thioxobutyl) -2-pyridyl] carbamate (0.36 g, 1.22 mmol) was suspended in ethanol (10 ml) and 1-bromo-3-methyl-2-
Butanone (0.20 g, 1.22 mmol) was added and 1
Heated to reflux for an hour. After evaporating the solvent, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound as a pale yellow oil. Compound (0.4
0 g, 90.8%). ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J
= 6.9 Hz), 1.54 (9H, s), 2.08-
2.20 (2H, m), 2.71 (2H, t, J = 7.
7 Hz), 3.01 (2H, t, J = 7.7 Hz),
3.02-3.12 (1H, m), 6.71 (1H,
d, J = 1.0 Hz), 6.80 (1H, dd, J =
5.1, 1.2 Hz), 7.85 (1H, brs),
8.19 (1H, d, J = 5.1 Hz), 8.89 (1
H, brs).

(F) 4- [3- (4-isopropyl-
1,3-thiazol-2-yl) propyl] -2-pyridineamine tert-butyl N-4- [3-
(4-Isopropyl-1,3-thiazol-2-yl)
Propyl] -2-pyridyl carbamate was prepared according to Example 22.
The same treatment as in (C) was performed to obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J
= 6.9 Hz), 2.03-2.18 (2H, m),
2.60 (2H, t, J = 7.7 Hz), 3.00 (2
H, t, J = 7.6 Hz), 3.00-3.12 (1
H, m), 4.41 (2H, brs), 6.35 (1
H, s), 6.51 (1H, d, J = 5.1 Hz),
6.72 (1H, brs), 7.95 (1H, d, J =
5.1 Hz).

(G) 8- [3- (4-isopropyl-
1,3-thiazol-2-yl) propyl] -3- [2
-(4-methoxybenzyl) -2H-1,2,3,4-
Tetrazol-5-yl] -4H-pyrido [1,2-
a] Pyrimidin-4-one 4- [3- (4-isopropyl-1,4) obtained with (F)
3-Thiazol-2-yl) propyl] -2-pyridinamine was treated in the same manner as in Example 59 (A) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J
= 7.1 Hz), 2.20-2.30 (2H, m),
2.91 (2H, t, J = 7.7 Hz), 2.98 −
3.08 (1H, m), 3.09 (2H, t, J = 7.
4Hz), 3.79 (3H, s), 5.81 (2H,
s), 6.74 (1H, s), 6.89 (2H, d, J
= 8.8 Hz), 7.17 (1H, dd, J = 7.1,
1.8Hz), 7.42 (2H, d, J = 8.8H)
z), 7.59 (1H, brs), 9.20 (1H,
d, J = 7.1 Hz), 9.20 (1H, s).

(H) 8- [3- (4-isopropyl-
1,3-thiazol-2-yl) propyl] -3- (2
H-1,2,3,4-tetrazol-5-yl) -4H
-Pyrido [1,2-a] pyrimidin-4-one 8- [3- (4-isopropyl-1,4) obtained with (G)
3-thiazol-2-yl) propyl] -3- [2-
(4-methoxybenzyl) -2H-1,2,3,4-tetrazol-5-yl] -4H-pyrido [1,2-a]
Pyrimidin-4-one was treated as in Example 59 (B) to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.22 (6H,
d, J = 7.1 Hz), 2.10-2.20 (2H,
m), 2.90-3.08 (5H, m), 7.08 (1
H, s), 7.51 (1H, d, J = 7.1 Hz),
7.73 (1H, brs), 9.08 (1H, s),
9.08-9.17 (1H, m). EI-MS; m / z: 381 (M ⁺ ). FAB-MS; m / z: 382 (MH ^<+> ).

Example 63: 8-[(4-isopropyl-
1,3-thiazol-2-yl) carbonyl] -3-
(2H-1,2,3,4-tetrazol-5-yl)-
4H-pyrido [1,2-a] pyrimidin-4-one (A) ethyl 2- (2- (tert-butoxycarbonyl) amino) -4-pyridyl acetate tert-butyl N- (4-methyl-2-pyridyl )
Carbamate (3.08 g, 14.8 mmol) was added to TH
F (80 mL), and n-butyllithium (1.5 M hexane solution, 20 m
After dropwise addition of L), the reaction solution was warmed to room temperature and stirred at room temperature for 30 minutes. The mixture was cooled again to -78 ° C, a solution of ethyl chloroformate (1.42 ml) in THF (10 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After adding a saturated ammonium chloride aqueous solution, the reaction solution was partitioned between ethyl acetate and saturated saline. The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography (chloroform) to give the title compound (2.6) as a white powder.
g, 63%). ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J
= 7.1 Hz), 1.54 (9H, s), 3.61 (2
H, s), 4.17 (2H, q, J = 7.1 Hz),
6.91 (1H, dd, J = 5.1, 1.5 Hz),
7.91 (1H, s), 8.22 (1H, d, J = 5.
1Hz), 8.49 (1H, brs).

(B) tert-butyl N- (4- (2
-Amino-2-oxoethyl) -2-pyridyl) carbamate Ethyl 2- (2- (tert-butoxycarbonyl) amino) -4-pyridyl acetate (550 mg, 1.96 mmol) obtained in (A) was added to THF (5 mL). )
And 28% aqueous ammonia (10 mL) was added thereto, followed by stirring at room temperature for 6 days. The precipitate was collected by filtration and dried to give the title compound (130 mg). The filtrate was extracted with chloroform, dried over magnesium sulfate, and the solvent was distilled off.
50 mg of the title compound were obtained. (Total yield 350 mg,
71%) ¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s),
3.57 (2H, s), 6.94 (1H, dd, J =
5.1, 1.5 Hz), 7.61 (1H, s), 7.9
0 (1H, s), 8.21 (1H, d, J = 5.1H
z). (C) tert-butyl N- [4- (2-amino-2
-Thioxoethyl) -2-pyridyl] carbamate tert-butyl N- (4- (2-
Amino-2-oxoethyl) -2-pyridyl) carbamate was treated in the same manner as in Example 11 (D) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s),
3.38-3.11 (2H, m), 3.99 (2H,
s), 7.10 (1H, dd, J = 5.1, 0.7H)
z), 7.32 (1H, brs), 7.83 (1H, b
rs), 8.15 (1H, d, J = 5.1 Hz).

(D) (2-amino-4-pyridyl) (4
-Isopropyl-1,3-thiazol-2-yl) methanone tert-butyl N- [4- (2-
[Amino-2-thioxoethyl) -2-pyridyl] carbamate (0.37 g, 1.38 mmol) was suspended in ethanol (10 ml) and 1-bromo-3-methyl-2- was added.
Butanone (0.23 g, 1.38 mmol) was added and 1
Heated to reflux for an hour. On TLC, the raw material remained, so 1-bromo-3-methyl-2-butanone (0.23
g, 1.38 mmol), and the mixture was further heated under reflux for 1 hour. After evaporating the solvent, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
The residue was purified by preparative TLC (chloroform: methanol = 30: 1, v / v) to give tert-butyl N-4-[(4-isopropyl-1,3-thiazole-2- as a pale orange oil. Yl) carbonyl] -2-
The title compound (71.9 mg, 21.0%) as pyridyl carbamate (94.8 mg) and pale orange oil
I got tert-butyl N-4-[(4-isopropyl-1,3-thiazol-2-yl) carbonyl]-
2-Pyridyl carbamate (94.8 mg) was dissolved in methylene chloride (2 ml), and trifluoroacetic acid (2
ml) was added dropwise and stirred at room temperature for 1 hour. After distilling off the solvent,
To the residue was added a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound (68.8 m
g) was obtained. (Total yield, 140.7 mg, 41.1
%) ¹ H-NMR (CDCl ₃ ) δ: 1.37 (6H, d, J
= 6.9 Hz), 3.17-3.28 (1H, m),
4.74 (2H, brs), 7.33 (1H, d, J =
0.7Hz), 7.51 (1H, brs), 7.60
(1H, dd, J = 5.3, 1.3 Hz), 8.25
(1H, dd, J = 5.3, 0.6 Hz).

(E) 8-[(4-isopropyl-1,3
-Thiazol-2-yl) carbonyl] -3- [2-
(4-methoxybenzyl) -2H-1,2,3,4-tetrazol-5-yl] -4H-pyrido [1,2-a]
Pyrimidin-4-one (2-amino-4-pyridyl) (4-) obtained in (D)
The isopropyl-1,3-thiazol-2-yl) methanone was treated in the same manner as in Example 59 (A) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (6H, d, J
= 7.1 Hz), 3.24-3.32 (1H, m),
3.80 (3H, s), 5.84 (2H, s), 6.9
0 (2H, d, J = 8.8 Hz), 7.43 (2H,
d, J = 8.8 Hz), 7.46 (1H, s), 8.0
6 (1H, dd, J = 7.6, 1.7 Hz), 9.17
(1H, d, J = 1.7 Hz), 9.34 (1H, d,
J = 7.6 Hz), 9.34 (1H, s).

(F) 8-[(4-isopropyl-1,3
-Thiazol-2-yl) carbonyl] -3- (2H-
1,2,3,4-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one 8-[(4-isopropyl-1,3-
Thiazol-2-yl) carbonyl] -3- [2- (4
-Methoxybenzyl) -2H-1,2,3,4-tetrazol-5-yl] -4H-pyrido [1,2-a] pyrimidin-4-one, treated as in Example 59 (B).
The title compound was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (6H,
d, J = 6.9 Hz), 3.20-3.30 (1H,
m), 7.89-7.96 (1H, m), 8.03 (1
H, s), 8.98-9.02 (1H, m), 9.02
−9.11 (1H, m), 9.17-9.23 (1H,
m). EI-MS; m / z: 367 (M ^<+> ).

Example 64: 8-2- [4- (tert-
Butyl) -1,3-thiazol-2-yl] ethyl-3
-(2H-1,2,3,4-tetrazol-5-yl)
-4H-pyrido [1,2-a] pyrimidin-4-one (A) tert-butyl N- (4-2- [4- (te
rt-butyl) -1,3-thiazol-2-yl] ethyl-2-pyridyl) carbamate tert-butyl N- (4-methyl-2-pyridyl)
Carbamate (1.74 g, 8.35 mmol) was added to TH
F (50 ml) and 1.63 N at -78 ° C
-Butyl lithium hexane solution (12.8 ml, 20.
9 mmol) was added dropwise over 10 minutes. After heating to room temperature and stirring for 30 minutes, the mixture was cooled again to -78 ° C, and THF of 2- (bromomethyl) -4- (tert-butyl) -1,3-thiazole (2.94 g, 12.6 mmol) was added.
(10 ml) solution was added dropwise over 10 minutes.
Stirred for minutes. Water was added to the reaction solution, the mixture was heated to room temperature, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform),
The title compound (1.90 g, 62.9) as a pale yellow solid.
%). ¹ H-NMR (CDCl ₃ ) δ: 1.33 (9H, s),
1.53 (9H, s), 3.10 (2H, t, J = 7.
9 Hz), 3.30 (2H, t, J = 7.9 Hz),
6.71 (1H, d, J = 0.5 Hz), 6.80 (1
H, d, J = 5.1 Hz), 7.87 (1H, br)
s), 8.12 (1H, brs), 8.14 (1H,
d, J = 5.1 Hz).

(B) 4-tert-butyl N- (4- (4- (tert-butyl) -1,3-thiazol-2-yl) ethyl-2-pyridineamine obtained in (A)) 2-
[4- (tert-butyl) -1,3-thiazole-2
[-Yl] ethyl-2-pyridyl) carbamate was treated as in Example 22 (C) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (9H, s),
2.98 (2H, t, J = 7.8 Hz), 3.26 (2
H, t, J = 7.8 Hz), 4.47 (2H, br)
s), 6.36 (1H, s), 6.51 (1H, dd,
J = 5.1, 0.5 Hz), 6.72 (1H, s),
7.95 (1H, d, J = 5.4 Hz).

(C) 8-2- [4- (tert-butyl) -1,3-thiazol-2-yl] ethyl-3-
[2- (4-methoxybenzyl) -2H-1,2,3
4-tetrazol-5-yl] -4H-pyrido [1,2
-A] Pyrimidin-4-one 4-2- [4- (tert-butyl) obtained in (B)
[1,3-thiazol-2-yl] ethyl-2-pyridinamine was treated in the same manner as in Example 59 (A) to give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (9H, s),
3.32 (2H, t, J = 7.1 Hz), 3.41 (2
H, t, J = 7.1 Hz), 3.78 (3H, s),
5.80 (2H, s), 6.73 (1H, s), 6.8
8 (2H, d, J = 8.7 Hz), 7.15 (1H, d
d, J = 7.3, 1.7 Hz), 7.41 (2H, d,
J = 8.7 Hz), 7.58 (1H, brs), 9.1
6 (1H, d, J = 7.3 Hz), 9.18 (1H,
s).

(D) 8-2- [4- (tert-butyl) -1,3-thiazol-2-yl] ethyl-3-
(2H-1,2,3,4-tetrazol-5-yl)-
8-2- [4- (tert-butyl) obtained with 4H-pyrido [1,2-a] pyrimidin-4-one (C)
-1,3-thiazol-2-yl] ethyl-3- [2-
(4-methoxybenzyl) -2H-1,2,3,4-tetrazol-5-yl] -4H-pyrido [1,2-a]
Pyrimidin-4-one was treated as in Example 59 (B) to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (9H,
s), 3.30 (2H, t, J = 7.1 Hz), 3.4
3 (2H, t, J = 7.1 Hz), 7.07 (1H,
s), 7.54 (1H, d, J = 6.9 Hz), 7.7
3 (1H, brs), 9.04 (1H, s), 9.09
(1H, brd, J = 5.4Hz). EI-MS; m / z: 381 (M ⁺ ). FAB-MS; m / z: 382 (MH ^<+> ).

Example 65: (E) -3- (2-Hydroxy-8- [2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4H-pyrido [1,
2-a] pyrimidin-4-one-3-yl) -2-propenoic acid (A) 2-hydroxy-8- [2- (4-isopropyl-1,3-thiazol-2-yl) -1 -Ethenyl]-
4H-pyrido [1,2-a] pyrimidin-4-one 4- [2- (4-isopropyl-1,3-thiazole-
2-yl) -1-ethenyl] -2-aminopyridine (1.15 g, 4.65 mmol) and di (2,4,6-
Trichlorophenyl) malonate (2.2 g, 4.7
5 mmol) was heated under reflux in xylene (6 mL) for 1 hour and purified by silica gel chromatography (chloroform-methanol, 20: 1, v / v) to give the title compound (900 mg, 61%) as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J
= 6.9 Hz), 3.06 (1H, m), 3.34 (2
H, m), 3.39 (2H, m), 5.33 (1H,
s), 6.73 (1H, s), 7.09 (1H, dd,
J = 7.1, 1.7 Hz), 7.38 (1H, s),
9.01 (1H, d, J = 7.1 Hz).

(B) tert-butyl (E) -3-
(2-Hydroxy-8- [2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl] -4
H-pyrido [1,2-a] pyrimidin-4-one-3-
Yl) -2-propenoate oxalyl chloride (100 μL) was added to methylene chloride (5 μL).
mL), DMF (155 μL) was added under ice cooling, and the mixture was stirred for 15 minutes. 2-hydroxy-8- [2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4H-pyrido [1, obtained in (A)
2-a] pyrimidin-4-one (95 mg, 0.30 m
mol) was added as a powder, and the mixture was stirred at room temperature for 3 hours.
The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to preparative thin-layer chromatography (chloroform-methanol, 93: 7, v / v)
2-hydroxy-8- [2- (4-isopropyl-1,
3-thiazol-2-yl) -1-ethenyl] -4H-
Pyrid [1,2-a] pyrimidin-4-one-3-carbaldehyde (76 mg) was obtained. To this (tert-
Butoxycarbonylmethylene) triphenylphosphorane (255 mg) and THF (5 mL) were added, and the mixture was added at 60 ° C.
For 10 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative thin-layer chromatography (chloroform-methanol, 9: 1, v / v) to give a yellow oil (64 m
g, 50%). ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.28
(6H, d, J = 6.8 Hz), 1.51 (9H,
s), 3.05 (1H, m), 3.22 (2H, m),
3.42 (2H, m), 6.81 (1H, s), 6.9
7 (1H, d, J = 15.9 Hz), 7.23 (1H,
s), 7.27 (1H, dd, J = 7.1, 1.7H)
z), 7.95 (1H, d, J = 15.9 Hz), 9.
01 (1H, d, J = 7.1 Hz).

(C) (E) -3 (-2-hydroxy-8
-[2- (4-isopropyl-1,3-thiazole-2
-Yl) -1-ethenyl] -4H-pyrido [1,2-
a] Pyrimidin-4-one-3-yl) -2-propenoic acid (tert-butyl (E) -3- (2) obtained from (B)
-Hydroxy-8- [2- (4-isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl] -4H-pyrido [1,2-a] pyrimidin-4-one-3-yl)
-2-propenoate (30 mg, 0.068 mmol
l) was dissolved in trifluoroacetic acid (1 mL) and stirred for 20 minutes. After evaporating the solvent under reduced pressure, the residue was separated by preparative thin-layer chromatography (chloroform-methanol, 9: 1,
v / v), and the title compound (10 m
g, 38%). ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.28
(6H, d, J = 6.8 Hz), 3.06 (1H,
m), 3.33 (2H, m), 3.41 (2H, m),
6.82 (1H, s), 7.03 (1H, d, J = 1
5.9 Hz), 7.23 (2H, m) 8.06 (1H,
d, J = 15.9 Hz), 9.01 (1H, d, J =
7.1 Hz).

Example 66: 2-hydroxy-8- [2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-Ethenyl] -3-[(1H-1,2,3,4-tetrazol-5-ylimino) methyl] -4H-pyrido [1,2-a] pyrimidin-4-one Example 65 (B) 2-hydroxy-8- [2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -4H-pyrido [1,2-a] pyrimidin-4-one-3-carbaldehyde (50 mg),
5-aminotetrazole (50 mg) was added to methanol (1
0 mL) and heated under reflux for 9 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative thin-layer chromatography (chloroform-methanol, 9: 1, v / v) to give the title compound (40 mg, 67%, a mixture of E and Z) as a yellow powder. I got _{^{1 H-NMR (CDCl 3 -CD}} 3 OD) δ: 1.29
(6H, m), 3.08 (1H, m), 3.13 (2
H, m), 3.35 (2H, m), 3.85 (1H,
s), 6.79 (1H, s), 6.92 (1H, m),
8.1-8.4 (total 2H, m), 8.96,
9.18 (total 1H, each s).

Example 67: 2-hydroxy-8- [2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -3-[(1H-1,2,3,4-tetrazol-5-ylimino) methyl] -4H-pyrido [1,2-a] pyrimidin-4-one (A) (E) -3- (2-hydroxy-8- [2- (4
-Isopropyl-1,3-thiazol-2-yl) -1
-Ethenyl] -4H-pyrido [1,2-a] pyrimidin-4-one-3-yl) -2-propenenitrile 2-hydroxy-8- [2- obtained in Example 65 (B)
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -4H-pyrido [1,2-a] pyrimidin-4-one-3-carbaldehyde (500 mg,
1.46 mmol) and cyanomethyltriphenylphosphorane (660 mg) were dissolved in THF (15 mL) and stirred for 30 minutes. The solvent was evaporated under reduced pressure, methylene chloride and ether were added to the residue, and the precipitated solid was collected by filtration and dried to give the title compound (255 mg, 48%) as a yellow solid. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.28
(6H, d, J = 6.8 Hz), 3.06 (1H,
m), 3.32 (2H, m), 3.41 (2H, m),
6.61 (1H, d, J = 16.4 Hz), 6.82
(1H, d, J = 1.0 Hz), 7.22 (2H,
m), 7.71 (1H, d, J = 16.4 Hz), 9.
001H, d, J = 7.6 Hz).

(B) 2-hydroxy-8- [2- (4-
Isopropyl-1,3-thiazol-2-yl) -1-
Ethenyl] -3-[(1H-1,2,3,4-tetrazol-5-ylimino) methyl] -4H-pyrido [1,
2-a] pyrimidin-4-one aluminum chloride (11
2 mg, 0.842 mmol) were suspended in DMF (3 mL) and sodium azide (180 mg, 2.77 mmol) was added.
l) was added and stirred for 10 minutes. (E) -3 obtained in (A)
-(2-hydroxy-8- [2- (4-isopropyl-
1,3-thiazol-2-yl) -1-ethenyl] -4
H-pyrido [1,2-a] pyrimidin-4-one-3-
Yl) -2-propenenitrile (100 mg, 0.27
3 mmol) and stirred at 100 ° C. for 2 days. ice,
After adding 1M hydrochloric acid to make a homogeneous solution, the pH was adjusted to 4-5 with saturated aqueous sodium hydrogen carbonate, and the precipitate was collected by filtration. This was subjected to preparative thin-layer chromatography (chloroform-methanol-water,
8: 3: 1 v / v, lower layer solution) to give the title compound (18 mg, 16%) as a yellow powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (6H,
d, J = 7.6 Hz), 3.0-3.3 (5H, m),
7.09 (1H, s), 7.15 (1H, s), 7.2
6 (1H, m), 7.74 (2H, s), 8.88 (1
H, d, J = 5.9 Hz).

Example 68: N- (1H-1,2,3,3
4, -tetrazol-5-yl) -1-ethyl-7-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4
-Dihydro-3-quinolinecarboxamide (A) diethyl 2-diethyl-3-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] anilinomethylene mmalonate N-ethyl-3-[(E) -2- (4-isopropyl-1,3
-Thiazol-2-yl) -1-ethenyl] aniline (297.4 mg, 1.09 mmol) and diethylethoxymethylene malonate (0.230 ml, 1.
A solution (14 mmol) of toluene (5 ml) was heated to reflux for 14 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15 → 1: 1) to give the title compound (44).
8.3 mg, 92.8%) as a yellow oil.

(B) Ethyl 1-ethyl-5-[(E)
-2- (4-Isopropyl-1,3-thiazole-2-
Yl) -1-ethenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylate (isomer A) and ethyl 1-ethyl-7-[(E) -2- (4-isopropyl-1, 3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylate (isomer B) diethyl 2- {ethyl-3-[(E) -2- ( 4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] anilinomethylene dimalonate (448.3 m
g, 1.01 mmol) was added pyrophosphoric acid (3 ml), and the mixture was heated with stirring at 110 ° C. for 45 minutes. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by PTLC (chloroform: methanol = 97: 3) to give isomer A (148.
0 mg, 36.8%) as a colorless solid. Then isomer B (189.4 mg, 47.2%) was obtained as a colorless solid. Isomer A ¹ H-NMR (CDCl ₃ ) δ: 1.33 (6H, d, J
= 6.8 Hz), 1.40 (3H, t, J = 7.1H)
z), 1.53 (3H, t, J = 7.2 Hz), 3.1
1 (1H, dq, J = 6.8 Hz), 4.24 (2H,
q, 7.2 Hz), 4.38 (2H, q, J = 7.1H)
z), 6.80 (1H, s), 7.03 (1H, d, J
= 16.1 Hz), 7.42 (1H, d, J = 8.5H)
z), 7.49 (1H, d, J = 7.6 Hz), 7.6
2 (1H, t, J = 8.5 Hz), 8.42 (1H, t, J = 8.5 Hz)
s), 8.81 (1H, d, J = 16.1 Hz). Isomer B ¹ H-NMR (CDCl ₃ ) δ: 1.35 (6H, d, J
= 7.1 Hz), 1.42 (3H, t, J = 7.1H)
z), 1.58 (3H, t, J = 7.2 Hz), 3.1
5 (1H, dq, J = 6.8 Hz), 4.28 (2H,
q, 7.2 Hz), 4.40 (2H, q, J = 7.1H)
z), 6.90 (1H, s), 7.45 (2H, br)
s), 7.51 (1H, br s), 7.03 (1H,
d, J = 16.1 Hz), 7.42 (1H, d, J =
8.5Hz), 7.59 (1H, dd, J = 8.5,
1.5 Hz), 8.49 (1H, s), 8.51 (1
H, d, J = 8.5 Hz).

(C) 1-ethyl-7-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -4-oxo-1,4-dihydro-3
Ethyl quinolinecarboxylate 1-ethyl-7-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4-dihydro-3 -Quinoline carboxylate (186.8 mg, 0.47 mmol)
To a mixed solution of methanol (1.5 ml) -tetrahydrofuran (1.5 ml) -water (1.5 ml) was added a 1 N aqueous sodium hydroxide solution (0.707 ml, 0.71 m
mol), and the mixture was stirred at room temperature for 6.5 hours. After evaporating the solvent, water was added, 1N hydrochloric acid (0.707 ml) was added, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound (137.8 mg, 79.4%) as a colorless solid. Was. ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (6H,
d, J = 6.8 Hz), 1.62 (3H, t, J = 7.
1 Hz), 3.09 (1H, dq, J = 6.8 Hz),
4.66 (2H, q, J = 7.1 Hz), 7.36 (1
H, s), 7.70 (1H, d, J = 16.1 Hz),
7.88 (1H, d, J = 16.1 Hz), 8.05
(1H, d, J = 8.3 Hz), 8.30 (1H, d, J = 8.3 Hz)
s), 8.35 (1H, d, J = 8.3 Hz), 9.0
6 (1H, s).

(D) N- (1H-1,2,3,4, -tetrazol-5-yl) -1-ethyl-7-[(E)-
2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide 1-ethyl-7-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4
-Dihydro-3-quinolinecarboxylic acid (39.6 mg,
0.11 mmol) in dimethylformamide (2 m
l)), ethyl chloroformate (15.3 μl) under ice cooling.
1, 0.16 mmol) and triethylamine (2
2.5 μl, 0.16 mmol) and stirred at the same temperature for 3 hours. Then, 5-aminotetrazole (13.7)
mg, 0.16 mmol) and triethylamine (4
4.9 µl, 0.32 mmol) and stirred at room temperature overnight. After evaporating the solvent, water was added and the precipitated solid was collected by filtration. After sufficiently washing with chloroform and drying, the title compound (14.6 mg, 31.2%) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (6H,
d, J = 6.8 Hz), 1.48 (3H, t, J = 7.
1 Hz), 3.09 (1H, dq, J = 6.8 Hz),
4.65-4.75 (2H, m), 7.35 (1H,
s), 7.70 (1H, d, J = 16.4 Hz), 7.
86 (1H, d, J = 16.4 Hz), 8.02 (1
H, d, J = 8.3 Hz), 8.27 (1H, s),
8.40 (1H, d, J = 8.3 Hz), 9.08 (1
H, s). FAB-MS; m / z: 436 (MH ⁺ )

Example 69: 1-ethyl-7-[(E)-
2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -3- (1H-1,2,3,4-
Tetrazol-5-yl) -1,4-dihydro-4-quinolinone (A) 1-ethyl-5-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1- Ethenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide (isomer A) and 1-ethyl-7-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4
-Dihydro-3-quinolinecarboxamide (isomer B) N-ethyl-3-[(E) -2- (4-isopropyl-
1,3-Thiazol-2-yl) -1-ethenyl] aniline (203.2 mg, 0.75 mmol) and ethyl 2-cyano-3-ethoxy-2-propenoate (total 252.4 mg, 1.49 mmol) in toluene The solution (5 ml) was heated under reflux for a long time. The solvent was distilled off, and pyrophosphoric acid (3 ml) was added to the residue.
The mixture was heated and stirred at ℃ for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (chloroform → chloroform: methanol = 99:
Purified in 1), and isomer A (41.1 mg, 15.1)
%) As a colorless solid. Then a mixture of isomers A and B (22.1 mg, 8.1%) was obtained. Further isomer B (65.3 mg, 23.8%) was obtained as a colorless solid. Isomer A ¹ H-NMR (CDCl ₃ ) δ: 1.33 (6H, d, J
= 6.8 Hz), 1.56 (3H, t, J = 7.3H)
z), 3.13 (1H, dq, J = 6.8 Hz), 4.
32 (2H, q, 7.3 Hz), 5.77 (1H, br
s), 6.83 (1H, s), 7.08 (1H, d,
J = 15.9 Hz), 7.51 (1H, d, J = 8.5)
Hz), 7.56 (1H, d, J = 7.3 Hz), 7.
70 (1H, m), 8.76 (1H, d, J = 15.9)
Hz), 8.78 (1H, s), 9.76 (1H, br)
s). FAB-MS; m / z: 368 (MH ⁺ ) Isomer B ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J
= 6.8 Hz), 1.60 (3H, t, J = 7.3H)
z), 3.15 (1H, dq, J = 6.8 Hz), 4.
35 (2H, q, 7.3 Hz), 5.75 (1H, br
s), 6.92 (1H, s), 7.49 (2H,
s), 7.59 (1H, s), 7.67 (1H, dd,
J = 8.5, 1.1 Hz), 8.52 (1H, d, J =
8.5 Hz), 8.80 (1 H, s), 9.74 (1
H, brs). FAB-MS; m / z: 368 (MH ⁺ )

(B) 1-ethyl-7-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -4-oxo-1,4-dihydro-3
Quinolinecarbonitrile dimethylformamide (24.3 μl, 0.32 mmol
Oxalyl chloride (25.6 μl, 0.30 mmol) was added to an acetonitrile solution (1 ml) of 1) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then 1-ethyl-7-
[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-1,4
-Dihydro-3-quinolinecarboxamide (72.0 m
g, 0.20 mmol) in acetonitrile (1 m
l) was added and the mixture was stirred at the same temperature for 10 minutes. To this was added pyridine (47.5 μl, 0.60 mmol) and stirred at the same temperature for 15 minutes. Further pyridine (23.7 μl,
0.30 mmol) and stirred at room temperature for 30 minutes. A solution of dimethylformamide (18.2 μl, 0.24 mmol) and oxalyl chloride (18.8 μl, 0.22 mmol) in acetonitrile (1 ml) prepared at 0 ° C. in advance was added, and then pyridine (34.
9 μl, 0.44 mmol) and stirred at room temperature for 20 minutes. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the residue was washed successively with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 99.5: 0.5) to give the title compound (61.5 mg). , 89.8%) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J
= 6.8 Hz), 1.55-65 (3H, m), 3.1
5 (1H, dq, J = 6.8 Hz), 4.25-4.3
5 (2H, m), 6.93 (1H, s), 7.47 (2
H, s), 7.55 (1H, s), 7.66 (1H, d
d, J = 8.5, 1.2 Hz), 8.05 (1H,
s), 8.45 (1H, d, J = 8.5 Hz). FAB-MS; m / z: 350 (MH ⁺ )

(C) 1-ethyl-7-[(E) -2-
(4-Isopropyl-1,3-thiazol-2-yl)
-1-ethenyl] -3- (1H-1,2,3,4-tetrazol-5-yl) -1,4-dihydro-4-quinolinone aluminum chloride (33.7 mg, 0.24 mmol)
To a dimethylformamide solution (1 ml) of above was added sodium azide (54.7 mg, 0.84 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Then, 1-ethyl-
7-[(E) -2- (4-isopropyl-1,3-thiazol-2-yl) -1-ethenyl] -4-oxo-
1,4-dihydro-3-quinolinecarbonitrile (2
A solution of 9.4 mg (0.08 mmol) in dimethylformamide (1 ml) was added and the mixture was stirred at 85-90 ° C for 2 days. The reaction solution was poured into ice water-1N hydrochloric acid (0.5 ml), 1N hydrochloric acid (0.5 ml) was gradually added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water and a small amount of ethanol, and dried, to give the title compound (14.4 mg,
43.6%) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (6H,
d, J = 6.8 Hz), 1.46 (3H, t, J = 7.
1 Hz), 3.08 (1H, m), 4.55-4.65
(2H, m), 7.34 (1H, s), 7.69 (1
H, d, J = 16.1 Hz), 7.83 (1H, d, J)
= 16.1 Hz), 7.96 (1H, d, J = 8.5H)
z), 8.21 (1H, s), 8.35 (1H, d, J
= 8.5 Hz), 9.11 (1H, s). FAB-MS; m / z: 393 (MH ⁺ )

Example 70: 1-cyclopropyl-6-fluoro-7-[(4-isopropyl-1,3-thiazol-2-yl) methoxy] -3- (1H-1,2,3,3
4-tetrazol-5-yl) -1,4-dihydro-4
-Quinolinone (A) 1-cyclopropyl-6,7-difluoro-4-
Oxo-1,4-dihydro-3-quinolinecarboxamide 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (10
0.3 mg, 0.38 mmol) in dimethylformamide suspension (2 ml) under a nitrogen stream at 0 ° C. at 0 ° C. with ethyl chloroformate (54.0 μl, 0.57 mmol) and triethylamine (79.1 μl, 0.57 mmol).
l), and the mixture was stirred at the same temperature for 1 hour, at room temperature for 30 minutes, and further at 0 ° C for 30 minutes.
l) was added and stirred overnight. Ethyl acetate was added, and the mixture was washed sequentially with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated saline. After drying over anhydrous sodium sulfate,
The solvent was distilled off to give the title compound (99.2 mg, 99.3).
%) As a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.15 to 1.25 (2
H, m), 1.35-1.45 (2H, m), 3.45
-3.55 (1H, m), 5.72 (1H, brs),
7.81 (1H, dd, J = 11.2, 6.3 Hz),
8.28 (1H, dd, J = 10.3, 8.8 Hz),
8.89 (1H, s), 9.52 (1H, brs).

(B) 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile dimethylformamide (61.9 μl, 0.79 mmol
Oxalyl chloride (63.4 μl, 0.72 mmol) was added to an acetonitrile solution (1 ml) of the above under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes, and then 1-cyclopropyl-6,7-difluoro-4 was added. -Oxo-1,4-dihydro-3-quinolinecarboxamide (96.0 mg, 0.3
(6 mmol) in acetonitrile (2 ml) was added, and the mixture was stirred at the same temperature for 5 minutes. Add pyridine (0.1
18 ml, 1.44 mmol) and stirred at the same temperature for 10 minutes and at room temperature for 20 minutes. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the residue was washed successively with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain the title compound (71.0 mg, 79.4%) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.20 (2
H, m), 1.35-1.45 (2H, m), 3.45
-3.55 (1H, m), 7.78 (1H, dd, J =
11.2, 6.3 Hz), 8.16 (1H, s), 8.
20 (1H, dd, J = 10.0, 8.8 Hz). (C) 1-cyclopropyl-6-fluoro-7-[(4
-Isopropyl-1,3-thiazol-2-yl) methoxy] -4-oxo-1,4-dihydro-3-quinolinecarbonitrile sodium hydride (13.4 mg, 0.34 mmol)
In a dimethylformamide solution (3 ml) at room temperature under a nitrogen stream at room temperature.
mmol) and 4-isopropyl-1,3-thiazol-2-ylmethanol (43.9 mg, 0.28 mm
ol) and stirred at the same temperature for 15 minutes. 1 in the reaction solution
-Cyclopropyl-6,7-difluoro-4-oxo-
1,4-dihydro-3-quinolinecarbonitrile (6
A solution of 8.8 mg (0.28 mmol) in dimethylformamide (3 ml) was added and stirred at the same temperature for 1.5 hours. Ethyl acetate, 1N hydrochloric acid (0.335 ml) and water were added and partitioned. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography (chloroform → chloroform: methanol = 99: 99).
Purified in 1) to give the title compound (77.6 mg, 72.4)
%) As a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.05-1.10 (2
H, m), 1.31 (6H, d, J = 7.1 Hz),
1.35-1.45 (2H, m), 3.05-3.15
(1H, m), 3.35-3.45 (1H, m), 5.
59 (2H, s), 6.98 (1H, s), 7.63
(1H, d, J = 6.6 Hz), 8.07 (1H, d,
J = 10.5 Hz), 8.08 (1H, s).

(D) 1-cyclopropyl-6-fluoro-7-[(4-isopropyl-1,3-thiazole-2
-Yl) methoxy] -3- (1H-1,2,3,4-tetrazol-5-yl) -1,4-dihydro-4-quinolinone aluminum chloride (41.0 mg, 0.30 mmol)
To a dimethylformamide solution (2 ml) was added sodium azide (66.6 mg, 1.02 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Then, 1-cyclopropyl-6-fluoro-7-[(4-isopropyl-
A solution of (1,3-thiazol-2-yl) methoxy] -4-oxo-1,4-dihydro-3-quinolinecarbonitrile (39.3 mg, 0.10 mmol) in dimethylformamide (2 ml) was added, and 85-90 was added. Stirred at C for 1 day. The reaction solution was poured into ice water-1N hydrochloric acid (1.1 ml) and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water and a small amount of ethanol, and dried to give the title compound (13.2 mg) as a colorless solid. Further, the mother liquor was adjusted to pH 4 with a 1N aqueous sodium hydroxide solution, and the precipitate was collected by filtration, washed with water and a small amount of ethanol, and dried to obtain the title compound (15.9 mg, total 66.6%) as a colorless solid. Was. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.20
(2H, m), 1.26 (6H, d, J = 6.8H
z), 1.30-1.40 (2H, m), 3.00-
3.15 (1H, m), 3.65-3.75 (1H,
m), 5.77 (2H, s), 7.39 (1H, s),
7.92 (1H, d, J = 7.3 Hz), 8.03 (1
H, d, J = 11.2 Hz), 8.79 (1H, s). FAB-MS; m / z: 427 (MH ⁺ )

Example 71: 1-ethyl-6-fluoro-
7-[(4-isopropyl-1,3-thiazole-2-
Yl) methyl] -4-oxo-1,4-dihydro-3-
Cinnoline Carboxylic Acid (A) Dimethyl 2-[(3,4-difluorophenyl) hydrazono] malonate 3,4-difluoroaniline (5.00 g, 38.7 m)
mol) was dissolved in 10% hydrochloric acid (15 ml), and an aqueous solution (10 ml) of sodium nitrite (2.81 g, 40.7 mmol) was slowly added dropwise at 0 ° C., followed by stirring for 30 minutes. The solution obtained by filtering off the insolubles was cooled to a previously cooled dimethyl malonate (8.84 g, 77.5 mm).
ol), sodium acetate (11.4 g, 139 mmol)
1) The reaction mixture was slowly dropped into a reaction vessel of ethanol (100 ml) and water (20 ml) and stirred at 0 ° C. overnight. The precipitated crystals were collected by filtration, dissolved in chloroform, and washed with water. After drying the chloroform layer, the solvent was distilled off to obtain the title compound (9.18 g, 87%) as a yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 3.88 (3H, s),
3.91 (3H, s), 6.98 (1H, m), 7.1
6 (1H, m), 7.29 (1H, m), 12.8 (1
H, brs).

(B) Dimethyl 2-[(3,4-difluorophenyl) -2-ethylhydrazono] malonate The dimethyl 2-[(3,4-difluorophenyl) hydrazono] malonate (7) obtained in (A) .18g, 2
6.4 mmol) in DMF (140 ml) and 95% sodium hydride (800
mg, 31.7 mmol) and stirred at room temperature for 1 hour. This was cooled on ice again, and ethyl iodide (4.24 m
1,52.8 mmol) and stirred at room temperature for 1 hour.
Stirred at 75 ° C. overnight. After cooling, acetic acid (10 ml) was added, and the mixture was concentrated. The obtained residue was diluted with chloroform and washed with saturated saline. The organic layer was dried, concentrated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, 20: 1, v / v).
The title compound was obtained (4.86 g, 61%). ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J
= 7.3 Hz) 3.64 (3H, s), 3.84 (3
H, s), 3.85 (m, 2H), 6.99 (1H,
m), 7.15-7.19 (2H, m).

(C) Methyl 1-ethyl-6,7-difluoro-4-oxo-1,4-dihydro-3-cinnolinecarboxylate Dimethyl 2-[(3,4-difluoro) obtained from (B) Phenyl) -2-ethylhydrazono] malonate (4.86 g, 16.2 mmol) and polyphosphoric acid (10
0 ml) and stirred at 110 ° C. for 20 hours. After cooling, the reaction solution was diluted with water and extracted twice with ethyl acetate.
The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate, 4: 1, v / v) to give the title compound as yellow crystals (959 mg, 21%). Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.57 (3H, t, J
= 7.3 Hz) 3.99 (3H, s), 4.48 (q,
2H, J = 7.3 Hz), 7.35 (1H, dd, J =
10.7, 6.1 Hz), 8.21 (2H, 1H, d)
d, J = 9.3, 8.8 Hz).

(D) Methyl 1-ethyl-6-fluoro-7-[(4-isopropyl-1,3-thiazole-2
-Yl) methyl] -4-oxo-1,4-dihydro-3
-Cinnoline carboxylate (4-isopropyl-1,3-thiazol-2-yl)
Methanol (182 mg, 0.60 mmol) in DMF
(3 ml) and dissolved in 18-crown-6 (337 m).
g, 1.28 mmol), sodium hydride (95%,
32.2 mg, 1.28 mmol) and stirred for 15 minutes under an argon atmosphere. Methyl 1 obtained in (C)
-Ethyl-6,7-difluoro-4-oxo-1,4-
Dihydro-3-cinnoline carboxylate (311m
g, 1.16 mmol), and the mixture was stirred at room temperature for 1 hour. Then, an aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is prepared by preparative TLC.
(Chloroform-ethyl acetate, 4: 1, v / v) to give the title compound as yellow crystals (380 mg, 81
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 6.8 Hz), 1.51 (3H, t, J = 7.1H)
z), 3.11 (1H, m), 3.98 (3H, s),
4.48 (2H, q, J = 7.1 Hz), 5.59 (2
H, s), 6.99 (1H, s), 7.26 (1H,
d, J = 6.4 Hz), 8.07 (1H, d, J = 1)
0.5 Hz).

(E) 1-ethyl-6-fluoro-7-
[(4-Isopropyl-1,3-thiazol-2-yl) methyl] -4-oxo-1,4-dihydro-3-cinnolinecarboxylic acid Methyl 1-ethyl-6 obtained from (D) Fluoro-
7-[(4-isopropyl-1,3-thiazole-2-
Yl) methyl] -4-oxo-1,4-dihydro-3-
Cinnoline carboxylate (380 mg, 0.937
mmol) was dissolved in acetic acid (5 ml) -hydrochloric acid (5 ml) and stirred at 110 ° C. for 2 hours. The reaction solution was ethyl acetate-
After partitioning the mixture in ice water and drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure to give the title compound (322m
g, 88%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 7.1 Hz), 1.57 (3H, t, J = 7.3H)
z), 3.12 (1H, m), 4.73 (2H, q, J
= 7.3 Hz), 5.72 (2H, s), 7.04 (1
H, s), 7.58 (1H, d, J = 6.6 Hz),
8.10 (1H, d, J = 10.0 Hz).

Example 72: 1-ethyl-6-fluoro-
7-[(4-Isopropyl-1,3-thiazole-2
-Yl) methyl] -3- (1H-1,2,3,4-tetrazol-5-yl) -1,4-dihydro-4-cinnolinone (A) N ^3- (2-cyanoethyl) -1-ethyl -6
Fluoro-7-[(4-isopropyl-1,3-thiazol-2-yl) methyl] -4-oxo-1,4-dihydro-3-cinnolinecarboxamide 1 obtained in (E) of Example 71 -Ethyl-6-fluoro-7-[(4-isopropyl-1,3-thiazole-
2-yl) methyl] -4-oxo-1,4-dihydro-
3-cinnoline carboxylic acid (322m
g, 0.823 mmol) was dissolved in DMF (6 ml), and ethyl chloroformate (0.117 ml, 1.
23 mmol), triethylamine (0.172 ml,
1.23 mmol) and stirred for 1 hour. The temperature was raised to room temperature, and the mixture was further stirred for 30 minutes. After ice-cooling again and stirring for 1 hour, cyanoethylamine (0.273 ml, 3.70 m
mol), and the mixture was stirred at room temperature for 3 days. The reaction solution was diluted with ethyl acetate, washed with an aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and water, and dried. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform-methanol, 200: 1, v / v) to obtain the title compound as yellow crystals (276 mg, 76%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J
= 7.1 Hz), 1.55 (3H, t, J = 7.3H)
z), 2.78 (2H, t, J = 6.8 Hz), 3.1
1 (1H, m), 3.76 (2H, m), 4.64 (2
H, q, J = 7.3 Hz), 5.62 (2H, s),
7.00 (1H, s), 7.39 (1H, d, J = 6.
6 Hz), 8.08 (1H, d, J = 10.3 Hz),
10.4 (1H, m).

(B) 2- (5- {1-ethyl-6-fluoro-7-[(4-isopropyl-1,3-thiazol-2-yl) methyl] -4-oxo-1,4- Dihydro-3-cinnolinyl {-1H-1,2,3,4-tetrazol-1-yl) ethyl cyanide N ^3- (2-cyanoethyl) -1-ethyl-6-fluoro-7- obtained by (A) [(4-isopropyl-1,
3-thiazol-2-yl) methyl] -4-oxo-
1,4-dihydro-3-cinnolinecarboxamide (2
76 mg, 0.622 mmol) in acetonitrile (6
sodium azide (48.5 mg, 0.747 mmol) and trifluoromethanesulfonic anhydride (0.126 ml, 0.74 ml) under an ice-cooled argon atmosphere.
7 mmol) and stirred at room temperature for 2 hours. Further, sodium azide (97 mg) and trifluoromethanesulfonic anhydride (0.252 ml) were added, and the mixture was stirred overnight. Further, sodium azide (97 mg) and trifluoromethanesulfonic anhydride (0.252 ml) were added, and the mixture was stirred for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography (toluene-acetone,
8: 1, v / v) to give the title compound (134 mg, 46%) as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J
= 6.8 Hz), 1.58 (3H, t, J = 7.3H)
z), 3.12 (1H, m), 3.19 (2H, t, J
= 7.1 Hz), 4.58 (2H, q, J = 7.3H)
z), 4.78 (2H, t, J = 7.1 Hz), 5.6
4 (2H, s), 7.02 (1H, s), 7.43 (1
H, d, J = 6.6 Hz), 8.07 (1H, d, J =
10.3 Hz).

(C) 1-ethyl-6-fluoro-7-
[(4-Isopropyl-1,3-thiazol-2-yl) methyl] -3- (1H-1,2,3,4-tetrazol-5-yl) -1,4-dihydro-4-cinnolinone ( 2- (5- {1-ethyl-6-fluoro-7-[(4-isopropyl-1,3-thiazol-2-yl) methyl] -4-oxo-1,4- obtained in B) Dihydro-3-cinnolinyl {-1H-1,2,3,4-tetrazol-1-yl) ethyl cyanide (134 mg,
0.286 mmol) in methylene chloride and DBU
(0.107 ml, 0.714 mmol) was added, and the mixture was stirred at room temperature for 3 hours. In addition, DBU (0.107 ml,
0.714 mmol), and stirred for 2 hours.
U (0.107 ml, 0.714 mmol) was added and the mixture was stirred for 2 hours. The reaction solution was diluted with chloroform, washed with 1N hydrochloric acid and water, and dried. The residue obtained by evaporating the solvent was purified by preparative TLC (chloroform-methanol-water, 8: 3: 0.5, v / v / v) to give the title compound as yellow crystals (101 mg, 85 mg). %)Obtained. ¹ H-NMR (CD ₃ OD) δ: 1.35 (6H, d, J
= 6.8 Hz), 1.57 (3H, t, J = 6.8H)
z), 3.14 (1H, m), 4.72 (2H, m),
5.67 (2H, s), 7.11 (1H, s), 7.4
9 (1H, m), 7.59 (1H, m). MS; m / z: 416 (MH ^<+> ).

Test Example 1 Effect of Combined Use with Antimicrobial Agent against Multidrug-Resistant Pseudomonas aeruginosa As the multidrug-resistant Pseudomonas aeruginosa, Pseudomonas aeruginosa PAM1723, which is a strain highly expressing a drug efflux pump was used. Levofloxacin (LVFX), a quinolone antibacterial drug, as a combination antibacterial drug
Alternatively, aztreonam (AZT), a monobactam antibiotic, was tested. Among the compounds of the present invention, the compounds described in the example numbers shown in the following table,
1/4 and 1 / of the minimum inhibitory concentrations for the PAM1723 strain
When used in combination with a concentration of 8 or less, the minimum concentration (μg / ml) of each compound required to enhance the antibacterial activity was measured. The numerical values in the table are shown as the minimum concentration (μg / ml) of each compound required to enhance the antibacterial activity when used in combination with a concentration of 1/8 or less of the minimum growth inhibitory concentration. Levofloxacin showed an effect when used together for 7.5 hours, and aztreonam showed an effect when used together for 18 hours. Mueller Hinton Broth (MHB, Difco) was used as the medium, and the amount of the inoculated bacteria was 1 × 10 ⁶ CFU / ml. The turbidity of the bacteria was measured optically with time, and the effect was determined by visually confirming the turbidity of the medium. As is clear from the table below, the compound of the present invention is clinically useful because it exhibits a combined effect against drug-resistant Pseudomonas aeruginosa, mainly by inhibiting resistance of the bacteria by a drug efflux pump. It was concluded that this is a group of compounds that can be expected to have properties.

[0336]

[Table 4]

[0337]

[Table 5]

[0338]

[Table 6]

[0339]

[Table 7]

[0340]

[Table 8]

[0341]

[Table 9]

[0342]

[Table 10]

[0343]

[Table 11]

[0344]

[Table 12]

[0345]

[Table 13]

[0346]

[Table 14]

[0347]

[Table 15]

[0348]

[Table 16]

Example 73 (1) Calculation of pharmacophore The compounds of Example 1, Example 10, Example 15, Example 27, Example 37, Example 49 and Example 70 shown in the above table were obtained. Using the conformation search function of CATALYST ^™ , the allowable energy range of the generated conformation was set to 20 kcal / mol and the maximum number of conformations was 250, and the calculation was performed with Best Quality. Next, all the generated conformations were registered in the compound information. Using all of these compounds, CATALYST ^™ is one of the pharmacophore-generating functions of CATALYST.
Pharmacophore was calculated using LYST / HipHop. Of the results obtained, the one with the highest relevance was selected.

The obtained pharmacophore is shown in FIG. Each site in the figure is displayed as a sphere having a radius of 1.7 ° from the center. However, the permissible range for sites 1 and 4 is the radius from each center (Tolerance)
2Å ball. FIG. 2 shows the result of superposing all the compounds on the obtained pharmacophore. Compound superposition is performed by Compare of CATALYST ^™
This was performed using the / Fit function. In FIG. 2, hydrogen atoms are not shown. Also, in the figure, the range corresponding to the sphere indicates each site, but the sites 1 and 4 are shown as spheres having a radius of 1.7 ° (the actual allowable range is a sphere having a radius of 2 °). . FIGS. 3 to 9 show how the respective compounds overlap with the present pharmacophore. 3 is the compound of Example 1, FIG. 4 is the compound of Example 10, FIG. 5 is the compound of Example 15,
6 shows the compound of Example 27, FIG. 7 shows the compound of Example 37, FIG. 8 shows the compound of Example 49, and FIG. 9 shows the compound of Example 70.

(2) Confirmation of whether or not the compound is compatible with the pharmacophore The confirmation of whether or not the compound is compatible with the pharmacophore can be performed as follows. The conformation of the compound is calculated using, for example, a molecular force field method such as CATALYST ^™ , CHARMm, and MMFF, and a molecular orbital method program such as MOPAC (these are examples, and are not limited to these programs). . Each conformation
Use a program such as CATALYST ^™ or manually and superimpose them individually on the pharmacophore. A compound whose partial structure occupies the above four sites or a compound whose partial structure touches four sites can be regarded as a compound compatible with pharmacophore, and has Pseudomonas aeruginosa drug efflux pump inhibitory activity The compound can be determined. More specifically, when the compound is superimposed on the pharmacophore, for each site, when the constituent atoms in the partial structure corresponding to the feature of the site are within 0.5 to 3 mm from the site , More preferably 2 mm for sites 1 and 4 and 1.7 mm for sites 2 and 3 (Tolerance).
If so, the compound is determined to be compatible with the pharmacophore.

For example, as shown in FIGS. 3 to 7 and FIG. 9, the partial structure of each compound occupies a sphere generated at a radius of 1.7 ° from the center of each site. I am satisfied with the range. In the compound shown in FIG. 8, the partial structure of site 2 and site 3 is contained in a sphere generated at a radius of 1.7 ° from the center of each site. The partial structure touches a sphere with a radius of 1.7 mm from the center of the generated 2 mm
Within. Therefore, it is determined that the above-mentioned allowable range is satisfied.

Test Example 2: Effect of increasing the activity of a drug efflux pump inhibitor on various antibacterial agents By using a drug efflux pump inhibitor together with an antibacterial agent that can be a substrate of a drug efflux pump, the antibacterial activity of the antibacterial agent was significantly improved It is possible to increase. As shown in the examples below, quinolone-based, β-lactam-based, novobiocin, clindamycin, vancomycin, and the like confirm the effect of enhancing the activity of the antibacterial agent. Combination therapy with a pump inhibitor and an antibacterial drug that is a substrate for a Pseudomonas aeruginosa Mex-based drug efflux pump containing these drugs is expected to be effective as a novel therapy in the treatment of infectious diseases in clinical practice.

(1) Effect of combined use of pump inhibitor with various antibacterial substances (a) Measurement of combined activity: PAM1020 which is a wild strain of Pseudomonas aeruginosa
Strain and PA with high expression of MexAB-OprM drug efflux pump
The combined activity of the antibacterial substance and the pump inhibitor against the M1032 strain was measured using the minimum inhibitory concentration (MIC) value as an index. The drug was serially diluted two-fold with MHB, and Mueller Hinton liquid medium (MHB, Difco) was used for the single acting group, and Compound I was diluted with MHB to a final concentration of 10 μg / ml for the Compound I combination group. Is added. Compound I is a compound having the following structure, and is a structure having excellent activity among the compounds of formula (I).

Compound I: 2-((N- (3- (2- (4-
Isopropylthiazol-2-yl)-(E) -ethenyl) phenyl) carbamoyl) methyl) benzoic acid

Embedded image

The inoculum of the test bacteria was 5 × 10 ⁴ CFU / ml,
After standing culture at 7 ° C for 18 hours, visual judgment was performed, and the control MHB was used.
The minimum concentration at which no turbidity was observed was determined as MIC. The concomitant antibacterial agents are as follows. Levofloxacin (LVFX), sparfloxacin (SPFX), trovafloxacin (TVFX), piperacillin (PIPC), carbenicillin (C
BPC), ceftazidime (CAZ), cefpirome (CPR), cefixime (CFIX), aztreonam (AZT), carmonam (CRM)
N), meropenem (MEPM), novobiocin (NB), clindamycin (CLDM), vancomycin (VCM)

The results are shown in the table below. Test 2 of Compound I
The MIC for each strain was ≧ 160 μg / ml.

[0358]

[Table 17] (B) Combination therapy that can be expected to have a high therapeutic effect by preventing the residual bacteria by using a drug efflux pump inhibitor and a plurality of antibacterial agents in combination. When used together, it became possible to significantly suppress the residual bacteria after drug treatment. Combination antibacterials include quinolone, β-lactam, tetracycline, macrolide, chloramphenicol, sulfonamide, trimethoprim, β-lactamase inhibitors and other Pseudomonas aeruginosa Mex-based drug efflux pumps Antimicrobial agents (antimicrobial preparations) are included. The combined use of a plurality of antibacterial drugs and the efflux pump inhibitor of the present invention makes it possible to significantly reduce the residual number of bacteria associated with drug treatment, and consequently the emergence of drug-resistant bacteria, mainly multidrug-resistant bacteria. Because it is suppressed, it is useful as a novel therapy in treating infectious diseases in clinical settings.

Test Example 3: Effect of reducing the number of remaining bacteria by using multiple antibacterial drugs and a drug efflux pump inhibitor Measurement of the frequency of emergence of resistant bacteria: PAM1020, a wild strain of Pseudomonas aeruginosa
Strain and PA with high expression of MexAB-OprM drug efflux pump
Using the M1032 strain, the residual frequency of the bacterium when Levofloxacin (LVFX), Aztreonam (AZT), and Compound I were combined was determined using the drug-containing Mueller Hinton agar (MH
A) It was calculated by measuring the number of colonies that appeared above. That is, a bacterial solution containing drug-containing MHA and pre-cultured with MHB was used.
A 1, 10, or 100-fold diluted bacterial solution was dispensed on 0.1 ml agar, and applied with a sterile conical rod. After culturing at 37 ° C. for 48 hours, the number of colonies that grew on each plate was divided by the number of viable bacteria when no drug was contained, and the result was used as the ratio of surviving bacteria. The results are shown in the table below. The MIC for LVAM PAM1020 is 0.25 μg / ml, PA
The MIC for M1032 is 2 μg / ml, AZT for PAM1020.
The IC was 2 μg / ml and the MIC for PAM1032 was 32 μg / ml. A clear decrease in the frequency of emergence of resistant bacteria was observed by the combination of the three drugs.

[0360]

[Table 18]

[0361]

The medicament of the present invention has an action of inhibiting the drug efflux pump of microorganisms, thereby preventing the microorganisms from becoming resistant to the antimicrobial agent, and inhibiting the microorganisms that have already become resistant. And has the effect of detolerating. By using the medicament of the present invention in combination with the administration of one or more antimicrobial agents, it is possible to exert extremely excellent effects in preventing and / or treating microbial infectious diseases.

[Brief description of the drawings]

[Figure 1] CATALYST ^TM pharmacophore (Hypo
Example 1, Example 10, Example 15, Example 27, using CATALYST / HipHop, which is one of the
FIG. 11 is a diagram showing a pharmacophore having the highest validity among the results obtained by calculating a pharmacophore from the compounds of Example 37, Example 49, and Example 70.

FIG. 2 shows the pharmacophore shown in FIG.
It is a figure which showed the result of having superimposed all the compounds of Example 10, Example 15, Example 27, Example 37, Example 49, and Example 70.

FIG. 3 is a view showing the result of superposing the compound of Example 1 on the pharmacophore shown in FIG. 1.

FIG. 4 is a view showing the result of superposing the compound of Example 10 on the pharmacophore shown in FIG. 1.

FIG. 5 is a view showing the result of superposing the compound of Example 15 on the pharmacophore shown in FIG. 1.

FIG. 6 is a view showing the result of superposing the compound of Example 27 on the pharmacophore shown in FIG. 1.

FIG. 7 is a view showing the result of superposing the compound of Example 37 on the pharmacophore shown in FIG. 1.

FIG. 8 is a view showing the result of superposing the compound of Example 49 on the pharmacophore shown in FIG. 1.

FIG. 9 is a view showing the result of superposing the compound of Example 70 on the pharmacophore shown in FIG. 1.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/437 A61K 31/437 4C055 31/4375 31/4375 4C056 31/44 31/44 4C063 31/4439 31 / 4439 4C065 31/47 31/47 4C072 31/4709 31/4709 4C086 31/519 31/519 31/5383 31/5383 A61P 31/04 A61P 31/04 43/00 121 43/00 121 C07D 213/30 C07D 213/30 215/14 215/14 263/56 263/56 277/28 277/28 277/30 277/30 277/40 277/40 285/08 285/08 307/54 307/54 409/12 409 / 12 417/04 417/04 417/06 417/06 417/12 417/12 417/14 417/14 471/04 112 471/04 112A 487/04 147 487/04 147 498/06 498/06 513/04 343 513/04 343 (72) Inventor Kazuki Hoshino 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo Inside the R & D Center (72) Inventor Yuko Ishida 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo First Pharmaceutical Co., Ltd. Tokyo R & D Center (72) Inventor Olga Romovskaya Mountain View, Mode, 94043 California, United States of America Avenue 850 Microside Pharmaceuticals Inc. (72) Inventor Mike Dudley United States, 94043 California, Mountain View, MODE Avenue 850 Microside Pharmaceuticals Inc. (72) Inventor Roger Reeger Canada, J4R 2V8 Quebec St. Lambert, Upper Edison 202 (72) Inventor William John Watkins United States, 94087 California, Oneny Drive, Sunnyvale, California 626 (72) Invention Jason Chizia Tuan United States, 94404 California, Foster City, Crane Avenue 770 (72) Inventor Thomas Eric Renau United States, 95051 California, Santa Clara, Pepper Tree Lane # 224 900 (72) Inventor Ving Jack Lee United States, 94024 1335 (72) Inventor Toshiharu Ota 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside the Tokyo Research and Development Center, Daiichi Pharmaceutical Co., Ltd. (72) Inventor Kiyoshi Nakayama Kita, Edogawa-ku, Tokyo 1-16-13 Kasai, Daiichi Pharmaceutical Co., Ltd., Tokyo R & D Center (72) Inventor Yohei Ishida 1-1-16-13 Kita Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd., Tokyo R & D Center (72) Invention Masami Otsuka 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. East Inside the R & D Center (72) Inventor Haruko Kawato 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo F-term in the Tokyo Research and Development Center, Daiichi Pharmaceutical Co., Ltd. 4C031 BA08 4C033 AD08 AD20 4C036 AD05 AD17 AD26 AD30 4C037 HA29 4C050 AA01 BB08 CC07 EE02 FF03 GG03 HH04 4C055 AA01 BA03 BA06 BA33 BB02 BB11 CA01 DA01 4C056 AA01 AB01 AC02 AD03 AE03 CA12 CC01 CD01 4C063 AA01 AA03 BB01 BB03 CC62 DD12 EE01 4C009 A01 BB01 BB04 CC11 EE07 FF07 GG09 HH08 UU01 4C086 AA01 AA02 BA03 BC17 BC28 BC70 BC82 BC86 CB27 GA02 GA07 GA08 GA09 GA10 MA02 MA03 MA04 NA05 NA14 ZB35 ZC75

Claims (13)

[Claims] 1. A method for preventing and / or treating a microbial infection.
A pharmaceutical agent of the following general formula (I):[Wherein, R¹And R^TwoAre each independently a hydrogen atom, halogen
Atom, carboxyl group, alkoxycarbonyl group,
An amino group which may have a substituent,
Alkyl group which may be substituted, aryl which may have a substituent
Or a heterocyclic group which may have a substituent
Or R¹And R^TwoAre bonded to each other and they are replaced
J¹Formed with two adjacent ring-constituting atoms of
R 5 represents a 5- to 7-membered saturated or unsaturated ring;^ThreeIs hydrogen field
A hydroxyl group, a hydroxyl group or an alkoxy group;¹Is 5 members or
Represents a 6-membered aromatic heterocycle;¹Is -CH = CH-,
-C≡C-, -CH_TwoCH_Two-, -OCH_Two-, -SCH_Two
-, -OCH_TwoO-, -CH_TwoO-, -CH_Two-, -CO
-, -CH_TwoCH_TwoCH_Two-, -CH_TwoNH-, -NHCH
_Two-, -CH_TwoS-, -CONH-, -CH_TwoSCH _Two−,
-CH = CH-CONH-, and -CH_TwoOCH_TwoFrom
A group selected from the group consisting of¹Ring configuration
A) or a single bond;¹Has a substituent
May have a phenylene group or a substituent
Pyridinediyl group, furan which may have a substituent
Diyl group, thiophenediyl optionally having substituent (s)
Group, a benzofurandiyl group which may have a substituent,
Benzo [b] thiophenedii which may have a substituent
Benzoxazoledi, which may have a substituent
Yl group, benzothiazole di which may have a substituent
Yl group, pyrido which may have a substituent [1,2-
a] a pyrimidinediyl group, an optionally substituted
Nazolinediyl group, benzoto which may have a substituent
Liazindiyl group, 2H-c which may have a substituent
Romenediyl group, quinoline optionally having substituent (s)
4-one-diyl group, Azaki optionally having substituent (s)
Norin-4-one-diyl group, which may have a substituent
Quinolinediyl group, thiazi optionally substituted
Azolo [3,2-a] pyrimidinediyl group or substituent
[3,2-a] pyrimidine optionally having
G represents a diyl group;¹Represents an oxygen atom, a carbonyl group,
Nyl group, -CH = N-, -N (R^Four) CO-,-(C
H_Two) -N (R^Five) -CO-, -N (R⁶)-, -N
(R⁷) -SO_Two-, -SO_TwoN (R⁸)-, -CON (R
⁹)-, -C (= CHR^Ten)-, -C (R¹¹) = C
(R¹²)-, -NHCO-C (R¹³) (R¹⁴)-, -C
ONH-C (R¹⁵) (R¹⁶)-Or -CH_TwoO (C
H_Two)_q-(Where R^Four, R^Five, R⁶, R⁷, R⁸, And R⁹Is
Each independently having a hydrogen atom, a hydroxyl group, or a substituent
R represents an optionally substituted alkyl group;^TenIs a cyano group, carbo
Xyl group or alkoxyca which may have a substituent
R represents a carbonyl group;¹¹And R¹²Are each independently hydrogen
Atom, halogen atom, alkyl optionally having substituent (s)
Or an aryl group which may have a substituent
Or R¹¹And R¹²Is a ring formed by bonding
R;¹³And R¹⁴Are each independently a hydrogen atom or a
Represents a alkyl group, or R¹³And R¹⁴Are joined to each other
Represents an alkylene group formed by¹⁵And R¹⁶Is it
Each independently represents a hydrogen atom or an alkyl group, or
R¹⁵And R¹⁶Are bonded to each other to form an alkylene group
And q is an integer of 0 to 5); p is 0 to 3
G;^TwoIs phenyl which may have a substituent
A len group, a frangiyl group which may have a substituent,
A tetrahydrofurandiyl group which may have a substituent,
A pyridinediyl group which may have a substituent,
With a thiazolinediyl group, which may have a substituent
Optionally having an isoxazolinediyl group, having a substituent
1,3-dioxolandiyl group which may have
Optionally having a thiophenediyl group or a substituent
A pyrimidinediyl group, -C (R¹⁷) = C
(R¹⁸)-[C (R¹⁹) = C (R²⁰)]_y-(Where R
¹⁷, R¹⁸, R¹⁹, And R²⁰Is independently a hydrogen atom,
A halogen atom, an alkyl group which may have a substituent,
Or an aryl group which may have a substituent,
Or R¹⁷And R¹⁸And a ring formed by bonding to each other; and
/ Or R¹⁹And R²⁰And a ring formed by bonding to each other,
y represents an integer of 0 to 3), or -C (R^{twenty one})
(R^{twenty two}) -C (R^{twenty three}) (R^{twenty four})-(Where R^{twenty one}, R^{twenty two},
R^{twenty three}, And R^{twenty four}Are each independently a hydrogen atom, phenyl
A group or an alkyl group having 1 to 6 carbon atoms,^{twenty one}And R
^{twenty two}And / or a ring formed by bonding to each other, and / or R^{twenty three}And R
^{twenty four}And a ring formed by bonding to each other. Or R^{twenty one}
And R^{twenty three}Represents a ring formed by bonding to each other);
G^ThreeIs -CH_Two-Or a single bond; m and n are each
Independently represents an integer of 0 or 1;¹Indicates an acidic group
A compound represented by the formula:
And a substance selected from the group consisting of their hydrates
Contained as an ingredient and combined with one or more antimicrobial agents
Also used for the prevention and / or treatment of microbial infections
Medicine. 2. A medicament for detolerizing a microorganism which has acquired resistance to an antimicrobial drug, wherein the compound represented by the general formula (I) according to claim 1 is physiologically acceptable. And a pharmaceutically acceptable salt thereof, comprising a substance selected from the group consisting of a salt thereof and a hydrate thereof as an active ingredient. 3. A medicament for inhibiting the acquisition of resistance of a microorganism to an antimicrobial agent, comprising the compound represented by the general formula (I) according to claim 1, a physiologically acceptable salt thereof, and A medicament comprising a substance selected from the group consisting of hydrates thereof as an active ingredient and used in combination with one or more antimicrobial agents. 4. A medicament for enhancing the action of an antimicrobial agent, which is a compound represented by the general formula (I) according to claim 1, a physiologically acceptable salt thereof, and a water thereof. Containing as an active ingredient a substance selected from the group consisting of Japanese
A medicament for use in combination with one or more antimicrobial agents. 5. A medicament for increasing the sensitivity of a microorganism to an antimicrobial agent, comprising the compound represented by the general formula (I) according to claim 1, a physiologically acceptable salt thereof, and a compound thereof. A medicament comprising a substance selected from the group consisting of hydrates as an active ingredient and used in combination with one or more antimicrobial agents. 6. The method according to claim 1, wherein the microorganism is Pseudomonas aeruginosa.
The medicament according to any one of the above. 7. A substance selected from the group consisting of the compound represented by the general formula (I) according to claim 1, a physiologically acceptable salt thereof, and a hydrate thereof, and one or two kinds thereof. A pharmaceutical composition for preventing and / or treating microbial infectious diseases, comprising the above antimicrobial agent. 8. A method for preventing and / or treating a microbial infection.
A pharmaceutical agent of the following general formula (II):[Wherein, R³¹And R³²Are each independently a hydrogen atom, halo
Gen atom, carboxyl group, alkoxycarbonyl
Group, an amino group which may have a substituent,
Alkyl group which may be substituted,
A reel group or a heterocyclic group which may have a substituent;
Show or R³¹And R³²Are joined to each other
Replaces J¹¹With two adjacent ring-constituting atoms of
Represents a 6-membered ring; J¹¹Is a 5- or 6-membered aromatic hete
Represents a ring; W¹¹Is -CH = CH-, -CH_TwoCH_Two−,
-OCH_Two-, -SCH_Two-, -OCH _TwoO-, -CH_TwoO
-, -CH_Two-, -CO-, -CH_TwoCH_TwoCH_Two-, -C
H_TwoNH-, -NHCH_Two-, -CH_TwoS-, -CONH
-, -CH_TwoSCH_Two-, -CH = CH-CONH-, and
And -CH_TwoOCH_Two-A group selected from the group consisting of
The left side of the group is J¹¹Or a single bond
A;¹¹Is pyridinediyl which may have a substituent
[1,2-a] pyrido which may have a group or a substituent
Limidinediyl group, quinoline optionally having substituent (s)
-4-one-diyl group, aza optionally having substituent (s)
Quinolin-4-one-diyl group, even if it has a substituent
Good quinolinediyl group, thia which may have a substituent
Diazolo [3,2-a] pyrimidinediyl group or substitution
Thiazolo [3,2-a] pyrimidi optionally having a group
G represents a diphenyl group;¹¹Represents an oxygen atom, a carbonyl group,
Tinyl group, -CH = N-, -N (R³³) CO-, -N
(R³⁴) SO_Two-, -SO_TwoN (R³⁵)-, -CON (R
³⁶)-, -C (= CHR³⁷)-Or -C (R³⁸) = C
(R³⁹)-(Where R³³, R³⁴, R³⁵, R³⁶, R³⁷, R
³⁸, And R³⁹Each independently have a hydrogen atom or a substituent
M represents 0 or
Represents an integer of 1; and Q¹¹Represents an acidic group].
Compounds, physiologically acceptable salts thereof, and their water
Contains a substance selected from the group consisting of
Only in combination with one or more antimicrobial agents
A medicament for preventing and / or treating a material infection. 9. A medicament for preventing and / or treating a microbial infection, wherein the following four sites are within the following allowable ranges: Effective for compounds selected from the group consisting of compounds characterized by having a partial structure occupied by Pseudomonas aeruginosa drug efflux pump inhibitor, physiologically acceptable salts thereof, and hydrates thereof A medicament which is contained as a component and is used for prevention and / or treatment of microbial infections in combination with one or more antimicrobial agents. 10. A Pseudomonas aeruginosa drug efflux pump inhibitory activity of 40.
The medicament according to claim 9, which is not more than μg / mL. 11. A compound comprising a compound selected from the group consisting of the compound represented by the general formula (I) according to claim 1, a physiologically acceptable salt thereof and a hydrate thereof as an active ingredient. The medicament according to claim 9 or 10. 12. A compound comprising a compound selected from the group consisting of the compound represented by the general formula (II) according to claim 8, a physiologically acceptable salt thereof, and a hydrate thereof as an active ingredient. The medicament according to claim 9 or 10. 13. An active ingredient comprising a substance selected from the group consisting of the compound according to claim 9 or 10, a physiologically acceptable salt thereof, and a hydrate thereof.
A drug efflux pump inhibitor for use in combination with one or more antimicrobial agents.