JP2007091597A - Pyrazolopyridin-4-ylpyrazolon derivative, addition salt thereof, and phosphodiesterase inhibitor comprising the same as effective ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel pyrazolopyridin-4-ylpyrazolon derivative useful as a pharmaceutical exhibiting a phosphodiesterase-inhibiting action. <P>SOLUTION: The pyrazolopyridin-4-ylpyrazolon derivative is represented by general formula (1). A concrete example thereof is 6-(2-ethyl-7-methoxy-pyrazolo[1,5-a]pyridin-4-yl)-4,4-dimethyl-2,4-dihydro-3-pyrazolon. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to pyrazolopyridin-4-ylpyrazolone derivatives useful as phosphodiesterase (hereinafter abbreviated as PDE) inhibitors, addition salts and hydrates thereof.

  PDE is an enzyme that degrades cyclic AMP (cAMP) and cyclic GMP (cGMP), which are second messengers in vivo. To date, PDE types 1 to 11 have been found, and it is determined for each type whether cAMP is specifically decomposed, cGMP is specifically decomposed, or both are decomposed. 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 agents, and PDE4 inhibitors are bronchial asthma It is expected as a therapeutic agent for chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Alzheimer, dementia, Parkinson's disease and the like. PDE5 inhibitors are already used clinically as therapeutic agents for male sexual dysfunction. Furthermore, recently, there has been a report that minocycline was effective as a PDE10A modulator in patients with Huntington's disease (Patent Document 1), and PDE10 inhibitors are various types such as Huntington, Alzheimer, dementia, Parkinson's disease, and schizophrenia. An open patent publication showing effectiveness as a therapeutic agent for mental disorders has also been disclosed (Patent Document 2).

  On the other hand, pyrazolopyridine derivatives having a PDE inhibitory action are disclosed in (Patent Documents 3 and 4), but do not include compounds in which a pyrazolopyridine ring and a pyrazolone ring are combined, which is a feature of the compound of the present application. Moreover, it has not been known until now that such a compound has a PDE inhibitory action. Further, pyrazolone derivatives having a PDE3 inhibitory action have been reported in (Non-patent Documents 1 and 2), but the structure is completely different from that of the compound of the present application.

WO01024781 pamphlet JP 2002-363103 JP Republished WO98 / 14448 Japanese Patent Laid-Open No. 10-109988 Sircar I et al., J. Med. Chem., 30, 1724 (1987) Scott D. Edmonson et al., Bio. Med. Chem. Lett., 13, 3983 (2003)

  An object of the present invention is to provide a pyrazolopyridin-4-ylpyrazolone derivative having an excellent PDE inhibitory action and less side effects.

  As a result of intensive studies to create a compound having PDE inhibitory activity and high safety, the present inventors have discovered a novel pyra having a structure different from that of PDE inhibitors known so far. The present invention was completed by finding that zolopyridin-4-ylpyridazinone derivatives have a strong PDE inhibitory action.

That is, the present invention is 1) General formula (1)

[Wherein, R ₁ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, an optionally substituted lower alkoxy group having 1 to 4 carbon atoms, carbon A lower alkylthio group having 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4 carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, a lower alkylamino group having 1 to 4 carbon atoms, or a lower alkanoyl group having 1 to 4 carbon atoms Group
R ₂ represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms,
R ₃ and R ₄ are the same or different and represent a lower alkyl group having 1 to 4 carbon atoms,
R ₅ represents a hydrogen atom, an optionally substituted benzyl group or a pyridylmethyl group]
A pyrazolopyridin-4-ylpyrazolone derivative, an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof,

2) The compound represented by the general formula (1) is represented by the general formula (1a)

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
1) The pyrazolopyridin-4-ylpyrazolone derivative according to 1), optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof,

3) The pyrazolopyridin-4-ylpyrazolone derivative according to 2) above, wherein R ₁ is a methoxy group in the general formula (1a), optical isomers and pharmaceutically acceptable salts thereof, and Its hydrate,

4) The pyrazolopyridin-4-ylpyrazolone derivative according to 2) above, wherein R ₁ is a methylthio group in the general formula (1a), optical isomers and pharmacologically acceptable salts thereof, and Its hydrate,

5) The pyrazolopyridin-4-ylpyrazolone derivative according to 2), wherein R ₁ is a methylamino group in the general formula (1a), optical isomers and pharmacologically acceptable salts thereof As well as its hydrates,

6) The compound represented by the general formula (1) is
6- (2-ethyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-ethyl-7-methylthio-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-ethyl-7-methylamino-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-ethyl-7-hydroxymethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (7-acetyl-2-ethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-cyclopropyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (7-Methoxy-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone or 6- (7-methoxy Pyrazolopyridine-4 according to 1), which is methyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone -Ylpyrazolone derivatives, and pharmacologically acceptable salts and hydrates thereof,

7) General formula (1)

[Wherein, R ₁ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, an optionally substituted lower alkoxy group having 1 to 4 carbon atoms, carbon A lower alkylthio group having 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4 carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, a lower alkylamino group having 1 to 4 carbon atoms, or a lower alkanoyl group having 1 to 4 carbon atoms Group
R ₂ represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms,
R ₃ and R ₄ are the same or different and represent a lower alkyl group having 1 to 4 carbon atoms,
R ₅ represents a hydrogen atom, an optionally substituted benzyl group or a pyridylmethyl group]
A PDE inhibitor comprising at least one or more of pyrazolopyridin-4-ylpyrazolone derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof, characterized in that ,

8) The compound represented by the general formula (1) is represented by the general formula (1a)

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
7) The pyrazolopyridin-4-ylpyrazolone derivative, its optical isomers, pharmacologically acceptable salts and hydrates thereof as described in 7) above, 7) The PDE inhibitor according to 7),

9) Effective at least one or more of the pyrazolopyridin-4-ylpyrazolone derivatives described in any one of 1 to 8 above, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof. A medicine containing as an ingredient,
It is about.

  The present invention has been found that a novel pyrazolopyridin-4-ylpyrazolone derivative and an addition salt thereof have an excellent PDE inhibitory action. Such compounds having a PDE inhibitor action include therapeutic agents for angina pectoris, heart failure, hypertension, platelet aggregation inhibitors, bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis It is useful as a prophylactic or therapeutic agent for various psychiatric disorders such as atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Huntington, Alzheimer, dementia, Parkinson's disease, schizophrenia, etc., and a male sexual dysfunction therapeutic agent.

  The above general formula (1) and general formula (1a) in the present invention are novel compounds.

  Examples of the pharmacologically acceptable salt of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, and citrate. Or an acid addition salt like tartrate is mentioned.

  In the general formula (1) of the present invention, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Further, “a lower alkyl group having 1 to 4 carbon atoms”, “a lower alkoxy group having 1 to 4 carbon atoms”, “a lower alkylthio group having 1 to 4 carbon atoms”, “a lower alkylsulfinyl group having 1 to 4 carbon atoms”, Examples of the “lower alkyl group” such as “lower alkylsulfonyl group having 1 to 4 carbon atoms” and “lower alkylamino group having 1 to 4 carbon atoms” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t- Examples thereof include linear or branched hydrocarbons having 1 to 4 carbon atoms such as butyl.

  The “lower alkyl group having 1 to 4 carbon atoms which may have a substituent” means having a halogen atom, a hydroxy group or a lower alkoxy group having 1 to 4 carbon atoms on a branched or straight chain carbon chain. Is mentioned.

  Examples of the “cycloalkyl group having 3 to 8 carbon atoms” include cyclic hydrocarbons having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

  Examples of the “lower alkanoyl group having 1 to 4 carbon atoms” include linear or branched lower alkanoyl groups having 1 to 4 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group or isobutyryl group. Examples of the “benzyl group which may have a substituent” include a benzyl group having a halogen atom, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms and a nitro group on the benzene ring. .

According to the present invention, among the compounds represented by the general formula (1), a compound in which R ₅ is a hydrogen atom, that is, the general formula (1b)

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above]
Can be produced by, for example, the synthetic route shown below.

<Synthesis route A>

  In the synthesis route A, the general formula (3a)

[Wherein R ₁ is as described above]
The compound represented by general formula (2a)

[Wherein R ₁ is as described above]
Can be produced by reacting the compound represented by the formula with O-mesitylenesulfonylhydroxyamine (MSH) (step A-1).

  In the reaction, the compound represented by the general formula (2a) is preferably dissolved in methylene chloride and a methylene chloride solution of MSH is allowed to act at 0 ° C. to room temperature.

  In the synthesis route A, the general formula (4a)

[Wherein, R represents a lower alkoxy group having 1 to 4 carbon atoms, a benzyloxy group or a lower alkyl group having 1 to 4 carbon atoms, and R ₁ and R ₂ are as described above]
The compound represented by the general formula (3a) and the compound represented by the general formula (10)

[Wherein R ₂ and R are as described above]
Can be produced by acting in the presence of a base (step A-2).

  Reaction is methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. In the presence of an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or in the presence of an organic base such as triethylamine, the reaction temperature is 0 ° C., preferably at room temperature. It can be carried out.

  In the synthesis route A, the general formula (5)

[Wherein R ₁ and R ₂ are as described above]
Can be produced by demethylating, hydrolyzing and decarboxylating or decarbonylating the compound represented by the general formula (4a) (step A-3).

  As a method for performing all the reactions at once, a method of using hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing is preferable. Further, after demethylation at 0 ° C. to room temperature using chloroform, preferably methylene chloride as a solvent, Lewis acid such as aluminum chloride and boron trichloride, preferably boron tribromide, methanol, ethanol, THF, DMSO In a DMF, 1,4-dioxane solvent, a potassium hydroxide aqueous solution, a lithium hydroxide aqueous solution, preferably a sodium hydroxide aqueous solution is allowed to act at room temperature to reflux under heating to hydrolyze to a carboxylic acid, followed by decarboxylation. You can also.

  For decarboxylation, an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, xylene is used, and the reaction is performed by heating to 100 to 160 ° C., or in ethanol or 1,4-dioxane, 2 to 10%. An aqueous sulfuric acid solution can be added and heated at 100 ° C., or stirred at 100 ° C. in 50% sulfuric acid. Decarbonylation is preferably carried out in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid under heating and reflux.

  In the synthesis route A, the general formula (6)

[Wherein R ₁ , R ₂ and R ₃ are as described above]
The compound represented by the general formula (5) is obtained by trifluoromethanesulfonylation of the compound represented by the general formula (5), and then the general formula (11).

[Wherein R ′ represents a lower alkyl group having 1 to 4 carbon atoms or a benzyl group, and R ₃ is as described above]
It can manufacture by attaching | subjecting to the compound represented by Heck reaction (process A-4).

  In the reaction, trifluoromethanesulfonate was obtained by reacting trifluoromethanesulfonic anhydride at 0 ° C. to room temperature in the presence of an organic base such as diisopropylethylamine or triethylamine in THF, chloroform, carbon tetrachloride, preferably methylene chloride solvent. Thereafter, it is obtained by subjecting to Heck reaction and acid hydrolysis. Although the solvent is not particularly limited for the Heck reaction, in general, DMF is used, palladium acetate and 1,3-bis (diphenylphosphino) propane are added as catalysts, various vinyl ethers in the presence of triethylamine, and room temperature, preferably After reacting at 80 ° C., the obtained compound can be dissolved in 1,4-dioxane, DMF, preferably THF, and hydrolyzed at room temperature by adding dilute hydrochloric acid.

  In the synthesis route A, the general formula (7)

[Wherein R ₁ , R ₂ , R ₃ , and R ′ are as described above]
The compound represented by general formula (6) and the general formula (12)

[Wherein R ′ is as described above]
Can be produced by acting in the presence of a base (step A-5).

  The reaction is preferably carried out under heating and reflux using a compound of the general formula (12) in the presence of an inorganic base such as sodium alkoxide, potassium alkoxide or potassium hydride, preferably sodium hydride, in a solvent amount.

  In the synthesis route A, the general formula (8)

[Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ′ are as described above]
The compound represented by general formula (13)

[Wherein X represents a halogen atom and R ₄ is as described above]
Can be produced by acting in the presence of a base (step A-6).

  In the reaction, the compound represented by the general formula (7) is converted into sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, lithium diisopropylamide (LDA), lithium-2,2,6,6-tetramethylpiperidide. , Lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide as a base, and then reacted with a compound represented by the general formula (13). Further, THF, 1,4-dioxane, 1,2-dimethoxyethane or the like can be used as a reaction solvent, and the reaction can be performed at −78 ° C. to room temperature.

  Further, in the synthesis route A, the compound represented by the general formula (8) is changed from the compound represented by the general formula (6) to the general formula (9).

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above]
It can manufacture also through the compound represented by these.

  The compound represented by the general formula (9) can be synthesized by reacting the compound represented by the general formula (6) with the compound represented by the general formula (13) in the presence of a base (step A). -7).

  In the reaction, a compound represented by the general formula (6) is converted into sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, LDA, lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, Sodium bistrimethylsilylamide and potassium bistrimethylsilylamide are treated as bases and then reacted with the compound represented by the general formula (13). Further, THF, 1,4-dioxane, 1,2-dimethoxyethane or the like can be used as a reaction solvent, and the reaction can be performed at −78 ° C. to room temperature.

  Conversion from the compound represented by the general formula (9) to the compound represented by the general formula (8) can be produced by reacting the compound represented by the general formula (12) in the presence of a base (step). A-8).

  The reaction is preferably carried out under heating and reflux using a compound of the general formula (12) in the presence of an inorganic base such as sodium alkoxide, potassium alkoxide or potassium hydride, preferably sodium hydride, in a solvent amount.

  The compound represented by General Formula (1b) in Synthesis Route A can be produced by reacting the compound represented by General Formula (8) with a hydrazine derivative (Step A-9).

  As the hydrazine derivative, hydrazine salts such as hydrazine, hydrazine acetate, and hydrazine hydrochloride, or carbazates such as t-butyl carbazate, methyl carbazate, and benzyl carbazate can be used.

  In the case of using hydrazine and its salt, the reaction can be carried out using benzene, toluene, acetic acid or ethanol as a reaction solvent at room temperature or preferably under heating and refluxing.

  In the case of using a carbazate, benzene, toluene, xylene, etc. are used as a reaction solvent, paratoluenesulfonic acid, pyridinium paratoluenesulfonate, etc. are used as an acid catalyst, preferably under dehydrating conditions using a Dean-Stark trap. The compound obtained after the reaction can be deprotected with trifluoroacetic acid, methanol containing hydrogen chloride, ethanol, ethyl acetate, diethyl ether or the like if necessary. .

  The intermediate compound represented by the general formula (6) in the synthesis route A can also be produced by the following synthesis route B.

<Synthetic route B>

  In the synthesis route B, the general formula (3b)

[Wherein R ₆ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, an acetyl group, a tetrahydropyranyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group or a triisopropylsilyl group; ₁ and R ₃ are as described above], the compound represented by the general formula (2b)

[Wherein R ₁ , R ₃ and R ₆ are as described above]
It can manufacture by making the compound represented by MSH act (process B-1).

  In the reaction, it is preferable to dissolve the compound represented by the general formula (2b) in methylene chloride and to act a methylene chloride solution of MSH at 0 ° C. to room temperature.

  In the synthesis route B, the general formula (4b)

[Wherein R ₁ , R ₂ , R ₃ , R ₆ and R are as described above]
Can be produced by allowing the compound represented by the general formula (3b) and the compound represented by the general formula (10) to act in the presence of a base (step B-2).

  For the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. are used as reaction solvents, and sodium bicarbonate, sodium carbonate, carbonate The reaction can be carried out in the presence of an inorganic base such as potassium hydrogen or potassium carbonate, or in the presence of an organic base such as triethylamine at a reaction temperature of 0 ° C., preferably at room temperature.

  In the synthesis route B, the general formula (14)

[Wherein R ₁ , R ₂ and R ₃ are as described above]
The compound represented by general formula (4b) can be produced by hydrolyzing and decarboxylating or decarbonylating the compound represented by the above general formula (4b) (step B-3).

In the reaction, when R ₆ is a lower alkyl group having 1 to 4 carbon atoms or a tetrahydropyranyl group, deprotection, hydrolysis and decarboxylation are performed by heating under reflux using hydrobromic acid or acetic acid containing hydrogen bromide. Can be done simultaneously. When R ₆ is an acetyl group, a potassium hydroxide aqueous solution, a lithium hydroxide aqueous solution, preferably a sodium hydroxide aqueous solution is allowed to act in a methanol, ethanol, THF, DMSO, DMF, or dioxane solvent at room temperature to under reflux with heating to a carboxylic acid. And can be decarboxylated after hydrolysis. Further, when R ₆ is a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, or a triisopropylsilyl group, tetrabutylammonium fluoride is reacted in a THF solvent to remove the silyl group, and then the acid or alkali method described above is used. After hydrolysis, it can be decarboxylated. For decarboxylation, an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, xylene is used, and the reaction is performed by heating to 100 to 160 ° C., or a 2 to 10% aqueous sulfuric acid solution is added in ethanol or dioxane. The mixture can be heated at 100 ° C. or stirred at 50 ° C. in 50% sulfuric acid. Decarbonylation is preferably carried out in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid under heating and reflux.

  The compound represented by General Formula (6) in Synthesis Route B can be produced by oxidizing the compound represented by General Formula (14) (Step B-4).

  The reaction can be carried out using a commonly used oxidative method of alcohols to aldehydes and ketones, such as chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, chromium oxide, silver carbonate, manganese dioxide, etc. And DMSO oxidation using various DMSO activators such as oxalyl chloride, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, dicyclohexylcarbodiimide (DCC), sulfur trioxide-pyridine complex, and Dess-Martin oxidation. .

  In the synthesis route B, the general formula (15)

[Wherein R ₁ , R ₂ , R ₃ and R are as described above]
The compound represented by general formula (4b) can be produced by deprotecting the compound represented by the general formula (4b), if necessary, followed by oxidation (step B-5).

For deprotection, when R ₆ is a lower alkyl group having 1 to 4 carbon atoms, boron trichloride or boron tribromide is preferably allowed to act from 0 ° C. to room temperature in methylene chloride. When R ₆ is a tetrahydropyranyl group, deprotection can be performed by various methods, but a method in which hydrochloric acid is allowed to act at room temperature in an alcohol solvent such as methanol or ethanol or THF is simple. In the case of an acetyl group, a general deacetylation reaction can be used, for example, a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide is allowed to act at room temperature in methanol or ethanol. Furthermore, in the case of a silyl protecting group, it is preferable to work tetrabutylammonium fluoride in THF. The oxidation reaction can be carried out by using generally used oxidative methods of alcohols to aldehydes and ketones, such as chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, chromium oxide, silver carbonate, manganese dioxide. And DMSO oxidation using various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, sulfur trioxide-pyridine complex, and Dess-Martin oxidation.

  The compound represented by the general formula (6) in the synthesis route B can be produced by hydrolyzing the compound represented by the general formula (15), followed by decarboxylation or decarbonylation (step B- 6).

  The reaction is carried out using hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing to simultaneously perform hydrolysis and decarboxylation, or an aqueous potassium hydroxide solution in methanol, ethanol, THF, DMSO, DMF, dioxane solvent, Lithium hydroxide aqueous solution, preferably sodium hydroxide aqueous solution is allowed to act at normal temperature to heating under reflux to hydrolyze to carboxylic acid, followed by decarboxylation. For decarboxylation, an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, xylene is used, and the reaction is performed by heating to 100 to 160 ° C., or a 2 to 10% aqueous sulfuric acid solution is added in ethanol or dioxane. The mixture can be heated at 100 ° C. or stirred at 50 ° C. in 50% sulfuric acid. Decarbonylation is preferably carried out in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid under heating and reflux.

  The intermediate compound represented by the general formula (6) in the synthesis route A can also be produced by the following synthesis route C.

<Synthetic route C>

  In the synthesis route C, the general formula (3c)

[Wherein R ₁ and R ₃ are as described above]
The compound represented by general formula (2c)

[Wherein R ₁ and R ₃ are as described above]
It can manufacture by making the compound represented by MSH act (process C-1).

  In the reaction, it is preferable to dissolve the compound represented by the general formula (2c) in methylene chloride, and to act a methylene chloride solution of MSH at 0 ° C. to room temperature.

  In the synthesis route E, the general formula (4c)

[Wherein R ₁ , R ₂ , R ₃ and R are as described above]
Can be produced by reacting the compound represented by the general formula (3c) and the compound represented by the general formula (10) in the presence of a base (step C-2).

  For the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. are used as reaction solvents, and sodium bicarbonate, sodium carbonate, carbonate The reaction can be carried out in the presence of an inorganic base such as potassium hydrogen or potassium carbonate, or in the presence of an organic base such as triethylamine at a reaction temperature of 0 ° C., preferably at room temperature.

  In the synthesis route C, the compound represented by the general formula (6) can be produced by decarboxylating or decarbonylating the compound represented by the general formula (4c) (Step C- 3).

The reaction is carried out using hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing to simultaneously perform hydrolysis and decarboxylation, or an aqueous potassium hydroxide solution in methanol, ethanol, THF, DMSO, DMF, dioxane solvent, Lithium hydroxide aqueous solution, preferably sodium hydroxide aqueous solution is allowed to act at normal temperature to heating under reflux to hydrolyze to carboxylic acid, followed by decarboxylation. For decarboxylation, an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, xylene is used, and the reaction is performed by heating to 100 to 160 ° C., or a 2 to 10% aqueous sulfuric acid solution is added in ethanol or dioxane. The mixture can be heated at 100 ° C. or stirred at 50 ° C. in 50% sulfuric acid. Decarbonylation is preferably carried out in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid under heating and reflux.

The intermediate compound represented by the general formula (14) in the synthesis route B is synthesized using the two compounds represented by the general formula (2d) and the general formula (2e) as raw materials as shown in the following synthesis route D. Can do.

<Synthesis route D>

  In the synthesis route D, the general formula (3d)

[Wherein R ₁ is as described above]
The compound represented by general formula (2d)

[Wherein R ₁ is as described above]
It can manufacture by making the compound represented by MSH act (process D-1).
In the reaction, it is preferable to dissolve the compound represented by the general formula (2d) in methylene chloride and to act a methylene chloride solution of MSH at 0 ° C. to room temperature.

  In the synthesis route D, the general formula (4d)

[Wherein R ₁ , R ₂ and R are as described above]
The compound represented by general formula (3d) and the compound represented by general formula (10) can be produced in the presence of a base (step D-2).

  For the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. are used as reaction solvents, and sodium bicarbonate, sodium carbonate, carbonate The reaction can be carried out in the presence of an inorganic base such as potassium hydrogen or potassium carbonate, or in the presence of an organic base such as triethylamine at a reaction temperature of 0 ° C., preferably at room temperature.

  In the synthesis route D, the general formula (16)

[Wherein R ₁ and R ₂ are as described above]
The compound represented by general formula (4d) can be produced by hydrolyzing and decarboxylating or decarbonylating the compound represented by the general formula (4d) (step D-3).

  The reaction is carried out using hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing to simultaneously perform hydrolysis and decarboxylation, or an aqueous potassium hydroxide solution in methanol, ethanol, THF, DMSO, DMF, dioxane solvent, Lithium hydroxide aqueous solution, preferably sodium hydroxide aqueous solution is allowed to act at normal temperature to heating under reflux to hydrolyze to carboxylic acid, followed by decarboxylation. For decarboxylation, an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, xylene is used, and the reaction is performed by heating to 100 to 160 ° C., or a 2 to 10% aqueous sulfuric acid solution is added in ethanol or dioxane. The mixture can be heated at 100 ° C. or stirred at 50 ° C. in 50% sulfuric acid. Decarbonylation is preferably carried out in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid under heating and reflux.

  In the synthesis route D, the general formula (17)

[Wherein R ₁ , R ₂ and R are as described above]
Can be produced by oxidizing the compound represented by the general formula (4d) (step D-4).

  The reaction can be performed using a commonly used oxidative method of alcohol to aldehyde, such as chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, and metal oxides such as chromium oxide, silver carbonate and manganese dioxide. And DMSO oxidation using various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, sulfur trioxide-pyridine complex, and Dess-Martin oxidation.

  In the synthesis route D, the general formula (3e)

[Wherein R ₁ is as described above]
The compound represented by general formula (2e)

[Wherein R ₁ is as described above]
Can be produced by allowing MSH to react with MSH (step D-5).
In the reaction, it is preferred to dissolve the compound represented by the general formula (2e) in methylene chloride and to act a methylene chloride solution of MSH at 0 ° C. to room temperature.

  In the synthesis route D, the general formula (4e)

[Wherein R ₁ , R ₂ and R are as described above]
The compound represented by general formula (3e) and the compound represented by general formula (10) can be produced in the presence of a base (step D-6).

  For the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, acetonitrile, etc. are used as reaction solvents, and sodium bicarbonate, sodium carbonate, carbonate The reaction can be carried out in the presence of an inorganic base such as potassium hydrogen or potassium carbonate, or in the presence of an organic base such as triethylamine at a reaction temperature of 0 ° C., preferably at room temperature.

  In the synthesis route D, the general formula (18)

[Wherein R ₁ and R ₂ are as described above]
Can be produced from the compounds represented by the general formulas (16), (17) and (4e).

  When manufacturing from the compound represented by General formula (16), it can manufacture by attaching | subjecting to an oxidation reaction (process D-7).

  The reaction can be performed using a commonly used oxidative method of alcohol to aldehyde, such as chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, and metal oxides such as chromium oxide, silver carbonate and manganese dioxide. And DMSO oxidation using various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, sulfur trioxide-pyridine complex, and Dess-Martin oxidation.

  Moreover, when manufacturing from the compound represented by General formula (17), it can manufacture by hydrolysis reaction and subsequent decarboxylation reaction or decarbonylation reaction (process D-8).

  The reaction is carried out using hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing to simultaneously perform hydrolysis and decarboxylation, or an aqueous potassium hydroxide solution in methanol, ethanol, THF, DMSO, DMF, dioxane solvent, Lithium hydroxide aqueous solution, preferably sodium hydroxide aqueous solution is allowed to act at normal temperature to heating under reflux to hydrolyze to carboxylic acid, followed by decarboxylation. For decarboxylation, an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, xylene is used, and the reaction is carried out by heating to 140 to 160 ° C., or a 2 to 10% aqueous sulfuric acid solution is added in ethanol or dioxane. The mixture can be heated at 100 ° C. or stirred at 50 ° C. in 50% sulfuric acid. Decarbonylation is preferably carried out in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid under heating and reflux.

  Furthermore, also when manufacturing from the compound represented by General formula (4e), it can manufacture similarly to the above by a hydrolysis reaction, a decarboxylation reaction, or a decarbonylation reaction (process D-9).

  In the synthesis route D, the compound represented by the general formula (14) is the same as the compound represented by the general formula (18) and the general formula (19).

[Wherein M represents Li, ClMg, BrMg, IMg, and R ₃ is as described above]
It can manufacture by making the compound represented by (process D-10) react.

  The reaction can be carried out at a reaction temperature of −78 ° C. to room temperature using THF, ether, 1,4-dioxane as a reaction solvent.

  The compound represented by the general formula (6) is represented by the general formula (6 ').

[Wherein R ₁ and R ₂ are as described above]
In the presence of a base, the compound represented by the general formula (20)

[Wherein R ₃ and X are as described above]
It can manufacture by making the compound represented by act.

In the reaction, the compound represented by the general formula (6 ′) is converted into sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, LDA, lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide. Sodium bistrimethylsilylamide and potassium bistrimethylsilylamide are treated as bases and then reacted with the compound represented by the general formula (20). Further, THF, 1,4-dioxane, 1,2-dimethoxyethane or the like can be used as a reaction solvent, and the reaction can be performed at −78 ° C. to room temperature.
The compound represented by the general formula (6 ′) is represented by the general formula (11 ′) instead of the compound represented by the general formula (11) in the synthesis route A.

[Wherein R ′ is as described above]
It can synthesize | combine like the process A-4 using the compound represented by these.

  Further, instead of the compound represented by the general formula (2b) in the synthesis route B, the general formula (2b ′)

[Wherein R ₁ and R ₆ are as described above]
The synthetic route B can also be produced by using the compound represented by

  Further, the compound represented by the general formula (6 ′) is represented by the general formula (2c ′) instead of the compound represented by the general formula (2c) in the synthesis route C.

[Wherein R ₁ is as described above]
The compound represented by the above can be used as a raw material, and can be produced according to synthesis route C.

Of the compounds represented by the general formula (6), general formula (6 ′) and general formula (18), a compound in which R ₁ is the 7-position of the pyrazolopyridine ring and is a halogen atom, that is, the general formula (21)

[Wherein R ₇ represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms, and R ₂ and X are as described above]
The compound represented by can also be synthesized by the following synthesis route E.

<Synthesis route E>

  In the synthesis route E, the general formula (22)

[Wherein, Pro represents an alcohol protecting group such as a methoxymethyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triisopropylsilyl group, a tetrahydropyranyl group or an acetyl group, and R ₂ and R ₇ are As mentioned above]
The compound represented by general formula (14) is a compound represented by general formula (14), in which R ₁ is a hydrogen atom, that is, general formula (14a)

[Wherein R ₂ and R ₃ are as described above]
And a compound represented by the general formula (14b)

[Wherein R ₂ is as described above]
Or a compound represented by the general formula (16) wherein R ₁ is a hydrogen atom, that is, the general formula (16a)

[Wherein R ₂ is as described above]
It can manufacture by attaching | subjecting the compound represented by various alcohol protective group introduction | transduction reaction (process E-1).

  When a methoxymethyl group is introduced, it is desirable that methoxymethyl chloride or methoxymethyl bromide is allowed to act in THF, acetonitrile, preferably methylene chloride at 0 ° C. to room temperature in the presence of sodium hydride, triethylamine, diisopropylethylamine, and the like. In addition, when a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, or a triisopropylsilyl group is introduced, the reaction is carried out in the presence of triethylamine, imidazole, etc. in the presence of the corresponding silyl chloride, silyl bromide, silyl trifluoromethanesulfonate. , DMF, acetonitrile, methylene chloride, etc. In order to introduce a tetrahydropyranyl group, it is preferable to add an acid catalyst such as p-toluenesulfonic acid in the presence of dihydropyran and to act in methylene chloride. Further, when introducing an acetyl group, acetyl chloride, acetyl bromide, or acetic anhydride is used in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, THF, 1,4-dioxane, methylene chloride as a solvent, Alternatively, the reaction can be performed at 0 ° C. to room temperature using pyridine as a solvent.

  In the synthesis route E, the general formula (23)

[Wherein R ₂ , R ₇ , X and Pro are as described above]
Can be produced by halogenating the compound represented by the general formula (22) (step E-2).

  In the reaction, butyllithium, lithium bistrimethylsilylamide, preferably LDA is used as a base, reacted in THF solvent at −78 to 0 ° C., and then N-chlorosuccinimide (NCS), N-bromosuccinimide ( NBS), N-iodosuccinimide (NIS), bromine, iodine, 1,2-dibromoethane or 1,2-diiodoethane is preferably used.

  In the synthesis route E, the compound represented by the general formula (21) can be produced by deprotecting and oxidizing the compound represented by the general formula (23) (step E-3).

  In the case of a methoxymethyl group and a tetrahydropyranyl group, the deprotection reaction is preferably carried out using hydrogen chloride-containing methanol, ethanol, ethyl acetate, and diethyl ether at 0 ° C. to room temperature. In the case of a silyl protecting group, it is preferable to use potassium fluoride, cesium fluoride, tetrabutylammonium fluoride in acetonitrile or THF solvent at 0 ° C. to room temperature. In the case of an acetyl group, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, or a lithium hydroxide aqueous solution is used, and THF, methanol, ethanol, 1,4-dioxane or the like can be used as a solvent at 0 ° C. to room temperature. Oxidation reactions include chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, metal oxidizers such as chromium oxide, silver carbonate and manganese dioxide, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, and trioxide. DMSO oxidation using various DMSO activators such as sulfur-pyridine complex, Dess-Martin oxidation and the like can be mentioned.

  The compound represented by the general formula (21) can also be produced by the following synthesis route F.

<Synthesis route F>

  In the synthesis route F, the general formula (24)

[Wherein R ₂ and R ₇ are as described above]
The compound represented by general formula (6) is a compound represented by general formula (6), in which R ₁ is a hydrogen atom, that is, general formula (6a)

[Wherein R ₂ and R ₃ are as described above]
And a compound represented by the general formula (6 ′) in which R ₁ is a hydrogen atom, that is, the general formula (6′a)

[Wherein R ₂ is as described above]
Or a compound represented by the general formula (18) wherein R ₁ is a hydrogen atom, that is, the general formula (18a)

[Wherein R ₂ is as described above]
It can manufacture by making the compound represented by ethylene glycol react (process F-1).

  The reaction is preferably carried out using benzene, toluene or xylene under heating and refluxing using a catalytic amount of paratoluenesulfonic acid or pyridinium paratoluenesulfonate. Dean-Stark can also be attached and dehydrated.

  In the synthesis route F, the general formula (25)

[Wherein R ₂ , R ₇ and X are as described above]
Can be produced by halogenating the compound represented by the general formula (24) (step F-2).

  The reaction is performed using butyllithium, lithium bistrimethylsilylamide, preferably LDA as a base, in a THF solvent at −78 to 0 ° C., then NCS, NBS, NIS, bromine, iodine, 1,2-dibromo. It is preferable to act on ethane or 1,2-diiodoethane.

  The compound represented by general formula (21) in the synthetic pathway F can be manufactured by deprotecting the compound represented by the said general formula (25) (process F-3).

  The reaction is carried out in an acetone solvent using an acid catalyst such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and the reaction is carried out at normal temperature to heating under reflux, or using hydrogen chloride-containing methanol, ethanol, ethyl acetate, diethyl ether at 0 ° C to It is preferable to make it react at normal temperature.

Of the compounds represented by the general formulas (6), (6 ′) and (18), R ₁ is the 7-position of the pyrazolopyridine ring and optionally having 1 to 4 carbon atoms. Group, a compound having a lower alkylthio group having 1 to 4 carbon atoms or a lower alkylamino group having 1 to 4 carbon atoms, that is, the general formula (26)

[In the formula, Y is an optionally substituted lower alkoxy group having 1 to 4 carbon atoms, a lower alkylthio group or a lower alkylamino group having 1 to 4 carbon atoms having 1 to 4 carbon atoms, R ₂ and R ₇ is as described above]
Can be produced by derivatizing the compound represented by the general formula (21) into the corresponding compound.

In the case of a lower alkoxy group having 1 to 4 carbon atoms and a lower alkylthio group having 1 to 4 carbon atoms which may have a substituent, sodium hydride or potassium hydride is added as a base to the corresponding alcohol or thiol, THF, It is preferable to use DMSO, preferably DMF as a solvent and heat at normal temperature to 60 ° C.
In the case of a lower alkylamino group having 1 to 4 carbon atoms, the corresponding amine is preferably reacted at 60 to 70 ° C. in methanol, THF, preferably DMF solvent.

Of the compounds represented by the general formulas (6), (6 ′) and (18), a compound in which R ₁ is the 7-position of the pyrazolopyridine ring and is a hydroxymethyl group, that is, the general formula (27)

[Wherein R ₂ and R ₇ are as described above]
As shown in the following synthesis route G, the compound represented by can be synthesized using the compound represented by the general formula (24) as a raw material.

<Synthetic route G>

  In the synthesis route G, the general formula (29)

[Wherein R ₂ and R ₇ are as described above]
Can be produced by formylating the compound represented by the general formula (24) (step G-1).

  In the reaction, butyl lithium, lithium bistrimethylsilylamide, preferably LDA is used as a base, and after reacting in THF solvent at −78 to 0 ° C., ethyl formate or DMF is preferably allowed to act.

  In the synthesis route G, the general formula (30)

[Wherein R ₂ and R ₇ are as described above]
Can be produced by reducing the compound represented by the general formula (29) (step G-2).

The reaction uses a reducing agent such as sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, and the reaction solvent is an ether solvent such as THF in the case of sodium borohydride, preferably In the case of lithium borohydride using an alcohol solvent such as ethanol and methanol, THF, preferably used by adding an alcohol solvent such as ethanol to THF, in the case of diisobutylaluminum hydride,
In the case of lithium aluminum hydride using THF, toluene, methylene chloride or the like, the reaction can be performed at 0 ° C. to room temperature using an ether solvent such as THF or diethyl ether.

  The compound represented by General Formula (27) in Synthesis Route G can be produced by deprotecting the compound represented by General Formula (30) (Step G-3).

  The reaction is carried out in an acetone solvent using an acid catalyst such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and the reaction is carried out at normal temperature to heating under reflux, or using hydrogen chloride-containing methanol, ethanol, ethyl acetate, diethyl ether at 0 ° C to It is preferable to make it react at normal temperature.

Among the compounds represented by the general formulas (6), (6 ′) and (18), R ₁ is the 7-position of the pyrazolopyridine ring and the lower alkyl group having 2 to 4 carbon atoms having a hydroxy group at the 1-position. A compound of the general formula (28)

[Wherein R ₈ represents a lower alkyl group having 1 to 3 carbon atoms, and R ₂ and R ₇ are as described above]
The compound represented by general formula (29) can be synthesized using the compound represented by the general formula (29) as a raw material, as shown in Synthesis Route H below.
<Synthetic route H>

  General formula (30) in synthesis route H

[Wherein R ₂ , R ₇ and R ₈ are as described above]
The compound represented by general formula (19 ′) is the same as the compound represented by general formula (29).

[Wherein R ₈ and M are as described above]
It can manufacture by making the compound represented by (process H-1) react.

  The reaction can be carried out using THF, ether, 1,4-dioxane as a reaction solvent and a reaction temperature of −78 ° C. to room temperature.

  The compound represented by general formula (28) in the synthetic pathway H can be manufactured by deprotecting the compound represented by the said general formula (30) (process H-2).

  The reaction is carried out in an acetone solvent using an acid catalyst such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and the reaction is carried out at normal temperature to heating under reflux, or using hydrogen chloride-containing methanol, ethanol, ethyl acetate, diethyl ether at 0 ° C to It is preferable to make it react at normal temperature.

Among the compounds represented by the general formulas (6), (6 ′) and (18), a compound in which R ₁ is a methyl group having a lower alkoxy group having 1 to 4 carbon atoms at the 7-position of the pyrazolopyridine ring That is, the general formula (2 ')

[Wherein R ₂ , R ₃ and R ₇ are as described above]
As shown in the following synthesis route I, the compound represented by can be synthesized using the compounds represented by the general formulas (22) and (30) as raw materials.

<Synthetic route I>

  In the synthesis route I, the general formula (29 ')

[Wherein R ₂ , R ₇ and Pro are as described above]
Can be produced by formylating the compound represented by the general formula (22) (step I-1).

  In the reaction, butyl lithium, lithium bistrimethylsilylamide, preferably LDA is used as a base, and after reacting in THF solvent at −78 to 0 ° C., ethyl formate or DMF is preferably allowed to act.

  In the synthesis route I, the general formula (30 ')

[Wherein R ₂ , R ₇ and Pro are as described above]
Can be produced by reducing the compound represented by the general formula (29 ′) (step H-2).

The reaction uses a reducing agent such as sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, and the reaction solvent is an ether solvent such as THF in the case of sodium borohydride, preferably In the case of lithium borohydride using an alcohol solvent such as ethanol and methanol, THF, preferably used by adding an alcohol solvent such as ethanol to THF, in the case of diisobutylaluminum hydride,
In the case of lithium aluminum hydride using THF, toluene, methylene chloride or the like, the reaction can be performed at 0 ° C. to room temperature using an ether solvent such as THF or diethyl ether.

  In the synthesis route I, the general formula (31)

[Wherein R ₂ , R ₃ , R ₇ and Pro are as described above]
The compound represented by general formula (30 ′) can be produced by reacting the compound represented by general formula (30 ′) with the compound represented by general formula (20) in the presence of silver oxide (step I-3). ).
The reaction can be performed at room temperature to 80 ° C. using acetonitrile, DMF or the like as a solvent.

  In the synthesis route I, the general formula (31 ')

[Wherein R ₂ , R ₃ and R ₇ are as described above]
The compound represented by general formula (30 ′) can be produced by reacting the compound represented by general formula (30 ′) with the compound represented by general formula (20) in the presence of silver oxide (step I-5). ).
The reaction can be performed at room temperature to 80 ° C. using acetonitrile or DMF as a solvent.

  In the synthesis route I, the general formula (27 ')

[Wherein R ₂ , R ₃ and R ₇ are as described above]
Can be produced by subjecting the compound represented by the general formula (31) to an oxidation reaction after deprotection (step I-4).

  In the case of a methoxymethyl group or a tetrahydropyranyl group, the deprotection reaction is preferably carried out using hydrogen chloride-containing methanol, ethanol, ethyl acetate, and diethyl ether at 0 ° C. to room temperature. In the case of a silyl protecting group, it is preferable to use potassium fluoride, cesium fluoride, tetrabutylammonium fluoride in acetonitrile or THF solvent at 0 ° C. to room temperature. In the case of an acetyl group, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, or a lithium hydroxide aqueous solution is used, and THF, methanol, ethanol, 1,4-dioxane or the like can be used as a solvent at 0 ° C. to room temperature. Oxidation reactions include chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, metal oxidizing agents such as chromium oxide, silver carbonate and manganese dioxide, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, Examples include DMSO oxidation using various DMSO activators such as sulfur oxide-pyridine complex, and Dess-Martin oxidation.

  The compound represented by the general formula (27 ') can also be produced by deprotecting the compound represented by the general formula (31') (Step I-6).

  The reaction is carried out using an acid catalyst such as p-toluenesulfonic acid and pyridinium p-toluenesulfonate in an acetone solvent at room temperature to heating under reflux, or using hydrogen chloride-containing methanol, ethanol, ethyl acetate, diethyl ether at 0 ° C. -It is preferable to make it react at normal temperature.

Of the compounds represented by the general formula (1b), a compound in which R ₁ is a lower alkanoyl group having 1 to 4 carbon atoms, that is, the general formula (32)

[Wherein R ₂ , R ₃ , R ₄ , and R ₈ are as described above]
The compound represented by general formula (33)

[Wherein R ₂ , R ₃ , R ₄ , and R ₈ are as described above]
It can manufacture by oxidizing the compound represented by these.

  Reactions include chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate, metal oxidants such as chromium oxide, silver carbonate, manganese dioxide, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, trioxide DMSO oxidation using various DMSO activators such as sulfur-pyridine complex, Dess-Martin oxidation and the like can be mentioned.

Among the compounds represented by the general formula (1), a compound in which R ₅ is a benzyl group or a pyridylmethyl group which may have a substituent, that is, the general formula (1c)

[Wherein R ₉ represents an optionally substituted phenyl group or pyridine ring, and R ₁ , R ₂ , R ₃ and R ₄ are as described above]
The compounds represented by general formula (1b) and general formula (34)

[Wherein R ₈ and X are as described above]
Can be produced by reacting in the presence of a base.

  The reaction is desirably performed at 0 ° C. to 60 ° C. using sodium hydride, sodium alkoxide, potassium alkoxide or the like as a base and THF or DMF as a reaction solvent.

EXAMPLES Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

<Example 1>
N-amino-3-chloropyridinium mesitylene sulfonate

While stirring a solution of ethyl N-hydroxyacetimidate (47.2 g) in DMF (200 mL) at 0 ° C., triethylamine (70.0 mL) and then mesitylenesulfonyl chloride (100 g) were slowly added. After stirring at the same temperature for 1.5 hours, ice water was added, and the mixture was extracted with a mixed solution of ethyl acetate: hexane = 1: 1, washed with water and then saturated brine, dried over anhydrous sodium sulfate, and concentrated to a colorless solid. Got. The resulting solid was dissolved in dioxane (100 mL), and slowly added dropwise 0 ℃ cooled stirred 70% under HClO ₄ (40.0 mL). After dropwise addition, the mixture is stirred at the same temperature for 30 minutes, ice water is added, and the precipitate is collected by filtration (Caution: If this solid is completely dried, it explodes). After washing with water, methylene chloride remains wet. After dissolving in about 300 mL, the organic layer was separated and dried over magnesium sulfate. While stirring a solution of 3-chloropyridine (43.0 g) in methylene chloride (40.0 mL) at 0 ° C., the methylene chloride solution dried over magnesium sulfate was added dropwise. Thereafter, the mixture was stirred at room temperature for 30 minutes, about 350 mL of diethyl ether was added, and the precipitated crystals were collected by filtration. After washing with ether, a dried product (69.0 g) was obtained as a colorless powder.
Elemental analysis (%): as C ₁₄ H ₁₇ ClN ₂ O ₃ S
CHN
Calculated 51.14 5.21 8.52
Actual value 51.20 5.10 8.47

<Example 2-16>
The compounds shown in Table 1 were synthesized by reacting in the same manner as in Example 1 using various pyridine derivatives.

Example 2: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.49 (6H, s), 6.74 (2H, s), 8.05-8.11 (1H, m), 8.28- 8.32 (1H, m), 8.68 (1H, t, J = 6.4 Hz), 8.71 (2H, brs), 9.06-9.08 (1H, m).

Example 3: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.16 (3H, s), 2.48 (3H, s), 2.49 (6H, s), 6.73 (2H, br s), 8.59-8.65 (1H, m), 8.91 (2H, brs), 9.00-9.01 (2H, m).

Example 4: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.16 (3H, s), 2.48 (3H, s), 2.49 (6H, s), 6.73 (2H, br s), 8.71 (2H , brs), 8.78-8.79 (1H, m), 9.01-9.02 (1H, m).

Example 5: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.49 (6H, s), 3.98 (3H, s), 6.74 (2H, s), 8.20-8.21 ( 1H, m), 8.58 (2H, brs), 8.59-8.60 (1H, m), 8.67-8.68 (1H, m).

Example 6: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.17 (3H, s), 2.49 (6H, s), 3.98 (3H, s), 6.74 (2H, s), 8.19 (1H, s), 8.60 (2H, brs), 8.67 (1H, s).

Example 7: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.33 (3H, s), 2.50 (6H, s), 4.69 (2H, s), 5.86 (1H, brs), 6.74 (2H, s), 7.96 (1H, dd, J = 6.1, 8.0 Hz), 8.15 (1H, d, J = 8.0 Hz), 8.50 (2H, s), 8.66 (1H, d, J = 6.1 Hz), 8.71 ( 1H, s).

Example 8: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.35 (3H, d, J = 6.7 Hz), 2.14 (3H, s), 2.47 (6H, s), 4.84 (1H, q, J = 6.7 Hz), 6.72 (2H, s), 7.63 (1H, dd, J = 4.9, 7.9 Hz), 8.07-8.09 (1H, m), 8.58 (1H, dd, J = 1.5, 4.9 Hz), 8.66 (1H, s).

Example 9: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.14 (3H, s), 2.47 (6H, s), 3.55 (3H, s), 3.72-3.78 (2H, m), 4.01- 4.04 (2H, m), 6.72 (2H, s), 7.98 (1H, dd, J = 6.7, 7.9 Hz), 8.22 (1H, d, J = 7.9 Hz), 8.70-8.72 (1H, m), 8.77 (1H, s).

Example 10: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.15 (3H, s), 2.47 (6H, s), 4.23 (3H, s), 4.56 (2H, s), 6.72 (2H, s ), 7.68-7.70 (3H, m), 8.14-8.17 (1H, s), 8.44 (1H, s).

Example 12: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.14 (3H, s), 2.49 (6H, s), 4.26 (3H, s), 6.74 (2H, s), 7.70 (1H, d, J = 9.2 Hz), 7.79 (2H, brs), 8.50 (1H, dd, J = 9.2, 1.8 Hz), 8.88 (1H, d, J = 2.4 Hz).

Example 13: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 0.81 (3H, t, J = 7.3 Hz), 1.54-1.66 (2H, m), 2.11 (3H, s), 2.44 (6H, s), 4.68 (1H, t, J = 6.7 Hz), 6.68 (2H, s), 7.89-7.93 (1H, m), 8.14 (1H, d, J = 7.9 Hz), 8.41 (2H, brs), 8.58-8.63 (1H, m), 8.68 (1H, s).

Example 14: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.44-1.69 (6H, m), 2.11 (3H, s), 2.44 (6H, s), 3.42-3.47 (1H, m), 3.68-3.73 (1H, m), 4.63 (1H, d, J = 14.1 Hz), 4.71 (1H, t, J = 3.3 Hz), 4.79 (1H, d, J = 14.1 Hz), 7.93 (1H, dd , J = 6.5, 7.9 Hz), 8.16 (1H, d, J = 7.9 Hz), 8.47 (2H, brs), 8.64 (1H, d, J = 6.5 Hz), 8.71 (1H, s)

Example 15: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 0.13 (6H, s), 0.92 (9H, s), 2.18 (3H, s), 2.50 (6H, s), 3.57 (3H, s), 4.25 (2H, d, J = 1.2 Hz), 6.76 (2H, s), 7.69-7.73 (2H, m), 8.11-8.16 (1H, m), 8.43-8.48 (1H, m).

Example 16: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.11 (3H, t, J = 7.3 Hz), 2.17 (3H, s), 2.50 (6H, s), 2.77 (3H, s) , 3.12 (2H, q, J = 7.3 Hz), 6.74 (2H, s), 8.10 (1H, d, J = 8.0 Hz), 8.23 (2H, brs), 8.64 (1H, d, J = 8.0 Hz) , 9.32 (1H, s).

<Example 17>
3-Acetyl-2-ethyl-4-methoxy-pyrazolo [1,5-a] pyridine

The compound of Example 5 (29.8 g) was dissolved in DMF (100 mL), 3-hexyn-2-one (10.0 mL) and potassium carbonate (37.9 g) were added, and the mixture was stirred at room temperature for 24 hours. Ice water was poured, and the mixture was extracted with ethyl acetate, washed successively with water (twice) and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1) to obtain the desired product (8.02 g) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32 (3H, t, J = 7.6 Hz), 2.63 (3H, s), 2.98 (2H, q, J = 7.6 Hz), 3.97 (3H, s), 6.61 (1H, d, J = 7.3 Hz), 6.76 (1H, t, J = 7.3 Hz), 8.11 (1H, d, J = 7.3 Hz).

<Examples 18 to 40>
The compounds shown in Table 2 were obtained by reacting with the various alkyne derivatives using the compounds of Examples 1 to 4 and 6 to 16.

Example 18: LRMS (EI ⁺ ): 254 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.6 Hz), 1.40 (3H, t, J = 7.0 Hz), 3.10 (2H, q, J = 7.6 Hz), 4.37 ( 2H, q, J = 7.0 Hz), 7.00-7.05 (1H, m), 8.27-8.29 (1H, m)

Example 19: LRMS (FAB ⁺ ): 353 [M + H] ^+
1 H-NMR (400 MHz, CDCl ₃ ) δ1.25 (6H, t, J = 7.3 Hz), 1.44 (3H, t, J = 7.3 Hz), 3.66-3.74 (4H, m), 4.12 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 4.77-4.81 (2H, m), 6.19 (1H, s), 6.22 (1H, d, J = 7.3 Hz), 7.31 (1H, d, J = 7.3 Hz)

Example 20: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.31 (3H, s), 4.15 (3H, s), 4.73-4.86 (5H, m), 5.39 (2H, s), 6.26 (1H, d, J = 7.9 Hz), 7.32-7.44 (4H, m), 7.50 (2H, d, J = 6.7 Hz)

Example 21: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.50-1.70 (2H, m), 1.70-1.90 (2H, m), 3.52-3.61 (2H, m), 3.80-3.88 (2H, m), 4.41 (2H, s), 4.83 (1H, t, J = 3.1 Hz).

Example 22: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89-1.06 (4H, m), 1.55 (3H, s), 2.48-2.53 (1H, m), 4.67 (1H, d, J = 5.5 Hz), 5.40 (1H, d, J = 12.2 Hz), 5.44 (1H, d, J = 12.2 Hz), 5.50-5.58 (1H, m), 6.87 (1H, t, J = 7.3 Hz), 7.38- 7.49 (6H, m), 8.28 (1H, dd, J = 1.2, 6.7 Hz).

Example 23: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (3H, t, J = 7.3 Hz), 0.99 (3H, t, J = 7.3 Hz), 1.76-1.82 (4H, m), 2.89 -2.91 (2H, m), 4.55-4.57 (1H, m), 5.36 (2H, s), 6.89 (1H, t, J = 6.7 Hz), 7.35-7.47 (6H, m), 8.35 (1H, d , J = 6.7 Hz)

Example 24: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.30 (3H, t, J = 7.3 Hz), 3.92 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 6.57 ( 1H, d, J = 7.3 Hz), 6.75 (1H, dd, J = 7.3, 7.3 Hz), 8.09 (1H, d, J = 7.3 Hz)

Example 25: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.43 (3H, t, J = 7.3 Hz), 2.63 (3H, s), 3.99 (3H, s), 4.39 (2H, q, J = 7.3 Hz), 6.62 (1H, d, J = 7.3 Hz), 6.78 (1H, dd, J = 7.3, 7.3 Hz), 8.09 (1H, d, J = 7.3 Hz)

Example 26: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, t, J = 6.7 Hz), 1.34 (3H, t, J = 7.3 Hz), 1.80 (3H, s), 2.77-2.83 (4H, m), 3.61-3.64 (2H, m), 3.96-3.99 (2H, m), 6.73 (1H, t, J = 6.7 Hz), 7.31 (1H, d, J = 6.7 Hz), 8.33 ( (1H, d, J = 6.7 Hz).

Example 27: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 1.84 (3H, s), 3.60-3.71 (2H, m), 3.97-4.07 (2H , m), 4.40 (2H, q, J = 7.3 Hz), 6.98 (1H, t, J = 7.3 Hz), 7.52 (1H, dd, J = 7.3, 1.2 Hz), 8.44-8.47 (1H, m)

Example 28: LRMS (EI ⁺ ): 248 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, t, J = 7.3 Hz), 1.44 (3H, t, J = 7.3 Hz), 3.08 (2H, q, J = 7.3 Hz), 4.41 ( 2H, q, J = 7.3 Hz), 4.86 (2H, d, J = 7.3 Hz), 5.02 (1H, t, J = 7.3 Hz), 6.87 (1H, t, J = 6.7 Hz), 7.30 (1H, d, J = 6.7 Hz), 8.40 (1H, d, J = 6.7 Hz).

Example 29: LRMS (EI ⁺ ): 278 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.34 (3H, t, J = 8.0 Hz), 1.44 (3H, t, J = 6.7 Hz), 3.12 (2H, q, J = 8.0 Hz), 4.16 (3H, s), 4.41 (2H, q, J = 6.7 Hz), 4.81 (2H, d, J = 7.3 Hz), 4.94 (1H, d, J = 7.3 Hz), 6.22 (1H, d, J = 7.3Hz), 7.30 (1H, d, J = 7.3 Hz)

Example 30: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.42 (3H, t, J = 7.0 Hz), 4.20 (3H, s), 4.43 (2H, q, J = 7.0 Hz), 4.62 (1H , t, J = 7.6Hz), 4.83 (2H, d, J = 7.6 Hz), 6.36 (1H, d, J = 7.6 Hz), 7.44 (1H, d, J = 7.6 Hz)

Example 31: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.02 (3H, t, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz), 1.83-1.91 (2H, m), 4.03 (1H, d, J = 5.7Hz), 4.19 (3H, s), 4.38-4.47 (2H, m), 5.17 (1H, q, J = 7.3 Hz), 6.39 (1H, d, J = 7.9 Hz) , 7.58 (1H, d, J = 7.9 Hz).

Example 32: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.99 (3H, s), 4.00 (3H, s), 4.17 (3H, s), 6.20 (1H, d, J = 7.9 Hz), 7.49 (1H, d, J = 8.6 Hz)

Example 33: LRMS (EI ⁺ ): 288 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.43 (3H, t, J = 7.3 Hz), 4.44 (2H, q, J = 7.3 Hz), 4.65 (1H, t, J = 7.3 Hz), 4.90 ( 2H, d, J = 7.3 Hz), 7.06 (1H, t, J = 7.3 Hz), 7.45 (1H, d, J = 7.3 Hz), 8.50 (1H, d, J = 7.3 Hz)

Example 34: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32 (3H, t, J = 7.3 Hz), 1.40 (3H, t, J = 7.3 Hz), 3.01 (2H, q, J = 7.3 Hz) ), 3.96 (3H, s), 4.36 (2H, q, J = 7.3 Hz), 6.56 (1H, s), 8.13 (1H, s).

Example 35: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21 (3H, t, J = 7.3 Hz), 1.33 (3H, t, J = 7.3 Hz), 2.93-2.99 (2H, m), 3.05 (2H, q, J = 7.3 Hz), 7.03-7.09 (1H, m), 8.31 (1H, brs).

Example 36: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.11 (6H, s), 0.95 (9H, s), 1.33 (3H, t, J = 7.3 Hz), 1.41 (3H, t, J = 7.3Hz), 3.09 (2H, q, J = 7.3Hz), 4.14 (3H, s), 4.35 (2H, q, J = 7.3Hz), 5.12 (2H, d, J = 1.8Hz), 6.24 (1H , d, J = 7.9Hz), 7.56 (1H, td, J = 1.8, 7.9 Hz)

Example 37: ¹ H-NMR (400 MHz, CDCl ₃ ) δ0.04 (6H, s), 0.87 (9H, s), 4.14 (3H, s), 4.63 (1H, brs), 4.81 (2H, s ), 5.08 (2H, s), 5.38 (2H, s), 6.23 (1H, d, J = 7.9 Hz), 7.30-7.42 (4H, m), 7.49 (2H, dd, J = 7.9, 1.2 Hz) , 8.14 (1H, d, J = 2.4 Hz).

Example 38: LRMS (EI ⁺ ): 232 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz), 2.97 (2H, q, J = 7.3 Hz), 3.09 ( 2H, q, J = 7.3 Hz), 4.75 (2H, d, J = 7.3 Hz), 5.04 (1H, t, J = 7.3 Hz), 5.89 (1H, t, J = 6.7 Hz), 7.30-7.32 ( 1H, m), 8.37-8.39 (1H, m).

Example 39: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.33 (3H, t, J = 7.6 Hz), 1.40 (3H, t, J = 7.0 Hz), 3.03 (2H, q, J = 7.6 Hz) ), 3.96 (3H, s), 4.37 (2H, q, J = 7.0 Hz), 6.59 (1H, d, J = 7.6 Hz), 6.75 (1H, t, J = 7.6 Hz), 8.09 (1H, d , J = 7.6 Hz).

Example 40: LRMS (EI ⁺ ): 288 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22 (3H, t, J = 7.3 Hz), 1.35 (3H, t. J = 7.3 Hz), 1.36 (3H, t, J = 7.3 Hz), 2.79 ( 3H, s), 2.84 (2H, q, J = 7.3 Hz), 3.10 (2H, q, J = 7.3 Hz), 4.33 (2H, q, J = 7.3 Hz), 6.76 (1H, d, J = 7.3 Hz), 7.29 (1H, d, J = 1.8 Hz).

<Example 41>
3-Ethoxycarbonyl-2-methylthio-4- (tetrahydropyran-2-yloxymethyl) -pyrazolo [1,5-a] pyridine

  The compound of Example 14 (45.6 g) was dissolved in ethanol (500 mL), carbon disulfide (10.3 mL) and dimethyl sulfate (16.3 mL) were added, and potassium hydroxide (14.5 g) in water (100 mL) was added. The solution was slowly added dropwise over 1.5 hours. Ice water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (hexane: ethyl acetate = 1: 4) gave a yellow oil (6.78 g). The obtained oil (8.64 g) was dissolved in chloroform (200 mL), ethyl bromoacetate (6.66 mL) was added, and the mixture was stirred at room temperature for 6 hr. After the solvent was distilled off, it was washed with diethyl ether to obtain a yellow oily substance. The obtained oil was dissolved in chloroform (290 mL), potassium carbonate (20.0 g) was added, and the mixture was stirred at room temperature for 16 hr. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain the desired product and 3-ethoxycarbonyl-2-methylthio-6- (tetrahydropyran-2-yloxymethyl). ) -Pyrazolo [1,5-a] pyridine was obtained as an inseparable mixture (3.71 g, 0.6: 1) as a yellow oil.

<Example 42>
4-acetyl-3-benzyloxycarbonyl-2-cyclopropyl-pyrazolo [1,5-a] pyridine

The compound of Example 22 (7.60 g) was dissolved in dichloromethane (100 mL), activated manganese dioxide (59.0 g) was added, and the mixture was stirred at room temperature for 30 hours. Celite filtration was carried out, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (hexane: ethyl acetate = 8: 1 → 1: 1) gave a yellow solid. Since it was confirmed that the raw material remained in the obtained solid, it was dissolved in dichloromethane (90.0 mL), active manganese dioxide (32.0 g) was added again, and the mixture was stirred again at room temperature for 24 hours. The target product (5.57 g) was obtained as a yellow powder by filtering through Celite and distilling off the solvent under reduced pressure.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.02 -1.05 (2H, m), 1.07-1.10 (2H, m), 2.42 (3H, s), 2.64-2.70 (1H, m), 5.35 (2H , s), 6.89 (1H, t, J = 6.7 Hz), 7.36-7.44 (6H, m), 8.41 (1H, d, J = 6.7 Hz).

<Example 43>
3-Ethoxycarbonyl-2-ethyl-6-fluoro-4-methoxypyrazolo [1,5-a] pyridine

Sodium methoxide (362 mg) was added to a solution of the compound of Example 18 (340 mg) in methanol (15.0 mL), and the mixture was heated to reflux for 3 hours. Further sodium methoxide (181 mg) was added and stirred for 2 hours. After allowing to cool, saturated ammonium chloride was added, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (302 mg) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.31 (3H, t, J = 7.6 Hz), 3.00 (2H, q, J = 7.6 Hz), 3.89 (3H, s), 3.98 (3H, s) , 6.55 (1H, dd, J = 1.8, 10.1 Hz), 8.05 (1H, dd, J = 1.8, 3.4 Hz).

<Example 44>
4-acetyloxymethyl-3-ethoxycarbonyl-2-diethoxymethyl-7-methoxy-pyrazolo [1,5-a] pyridine

The compound of Example 19 (2.10 g) was dissolved in pyridine (20.0 mL), acetic anhydride (1.12 mL) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the desired product (2.01 g) was obtained as a colorless oil.
LRMS (EI ⁺ ): 394 [M ⁺ ]
¹ H-NMR (400MHz, CDCl ₃ ) δ1.25 (6H, t, J = 7.3 Hz), 1.41 (3H, t, J = 7.3 Hz), 2.04 (3H, s), 3.67-3.75 (4H, m ), 4.13 (3H, s), 4.37 (2H, q, J = 7.3 Hz), 5.47 (2H, s), 6.17 (1H, s), 6.19 (1H, d, J = 8.0 Hz), 7.35 (1H , d, J = 8.0 Hz).

<Example 45>
4-acetyloxymethyl-3-ethoxycarbonyl-2-formyl-7-methoxy-pyrazolo [1,5-a] pyridine

The compound of Example 44 (2.01 g) was dissolved in a mixed solvent of acetone-water (2: 1), paratoluenesulfonic acid monohydrate (97.3 mg) was added, and the mixture was heated with stirring at 70 ° C. for 2 hours. The mixture was allowed to cool, extracted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain the desired product (1.47 g) as a colorless powder.
LRMS (EI ⁺ ): 320 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ): δ1.43 (3H, t, J = 7.3 Hz), 2.05 (3H, s), 4.21 (3H, s), 4.45 (2H, q, J = 7.3 Hz) , 5.50 (2H, s), 6.36 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz), 10.5 (1H, s).

<Example 46>
4-acetyloxymethyl-3-ethoxycarbonyl-2-difluoromethyl-7-methoxy-pyrazolo [1,5-a] pyridine

In an argon gas atmosphere, the compound of Example 45 (1.47 g) was dissolved in dichloromethane (23.0 mL), and diethylaminosulfur trifluoride (1.52 mL) was added dropwise under ice cooling, followed by stirring at room temperature for 1.5 hours. did. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to obtain the desired product (1.21 g, 3.54 mmol) as a colorless powder.
LRMS (EI ⁺ ): 342 [M ⁺ ]
¹ H-NMR (400MHz, CDCl ₃ ) δ1.42 (3H, t, J = 7.3 Hz), 2.06 (3H, s), 4.20 (3H, s), 4.40 (2H, q, J = 7.3 Hz), 5.60 (2H, s), 6.35 (1H, d, J = 7.9 Hz), 7.26 (1H, t, J = 53.8 Hz), 7.49 (1H, d, J = 7.9 Hz).

<Example 47>
2-Ethyl-4-hydroxypyrazolo [1,5-a] pyridine

Under an argon gas atmosphere, the compound of Example 17 (4.00 g) was dissolved in dichloromethane (50.0 mL), and a 1.00 mol / L boron tribromide / dichloromethane solution (27.5 mL) was added with stirring under ice cooling. Stir at warm for 30 minutes. Ice water was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1) to obtain the desired product (1.85 g) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.44 (3H, t, J = 7.3 Hz), 2.62 (3H, s), 3.08 (2H, q, J = 7.3 Hz), 6.81 (1H, dd, J = 0.9, 7.6 Hz), 6.90 (1H, dd, J = 6.4, 7.6 Hz), 8.00 (1H, dd, J = 0.9, 6.4 Hz), 13.0 (1H, s).
The obtained phenol compound (1.85 g) was suspended in a 50% aqueous sulfuric acid solution (70.0 mL) and stirred at 150 ° C. for 10 hours. The mixture was allowed to cool, diluted with water, neutralized with potassium carbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the object product (1.42 g) as a brown powder. (Method A).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 7.6 Hz), 2.87 (2H, q, J = 7.6 Hz), 5.68 (1H, brs), 6.41-6.43 (2H, m) , 6.54 (1H, t, J = 7.0 Hz), 8.06 (1H, d, J = 7.0 Hz).

<Example 48>
2-Ethyl-6-fluoro-4-hydroxypyrazolo [1,5-a] pyridine

The compound of Example 43 (4.53 g) was dissolved in dichloromethane (50.0 mL), and a 1.00 mol / L boron tribromide / dichloromethane solution (21.6 mL) was added at 0 ° C., followed by stirring for 1 hour. Water was added and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine. It dried with sodium sulfate and the solvent was distilled off under reduced pressure. The obtained solid (4.29 g) was dissolved in ethanol (40.0 mL), water (40.0 mL) and potassium hydroxide (4.10 g) were added, and the mixture was stirred under heating under reflux for 2 hr. Water and concentrated hydrochloric acid were added to acidify, extraction was performed 3 times with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained solid (3.58 g) was dissolved in ethanol (100 mL), concentrated sulfuric acid (2.00 mL) was added, and the mixture was stirred under heating under reflux for 7.5 hours. After the solvent was distilled off, extraction was performed three times with ethyl acetate, and the organic layer was washed with saturated brine. Drying with sodium sulfate and evaporation of the solvent gave the desired product (2.88 g) as a gray powder. (Method B).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 8.0 Hz), 2.84 (2H, q, J = 8.0 Hz), 6.42-6.45 (2H, m), 8.03 (1H, d, J = 3.0 Hz).

<Example 49>
4-Hydroxypyrazolo [1,5-a] pyridine

In an argon gas atmosphere, the compound of Example 24 (4.30 g,) was dissolved in dichloromethane (50 mL), and a 1.0 mol / L boron tribromide / dichloromethane solution (23.4 mL) was added at 0 ° C. Stir for hours. A 1.0 mol / L boron tribromide / dichloromethane solution (23.4 mL) was further added, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain a yellow powder (4.80 g). 47% hydrobromic acid (100 mL) was added to the obtained solid, and the mixture was stirred for 5 hours under reflux with heating. The mixture was basified with sodium hydroxide, acidified with hydrochloric acid, extracted three times with ethyl acetate, and the organic layer was washed with saturated brine. After drying over sodium sulfate, the solvent was distilled off to obtain the desired product (2.10 g) as a yellow powder. (Method C)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.76 (1H, brs), 6.47 (1H, d, J = 7.3 Hz), 6.62-6.65 (2H, m), 7.92 (1H, d, J = 2.4 Hz) , 8.17 (1H, d, J = 6.7 Hz).

<Example 50>
4-acetyl-2-cyclopropylpyrazolo [1,5-a] pyridine

The compound of Example 42 (5.57 g) was dissolved in ethanol (30.0 mL) and water (30.0 mL), potassium hydroxide (3.70 g) was added, and the mixture was stirred under heating under reflux for 3.5 hours. The mixture was neutralized with concentrated hydrochloric acid, extracted three times with ethyl acetate, and the organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off. The obtained solid was dissolved in toluene (150 mL) and stirred for 6 hours under heating under reflux. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 1: 1) to obtain the desired product (2.64 g) as a yellow powder. (Method D)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.85-0.89 (2H, m), 0.98-1.03 (2H, m), 2.04-2.11 (1H, m), 2.58 (3H, s), 6.66 (1H, t , J = 6.7 Hz), 6.88 (1H, s), 7.68 (1H, d, J = 6.7 Hz), 8.44 (1H, d, J = 6.7 Hz).

<Example 51>
2-Ethyl-4-methoxy-pyrazolo [1,5-a] pyridine

The compound of Example 39 (2.80 g) was dissolved in ethanol (30.0 mL), water (30.0 mL) and potassium hydroxide (3.35 g) were added, and the mixture was stirred under heating under reflux for 1.5 hours. After partially distilling off the solvent under reduced pressure, a large amount of water and concentrated hydrochloric acid were added to make it acidic. The mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure. The obtained colorless powder was dissolved in ethanol (75.0 mL), concentrated sulfuric acid (1.50 mL) was added, and the mixture was stirred under heating under reflux for 4 hr. Part of the solvent was distilled off, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine. After drying over sodium sulfate, the solvent was distilled off to obtain the desired product as a gray oil (2.07 g). (Method E)
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.35 (3H, t, J = 8.0 Hz), 2.84 (2H, q, J = 8.0 Hz), 3.94 (3H, s), 6.32 (1H, d, J = 7.3 Hz), 6.42 (1H, s), 6.57 (1H, t, J = 7.3 Hz), 8.03 (1H, t, J = 7.3 Hz).

<Example 52>
6-chloro-2-ethyl-4-hydroxy-pyrazolo [1,5-a] pyridine

The compound of Example 34 (220 mg) was suspended in 47% hydrobromic acid and heated to reflux for 5 hours. The mixture was made alkaline with 20% aqueous potassium hydroxide solution, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, evaporated, and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the desired product (80.0 mg) as a colorless powder. Obtained. (Method F)
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.24 (3H, t, J = 7.6 Hz), 2.71 (2H, q, J = 7.6 Hz), 6.40 (1H, d, J = 1.5 Hz), 6.48 (1H, s), 8.35 (1H, dd, J = 0.9, 1.5 Hz), 10.91 (1H, brs).

<Examples 53 to 65>
Using the compounds shown in Table 2 and Examples 41 and 46, the compounds shown in Table 3 were synthesized by reacting in the same manner as in Examples 47 to 52.

Example 53: LRMS (EI ⁺ ): 228 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.77 (1H, t, J = 5.5 Hz), 4.18 (3H, s), 4.87 (2H, d, J = 5.5 Hz), 6.17 (1H, d, J = 7.3 Hz), 6.86 (1H, s), 6.94 (1H, t, J = 54.4 Hz), 7.22 (1H, d, J = 7.3 Hz)

Example 54: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.76 (1H, brs), 3.45 (3H, s), 4.14 (3H, s), 4.74 (2H, s), 4.83 (2H, s ), 6.05 (1H, d, J = 7.9 Hz), 6.64 (1H, s), 7.13 (1H, d, J = 6.7 Hz).

Example 55: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.28 (3H, t, J = 7.3 Hz), 3.03 (2H, q, J = 7.3 Hz), 4.27 (3H, s), 6.31 ( 1H, d, J = 7.9 Hz), 7.69 (1H, s), 8.01 (1H, d, J = 7.9 Hz).

Example 56: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.97 (3H, t, J = 7.3 Hz), 1.01 (3H, t, J = 7.3 Hz), 1.75-1.90 (4H, m), 2.77-2.81 (2H, m), 4.86 (1H, t, J = 6.1 Hz), 6.38 (1H, s), 6.66 (1H, t, J = 6.7 Hz), 7.07 (1H, d, J = 6.7 Hz) ), 8.29 (1H, d, J = 6.7 Hz).

Example 57: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.49 (3H, s), 6.38 (1H, s), 6.42 (1H, d, J = 7.3 Hz), 6.54 (1H, dd, J = 7.3, 7.3 Hz), 8.05 (1H, d, J = 7.3 Hz).

Example 58: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.70 (3H, s), 7.04 (1H, t, J = 6.7 Hz), 7.62 (1H, s), 7.92 (1H, d, J = 7.9 Hz), 8.67 (1H, d, J = 6.7 Hz).

Example 59: LRMS (EI ⁺ ): 176 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.3 Hz), 2.87 (2H, q, J = 7.3 Hz), 4.86 (2H, brs), 6.38 (1H, s), 6.68 (1H, t, J = 7.3 Hz), 7.09-7.10 (1H, m), 8.33 (1H, d, J = 7.3 Hz).

Example 60: LRMS (EI ^<+> ): 206 [M ^<+ >]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.36 (3H, t, J = 8.0 Hz), 1.65 (1H, brs), 2.92 (2H, q, J = 8.0 Hz), 4.13 (3H, s) , 4.81 (2H, s), 5.99 (1H, d, J = 7.3 Hz), 6.43 (1H, s), 7.08 (1H, d, J = 7.3 Hz).

Example 61: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.56 (1H, brs), 4.18 (3H, s), 4.87 (2H, d, J = 0.9 Hz), 6.22 (1H, d, J = 7.6 Hz), 6.92 (1H, s), 7.24-7.27 (1H, m).

Example 62: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.3 Hz), 1.88-1.96 (2H, m), 1.98 (1H, brs), 4.17 (3H, s) , 4.87 (1H, t, J = 5.8 Hz), 6.23 (1H, d, J = 7.6 Hz), 6.93 (1H, s), 7.25 (1H, d, J = 7.6 Hz).

Example 63: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.44 (3H, t, J = 7.3 Hz), 4.15 (3H, s), 4.48 (2H, q, J = 7.3 Hz), 6.12 ( 1H, d, J = 7.9 Hz), 7.20 (1H, s), 7.37 (1H, d, J = 7.9 Hz).

Example 64: Same compound as Example 50. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.6 Hz), 2.84 (2H, q, J = 7.6 Hz), 6.12 (1H, brs), 6.43 (1H, s), 6.46 (1H, d, J = 1.5 Hz), 8.10-8.11 (1H, m).

Example 65: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.57-1.86 (6H, m), 2.61 (3H, s), 3.55-3.60 (1H, m), 3.89-3.92 (1H, m), 4.64 (1H, d, J = 12.8 Hz), 4.72-4.74 (1H, m), 4.90 (1H, d, J = 12.8 Hz), 6.65 (1H, s), 6.66 (1H, t, J = 7.3 Hz ), 7.11 (1H, d, J = 7.3 Hz), 8.30 (1H, d, J = 7.3 Hz).

Example 66: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 1.39 (3H, t. J = 7.3 Hz), 2.81 (3H, s), 2.93 (2H , q, J = 7.3 Hz), 3.04 (2H, q, J = 7.3 Hz), 6.62 (1H, d, J = 7.3 Hz), 7.21 (1H, s), 7.76 (1H, d, J = 7.3 Hz ).
LRMS (EI ⁺ ): 216 [M ⁺ ]

<Example 67>
4-Hydroxymethyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

  The compound of Example 33 (10.0 g) was dissolved in a 40% aqueous sulfuric acid solution (300 mL) and stirred at 100 ° C. for 2.5 hours. After allowing to cool, the reaction solution was poured into ice water, neutralized with potassium carbonate, and acidified with concentrated hydrochloric acid. This was extracted three times with ethyl acetate, and the organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (5.17 g, crude) as a brown powder. This was directly used in the next reaction.

<Example 68>
2-Ethyl-6-fluoro-4-trifluoromethanesulfonyloxy-pyrazolo [1,5-a] pyridine

The compound of Example 48 (2.88 g) was dissolved in dichloromethane (100 mL), triethylamine (4.51 mL) was added, trifluoromethanesulfonic anhydride (2.97 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. did. Water was added, and the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the desired product (4.25 g) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 8.0 Hz), 2.87 (2H, q, J = 8.0 Hz), 6.51 (1H, s), 7.10 (1H, dd, J = 1.8, 8.6 Hz), 8.39-8.40 (1H, m).

<Examples 69 to 72>
The compounds shown in Table 4 were synthesized by reacting the compounds of Examples 47, 49, 52 (64) and 57 in the same manner as in Example 68 above.

Example 69: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.70 (1H, d, J = 2.1 Hz), 6.79 (1H, t, J = 7.3 Hz), 7.13 (1H, d, J = 7.3 Hz) ), 8.03 (1H, d, J = 2.1 H), 8.50 (1H, d, J = 7.3 Hz).

Example 70: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.51 (3H, s), 6.47 (1H, s), 6.67 (1H, t, J = 7.3 Hz), 7.06 (1H, d, J = 7.3 Hz), 8.37 (1H, d, J = 7.3 Hz).

Example 71: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.6 Hz), 2.89 (2H, q, J = 7.6 Hz), 6.49 (1H, s), 6.68 (1H, dd, J = 7.0, 7,6Hz), 7.07 (1H, d, J = 7.6 Hz), 8.39 (1H, d, J = 7.0 Hz).

Example 72: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 7.6 Hz), 2.87 (2H, q, J = 7.6 Hz), 6.51 (1H, s), 7.10 (1H, d, J = 1.5 Hz), 8.43-8.44 (1H, m).

<Experimental example 73>
2-Ethyl-6-fluoro-4-propionyl-pyrazolo [1,5-a] pyridine

In an argon gas atmosphere, palladium acetate (102 mg) was dissolved in DMF (25.0 mL), 1,3-bis (diphenylphosphino) propane (374 mg) was added, and the mixture was stirred at room temperature for 15 minutes. The compound of Example 68 (4.25 g), ethyl-1-propenyl ether (15.0 mL) and triethylamine (3.80 mL) dissolved in DMF (65.0 mL) were added, and the mixture was stirred at 80 ° C. for 20 hours. After adding water, extraction was performed three times with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate and distilling off the solvent, THF (50.0 mL) and 3 mol / L hydrochloric acid (50.0 mL) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. After drying over sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain the desired product (670 mg) as a yellow powder.
¹ H-NMR (400MHz, CDCl ₃ ) δ 1.29 (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 7.6 Hz), 2.89 (2H, q, J = 7.6 Hz), 3.06 (2H , q, J = 7.3 Hz), 7.13 (1H, s), 7.71 (1H, dd, J = 2.1, 7.8 Hz), 8.53 (1H, t, J = 2.4 Hz).

<Examples 74 to 78>
The compounds shown in Table 5 were synthesized using the compounds shown in Table 4 in the same manner as in Example 73. In addition, the compound whose R is methyl used butyl vinyl ether.

Example 74: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.64 (3H, s), 6.85 (1H, t, J = 7.3 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.82 (1H, d, J = 7.3 Hz), 8.10 (1H, d, J = 1.8 Hz), 8.66 (1H, d, J = 7.3 Hz).

Example 75: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.53 (3H, s), 2.67 (3H, s), 6.75 (1H, dd, J = 7.3, 7.3 Hz), 7.09 (1H, s), 7.77 (1H, d, J = 7.3 Hz), 8.54 (1H, d, J = 7.3 Hz).

Example 76: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.6 Hz), 2.67 (3H, s), 2.90 (2H, q, J = 7.6 Hz), 6.75 (1H, t, J = 7.0 Hz), 7.78 (1H, dd, J = 0.9, 7.0 Hz), 8.55 (1H, td, J = 0.9, 7.0 Hz).

Example 77: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 7.6 Hz), 2.67 (3H, s), 2.88 (2H, q, J = 7.6 Hz), 7.11 (1H, s), 7.71 (1H, d, J = 1.8 Hz), 8.58-8.59 (1H, m).

Example 78: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 1.36 (3H, t, J = 7.6 Hz), 2.88 (2H, q, J = 7.6 Hz) , 3.04 (2H, q, J = 7.3 Hz), 7.12 (1H, s), 7.72 (1H, d, J = 1.8 Hz), 8.58 (1H, d, J = 1.8 Hz).

<Example 79>
2-Ethyl-4-propionyl-pyrazolo [1,5-a] pyridine

Under an argon gas atmosphere, the compound of Example 76 (3.08 g) was dissolved in THF (160 mL), and a 1.00 mol / L lithium bistrimethylsilylamide / THF solution (18.0 mL) was added dropwise at -78 ° C. The mixture was stirred for 3.5 hours while gradually raising the temperature to -30 ° C. Thereafter, methyl iodide (1.10 mL) was appropriately dropped at −78 ° C., and the mixture was stirred for 6 hours while gradually warming to room temperature. 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 the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (1.37 g) as a yellow powder.
LRMS (EI +) 202 [M +]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.05 (2H , q, J = 7.3 Hz), 6.75 (1H, t, J = 7.3 Hz), 7.13 (1H, s), 7.80 (1H, dd, J = 1.2, 7.3 Hz), 8.55 (1H, dd, J = 1.2, 7.3 Hz).

<Example 80>
4-propionyl-2-propyl-pyrazolo [1,5-a] pyridine

The compound of Example 56 (3.17 g) was dissolved in toluene (72.5 mL), activated manganese dioxide (6.31 g) was added, and the mixture was stirred for 7 hours under heating to reflux. Activated manganese dioxide (6.31 g) was further added, and the mixture was stirred with heating under reflux for 6 hours. After filtration through celite, the filtrate was distilled off and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1). The obtained yellow oil was again oxidized and purified in the same manner to obtain the desired product (850 mg) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.01 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.76-1.84 (2H, m), 2.84 (2H, t, J = 7.3 Hz), 3.05 (2H, q, J = 7.3 Hz), 6.74 (1H, t, J = 6.7 Hz), 7.12 (1H, s), 7.79 (1H, d, J = 6.7 Hz), 8.54 (1H, d, J = 6.7 Hz).

<Example 81>
2-Ethyl-4- (2-ethyl- [1,3] dioxolan-2-yl) -pyrazolo [1,5-a] pyridine

The compound of Example 79 (1.37 g) was dissolved in toluene (50.0 mL), ethylene glycol (5.00 mL) and paratoluenesulfonic acid monohydrate (137 mg) were added, and the mixture was heated under reflux using a Dean-Stark trap. Stirred under for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (1.51 g) as a yellow oil.
LRMS (EI ⁺ ): 246 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 2.07 (2H, q, J = 7.3 Hz), 2.86 ( 2H, q, J = 7.3 Hz), 3.80-3.84 (2H, m), 4.05-4.08 (2H, m), 6.54 (1H, s), 6.64 (1H, t, J = 7.3 Hz), 7.13-7.15 (1H, m), 8.32 (1H, d, J = 7.3 Hz).

<Examples 82 to 93>
The compounds shown in Table 6 were synthesized by reacting the compounds of Examples 50, 58, 74, 75, 76 and 80 in the same manner as in Example 81.

Example 82: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.77 (3H, s), 3.79-3.85 (2H, m), 4.05-4.13 (2H, m), 6.73 (1H, t, J = 7.3 Hz), 6.78 (1H, d, J = 2.4 Hz), 7.22 (1H, d, J = 7.3 Hz), 7.95 (1H, d, J = 2.4 Hz), 8.42 (1H, d, J = 7.3 Hz) .

Example 83: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.76 (3H, s), 2.49 (3H, s), 3.79-3.82 (2H, m), 4.07-4.10 (2H, m), 6.53 ( 1H, s), 6.63 (1H, t, J = 7.3 Hz), 7.17 (1H, d, J = 7.3 Hz), 8.30 (1H, d, J = 7.3 Hz).

Example 84: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.6 Hz), 1.77 (3H, s), 2.87 (2H, q, J = 7.6 Hz), 3.79-3.83 ( 2H, m), 4.07-4.10 (2H, m), 6.56 (1H, s), 6.65 (1H, t, J = 6.7 Hz), 7.18 (1H, d, J = 6.7 Hz), 8.35 (1H, d , J = 6.7 Hz).

Example 85: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.3 Hz), 1.02 (3H, t, J = 7.3 Hz), 1.77-1.83 (2H, m), 2.06 (2H, q, J = 7.3 Hz), 2.80 (2H, t, J = 7.3 Hz), 3.82-3.84 (2H, m), 4.04-4.08 (2H, m), 6.53 (1H, s), 6.64 ( 1H, t, J = 6.7 Hz), 7.14 (1H, d, J = 6.7 Hz), 8.32 (1H, d, J = 6.7 Hz).

Example 86: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90-0.92 (2H, m), 0.92-1.04 (2H, m), 2.07-2.12 (1H, m), 3.78-3.84 (2H, m ), 4.03-4.09 (2H, m), 6.41 (1H, s), 6.61 (1H, t, J = 7.3 Hz), 7.15 (1H, d, J = 7.3 Hz).

Example 87: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.76 (3H, s), 3.75-3.86 (2H, m), 4.06-4.16 (2H, m), 6.90 (1H, t, J = 6.7 Hz), 7.08 (1H, s), 7.35 (1H, dd, J = 6.7, 1.2 Hz), 8.44 (1H, d, J = 6.7 Hz).

<Example 88>
4-t-butyldimethylsilyloxymethyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 67 (5.17 g, crude) was dissolved in DMF (100 mL), imidazole (4.89 g) and t-butyldimethylsilyl chloride (4.33 g) were added, and the mixture was stirred at room 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 water and saturated brine in that order and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (3.42 g) as a yellow oil.
LRMS (EI ⁺ ): 330 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.14 (6H, s), 0.96 (9H, s), 4.90 (2H, s), 6.78 (1H, s), 6.93 (1H, t, J = 7.3 Hz), 7.28 (1H, m), 8.41 (1H, d, J = 7.3 Hz).

<Example 89>
4-t-butyldimethylsilyloxymethyl-7-iodo-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

After dissolving the compound of Example 88 (3.42 g) in THF (30.0 mL) under an argon gas atmosphere, a 1.59 mol / L n-butyllithium / n-hexane solution (8.50 mL) at −78 ° C. Was stirred for 1 hour. Thereafter, a THF solution (30.0 mL) of 1,2-diiodoethane (3.52 g) was added dropwise at −78 ° C., followed by stirring for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain the desired product (4.57 g) as a pale yellow powder.
LRMS (EI ⁺ ): 456 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.14 (6H, s), 0.96 (9H, s), 4.89 (2H, s), 7.01 (1H, s), 7.04 (1H, d, J = 7.3 Hz), 7.49 (1H, d, J = 7.3 Hz).

<Examples 90 to 96>
The compounds shown in Table 7 were synthesized by reacting in the same manner as in Example 89 using the compounds in Table 6 and the compounds of Example 81.

Example 90: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.77 (3H, s), 3.75-3.81 (2H, m), 4.08-4.11 (2H, m), 6.99 (1H, d, J = 7.3 Hz), 7.04 (1H, d, J = 2.1 Hz), 7.32 (1H, d, J = 7.3 Hz), 8.06 (1H, d, J = 2.1 Hz).

Example 91: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.75 (3H, s), 2.55 (3H, s), 3.77-3.80 (2H, m), 4.03-4.10 (2H, m), 6.80 ( 1H, s), 6.92 (1H, d, J = 7.3 Hz), 7.21 (1H, d, J = 7.3 Hz).

Example 92: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.6 Hz), 1.76 (3H, s), 2.93 (2H, q, J = 7.6 Hz), 3.77-3.81 ( 2H, m), 4.06-4.13 (2H, m), 6.83 (1H, s), 6.92 (1H, d, J = 7.3 Hz), 7.21 (1H, d, J = 7.3 Hz).

Example 93: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.3 Hz), 1.04 (3H, t, J = 7.3 Hz), 1.78-1.84 (2H, m), 2.04 (2H, q, J = 7.3 Hz), 2.85 (2H, t, J = 7.3 Hz), 3.78-3.82 (2H, m), 4.04-4.07 (2H, m), 6.80 (1H, s), 6.88 ( 1H, d, J = 7.3 Hz), 7.21 (1H, d, J = 7.3 Hz).

Example 94: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89-0.93 (2H, m), 1.04-1.09 (2H, m), 1.73 (3H, s), 2.19-2.23 (1H, m), 3.76-3.79 (2H, m), 4.05-4.09 (2H, m), 6.60 (1H, s), 6.90 (1H, d, J = 7.3 Hz), 7.19 (1H, d, J = 7.3 Hz).

Example 95: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.75 (3H, s), 3.74-3.84 (2H, m), 4.06-4.16 (2H, m), 7.09 (1H, d, J = 7.3 Hz), 7.33 (1H, s), 7.47 (1H, d, J = 7.3 Hz).

Example 96: LRMS (EI ⁺ ): 372 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 2.06 (2H, q, J = 7.3 Hz), 2.92 ( 2H, q, J = 7.3 Hz), 3.79-3.82 (2H, m), 4.04-4.08 (2H, m), 6.81 (1H, s), 6.89 (1H, d, J = 7.3 Hz), 7.22 (1H , d, J = 7.3 Hz).

<Example 97>
7-Iodo-2-methylthio-4- (tetrahydropyran-2-yloxymethyl) -pyrazolo [1,5-a] pyridine

The compound of Example 65 containing an inseparable isomer was used in the same manner as in Example 89 to obtain the desired product as a brown oil containing an inseparable isomer.
¹ H-NMR (400 MHz, CDCl ₃ ): δ1.55-1.87 (6H, m), 2.65 (3H, s), 3.53-3.57 (1H, m), 3.87-3.92 (1H, m), 4.63 ( 1H, d, J = 7.9 Hz), 4.71 (1H, t, J = 6.7 Hz), 4.88 (1H, d, J = 7.9 Hz), 6.68 (1H, s), 6.87 (1H, d, J = 7.3 Hz), 7.21 (1H, d, J = 7.3 Hz).

<Example 98>
2-Ethyl-7-iodo-4-propionyl-pyrazolo [1,5-a] pyridine

The compound of Example 96 (1.97 g) was dissolved in acetone (50.0 mL) and water (25.0 mL), paratoluenesulfonic acid monohydrate (197 mg) was added, and the mixture was stirred at 60 ° C. for 4 hr. The reaction mixture was evaporated and extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (1.64 g) as a yellow powder.
LRMS (EI ⁺ ) 328 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 2.95 (2H, q, J = 7.3 Hz), 3.04 ( 2H, q, J = 7.3 Hz), 7.34 (1H, d, J = 7.3 Hz), 7.41 (1H, s), 7.49 (1H, d, J = 7.3 Hz).

<Examples 99 to 104>
The compounds shown in Table 8 were synthesized by reacting the compounds of Examples 90 to 95 in the same manner as in Example 98.

Example 99: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.70 (3H, s), 7.47 (1H, d, J = 7.3 Hz), 7.54 (1H, d, J = 7.3 Hz), 7.61 (1H , d, J = 2.1 Hz), 8.20 (1H, d, J = 2.1 Hz).

Example 100: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.58 (3H, s), 2.65 (3H, s), 7.34 (1H, d, J = 7.3 Hz), 7.36 (1H, s), 7.46 (1H, d, J = 7.3 Hz).

Example 101: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.6 Hz), 2.66 (3H, s), 2.95 (2H, q, J = 7.6 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.40 (1H, s), 7.46 (1H, d, J = 7.6 Hz).

Example 102: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.03 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.79-1.85 (2H, m), 2.89 (2H, t, J = 7.3 Hz), 3.03 (2H, q, J = 7.3 Hz), 7.33 (1H, d, J = 7.9 Hz), 7.40 (1H, s), 7.48 (1H, d, J = (7.9 Hz).

Example 103: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.96-0.98 (2H, m), 1.10-1.14 (2H, m), 2.23-2.29 (1H, m), 2.67 (3H, s), 7.19 (1H, s), 7.34 (1H, d, J = 7.3 Hz), 7.47 (1H, d, J = 7.3 Hz).

Example 104: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.69 (3H, s), 7.59 (2H, d, J = 7.3 Hz), 7.62 (2H, d, J = 7.9 Hz), 7.87 ( 1H, s).

<Example 105>
4-Hydroxymethyl-7-iodo-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 89 (4.57 g) was dissolved in THF (50.0 mL), and 1.00 mol / L tetra-n-butylammonium fluoride / THF solution (12.0 mL) was added under ice-cooling. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (3.26 g) as a pale yellow powder.
LRMS (EI ⁺ ): 342 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.88 (1H, t, J = 5.5 Hz), 4.93 (2H, d, J = 5.5 Hz), 7.04 (1H, d, J = 7.3 Hz), 7.11 ( 1H, s), 7.50 (1H, d, J = 7.3 Hz).

<Example 106>
4-Formyl-7-iodo-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 105 (3.26 g) was dissolved in dichloromethane (50.0 mL), activated manganese dioxide (8.29 g) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, the filtrate was evaporated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (2.97 g) as a yellow powder.
LRMS (EI ⁺ ): 340 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.52 (1H, d, J = 7.3 Hz), 7.74 (1H, d, J = 7.3 Hz), 7.86 (1H, s), 10.1 (1H, s).

<Example 107>
4-Formyl-7-iodo-2-methylthio-pyrazolo [1,5-a] pyridine

The compound of Example 97 (665 mg, 1.64 mmol) containing an inseparable isomer was dissolved in methanol (15.0 mL), paratoluenesulfonic acid monohydrate (31.2 mg) was added, and the mixture was stirred at room temperature for 2 hours. . Saturated aqueous sodium hydrogen carbonate solution was added, extracted three times with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over sodium sulfate and evaporated. The obtained solid was dissolved in dichloromethane (20.0 mL), activated manganese dioxide (1.37 g) was added, and ultrasonic irradiation was performed at room temperature for 3 hours. After filtration through celite, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the desired product (333 mg) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.69 (3H, s), 7.36 (3H, d, J = 7.3 Hz), 7.43 (1H, d, J = 7.3 Hz), 7.44 (1H, s), 10.0 (1H, s).

<Example 108>
4-Formyl-7-methoxy-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 106 (2.97 g) was dissolved in methanol (50.0 mL), sodium methoxide (1.42 g) was added, and the mixture was stirred with heating under reflux for 2 hr. After allowing to cool, the reaction mixture was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent, diisopropyl ether was added and suspended, and the solid was collected by filtration to obtain the desired product (1.93 g) as a yellow-green powder.
LRMS (EI ⁺ ): 244 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.41 (3H, s), 6.43 (1H, d, J = 7.3 Hz), 7.65 (1H, s), 7.87 (1H, d, J = 7.3 Hz), 9.98 (1H, s).

<Examples 109 to 115>
The compounds shown in Table 9 were synthesized by reacting the compounds of Examples 99 to 104 and 107 in the same manner as in Example 108 above.

Example 109: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.64 (3H, s), 4.25 (3H, s), 6.16 (1H, d, J = 8.0 Hz), 7.37 (1H, d, J = 2.4 Hz), 7.90 (1H, d, J = 8.0 Hz), 8.12 (1H, d, J = 2.4 Hz).

Example 110: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.55 (3H, s), 2.62 (3H, s), 4.23 (3H, s), 6.08 (1H, d, J = 7.9 Hz), 7.14 (1H, s), 7.85 (1H, d, J = 7.9 Hz).

Example 111: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.6 Hz), 2.62 (3H, s), 2.93 (2H, q, J = 7.6 Hz), 4.23 (3H , s), 6.09 (1H, d, J = 7.9 Hz), 7.19 (1H, s), 7.86 (1H, d, J = 7.9 Hz).

Example 112: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.00 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.78-1.84 (2H, m), 2.87 (2H, t, J = 7.3 Hz), 3.00 (2H, q, J = 7.3 Hz), 4.22 (3H, s), 6.07 (1H, d, J = 7.9 Hz), 7.19 (1H, s), 7.88 (1H, d, J = 7.9 Hz).

Example 113: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90-0.94 (2H, m), 1.04-1.08 (2H, m), 2.20-2.26 (1H, m), 2.60 (3H, s), 4.22 (3H, s), 6.06 (1H, d, J = 8.2 Hz), 6.94 (1H, s), 7.83 (1H, d, J = 8.2 Hz).

Example 114: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.65 (3H, s), 4.28 (3H, s), 6.31 (1H, d, J = 7.9 Hz), 7.67 (1H, s), 7.98 (1H, d, J = 7.9 Hz).

Example 115: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.66 (3H, s), 4.25 (3H, s), 6.20 (1H, d, J = 7.9 Hz), 7.22 (1H, s), 7.72 (1H, s), 7.72 (1H, d, J = 7.9 Hz), 9.91 (1H, s).

<Example 116>
2-Ethyl-7-methylthio-4-propionyl-pyrazolo [1,5-a] pyridine

The compound of Example 98 (400 mg) was dissolved in DMF (10.0 mL), sodium thiomethoxide (128 mg) was added, and the mixture was stirred at 60 ° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (253 mg) as a yellow powder.
LRMS (EI ⁺ ): 248 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 2.66 (3H, s), 2.94 (2H, q, J = 7.3 Hz), 3.04 (2H, q, J = 7.3 Hz), 6.52 (1H, d, J = 8.0 Hz), 7.20 (1H, s), 7.82 (1H, d, J = 8.0 Hz).

<Example 117>
7-Dimethylamino-2-ethyl-4-propionyl-pyrazolo [1,5-a] pyridine

The compound of Example 98 (400 mg) was dissolved in a 2.00 mol / L dimethylamine / methanol solution (6.10 mL) and stirred at 60 ° C. for 7 hours. After evaporating the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (289 mg) as a yellow oil.
LRMS (EI ⁺ ): 245 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 2.91 (2H, q, J = 7.3 Hz), 2.98 ( 2H, q, J = 7.3 Hz), 3.25 (6H, s), 6.04 (1H, d, J = 8.0 Hz), 7.21 (1H, s), 7.82 (1H, d, J = 8.0 Hz).

<Example 118>
2-Ethyl-7-methylamino-4-propionyl-pyrazolo [1,5-a] pyridine

The compound of Example 98 (400 mg) was dissolved in a 2.00 mol / L methylamine / THF solution (6.10 mL) and stirred at 60 ° C. for 10 hours. After the solvent of the reaction solution was distilled off, the residue was dissolved in a 2.00 mol / L methylamine / THF solution (6.10 mL), and the mixture was further stirred at 60 ° C. for 4 hours. After evaporating the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (209 mg) as a yellow powder.
LRMS (EI ⁺ ): 231 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (3H, t, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 2.86 (2H, q, J = 7.3 Hz), 2.96 ( 2H, q, J = 7.3 Hz), 3.15 (3H, d, J = 5.5 Hz), 5.82 (1H, d, J = 8.0 Hz), 6.54 (1H, brs), 7.14 (1H, s), 7.89 ( 1H, d, J = 8.0 Hz).

<Example 119>
Nt-butoxycarbonyl-2-ethyl-7-methylamino-4-propionyl-pyrazolo [1,5-a] pyridine

The compound of Example 118 (208 mg) was dissolved in acetonitrile (10.0 mL), di-t-butyl-di-carbonate (236 mg) and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was heated under reflux. Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (298 mg) as a yellow powder.
LRMS (EI ⁺ ): 331 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 1.31 (9H, s), 1.36 (3H, t, J = 7.3 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.05 (2H, q, J = 7.3 Hz), 3.35 (3H, s), 6.66 (1H, d, J = 8.0 Hz), 7.20 (1H, s), 7.80 (1H, d, J = 8.0 Hz).

<Example 120>
2-Ethyl-4-formyl-7-iodo-pyrazolo [1,5-a] pyridine

Using the compound of Example 59, the reaction was carried out in the order of Examples 88, 89, 105, and 106 to obtain the desired product as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.97 (2H, q, J = 7.3 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.40 ( 1H, s), 7.46 (1H, d, J = 7.3 Hz), 10.1 (1H, s).

<Example 121>
7-acetylamino-2-ethyl-4-formyl-pyrazolo [1,5-a] pyridine

Under an argon gas atmosphere, the compound of Example 120 (100 mg), acetamide (23.6 mg), tris (dibenzylideneacetone) dipalladium (15.3 mg), Xantphos (28.9 mg) and cesium carbonate (152 mg) were added. The suspension was suspended in dioxane (3.00 mL), and the mixture was stirred at 100 ° C. for 5 hours. The reaction solution was diluted with methylene chloride, filtered through celite, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (62.5 mg) as a yellow powder.
LRMS (EI ⁺ ): 231 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 2.42 (3H, s), 2.90 (2H, q, J = 7.3 Hz), 7.16 (1H, s), 7.74 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 8.0 Hz), 9.56 (1H, brs), 9.95 (1H, brs).

<Example 122>
4- (1-Hydroxyethyl) -7-methoxy-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

Under an argon gas atmosphere, the compound of Example 108 (1.63 g) was dissolved in THF (70.0 mL), and a 0.90 mol / L methylmagnesium bromide / THF solution (8.90 mL) was added dropwise at -78 ° C. The mixture was stirred for 1.5 hours while gradually raising the temperature to −40 ° C. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (1.64 g) as a colorless powder.
LRMS (EI ⁺ ): 260 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.62 (3H, d, J = 6.1 Hz), 1.92 (1H, d, J = 3.7 Hz), 4.17 (3H, s), 5.15-5.17 (1H, m ), 6.22 (1H, d, J = 8.0 Hz), 6.93 (1H, s), 7.28 (1H, d, J = 8.0 Hz).

<Example 123>
4- (1-hydroxypropyl) -7-methoxy-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

In the same manner as in Example 122, the compound of Example 108 was reacted with ethyl magnesium bromide to obtain the desired product as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.6 Hz), 1.88-1.96 (3H, m), 4.17 (3H, s), 4.87 (1H, t, J = 6.4 Hz) ), 6.23 (1H, d, J = 7.6 Hz), 6.93 (1H, s), 7.25 (1H, d, J = 7.6 Hz).

<Experimental example 124>
4-acetyl-7-methoxy-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

Dissolve the compound of Example 122 (1.64 g) in dichloromethane (30.0 mL), add active manganese dioxide (5.48 g), stir at room temperature for 16 hours, and then add active manganese dioxide (5.48 g) to the reaction mixture. And stirred for 10 hours at room temperature. Thereafter, active manganese dioxide (5.48 g) was further added, and the mixture was stirred at room temperature for 10.5 hours. Then, active manganese dioxide (2.74 g) was added again and stirred for 13.5 hours. The reaction mixture was filtered through celite, and the filtrate was evaporated to give the object product (1.08 g) as a pale-yellow powder.
LRMS (EI ⁺ ): 258 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.65 (3H, s), 4.28 (3H, s), 6.32 (1H, d, J = 8.0 Hz), 7.68 (1H, s), 7.99 (1H, d , J = 8.0 Hz).

<Example 125>
7-Methoxy-4-propionyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

  Using the compound of Example 123, the target product was obtained as a colorless powder in the same manner as in Example 124 above.

Also, in an argon gas atmosphere, the compound of Example 123 (32.1 g) was dissolved in DMSO (780 mL), and triethylamine (163 mL) and sulfur trioxide pyridine complex (93.1 g) were added in that order at room temperature. Stir for 1 hour. The reaction solution was poured into ice water, and the resulting solid was collected by filtration and washed with water. The obtained solid was dissolved in ethyl acetate and then dried over anhydrous sodium sulfate. After evaporating the solvent, the desired product (24.0 g) was obtained as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.28 (3H, t, J = 7.3 Hz), 3.03 (2H, q, J = 7.3 Hz), 4.27 (3H, s), 6.31 (1H, d, J = 8.0 Hz), 7.70 (1H, s), 8.01 (1H, d, J = 8.0 Hz).

<Example 126>
7-Methoxy-2-methoxymethyl-4-propionyl-pyrazolo [1,5-a] pyridine

Using the compound of Example 54, oxidation was carried out in the same manner as in Example 124. After alkylation in the same manner as in Example 123, oxidation was again carried out in the same manner as in Example 124 to obtain the desired product as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.26 (3H, t, J = 7.3 Hz), 3.02 (2H, q, J = 7.3 Hz), 3.45 (3H, s), 4.23 (3H, s) , 4.75 (2H, s), 6.14 (1H, d, J = 7.9 Hz), 7.39 (1H, s), 7.92 (1H, d, J = 7.9 Hz).

<Example 127>
2-Difluoromethyl-7-methoxy-4-propionyl-pyrazolo [1,5-a] pyridine

Using the compound of Example 53, oxidation was carried out in the same manner as in Example 124. After alkylation in the same manner as in Example 123, oxidation was again carried out in the same manner as in Example 124 to obtain the desired product as a colorless powder.
LRMS (EI ⁺ ): 254 [M ⁺ ]
¹ H-NMR (400MHz, CDCl ₃ ) δ1.27 (3H, t, J = 7.3 Hz), 3.03 (2H, q, J = 7.3 Hz), 4.27 (3H, s), 6.26 (1H, d, J = 8.0 Hz), 6.94 (1H, t, J = 55.0 Hz), 7.62 (1H, s), 7.98 (1H, d, J = 8.0 Hz).

<Example 128>
7-Methoxy-4-propionyl-2- (tetrahydropyranyl-2-yloxymethyl) -pyrazolo [1,5-a] pyridine

Using the compound of Example 55, oxidation was carried out in the same manner as in Example 124. After alkylation in the same manner as in Example 123, oxidation was again carried out in the same manner as in Example 124 to obtain the desired product as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26 (3H, t, J = 7.3 Hz), 1.48−1.80 (5H, m), 1.81-1−1.95 (1H, m), 3.02 (2H, q, J = 7.3 Hz), 3.53−3.61 (1H, m), 3.91−4.00 (1H, m), 4.23 (3H, s), 4.80 (1H, d, J = 12.8 Hz), 4.81−4.84 (1H, m) , 5.03 (1H, d, J = 12.8 Hz), 6.13 (1H, d, J = 7.9 Hz), 7.42 (1H, s), 7.91 (1H, d, J = 7.9 Hz).

<Example 129>
7-acetylamino-2-ethyl-4-propionyl-pyrazolo [1,5-a] pyridine

Using the compound of Example 121, alkylation was conducted in the same manner as in Example 123, followed by oxidation in the same manner as in Example 124 to obtain the desired product as a yellow powder.
LRMS (EI ⁺ ): 259 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.26 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 2.40 (3H, s), 2.89 (2H, q, J = 7.3 Hz), 3.03 (2H, q, J = 7.3 Hz), 7.20 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.90 (1H, d, J = 8.0 Hz), 9.55 (1H, brs).

<Example 130>
7-Methoxy-4-propionyl-pyrazolo [1,5-a] pyridine

In an argon gas atmosphere, the compound of Example 109 (1.0 g) was dissolved in THF (50.0 mL), and a 1.00 mol / L lithium bistrimethylsilylamide / THF solution (6.30 mL) was added at -78 ° C. The mixture was stirred at 78 ° C to room temperature for 30 minutes. Thereafter, methyl iodide (393 μL) was added at −78 ° C., and the mixture was stirred at −78 ° C. at room temperature for 4.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction three times with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 5) to obtain the desired product (647 mg) as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 3.03 (2H, q, J = 7.3 Hz), 4.25 (3H, s), 6.15 (1H, d, J = 7.9 Hz), 7.38 (1H, d, J = 1.8 Hz), 7.93 (1H, d, J = 7.9 Hz), 8.12 (1H, d, J = 1.8 Hz).

<Examples 131 to 133>
The compounds shown in Table 10 were synthesized by reacting the compounds of Examples 110, 113 and 114 in the same manner as in Example 130 above.

Example 131: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (1H, t, J = 7.3 Hz), 2.55 (3H, s), 3.00 (2H, q, J = 7.3 Hz), 4.22 (3H , s), 6.08 (1H, d, J = 7.9 Hz), 7.15 (1H, s), 7.88 (1H, d, J = 7.9 Hz).

Example 132: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91-0.93 (2H, m), 1.05-1.08 (2H, m), 1.25 (3H, t, J = 7.3 Hz), 2.21-2.26 ( 1H, m), 2.99 (2H, q, J = 7.3 Hz), 4.22 (3H, s), 6.05 (1H, d, J = 7.9 Hz), 6.96 (1H, s), 7.86 (1H, d, J = 7.9 Hz).

Example 133: Same as Example 125

<Example 134>
7-Methoxy-3-methylthio-4-propionyl-pyrazolo [1,5-a] pyridine

Using the compound of Example 115, alkylation was carried out in the same manner as in Example 123, followed by oxidation in the same manner as in Example 124 to obtain the desired product as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.27 (3H, t, J = 7.3 Hz), 2.66 (3H, s), 3.01 (2H, q, J = 7.3 Hz), 4.23 (3H, s) , 6.10 (1H, d, J = 7.9Hz), 7.30 (1H, s), 7.90 (1H, d, J = 7.9 Hz).

<Example 135>
2-Ethyl-4- (2-ethyl- [1,3] dioxolan-2-yl) -7-formyl-pyrazolo [1,5-a] pyridine

Under an argon gas stream, the compound of Example 81 (415 mg) was dissolved in THF (10.0 mL), and 1.54 mol / L n-butyllithium / hexane solution (1.40 mL) was added dropwise at -78 ° C. For 30 minutes. Then, a THF solution (10.0 mL) of ethyl formate (164 μL) was appropriately applied at −78 ° C., and the mixture was stirred for 3 hours while gradually warming to room temperature. 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 then saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (322 mg) as a yellow powder.
LRMS (EI ⁺ ): 274 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.3 Hz), 1.40 (3H, t, J = 7.3 Hz), 2.07 (2H, q, J = 7.3 Hz), 2.92 (2H , q, J = 7.3 Hz), 3.08-3.84 (2H, m), 4.07-4.10 (2H, m), 6.74 (1H, s), 7.25 (1H, d, J = 7.3 Hz), 7.38 (1H, d, J = 7.3 Hz), 10.9 (1H, s).

<Example 136>
2-Ethyl-4- (2-ethyl- [1,3] dioxolan-2-yl) -7- (1-hydroxyethyl) -pyrazolo [1,5-a] pyridine

In an argon gas atmosphere, the compound of Example 135 (321 mg) was dissolved in THF (12.0 mL), and 0.90 mol / L methylmagnesium bromide / THF solution (1.70 mL) was added dropwise at -78 ° C. The mixture was stirred for 3.5 hours while warming to room temperature. 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 then saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the desired product (340 mg) as a yellow oil.
LRMS (EI ⁺ ): 290 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (3H, t, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 1.73 (3H, d, J = 6.1 Hz), 2.06 (2H , q, J = 7.3 Hz), 2.87 (2H, q, J = 7.3 Hz), 3.78-3.82 (2H, m), 4.04-4.08 (2H, m), 5.28 (1H, q, J = 6.1 Hz) , 5.73 (1H, brs), 6.58 (1H, s), 6.61 (1H, d, J = 8.0 Hz), 7.17 (1H, d, J = 8.0 Hz).

<Example 137>
2-Ethyl-7- (1-hydroxyethyl) -4-propionyl-pyrazolo [1,5-a] pyridine

The target product was obtained as a yellow oil by reacting in the same manner as in Example 98 using the compound of Example 136.
LRMS (EI ⁺ ): 246 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 1.75 (3H, d, J = 6.1 Hz), 2.91 (2H , q, J = 7.3 Hz), 3.05 (2H, q, J = 7.3 Hz), 5.34 (1H, q, J = 6.1 Hz), 5.46 (1H, brs), 6.73 (1H, d, J = 8.0 Hz ), 7.18 (1H, s), 7.82 (1H, d, J = 8.0 Hz).

<Example 138>
7- (1-t-Butyldimethylsiloxyethyl) -2-ethyl-4-propionyl-pyrazolo [1,5-a] pyridine

The target product was obtained as a yellow oil by reacting in the same manner as in Example 88 using the compound of Example 137.
LRMS (EI ⁺ ): 360 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.05 (3H, s), 0.14 (3H, s), 0.96 (9H, s), 1.27 (3H, t, J = 7.3 Hz), 1.37 (3H, t, J = 7.3 Hz), 1.60 (3H, d, J = 6.1 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.05 (2H, q, J = 7.3 Hz), 5.65 (1H, q, J = 6.1 Hz), 7.00 (1H, d, J = 7.3 Hz), 7.19 (1H, s), 7.86 (1H, d, J = 7.3 Hz).

<Example 139>
4-t-butyldimethylsilyloxymethyl-7-formyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

  The target product was obtained by reacting in the same manner as in Example 135 using the compound of Example 88. This was used in the next reaction without purification.

<Example 140>
4-t-butyldimethylsilyloxymethyl-7-hydroxymethyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 139 (12.3 g, crude) was dissolved in methanol (200 mL), sodium borohydride (1.56 g) was added under ice cooling, and the mixture was stirred as it was for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (9.86 g) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.14 (6H, s), 0.96 (9H, s), 4.91 (2H, d, J = 1.2 Hz), 5.06 (2H, s), 6.85 (1H, s ), 6.94 (1H, d, J = 7.3 Hz), 7.30 (1H, dt, J = 1.2, 7.3 Hz).

<Example 141>
4-t-butyldimethylsilyloxymethyl-7-methoxymethyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 140 (9.53 g) was dissolved in acetonitrile (300 mL), silver oxide (30.0 g) and methyl iodide (16.1 mL) were added thereto, and the mixture was stirred at room temperature for 85 hours. The reaction solution was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the desired product (8.76 g) as a pale yellow powder. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.13 (6H, s), 0.95 (9H, s), 3.60 (3H, s), 4.91 (2H, s), 4.97 (2H, s), 6.83 (1H , s), 7.07 (1H, d, J = 7.3 Hz), 7.32 (1H, d, J = 7.3 Hz).

<Example 142>
4-Hydroxymethyl-7-methoxymethyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The target product was obtained as a colorless powder by reacting in the same manner as in Example 105 using the compound of Example 141.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.79 (1H, brs), 3.61 (3H, s), 4.93 (2H, s), 4.98 (2H, s), 6.93 (1H, s), 7.07 (1H, d, J = 7.3 Hz), 7.31 (1H, d, J = 7.3 Hz).

<Example 143>
4- (1-Hydroxypropyl) -7-methoxymethyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 142 was used, oxidized in the same manner as in Example 124, and then alkylated in the same manner as in Example 125 to obtain the desired product as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.98 (3H, t, J = 7.3 Hz), 1.84−2.01 (2H, m), 3.61 (3H, s), 4.93 (1H, t, J = 6.7 Hz) , 4.97 (2H, s), 6.95 (1H, s), 7.06 (1H, d, J = 7.3 Hz), 7.30 (1H, d, J = 7.3 Hz).

<Example 144>
7-Methoxymethyl-4-propionyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridine

The compound of Example 143 was used and oxidized in the same manner as in Example 124 to obtain the target product as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.29 (3H, t, J = 7.3 Hz), 3.09 (2H, q, J = 7.3 Hz), 3.64 (3H, s), 5.04 (2H, d, J = 1.2 Hz), 7.20 (1H, dt, J = 1.2, 7.3 Hz), 7.69 (1H, s), 7.99 (1H, d, J = 7.3 Hz).

<Example 145>
2-Ethyl-7-formyl-4- (2-methyl- [1,3] dioxolan-2-yl) -pyrazolo [1,5-a] pyridine

The target product was obtained as a yellow oil by reacting in the same manner as in Example 135 using the compound of Example 84.
LRMS (EI ⁺ ): 260 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 1.77 (3H, s), 2.93 (2H, q, J = 7.3 Hz), 3.79-3.83 (2H, m) , 4.09-4.13 (2H, m), 6.75 (1H, s), 7.28 (1H, d, J = 6.7 Hz), 7.37 (1H, d, J = 6.7 Hz), 10.9 (1H, s).

<Example 146>
2-Ethyl-7-hydroxymethyl-4- (2-methyl- [1,3] dioxolan-2-yl) -pyrazolo [1,5-a] pyridine

The target product was obtained as a yellow powder by reacting in the same manner as in Example 140 using the compound of Example 145.
LRMS (EI ⁺ ): 262 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.38 (3H, t, J = 7.3 Hz), 1.76 (3H, s), 2.88 (2H, q, J = 7.3 Hz), 3.78-3.81 (2H, m ), 4.07-4.10 (2H, m), 4.82 (1H, brs), 4.99 (2H, s), 6.61 (1H, s), 6.62 (1H, d, J = 6.7 Hz), 7.19 (1H, d, J = 6.7 Hz).

<Example 147>
2-Ethyl-7- (1-hydroxyethyl) -4- (2-methyl- [1,3] dioxolan-2-yl) -pyrazolo [1,5-a] pyridine

The target product was obtained as a yellow oil by reacting in the same manner as in Example 122 using the compound of Example 145.
LRMS (EI ⁺ ): 276 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 1.72 (3H, d, J = 6.7 Hz), 1.76 (3H, s), 2.88 (2H, q, J = 7.3 Hz), 3.77-3.84 (2H, m), 4.06-4.10 (2H, m), 5.28 (1H, q, J = 6.7 Hz), 5.70 (1H, brs), 6.60 (1H, s), 6.61 ( 1H, d, J = 7.3 Hz), 7.20 (1H, d, J = 7.3 Hz).

<Example 148>
4-acetyl-2-ethyl-7- (1-hydroxyethyl) -pyrazolo [1,5-a] pyridine

  Using the compound of Example 147, reaction was carried out in the same manner as in Example 98 to obtain the desired product. The product was used in the next reaction without purification.

<Example 149>
4-acetyl-7- (1-tert-butyldimethylsilyloxyethyl) -2-ethyl-pyrazolo [1,5-a] pyridine

The target product was obtained as a yellow powder by reacting in the same manner as Example 88 using the compound of Example 148.
LRMS (FAB ⁺ ): 347 [M + H ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.05 (3H, s), 0.14 (3H, s), 0.96 (9H, s), 1.37 (3H, t, J = 7.3 Hz), 1.61 (3H, d, J = 6.1 Hz), 2.66 (3H, s), 2.91 (1H, q, J = 6.1 Hz), 7.01 (1H, d, J = 7.3 Hz), 7.18 (1H, s), 7.84 (1H, d, J = 7.3 Hz).

<Example 150>
4-acetyl-2-ethyl-7-hydroxymethyl-pyrazolo [1,5-a] pyridine

  The target product was obtained by reacting in the same manner as in Example 98, using the compound of Example 146. The product was used in the next reaction without purification.

<Example 151>
4-acetyl-7-t-butyldimethylsilyloxymethyl-2-ethyl-pyrazolo [1,5-a] pyridine

The compound of Example 150 was reacted in the same manner as in Example 88 to obtain the target product as a yellow powder.
LRMS (FAB ⁺ ): 333 [M + H ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.19 (6H, s), 1.01 (9H, s), 1.38 (3H, t, J = 7.3 Hz), 2.67 (3H, s), 2.91 (2H, q, J = 7.3 Hz), 5.21 (2H, d, J = 1.2 Hz), 7.01 (1H, dd, J = 1.2, 7.3 Hz), 7.19 (1H, s), 7.87 (1H, d, J = 7.3 Hz) .

<Example 152>
3- (2-Ethyl-7-methyl-pyrazolo [1,5-a] pyridin-4-yl) -2-methyl-3-oxopropionic acid methyl ester

Under an argon gas atmosphere, the compound of Example 66 (250 mg) was dissolved in dimethyl carbonate (10.0 mL), 60% sodium hydride (137 mg) was added, and the mixture was stirred with heating under reflux for 1 hr. 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 the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (307 mg) as a yellow powder.
LRMS (EI ⁺ ): 274 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 1.54 (3H, d, J = 7.3 Hz), 2.82 (3H, s), 3.69 (3H, s), 4.47 (1H, q, J = 7.3 Hz), 6.65 (1H, d, J = 7.3 Hz), 7.25 (1H, s), 7.81 (1H, d, J = 7.3 Hz).

<Examples 153 to 163>
Using the compounds of Examples 109, 111, 113, 114 (124), 116 (134), 119, 126, 127, 130, 149, and 151, the reaction was carried out in the same manner as in Example 152, and the compounds shown in Table 11 were obtained. Synthesized.

Example 153: The next reaction was directly performed without purification.

Example 154: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.6 Hz), 2.93 (2H, q, J = 7.6 Hz), 3.76 (3H, s), 4.01 (2H, s), 4.24 (3H, s), 6.11 (1H, d, J = 7.9 Hz), 7.22 (1H, s), 7.86 (1H, d, J = 7.9 Hz).

Example 155: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92-0.96 (2H, m), 1.08-1.12 (2H, m), 2.22-2.29 (1H, m), 3.78 (3H, s), 4.03 (2H, s), 4.26 (3H, s), 6.11 ( 1H, d, J = 7.9 Hz), 6.99 (1H, s), 7.86 (1H, d, J = 7.9 Hz).

Example 156: LRMS (EI ⁺ ): 316 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.77 (3H, s), 4.03 (2H, s), 4.29 (3H, s), 6.34 (1H, d, J = 8.0 Hz), 7.70 (1H, s ), 8.00 (1H, d, J = 8.0 Hz).

Example 157: LRMS (EI ⁺ ): 306 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 1.54 (3H, d, J = 7.3 Hz), 2.67 (3H, s), 2.94 (2H, q, J = 7.3 Hz), 3.69 (3H, s), 4.46 (1H, q, J = 7.3 Hz), 6.54 (1H, d, J = 8.0 Hz), 7.24 (1H, s), 7.86 (1H, d, J = 8.0 Hz).

Example 158: LRMS (EI ⁺ ): 389 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (9H, s), 1.36 (3H, t, J = 7.3 Hz), 1.54 (3H, d, J = 7.3 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.36 (3H, s), 3.70 (3H, s), 4.46 (1H, q, J = 7.3 Hz), 6.68 (1H, d, J = 7.3 Hz), 7.24 (1H, s), 7.85 (1H, d, J = 7.3 Hz).

Example 159: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.53 (3H, d, J = 7.3 Hz), 3.44 (3H, s), 3.69 (3H, s), 4.25 (3H, s), 4.43 ( 1H, q, J = 7.3 Hz), 4.74 (2H, s), 6.17 (1H, d, J = 8.6 Hz), 7.43 (1H, s), 7.98 (1H, d, J = 8.6 Hz).

Example 160: LRMS (EI ⁺ ): 312 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.54 (3H, d, J = 8.0 Hz), 3.70 (3H, s), 4.28 (3H, s), 4.42 (1H, q, J = 8.0 Hz) , 6.29 (1H, t, J = 8.0 Hz), 6.94 (1H, t, J = 54.4 Hz), 7.65 (1H, s), 8.05 (1H, d, J = 8.0 Hz).

Example 161: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.56 (3H, d, J = 6.7 Hz), 3.64 (3H, s), 3.70 (3H, s), 4.48 (1H, q, J = 6.7 Hz), 5.04 (2H, brs), 7.23 (1H, dt, J = 1.2, 7.3 Hz), 7.70 (1H, s), 8.03 (1H, d, J = 7.3 Hz).

Example 162: LRMS (FAB ⁺ ): 391 [M + H ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.19 (6H, s), 1.01 (9H, s), 1.37 (3H, t, J = 7.3 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.77 (3H, s), 4.06 (2H, s), 5.21 (2H, s), 7.04 (1H, d, J = 7.3 Hz), 7.21 (1H, s), 7.85 (1H, d, J = 7.3 Hz) .

Example 163: LRMS (FAB ⁺ ): 404 [M + H ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.05 (3H, s), 0.15 (3H, s), 0.96 (9H, s), 1.37 (3H, t, J = 7.3 Hz), 1.61 (3H, d, J = 6.1 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.77 (3H, s), 4.06 (2H, s), 5.66 (1H, q, J = 6.1 Hz), 7.03 (1H, d, J = 7.3 Hz), 7.21 (1H, s), 7.82 (1H, d, J = 7.3 Hz).

<Examples 164 and 165>
3- (2-Ethyl-7-methyl-pyrazolo [1,5-a] pyridin-4-yl) -2,2-dimethyl-3-oxopropionic acid methyl ester

3- (2,7-Diethyl-pyrazolo [1,5-a] pyridin-4-yl) -2,2-dimethyl-3-oxopropionic acid methyl ester

Under an argon gas atmosphere, dissolve the compound of Example 152 (306 mg) in DMF (10.0 mL), add 60% sodium hydride (58.0 mg) under ice cooling, and stir at room temperature for 30 minutes. Then, methyl iodide (105 μL) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 4 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 then saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and the 7-methyl compound, Example 164 (170 mg) was yellow powder, 7-ethyl compound, Example 165. (75.1 mg) was obtained as a yellow oil.
7-methyl: LRMS (EI ⁺ ): 288 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 1.59 (6H, s), 2.79 (3H, s), 2.93 (2H, q, J = 7.3 Hz), 3.64 (3H, s), 6.56 (1H, d, J = 7.3 Hz), 7.24 (1H, s), 7.52 (1H, d, J = 7.3 Hz).
7-ethyl form: LRMS (EI ⁺ ): 302 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 1.44 (3H, t, J = 7.3 Hz), 1.59 (6H, s), 2.92 (2H, q, J = 7.3 Hz), 3.23 (2H, q, J = 7.3 Hz), 3.65 (3H, s), 6.56 (1H, d, J = 8.0 Hz), 7.23 (1H, s), 7.56 (1H, d, J = 8.0 Hz).

<Example 166>
3- (2-Ethyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -2,2-dimethyl-3-oxopropionic acid methyl ester

In an argon gas atmosphere, Example 154 (412 mg) was dissolved in DMF (15.0 mL), 60% sodium hydride (77.6 mg) was added with ice cooling, and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (139 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. 60% sodium hydride (77.6 mg) was added again, and the mixture was stirred at room temperature for 30 minutes, methyl iodide (139 μL) was added, 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, and washed with water and saturated brine in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (380 mg) as a yellow oil. (Method A)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.6 Hz), 1.59 (6H, s), 2.93 (2H, q, J = 7.6 Hz), 3.65 (3H, s), 4.22 (3H, s), 6.03 (1H, d, J = 8.3 Hz), 7.25 (1H, s), 7.67 (1H, d, J = 8.3 Hz).

<Example 167>
3- (2-Ethyl-7-methylthio-pyrazolo [1,5-a] pyridin-4-yl) -2,2-dimethyl-3-oxopropionic acid methyl ester

Under an argon gas atmosphere, dissolve the compound of Example 157 (87.0 mg) in DMF (5.00 mL), add 60% sodium hydride (14.0 mg) under ice cooling, and stir at room temperature for 30 minutes. After that, methyl iodide (27.0 μL) was added to the reaction solution 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 then saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (83.2 mg) as a yellow oil. (Method B)
LRMS (EI ⁺ ): 320 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 1.59 (6H, s), 2.65 (3H, s), 2.94 (2H, q, J = 7.3 Hz), 3.65 (3H, s), 6.46 (1H, d, J = 8.0 Hz), 7.25 (1H, s), 7.59 (1H, d, J = 8.0 Hz).

<Examples 168 to 176>
Using the compounds of Examples 153, 155, 156, and 158 to 163, the compounds shown in Table 12 were synthesized by reacting in the same manner as in Examples 166 and 167.

Example 168: The next reaction was directly performed without purification.

Example 169: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89-0.93 (2H, m), 1.04-1.09 (2H, m), 1.58 (6H, s), 2.22-2.26 (1H, m), 6.00 (1H, d, J = 7.9 Hz), 6.99 (1H, s), 7.65 (1H, d, J = 7.9 Hz).

Example 170: LRMS (EI ⁺ ): 344 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.60 (6H, s), 4.00 (3H, s), 4.27 (3H, s), 6.33 (1H, d, J = 8.0 Hz), 7.42 (1H, s) , 8.16 (1H, d, J = 8.0 Hz).

Example 171: The next reaction was directly performed without purification.

Example 172: The next reaction was directly performed without purification.

Example 173: LRMS (EI ⁺ ): 326 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.60 (6H, s), 3.66 (3H, s), 4.26 (3H, s), 6.20 (1H, d, J = 7.9 Hz), 6.94 (1H, t, J = 54.4 Hz), 7.66 (1H, s), 7.77 (1H, d, J = 7.9 Hz).

Example 174: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.61 (6H, s), 3.63 (3H, s), 3.66 (3H, s), 5.02 (2H, d, J = 1.2 Hz), 7.14 ( 1H, dt, J = 1.2, 7.3 Hz), 7.69 (1H, s), 7.74 (1H, d, J = 7.3 Hz).

Example 175: LRMS (FAB ⁺ ): 419 [M + H ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.19 (6H, s), 1.01 (9H, s), 1.37 (3H, t, J = 7.3 Hz), 1.69 (6H, s), 2.90 (2H, q, J = 7.3 Hz), 3.66 (3H, s), 5.20 (2H, s), 6.95 (1H, d, J = 7.3 Hz), 7.22 (1H, s), 7.65 (1H, d, J = 7.3 Hz) .

Example 176: LRMS (FAB ⁺ ): 433 [M + H ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.04 (3H, s), 0.14 (3H, s), 0.95 (9H, s), 1.37 (3H, t, J = 7.3 Hz), 1.60 (6H, s) , 1.60 (3H, d, J = 6.1 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.66 (3H, s), 5.63 (1H, q, J = 6.1 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.21 (1H, s), 7.61 (1H, d, J = 8.0 Hz).

<Example 177>
3- (2-Ethyl-7-hydroxymethyl-pyrazolo [1,5-a] pyridin-4-yl) -2,2-dimethyl-3-oxopropionic acid methyl ester

The target product was obtained as a yellow oil by reacting in the same manner as in Example 105 using the compound of Example 175.
LRMS (EI ⁺ ): 304 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 1.59 (6H, s), 2.91 (2H, q, J = 7.3 Hz), 3.65 (3H, s), 4.54 (1H, brs), 5.04 (2H, s), 6.68 (1H, d, J = 7.3 Hz), 7.20 (1H, s), 7.57 (1H, d, J = 7.3 Hz).

<Example 178>
5- (2-Ethyl-7-methyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

The compound of Example 164 (170 mg) was dissolved in ethanol (5.00 mL), hydrazine monohydrate (287 μL) was added thereto, and the mixture was stirred for 5 hours under reflux with heating. After evaporating the solvent of the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (138 mg) as a colorless powder. (Method A)
Elemental analysis (%): C _{1 5} H ₁₈ N ₄ O As
CHN
Calculated value 66.64 6.71 20.73
Actual value 66.47 6.76 20.64
HRMS (EI ⁺ ): 270.1521 (+4.0 mmu) [M ⁺ ]
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.39 (3H, t, J = 7.3 Hz), 1.58 (6H, s), 2.80 (3H, s), 2.93 (2H, q, J = 7.3 Hz), 6.61 (1H, d, J = 7.3 Hz), 7.18 (1H, s), 7.38 (1H, d, J = 7.3 Hz), 8.65 (1H, brs).

<Example 179>
5- (2-Ethyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

The compound of Example 166 (298 mg) was dissolved in ethanol (10.0 mL), acetic acid (2.47 mL) and hydrazine monohydrate (951 μL) were added, and the mixture was stirred for 20 hours under heating to reflux. After evaporating the solvent, the residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2 to 1: 4) to obtain the desired product (86.0 mg) as a light brown powder. (Method B)
HRMS (EI +): 286.1431 (+0.1 mmu) [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.6 Hz), 1.57 (6H, s), 2.94 (2H, q, J = 7.6 Hz), 4.20 (3H, s), 6.08 (1H, d, J = 7.9 Hz), 7.16 (1H, s), 7.46 (1H, d, J = 7.9 Hz), 8.57 (1H, brs).

<Examples 180 to 189>
Using the compounds of Examples 165, 167 to 173, 176, and 177, the compounds shown in Table 13 were synthesized by reacting in the same manner as in the above Examples 178 and 179.

Example 180: HRMS (EI ⁺ ) 259.1151 (-4.4 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.58 (6H, s), 4.22 (3H, s), 6.15 (1H, d, J = 7.9 Hz), 7.34 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 7.9 Hz), 8.10 (1H, d, J = 7.9 Hz), 8.65 (1H, brs).

Example 181: Elemental analysis (%): as C _{1 6} H ₁₈ N ₄ O ₂ 1/10 H ₂ O
CHN
Calculated value 64.03 6.11 18.67
Actual value 64.20 6.13 18.33
HRMS (EI ⁺ ): 298.1460 (+3.0 mmu)
¹ H-NMR (400MHz, CDCl ₃ ) δ 0.91-0.92 (2H, m), 1.06-1.08 (2H, m), 1.56 (6H, s), 2.23-2.27 (1H, m), 6.06 (1H, d , J = 7.9 Hz), 6.91 (1H, s), 7.44 (1H, d, J = 7.9 Hz), 8.53 (1H, brs).

Example 182: Elemental analysis (%): as _{C 14 H 13 F 3 N 4} O 2
CHN
Calculated 51.54 4.02 17.17
Actual value 51.33 4.10 17.10
HRMS (EI ⁺ ): 326.0961 (-2.9 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.59 (6H, s), 4.24 (3H, s), 6.30 (1H, d, J = 8.0 Hz), 7.58 (1H, d, J = 8.0 Hz), 7.68 (1H, s), 8.89 (1H, brs).

Example 183: HRMS (EI ⁺ ): 302.1205 (+0.4 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 1.58 (6H, s), 2.65 (3H, s), 2.95 (2H, q, J = 7.3 Hz), 6.52 (1H, d, J = 8.0 Hz), 7.18 (1H, s), 7.44 (1H, d, J = 8.0 Hz), 8.69 (1H, brs).

Example 184: LRMS (EI ⁺ ): 385 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (9H, s), 1.37 (3H, t, J = 7.3 Hz), 1.58 (3H, s), 2.90 (2H, q, J = 7.3 Hz), 3.35 (3H, s), 6.65 (1H, d, J = 7.3 Hz), 7.19 (1H, s), 7.41 (1H, d, J = 7.3 Hz), 8.95 (1H, brs).

Example 185: LRMS (EI ⁺ ): 302 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.57 (6H, s), 3.45 (3H, s), 4.21 (3H, s), 4.76 (2H, s), 6.14 (1H, d, J = 7.9 Hz) , 7.38 (1H, s), 7.48 (1H, d, J = 7.9 Hz), 8.59 (1H, s).

Example 186: HRMS (EI ⁺ ): 308.1084 (−0.1 mmu) [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ1.58 (6H, s), 4.24 (3H, s), 6.25 (1H, d, J = 8.0 Hz), 6.95 (1H, t, J = 55.0 Hz) , 7.55 (1H, d, J = 8.0 Hz), 7.61 (1H, s), 8.64 (1H, brs).

Example 187: Elemental analysis (%): as C _{1 6} H ₂₀ N ₄ O
CHN
Calculated 67.58 7.09 19.70
Actual value 67.34 7.09 19.50
HRMS (EI ⁺ ): 284.1661 (+2.4 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 1.45 (3H, t, J = 7.3 Hz), 1.58 (6H, s), 2.93 (2H, q, J = 7.3 Hz), 3.24 (2H, q, J = 7.3 Hz), 6.61 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.41 (1H, d, J = 7.3 Hz), 8.59 (1H , brs).

Example 188: Elemental analysis (%): As _{C 1 5 H 18 N 4 O} 2
CHN
Calculated 62.92 6.34 19.57
Actual value 62.61 6.31 19.23
HRMS (EI ⁺ ): 286.1404 (-2.6 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 1.58 (6H, s), 2.91 (2H, q, J = 7.3 Hz), 4.63 (1H, brs), 5.05 (2H, s), 6.72 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.42 (1H, d, J = 7.3 Hz), 8.74 (1H, brs).

Example 189: LRMS (FAB ⁺ ): 415 [M + H ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.06 (3H, s), 0.15 (3H, s), 0.97 (9H, s), 1.38 (3H, t, J = 7.3 Hz), 1.58-1.62 (9H, m), 2.91 (2H, q, J = 7.3 Hz), 5.66 (1H, q, J = 6.1 Hz), 6.98 (1H, d, J = 7.3 Hz), 7.15 (1H, s), 7.48 (1H, d, J = 7.3 Hz), 8.61 (1H, brs).

<Example 190>
5- (7-Methoxy-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

The compound of Example 170 (1.15 g) was dissolved in xylene (30.0 mL), t-butyl carbadate (1.32 g) and pyridinium p-toluenesulfonate (100 mg) were added, and the mixture was heated under reflux using a Dean-Stark trap. And stirred for 16 hours. The reaction solution was directly purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 2) to obtain the desired product (367 mg) as a colorless powder.
Same as Example 182.

<Example 191>
5- [2-Ethyl-7- (1-hydroxyethyl) -pyrazolo [1,5-a] pyridin-4-yl] -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

The target product was obtained as a pale yellow powder by reacting in the same manner as in Example 105 using the compound of Example 189.
Elemental analysis (%): As C _{1 6} H ₂₀ N ₄ O ₂
CHN
Calculated 63.98 6.71 18.65
Actual value 63.83 6.71 18.39
HRMS (EI ⁺ ): 300.1598 (+1.1 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 1.57 (6H, s), 1.75 (3H, d, J = 6.7 Hz), 2.91 (2H, q, J = 7.3 Hz), 5.35 (1H, q, J = 6.7 Hz), 5.45 (1H, brs), 6.71 (1H, d, J = 7.3 Hz), 7.15 (1H, s), 7.44 (1H, d, J = 7.3 Hz), 8.67 (1H, brs).

<Example 192>
5- (7-acetyl-2-ethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

Under an argon gas atmosphere, the compound of Example 191 (250 mg) was dissolved in DMSO (10.0 mL), triethylamine (1.20 mL) and sulfur trioxide-pyridine complex (662 mg) were added thereto, and the mixture was cooled to room temperature. And stirred for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (94.8 mg) as a yellow powder.
Elemental analysis (%): as C _{1 6} H ₁₈ N ₄ O ₂
CHN
Calculated 64.41 6.08 18.78
Actual value 64.22 5.98 18.65
HRMS (EI ⁺ ): 298.1435 (+0.5 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 1.58 (6H, s), 2.93 (2H, q, J = 7.3 Hz), 2.99 (3H, s), 7.24 (1H, d, J = 7.3 Hz), 7.26 (1H, s), 7.44 (1H, d, J = 7.3 Hz), 8.81 (1H, brs).

<Example 193>
5- [2-Ethyl-7- (1-hydroxyethyl) -pyrazolo [1,5-a] pyridin-4-yl] -4,4-dimethyl-2-methyl-2,4-dihydro-pyrazole-3 -ON

In an argon gas atmosphere, dissolve the compound of Example 191 (266 mg) in DMF (10.0 mL), add potassium carbonate (245 mg) and methyl iodide (65.0 μL), and stir at room temperature for 10 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed in turn with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (199 mg) as a yellow powder.
HRMS (EI ⁺ ): 314.1744 (+0.1 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 1.54 (6H, s), 1.75 (3H, d, J = 6.7 Hz), 2.92 (2H, q, J = 7.3 Hz), 3.52 (3H, s), 5.34 (1H, q, J = 6.7 Hz), 6.70 (1H, d, J = 7.3 Hz), 7.18 (1H, s), 7.42 (1H, d, J = (7.3 Hz).

<Example 194>
5- (2-Ethyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2- (pyridin-3-ylmethyl) -2,4-dihydro-pyrazole- 3-on

Under an argon gas atmosphere, the compound of Example 179 (60.0 mg) was dissolved in DMF (2.00 mL), 60% sodium hydride (18.5 mg) was added thereto, and the mixture was stirred at room temperature for 15 minutes. Thereafter, 3-chloromethylpyridine hydrochloride (37.9 mg) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by preparative thin layer chromatography (ethyl acetate: methanol = 10: 1) to obtain the desired product (18.0 mg) as a brown amorphous.
HRMS (EI ⁺ ): 377.1883 (+ 3.1mmu) [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 7.6 Hz), 1.56 (6H, s), 2.92 (2H, q, J = 7.6 Hz), 4.18 (3H, s), 5.02 (2H, s), 6.07 (1H, d, J = 7.9 Hz), 7.00 (1H, s), 7.31 (1H, dd, J = 4.9, 7.9 Hz), 7.44 (1H, d, J = 7.9 Hz) , 7.76 (1H, td, J = 1.8, 7.9 Hz), 8.58 (1H, d, J = 4.9 Hz), 8.73 (1H, d, J = 1.8 Hz).

<Example 195>
5- (2-Ethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

Using the compound of Example 79, Example 152 was then reacted in the same manner as in Example 166 and Example 178 to obtain the desired product as a yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.6 Hz), 2.90 (2H, q, J = 7.6 Hz), 3.77 (3H, s), 4.06 (2H, s), 6.77 (1H, t, J = 7.0 Hz), 7.16 (1H, s), 7.77 (1H, dd, J = 0.9, 7.0 Hz), 8.58 (1H, td, J = 0.9, 7.0 Hz).

<Example 196>
5- (2-Ethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2- (pyridin-3-ylmethyl) -2,4-dihydro-pyrazol-3-one

The target product was obtained as a pale yellow powder by reacting in the same manner as in Example 194 using the compound of Example 195.
HRMS (EI ⁺ ): 347.1741 (-0.5 mmu) [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 7.3 Hz), 1.56 (6H, s), 2.88 (2H, q, J = 7.3 Hz), 5.04 (2H, s), 6.72 (1H, d, J = 7.9 Hz), 6.94 (1H, s), 7.31 (1H, dd, J = 4.9, 7.9 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.75 (1H, td, J = 1.8, 7.9 Hz), 8.42 (1H, d, J = 4.9 Hz), 8.58 (1H, dd, J = 1.8, 4.9 Hz), 8.73 (1H, d, J = 1.8 Hz).

<Example 197>
5- (2-Ethyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2- (3-nitrobenzyl) -2,4-dihydro-pyrazole-3 -ON

The compound of Example 179 was used and reacted in the same manner as in Example 196 using 3-nitrobenzyl chloride to obtain the desired product as a yellow powder.
HRMS (EI ⁺ ): 421.1776 (2.6mmu) [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, t, J = 7.6 Hz), 1.56 (6H, s), 2.92 (2H, q, J = 7.6 Hz), 4.19 (3H, s), 5.10 (2H, s), 6.08 (1H, d, J = 7.9Hz), 7.01 (1H, s), 7.46 (1H, d, J = 7.9 Hz), 7.56 (1H, t, J = 7.9 Hz), 7.75 (1H, d, J = 7.9 Hz), 8.17-8.20 (1H, m), 8.33 (1H, t, J = 1.8 Hz).

<Example 198>
5- (2-Ethyl-7-methylamino-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

The compound of Example 184 (10.0 mg) was dissolved in dichloromethane (1.00 mL), trifluoroacetic acid (500 μL) was added thereto, and the mixture was stirred at room temperature for 1 hour. After evaporating the reaction solution, the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (7.60 mg) as a colorless powder.
HRMS (EI ⁺ ): 285.1573 (-1.7 mmu)
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 1.57 (6H, s), 2.87 (2H, q, J = 7.3 Hz), 3.12 (2H, d, J = 4.9 Hz), 5.82 (1H, d, J = 8.0 Hz), 6.43 (1H, brs), 7.07 (1H, s), 7.48 (1H, d, J = 8.0 Hz), 8.53 (1H, brs).

<Example 199>
2-Benzyl-5- (2-ethyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

The compound of Example 179 was used and reacted in the same manner as in Example 196 using benzyl chloride to obtain the desired product as a colorless powder.
HRMS (EI ⁺ ): 376.1900 (+0.1 mmu) [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.33 (3H, t, J = 7.6 Hz), 1.55 (6H, s), 2.91 (2H, q, J = 7.6 Hz), 4.18 (3H, s), 5.00 (2H, s), 6.06 (1H, d, J = 7.9 Hz), 7.02 (1H, s), 7.30-7.40 (5H, m), 7.42 (1H, d, J = 7.9 Hz).

<Example 200>
5- (7-Methoxymethyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-pyrazol-3-one

The target product was obtained as a colorless powder by reacting in the same manner as in Example 178 using the compound of Example 174.
Elemental analysis (%): as C _{1 5} H ₁₅ N ₄ O ₂
CHN
Calculated value 52.94 4.44 16.46
Actual value 52.74 4.39 16.45
LRMS (EI ⁺ ): 340 [M ⁺ ]
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.60 (6H, s), 3.64 (3H, s), 5.04 (2H, d, J = 1.2 Hz), 7.15 (1H, dt, J = 1.2, 7.3 Hz) , 7.60 (1H, d, J = 7.3 Hz), 7.67 (1H, s), 8.82 (1H, brs).
Next, the results of supporting the usefulness of the compounds of the present invention are shown by experimental examples.

<Experimental Example 1> Phosphodiesterase inhibitory activity
The PDE3A catalytic region (hereinafter abbreviated as Cat), PDE4Bcat, PDE5Acat, and PDE10A1 cDNAs were isolated from human-derived RNA by RT-PCR. Each isolated cDNA fragment was introduced into insect cells Sf9 by Gateway system (Invitrogen) and Bac-to-Bac (registered trademark) Baculovirus Expression system (Invitrogen) to express each target PDE protein. These recombinant PDE3Acat, PDE4Bcat, PDE5Acat, and PDE10A1 were purified by ion exchange chromatography from the culture supernatant or cell extract of Sf9 cells that highly expressed these PDE proteins, respectively, and used in the following experiments.

For the test compound, a 4 mmol / L solution was diluted 4-fold with a 15% DMSO stepwise to prepare a solution having a concentration of 15 nmol / L to 4 mmol / L (the final concentration in the experiment was 1.5 nmol / L). L to 400 μmol / L). [ ³ H] cAMP or [ ³ H] cGMP 50 diluted with a buffer solution [40 mmol / L Tris-HCl (pH 7.4), 10 mmol / L MgCl ₂ ] to a concentration shown in Table 14 for 10 μL of these test compound solutions. μL and 40 μL of each human-derived recombinant PDE protein in the unit amount shown in Table 14 were added to a 96-well plate and reacted at 30 ° C. for 20 minutes. After reacting at 65 ° C. for 2 minutes, 25 μL of 1 mg / mL 5 ′ nucleotidase (Crotalus atrox venom, Sigma) was added and reacted at 30 ° C. for 10 minutes. After completion of the reaction, add 200 μL of Dowex solution [300 mg / mL Dowex 1x8-400 (Sigma Aldrich), 33% Ethanol], shake and mix at 4 ° C for 20 minutes, then add 200 μL of MicroScint 20 (Packard) And it measured using the scintillation counter (made by Topcount, Packard). The IC ₅₀ value was calculated using GraphPad Prism v3.03 (GraphPad Software).

IC ₅₀ value ≥ 10 μmol / L (−), 10 μmol / L> IC ₅₀ value ≧ 1 μmol / L (+), 1 μmol / L> IC ₅₀ value ≧ 0.1 μmol / L (++), 0.1 μmol / L> IC Expressed as ₅₀ values (++++).

  The results are shown in Table 15.

<Experimental example 2> Relaxing effect on histamine contraction of isolated guinea pig tracheal muscle The guinea pig was lethal to death, the trachea was quickly removed, and a tracheal ring specimen with a unit of 2 to 3 cartilage was prepared. This sample was suspended in 10 mL of Tyrode solution which was aerated with 95% O ₂ + 5% CO ₂ mixed gas and kept at 37 ° C. The composition of the Tyrode solution (mmol / L) is NaCl: 136.9, KCl: 2.7, CaCl 2: 1.8, MgCl 2: 1.0, NaH 2 PO 4: 0.4, NaHCO 3: 11.9, Gucose: was 5.6. Contractile response was measured via an isometric transducer (UM-203 KISHIMOTO) and recorded on a recorder (GRAPHTEC SERVOCORDER SR6221). After applying a load of 1.5 g and equilibrating for about 1 hour, histamine (10 ^-5 mol / L) was added, and after confirming the contraction reaction, it was washed with Tyrode (3 times with 10 mL), and indomethacin (10 ^-5 mol / L) was added and equilibrated for 30 minutes or more with a load of 1.5 g. And histamine (10 ^<-5 > mol / L) was added again, and after shrinkage | contraction became stable, the compound was added cumulatively (10 < ^-8 > mol / L-3 * 10 < ^-5 > mol / L). The compound used was a solution of 10 ⁻¹ mol / L prepared in DMSO and diluted with distilled water. After completion of compound addition, papaverine (10 ⁻⁴ mol / L) was added to determine maximum relaxation. The relaxation effect of the test compound was expressed as a relaxation rate (%) with respect to the maximum relaxation by papaverine, and the compound concentration required for 50% relaxation was determined as an IC ₅₀ value. DMSO was used as a control.

  The results are shown in Table 16.

<Experimental Example 3> Histamine-induced airway contraction in guinea pigs Guinea pigs are anesthetized with sodium pentbarbital (30 mg / kg, ip), the left external jugular vein is a cannula for intravenous administration, the right internal carotid artery is a blood collection and blood pressure measurement cannula, the trachea A tracheal cannula was inserted. After artificial respiration at 60 times / min, 10 mL / kg / stroke, the air (airflow) overflowing from the side branch of the tracheal cannula was measured with a bronchospasm transducer (Ugo-Basile) and via Power Lab (AD Instruments Japan) Recorded on a computer. After immobilization with Gallamine triethiodide (10 mg / kg, iv), Histamine dihydrochloride (12.5 μg / kg, iv) was administered every 10 minutes. After the airway contraction by histamine was stabilized, the compound (1 mg / kg, iv) was administered, and the airway contraction response by histamine 30 seconds after administration was measured to examine the inhibitory effect of the compound on the airway contraction. Airway contraction was recorded as an airflow value, and the result was expressed as a ratio of the maximum value of airflow caused by histamine 30 seconds after administration to the maximum value before administration. The test compound was dissolved in DMSO and adjusted to 10 mg / mL. Gallamine triethiodide was dissolved in physiological saline and adjusted to 10 mg / mL. Histamine dihydrochloride was dissolved in physiological saline to 0.1 mg / mL and then diluted to 62.5 μg / mL with physiological saline.

  In addition, the case where the suppression rate was 90% or more was expressed as (++), and the case where it was less than 50% was displayed as (−).

  The results are shown in Table 17.

  As described above, the compound of the present invention represented by the general formula (1) has PDE inhibitory activity, and its effectiveness has been confirmed in various animal experimental models.

  The novel pyrazolopyridin-4-ylpyrazolone derivative and its addition salt of the present invention have an excellent PDE inhibitory action. Therefore, the novel pyrazolopyridine pyrazolone derivative and its addition salt of the present invention are useful for treating angina, heart failure, hypertension and the like, platelet aggregation inhibitors, bronchial asthma, chronic obstructive pulmonary disease (COPD), stroma. Preventive or therapeutic agents for various mental disorders such as pneumonia, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Huntington, Alzheimer, dementia, Parkinson's disease, schizophrenia, and male sexual dysfunction treatment Useful as a medicine.

Claims (9)

General formula (1)

[Wherein, R ₁ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, an optionally substituted lower alkoxy group having 1 to 4 carbon atoms, carbon A lower alkylthio group having 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4 carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, a lower alkylamino group having 1 to 4 carbon atoms, or a lower alkanoyl group having 1 to 4 carbon atoms Group
R ₂ represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms,
R ₃ and R ₄ are the same or different and represent a lower alkyl group having 1 to 4 carbon atoms,
R ₅ represents a hydrogen atom, an optionally substituted benzyl group or a pyridylmethyl group]
Pyrazolopyridin-4-ylpyrazolone derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
The pyrazolopyridin-4-ylpyrazolone derivative according to claim 1, its optical isomer, pharmacologically acceptable salt, and hydrate thereof, wherein The pyrazolopyridin-4-ylpyrazolone derivative according to claim 2, an optical isomer thereof, a pharmacologically acceptable salt thereof, and a salt thereof, wherein R ₁ in the general formula (1a) is a methoxy group Hydrate. The pyrazolopyridin-4-ylpyrazolone derivative according to claim 2, the optical isomer and pharmacologically acceptable salt thereof, and R ₁ in the general formula (1a), wherein R ₁ is a methylthio group Hydrate. The pyrazolopyridin-4-ylpyrazolone derivative according to claim 2, wherein R ₁ is a methylamino group in the general formula (1a), optical isomers and pharmacologically acceptable salts thereof, Its hydrate. The compound represented by the general formula (1) is
6- (2-ethyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-ethyl-7-methylthio-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-ethyl-7-methylamino-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-ethyl-7-hydroxymethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (7-acetyl-2-ethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (2-cyclopropyl-7-methoxy-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone,
6- (7-Methoxy-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone or 6- (7-methoxy The pyrazolopyridine-4 according to claim 1, which is methyl-2-trifluoromethyl-pyrazolo [1,5-a] pyridin-4-yl) -4,4-dimethyl-2,4-dihydro-3-pyrazolone. -Ylpyrazolone derivatives, and pharmacologically acceptable salts and hydrates thereof. General formula (1)

[Wherein, R ₁ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, an optionally substituted lower alkoxy group having 1 to 4 carbon atoms, carbon A lower alkylthio group having 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4 carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, a lower alkylamino group having 1 to 4 carbon atoms, or a lower alkanoyl group having 1 to 4 carbon atoms Group
R ₂ represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms,
R ₃ and R ₄ are the same or different and represent a lower alkyl group having 1 to 4 carbon atoms,
R ₅ represents a hydrogen atom, an optionally substituted benzyl group or a pyridylmethyl group]
A phosphodiesterase inhibitor comprising at least one of a pyrazolopyridin-4-ylpyrazolone derivative, an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof, characterized in that . The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above]
The active ingredient is at least one of a pyrazolopyridin-4-ylpyrazolone derivative represented by the following formula, an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof. The phosphodiesterase inhibitor described in 1. An active ingredient comprising at least one of the pyrazolopyridin-4-ylpyrazolone derivative according to any one of claims 1 to 6, an optical isomer thereof, a pharmacologically acceptable salt, and a hydrate thereof. As a medicinal product.