WO2013018372A1 - Amide derivative and drug containing same - Google Patents

Abstract

[Problem] To provide a novel amide derivative having greater safety and having superior phosphodiesterase 4 inhibition. [Solution] The novel amide derivative, which is represented by general formula (1), has strong PDE 4 inhibiting activity, and is rapidly metabolized in the body, thus having an activity that attenuates, and so it is possible to suppress systemic adverse effects from arising. From said characteristics, the compound of the present invention is particularly suited to localized administration. In formula (1), A represents a condensed aromatic heterocyclic group represented by formula (a) or formula (b).

Description

Amide derivatives and pharmaceuticals containing the same

The present invention relates to an amide derivative useful as, for example, a phosphodiesterase 4 (PDE4) inhibitor.

Phosphodiesterase 4 (PDE4) is an enzyme that degrades cyclic AMP (cAMP) and cyclic GMP (cGMP), which are second messengers in vivo. To date, 11 types of PDEs 1 to 11 have been found, and each type determines whether cAMP is specifically decomposed, cGMP is specifically decomposed, or both cAMP and cGMP are decomposed. ing. There is a difference in the distribution of each type of PDE, and it is considered that the cell reaction is controlled by various types of PDEs depending on the type of organ.

Many PDE inhibitors have been developed so far. For example, PDE3 inhibitors are therapeutic agents for angina pectoris, heart failure, hypertension, etc., platelet aggregation inhibitors or anti-asthma drugs, and PDE5 inhibitors are male. Already used clinically as a dysfunction drug.
Furthermore, recently, there was a report that minocycline was effective as a PDE10A modulator by using it for a Huntington's disease patient (Patent Document 1). It is also disclosed that PDE10 inhibitors are effective as therapeutic agents for various psychiatric disorders such as Huntington's disease, Alzheimer's disease, dementia, Parkinson's disease, and schizophrenia (Patent Document 2).
In addition, a pyrazolopyridine-carboxamide derivative has been reported as a compound having a PDE inhibitory action (Patent Document 7). Further, pyrazolopyridine derivatives (Patent Documents 3 to 6) and carboxamide derivatives (Patent Documents 8 to 32 and Non-Patent Documents 3 to 9) have been reported as compounds having a PDE inhibitory action.
PDE4 inhibitors are therapeutic agents for bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia, Parkinson's disease, etc. As expected. However, conventional PDE4 inhibitors are known to have systemic side effects such as vomiting and vasculitis, and there is a risk even when a PDE4 inhibitor is administered to the affected area in the form of an external preparation. Is known (Non-Patent Document 1).

Incidentally, anti-inflammatory steroids developed for the purpose of reducing systemic side effects have recently been reported (Non-patent Document 2). The anti-inflammatory steroid has an activity locally, and when it enters the body, it is rapidly metabolized and inactivated, or exhibits a kinetics such that the activity becomes low.

International Publication No. 01024781 Pamphlet JP 2002-363103 A WO9814448 pamphlet Japanese Patent Laid-Open No. 10-109988 JP 2006-117647 A JP 2006-109138 A International Publication No. 2008029829 International Publication No. 2006004040 Pamphlet WO2004089940 pamphlet International Publication No. 2004069831 Pamphlet WO2004048377 pamphlet International Publication No. 2004037805 Pamphlet International Publication No. 2003105902 Pamphlet International Publication No. 2003078397 Pamphlet International Publication No. 2003066044 Pamphlet International Publication No. 2002034747 Pamphlet International Publication No. 2002028353 Pamphlet International Publication No. 2000048998 Pamphlet WO9916768 pamphlet International Publication No. 9822460 Pamphlet International Publication No.9809961 Pamphlet WO9748697 pamphlet WO9744036 Pamphlet International Publication No. 9501338 Pamphlet US Patent Publication No. 2005027129 US Patent Publication No. 2004102472 US Patent Publication No. 2002128290 U.S. Pat.No. 6,127,363 JP-A-8-307982 British Patent No. 2327675 German patent 19633051 German Patent No. 10253426

CurrentOpinion in Chemical Biology (1999), 3 (4), 466-473. Chemical Review (2008), 108 (12), 5131-5145. Bioorganic & Medicinal ist Chemistry etter Letters (2002), 12 (12), 1621-1623. Bioorganic & Medicinal ist Chemistry etter Letters (2002), 12 (12), 1613-1615. Bioorganic & Medicinal Chemistry Letters (2002), 12 (3), 509-512. Bioorganic & Medicinal Chemistry Letters (2000), 10 (18), 2137-2140. Bioorganic & Medicinal Chemistry Letters (1998), 8 (14), 1867-1872. Bioorganic & Medicinal Chemistry (1999), 7 (6), 1131-1139. European Journal of Medicinal Chemistry (2003), 38, 975-982.

An object of the present invention is to provide a novel amide derivative that has an excellent phosphodiesterase 4 inhibitory action and is rapidly metabolized in vivo to enhance its safety by reducing its activity.

The inventors of the present invention have made extensive studies with the aim of creating a compound having an excellent PDE4 inhibitory action and being rapidly metabolized in vivo and having reduced activity. As a result, it was found that a novel amide derivative has a strong PDE4 inhibitory activity and is rapidly metabolized in vivo to reduce the activity, thereby completing the present invention.

That is, the first invention relates to an amide derivative represented by the general formula (1), a pharmacologically acceptable salt thereof, or a hydrate thereof.

In formula (1), A represents a condensed aromatic heterocyclic group represented by the following formula a) or formula b).
R ¹ represents a C _1-6 alkyl group or a C _7-10 aralkyl group,
R ² is _{C 1-6} alkoxy groups, one or two _{C 1-6} alkyl amino group which may be substituted with a _{group, C 1-6} alkylsulfanyl _{group, C 1-6} alkylsulfinyl group or a _{C 1-} Represents a ₆ alkylsulfonyl group,
R ³ represents a hydrogen atom or a halogen atom,
R ⁴ and R ⁵ represent a hydrogen atom or a halogen atom. R ⁴ and R ⁵ may be the same atom, or R ⁴ and R ⁵ may be different from each other.

The second invention is an amide derivative according to the first invention, wherein the compound represented by the general formula (1) is a compound represented by the following formula (1a) or a compound represented by the following formula (1b): It relates to a pharmacologically acceptable salt thereof or a hydrate thereof.

In the formulas (1a) and (1b), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described in the first invention.

Further, the third invention is an amide derivative according to the first invention, wherein the compound represented by the general formula (1) is a compound represented by the following formula (1aa) or a compound represented by the following formula (1bb): It relates to a pharmacologically acceptable salt thereof or a hydrate thereof.

In formulas (1aa) and (1bb), R ^1a represents a C _1-6 alkyl group, R ^4a and R ^5a represent a halogen atom, and R ² and R ³ are as described in the first invention.

Moreover, 4th invention is a compound represented by General formula (1) in 1st invention,
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methoxypyrazolo [1,5-a] pyridine-2-carboxylate,
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylaminopyrazolo [1,5-a] pyridine-2-carboxylate,
Ethyl 3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methoxyimidazo [1,2-a] pyridine-2-carboxylate,
Ethyl 3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methylaminoimidazo [1,2-a] pyridine-2-carboxylate,
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylthiopyrazolo [1,5-a] pyridine-2-carboxylate,
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylsulfinylpyrazolo [1,5-a] pyridine-2-carboxylate, or
The amide derivative according to the first invention, which is ethyl 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylsulfonylpyrazolo [1,5-a] pyridine-2-carboxylate, pharmacologically It relates to acceptable salts or hydrates thereof.

The fifth invention also relates to a medicament comprising the amide derivative according to any one of the first to fourth inventions, a pharmacologically acceptable salt thereof or a hydrate thereof.
The sixth invention relates to an external preparation containing the amide derivative according to any one of the first invention to the fourth invention, a pharmacologically acceptable salt thereof or a hydrate thereof.
Further, the seventh invention provides bronchial asthma and chronic obstructive lung containing the amide derivative according to any one of the first invention to the fourth invention, a pharmacologically acceptable salt thereof or a hydrate thereof. The present invention relates to a therapeutic or preventive drug for disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia or Parkinson's disease.
Further, an eighth invention provides bronchial asthma and chronic obstructive lung containing the amide derivative according to any one of the first invention to the fourth invention, a pharmacologically acceptable salt thereof or a hydrate thereof. The present invention relates to an external preparation for treatment or prevention of disease (COPD), atopic dermatitis or psoriasis.

The novel amide derivatives, addition salts and hydrates thereof according to the present invention have excellent PDE4 inhibitory activity and are rapidly metabolized in vivo to reduce the activity. Therefore, the novel amide derivatives (including addition salts and hydrates) according to the present invention are suitable for topical administration, for example. In particular, it is useful as a preventive or therapeutic agent for bronchial asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, psoriasis and the like.

Hereinafter, one embodiment of the present invention will be described in detail.
The compound according to this embodiment is an amide derivative represented by the general formula (1). Further, the compound according to this embodiment may be a pharmacologically acceptable salt of the amide derivative, or may be a hydrate of the amide derivative or a hydrate of the salt of the amide derivative. .

In formula (1), A represents a condensed aromatic heterocyclic group represented by the following formula a) or formula b).
R ¹ represents a C _1-6 alkyl group or a C _7-10 aralkyl group,
R ² is _{C 1-6} alkoxy groups, one or two _{C 1-6} alkyl amino group which may be substituted with a _{group, C 1-6} alkylsulfanyl _{group, C 1-6} alkylsulfinyl group or a _{C 1-} Represents a ₆ alkylsulfonyl group,
R ³ represents a hydrogen atom or a halogen atom,
R ⁴ and R ⁵ represent a hydrogen atom or a halogen atom. R ⁴ and R ⁵ may be the same atom, or R ⁴ and R ⁵ may be different from each other.

In the present specification, the “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the C _1-6 alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like.
The “C _7-10 aralkyl group” is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a phenyl group. Examples of the C _7-10 aralkyl group include a benzyl group, a phenethyl group, a 3-phenylpropyl group, and a 4-phenylbutyl group.
The “C _1-6 alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the C _1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. It is done.
The “amino group optionally substituted with 1 or 2 C _1-6 alkyl groups” means an amino group in which the hydrogen atom contained is unsubstituted, or 1 or 2 hydrogen atoms contained in the group is C _1-1. An amino group substituted with a ₆ alkyl group. Examples of the amino group which may be substituted with 1 or 2 C _1-6 alkyl groups include, for example, an amino group, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, and an isobutylamino group. Group, sec-butylamino group, tert-butylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, ethylmethylamino group and the like. In the present specification, the C _1-6 alkylamino group is an amino group substituted with one C _1-6 alkyl group. Examples of the C _1-6 alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, and a tert-butylamino group. It is done.
The “C _1-6 alkylsulfanyl group” is a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms. Examples of the C _1-6 alkylsulfanyl group include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanyl group, a sec-butylsulfanyl group, a tert-butylsulfanyl group, and a pentylsulfanyl group. Group, hexylsulfanyl group and the like.
The “C _1-6 alkylsulfinyl group” is a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms. Examples of the C _1-6 alkylsulfinyl group include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, an isobutylsulfinyl group, a sec-butylsulfinyl group, a tert-butylsulfinyl group, and a pentylsulfinyl group. Group, hexylsulfinyl group and the like.
The “C _1-6 alkylsulfonyl group” is a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. Examples of the C _1-6 alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, and a pentylsulfonyl group. Group, hexylsulfonyl group and the like.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

Examples of the pharmacologically acceptable salt of the compound according to this embodiment include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, citrate, and tartrate. There may be mentioned acid addition salts.

In the compound represented by the general formula (1),
R ¹ is preferably a C _1-6 alkyl group, and more preferably an ethyl group.
R ² is preferably a C _1-6 alkoxy group, a C _1-6 alkylamino group, a C _1-6 alkylsulfanyl group, a C _1-6 alkylsulfinyl group or a C _1-6 alkylsulfonyl group, and a C _1-6 alkoxy group Group or a C _1-6 alkylamino group is more preferable, and a methoxy group or a methylamino group is particularly preferable.
R ⁴ is preferably a halogen atom, particularly preferably a chlorine atom.
R ⁵ is preferably a halogen atom, particularly preferably a chlorine atom.

Examples of the compound represented by the general formula (1) include a compound represented by the following formula (1a) or a compound represented by the following formula (1b).

In formulas (1a) and (1b), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.
In the compound represented by the general formula (1a), R ³ is preferably a hydrogen atom. In the compound represented by the general formula (1b), R ³ is preferably a halogen atom, and more preferably a chlorine atom.

In addition, examples of the compound represented by the general formula (1) include a compound represented by the following formula (1aa) or a compound represented by the following formula (1bb).

In formulas (1aa) and (1bb), R ^1a represents a C _1-6 alkyl group, R ^4a and R ^5a represent a halogen atom, and R ² and R ³ have the same meanings as described above. In the compound represented by the general formula (1aa), R ³ is preferably a hydrogen atom. In the compound represented by the general formula (1bb), R ³ is preferably a halogen atom, and more preferably a chlorine atom.

The compound represented by the general formula (1) according to this embodiment can be produced by various synthesis methods. Next, a typical production method of the compound represented by the general formula (1) according to this embodiment will be described.

Among the compounds represented by the general formula (1aa), a compound in which R ³ is a hydrogen atom, that is, a compound represented by the general formula (1c) can be produced, for example, by the synthesis route A shown below.

In formula (1c), R ^1a , R ² , R ^4a and R ^5a are as defined above.

<Synthesis route A>

In general formula (2a), R ² has the same meaning as described above.
In the structural formula representing a compound contained in a mixture represented as (3a) (hereinafter abbreviated as mixture (3a)), R ² has the same meaning as described above.
In the general formula (4a), R ⁶ represents a C _1-6 alkyl group or a benzyl group, and Pro represents a paramethoxybenzyl group, a tetrahydropyranyl group, a methoxymethyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group. Represents an alcohol protecting group such as a group and a triisopropylsilyl group, and R ² has the same meaning as described above.
In the general formula (5a), R ² and Pro are as defined above.
In the general formula (6a), R ² and Pro have the same meanings as described above.
In the general formula (7a), R ² and Pro have the same meanings as described above.
In the general formula (8a), R ² and Pro are as defined above.
In the general formula (9a), R ² , R ^4a , R ^5a and Pro are as defined above.
In general formula (10a), R ² , R ^4a and R ^5a have the same ^meanings as described above.
In general formula (11a), R ² , R ^4a and R ^5a have the same ^meanings as described above.
In general formula (12a), R ² , R ^4a and R ^5a have the same ^meanings as described above.

The mixture (3a) in the synthesis route A can be produced by reacting the compound represented by the general formula (2a) with O-mesitylenesulfonylhydroxylamine (MSH) (step A-1).

In a preferred reaction example, first, a compound represented by the general formula (2a) is dissolved in dichloromethane to prepare a dichloromethane solution of the compound represented by the general formula (2a). Next, MSH acts on the compound represented by the general formula (2a) by mixing the obtained dichloromethane solution of the compound represented by the general formula (2a) with a dichloromethane solution of MSH at 0 ° C. to room temperature. Let
In this specification, normal temperature means 15 to 25 ° C. as defined in the Japanese Pharmacopoeia.

In the synthetic route A, the compound represented by the general formula (4a) can be produced by reacting the mixture (3a) and the compound represented by the general formula (13) in the presence of a base (step A- 2).

In the formula (13), R ⁶ and Pro have the same meaning as described above.
Specifically, for example, the mixture (3a) is reacted with the compound represented by the general formula (13) in a solvent in the presence of a base. Examples of the solvent include methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), toluene, benzene, cyclohexane, Cyclopentane, dichloromethane, chloroform, acetonitrile and the like can be used. As the base, for example, an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, or an organic base such as triethylamine can be used. The reaction temperature can be, for example, 0 ° C. to room temperature.

In the synthesis route A, the compound represented by the general formula (5a) can be produced by hydrolyzing the compound represented by the general formula (4a) (step A-3).
Specifically, an aqueous solution of a base is added to a solution of the compound represented by the general formula (4a), and the base is allowed to act on the compound represented by the general formula (4a) at a temperature from room temperature to heating reflux. Examples of the solvent for preparing the solution of the compound represented by the general formula (4a) include methanol, ethanol, THF, CPME, DMSO, DMF, 1,4-dioxane and the like. Examples of the aqueous solution of the base to be added include an aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution, and an aqueous lithium hydroxide solution, preferably an aqueous sodium hydroxide solution.

In the synthesis route A, the compound represented by the general formula (6a) can be produced by decarboxylating the compound represented by the general formula (5a) (step A-4).
Specifically, first, a solution of the compound represented by the general formula (5a) is prepared using an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, and xylene. Next, the prepared compound solution represented by the general formula (5a) is heated to 100 ° C. to 160 ° C. to decarboxylate the compound represented by the general formula (5a).

In the synthesis route A, the compound represented by the general formula (7a) can be produced by oxidizing the compound represented by the general formula (6a) (step A-5).
This reaction can be performed using a technique generally used for converting alcohols to aldehydes or ketones by oxidation. For example, oxidation using chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, oxidation using metal oxidants such as chromium oxide and manganese dioxide, sulfur trioxide-pyridine complex, oxalyl chloride, anhydrous tri Mention may be made of oxidation using a hypervalent iodine oxidant such as DMSO oxidation or Dess-Martin oxidation using a DMSO activator such as fluoroacetic acid, acetic anhydride, N, N-dicyclohexylcarbodiimide (DCC). The reaction temperature can be, for example, −78 ° C. to 100 ° C.
In addition, a compound represented by the general formula (6a) using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) or 1-methylazaadamantane N-oxyl (1-Me-AZADO) By oxidation, the compound represented by the general formula (7a) can also be obtained. In this case, sodium hypochlorite or bisacetoxyiodobenzene that acts as a reoxidant may be used as necessary. The reaction temperature can be, for example, 0 ° C. to room temperature.

In the synthesis route A, the compound represented by the general formula (8a) can be produced by oxidizing the compound represented by the general formula (7a) (step A-6).
The reaction can be carried out using sodium chlorite in the presence of 2-methyl-2-butene and sodium dihydrogen phosphate in a mixed solvent of t-butanol, THF or DMSO and water.

In the synthesis route A, the compound represented by the general formula (9a) can be produced by reacting the compound represented by the general formula (8a) with the compound represented by the general formula (14) (process) A-7).

In formula (14), R ^4a and R ^5a have the same ^meanings as described above.
This reaction can be performed based on a synthesis reaction of amides by a condensation reaction of carboxylic acids and amines that are generally used.
For example, the compound represented by the general formula (8a) is converted to acid chloride using thionyl chloride, oxalyl chloride or the like. Alternatively, the compound represented by the general formula (8a) is converted into a mixed acid anhydride using ethyl chloroformate, isopropyl chloroformate, pivaloyl chloride, or the like. Next, the resulting acid chloride or mixed acid anhydride of the compound represented by the general formula (8a) is treated with a base such as sodium hydride or n-butyl lithium. Reaction with the resulting compound.
As another method, first, the compound represented by the general formula (8a) is converted to a so-called active ester such as 4-nitrophenyl ester or 1-hydroxybenzotriazole ester, and then represented by the general formula (14). The compound obtained by treating the resulting compound with a base such as sodium hydride or n-butyllithium is reacted with the resulting active ester.
Further, as another method, a mixture of the compound represented by the general formula (8a) and the compound represented by the general formula (14) is added to N, N-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl). The reaction can also be carried out by the action of a dehydration condensing agent such as —N′-ethylcarbodiimide (EDC). The reaction temperature can be, for example, 0 ° C. to 100 ° C.

In the synthesis route A, the compound represented by the general formula (10a) can be produced by deprotecting the compound represented by the general formula (9a) (step A-8).
The reaction can be performed, for example, as follows when the protecting group represented as Pro is a paramethoxybenzyl group. For example, the deprotection is carried out by treating the compound represented by the general formula (9a) with an acid such as trifluoroacetic acid, preferably in the presence of anisole in a solvent such as dichloromethane or chloroform at 0 ° C. to room temperature. As another example, an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ceric ammonium nitrate (CAN) is used, and a solvent such as dichloromethane is used in the presence of water. The deprotection is carried out by treating the compound represented by the general formula (9a) at 0 ° C. to room temperature.
When the protecting group represented by Pro is a methoxymethyl group or a tetrahydropyranyl group, for example, methanol, ethanol, ethyl acetate or diethyl ether containing trifluoroacetic acid or hydrogen chloride is used at a general formula (0 Deprotection is carried out by treating the compound represented by 9a).
When the protecting group represented by Pro is a silyl group such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group, for example, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, fluorine Deprotection is carried out by treating the compound represented by the general formula (9a) with hydrofluoric acid in a solvent such as acetonitrile or THF at 0 ° C. to room temperature.

In the synthesis route A, the compound represented by the general formula (11a) can be produced by oxidizing the compound represented by the general formula (10a) (step A-9).
This reaction can be carried out by the same method as in Step A-5.

The compound represented by the general formula (12a) in the synthesis route A can be produced by oxidizing the compound represented by the general formula (11a) (step A-10).
This reaction can be carried out by the same method as in Step A-6.

In the synthesis route A, the compound represented by the general formula (1c) is produced by reacting the compound represented by the general formula (12a) with the compound represented by the general formula (15) in the presence of a base. (Step A-11).

In formula (15), X represents a chlorine atom, a bromine atom or an iodine atom, and R ^1a has the same ^meaning as described above.
Specifically, in the presence of an inorganic base such as potassium carbonate or sodium carbonate or an organic base such as triethylamine or diisopropylethylamine in a solvent such as DMF or THF, it is represented by the general formula (12a) at a temperature of 0 ° C. to heating under reflux. And the compound represented by the general formula (15) are reacted.
In addition, when R ^{1a of the} compound represented by the general formula (1c) is a methyl group, the compound represented by the general formula (12a) may be reacted with diazomethane or trimethylsilyldiazomethane in the general formula (1c). The compounds represented can be produced.
When diazomethane is used, for example, the compound represented by the general formula (12a) is reacted with diazomethane in a solvent such as diethyl ether at 0 ° C. to room temperature. When trimethylsilyldiazomethane is used, for example, it is carried out by reacting the compound represented by the general formula (12a) with trimethylsilyldiazomethane in the presence of methanol in a solvent such as diethyl ether, toluene, benzene or chloroform at 0 ° C. to room temperature. be able to.

The compound represented by the general formula (11a) in the synthesis route A can also be produced by the following synthesis route B.

<Synthetic route B>

In the mixture of compounds represented as (3b) (hereinafter abbreviated as mixture (3b)), R ² has the same meaning as described above. The mixture (3b) is the same as the mixture (3a) and can be prepared by the same method as the mixture (3a).
In general formula (4b), R ² , R ⁶ and R ⁷ are as defined above.
In general formula (5b), R ⁷ represents a C _1-6 alkyl group, and R ² has the same meaning as described above.
In the general formula (6b), R ² and R ⁷ are as defined above.
In general formula (7b), R ² and R ⁷ are as defined above.
In the general formula (8b), R ² and R ⁷ are as defined above.
In the general formula (9b), R ² , R ^4a , R ^5a and R ⁷ are as defined above.

In the synthesis route B, the compound represented by the general formula (4b) can be produced by reacting the mixture (3b) and the compound represented by the general formula (16) in the presence of a base (Step B- 1).

In formula (4b), R ² , R ⁶ and R ⁷ are as defined above.

In formula (16), R ⁶ and R ⁷ are as defined above.
This reaction can be carried out by the same method as in step A-2.
The compound is produced by a process B-1 of the formula the two R ⁷ being represented in (4b) is formed by connecting, C _1-6 alkyl optionally substituted by a group C _{2 It} may be a compound having a _-4 methylene chain.

In the synthesis route B, the compound represented by the general formula (5b) can be produced by hydrolyzing the compound represented by the general formula (4b) (step B-2).
This reaction can be carried out by the same method as in step A-3.

In the synthesis route B, the compound represented by the general formula (6b) can be produced by decarboxylating the compound represented by the general formula (5b) (step B-3). This reaction can be carried out by the same method as in Step A-4.

In the synthesis route B, the compound represented by the general formula (7b) can be produced by oxidizing the compound represented by the general formula (6b) (step B-4).
This reaction can be carried out by the same method as in Step A-5.

In the synthesis route B, the compound represented by the general formula (8b) can be produced by oxidizing the compound represented by the general formula (7b) (step B-5).
This reaction can be carried out by the same method as in Step A-6.

In the synthesis route B, the compound represented by the general formula (9b) can be produced by reacting the compound represented by the general formula (8b) with the compound represented by the general formula (14) (process) B-6). This reaction can be carried out by the same method as in Step A-7.

In the synthesis route B, the compound represented by the general formula (11a) can be produced by deprotecting the compound represented by the general formula (9b) (step B-7).
In the reaction, an acid catalyst such as paratoluenesulfonic acid monohydrate or pyridinium paratoluenesulfonate (PPTS) is used in acetone, and the compound represented by the general formula (9b) is treated at a temperature ranging from room temperature to heating reflux. Can be done. The reaction can also be carried out by treating the compound represented by the general formula (9b) with methanol, ethanol, ethyl acetate or diethyl ether containing hydrogen chloride at 0 ° C. to room temperature.

Among the compounds represented by the general formula (7b) in the synthesis route B, R ² is an amino group optionally substituted with a C _1-6 alkoxy group, 1 or 2 C _1-6 alkyl groups, or C 2 _A compound having a _1-6 alkylsulfanyl group, that is, a compound represented by the general formula (7c) can also be produced by the synthesis route C shown below.

Wherein ^{(7c), R 2a} is _{C 1-6} alkoxy groups, one or two _{C 1-6} alkyl amino group which may be substituted with a _group, represents a _{C 1-6} alkylsulfanyl group, ^{R 7} is Same meaning as above.

<Synthetic route C>

In general formula (4c), R ⁶ and R ⁷ are as defined above.
In general formula (5c), R ⁷ has the same meaning as described above.
In general formula (6c), R ⁷ has the same meaning as described above.
In the general formula (17), Pro ′ represents an alcohol protecting group such as a paramethoxybenzyl group, a tetrahydropyranyl group, a methoxymethyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triisopropylsilyl group, R ⁷ has the same meaning as described above.
In the general formula (18), Xa represents a halogen atom, and R ⁷ and Pro ′ are as defined above.
In the general formula (19), Xa and R ⁷ are as defined above.
In the general formula (20), Xa and R ⁷ are as defined above.

A mixture of compounds represented as (3c) in the synthetic pathway C (hereinafter abbreviated as mixture (3c)) is obtained by reacting the compound represented by formula (2c) with O-mesitylenesulfonylhydroxylamine (MSH). It can be manufactured (Step C-1).
This reaction can be carried out by the same method as in step A-1.

In the synthesis route C, the compound represented by the general formula (4c) can be produced by reacting the mixture (3c) and the compound represented by the general formula (16) in the presence of a base (Step C- 2).
This reaction can be carried out by the same method as in step A-2.

In the synthesis route C, the compound represented by the general formula (5c) can be produced by hydrolyzing the compound represented by the general formula (4c) (step C-3). The reaction can be carried out by the same method as in step A-3.

In the synthesis route C, the compound represented by the general formula (6c) can be produced by decarboxylation of the compound represented by the general formula (5c) (step C-4).
This reaction can be carried out by the same method as in Step A-4.

In the synthesis route C, the compound represented by the general formula (17) can be produced by subjecting the compound represented by the general formula (6c) to various alcohol protection reactions (step C-5).

In formula (17), Pro ′ and R ⁷ are as defined above.

Specifically, for example, when Pro ′ is a paramethoxybenzyl group, paramethoxybenzyl chloride or paramethoxybenzyl bromide is represented by the general formula (6c) at 0 ° C. to room temperature in the presence of a base in a solvent. It acts on the compound. As the base, for example, sodium hydride, potassium hydride, lithium hydride and the like can be used. As the solvent, for example, DMF, THF, diethyl ether and the like can be used.
For example, when Pro ′ is a tetrahydropyranyl group, dihydropyran is a compound represented by the general formula (6c) in the presence of an acid catalyst such as p-toluenesulfonic acid in a solvent such as dichloromethane at 0 ° C. to room temperature. It is preferable to act on.
For example, when Pro ′ is a methoxymethyl group, chloromethyl methyl ether or bromomethyl methyl ether is allowed to act on the compound represented by the general formula (6c) at 0 ° C. to room temperature in the presence of a base in a solvent. . As the base, for example, sodium hydride, diisopropylethylamine, triethylamine and the like can be used. As the solvent, for example, DMF, THF, diethyl ether, dichloromethane or the like can be used.
Further, for example, when Pro ′ is a silyl protecting group such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group, etc., an alkyl corresponding to the protecting group to be introduced in a solvent in the presence of a base Silyl chloride, alkylsilyl bromide, or alkylsilyl trifluoromethanesulfonate is allowed to act on the compound represented by the general formula (6c) at 0 ° C. to room temperature. As the base, imidazole, triethylamine or the like can be used. As the solvent, DMF, THF, diethyl ether, dichloromethane, or the like can be used.

In the synthetic pathway C, the compound represented by the general formula (18) can be produced by halogenating the compound represented by the general formula (17) (step C-6).

In the formula (18), Xa, R ⁷ and Pro ′ are as defined above.

Specifically, the compound represented by the general formula (17) is first treated with a base in a solvent such as THF or CPME at −78 ° C. to 0 ° C. As the base, butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazane (LHMDS), sodium hexamethyldisilazane (NaHMDS), or the like can be used. Next, a halogenating agent is allowed to act on the compound represented by the general formula (17) treated with a base at −78 ° C. to room temperature. Halogenating agents include N-fluorobenzenesulfonimide, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 1,2-dibromoethane, bromine, N-iodosuccinimide (NIS), iodine, 1,2 -Diiodoethane or the like can be used.

In the synthesis route C, the compound represented by the general formula (19) can be produced by deprotecting the compound represented by the general formula (18) (step C-7).
This reaction can be carried out by the same method as in Step A-8.

In the synthesis route C, the compound represented by the general formula (20) can be produced by oxidizing the compound represented by the general formula (19) (step C-8). This reaction can be carried out by the same method as in Step A-5.

In the synthesis route C, the compound represented by the general formula (7c) can be produced by alkoxylation, amination, or sulfanylation of the compound represented by the general formula (20) (step C-9). .
When R ^2a is a C _1-6 alkoxy group, that is, when alkoxylation is performed, the reaction can be performed, for example, as follows. Specifically, a sodium salt, a potassium salt, or a lithium salt of an alcohol (compound represented by R ^2a —H) corresponding to the introduced C _1-6 alkoxy group is represented by the general formula in a solvent at room temperature to 80 ° C. It is made to act on the compound represented by (20). As the solvent, an alcohol corresponding to the C _1-6 alkoxy group, DMF, DMSO, THF and the like can be used, and an alcohol corresponding to the C _1-6 alkoxy group is preferable.
When R ^2a is an amino group which may be substituted with 1 or 2 C _1-6 alkyl groups, that is, when amination is performed, the reaction can be performed, for example, as follows. Specifically, an amine (compound represented by R ^2a -H) corresponding to an amino group which may be substituted with 1 or 2 C _1-6 alkyl groups to be introduced is allowed to react at room temperature in a solvent. The compound represented by the general formula (20) is allowed to act at 80 ° C. As the solvent, DMF, DMSO, THF, or the like can be used.
When R ^2a is a C _1-6 alkylsulfanyl group, that is, when sulfanylation is performed, the reaction can be performed, for example, as follows. Specifically, sodium salt, potassium salt and lithium salt of thiol (compound represented by R ^2a -H) corresponding to the introduced C _1-6 alkylsulfanyl group are generally used in a solvent at ordinary temperature to 80 ° C. It is made to act on the compound represented by Formula (20). As the solvent, DMF, DMSO, THF, or the like can be used.

Among the compounds represented by the general formula (7a) in the synthetic pathway A, R ² is an amino group optionally substituted with a C _1-6 alkoxy group, 1 or 2 C _1-6 alkyl groups, or C 2 _A compound having a _1-6 alkylsulfanyl group, that is, a compound represented by the general formula (7d) can also be produced by the synthesis route D shown below.

In the formula (7d), R ^2a and Pro are as defined above.

<Synthesis route D>

In general formula (4d), R ⁶ and Pro are as defined above.
In general formula (5d), Pro has the same meaning as described above.
In general formula (6d), Pro has the same meaning as described above.
In general formula (17d), Pro and Pro ′ are as defined above.
In general formula (18d), Xa, Pro, and Pro ′ are as defined above.
In general formula (19d), Xa and Pro are as defined above.
In the general formula (20d), Xa and Pro are as defined above.

In the synthesis route D, the compound represented by the general formula (4d) can be produced by reacting the mixture (3c) and the compound represented by the general formula (13) in the presence of a base (step D-1). ).
This reaction can be carried out by the same method as in step A-2.

In the synthesis route D, the compound represented by the general formula (5d) can be produced by hydrolyzing the compound represented by the general formula (4d) (step D-2).
This reaction can be carried out by the same method as in step A-3.

In the synthesis route D, the compound represented by the general formula (6d) can be produced by decarboxylating the compound represented by the general formula (5d) (Step D-3).
This reaction can be carried out by the same method as in Step A-4.

In the synthesis route D, the compound represented by the general formula (17d) can be produced by subjecting the compound represented by the general formula (6d) to various alcohol protection reactions (step D-4).
This reaction can be carried out by the same method as in Step C-5.

In the synthesis route D, the compound represented by the general formula (18d) can be produced by halogenating the compound represented by the general formula (17d) (step D-5).
This reaction can be carried out by the same method as in Step C-6.

In the synthesis route D, the compound represented by the general formula (19d) can be produced by deprotecting the compound represented by the general formula (18d) (step D-6).
This reaction can be carried out by the same method as in Step C-7.

In the synthesis route D, the compound represented by the general formula (20d) can be produced by oxidizing the compound represented by the general formula (19d) (step D-7).
This reaction can be carried out by the same method as in Step A-5.

In the synthesis route D, the compound represented by the general formula (7d) can be produced by alkoxylation, amination, or sulfanylation of the compound represented by the general formula (20d) (step D-8). .
This reaction can be carried out by the same method as in Step C-9.

Among the compounds represented by the general formula (1bb), a compound in which R ³ is a chlorine atom, that is, a compound represented by the general formula (1e) can be produced by the synthesis route E shown below.

In formula (1e), R ^1a , R ² , R ^4a and R ^5a have the same ^meaning as described above.

<Synthesis route E>

In general formula (21), R ² has the same meaning as described above.
In general formula (22), R ² and R ⁶ have the same meanings as described above.
In general formula (23), R ² and R ⁶ are as defined above.
In general formula (24), R ² and R ⁶ have the same meanings as described above.
In general formula (25), R ² has the same meaning as described above.
In General Formula (26), R ² and Pro have the same meanings as described above.
In general formula (27), R ² and Pro have the same meanings as described above.
In the general formula (28), R ² , R ^4a , R ^5a and Pro are as defined above.
In general formula (29), R ² , R ^4a and R ^5a have the same ^meanings as described above.
In general formula (30), R ² , R ^4a and R ^5a have the same ^meanings as described above.
In the general formula (31), R ² , R ^4a and R ^5a are as defined above.

In the synthesis route E, the compound represented by the general formula (22) can be produced by reacting the compound represented by the general formula (21) with the compound represented by the general formula (32) (process) E-1).

In formula (32), R ⁶ and X are as defined above.
Specifically, the compound represented by the general formula (21) is reacted with the compound represented by the general formula (32) at a temperature ranging from room temperature to heating reflux using methanol, ethanol, isopropanol or the like as a solvent.

In the synthesis route E, the compound represented by the general formula (23) can be produced by chlorinating the compound represented by the general formula (22) (step E-2).
Specifically, a chlorinating agent such as NCS is allowed to act on the compound represented by the general formula (22) at room temperature to 100 ° C. in a solvent such as DMF or acetonitrile.

In the synthesis route E, the compound represented by the general formula (24) can be produced by brominating the compound represented by the general formula (23) (step E-3).
Specifically, a brominating agent such as NBS is allowed to act on the compound represented by the general formula (23) at room temperature to 100 ° C. in a solvent such as DMF or acetonitrile.

In the synthesis route E, the compound represented by the general formula (25) can be produced by reducing the compound represented by the general formula (24) (step E-4).
Specifically, a metal hydride such as diisobutylaluminum hydride, lithium borohydride, lithium aluminum hydride or the like is used in a solvent to reduce the compound represented by the general formula (24) at −78 ° C. to room temperature. As the solvent, THF, diethyl ether, 1,4-dioxane and the like can be used.
Further, the compound represented by the general formula (25) can also be produced by reducing the mixed acid anhydride obtained after derivatizing the compound represented by the general formula (24) into the mixed acid anhydride. . Specifically, first, a solution of the compound represented by the general formula (24) is prepared using a solvent such as methanol, ethanol, THF, CPME, DMSO, DMF, and 1,4-dioxane. Next, an aqueous solution of a base such as an aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution, or an aqueous lithium hydroxide solution is added to the resulting solution of the compound represented by the general formula (24), and the solution is generally treated at a temperature of 0 ° C to heating reflux. A base is allowed to act on the compound represented by the formula (24) to obtain a carboxylic acid form. Subsequently, in the presence of a base such as triethylamine, diisopropylethylamine, or N-methylmorpholine in a solvent such as THF or dichloromethane, the resulting carboxylic acid compound is mixed with ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, etc. at 0 ° C to Let it react at room temperature to make a mixed acid anhydride. Then, the obtained solution containing the mixed acid anhydride is added to an aqueous sodium borohydride solution, and sodium borohydride is allowed to act on the mixed acid anhydride obtained at 0 ° C. to room temperature.

In the synthetic route E, the compound represented by the general formula (26) can be produced by introducing a protecting group into the compound represented by the general formula (25) (step E-5).
This reaction can be carried out by the same method as in Step C-5.
It can also be produced by subjecting the compound represented by the general formula (22) to the reaction in the order of reduction, introduction of a protecting group, chlorination, and bromination (step E-13).
Among the reactions, the reduction can be performed by the same method as in Step E-4. The introduction of the protecting group can be performed by the same method as in Step E-5. Chlorination can be performed by the same method as in Step E-2. Bromination can be performed by the same method as in Step E-3.

In the synthesis route E, the compound represented by the general formula (27) can be produced by carboxylating the compound represented by the general formula (26) (step E-6).
Specifically, first, n-butyllithium, sec-butyllithium, tert-butyllithium or the like is used in a solvent such as THF or diethyl ether, and is represented by the general formula (26) at −78 ° C. to 0 ° C. A halogen-lithium exchange reaction is performed on the compound. Next, carbon dioxide gas is allowed to act on the obtained compound at −78 ° C. to room temperature.

In the synthesis route E, the compound represented by the general formula (28) can be produced by reacting the compound represented by the general formula (27) with the compound represented by the general formula (14) (step E). -7).
This reaction can be carried out by the same method as in Step A-7.

In the synthesis route E, the compound represented by the general formula (29) can be produced by deprotecting the compound represented by the general formula (28) (step E-8).
This reaction can be carried out by the same method as in Step A-8.

In the synthesis route E, the compound represented by the general formula (30) can be produced by oxidizing the compound represented by the general formula (29) (step E-9).
This reaction can be carried out by the same method as in Step A-5.

In the synthesis route E, the compound represented by the general formula (31) can be produced by oxidizing the compound represented by the general formula (30) (step E-10).
This reaction can be carried out by the same method as in Step A-6.

In the synthesis route E, the compound represented by the general formula (1e) can be produced by reacting the compound represented by the general formula (31) with the compound represented by the general formula (15) in the presence of a base. Yes (step E-11).
This reaction can be carried out by the same method as in Step A-11.

Of the compounds represented by the general formula (1bb), a compound in which R ² is an amino group substituted with one C _1-6 alkyl group and R ³ is a chlorine atom, that is, a compound represented by the general formula (1f) The compound to be produced can also be produced by the synthesis route F shown below.

In formula (1f), R ⁸ represents a C _1-6 alkyl group, and R ^1a , R ^4a and R ^5a have the same meanings as described above.

<Synthesis route F>

In general formula (33), R ⁶ has the same meaning as described above.
In the general formula (34), ^{R 9} represents t- butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz) group, a methoxycarbonyl group, a protecting group of a general amino group such as an ethoxycarbonyl group, ^{R 6} is Same meaning as above.
In general formula (35), R ⁶ , R ⁸ and R ⁹ are as defined above.
In general formula (23f), R ⁶ , R ⁸ and R ⁹ are as defined above.
In general formula (24f), R ⁶ , R ⁸ and R ⁹ have the same meanings as described above.
In general formula (25f), R ⁸ and R ⁹ are as defined above.
In the general formula (26f), R ⁸ , R ⁹ and Pro are as defined above.
In general formula (27f), R ⁸ , R ⁹ and Pro have the same meanings as described above.
In the general formula (28f), R ^4a , R ^5a , R ⁸ , R ⁹ and Pro have the same meanings as described above.
In general formula (29f), R ^4a , R ^5a and R ⁸ have the same meanings as described above.
In general formula (30f), R ^4a , R ^5a, and R ⁸ are as defined above.
In general formula (31f), R ^4a , R ^5a and R ⁸ have the same meanings as described above.

In the synthesis route F, the compound represented by the general formula (33) can be produced by reacting the compound represented by the general formula (21f) with the compound represented by the general formula (32) (process) F-1).
This reaction can be carried out by the same method as in Step E-1.

In the synthesis route F, the compound represented by the general formula (34) can be produced by introducing a protecting group for the compound represented by the general formula (33) (step F-2).

In formula (34), R ⁶ and R ⁹ are as defined above.
For example, when R ⁹ is a Boc group, di-t-butyl dicarbonate is allowed to act on the compound represented by the general formula (33) at a temperature of 0 ° C. to heating under reflux in a solvent such as dichloromethane, acetonitrile, or THF. . A base such as triethylamine, diisopropylamine or diisopropylethylamine may be used as necessary. Furthermore, 4-dimethylaminopyridine (DMAP) may be used as necessary.
Further, LHMDS or NaHMDS is added as a base to a mixture of the compound represented by the general formula (33) and di-t-butyl dicarbonate in a solvent such as THF and diethyl ether, and the general formula (33 The compound represented by the general formula (34) can also be produced by reacting the compound represented by) with di-t-butyl dicarbonate.
When R ⁹ is a Cbz group, for example, in a solvent such as 1,4-dioxane to which an aqueous sodium hydroxide solution or an aqueous sodium carbonate solution is added, benzyloxycarbonyl chloride is represented by the general formula (33) at 0 ° C. to room temperature. By reacting with the compound to be produced, the compound represented by the general formula (34) can be produced.
When R ⁹ is a methoxycarbonyl group or an ethoxycarbonyl group, methoxycarbonyl chloride or ethoxycarbonyl chloride and a compound represented by the general formula (33) at a temperature of 0 ° C. to heating under reflux in a solvent containing a base such as THF, dichloromethane, and acetone. The compound represented by General formula (34) can be manufactured by making the compound represented by these react. As the base, for example, an inorganic base such as potassium carbonate, or an organic base such as triethylamine, diisopropylethylamine, or pyridine can be used.

In the synthetic pathway F, the compound represented by the general formula (35) can be produced by reacting the compound represented by the general formula (34) with the compound represented by the general formula (36) (process) F-3).

In the formula (36), R ⁸ and X are as defined above.
Specifically, a compound represented by the general formula (34) in a solvent such as DMF, THF, or diethyl ether in the presence of a base such as sodium hydride, lithium hydride, or potassium hydride at 0 ° C. to room temperature. And a compound represented by the general formula (36) are reacted.

In the synthesis route F, the compound represented by the general formula (23f) can be produced by chlorinating the compound represented by the general formula (35) (step F-4).
This reaction can be carried out by the same method as in Step E-2.

In the synthesis route F, the compound represented by the general formula (24f) can be produced by brominating the compound represented by the general formula (23f) (step F-5).
This reaction can be carried out by the same method as in Step E-3.

The compound represented by the general formula (25f) in the synthesis route F can be produced by reducing the compound represented by the general formula (24f) (step F-6).
This reaction can be carried out by the same method as in Step E-4.

In the synthesis route F, the compound represented by the general formula (26f) can be produced by introducing a protecting group into the compound represented by the general formula (25f) (step F-7).
This reaction can be carried out by the same method as in Step C-5.
In addition, the compound represented by the general formula (26f) can also be produced by subjecting the compound represented by the general formula (35) to the reaction in the order of reduction, introduction of a protecting group, chlorination, and bromination. (Step F-15).
Among the reactions, the reduction can be performed by the same method as in Step E-4. The introduction of the protecting group can be performed by the same method as in Step E-5. Chlorination can be performed by the same method as in Step E-2. Bromination can be performed by the same method as in Step E-3.

In the synthetic pathway F, the compound represented by the general formula (27f) can be produced by carboxylating the compound represented by the general formula (26f) (Step F-8).
This reaction can be carried out by the same method as in Step E-6.

In the synthesis route F, the compound represented by the general formula (28f) can be produced by reacting the compound represented by the general formula (27f) with the compound represented by the general formula (14) (Step F). -9).
This reaction can be carried out by the same method as in Step A-7.

The compound represented by the general formula (29f) in the synthesis route F can be produced by deprotecting the compound represented by the general formula (28f) (step F-10).
Removal of R ^9, when R ⁹ is a Boc group, methanol containing trifluoroacetic acid or hydrogen chloride, ethanol, with ethyl acetate or diethyl ether, compounds represented by the general formula (28f) at 0 ° C. ~ room temperature This can be done by processing.
When R ⁹ is a Cbz group, palladium-activated carbon, palladium hydroxide-activated carbon, etc. are used as a catalyst in a solvent such as ethanol, methanol, THF, ethyl acetate, etc. under hydrogen atmosphere (normal to medium pressure) By treating the compound represented by the formula (28f), R ⁹ can be removed.
When R ⁹ is a methoxycarbonyl group or an ethoxycarbonyl group, R ⁹ can be removed by treating the compound represented by the general formula (28f) with hydrobromic acid-acetic acid or trimethylsilyl iodide. it can. When R ⁹ is a methoxycarbonyl group or an ethoxycarbonyl group, R ⁹ can also be removed by applying alkaline hydrolysis conditions to the compound represented by the general formula (28f).
Pro can be removed by the same method as in Step A-8. Pro and R ⁹ can be removed stepwise and in some cases simultaneously.

In the synthesis route F, the compound represented by the general formula (30f) can be produced by oxidizing the compound represented by the general formula (29f) (Step F-11).
This reaction can be carried out by the same method as in Step A-5.

In the synthetic pathway F, the compound represented by the general formula (31f) can be produced by oxidizing the compound represented by the general formula (30f) (step F-12).
This reaction can be carried out by the same method as in Step A-6.

In the synthesis route F, the compound represented by the general formula (1f) can be produced by reacting the compound represented by the general formula (31f) with the compound represented by the general formula (15) in the presence of a base. Yes (step F-13).
This reaction can be carried out by the same method as in Step A-11.

Of the compounds represented by the general formula (1aa), a compound in which R ² is a C _1-6 alkylsulfinyl group or a C _1-6 alkylsulfonyl group and R ³ is a hydrogen atom, that is, a compound represented by the general formula (1g) Can also be produced by the synthetic route G shown below.

In the formula (1g), l represents 1 or 2, and R ^1a , R ^4a , R ^5a and R ⁸ have the same meanings as described above.

<Synthetic route G>

In the synthesis route G, the compound represented by the general formula (1g) can be produced by oxidizing the compound represented by the general formula (1g ′) (step G-1). In general formula (1g ′), R ^1a , R ^4a , R ^5a and R ⁸ have the same meanings as described above.
Specifically, a compound represented by the general formula (1g ′) at a temperature of 0 ° C. to heating under reflux using peracetic acid, pertrifluoroacetic acid, hydrogen peroxide metachloroperbenzoic acid in a solvent such as dichloromethane or chloroform. Oxidize.
In addition, the compound represented by the general formula (1g) can be produced by oxidizing the compound represented by the general formula (1g ′) at 0 ° C. to room temperature using oxone in a THF-water mixed solvent. .
In addition, the compound represented by general formula (1g ') can be manufactured by the synthetic pathway A.

Among the compounds represented by the general formula (1bb), a compound in which R ² is a C _1-6 alkylsulfinyl group or a C _1-6 alkylsulfonyl group and R ³ is a chlorine atom, that is, a compound represented by the general formula (1h) The compound can also be produced by the synthetic route H shown below.

In formula (1h), R ^1a , R ^4a , R ^5a , R ⁸ and l are as defined above.

<Synthetic route H>

In the reaction path H, the compound represented by the general formula (1h) can be produced by oxidizing the compound represented by the general formula (1h ′) (step H-1). In general formula (1h ′), R ^1a , R ^4a , R ^5a and R ⁸ have the same meanings as described above.
This reaction can be carried out by the same method as in Step G-1.
In addition, the compound represented by general formula (1h ') can be manufactured by the synthetic pathway E.

Of the compounds represented by the general formula (1aa), R ² is an amino group optionally substituted with 1 or 2 C _1-6 alkyl groups, and R ³ is a hydrogen atom, that is, the compound represented by the general formula (1) The compound represented by 1i) can also be produced by the synthetic route I shown below.

In formula (1i), R ^{8 ′} and R ¹⁰ represent a hydrogen atom or a C _1-6 alkyl group, and R ^1a , R ^4a and R ^5a have the same meanings as described above.

<Synthetic route I>

In the synthesis route I, the compound represented by the general formula (1i) can be produced by amination of the compound represented by the general formula (1i ′) (Step I-1).

In the formula (1i ′), R ¹¹ represents a C _1-6 alkyl group, and R ^1a , R ^4a and R ^5a are as defined above.
Specifically, an amine (compound represented by R ^{8 ′} —NH—R ¹⁰ ) corresponding to an amino group which may be substituted with 1 or 2 C _1-6 alkyl groups to be introduced is used. The compound represented by the general formula (1i ′) is aminated in a solvent such as DMF, DMSO, and THF at room temperature to 80 ° C.
In addition, the compound represented by general formula (1i ') can be manufactured by the synthetic pathway A.

The compound of the present embodiment shows excellent PDE4 inhibitory activity. The compound of this embodiment is a disease in which a PDE4 inhibitor is effective as a preventive or therapeutic agent, such as bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis Can be used to treat or prevent psoriasis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia, or Parkinson's disease. Or treating bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia, or Parkinson's disease It can also be used to manufacture a medicament for prevention.
Therefore, the medicament containing the compound of this embodiment as an active ingredient is, for example, bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, psoriasis, rheumatoid arthritis, multiple It can be used as a preventive or therapeutic agent for systemic sclerosis, Alzheimer's disease, dementia and Parkinson's disease.

In addition, the compound of the present embodiment has an excellent PDE4 inhibitory action, but is rapidly metabolized in vivo to reduce its activity.
For example, the compound of this embodiment shows an excellent PDE4 inhibitory action when taken into a living body. In addition, the compound of this embodiment is rapidly metabolized, for example, after being absorbed into the living body, and as a result of the ester moiety of the amide derivative represented by formula (1) being changed to a carboxyl group, the PDE4 inhibitory activity is attenuated. Therefore, the occurrence of systemic side effects such as vomiting and vasculitis can be suppressed as compared with conventional PDE4 inhibitors.
Therefore, the compound of this embodiment is suitably used when performing local administration such as transdermal administration or inhalation administration.

The medicine containing the compound of the present embodiment can be in the form of a pharmaceutical composition, for example. Specifically, the pharmaceutical composition containing the compound of the present embodiment may be in any form of a solid composition, a liquid composition, and other compositions, and the optimal one is selected as necessary.
For example, a pharmaceutical composition containing the compound of this embodiment can be produced by blending the compound of this embodiment with a pharmacologically acceptable carrier. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers, aqueous or non-aqueous solvents, etc. are added, and by conventional formulation techniques, It can be prepared into powders, granules, tablets, capsules, liquids and the like. These can be further used as internal preparations, external preparations, injections and the like.
External preparations refer to all drugs used directly on the living body, excluding internal preparations and injections. Examples of external preparations include coating agents, eye drops, nasal drops, ear drops, inhalants, sprays, suppositories and the like. For example, as an external preparation for treatment or prevention of bronchial asthma and chronic obstructive pulmonary disease (COPD), an inhalant and a spray are suitable, and as an external preparation for treatment or prevention of atopic dermatitis and psoriasis, an application agent is used. Is suitable.
In other words, since the compound of this embodiment is particularly suitable for local administration such as transdermal administration and inhalation administration for the reasons described above, the compound of this embodiment is suitable for bronchial asthma and chronic obstructive lung among the above-mentioned diseases. Particularly suitable for use in treating or preventing disease (COPD), atopic dermatitis or psoriasis.

The dose of the compound of the present embodiment is not particularly limited and varies depending on the disease, symptoms, body weight, age, sex, administration route and the like. For example, for oral administration to an adult, it is preferably about 0.01 to about 1000 mg / kg body weight / day, more preferably about 0.5 to about 200 mg / kg body weight / day, It can be administered once or divided into several times.
Further, those skilled in the art can appropriately determine the disease, symptom, body weight, age, sex, administration route and the like. For example, the medicament according to this embodiment includes, for example, about 0 of the compound of this embodiment. About 0.01% to about 95% by weight is contained. A topical application (for example, an ointment) for the treatment of atopic dermatitis or psoriasis contains the compound of the present embodiment at a concentration of 0.01 to 95%, for example. The dose of the compound of the present embodiment by inhalation is 0.5 to 200 mg per day.

Next, although the compound of this embodiment is demonstrated by a specific example, this invention is not limited by these examples.
<Reference Example 1>
4- (4-Methoxybenzyloxy) butyric acid ethyl ester

Propargyl alcohol (1 g) was dissolved in N, N-dimethylformamide (60 mL) to prepare a reaction solution. Under ice-cooling, 60% sodium hydride (785 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hr. 4-Methoxybenzyl chloride (2.7 mL) was added dropwise to the reaction solution at the same temperature, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 1-methoxy-4-propynyloxymethylbenzene (2.24 g) as a colorless oil.
In an argon gas atmosphere, 1-methoxy-4-propynyloxymethylbenzene (2.24 g) synthesized as described above was dissolved in tetrahydrofuran (60 mL) to obtain a reaction solution. N-Butyllithium (1.65 mol / L hexane solution, 8.5 mL) was added dropwise to the reaction solution at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. At the same temperature, ethyl chloroformate (3.6 mL) was added to the reaction solution all at once, and the mixture was stirred as it was for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (2.44 g) as a colorless oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.33 (3H, t, J = 7.3 Hz), 3.81 (3H, s), 4.257 (3H, s), 4.260 (2H, q, J = 7.3 Hz), 4.55 (2H, s), 6.89 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz).

<Reference Example 2>
Ethyl 4-hydroxymethyl-7-methoxy-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine-3-carboxylate

The compound of Reference Example 1 (2.44 g) and the compound of Example 2 of International Publication No. 2008/026687 (5.23 g) were dissolved in ethanol (50 mL) to give a reaction solution. Potassium carbonate (4.08 g) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The insoluble material was filtered off using celite, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3 → ethyl acetate alone) to obtain the title compound (1.74 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, t, J = 7.3 Hz), 3.80 (3H, s), 4.16 (3H, s), 4.36 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 4.81 (2H, d, J = 6.7 Hz), 4.91 (1H, dd, J = 8.6, 6.7 Hz), 4.94 (2H, s), 6.25 (1H, d, J = 8.0 Hz ), 6.86 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.0 Hz).
ESIMS (+): 401 [M + H] ⁺ .

<Reference Example 3>
4-Hydroxymethyl-7-methoxy-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine

The compound of Reference Example 2 (1.74 g) was dissolved in ethanol (44 mL) to obtain a reaction solution. A 1 mol / L aqueous sodium hydroxide solution (13 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours under heating to reflux. After evaporating the solvent under reduced pressure, the residue was dissolved in water, and acidified (pH 3-4) by adding 1 mol / L hydrochloric acid under ice cooling. The resulting solid was collected by filtration, washed with water, and dried at 60 ° C. under reduced pressure to obtain a carboxylic acid compound (1.57 g) as a light aqua solid.
The carboxylic acid compound (1.57 g,) obtained above was suspended in o-dichlorobenzene (50 mL), and the suspension was stirred at 130 ° C. for 8 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4 → ethyl acetate alone) to obtain the title compound (1.36 g) as a yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.77 (1H, t, J = 6.1 Hz), 3.80 (3H, s), 4.14 (3H, s), 4.56 (2H, s), 4.83 (2H, d , J = 6.1 Hz), 6.05 (1H, d, J = 8.0 Hz), 6.67 (1H, s), 6.88 (2H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.6 Hz).
CIMS (+): 329 [M + H] ⁺ .

<Reference Example 4>
7-Methoxy-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine-4-carbaldehyde

The compound of Reference Example 3 (1.36 g) was dissolved in chloroform (20 mL) to prepare a reaction solution. Manganese dioxide (75%, 2.4 g) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 7 hours. The insoluble material was filtered off using celite, and the filtrate was evaporated under reduced pressure to give the title compound (1.35 g) as a yellow oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 3.81 (3H, s), 4.27 (3H, s), 4.57 (2H, s), 4.82 (2H, s), 6.26 (1H, d, J = 8.0 Hz ), 6.89 (2H, s), 7.31 (2H, d, J = 8.6 Hz), 7.75 (1H, d, J = 8.0 Hz), 9.95 (1H, s).
CIMS (+): 327 [M + H] ⁺ .

<Reference Example 5>
7-Methoxy-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine-4-carboxylic acid

The compound of Reference Example 4 (1.35 g) was dissolved in tetrahydrofuran (18 mL) and tert-butanol (18 mL) to obtain a reaction solution. 2-Methyl-2-butene (4.4 mL) was added to the reaction mixture, and then mixed with sodium chlorite (80%, 1.4 g) and sodium dihydrogen phosphate dihydrate (3.23 g) under ice cooling An aqueous solution (6 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. Ice water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The obtained solid was suspended in diisopropyl ether and collected by filtration to give the title compound (1.15 g) as a colorless solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 3.74 (3H, s), 4.16 (3H, s), 4.48 (2H, s), 4.67 (2H, s), 6.48 (1H, d, J = 8.0 Hz), 6.91 (2H, s), 7.27 (2H, d, J = 8.6 Hz), 7.98 (1H, d, J = 8.0 Hz), 12.98 (1H, brs).
ESIMS (+): 343 [M + H] ⁺ .

<Reference Example 6>
N- (3,5-dichloropyridin-4-yl) -7-methoxy-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine-4-carboxamide

The compound of Reference Example 5 (1.15 g) was dissolved in dichloromethane (34 mL) to give a reaction solution. To the first reaction solution, 4-nitrophenol (514 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (837 mg), and 4-dimethylaminopyridine (41.1 mg) were added. Stir at ambient temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain 4-nitrophenyl ester (1.65 g) as a yellow solid.
3,5-Dichloro-4-aminopyridine (822 mg) was dissolved in N, N-dimethylformamide (30 mL) to prepare a reaction solution. Under ice-cooling, 60% sodium hydride (269 mg) was added to the reaction mixture. After stirring the reaction solution at room temperature for 30 minutes, an N, N-dimethylformamide solution (20 mL) of the 4-nitrophenyl ester compound (1.65 g) synthesized above was added dropwise to the reaction solution under ice cooling. After stirring at room temperature for 3 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (1.16 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 3.79 (3H, s), 4.26 (3H, s), 4.58 (2H, s), 4.83 (2H, s), 6.24 (1H, d, J = 8.0 Hz ), 6.86 (2H, d, J = 8.6 Hz), 7.09 (1H, s), 7.30 (2H, d, J = 8.6 Hz), 7.72 (1H, brs), 7.92 (1H, d, J = 8.0 Hz ), 8.59 (2H, s).
ESIMS (+): 487 [M + H] ⁺ .

<Reference Example 7>
N- (3,5-dichloropyridin-4-yl) -2-hydroxymethyl-7-methoxypyrazolo [1,5-a] pyridine-4-carboxamide

The compound of Reference Example 6 (694 mg) was dissolved in dichloromethane (35 mL) to obtain a reaction solution. Anisole (4.6 mL) and trifluoroacetic acid (4.2 mL) were added to the reaction solution under ice cooling. After stirring at the same temperature for 2 hours, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, sodium chloride was further added, and the mixture was extracted with tetrahydrofuran. The organic layer was dried using anhydrous magnesium sulfate and anhydrous sodium sulfate was removed by filtration, and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the resulting solid was collected by filtration to give the title compound (158 mg) as a colorless solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.18 (3H, s), 4.64 (2H, d, J = 6.1 Hz), 5.31 (1H, t, J = 6.1 Hz), 6.53 (1H, d , J = 8.0 Hz), 6.99 (1H, s), 8.07 (1H, d, J = 8.0 Hz), 8.75 (2H, s), 10.54 (1H, s).
ESIMS (+): 367 [M + H] ⁺ .

<Reference Example 8>
N- (3,5-dichloropyridin-4-yl) -2-formyl-7-methoxypyrazolo [1,5-a] pyridine-4-carboxamide

The compound of Reference Example 7 (488 mg) was dissolved in N, N-dimethylformamide (13 mL) to prepare a reaction solution. Manganese dioxide (75%, 771 mg) was added to the reaction mixture, and the mixture was stirred at 80 ° C. for 7 hr. Manganese dioxide (75%, 771 mg) was added to the reaction solution, and the mixture was further stirred for 21 hours. The insoluble material was removed by filtration using celite and silica gel, and the filtrate was evaporated under reduced pressure. The resulting solid was suspended in a mixed solution of ethyl acetate-diisopropyl ether and collected by filtration to give the title compound (261 mg) as a green solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.26 (3H, s), 6.83 (1H, d, J = 8.0 Hz), 7.43 (1H, s), 8.22 (1H, d, J = 8.0 Hz) ), 8.77 (2H, s), 10.19 (1H, s), 10.72 (1H, brs).
ESIMS (+): 365 [M + H] ⁺ .

<Reference Example 9>
4- (3,5-Dichloropyridin-4-yl) carbamoyl-7-methoxypyrazolo [1,5-a] pyridine-2-carboxylic acid

The compound of Reference Example 8 (260 mg) was dissolved in dimethyl sulfoxide (6 mL) to prepare a reaction solution. After adding 2-methyl-2-butene (0.76 mL) to the reaction mixture, a mixed aqueous solution of sodium chlorite (80%, 242 mg) and sodium dihydrogen phosphate dihydrate (555 mg) at room temperature ( 1 mL) was added dropwise to the reaction solution and stirred at room temperature for 1.5 hours. A 1 mol / L aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and the mixture was stirred for 15 minutes, and then the aqueous layer was separated. The aqueous layer was acidified with 1 mol / L hydrochloric acid under ice-cooling (pH 2-3), and the resulting solid was collected by filtration to give the title compound (203 mg) as a yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.23 (3H, s), 6.75 (1H, d, J = 8.0Hz), 7.40 (1H, s), 8.18 (1H, d, J = 8.0 Hz) ), 8.76 (2H, s), 10.66 (1H, s).
HRESIMS (+): 381.01527: Calculated _{C 15 H 11 Cl 2 N 4} O 4 381.01573.

<Example 1>
Ethyl 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methoxypyrazolo [1,5-a] pyridine-2-carboxylate

The compound of Reference Example 9 (200 mg) was dissolved in N, N-dimethylformamide (10 mL) to obtain a reaction solution. To the reaction solution were added iodoethane (50 mL) and potassium carbonate (94.5 mg), and the mixture was stirred at room temperature for 15 hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate) to give the title compound (158 mg) as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.44 (3H, t, J = 7.3 Hz), 4.27 (3H, s), 4.49 (2H, q, J = 7.3 Hz), 6.36 (1H, d, J = 8.0 Hz), 7.60 (1H, s), 7.68 (1H, brs), 7.95 (1H, d, J = 8.0 Hz), 8.60 (2H, s).
HRESIMS (+): 409.04668: Calculated as C ₁₇ H ₁₅ Cl ₂ N ₄ O ₄ 409.04703.
Elemental analysis: Calculated as C 49.89%, H 3.45%, N13.69% as measured values C 49.73%, H 3.32%, N 13.40%, C ₁₇ H ₁₅ Cl ₂ N ₄ O ₄ .

<Example 2>
Ethyl 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylaminopyrazolo [1,5-a] pyridine-2-carboxylate

The compound of Example 1 (83 mg) was dissolved in N, N-dimethylformamide (2 ml) to give a reaction solution. Methylamine (2 mol / L tetrahydrofuran solution, 1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Methylamine (2 mol / L tetrahydrofuran solution, 1 mL) was added to the reaction solution, and the mixture was further stirred at 60 ° C. for 7 hours. Ice water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the resulting solid was collected by filtration to give the title compound (48.5 mg) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, t, J = 6.7 Hz), 3.19 (3H, d, J = 5.5 Hz), 4.47 (2H, q, J = 6.7 Hz), 6.06 ( 1H, d, J = 8.0 Hz), 6.78 (1H, q, J = 5.5 Hz), 7.54 (1H, s), 7.61 (1H, brs), 7.96 (1H, d, J = 8.0 Hz), 8.57 ( 2H, s).
HRESIMS (+): 408.06344: Calculated as C ₁₇ H ₁₆ Cl ₂ N ₅ O ₄ 408.06302.

<Reference Example 10>
8-Methoxyimidazo [1,2-a] pyridine-2-carboxylic acid ethyl ester

2-Amino-3-methoxypyridine (15.0 g) and ethyl bromopyruvate (35.1 g) were dissolved in ethanol (240 mL) to obtain a reaction solution. The reaction solution was stirred with heating under reflux for 8 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the mixture was separated into an aqueous layer and an organic layer. The aqueous layer was extracted 3 times with ethyl acetate, and the extract was combined with the organic layer. The organic layer was dried using anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 4 → ethyl acetate), and the resulting solid was suspended in ethanol and collected by filtration to give the title compound (16.2 g) as a colorless solid. Obtained.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.42 (3H, t, J = 7.3 Hz), 4.01 (3H, s), 4.44 (2H, q, J = 7.3 Hz), 6.49 (1H, d, J = 7.9 Hz), 6.77 (1H, dd, J = 7.9, 6.7 Hz), 7.78 (1H, dd, J = 6.7, 1.2 Hz), 8.16 (1H, s).
EIMS (+): 220 [M] ⁺ .

<Reference Example 11>
(8-Methoxyimidazo [1,2-a] pyridin-2-yl) methanol

The compound (5.00 g) of Reference Example 10 was added little by little to a tetrahydrofuran suspension (98.7 mL) of lithium aluminum hydride (1.03 g) under ice cooling to prepare a reaction solution. The reaction solution was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. A saturated Rochelle salt aqueous solution was added to the reaction solution under ice-cooling, ethyl acetate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (3.41 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 4.01 (3H, s), 4.83 (2H, s), 6.46 (1H, d, J = 6.7 Hz), 6.69 (1H, t, J = 6.7 Hz), 7.52 (1H, s), 7.73 (1H, d, J = 6.7 Hz).
EIMS (+): 178 [M] ⁺ .

<Reference Example 12>
2-tert-Butyldimethylsilyloxymethyl-8-methoxyimidazo [1,2-a] pyridine

To a solution of the compound of Reference Example 11 (3.41 g) in N, N-dimethylformamide (127 mL), imidazole (5.20 g) and tert-butyldimethylchlorosilane (5.76 g) were added under ice cooling to prepare a reaction solution. The reaction solution was stirred at room temperature for 7 hours. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. Hexane was added to the combined organic layers, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to give the title compound (5.03 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.12 (6H, s), 0.96 (9H, s), 3.99 (3H, s), 4.96 (2H, s), 6.41 (1H, d, J = 7.9 Hz ), 6.64 (1H, t, J = 6.7 Hz), 7.49 (1H, s), 7.72 (1H, d, J = 6.7 Hz).
EIMS (+): 292 [M] ⁺ .

<Reference Example 13>
2-tert-Butyldimethylsilyloxymethyl-3-chloro-8-methoxyimidazo [1,2-a] pyridine

The compound of Reference Example 12 (5.05 g) was dissolved in N, N-dimethylformamide (18 mL) to obtain a reaction solution. N-chlorosuccinimide (2.54 g) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction solution, and the resulting solid was collected by filtration and washed with water. The obtained solid was dissolved in ethyl acetate and dried using anhydrous magnesium sulfate. After removing anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (4.62 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.13 (6H, s), 0.93 (9H, s), 4.01 (3H, s), 4.91 (2H, s), 6.49 (1H, d, J = 7.3 Hz ), 6.81 (1H, t, J = 6.7 Hz), 7.70 (1H, d, J = 6.7 Hz) .CIMS (+): 327 [M + H] ⁺ .

<Reference Example 14>
5-Bromo-2-tert-butyldimethylsilyloxymethyl-3-chloro-8-methoxyimidazo [1,2-a] pyridine

The compound of Reference Example 13 (4.62 g) was dissolved in N, N-dimethylformamide (14 mL) to obtain a reaction solution. N-bromosuccinimide (2.76 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 hours. Ice water was added to the reaction solution, and the resulting solid was collected by filtration and washed with water. The obtained solid was dissolved in ethyl acetate and dried using anhydrous magnesium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (2.56 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.13 (6H, s), 0.93 (9H, s), 3.98 (3H, s), 4.84 (2H, s), 6.34 (1H, d, J = 7.9 Hz ), 6.90 (1H, d, J = 7.9 Hz).
CIMS (+): 407 [M + H] ⁺ .

<Reference Example 15>
2- (tert-Butyldimethylsilyloxymethyl) -3-chloro-8-methoxyimidazo [1,2-a] pyridine-5-carboxylic acid

Under an argon gas atmosphere, the compound of Reference Example 14 (1.25 g) was dissolved in tetrahydrofuran (16 mL) to obtain a reaction solution. N-Butyllithium (1.65 mol / L hexane solution, 2.1 mL) was added dropwise to the reaction solution at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Carbon dioxide gas was blown into the reaction solution at −78 ° C. for 15 minutes, followed by stirring for 1.5 hours while gradually raising the temperature to room temperature. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction solution under ice-cooling, followed by washing with diethyl ether. The separated aqueous layer was adjusted to pH 3-4 by adding 1 mol / L hydrochloric acid under ice cooling. The resulting solid was collected by filtration, washed with water, and dried at room temperature under reduced pressure. The obtained solid was dissolved in chloroform and dried using anhydrous magnesium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (990 mg) as a colorless solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ0.08 (6H, s), 0.87 (9H, s), 3.99 (3H, s), 4.74 (2H, s), 6.79 (1H, d, J = 8.0 Hz), 7.42 (1H, d, J = 8.0 Hz), 13.82 (1H, brs).
ESIMS (+): 371 [M + H] ⁺ .

<Reference Example 16>
2-tert-Butyldimethylsilyloxymethyl-3-chloro-N- (3,5-dichloropyridin-4-yl) -8-methoxyimidazo [1,2-a] pyridine-5-carboxamide

Under an argon gas atmosphere, the compound of Reference Example 15 (50 mg) was dissolved in N, N-dimethylformamide (1 mL) to give a reaction solution. Triethylamine (25 μL) and ethyl chloroformate (15.5 μL) were added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure to obtain a mixed acid anhydride.
Under an argon gas atmosphere, 4-amino-3,5-dichloropyridine (33 mg) was dissolved in N, N-dimethylformamide (1 mL) to prepare a reaction solution. 60% sodium hydride (10.8 mg) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added dropwise an N, N-dimethylformamide solution (1 mL) of the mixed acid anhydride obtained above under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2 → 0: 1) to obtain the title compound (15 mg) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ0.12 (6H, s), 0.92 (9H, s), 4.08 (3H, s), 4.89 (2H, s), 6.51 (1H, d, J = 8.0 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.67 (1H, brs), 8.62 (2H, s).
ESIMS (+): 515 [M + H] ⁺ .

<Reference Example 17>
3-Chloro-N- (3,5-dichloropyridin-4-yl) -2-hydroxymethyl-8-methoxyimidazo [1,2-a] pyridine-5-carboxamide

The compound of Reference Example 16 (140 mg) was dissolved in tetrahydrofuran (3 mL) to give a reaction solution. Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.33 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Ice water was added to the reaction solution, and the resulting solid was collected by filtration, washed with water, and dried at room temperature under reduced pressure. The obtained solid was dissolved in a chloroform-methanol mixed solvent and dried using anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (109 mg) as a colorless solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.00 (3H, s), 4.53 (2H, d, J = 5.5 Hz), 5.24 (1H, t, J = 5.5 Hz), 6.87 (1H, d , J = 8.0 Hz), 7.37 (1H, d, J = 8.0 Hz), 8.74 (2H, s), 11.31 (1H, brs).
ESIMS (+): 401 [M + H] ⁺ .

<Reference Example 18>
3-Chloro-N- (3,5-dichloropyridin-4-yl) -2-formyl-8-methoxyimidazo [1,2-a] pyridine-5-carboxamide

The compound of Reference Example 17 (109 mg) was dissolved in dimethyl sulfoxide (2.7 mL) to obtain a reaction solution. Triethylamine (0.38 mL) and sulfur trioxide-pyridine complex (216 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Ice water was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give the titled compound (77 mg) as a colorless solid.
1H NMR (DMSO-d ₆ , 400 MHz): δ 4.05 (3H, s), 7.00 (1H, d, J = 8.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 8.78 (2H, s) , 10.09 (1H, s), 11.51 (1H, brs).
ESIMS (+): [M + H] +.

<Reference Example 19>
3-Chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methoxyimidazo [1,2-a] pyridine-2-carboxylic acid

Using the compound of Reference Example 18 (77 mg), the reaction was carried out in the same manner as in Reference Example 9 to obtain the title compound (70.5 mg) as a colorless solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.04 (3H, s), 6.97 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 8.0 Hz), 8.78 (2H, s ), 11.38 (1H, brs).
ESIMS (+): [M + H] ⁺ .

<Example 3>
3-Chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methoxyimidazo [1,2-a] pyridine-2-carboxylate

The compound of Reference Example 19 (130 mg) was dissolved in N, N-dimethylformamide (6 mL) to give a reaction solution. To the reaction solution were added iodoethane (27.5 μL) and diisopropylethylamine (60 μL), and the mixture was stirred at room temperature for 21 hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate) to give the title compound (55 mg) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ1.43 (3H, t, J = 7.3 Hz), 4.08 (3H, s), 4.47 (2H, q, J = 7.3 Hz), 6.57 (1H, d, J = 7.3 Hz), 7.41 (1H, d, J = 7.3 Hz), 7.78 (1H, brs), 8.63 (2H, s).
HRESIMS (+): 443.00737: Calculated _{C 17 H 14 Cl 3 N 4} O 4 443.00806.

<Reference Example 20>
8-{(tert-Butoxycarbonyl) amino} imidazo [1,2-a] pyridine-2-carboxylate ethyl

2,3-Diaminopyridine (18.4 g) and ethyl bromopyruvate (36.1 g,) were suspended in ethanol (330 mL) to prepare a reaction solution. The reaction solution was stirred for 14 hours under heating to reflux. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the solvent was distilled off under reduced pressure. The solid was filtered off using celite and the filtrate was extracted with ethyl acetate. The organic layer was dried using anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 4 → ethyl acetate), and the resulting solid was suspended in diisopropyl ether and collected by filtration. The obtained red solid (9.66 g) and tert-butyl dicarbonate (10.3 g) were dissolved in tetrahydrofuran (235 mL) under an argon gas atmosphere to obtain a reaction solution. Sodium hexamethyldisilazane (1.0 mol / L tetrahydrofuran solution, 94.2 mL) was quickly added to the reaction solution at 10 ° C., and the mixture was stirred at room temperature for 25 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution under ice cooling, water and ethyl acetate were added, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the title compound (7.80 g) as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, t, J = 7.3 Hz), 1.54 (9H, s), 4.47 (2H, q, J = 7.3 Hz), 6.84 (1H, t, J = 7.3 Hz), 7.76-7.78 (1H, m), 7.85 (1H, d, J = 7.3 Hz), 8.02 (1H, brs), 8.14 (1H, s).
ESIMS (+): 306 [M + H] ⁺ .

<Reference Example 21>
8-{(tert-Butoxycarbonyl) methylamino} imidazo [1,2-a] pyridine-2-carboxylate ethyl

Under an argon gas atmosphere, the compound of Reference Example 20 (7.79 g) was dissolved in N, N-dimethylformamide (100 mL) to obtain a reaction solution. To the reaction solution was added 60% sodium hydride (1.22 g) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, iodomethane (1.90 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration to give the title compound (6.91 g) as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.42 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 3.44 (3H, s), 4.45 (2H, q, J = 7.3 Hz), 6.85 (1H, dd, J = 7.3, 6.7 Hz), 7.17 (1H, brd, J = 7.3 Hz), 8.02 (1H, dd, J = 6.7, 1.2 Hz), 8.19 (1H, s).
ESIMS (+): 320 [M + H] ⁺ .

<Reference Example 22>
8-{(tert-Butoxycarbonyl) methylamino} -3-chloroimidazo [1,2-a] pyridine-2-carboxylate ethyl

Under an argon gas atmosphere, the compound of Reference Example 21 (3.90 g) was dissolved in N, N-dimethylformamide (61 mL) to obtain a reaction solution. N-chlorosuccinimide (1.71 g) was added to the reaction solution, and the mixture was stirred at 70 ° C. for 2 hours, cooled to room temperature, and saturated aqueous sodium carbonate solution was added. Subsequently, water and ethyl acetate were added to the reaction solution, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 1: 1) to obtain the title compound (3.33 g) as a colorless oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.43 (9H, s), 1.45 (3H, t, J = 7.3Hz), 3.43 (3H, s), 4.48 (2H, q, J = 7.3 Hz), 6.99 (1H, dd, J = 7.3, 6.7 Hz), 7.23-7.25 (1H, m), 8.04 (1H, dd, J = 6.7, 1.2 Hz).
ESIMS (+): 354 [M + H] ⁺ .

<Reference Example 23>
5-Bromo-8-{(tert-butoxycarbonyl) methylamino} -3-chloroimidazo [1,2-a] pyridine-2-carboxylate

Under an argon gas atmosphere, the compound of Reference Example 22 (3.31 g) was dissolved in N, N-dimethylformamide (47 mL) to obtain a reaction solution. N-bromosuccinimide (1.83 g) was added to the reaction mixture, and the mixture was stirred at 70 ° C. for 1.5 hr. After cooling the reaction solution to room temperature, a saturated aqueous sodium carbonate solution was added. Next, water and ethyl acetate were added, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 5: 2) to obtain the title compound (3.17 g) as a colorless amorphous substance.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.42 (9H, s), 1.43 (3H, t, J = 7.3Hz), 3.37 (3H, s), 4.47 (2H, q, J = 7.3 Hz), 7.02 (1H, d, J = 7.3 Hz), 7.10 (1H, d, J = 7.3 Hz).
ESIMS (+): 432 [M + H] ⁺ .

<Reference Example 24>
tert-Butyl (5-bromo-3-chloro-2-hydroxymethylimidazo [1,2-a] pyridin-8-yl) (methyl) carbamate

To an ethanol solution (16.2 mL) of the compound of Reference Example 23 (1.40 g) was added 1 mol / L aqueous sodium hydroxide solution (4.86 mL), and the mixture was heated to reflux for 1 hour. After allowing to cool, the solvent was distilled off under reduced pressure, and the residue was dissolved in water. The aqueous solution was adjusted to pH 2-3 by adding 1 mol / L hydrochloric acid under ice cooling. The precipitated solid was collected by filtration to give a colorless solid (1.18 g). The colorless solid (1.18 g) obtained above was dissolved in dichloromethane (9.73 mL) to obtain a reaction solution. N-methylmorpholine (0.38 mL) and isobutyl chloroformate (0.45 mL) were added to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain a brown oil.
The brown oil solution (14.6 mL) of the brown oil obtained above was slowly added dropwise to an aqueous solution (7.3 mL) of sodium borohydride (481 mg) under ice cooling to prepare a reaction solution. The reaction was stirred at the same temperature for 1 hour. To this reaction solution was added 1 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate and collected by filtration to give the title compound (894 mg) as a colorless solid. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1 → 0: 1) to give the title compound (116 mg) as a colorless solid. Together, the title compound (1.01 g) was obtained as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.42 (9H, s), 2.81 (1H, brt), 3.33 (3H, s), 4.80 (2H, d, J = 4.9 Hz), 6.97 (1H, d , J = 7.9 Hz), 7.03 (1H, d, J = 7.9 Hz).
ESIMS (+): 392 [M + H] ⁺ .

<Reference Example 25>
tert-Butyl [5-bromo-3-chloro-2-methoxymethoxymethylimidazo [1,2-a] pyridin-8-yl] (methyl) carbamate

Under an argon gas atmosphere, diisopropylethylamine (0.53 mL) and chloromethyl methyl ether (0.24 mL) were added dropwise to a dichloromethane solution (13 mL) of the compound of Reference Example 24 (1.01 g) under ice cooling to prepare a reaction solution. . The reaction was stirred at ambient temperature for 19 hours. Further, diisopropylethylamine (0.44 mL) and chloromethyl methyl ether (0.20 mL) were added dropwise to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 2: 3) to give the title compound (1.09 g) as a colorless oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.41 (9H, s), 3.34 (3H, s), 3.45 (3H, s), 4.74 (2H, s), 4.77 (2H, s), 6.95 (1H , d, J = 7.9 Hz), 7.01 (1H, d, J = 7.9 Hz).
ESIMS (+): 436 [M + H] ⁺ .

<Reference Example 26>
8-{(tert-Butoxycarbonyl) methylamino} -3-chloro-2-methoxymethoxymethylimidazo [1,2-a] pyridine-5-carboxylic acid

Using the compound of Reference Example 25 (1.86 g), the reaction was carried out in the same manner as in Reference Example 15 to obtain the title compound (1.25 g) as a pale yellow solid.
¹ H NMR (DMSO, 400 MHz): δ 1.31 (9H, s), 3.24 (3H, s), 3.30 (3H, s), 4.63 (2H, s), 4.66 (2H, s), 7.32 (1H, d, J = 7.3 Hz), 7.40 (1H, d, J = 7.3 Hz).
ESIMS (+): 400 [M + H] ⁺ .

<Reference Example 27>
tert-butyl [3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-2-methoxymethoxymethylimidazo [1,2-a] pyridin-8-yl] (methyl) carbamate

Under an argon gas atmosphere, the compound of Reference Example 26 (1.25 g) was dissolved in N, N-dimethylformamide (10 mL) to obtain a reaction solution. Triethylamine (0.65 mL) and pivaloyl chloride (0.46 mL) were added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain an acid anhydride as a brown oil.
On the other hand, 3,5-dichloro-4-aminopyridine (765 mg) was dissolved in N, N-dimethylformamide (10 mL) to obtain a reaction solution. To this reaction solution, 60% sodium hydride (250 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added an N, N-dimethylformamide (10 mL) solution of the acid anhydride obtained above under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (353 mg) as a pale yellow amorphous product.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.45 (9H, s), 3.44 (3H, s), 3.45 (3H, s), 4.77 (2H, s), 4.79 (2H, s), 7.21 (1H , d, J = 8.0 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.74 (1H, brs), 8.63 (2H, s).
ESIMS (+): 544 [M + H] ⁺ .

<Reference Example 28>
3-Chloro-N- (3,5-dichloropyridin-4-yl) -2-hydroxymethyl-8-methylaminoimidazo [1,2-a] pyridine-5-carboxamide

The compound of Reference Example 27 (353 mg) was dissolved in 4 mol / L hydrochloric acid-ethyl acetate solution (6.5 mL) to give a reaction solution. The reaction solution was stirred at room temperature for 3 hours and at 50 ° C. for 1 hour. After the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was further neutralized by adding a 1 mol / L aqueous sodium hydroxide solution under ice cooling. Further, sodium chloride was added to the resulting mixture and extracted with tetrahydrofuran. The organic layer was dried using anhydrous magnesium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The resulting solid was suspended in ethyl acetate and collected by filtration to give the title compound (211 mg) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.89 (3H, d, J = 5.5 Hz), 4.54 (2H, d, J = 5.5 Hz), 5.11 (1H, t, J = 5.5 Hz), 6.18 (1H, d, J = 8.0 Hz), 6.91 (1H, brs), 7.37 (1H, d, J = 8.0 Hz), 8.70 (2H, s), 10.94 (1H, brs).
ESIMS (+): 400 [M + H] ⁺ .

<Reference Example 29>
3-Chloro-N- (3,5-dichloropyridin-4-yl) -2-formyl-8-methylaminoimidazo [1,2-a] pyridine-5-carboxamide

Using the compound of Reference Example 28 (211 mg), the reaction was carried out in the same manner as in Reference Example 18 to obtain the title compound (167 mg) as a yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.91 (3H, d, J = 4.9 Hz), 6.29 (1H, d, J = 8.0 Hz), 7.44 (1H, q, J = 4.9 Hz), 7.55 (1H, d, J = 8.0 Hz), 8.76 (2H, s), 10.08 (1H, s), 11.05 (1H, brs).
ESIMS (+): 398 [M + H] ⁺ .

<Reference Example 30>
3-Chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methylaminoimidazo [1,2-a] pyridine-2-carboxylic acid

Using the compound of Reference Example 29 (167 mg), the reaction was carried out in the same manner as in Reference Example 9 to obtain the title compound (75.8 mg) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.90 (3H, d, J = 4.5 Hz), 6.25 (1H, d, J = 8.6 Hz), 7.24 (1H, q, J = 4.5 Hz), 7.49 (1H, d, J = 8.6 Hz), 8.75 (2H, s), 11.02 (1H, s).
ESIMS (+): 414 [M + H] ⁺ .

<Example 4>
Ethyl 3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methylaminoimidazo [1,2-a] pyridine-2-carboxylate

Using the compound of Reference Example 30 (56 mg), the reaction was carried out in the same manner as in Example 3 to obtain the title compound (12 mg) as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.44 (3H, t, J = 7.3 Hz), 3.05 (3H, d, J = 4.9 Hz), 4.48 (2H, q, J = 7.3 Hz), 5.97 ( 1H, q, J = 4.9 Hz), 6.10 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 8.0 Hz), 7.59 (1H, brs), 8.60 (2H, s).
HRESIM S (+): 442.002368: Calculated as C ₁₇ H ₁₅ Cl ₃ N ₅ O ₃ 442.02405.

<Reference Example 31>
Ethyl 4-hydroxymethyl-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine-3-carboxylate

Potassium carbonate (16.7 g) was added to an ethanol solution (200 mL) of the compound of Reference Example 1 (10.0 g) and the compound of Example 3 of International Publication No. 2008/029829 (24.7 g) to prepare a reaction solution. The reaction was stirred at ambient temperature for 17 hours. The insoluble material was filtered off using celite, and the filtrate was evaporated under reduced pressure. The residue was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 2) to obtain the title compound (5.13 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36 (3H, t, J = 7.3 Hz), 3.81 (3H, s), 4.35 (2H, q, J = 7.3 Hz), 4.66 (2H, s), 4.83-4.97 (4H, m), 6.85-6.95 (3H, m), 7.30-7.38 (3H, m), 8.50 (1H, dd, J = 6.7, 1.2 Hz).
ESIMS (+): 371 [M + H] ⁺ .

<Reference Example 32>
[2- (4-Methoxybenzyl) oxymethylpyrazolo [1,5-a] pyridin-4-yl] methanol

Using the compound of Reference Example 31 (4.43 g), the reaction was carried out in the same manner as in Reference Example 3 to obtain the title compound (3.62 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.92 (1H, t, J = 5.5 Hz), 3.81 (3H, s), 4.58 (2H, s), 4.74 (2H, s), 4.87 (2H, d , J = 5.5 Hz), 6.59 (1H, s), 6.74 (1H, t, J = 6.7 Hz), 6.84-6.94 (2H, m), 7.14 (1H, dd, J = 6.7, 1.2 Hz), 7.28 -7.36 (2H, m), 8.36 (1H, d, J = 6.7 Hz).
CIMS (+): 299 [M + H] ⁺ .

<Reference Example 33>
4-tert-Butyldimethylsilyloxymethyl-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine

The compound of Reference Example 32 (3.59 g) was dissolved in N, N-dimethylformamide (80 mL) to obtain a reaction solution. To the reaction solution were added imidazole (2.45 g) and t-butyldimethylsilyl chloride (2.17 g), and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (5.03 g) as a colorless oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.13 (6H, s), 0.96 (9H, s), 3.81 (3H, s), 4.57 (2H, s), 4.74 (2H, s), 4.87 (2H , s), 6.49 (1H, s), 6.74 (1H, t, J = 7.3 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.16 (1H, d, J = 7.3 Hz), 7.32 (2H , d, J = 8.6 Hz), 8.33 (1H, d, J
= 7.3 Hz).
ESIMS (+): 413 [M + H] ⁺ .

<Reference Example 34>
4-tert-Butyldimethylsilyloxymethyl-7-iodo-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine

Under an argon gas atmosphere, n-butyllithium (1.65 mol / L hexane solution, 9.45 mL) was slowly added dropwise to a tetrahydrofuran solution (35 mL) of the compound of Reference Example 33 (4.95 g) at -78 ° C to prepare a reaction solution. . The reaction was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (35 mL) of 1,2-diiodoethane (4.06 g) was slowly added dropwise to the reaction solution at −78 ° C., and the reaction solution was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (6.33 g,) as a brown oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.13 (6H, s), 0.95 (9H, s), 3.81 (3H, s), 4.58 (2H, s), 4.81 (2H, s), 4.86 (2H , s), 6.76 (1H, s), 6.89 (2H, d, J = 7.9 Hz), 6.94 (1H, d, J = 7.3 Hz), 7.28-7.40 (3H, m).
ESIMS (+): 539 [M + H] ⁺ .

<Reference Example 35>
[7-Iodo-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridin-4-yl] methanol

The compound of Reference Example 34 (6.33 g) was dissolved in tetrahydrofuran (60 mL) to give a reaction solution. Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 14.2 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (4.84 g) as a colorless solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 3.81 (3H, s), 4.59 (2H, s), 4.80 (2H, s), 4.85 (2H, s), 6.83 (1H, s), 6.85-6.95 (3H, m), 7.29 (1H, d, J = 7.3 Hz), 7.33 (2H, d, J = 7.3 Hz).
ESIMS (+): 425 [M + H] ⁺ .

<Reference Example 36>
7-Iodo-2- (4-methoxybenzyloxymethyl) pyrazolo [1,5-a] pyridine-4-carbaldehyde

Using the compound of Reference Example 35 (4.84 g), the reaction was carried out in the same manner as in Reference Example 4 to obtain the title compound (4.49 g) as a yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 3.82 (3H, s), 4.60 (2H, s), 4.83 (2H, s), 6.86-6.94 (2H, m), 7.30-7.37 (2H, m) , 7.39 (1H, d, J = 7.3 Hz), 7.52 (1H, d, J = 7.3 Hz), 7.62 (1H, s), 10.07 (1H, s).
CIMS (+): 423 [M + H] ⁺ .

<Reference Example 37>
2- (4-Methoxybenzyloxymethyl) -7-methylthiopyrazolo [1,5-a] pyridine-4-carbaldehyde

Sodium thiomethoxide (655 mg) was added to an N, N-dimethylformamide solution (50 mL) of the compound of Reference Example 36 (2.50 g) to prepare a reaction solution. The reaction was stirred at ambient temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 0: 1) to obtain the title compound (1.88 g) as a yellow oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.69 (3H, s), 3.18 (3H, s), 4.58 (2H, s), 4.83 (2H, s), 6.68 (1H, d, J = 7.3 Hz ), 6.86-6.94 (2H, m), 7.29-7.38 (2H, m), 7.41 (1H, s), 7.69 (1H, d, J = 7.3 Hz), 10.03 (1H, s).
CIMS (+): 343 [M + H] ⁺ .

<Reference Example 38>
2- (4-Methoxybenzyloxymethyl) -7-methylthiopyrazolo [1,5-a] pyridine-4-carboxylic acid

Using the compound of Reference Example 37 (1.88 g), the reaction was carried out in the same manner as in Reference Example 5 to obtain the title compound (1.72 g) as a yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.67 (3H, s), 3.74 (3H, s), 4.50 (2H, s), 4.70 (2H, s), 6.89 (1H, d, J = 8.0 Hz), 6.90-6.92 (2H, m), 7.05 (1H, s), 7.28-7.30 (2H, m), 7.94 (1H, d, J = 8.0 Hz).
ESIMS (+): 358 [M + H] ⁺ .

<Reference Example 39>
N- (3,5-dichloropyridin-4-yl) -2- (4-methoxybenzyloxymethyl) -7-methylthiopyrazolo [1,5-a] pyridine-4-carboxamide

Using the compound of Reference Example 38 (1.72 g), the reaction was carried out in the same manner as in Reference Example 6 to obtain the title compound (1.02 g) as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.69 (3H, s), 3.79 (3H, s), 4.59 (2H, s), 4.84 (2H, s), 6.65 (1H, d, J = 8.0 Hz ), 6.85-6.87 (2H, m), 7.10 (1H, s), 7.29-7.32 (2H, m), 7.78 (1H, brs), 7.83 (1H, d, J = 8.0 Hz), 8.59 (2H, s).
ESIMS (+): 503 [M + H] ⁺ .

<Reference Example 40>
N- (3,5-dichloropyridin-4-yl) -2-hydroxymethyl-7-methylthiopyrazolo [1,5-a] pyridine-4-carboxamide

Using the compound of Reference Example 39 (1.02 g), the reaction was carried out in the same manner as in Reference Example 7 to obtain the title compound (749 mg) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.70 (3H, s), 4.68 (2H, d, J = 6.1 Hz), 5.36 (1H, t, J = 6.1 Hz), 6.92 (1H, d , J = 8.0 Hz), 7.03 (1H, s), 8.00 (1H, d, J = 8.0 Hz), 8.76 (2H, s), 10.68 (1H, brs).
ESIMS (+): 383 [M + H] ⁺ .

<Reference Example 41>
N- (3,5-dichloropyridin-4-yl) -2-formyl-7-methylthiopyrazolo [1,5-a] pyridine-4-carboxamide

Using the compound of Reference Example 40 (749 mg), the reaction was carried out in the same manner as in Reference Example 8 to obtain the title compound (599 mg) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.77 (3H, s), 7.22 (1H, d, J = 8.0 Hz), 7.51 (1H, s), 8.15 (1H, d, J = 8.0 Hz) ), 8.76 (2H, s), 10.21 (1H, s), 10.85 (1H, brs).
ESIMS (+): 381 [M + H] ⁺ .

<Reference Example 42>
4- (3,5-Dichloropyridin-4-yl) carbamoyl-7-methylthiopyrazolo [1,5-a] pyridine-2-carboxylic acid

The reaction of Reference Example 41 (599 mg) was performed in the same manner as in Reference Example 9 to give the title compound (617 mg) as a pale yellow solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.74 (3H, s), 7.15 (1H, d, J = 8.0 Hz), 7.45 (1H, s), 8.12 (1H, d, J = 8.0 Hz ), 8.78 (2H, s), 10.81 (1H, brs), 13.32 (1H, brs).
ESIMS (+): [M + H] ⁺ .

<Example 5>
Ethyl 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylthiopyrazolo [1,5-a] pyridine-2-carboxylate

Using the compound of Reference Example 42 (400 mg), the reaction was carried out in the same manner as in Example 3 to obtain the title compound (226 mg) as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.44 (3H, t, J = 7.3 Hz), 2.71 (3H, s), 4.48 (2H, q, J = 7.3 Hz), 6.79 (1H, d, J = 7.3 Hz), 7.62 (1H, s), 7.73 (1H, brs), 7.88 (1H, d, J = 7.3 Hz), 8.61 (2H, s).
HRESIMS (+): 425.02451: Calculated as C ₁₇ H ₁₅ Cl ₂ N ₄ O ₃ S 425.02419.

<Example 6>
Ethyl 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylsulfinylpyrazolo [1,5-a] pyridine-2-carboxylate

The compound of Example 5 (171 mg) was dissolved in tetrahydrofuran (8 mL) and water (2 mL) to give a reaction solution. To the reaction solution was added an aqueous solution (2 mL) of oxone (185 mg), and the mixture was stirred at room temperature for 5 hours. Oxone (25 mg) was added to the reaction solution, and the mixture was further stirred for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 10: 1) to obtain the title compound (165 mg) as a yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, t, J = 7.3 Hz), 3.20 (3H, s), 4.47 (2H, q, J = 7.3 Hz), 7.67 (1H, d, J = 7.3 Hz), 7.70 (1H, s), 7.87 (1H, brs), 8.02 (1H, d, J = 7.3 Hz), 8.64 (2H, s).
HRESIMS (+): 441.01877: Calculated as C ₁₇ H ₁₅ Cl ₂ N ₄ O ₄ S 441.01911.

<Example 7>
Ethyl 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylsulfonylpyrazolo [1,5-a] pyridine-2-carboxylate

The compound of Example 6 (115 mg) was dissolved in chloroform (6 mL) to give a reaction solution. 3-Chloroperbenzoic acid (70%, 77.1 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 10 hours. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1) to obtain the title compound (36 mg) as a pale yellow solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.43 (3H, t, J = 7.3 Hz), 3.69 (3H, s), 4.47 (2H, q, J = 7.3 Hz), 7.75 (1H, d, J = 7.3 Hz), 7.77 (1H, brs), 7.91 (2H, s), 8.64 (2H, s).
HRESIMS (+): 457.01401: Calculated as C ₁₇ H ₁₅ Cl ₂ N ₄ O ₅ S 457.01402.

<Experimental Example 1> PDE4 Inhibitory Activity The compounds of Examples 1 and 2 were each dissolved in dimethyl sulfoxide (hereinafter abbreviated as DMSO) to prepare a 10 mmol / L test compound solution. The obtained 10 mmol / L test compound solution was serially diluted with DMSO to prepare a test compound solution having a concentration of 0.5 nmol / L to 50 μmol / L. 2 μL of test compound solution, substrate solution [100 nmol / LcAMP, 16 nmol / L [ ³ H] cAMP, 40 mmol / L Tris-HCl (pH 7.4), 10 mmol / L MgCl] 50 μL and enzyme solution [0.05 unit amount 48 μL of human-derived recombinant PDE4 catalytic region (hereinafter abbreviated as PDE4cat; manufactured by Scottish Biomedicals), 20 mmol / L Tris-HCl (pH 7.4)] was added to a 1.5 mL tube and reacted at 30 ° C. for 40 minutes. Then, after standing at 70 ° C. for 2 minutes, 25 μL of 1 mg / mL snake venom (manufactured by Sigma Aldrich) was added thereto and reacted at 30 ° C. for 10 minutes. The concentration of each component in the substrate solution represents the concentration in the substrate solution. With respect to the enzyme solution, 1 unit represents the amount of PDE that decomposes 1 pmol of cAMP in 1 minute under the conditions of pH 7.4 and 30 ° C. The concentration of Tris-HCl represents the concentration in the enzyme solution.
After the reaction is complete, add 500 μL of AG1-X8Resin solution [250 mg / mL AG1-X8 Resin (Bio-Rad), Methanol-water mixed solvent (2: 1)] and shake-mix every 10 minutes. Placed at room temperature for 30 minutes with shaking mixing. The concentration of AG1-X8 Resin represents the concentration in the AG1-X8 Resin solution. After centrifuging the reaction solution for 5 minutes, 300 μL of the supernatant is taken and added to 5 mL of ACS IIScintillation Cocktail (Amersham). Radiation dose was measured using Tri-Carb 2910 TR (manufactured by PerkinElmer). The residual PDE4 activity was calculated from the measured radiation dose. IC ₅₀ value was calculated by the following formula.

A: Minimum compound concentration at which PDE4 activity is less than 50%
B: Maximum compound concentration at which PDE4 activity is greater than 50%
C: PDE4 activity remaining rate at the minimum compound concentration at which PDE4 activity is less than 50%
D: PDE4 activity remaining rate at the maximum compound concentration at which PDE4 activity is greater than 50%

The results are shown in Table 1. In the table, IC ₅₀ ≧ 100 μmol / L is (NI), 100 μmol / L> IC ₅₀ ≧ 1 μmol / L is (−), 1 μmol / L> IC ₅₀ ≧ 0.1 μmol / L is (+), 0.1 μmol / L L> IC ₅₀ ≧ 0.01 μmol / L was expressed as (++), and 0.01 μmol / L> IC ₅₀ was expressed as (++++).

Incidentally, the compounds according to the present embodiment is an ester body is rapidly metabolized when absorbed into the body, in the compounds of ester moiety becomes a carboxyl group (formula (1), R ¹ is represented by H Compound, hereinafter referred to as carboxylic acid form).
Since the carboxylic acid form has weaker PDE4 inhibitory activity than the ester form, the risk of developing systemic side effects derived from the PDE4 inhibitory action is low. Therefore, it can be said that a compound having a larger PDE4 inhibitory activity ratio between the ester form and the carboxylic acid form is preferable as a topical administration agent. Therefore, IC ₅₀ values were similarly calculated for the carboxylic acid compounds of the compounds of Examples 1 and 2. The compounds of Examples 1 and 2 is an ester body and PDE4 inhibitory activity ratio of their carboxylic acid form for (carboxylic acid form IC ₅₀ / ester IC _50), 1 ≦ activity ratio <10 (-), 10 ≦ Activity ratio <100 is represented in Table 1 as (+), and 100 ≦ Activity ratio <1000 is represented as (++).

From the above results, it can be seen that the compound of this embodiment has potent PDE4 inhibitory activity.

<Experimental example 2> TDI-induced dermatitis model in mice On the 0th, 1st, 2nd and 7th days after the start of the test, 5v / v% tolylene 2,4-diisocyanate dissolved in acetone containing 20% olive oil 10 μL of the solution was applied to each mouse left and right hind limbs. On the 21st day after the start of the test, after measuring the thickness of the left and right pinna of the mouse, a compound solution containing the compound of Example 2 at a concentration of 0.03 w / v% dissolved in 10% DMSO-containing acetone was added to the left and right pinna. 20 μL each was applied. One hour after application of the compound solution, 20 μL of a 0.5 v / v% concentration TDI solution was applied to the left and right auricles. Similarly, on the 22nd day after the start of the test, 20 μL each of the compound solution containing the compound of Example 2 at a concentration of 0.03 w / v% was applied to the left and right auricles, and 1 hour later, TDI having a concentration of 0.5 v / v% 20 μL of the solution was applied to the left and right auricles. After applying the TDI solution on the 21st day after the start of the test, the thickness of the left and right auricles was measured between 45 hours and 51 hours, and the inhibitory action of the compound of Example 2 on the increase in the auricle thickness was calculated.

As a result of measurement by the above method, the compound of Example 2 showed an inhibitory action of 50% or more.
As described above, the effectiveness of the compound of this embodiment was also confirmed in animal experimental models.

<Experimental Example 3> Preparation of Plasma Stability Test Addition Solution in Rats Test compounds were weighed and dissolved by adding DMSO to a concentration of 30 mM (standard stock solution). This standard stock solution was diluted with DMSO to prepare a 1 mM addition solution.

Preparation of standard solution for calibration curve A standard stock solution was diluted with acetonitrile to 10 mM, and further diluted with acetonitrile to prepare a standard solution for calibration curve of 0.01 to 10 μM.

Preparation of internal standard solution The internal standard substance was weighed, and DMSO was added and dissolved to 30 mM. This was diluted with acetonitrile to 1 μM to prepare an internal standard solution.

Animal treatment Rat: Crl: CD (SD), male was used. Whole blood was collected from the abdominal aorta under ether anesthesia and collected in a vacuum blood collection tube containing ethylenediaminotetraacetate dipotassium (EDTA-2K). The collected blood was centrifuged (2,000 × g, 10 minutes, 4 ° C.), and the supernatant was used as plasma.

Reaction Rat blank plasma was mixed with an additive solution to a final concentration of 10 μM, and incubated at 37 ° C. Take 20 μL after 0.5 min, 1 min, 2 min, 5 min (5 min, 10 min, 30 min, 60 min for non-ester compounds), and then add 20 μL of acetonitrile and internal standard. The reaction was stopped by adding 20 μL of the solution and stirring.

Measurement sample The reaction stop solution was centrifuged (10,600 × g, 5 minutes), and the supernatant was prepared by diluting with a mixture of acetonitrile: purified water = 1: 1. For the calibration curve sample, add 20 μL of rat blank plasma and 20 μL of internal standard solution to 20 μL of the standard solution for calibration curve. Stir well, and then centrifuge the supernatant (10,600 × g, 5 minutes) with acetonitrile: purified water = 1: 1. Prepared by diluting with a mixture.

Measurement conditions were measured using LC-MS / MS. The conditions are as follows.
MS / MS: Micromass Quattro Ultima
HPLC: Agilent 1100 (Agilent)
Mobile phase: A, 0.05% formic acid aqueous solution, B, 0.05% formic acid acetonitrile solution Analysis column: Develosil ODS-UG-5 (2.0 mmI.D. × 150 mm, 5μm, Nomura Chemical)
Guard column: Phenomenex security guard (2.0 mml.D. × 4 mm, Phenomenex)
Column temperature: 40 ° C
Injection volume: 5μL

The drug concentration was calculated by the internal standard method using the peak area ratio between the test drug and the internal standard substance. Further, the calibration curve measurement value was obtained by using the peak area of the calibration curve sample measured before and after the sample measurement, and the drug concentration in the sample was calculated from the standard calibration curve obtained by the weighted least square method (weight: 1 / Conc.). LC-MS / MS operation software Masslynx was used for peak identification, area ratio calculation, calibration curve creation and sample concentration calculation.

In accordance with the above method, the half-life (t _1/2 ) was calculated. As a result, for example, the compound of Example 1 has a half-life of 1.1 minutes, whereas the compound of Example 78 (non-ester compound) of WO2008026687 has a half-life of 120 minutes.
From the above results, it can be seen that the compound of this embodiment is rapidly metabolized in vivo and the activity is attenuated.

As described above, the novel amide derivatives, their addition salts, and their hydrates according to this embodiment have excellent PDE4 inhibitory activity and are rapidly metabolized in vivo to reduce the activity. I found. Such a compound is useful as a preventive or therapeutic agent for bronchial asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, psoriasis and the like.

Claims (8)

An amide derivative represented by the general formula (1), a pharmacologically acceptable salt thereof, or a hydrate thereof.

In formula (1), A represents a condensed aromatic heterocyclic group represented by the following formula a) or formula b).
R ¹ represents a C _1-6 alkyl group or a C _7-10 aralkyl group,
R ² is _{C 1-6} alkoxy groups, one or two _{C 1-6} alkyl amino group which may be substituted with a _{group, C 1-6} alkylsulfanyl _{group, C 1-6} alkylsulfinyl group or a _{C 1-} Represents a ₆ alkylsulfonyl group,
R ³ represents a hydrogen atom or a halogen atom,
R ⁴ and R ⁵ represent a hydrogen atom or a halogen atom. R ⁴ and R ⁵ may be the same atom, or R ⁴ and R ⁵ may be different from each other.

The amide derivative according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following formula (1a) or a compound represented by the following formula (1b): Or a hydrate thereof.

In the formulas (1a) and (1b), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. The amide derivative according to claim 1, wherein the compound represented by the general formula (1) is represented by the following formula (1aa) or (1bb), a pharmacologically acceptable salt thereof, or a hydrate thereof.

In formulas (1aa) and (1bb), R ^1a represents a C _1-6 alkyl group, R ^4a and R ^5a represent a halogen atom, and R ² and R ³ are as defined in claim 1. The compound represented by the general formula (1) is
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methoxypyrazolo [1,5-a] pyridine-2-carboxylate,
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylaminopyrazolo [1,5-a] pyridine-2-carboxylate,
Ethyl 3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methoxyimidazo [1,2-a] pyridine-2-carboxylate,
Ethyl 3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methylaminoimidazo [1,2-a] pyridine-2-carboxylate,
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylthiopyrazolo [1,5-a] pyridine-2-carboxylate,
4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylsulfinylpyrazolo [1,5-a] pyridine-2-carboxylate, or
The amide derivative according to claim 1, which is ethyl 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylsulfonylpyrazolo [1,5-a] pyridine-2-carboxylate Acceptable salts or hydrates thereof. A medicament comprising the amide derivative according to any one of claims 1 to 4, a pharmacologically acceptable salt thereof, or a hydrate thereof. An external preparation containing the amide derivative according to any one of claims 1 to 4, a pharmacologically acceptable salt thereof, or a hydrate thereof. Bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia containing the amide derivative according to any one of claims 1 to 4, a pharmacologically acceptable salt thereof, or a hydrate thereof , Treatment or prevention of allergic rhinitis, atopic dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia or Parkinson's disease. Bronchial asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis containing the amide derivative according to any one of claims 1 to 4, a pharmacologically acceptable salt thereof or a hydrate thereof Or an external preparation for the treatment or prevention of psoriasis.