KR100617992B1 - 2-Aryl-7-(3′,4′-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidine compounds, process for preparing thereof, and pharmaceutical composition for treating asthma and COPD comprising the same - Google Patents

Abstract

The present invention provides a novel 2-aryl-7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-а] pyrimidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, The present invention relates to a pharmaceutical composition for the treatment of inflammation-related diseases, including asthma and chronic obstructive pulmonary disease, characterized in that the preparation method and containing it as an active ingredient.

[Formula 1]

Description

2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compounds, methods for preparing the same, and agents for treating inflammation-related diseases including asthma and chronic obstructive pulmonary diseases {2-Aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compounds, process for preparing compositions, and pharmaceutical composition for treating asthma and COPD comprising the same}

The present invention relates to 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compounds, pharmaceutically acceptable salts thereof, methods for preparing the same and to The present invention relates to a composition for treating inflammation-related diseases including asthma and chronic obstructive pulmonary diseases.

Various compounds have been studied for the development of a therapeutic agent for asthma and chronic obstructive pulmonary disease based on PDE-4 inhibition on which the present invention is based [Peter Norman, Expert Opin. Ther. Patents. 2002 , 12 (1) , pp 93-111], among which the most representative compounds are Rolipram [EP 0660711, July 5, 1995], Cilomilast [USP 6,013,827, January 11, 2000] and Roflumilast [USP 5,712,298] January 27, 1998]. Rolipram, the first of these compounds to enter the clinic, was stopped due to side effects such as weak clinical effects and vomiting. In addition, Cilomilast, a clinical trial, has been discontinued as an asthma treatment due to its low therapeutic effect on asthma, and a clinical trial for Chronic Obstructive Pulmonary Disease (COPD) is underway. [Peter Norman, Expert Opin. Ther. Patents 2002 , 12 (1) , 93-111; Compton C., Edelson JD., Cedar E ,. Am. J. Respir. Crit. Care Med. 2001 , 163 , A909. Roflumilast (Zheng Huang, Yves Ducharme, Dwight Macdonald and Annette Robichaud, Current Opinion in Chemical Biology 2001 , 5, 432-438) developed by Altana, Germany, has the highest PDE-4 inhibitory effect. (IC ₅₀ = 0.8 nM) Animal studies have also shown excellent effects on asthma and COPD [Armin Hatzelman and Christian Schudt, The Journal of Pharmacology and Experimental Therapeutics 2001 , 297 (1) , 267-279; Daniela S. Bundschuh, Manfrid Eltze, Johannes Barsig, Lutz Wollin, Armin Hatzelmann, and Rolf Beume, The Journal of Pharmacology and Experimental Therapeutics 2001 , 297 (1 ), 280-290]. The compound has completed a clinical trial and has submitted a new drug application in Europe in February 2004 for the treatment of asthma.

As mentioned above, the development of drugs for the treatment of inflammation-related diseases including asthma and chronic obstructive pulmonary disease based on PDE-4 inhibition is often stopped due to low clinical effects and vomiting-related side effects. As a result, there is a need for development of a therapeutic agent having excellent clinical therapeutic effects and safety. In other words, high selectivity to PDE-4 isozyme (compared to PDE-3, PDE-5 and PDE-7) and low binding to HARBS (High Affinity Rolipram Binding Site) are required to overcome vomiting-related side effects. Problems in which good therapeutic effect should be maintained must be overcome.

Although 2,7-diphenyl-pyrazolo [1,5-a] pyrimidine derivatives similar to the general formula (1) to be provided herein have been reported for their synthesis (Mohamed H. Elnagdi and Ayman W. Erian, Bull. Chem. Soc. Jpn. , 1990 , 63 , 1854-1856) It is not related to the inhibitory activity in the field of inflammation, such as asthma and chronic obstructive pulmonary disease, compounds represented by the formula (1) to be provided in the present invention Position 7 is a dialkoxyphenyl group, and the position 2 is an aryl derivative substituted with a new chemical structure.

Therefore, the present inventors have excellent in vitro and in vivo effects as a compound of a novel structure for the development of a therapeutic agent for asthma and inflammation-related diseases, and have high affinity for PDE-4 enzyme and low affinity for HARBS to overcome the side effects related to vomiting. To develop a PDE-4 inhibitor, a novel 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine derivative was prepared and the compounds according to the present invention Red and pharmacological tests showed excellent inhibitory activity, high selectivity, and low HARBS affinity for the PDE-4 enzyme, and animal experiments by oral administration confirmed that it had superior in vivo asthma treatment effect compared to conventional Roflumilast. It became.

Accordingly, an object of the present invention is to provide a novel 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound of formula 1 and pharmaceutically acceptable salts thereof To provide a novel 2-aryl-7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound according to the present invention, and To provide a composition for treating inflammation-related diseases, including asthma and chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease) comprising the same.

The present invention provides a novel 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof And a process for preparing 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine derivatives of formula (1) and 2 represented by formula (1). Bronchial asthma and chronic obstructive pulmonary disease characterized by containing -aryl-7- (3 ', 4'- dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine derivative as an active ingredient It relates to a pharmaceutical composition for the treatment and prevention of inflammation-related diseases, including diseases.

2-aryl-7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

[Wherein A is N or NO; R ₁ and R ₂ may be the same or different from each other, and each independently a hydrogen atom, a straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C _4- C ₁₀ ) cycloalkylalkyl group, phenyl, benzyl or R ₁ and R ₂ may be linked by (C ₁ -C ₃ ) alkylene; R ₃ is hydrogen atom, halogen atom, formyl, straight or branched saturated and unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkyl ketone, (C ₁ -C ₇ ) alkoxy, (C ₁ C ₇ ) alkoxyalkyl, hydroxy (C ₁ -C ₇ ) alkyl groups, carboxylic acids, carboxyesters, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono or di (C ₁ -C ₇ ) Alkylaminocarbonyl; X may be the same or different from each other and is a hydrogen atom, a crushed or straight chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxyalkyl , Halogen, cyano, nitro, amino, mono- or di (C ₁ -C ₇ ) alkyl amino, (C ₃ -C ₇ ) cycloalkylamine, morpholine, morpholine oxide, piperazine, piperazine oxide , Guanidine, urea, phenyl, benzyl, benzyloxy, carboxylic acid, carboxyl ester, carboxyamide, (C ₁ -C ₇ ) alkyl ketone, aryl ketone; n is an integer from 0 to 4; Provided that the (C ₁ -C ₇ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl group, (C ₄ -C ₁₀ ) cycloalkylalkyl group, phenyl group or benzyl group of R ₁ and R ₂ and X is (C ₁ -C ₇ It may be substituted with halogen, nitro, cyano, hydroxy, carboxyl or amino group including alkoxy, pulloline.]

Compounds according to the present invention are novel compounds, have excellent activity and selectivity against PDE-4 enzymes, and have excellent in vivo effects in animal experiments, thereby preventing asthma and chronic obstructive pulmonary disease. It is useful as a therapeutic agent for inflammation-related diseases.

Specific examples of the 2-aryl-7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof Is R_OneAnd R₂May be the same as or different from each other, and each independently a hydrogen atom, a straight chain or a saturation or unsaturated (C)_One -C₇) Alkyl, (C₃ -C₇) Cycloalkyl, (C₄ -C₁₀Cycloalkylalkyl group, phenyl, benzyl or R_OneAnd R₂Is (C_One -C₃Alkylene; R₃Are saturated and unsaturated (C) hydrogen atoms, halogen atoms, formyl, straight chain or_One -C₇) Alkyl, (C_One -C₇) Alkyl ketones, (C)_One -C₇) Alkoxy, (C_One -C₇Alkoxyalkyl, hydroxy (C_One -C₇Alkyl groups, carboxylic acids, carboxyesters, amino, mono or di (C_One -C₇Alkylamino, mono or di (C)_One -C₇) Alkylaminocarbonyl; X may be the same or different from each other, and may be hydrogen, crushed or straight-chain saturated or unsaturated (C_One -C₇) Alkyl, hydroxy, (C_One -C₇) Alkoxy, (C_One -C₇Alkoxyalkyl, halogen, cyano, nitro, amino, mono- or di (C)_One -C₇Alkylamino, (C₃ -C₇Cycloalkylamine, morpholin, morpholin oxide, piperazine, piperazine oxide, guanidine, urea, phenyl, benzyl, benzyloxy, carboxylic acid, carboxyl ester, carboxyamide, (C_One -C₇) Alkyl ketones, aryl ketones; n is an integer from 0 to 4; R above_OneAnd R₂And X's (C_One -C₇) Alkyl group, (C₃ -C₇) Cycloalkyl group, (C₄ -C₁₀The cycloalkylalkyl group, phenyl group or benzyl group is (C_One -C₇A) substituted with halogen, nitro, cyano, hydroxy, carboxyl or amino group including alkoxy, pullulin.

Preferred compounds of the formula (1) according to the present invention, R _1, saturation of the straight or branched chain or unsaturated (C ₁ - C ₇₎ alkyl or a fluorine atom is substituted by a straight chain or a saturated or unsaturated grinding (C ₁ - C ₇ Is alkyl, R ₂ is straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, cyclopropylmethyl, cyclopropyl, cyclopentyl or allyl group, R ₃ is hydrogen atom or halogen, X is benzyl ether , Hydroxy, thiobenzyl, carboxylic acid, carboxyl ester, carboxyamide, halogen, crushed or straight-chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, amino group, n Is a compound containing a substituent which is an integer of 0 to 3.

Particularly preferred ranges of compounds include the following general formula (2) compounds.

[Formula 2]

[A is N or NO, X is hydroxy, carboxylic acid, carboxyester, carboxyamide, halogen, crushed or straight chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) An alkoxy group, n is an integer from 0 to 3.]

Most preferred compound according to the present invention is X in the compound of Formula 2

Hydroxy, carboxylic acid, carboxyl ester, carboxylamide or when A is N or NO.

[Formula 3]

[A is N or NO, X is hydroxy, carboxylic acid, carboxyl ester, carboxyamide, and n is a compound containing a substituent of 1.]

Representative compounds of the general formula (3) include the following compounds.

Scheme 1 and Scheme 2 exemplify the preparation method according to the present invention, and the following preparation method does not limit the method for preparing the compound of Formula 1 according to the present invention, modifications of the following preparation method will be apparent to those skilled in the art. Unless otherwise stated, the definitions of substituents in the following schemes are the same as in Formula 1.

As shown in Scheme 1, 2-amino-5- (substituted phenyl) pyrazole compound (3) and aminopropenone compound (4) are reacted in an acetic acid medium to give 2- Aryl-7- (3 ', 4'- dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compounds can be prepared.

Scheme 1

2-aryl-7- (3,4-dialkoxyphenyl) represented by formula 1 according to the present invention from 3-amino-5- (substituted phenyl) pyrazole compound (3) and aminopropenone compound (4) In the preparation of pyrazolo [1,5-a] pyrimidine compounds, piperidine and other bases and alcohols may be used (KM Al-Zaydi, MAA Al-Shiekh, EAA Hafez, J. Chem. Res. Synop). , 2000, 1, 13 -15 EI Al-Afaleq, Synth Commun, 2000, 30 (11), 1985 -. 1999), is preferred as a solvent is also ethyl.

In addition, as another method for preparing the 2-aryl-7- (3,4-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound of formula 1, 3-amino as shown in Scheme 2 -5- (substituted phenyl) pyrazole compound (3) and 3- (3,4-dialkoxyphenyl) -3-oxopropionaldehyde compound (5) can be prepared by reacting in the presence of acetic acid.

Scheme 2

Among the compounds prepared by the above route of Scheme 1 or Scheme 2, X substituents may be prepared as a compound of Formula 1 including a new substituent by a reaction of converting some substituents to other substituents, such as converting a carboxylic acid to a carboxylic acid ester.

3-amino-5- (substituted phenyl) pyrazole compound (3), which is a substance used for preparing the compound of Formula 1, reacts α -cyanomethylphenylketone compound (6) with hydrazine as shown in Scheme 3. The aminopropene compound (4) can be prepared by reacting the catechol ketone compound (7) with an acetal of dimethylformamide.

Scheme 3

In the step of preparing the 3-amino-5- (substituted phenyl) pyrazole compound (3) from the α -cyanomethylphenyl ketone compound (6) and hydrazine, alcohol is mainly used as a solvent, and a catechol ketone compound ( 7) and the reaction for preparing the aminopropene compound (4) from the acetal of dimethylformamide can be synthesized in a similar manner as known in the prior art (F. Al-Omran, N. Al-Awadhi, MM Abdel Khalik, K. Kaul, AA El-Khair, and MH Elnadgi, J. Chem. Res , Synop , 1997 , 3 , 84-85 ), where DMF-acetal is used as a reactant and solvent.

In addition, the α -cyanomethylphenyl ketone compound (6) may be prepared according to the method exemplified in British Patent Publication No. 2,127,410, but is not limited thereto, and may be synthesized by other methods.

As can be seen in Table 1, the compound of Formula 1 has excellent activity and enzyme selectivity for PDE-4 enzyme and has low HARBS affinity, so that side effects such as vomiting are expected to be insignificant, in particular by oral administration. Animal studies have shown excellent therapeutic effects on asthma.

The compound represented by Formula 1 according to the present invention is suitable as a therapeutic agent for inflammation-related diseases including asthma and Chronic Obstructive Pulmonary Disease, wherein the compound of Formula 1 is suitable for use in medicine. Salts of the compounds include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include hydrochloric acid, bromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, phenylacetic acid, substituted phenylacetic acid, for example methoxy Phenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acid (e.g. p-toluenesulfate) Phonic acid, benzenesulfonic acid, naphthalenesulfonic acid or naphthalenedisulfonic acid), salicylic acid, glutaric acid, gluconic acid, tricavalylic acid, mandelic acid, cinnamic acid, substituted cinnamic acid (e.g. 4-methyl and 4-methok) Methyl, methoxy, halo or phenyl substituted cinnamic acid, including cycinnamic acid and α-phenyl cinnamic acid), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (eg 1- or 3-hydroxy) -2-naphthoic acid), b Taleneacrylic acid (eg, naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2 or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (eg, 1,4 Benzenediacrylic acid) and isethionic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts and organic bases such as dicyclohexylamine and N-methyl-D -Salts with glucamine.

The compounds according to the invention also have the potential of combining long lasting effects and rapid onset of action. Certain compounds also exhibit improved therapeutic indicators in animal models compared to existing long-lasting PDE-4 inhibitors. In addition, the compounds of the present invention may be suitable for administration once to three times a day.

The amount of the compound of formula 1, or a pharmaceutically acceptable salt thereof, used to achieve a therapeutic effect depends, of course, on the particular compound, the method of administration, the subject to be treated and the extent of treatment, disorder or disease.

It is possible to administer the compound of formula (1) or a pharmaceutically acceptable salt thereof alone, but preferably in a pharmaceutical formulation. Accordingly, the present invention is also preferably provided as a pharmaceutical formulation comprising Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, and any one or more therapeutic ingredients.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

[Production Example 1]

Preparation of the compound of formula 1 by reaction of 3-amino-5- (substituted phenyl) pyrazole compound (3) with 3- (3 ', 4'-dialkoxyphenyl) -3-oxopropionaldehyde compound (5)

3-aminopyrazole derivative (3) 0.60 mmol and 3- (3,4-dialkoxyphenyl) -3-oxopropionaldehyde (3- (3,4-Dialkoxyphenyl) -3-oxopropionaldehyde in acetic acid ) 0.60 mmol of compound (5) was added, followed by stirring at room temperature. NaHCO ₃ saturated aqueous solution was added to the reaction solution, extracted three times with ethyl acetate, and the organic layer was washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (silica gel, n-hexene / ethyl acetate, 3/1) to obtain the desired compound of formula (1). The yield and physical properties of each compound of Formula 1 are as follows.

7- ( 3′-cyclopentyloxy-4′- methoxyphenyl) -2- (3-fluorophenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 1)

Yield: 25%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (d, 1H, J = 4.5 Hz, Ar), 7.99 (m, 1H, Ar), 7.79∼6.92 (m, 8H, Ar), 4.88 (t, 1H , J = 4.84 Hz), 3.96 (s, 3H, -OCH ₃ ), 1.82-2.17 (m, 8H). MS m / z (relative intensity): 403 (M ⁺ , 23.3)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2-o-tolylpyrazolo [1,5- a ]

pyrimidine (compound 2)

Yield: 46%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (d, 1H, J = 4.6 Hz, Ar), 7.91 (m, 1H, Ar), 6.91∼7.78 (m, 8H, Ar), 4.87 (m, 1H ), 3.94 (s, 3H, -OCH ₃ ), 2.60 (s, 3H, -CH ₃ ), 2.10-1.26 (m, 8H). MS m / z (relative intensity): 399.4 (M ⁺ , 42.3)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2-p-tolylpyrazolo [1,5- a ]

pyrimidine (compound 3)

Yield: 62%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.45 (d, 1H, J = 4.6 Hz, Ar), 8.17 (m, 1H, Ar), 7.95 (m, 1H, Ar), 7.91 (m, 1H, Ar ), 7.73-7.02 (m, 5H, Ar), 4.88 (t, 1H, J = 6.9 Hz), 3.96 (s, 3H, -OCH ₃ ), 2.40 (s, 3H, -CH ₃ ), 2.10-1.56 (m, 8 H). MS m / z (relative intensity): 399.4 (M ⁺ , 13.49)

7- ( 3′-cyclopentyloxy-4′- methoxyphenyl) -2- (4-Chlorophenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 4)

Yield: 52%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.47 (d, 1H, J = 4.4 Hz, Ar), 7.98∼6.90 (m, 8H, Ar), 4.87 (t, 1H, J = 4.50 Hz), 3.96 ( s, 3H, -OCH ₃ ), 2.03 to 1.25 (m, 8H). MS m / z (relative intensity): 355 (M ⁺ , 1.49)

[Production Example 2]

Preparation of the compound of formula 1 by reaction of 3-amino-5- (substituted phenyl) pyrazole compound (3) with aminopropenone compound (4)

5-amino-pyrazol derivative (3) 0.69 mmol and 1- (3-dialkoxyphenylpropenone (1- (3 ', 4'-dialkoxyphenyl) -3-dimethylamino-propenone) in acetic acid (4) 0.69 mmol was added, followed by stirring at room temperature, saturated aqueous NaHCO ₃ solution was added to the reaction solution, extracted three times with ethyl acetate, and then the organic layer was washed twice with brine, dried over MgSO _4, and dried under reduced pressure. The solvent was removed, the organic layer was dried over MgSO ₄ , the solvent was removed under reduced pressure, and the mixture was separated by silica gel column chromatography to obtain the target compound of Chemical Formula 1. The yield and physical properties of each compound of Chemical Formula 1 were as follows.

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2-phenylpyrazolo [1,5- a ] pyrimidine

(Compound 5)

Yield: 42.3%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (d, 1H, J = 4.5 Hz, Ar), 8.01 to 8.05 (m, 3H, Ar), 7.71 (m, 1H, Ar), 7.47 to 7.38 (m , 3H, Ar), 7.04 (m, 2H, Ar), 6.90 (m, 1H, Ar), 4.87 (t, 1H, J = 7.05 Hz), 3.96 (s, 3H, -OCH ₃ ), 2.06-1.58 (m, 8 H). MS m / z (relative intensity): 385 (M ⁺ , 23.38)

2- (3-Bromophenyl) -7- ( 3'-cyclopentyloxy-4'- methoxyphenyl) -pyrazolo [1,5 a ]

pyrimidine (compound 6)

Yield: 25%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (d, 1H, J = 4.40 Hz, Ar), 8.24∼6.93 (m, 9H, Ar), 5.03 (t, 1H, J = 3.09 Hz), 3.97 ( s, 3H, -OCH ₃ ), 2.06-1.25 (m, 8H). MS m / z (relative intensity): 464 (M ⁺ , 61.4)

2- (2-Bromophenyl) -7- ( 3'-cyclopentyloxy-4'- methoxyphenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 7)

Yield: 26%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (d, 1H, J = 4.5 Hz, Ar), 7.94 (m, 1H, Ar), 7.88∼6.93 (m, 8H, Ar), 4.88 (m, 1H ), 3.97 (s, 3H, -OCH ₃ ), 1.89-1.54 (m, 8H). MS m / z (relative intensity): 464 (M ⁺ , 61.32)

2- (4-Bromophenyl) -7- ( 3'-cyclopentyloxy-4'- methoxyphenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 8)

Yield: 32%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.47 (d, 1H, J = 4.50 Hz, Ar), 7.95 (m, 1H, Ar), 7.90 (m, 1H, Ar), 7.68∼7.02 (m, 6H , Ar), 6.91 (m, 1H, Ar), 4.86 (t, 1H, J = 9.50 Hz), 3.96 (s, 3H, -OCH ₃ ), 2.01-1.25 (m, 8H). MS m / z (relative intensity): 464 (M ⁺ , 53.2)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2- (2,5-dichlorophenyl) -pyrazolo [1,5

a pyrimidine (Compound 9)

Yield: 24.3%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.55 (d, 1H, J = 4.40 Hz, Ar), 8.06 to 8.04 (m, 2H, Ar), 7.67 to 7.45 (m, 2H, Ar), 7.39 to 7.28 (m, 2H, Ar), 7.03 (m, 1H, Ar), 6.99 (m, 1H, Ar), 4.92 (t, 1H, J = 9.5 Hz), 3.97 (s, 3H, -OCH ₃ ), 2.05 ～ 1.28 (m, 8H). MS m / z (relative intensity): 454 (M ⁺ , 45.3)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2- (2,6-difluorophenyl) -pyrazolo

[1,5- a pyrimidine (Compound 10)

Yield: 22.3%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (d, 1H, J = 4.40 Hz, Ar), 8.00∼6.76 (m, 8H, Ar), 5.20 (t, 1H, J = 21.4 Hz), 3.91 ( s, 3H, -OCH ₃ ), 2.04-1.25 (m, 8H). MS m / z (relative intensity): 421 (M ⁺ , 21.49)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2- (4-fluorophenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 11)

Yield: 54%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48-6.89 (m, 10H, Ar), 4.88 (t, 1H, J = 4.80 Hz), 3.95 (s, 3H, -OCH ₃ ), 2.10-1.64 (m , 8H). MS m / z (relative intensity): 403 (M ⁺ , 21.49)

7- ( 3′-Cyclopentyloxy- 4′-methoxyphenyl) -2- (4-methoxyphenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 12)

Yield: 62%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (d, 1H, J = 4.4 Hz, Ar), 8.00-7.94 (m, 3H, Ar), 7.71-7.69 (m, 1H, Ar), 7.05-6.95 (m, 4H, Ar), 6.86 (m, 1H, Ar), 4.88 (t, 1H, J = 4.80 Hz), 3.95 (s, 3H, -OCH ₃ ), 3.86 (s, 3H, Ar-OCH ₃ ), 2.11-1.23 (m, 8H). MS m / z (relative intensity): 415 (M ⁺ , 31.49)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2- (4-nitrophenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 13)

Yield: 28.3%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.44 (d, 1H, J = 4.38 Hz, Ar), 8.00∼6.87 (m, 9H, Ar), 4.88 (t, 1H, J = 4.59 Hz), 3.92 ( s, 3H, -OCH ₃ ), 2.17-1.56 (m, 8H). MS m / z (relative intensity): 430 (M ⁺ , 16.3)

7- ( 3′-cyclopentyloxy-4′- methoxyphenyl) -2- (3-Chlorophenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 14)

Yield: 42%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (d, 1H, J = 4.2 Hz, Ar), 8.07 (m, 1H, Ar), 8.03 (m, 1H, Ar), 7.88∼7.03 (m, 6H , Ar), 6.93 (m, 1H, Ar), 4.89 (t, 1H, J = 4.8 Hz), 3.96 (s, 3H, -OCH ₃ ), 2.05-1.63 (m, 8H). MS m / z (relative intensity): 419 (M ⁺ , 31.4)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2-m-tolylpyrazolo [1,5- a ] pyrimidine

 (Compound 15)

Yield: 37.8%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.45 (d, 1H, J = 4.5 Hz, Ar), 8.06-6.88 (m, 9H, Ar), 4.89 (t, 1H, J = 4.80 Hz), 3.96 ( s, 3H, -OCH ₃ ), 2.42 (s, 3H, -ArCH ₃ ), 2.07-1.62 (m, 8H). MS m / z (relative intensity): 399 (M ⁺ , 11.5)

7- ( 3′-Cyclopentyloxy- 4′-methoxyphenyl) -2- (3-methoxyphenyl) -pyrazolo [1,5- a ]

pyrimidine (compound 16)

Yield: 43%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.45 (d, 1H, J = 4.4 Hz, Ar), 8.01 (m, 1H, Ar), 7.70-6.88 (m, 8H, Ar), 4.88 (t, 1H , J = 4.77 Hz), 3.95 (s, 3H, -OCH ₃ ), 3.87 (s, 3H, Ar-OCH ₃ ), 2.05-1.61 (m, 8H). MS m / z (relative intensity): 415 (M ⁺ , 23.2)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2- (3-trifluoromethylphenyl) pyrazolo

[1,5- a pyrimidine (Compound 17)

Yield: 22.4%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (m, 1H, J = 4.50 Hz, Ar), 8.23 (m, 1H, Ar), 8.14 (m, 2H, Ar), 7.94 (m, 1H, Ar ), 7.76∼7.68 (m, 2H, Ar), 7.26∼7.04 (m, 2H, Ar), 6.94 (m, 1H, Ar), 4.89 (t, 1H, J = 4.65 Hz), 3.97 (s, 3H , -OCH ₃ ), 2.03-1.61 (m, 8H). MS m / z (relative intensity): 453 (M ⁺ , 26.3)

7- ( 3′-Cyclopentyloxy-4′- methoxyphenyl) -2- (4-trifluoromethylphenyl) pyrazolo

[1,5- a pyrimidine (Compound 18)

Yield: 32%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (m, 1H, J = 4.50 Hz, Ar), 8.32 (m, 1H, Ar), 8.15 (m, 1H, Ar), 8.05 (m, 1H, Ar ), 7.69-7.54 (m, 3H, Ar), 7.08-7.02 (m, 2H, Ar), 6.93 (m, 1H, Ar), 4.88 (t, 1H, J = 4.65 Hz), 3.96 (s, 3H , -OCH ₃ ), 2.05-1.59 (m, 8H). MS m / z (relative intensity): 453 (M ⁺ , 12.3)

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2-phenylpyrazolo [1,5- a ]

pyrimidine (compound 19)

Yield: 32.7%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (1H, d, J = 4.2 Hz, Ar), 8.10 (1H, s, Ar), 7.99 (2H, m, Ar), 7.62 (1H, m, Ar ), 7.39 (4H, m, Ar), 7.08 (1H, s, Ar), 6.84 (1H, m, Ar), 6.77 (1H, t, J = 75 Hz, -CHF ₂ ), 4.01 (2H, d , J = 6.9 Hz, -OCH _2- ), 1.42 (1H, m, J = 4.09 Hz, -CH-), 0.68 (2H, q, J = 6.19 Hz, -CH _2- ), 0.40 (2H, q , J = 5.1 Hz, -CH _2- ).

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-fluorophenyl)

pyrazolo [1,5- a pyrimidine (Compound 20)

Yield: 30%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (1H, d, Ar, J = 4.2 Hz), 8.08 (1H, d, Ar), 7.76∼7.60 (3H, m, Ar), 7.43∼7.35 (2H , m, Ar), 7.26 (2H, d, Ar), 7.07 (1H, m, Ar), 6.79 (1H, t, -CHF ₂ , J = 75.0 Hz), 4.03 (2H, d, -OCH _2- , J = 6.9 Hz), 0.70 (2H, m, -CH _2- ), 0.42 (2H, m, -CH _2- )

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-trifluoromethyl

phenyl) -pyrazolo [1,5- a pyrimidine (Compound 21)

Yield: 30.8%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (1H, d, J = 4.35 Hz, Ar), 8.26 (1H, s, Ar), 8.14 to 8.11 (2H, m, Ar), 7.66 to 7.55 (3H , m, Ar), 7.36 (1H, d, J = 8.37 Hz, Ar), 7.11 (1H, s, Ar), 6.96 (1H, s, J = 4.38 Hz, Ar), 6.79 (1H, t, J = 75 Hz, -CHF ₂ ), 4.02 (2H, d, J = 6.96 Hz, -OCH _2- ), 1.39 (1H, m, -CH-), 0.68 (2H, m, -CH _2- ), 0.40 (2H, m, -CH _2- ).

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-methoxyphenyl)

-pyrazolo [1,5- a pyrimidine (Compound 22)

Yield: 43.2%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, 1H, J = 4.5 Hz), 8.11-6.52 (m, 9H, Ar), 6.77 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.02 (d, 2H, J = 6.9 Hz, -OCH _2- ), 3.88 (s, 3H, -CH ₃ ), 0.66 (m, 2H, -CH _2- ), 0.40 (m, 2H, -CH _2- ). MS m / z (relative intensity): 437.2 (M ⁺ , 32.2)

(2- (3-Benzyloxyphenyl) -7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidine (Compound 23)

Yield: 62.9%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, 1H, J = 1.2 Hz), 6.82 (t, 1H, J = 75 Hz, -CHF ₂ ), 6.39-8.48 (m, 14 H, Ar) , 4.01 (d, 2H, J = 6.5 Hz, -OCH _2- ), 0.65 (m, 2H, -CH _2- ), 0.36 (m, 2H, -CH _2- ). MS m / z (relative intensity): 513.5 (M ⁺ , 70.5)

2- (3-Bromophenyl) -7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidine (Compound 24)

Yield: 68%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (d, 1H, J = 4.38 Hz), 6.53-8.15 (m, 8H, Ar), 6.65 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.02 (d, 2H, J = 6.93 Hz, OCH _2- ), 0.68 (m, 2H, -CH _2- ), 0.41 (m, 2H, -CH _2- ). MS m / z (relative intensity): 486.25 (M ⁺ , 11.13)

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidin-2-yl] -benzoic acid methyl ester (Compound 25)

Yield: 10%

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.4 (m, 2H, -CH ₂ ), 0.65 (m, 2H, -CH _2- ), 4.0 (s, 3H, -OCH ₃ ), 4.03 (d, 2H , J = 6.9 Hz, -O-CH _2- ), 6.5 (s, 1H), 6.78 (t, 1H, J = 75 Hz, -CHF ₂ ), 6.9 (d, 1H), 6.9 (d, 1H) , 7.1 (t, 2H), 7.3 (d, 1H), 7.5 (t, 1H), 7.6 (d, 1H), 8.0 (t, 2H) 8. 1 (d, 1H), 8.5 (d, 1H) , 8.6 (s, 1H)

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3,5-dichlorophenyl) -pyrazolo [1,5- a ] pyrimidine (Compound 26)

Yield: 31.5%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (1H, d, J = 4.5 Hz, Ar), 8.07 (1H, d, J = 2.1 Hz, Ar), 7.84-7.83 (2H, m, Ar), 7.55 (1H, m, Ar), 7.38-7.30 (2H, m, Ar), 7.05-6.95 (2H, m, Ar), 6.79 (1H, t, J = 75.0 Hz, -CHF ₂ ), 4.02 (2H , d, J = 6.9 Hz, -OCH _2- ), 1.40 (1H, m, -CH-), 0.70 (2H, m, -CH _2- ), 0.43 (2H, m, -CH _2- ).

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-nitrophenyl)

pyrazolo [1,5- a pyrimidine (Compound 27)

Yield: 51%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.85 (1H, s), 8.56 (1H, d, J = 4.4 Hz), 8.30-8.24 (2H, m), 8.09 (1H, d, J = 1.9 Hz) , 7.67-7.58 (2H, m), 7.38 (1H, d, J = 8.3 Hz), 7.16 (1H, s), 6.99 (1H, d, J = 4.4 Hz), 6.80 (1H, t, J = 75 Hz), 4.06 (2H, d, J = 7.0 Hz), 1.44-1.37 (1H, m), 0.72-0.66 (2H, m), 0.45-0.40 (2H, m)

7- ( 3′-Allyloxy-4′- difluoromethoxyphenyl) -2- (3-benzyloxyphenyl) -pyrazolo

[1,5- a pyrimidine (Compound 28)

Yield: 68%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (d, 1H, J = 5.8 Hz), 6.33 to 8.07 (m, 14H, Ar), 6.71 (t, 1H, J = 75 Hz, -CHF ₂ ), 6.09 (m, 1H, OCH ₂ CH-), 5.37 (d, 2H, J = 7.2 Hz, -CHCH _2- ), 5.13 (s, 2H, OCH ₂ Ar), 4.37 (d, 2H, J = 6.4 Hz , -OCH _2- ). MS m / z (relative intensity): 499 (M ⁺ , 5.62)

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-ethoxyphenyl) -pyrazolo [1,5- a ] pyrimidine (Compound 29)

Yield: 35.4%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (1H, d, J = 2 Hz, Ar), 8.13 (1H, d, J = 2 Hz, Ar), 7.39 (3H, m, Ar), 7.25 ( 2H, m, Ar), 6.93 (2H, m, Ar), 6.77 (1H, t, J = 74.8 Hz, -OCHF 2), 4.02 (4H, m, -OCH 2 -), 1.39 (4H, m, -CH, -CH ₃ ), 0.67 (2H, m, -CH _2- ), 0.41 (2H, m, -CH _2- ).

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-isopropoxyphenyl)

-pyrazolo [1,5- a pyrimidine (compound 30)

Yield: 32.6%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (1H, m, Ar), 812 (1H, d, J = 1.6 Hz, Ar), 7.56 (3H, m, Ar), 7.34 (2H, m, Ar ), 7.12 (1H, m, Ar), 6.92 (2H, m, Ar), 6.77 (1H, t, J = 76.8 Hz, -OCHF ₂ ), 4.62 (1H, m, -OCH-), 4.01 (2H , d, J = 7.0 Hz, -OCH _2- ), 1.39 (7H, m, -CH-, -CH _3- ), 0.69 (2H, m, -CH _2- ), 0.40 (2H, m, -CH _2- ).

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3,4-dimethoxyphenyl)

-pyrazolo [1,5- a pyrimidine (Compound 31)

Yield: 36.2%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (1H, d, J = 4.2 Hz, Ar), 8.08 (1H, d, J = 2 Hz, Ar), 7.58 (3H, m, Ar), 7.34 ( 1H, m, Ar), 7.14 ~ 6.82 (3H, m, Ar), 6.77 (1H, t, J = 75.0 Hz, -OCHF 2), 4.04 ~ 3.87 (8H, m, -OCH 2 -, -OCH 3 ), 1.35 (1H, m, -CH-), 0.69 (2H, m, -CH _2- ), 0.43 (2H, m, -CH _2- ).

7- ( 3′-Cyclopropylmethoxy- 4′-difluoromethoxyphenyl) -2- (3-difluoromethoxy

phenyl) pyrazolo [1,5- a pyrimidine (compound 32)

Yield: 22.8%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.52-6.09 (m, 10H, Ar), 6.78 (t, 1H, J = 37.7 Hz, -CHF ₂ ), 6.57 (t, 1H, J = 75 Hz,- CHF ₂ ), 4.01 (d, 2H, J = 6.8 Hz, OCH _2- ), 0.70-0.64 (m, 2H, -CH2-), 0.44-0.36 (m, 2H, -CH _2- ). MS m / z (relative intensity): 512.3 (M ⁺ , 19.5)

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3,5-dimethoxyphenyl) -pyrazolo [1,5- a ] pyrimidine (Compound 33)

Yield: 32.6%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (1H, d, J = 4.2 Hz, Ar), 8.12 (1H, s, Ar), 7.60 (1H, d, J = 8.4 Hz, Ar), 7.34 ( 1H, d, J = 8.4 Hz, Ar), 7.14 (2H, m, Ar), 7.03 (2H, d, J = 7.8 Hz, Ar), 6.92 (1H, d, J = 4.2 Hz, Ar), 6.77 (1H, t, J = 75.3 Hz, -OCHF ₂ ), 4.01 (2H, d, J = 7.2 Hz, -OCH _2- ), 3.86 (6H, s, -CH ₃ ), 1.38 (1H, m,- CH-), 0.68 (2H, q, J = 6.10 Hz, -CH _2- ), 0.40 (2H, q, J = 5.00 Hz, -CH _2- ).

2- (3-Benzyloxy-4-methoxyphenyl) -7- ( 3′-cyclopropylmethoxy-4 ′ difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidine (Compound 34)

Yield: 40.7%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.4 (d, 1H, J = 4.4 Hz), 6.39-8.44 (m, 13H, Ar), 6.76 (t, 1H, J = 75 Hz, -CHF ₂ ), 5.18 (s, 2H, -OCH ₂ Ar), 3.99 (d, 2H, J = 7.2 Hz, OCH _2- ), 3.93 (s, 3H, -CH ₃ ), 0.64 (q, 2H, J = 2.7 Hz, -CH _2- ), 0.36 (q, 2H, J = 3.6 Hz, -CH _2- ). MS m / z (relative intensity): 453.5 (M ⁺ , 25.5)

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-iodophenyl)

-pyrazolo [1,5- a pyrimidine (Compound 35)

Yield: 33.2%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (1H, d, J = 4.4 Hz, Ar), 8.34 (1H, d, J = 1.8 Hz, Ar), 8.21 (1H, m, Ar), 7.91 ( 1H, m, Ar), 7.73 (1H, m, Ar), 7.57 (1H, m, Ar), 7.35 (1H, m, Ar), 7,17 (1H, m, Ar), 7.03 (1H, s , Ar), 6.92 (1H, m, Ar), 6.78 (1H, t, J = 75.0 Hz, -OCHF ₂ ), 4.02 (2H, d, J = 7.0 Hz, -OCH _2- ), 1.41 (1H, m, -CH-), 0.70 (2H, m, -CH _2- ), 0.44 (2H, m, -CH _2- ).

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (2,5-dichlorophenyl)

-pyrazolo [1,5- a pyrimidine (Compound 36)

Yield: 32%

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.56 (1H, d, J = 4.2 Hz, Ar), 8.08 (1H, d, J = 4.2 Hz, Ar), 7.9 (1H, d, Ar), 7.58 ( 1H, d, Ar), 7.4 (2H, d, Ar), 7.36-7.32 (2H, m, Ar), 6.99 (1H, m, Ar), 6.79 (1H, t, J = 75.0 Hz, -CHF ₂ ), 4.02 (2H, d, J = 6.9 Hz, -OCH _2- ), 0.68 (2H, m, -CH _2- ), 0.41 (2H, m, -CH _2- )

[Manufacture example 3]

Preparation of 3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidin-2-yl] -benzoic acid (Compound 37)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidin-2-yl] -benzoic acid methyl ester (0.1 g, 2.15 × 10 ^-4 mol) was dissolved in MeOH / H ₂ After dissolving in a mixed solution of O = 3/1, LiOH (0.017 g, 3.23 × 10 ^-4 mol) was added thereto and stirred. The reaction solution was neutralized with 1N-HCl solution, and extracted with ethyl acetate. The organic layer was washed twice with brine, dried over MgSO ₄ , and the solvent was removed under reduced pressure to obtain a target compound 37 (0.08 g, 83%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 8.54 (d, 1H), 8.2 (d, 1H), 8.1 (d, 1H), 7.5 (m, 2H), 7.3 (d, 1H), 7.2 (d, 2H), 7.1 (d, 1H), 6.9 (d, 1H), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.3 (t, 1H, J = 6.9 Hz , -O-CH _2- ), 4.0 (d, 2H, OCH ₃ ), 0.695 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ ).

[Production Example 4]

Preparation of 3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidin-2-yl] -benzoic acid isopropyl ester (Compound 38)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl) -pyrazolo [1,5- a ] pyrimidin-2-yl] -benzoic acid (0.2 g, 4.2 × 10 ^-4 mol obtained from Preparation Example 3 ) Was dissolved in methylene chloride and isopropyl alcohol was added (ice bath, N ₂ ). After 5 minutes DIC (0.052 g, 4.27 × 10 ⁻⁴ mol) was added and stirred. The reaction was extracted with ethyl acetate and the organic layer was washed twice with brine, dried over MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was separated by column chromatography (n-hexane / ethyl acetate, 2/1) to obtain the title compound 38 (0.1 g, 49%) and compound 38.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.53 (d, 1H), 8.1 (d, 1H), 8.0 (d, 2H), 7.66 (d, 1H), 7.5 (t, 1H), 7.3 (d, 1H), 7.2 (s, 1H), 7.1 (s, 1H), 6.9 (d, 1H), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 5.2 (m , 1H, OCH- (CH ₃ ) ₂ ), 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 1.5 (s, 3H, -CH ₃ ), 1.4 (s, 3H, -CH ₃ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ )

1-3- (7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo

[1,5-a] pyrimidin-2-yl] -benzoyl-1,3-diisopropylurea (Compound 87)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.52 (d, 1H, J = 4.4 Hz, Ar), 8.14-6.92 (m, 10 H, Ar), 6.78 (t, 1H, J = 75 Hz, -C H F ₂ ), 4.41 (m, 1H, -C H -Me ₂ ), 4.01 (d, 2H, J = 6.9 Hz, -OC H _2- ), 3.88 (m, 1H, -C H -Me ₂ ) , 1.46 (d, J = 6.6 Hz, -CH- (C H ₃ ) ₂ ), 1.02 (d, J = 6.6 Hz, -CH- (C H ₃ ) ₂ ), 3.8 (s, 3H, -CH ₃ ), 1.4 (s, 3H, -CH ₃ ), 0.67 (m, 2H, -CH _2- ), 0.41 (m, 2H, -CH ₂ )

Production Example 5

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ]

Preparation of pyrimidin-2-yl] -benzoic acid methoxymethyl ester (Compound 39)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidin-2-yl] -benzoic acid (Compound 37, 0.2 g, 4.2 × 10 ^-4 mol) in dichloromethane After dissolving methoxyethanol was added (ice bath, N ₂ ). After 5 minutes DIC (0.052 g, 4.27 × 10 ⁻⁴ mol) was added and stirred. The reaction was extracted with ethyl acetate and the organic layer was washed twice with brine, dried over MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was separated by column chromatography (n-hexane / ethyl acetate, 2/1) to obtain the desired compound 39 (0.1 g, 49%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.64 (s, 1H), 8.53 (d, 1H), 8.5 (d, 1H), 8.2 (d, 1H), 8.0 (t, 2H), 7.66 (d, 1H), 7.5 (t, 1H), 7.3 (d, 1H), 7.2 (s, 1H), 7.1 (s, 1H), 6.9 (d, 1H), 6.7 (t, 1H, J = 75 Hz,- CHF ₂ ), 4.5 (t, 2H, -OCH _2- ), 4.1 (d, 2H, -OCH _2- ), 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 3.8 (m , 2H, -OCH ₃ ), 3.71. (S, 3H, -OCH ₃ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ )

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ]

Preparation of pyrimidin-2-yl] -N-ethylbenzamide (Compound 40)

Compound 37 (0.2 g, 4.2 × 10 ⁻⁴ mol) obtained in Preparation Example 3 was dissolved in dichloromethane chloride and ethylamine was added (ice bath, N ₂ ). After 5 minutes DIC (0.052 g, 4.27 x 10-4 mol) was added and stirred. The reaction was extracted with ethyl acetate and the organic layer was washed twice with brine, dried over MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was separated by column chromatography (n-hexane / ethyl acetate, 2/1) to obtain the title compound 40 (0.1 g, 45%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, 1H), 8.35 (s, 1H), 8.1 (d, 1H), 8.0 (s, 1H), 7.7 (d, 1H), 7.66 (d, 1H), 7.5 (t, 2H), 7.4 (s, 1H), 7.1 (s, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 6.7 (t, 1H, J = 75 Hz,- CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 3.5 (m, 2H, -N-CH _2- ), 1.2 (m, 3H, -CH ₃ ), 0.65 ( m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ )

[Manufacture example 7]

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo

[1,5- a pyrimidin-2-yl]- N, N Preparation of -dimethylbenzamide (Compound 41)

Compound 37 (0.15 g, 3.34 × 10 ⁻⁴ mol) was dissolved in dichloromethane and dimethylamine was added (ice bath, N2). After 5 minutes DIC (0.052 g, 4.27 × 10 ⁻⁴ mol) was added and stirred. The reaction was extracted with ethyl acetate and the organic layer was washed twice with brine, dried over MgSO ₄ , and the solvent was removed under reduced pressure. The mixture was separated by column chromatography (n-hexane / ethyl acetate, 1/1) to obtain the title compound 41 (0.09 g, 52%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, 1H), 8.0 (s, 3H), 7.7 (s, 1H), 7.6 (d, 1H), 7.4 (t, 2H), 7.2 (s, 1H), 7.0 (s, 1H), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 3.1 (s, 3H , -N-CH ₃ ), 3.0 (s, 3H, -N-CH ₃ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ )

[Manufacture example 8]

{3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo

[1,5- a ] pyrimidin-2-yl] -benzyl} -dimethylamine (Compound 42)

LiAlH ₄ was added to THF at 0 ^° C. and stirred, and then Compound 41 (0.05 g, 1.0 × 10 ⁻⁴ mol) obtained from Preparation Example 7 was added and reacted. After 5 hours, the temperature was raised to room temperature and the reaction was continued. After completion of the reaction, the reaction was extracted with ethyl acetate and the organic layer was washed twice with brine, dried over MgSO ₄ and the solvent was removed under reduced pressure. The mixture was separated by column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound 42 (0.03 g, 62%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, 1H), 8.49 (s, 2H), 8.1 (d, 2H), 7.9 (d, 1H), 7.6 (m, 3H), 7.4 (s, 1H), 7.3 (s, 1H), 7.0 (d, 1H), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 3.5 (s, 2H, -CH ₂ -N), 2.3 (s, 6H, -N- (CH ₃ ) 2), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H,- CH2)

[Manufacture example 9]

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a ] Preparation of pyrimidin-2-yl] phenylamine (Compound 43)

7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -2- (3-nitrophenyl)

pyrazolo [1,5-a] Pyrimidine (Compound 27) (0.34 g, 0.74 mmol) and 10% Pd / C (50 mg) in methanol (10 ml)₂ After stirring for 4 hours under atmosphere, the mixture was filtered using Celite. The filtered solution was concentrated and purified by column chromatography (EtOAc / Hx = 1/2) to give a compound 43 (0.25 g, 78%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (1H, d, J = 7.4 Hz), 7.82 (1H, d, J = 1.9 Hz), 7.57 to 7.54 (1H, m), 7.39 to 7.19 (5H, m), 6.96 (1H, s), 6.77-6.74 (1H, m), 6.73 (1H, t, J = 75 Hz), 4.04 (2H, d, J = 7.0 Hz), 3.80 (2H, bs), 1.39-1.32 (1H, m), 0.72-0.66 (2H, m), 0.44-0.39 (2H, m)

[Production Example 10]

Benzyl-3- [7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a ] Preparation of pyrimidin-2-yl] phenylamine (Compound 44)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ]

NaBH in a solution of pyrimidin-2-yl] phenylamine (Compound 43) (0.60 g, 1.42 mmol) and benzaldehyde (0.30 ml, 2.84 mmol) in methanol (6 ml)₃CN (0.18 g, 2.84 mmol) was added and then stirred for 10 hours. Water (0.05 ml) was added and the mixture was stirred for 5 minutes and then distilled under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (EtoAc / Hx = 1/3) to give compound 44 (0.43 g, 57%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (1H, d, J = 4.2 Hz), 7.96 (1H, d, J = 2.0 Hz), 7.65∼7.24 (10H, m), 7.00 (1H, m) , 6.95 (1H, s), 6.87 (1H, d, J = 4.2 Hz), 6.77 (1H, t, J = 75 Hz), 4.41 (2H, s), 4.00 (2H, d, J = 7.2 Hz) , 1.43-1.37 (1H, m), 0.69-0.60 (2H, m), 0.42-0.35 (2H, m)

[Production Example 11]

N- 3- (7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a Preparation of] pyrimidin-2-yl] phenylmethanesulfonamide (Compound 45)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ]

MsCl (0.013 ml, 0.17 mmol) was added to a mixture of pyrimidin-2-yl] phenylamine (Compound 43) (20 mg, 0.057 mmol), Et ₃ N (0.05 ml) and CH ₂ Cl ₂ (0.3 ml). Stir at room temperature for 2 hours. Saturated NH ₄ Cl aqueous solution (0.5 ml) was added, extracted with EtOAc, and distilled under reduced pressure to remove the solvent. The concentrate was purified by tube chromatography (EtOAc / Hx = 2/3) to give compound 45 (15 mg, 51%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (1H, d, J = 4.6 Hz), 8.12 to 8.07 (1H, m), 8.02 to 7.95 (2H, m), 7.61 to 7.52 (2H, m), 7.41-7.34 (2H, m), 7.10 (1H, s), 6.94 (1H, d, J = 4.0 Hz), 6.79 (1H, t, J = 75 Hz), 3.99 (2H, d, J = 7.0 Hz ), 3.45 (3H, s), 1.42-1.37 (1H, m), 0.72-0.62 (2H, m), 0.44-0.36 (2H, m)

[Manufacture example 12]

N-3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a of pyrimidin-2-yl] phenylacetamide (Compound 46)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5-aExcept for using AcCl instead of MsCl from] pyrimidin-2-yl] phenylamine (Compound 43) The reaction was carried out under the same conditions.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (1H, d, J = 4.2 Hz), 8.03 (1H, s), 7.73˜7.30 (6H, m), 7.06 (1H, s), 6.90 (1H, d, J = 4.0 Hz), 6.77 (1H, t, J = 75 Hz), 4.02 (2H, d, J = 7.0 Hz), 2.20 (3H, s), 1.45-1.40 (1H, m), 0.72- 0.65 (2H, m), 0.44-0.38 (2H, m)

[Production Example 13]

N-3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a Preparation of] pyrimidin-2-yl] phenylbenzamide (Compound 47)

Compound 47 was prepared under the same conditions as in Preparation Example 11.

Under the same conditions as in Preparation Example 11, except that benzyl chloride was used instead of MsCl from 3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ] pyrimidin-2-yl] phenylamine (Compound 43). The reaction proceeded.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.52 (1H, d, J = 4.2 Hz), 8.21 (1H, s), 8.13-8.05 (2H, m), 7.99-7.88 (2H, m), 7.80- 7.76 (2H, m), 7.70-7.33 (2H, m), 7.12 (1H, s), 6.91 (1H, d, J = 4.6 Hz), 6.76 (1H, t, J = 75 Hz), 4.03 (2H , d, J = 6.8 Hz), 1.41 to 1.34 (1H, m), 0.67 to 0.58 (2H, m), 0.42 to 0.34 (2H, m)

Production Example 14

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a ] Preparation of pyrimidin-2-yl] phenyl cyanamide (Compound 48)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ] pyrimidin-2-yl] phenylamine (Compound 43) (20 mg, 0.056 mmol) in a solution of methanol (1 ml) NaOAc (13.5 mg, 0.17 mmol) and CNBr (11.9 mg, 0.11 mmol) were added and stirred at room temperature for 7 hours. After distilling the reaction solution under reduced pressure, the concentrated solution was purified by column chromatography (EtOAc / Hx = 2/3) to obtain Compound 48 (0.029 mmol, 52%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.52 (1H, d, J = 4.4 Hz), 7.97 (1H, d, J = 2.2 Hz), 7.65 to 7.59 (3H, m), 7.46 to 7.35 (2H, m), 7.11-7.05 (2H, m), 6.93 (1H, d, J = 4.4 Hz), 0.73 (1H, t, J = 75 Hz), 4.01 (2H, d, J = 7.0 Hz), 1.42- 1.37 (1H, m), 0.70-0.62 (2H, m), 0.43-0.37 (2H, m)

[Production Example 15]

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a ] Preparation of pyrimidin-2-yl] phenyldimethylamine (Compound 49)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ] pyrimidin-2-yl] phenylamine (Compound 43) (20 mg, 0.046 mmol) and 37% aqueous formaldehyde solution (0.04 ml, 0.54 mmol) was dissolved in methanol (2 ml) and 10% Pd / C (5 mg) was added and stirred under H ₂ stream for 10 hours. The reaction solution was filtered using Celite, the filtrate was concentrated and purified by column chromatography (EtOAc / Hx = 1/2) to give the compound 49 (13 mg, 63%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.49 (1H, d, J = 4.8 Hz), 8.15 (1H, d, J = 1.8 Hz), 7.63 to 7.58 (1H, m), 7.36 to 7.31 (4H, m), 7.07 (1H, s), 6.90 (1H, d, J = 4.8 Hz), 6.84-6.78 (1H, m), 6.77 (1H, t, J = 75 Hz), 4.01 (2H, d, J = 7.2 Hz), 3.02 (6H, s), 1.43-1.37 (1H, m), 0.72-0.63 (2H, m), 0.44-0.38 (2H, m)

[Production Example 16]

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2-

(3-piperidin-1-yl-phenyl) -pyrazolo [1,5- a ] Preparation of pyrimidine (Compound 50)

Except for using pentandial from 3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ] pyrimidin-2-yl] phenylamine (Compound 43), Compound 50 was prepared under the same conditions as in Preparation Example 10. Prepared.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.49 (1H, d, J = 4.0 Hz), 8.15 (1H, d, J = 2.0 Hz), 7.63-7.56 (2H, m), 7.47-7.26 (3H, m), 7.06 (1H, s), 7.02 to 6.96 (1H, m), 6.90 (1H, d, J = 4.6 Hz), 6.77 (1H, t, J = 75 Hz), 4.01 (2H, d, J = 6.8 Hz), 3.23 (4H, t, J = 5.5 Hz), 1.85 to 1.71 (7H, m), 1.45 to 1.40 (1H, m), 0.74 to 0.65 (2H, m), 0.45 to 0.38 (2H, m)

[Production Example 17]

4-3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a ] pyrimidin-2-yl] phenylpiperazine-1-carboxylic acid tert -butyl ester (compound 51)

Using bis (2-oxo-ethyl) carbamic acid tert -butylester from 3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ] pyrimidin-2-yl] phenylamine (Compound 43) A compound 51 was prepared except under the same conditions as in Preparation Example 10.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.50 (1H, d, J = 4.4 Hz), 8.10 (1H, d, J = 2.0 Hz), 7.68-7.50 (3H, m), 7.40-7.32 (2H, m), 7.06 (1H, s), 7.00-6.95 (1H, m), 6.91 (1H, d, J = 4.6 Hz), 6.77 (1H, t, J = 75 Hz), 4.01 (2H, d, J = 6.8 Hz), 3.62 (4H, t, J = 5.2 Hz), 3.21 (4H, t, J = 4.8 Hz), 1.56 (1H, s), 1.45-1.40 (1H, m), 0.72-0.65 (2H , m), 0.42 to 0.36 (2H, m)

[Production Example 18]

( 2-3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo

[1,5- a ] pyrimidin-2-yl] phenylaminoethyl) carbamic acid tert Preparation of -butyl ester (Compound 52)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ]

Compound 52 was prepared from the pyrimidin-2-yl] phenylamine (compound 43) under the same conditions as in Preparation Example 10, except that (2-oxo-ethyl) carbamic acid tert- butylester was used.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.49 (1H, d, J = 4.6 Hz), 8.08 (1H, d, J = 2.0 Hz), 7.67∼7.62 (1H, m), 7.37∼7.22 (4H, m), 7.04 (1H, s), 6.89 (1H, d, J = 4.2 Hz), 6.77 (1H, t, J = 75 Hz), 6.68-6.62 (1H, m), 4.01 (2H, d, J = 7.0 Hz), 3.47-3.32 (4H, m), 1.46 (9H, s), 1.42-1.36 (1H, m), 0.82-0.64 (2H, m), 0.44-0.37 (2H, m)

[Production Example 19]

[2- (3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a ] pyrimidin-2-yl] phenylmethylamino) ethyl] carbamic acid tert Preparation of -butyl ester (Compound 53)

(2-3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl) -pyrazolo [1,5- prepared from Preparation Example 18a] pyrimidin-2-yl] phenylaminoethyl) carbamic acidtert-NaHCO in a solution of butyl ester (0.33 g, 0.58 mmol) and MeI (0.36 ml, 5.83 mmol) in methanol (3 ml)₃ (98 mg, 1.17 mmol) was added and stirred at room temperature for 48 hours. Concentrated and distilled under reduced pressure, and then purified by column chromatography (EtOAc / Hx = 2/3) to give compound 53 (0.15 g, 43%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.50 (1H, d, J = 4.4 Hz), 8.14 (1H, d, J = 2.0 Hz), 7.64-7.7.5 (1H, m), 7.37-7.25 (4H, m), 7.07 (1H, s), 6.90 (1H, d, J = 4.4 Hz), 6.83-6.67 (1H, m), 6.77 (1H, t, J = 75 Hz), 4.01 (2H, d, J = 7.2 Hz), 3.56-3.42 (4H, m), 3.04 (3H, s), 1.44 (9H, s), 1.41-1.36 (1H, m), 0.74-0.66 (2H, m), 0.45-0.39 ( 2H, m)

[Production Example 20]

N -1-3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo

[1,5- a ] pyrimidin-2-yl] phenylethane-1,2-diamine (Compound 54)

(2-3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl) -pyrazolo [1,5- a ] pyrimidin-2-yl] phenylaminoethyl) carbamic acid tert -butyl ester (0.31) prepared from Preparation Example 18. g, 0.55 mmol) was added CF ₃ COOH (0.21 ml, 2.77 mmol) in a solution of CH ₂ Cl ₂ (3 ml) and stirred at room temperature for 5 minutes. Concentrated and distilled under reduced pressure, and then purified by column chromatography (EtOAc / Hx = 3/1) to give compound 54 (0.17 g, 67%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (1H, d, J = 4.4 Hz), 7.93 (1H, d, J = 1.9 Hz), 7.65 (1H, dd, J = 8.4, 1.9 Hz), 7.37 ~ 7.19 (4H, m), 7.02 (1H, s), 6.90 (1H, d, J = 4.4 Hz), 6.76 (1H, t, J = 75 Hz), 6.66 (1H, dd, J = 7.9, 1.6 Hz), 3.97 (2H, d, J = 7.0 Hz), 3.52 to 3.48 (2H, m), 3.16 to 3.13 (2H, m), 1.41 to 1.34 (1H, m), 0.69 to 0.62 (2H, m) , 0.39 to 0.34 (2H, m)

[Production Example 21]

{3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo [1,5- a ]

Preparation of pyrimidin-2-yl] phenyl} methylamine (Compound 55)

Compound 55 was prepared under the same conditions as in Preparation Example 19.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.49 (1H, d, J = 4.6 Hz), 8.10 (1H, d, J = 2.0 Hz), 7.64 to 7.59 (1H, m), 7.37 to 7.23 (4H, m), 7.05 (1H, s), 6.89 (1H, d, J = 4.2 Hz), 6.77 (1H, t, J = 75 Hz), 6.69-6.62 (1H, m), 4.01 (2H, d, J = 7.0 Hz), 2.91 (3H, s), 1.43-1.38 (1H, m), 0.73-0.63 (2H, m), 0.44-0.37 (2H, m)

[Production Example 22]

{3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo [1,5- a ]

Preparation of pyrimidin-2-yl] phenyl} urea (Compound 56)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ]

A solution of pyrimidin-2-yl] phenylamine (Compound 43) (10 mg, 0.023 mmol) and NaCNO (3 mg, 0.047 mmol) in acetic acid (0.2 ml) and water (0.2 ml) was stirred at room temperature for 1 hour. . The concentrated solution obtained by distillation under reduced pressure was purified by column chromatography (EtOAc) to give 56 (10 mg, 90%).

¹ H NMR (300 MHz, CDCl ₃ , trace MeOH-d ₄ ) 8.58 (1H, s), 8.52 (1H, d, J = 4.5 Hz), 8.08 (1H, bs), 8.03 (1H, s), 7.72 ~ 7.69 (1H, m), 7.55-7.49 (2H, m), 7.37-7.30 (2H, m), 7.06 (1H, d, J = 4.5 Hz), 6.95 (1H, t, J = 75 Hz), 4.05 (2H, d, J = 6.9 Hz), 1.43-1.36 (1H, m), 0.69-0.62 (2H, m), 0.45-0.38 (2H, m)

[Manufacture example 23]

Preparation of N- 3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo [1,5- a ] pyrimidin-2-yl] phenylguanidine (Compound 57)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) pyrazolo [1,5- a ] pyrimidin-2-yl] phenylamine (Compound 43) (9 mg, 0.020 mmol) and N- di-Boc-2-methyl HgCl ₂ (11 mg, 0.040 mmol) was added to a solution of isothiourea (11 mg, 0.040 mmol) and Et ₃ N (0.005 ml, 0.040 mmol) in DMF (0.5 ml), followed by stirring at room temperature for 24 hours. Saturated NH ₄ Cl solution was added, extracted with EtOAc, and the solvent was removed by distillation under reduced pressure. The resulting concentrate was purified by tube chromatography (EtOAc / Hx = 1/3). The resultant (12 mg, 0.018 mmol) was dissolved in CH ₂ Cl ₂ (0.5 ml), and CF ₃ COOH (0.006 ml, 0.092 mmol) was added thereto, followed by stirring at room temperature for 10 minutes. The concentrated solution obtained by distillation under reduced pressure was purified by column chromatography (EtOAc / Hx = 2/1) to obtain the title compound 57 (6 mg, 66%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (1H, d, J = 4.5 Hz), 8.02 (1H, d, J = 2.1 Hz), 7.82-7.77 (2H, m), 7.63 (1H, dd, J = 8.4, 1.8 Hz), 7.47 (1H, t, J = 7.8 Hz), 7.37 (1H, d, J = 8.4 Hz), 7.18-7.15 (1H, m), 7.07 (1H, s), 6.93 ( 1H, d, J = 4.2 Hz), 6.78 (1H, t, J = 75 Hz), 4.01 (2H, d, J = 6.9 Hz), 1.43-1.37 (1H, m), 0.69-0.65 (2H, m ), 0.43 to 0.37 (2H, m)

[Manufacture example 24]

Preparation of 7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo [1,5-a] pyrimidine (Compound 58)

1- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -3-dimethylamino

Propenone (0.54 g, 1.31 mmol) was dissolved in acetic acid and 3-amino-5-pyridin-3-yl-2H-pyrazole (0.21 g, 1.31 mmol) was added thereto and stirred at room temperature for 12 hours. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 100/1) to obtain the title compound Compound 58 (0.19 g, 36.2%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.19 (1H, s, Ar), 8.61 (1H, m, Ar), 8.49 (1H, m, Ar), 8.20 (1H, m, Ar), 8.00 (1H , m, Ar), 7.60 (1H, m, Ar), 7.33 (2H, m, Ar), 7.08 (1H, m, Ar), 6.91 (1H, m, Ar), 6.79 (1H, t, J = 75 Hz, -CHF ₂ ), 4.00 (2H, d, J = 6.90 Hz, -OCH _2- ), 1.39 (1H, m, -CH-), 0.68 (2H, q, J = 6.22 Hz, -CH ₂ 0.40 (2H, q, J = 5.04 Hz, -CH _2- ).

Production Example 25

Preparation of 7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (1-oxypyridin-3-yl) -pyrazolo [1,5-a] pyrimidine (Compound 59)

Dissolve 7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo [1,5-a] pyrimidine (1.77 g, 4.33 mmol) in dichloromethane, dissolve a small amount of NaHCO _3, and then under ice bath m-Chloroperoxybenzoic acid (3.2 g, 13.0 mmol) was added slowly and stirred for 12 hours. 5% NaOH (aq) was added to the reaction solution, extracted three times with dichloromethane, and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 100/1) to obtain the title compound Compound 59 (1.06 g, 57.6%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.86 (1H, s, Ar), 8.57 (1H, m, Ar), 8.22 (1H, m, Ar), 7.82 (2H, m, Ar), 7.64 (1H , m, Ar), 7.36 (2H, m, Ar), 7.26 (1H, s, Ar), 6,98 (1H, m, Ar), 6.78 (1H, t, J = 75 Hz, -CHF ₂ ) , 3.99 (2H, d, J = 6.90 Hz, -OCH _2- ), 1.37 (1H, m, -CH-), 0.69 (2H, q, J = 6.23 Hz, -CH _2- ), 0.41 (2H, q, J = 5.15 Hz, -CH _2- ).

Production Example 26

7- (3 ′ , 4′-Bisdifluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo [1,5-a]

Preparation of Pyrimidine (Compound 60)

1- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -3-dimethylamino

propenone (0.96 g, 3.12 mmol) was dissolved in acetic acid and 3-amino-5-pyridin-3-yl-2H-pyrazole (0.5 g, 3.12 mmol) was added thereto and stirred at room temperature for 12 hours. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (hexane / ethyl acetate, 3/1) to obtain the title compound Compound 60 (0.6 g, 47.6%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23 (1H, d, J = 2.1 Hz, Ar), 8.64 (1H, m, Ar), 8.56 (1H, m, Ar), 8.29 (2H, m, Ar ), 8.03 (1H, m, Ar), 7.49 (1H, m, Ar), 7.15 (1H, s, Ar), 6.97 (1H, d, J = 4.2 Hz, Ar), 6.66 (2H, t, J = 75 Hz, -OCHF ₂ ).

[Production Example 27]

7- (3 ′ , 4′-Bisdifluoromethoxyphenyl) -2- (1-oxypyridin-3-yl) -pyrazolo

Preparation of [1,5-a] pyrimidine (Compound 61)

Dissolve 7- (3,4-Bisdifluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo [1,5-a] pyrimidine (0.1 g, 0.2 mmol) in methylene chloride, dissolve a small amount of NaHCO _3, and then m- under ice bath. Chloroperoxybenzoic acid (0.129 g, 0.6 mmol) is slowly added to dissolve and stirred for 12 hours. 5% NaOH (aq) was added to the reaction solution, which was extracted three times with methylene chloride and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 20/1) to obtain the title compound Compound 61 (0.05 g, 57.5%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.00 (1H, d, J = 1.2 Hz, Ar), 8.61 (1H, d, J = 4.4 Hz, Ar), 8.35 (1H, m, Ar), 8.17 ( 1H, m, Ar), 8.00 (2H, m, Ar), 7.46 (2H, m, Ar), 7.14 (1H, d, J = 2.4 Hz, Ar), 7.02 (1H, m, Ar), 6.66 ( 2H, t, J = 75, -OCHF ₂ ).

Production Example 28

7- ( 3′-Allyloxy-4′- difluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo

Preparation of [1,5-a] pyrimidine (Compound 62)

Dissolve 1- (3-Allyloxy-4-difluoromethoxyphenyl) -3-dimethylaminopropenone (0.62 g, 3.12 mmol) in acetic acid and add 3-amino-5-pyridin-3-yl-2H-pyrazole (0.5 g, 3.12 mmol) Stirred at room temperature for 12 hours. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (hexane / ethyl acetate, 3/1) to obtain the title compound Compound 62 (0.44 g, 35.4%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23 (1H, m, Ar), 8.69 (2H, m, Ar), 8.30 (1H, m, Ar), 7.88 (1H, d, J = 1 Hz, Ar ), 7.60 (1H, m, Ar), 7.42 (1H, m, Ar), 7.27 (2H, m, Ar), 7.05 (1H, d, J = 0.8 Hz, Ar), 6.68 (1H, t, J = 75 Hz, -OCHF ₂ ), 6.13 (1H, m, -CH =), 5.45 (2H, m, = CH ₂ ), 4.77 (2H, m, -CH _2- ).

[Manufacture example 29]

7- ( 3′-Allyloxy-4′- difluoromethoxyphenyl) -2- (1-oxypyridin-3-yl)-

Preparation of pyrazolo [1,5-a] pyrimidine (Compound 63)

7- (3-Allyloxy-4-difluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo [1,5-a] pyrimidine (0.95 g, 2.4 mmol) was dissolved in dichloromethane and a small amount of NaHCO ₃ was dissolved in an ice bath. M-Chloroperoxybenzoic acid (1.25 g, 7.23 mmol) was slowly added thereto and stirred for 12 hours. 5% NaOH (aq) was added to the reaction solution, which was extracted three times with methylene chloride and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 20/1) to obtain the title compound Compound 63 (0.16 g, 36.3%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.95 (1H, m, Ar), 8.58 (1H, d, J = 4.5 Hz, Ar), 8.29 (1H, m, Ar), 7.86 (2H, m, Ar ), 7.66 (1H, m, Ar), 7.37 (2H, m, Ar), 7.11 (1H, s, Ar), 6.99 (1H, m, Ar), 6.72 (1H, t, J = 75 Hz,- OCHF ₂ ), 6.08 (1H, m, -CH =), 5.43 (2H, m, = CH ₂ ), 4.71 (2H, d, J = 5.1 Hz, -OCH _2- ).

Production Example 30

7- ( 4′-Difluoromethoxy-3′- methoxyphenyl) -2-pyridin-3-yl-pyrazolo

Preparation of 1,5-a] pyrimidine (Compound 64)

Dissolve 1- (4-Difluoromethoxy-3-methoxyphenyl) -3-dimethylaminopropenone (0.1 g, 0.39 mmol) in acetic acid and add 3-amino-5-pyridin-3-yl-2H-pyrazole (0.067 g, 0.39 mmol) Stir at room temperature for 12 hours. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by silica gel column chromatography (hexane / ethyl acetate, 5/1) to obtain the title compound Compound 64 (0.48 g, 35.2%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24 (1H, s, Ar), 8.64 (1H, d, J = 4.6 Hz, Ar), 8.56 (1H, J = 4.4 Hz, Ar), 8.27 (1H, d, J = 8.2 Hz, Ar), 8.03 (1H, s, Ar), 7.64 (1H, d, J = 8.6 Hz, Ar), 7.38 (2H, m, Ar), 7.14 (1H, s, Ar) , 6.91 (1H, m, Ar), 6.70 (1H, t, J = 75 Hz, -OCHF _2- ), 4.01 (3H, s, -OCH ₃ ).

Preparation Example 31

7- ( 3′-Benzyloxy-4′- difluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo

Preparation of 1,5-a] pyrimidine (Compound 65)

Dissolve 1- (3-Benzyloxy-4-difluoromethoxyphenyl) -3-dimethylaminopropenone (0.1 g, 0.39 mmol) in acetic acid and add 3-amino-5-Pyridin-3-yl-2H-pyrazole (0.067 g, 0.39 mmol) Stirred at room temperature for 12 hours. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (hexane / ethyl acetate, 5/1) to obtain the title compound Compound 65 (0.17 g, 33.2%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23 (1H, s, Ar), 8.64 (1H, m, Ar), 8.24 (1H, m, Ar), 8.01 (1H, d, J = 2.1 Hz, Ar ), 7.47-7.34 (9H, m, Ar), 7.13 (1H, s, Ar), 6.89 (1H, d, J = 4.5 Hz, Ar), 6.72 (1H, t, J = 75 Hz, -OCHF ₂ -5.27 (2H, d, J = 11.4 Hz, -OCH _2- ).

[Production Example 32]

Preparation of 2-Difluoromethoxy-5- (2-pyridin-3-yl-pyrazolo [1,5-a] pyrimidin-7-yl) -phenol (Compound 66)

Dissolve 7- (3-Benzyloxy-4-difluoromethoxyphenyl) -2-pyridin-3-yl-pyrazolo [1,5-a] pyrimidine (0.1 g, 0.23 mmol) in ethanol / H ₂ O with 10/1 and then add Pd. Add a small amount of / C to the hydrogenater. The reaction solution was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by silica gel column chromatography (methylene chloride / methanol, 20/1) to obtain the title compound 66 (0.02 g, 24.6%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.63 (1H, s, Ar), 9.26 (1H, d, J = 17.4 Hz, Ar), 8.63 (1H, m, Ar), 8.53 (1H, d, J = 4.2 Hz, Ar), 8.30 (1H, d, J = 1.8 Hz, Ar), 8.01 (1H, d, J = 2.4 Hz, Ar), 7.59 (2H, m, Ar), 7.30 (1H, d, J = 8.1 Hz, Ar), 6.98 (1H, m, Ar), 6.77 (1H, t, J = 75.0 Hz, -OCHF _2- ), 4.3 (1H, m, OH).

[Manufacture example 33]

3-Bromo-7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxyphenyl)

Preparation of -2-phenylpyrazolo [1,5-a] pyrimidine (Compound 67)

7- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2-phenylpyrazolo [1,5-a] pyrimidine (Compound 19, 0.1 g, 0.24 mmol) was dissolved in chloroform and N- bromosuccinimide (0.05 g, 0.29 mmol) was dissolved. It was heated to 40 ^o C for 4 hours. Dichloromethane and H ₂ O were added to the reaction mixture and extracted. The organic layer was dried over MgSO ₄ , the solvent was distilled off under reduced pressure, and the mixture was separated by silica gel column chromatography to obtain the title compound Compound 67 (0.141 g, 120.8%).

¹ H NMR (200 MHz, CDCl ₃ ) 8.61 (d, 1H, J = 4.6 Hz, Ar), 8.13-7.13 (m, 9H, Ar), 6.76 (t, 1H, J = 75 Hz, -CHF ₂ ) , 3.99 (d, 2H, J = 7.2 Hz, -OCH _2- ), 0.66-0.63 (m, 2H, -CH _2- ), 0.38 (q, 2H, J = 2.1 Hz, -CH _2- ).

[Manufacture example 34]

3-Bromo-7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxyphenyl)

Preparation of -2- (3-methoxphenyl) pyrazolo [1,5-a] pyrimidine (Compound 68)

Chloroform dissolved 7- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2- (3-methoxyphenyl) pyrazolo [1,5-a] pyrimidine (Compound 22, 0.2 g, 0.45 mmol) and then N- bromosuccinimide (0.09 g, 0.55 mmol) was added and heated to 40 ^° C. for 4 hours. Dichloromethane and water were added to the reaction mixture. The organic layer was dried over MgSO ₄ , the solvent was distilled off under reduced pressure, and the mixture was separated by silica gel column chromatography (dichloromethane) to obtain the desired title compound Compound 68 (0.21 g, 90.4%).

¹ H NMR (200 MHz, CDCl3) 8.61 (d, 1H, J = 4.1 Hz, Ar), 8.02 (d, 1H, J = 2.1 Hz, Ar) 7.71-7.57 (m, 7H, Ar), 6.75 (t , 1H, J = 75 Hz, -CHF2), 3.97 (d, 2H, J = 16.2 Hz, -OCH2-), 3.88 (s, 3H, -0CH3), 0.66 (q, 2H, J = 4.3 Hz -CH _2- ), 0.38 (q, 2H, J = 5.1 Hz, -CH2-).

Preparation Example 35

Preparation of 3- [ 3′-Chloro-7- ( 2′-cyclopropylmethoxy-4′- difluoromethoxy phenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoicacidisopropyl ester (Compound 69)

Bezene 3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid isopropyl ester (Compound 38, 0.1 g, 2.0 × 10 ^-4 mol) After dissolving in, thionyl chloride was added and refluxed. The reaction was extracted with Ethyl acetate and the organic layer was neutralized with NaHCO ₃ , washed twice with brine, dried over MgSO ₄ , and distilled under reduced pressure to remove the solvent. The mixture was separated by column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound Compound 69 (0.05 g, 47%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.82-7.02 (m, 9H, Ar), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 5.2 (m, 1H, OCH- (CH ₃ ) ₂ ), 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 1.5 (s, 3H, -CH ₃ ), 1.4 (s, 3H, -CH ₃ ), 0.65 (m, 2H,- CH _2- ), 0.4 (m, 2H, -CH ₂ )

[Manufacture example 36]

Preparation of 3- [ 3′-Bromo-7- ( 2′-cyclopropylmethoxy-4′- difluoromethoxy phenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoicacidisopropyl ester (Compound 70)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid isopropyl ester (Compound 38, 0.1g, 2.0 × 10^-4 mol) CCl₄After melting inN-bromosuccinimide was added and refluxed. The reaction was extracted with Ethyl acetate and the organic layer was NaHCO₃Neutralize and wash with brine 2 times, MgSO₄Dried over and distilled under reduced pressure to remove the solvent. The mixture was separated by column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound. Compound 70 (0.06 g, 54%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.80 to 7.02 (m, 9H, Ar), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 5.3 to 5.2 (m, 1H, OCH- (CH ₃ ) ₂ ), 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 1.5-14. (M, 6H, -CH ₃ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ ).

Production Example 37

Preparation of N - tert- Butyl-3- [7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxy phenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzamide (Compound 71)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid (Compound 37, 10mg, 2.2 × 10^-5 mol) was dissolved in methylene dichloride, cooled with ice water, and oxalylchloride (1.2eq) was added and reacted for 5 minutes. Put DMF (2-3 drop) into the reaction solutiontExcess -butylamine was added and stirred (icebath, N₂). Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed twice with brine.₄Dried over and distilled under reduced pressure to remove the solvent. The mixture was separated by column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound Compound 71 (7 mg, 77%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.5 to 6.5 (m, 10H, Ar), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz,- O-CH _2- ), 1.5 to 14 (m, 9H, -3 CH ₃ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ ).

[Manufacture example 38]

Preparation of {3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -phenyl} -piperidin-1-yl-methanone (Compound 72)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid (Compound 37, 10 mg, 2.2 × 10^-5 mol) was dissolved in methylene dichloride, cooled with ice water, and oxalyl chloride (1.2 eq) was added and reacted for 5 minutes. After adding DMF (2-3 drop) to the reaction solution, excess piperidine was added and stirred (icebath, N₂). Water and Ethyl acetate were added to the reaction mixture, the organic layer was washed twice with brine, and then MgSO₄Dried over and distilled under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound Compound 72 (5 mg, 55%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.5 to 6.7 (m, 10H, Ar), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz,- O-CH _2- ), 3.9 to 3.2 (m, 4H, -N (CH ₂ ) ₂ ) 1.6 to 1.2 (m, 6H, -3 CH ₂ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ )

[Manufacture example 39]

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo

[1,5-a] pyrimidin-2-yl]- N, N Preparation of -diethylbenzamide (Compound 73)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid (Compound 37, 10mg, 2.2 × 10^-5 mol) was dissolved in methylene dichloride, cooled with ice water, and oxalylchloride (1.2eq) was added and reacted for 5 minutes. After adding DMF (2-3 drop) to the reaction solution, an excess of diethylamine was added and stirred. Water and Ethyl acetate were added to the reaction solution, and the organic layer was washed twice with brine, and then MgSO₄Dried over and distilled under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound Compound 73 (5 mg, 55%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.5 to 6.7 (m, 10H, Ar), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz,- O-CH _2- ), 3.9 to 3.2 (m, 4H, -N (CH ₂ ) ₂ ) 1.6-1.2 (m, 6H, -3 CH ₂ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ ).

[Manufacture example 40]

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo

Preparation of [1,5-a] pyrimidin-2-yl] -benzoic acid ethyl ester (Compound 74)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid (Compound 37, 10mg, 2.2 × 10^-5 mol) was dissolved in methylene dichloride, cooled with ice water, and oxalyl chloride (1.2 eq) was added and reacted for 5 minutes. After adding DMF (2-3 drop) to the reaction solution, anhydrous ethanol was added in excess and stirred. Water and Ethyl acetate were added to the reaction solution, and the organic layer was washed twice with brine.₄Dried over and distilled under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound Compound 74 (7 mg, 70%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.63 to 6.9 (m, 10H, Ar), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.2 (2H, s, O-CH _2- ) , 4.0 (d, 2H, J = 6.9 Hz, -O-CH _2- ), 1.4 (s, 3H, -CH ₃ ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H,- CH ₂ )

Production Example 41

Preparation of N- (2- Cyanoethyl ) -3- [7- ( 3′-cyclopropylmethoxy-4′- difluoro methoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzamide (Compound 75)

Methylene chloride 3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid (Compound 37, 10mg, 2.2 × 10 ^-5 mol) After dissolving in and cooling with ice water, oxalyl chloride (1.2eq) was added and reacted for 5 minutes. After adding DMF (2-3 drop) to the reaction solution, an excess of 3-aminopropionitrile was added and stirred for 2 hours. Water and Ethyl acetate were added to the reaction mixture, and the organic layer was washed twice with brine, dried over MgSO ₄ , and distilled under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (n-hexane / ethylacetate, 1/1) to obtain the title compound Compound 75 (7 mg, 63%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.6 to 6.7 (m, 10H, Ar), 6.7 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz,- O-CH _2- ), 3.1-3.0 (m, 2H, -NCH ₂ )

2.5 (s, 2H, -CH ₂ CN), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ )

Production Example 42

Preparation of 7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (1-oxypyridin-4-yl) -pyrazolo [1,5-a] pyrimidine (Compound 76)

7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -2- (1-oxypyridin-4-yl) -pyrazolo [1,5-a] pyrimidine (Compound 93, 3 g, 9.4 mmol) was dissolved in methylene chloride and iced water. MCPBA (1 g, 9.4 mmol) was added thereto while cooling with water, followed by stirring at room temperature for 12 hours. The reaction solution was neutralized with saturated NaHCO ₃ (aq), extracted three times with ethyl acetate and washed twice with brine. Drying with MgSO ₄ removed the solvent under reduced pressure. The mixture was separated by silica gel column chromatography (hexane / ethyl acetate, 3/1) to obtain the title compound 76 (1.3 g, 28%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.57-6.9 (m, 10H, Ar), 6.7 (t, 1H, J = 75 Hz, CHF ₂ ), 4.0 (d, 2H, J = 6.9 Hz, -O -CH _2- ), 0.65 (m, 2H, -CH _2- ), 0.4 (m, 2H, -CH ₂ ).

Production Example 43

Preparation of 3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -3-formyl pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid isopropyl ester (Compound 77)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a]

Dissolve pyrimidin-2-yl] -benzoic acid isopropyl ester (Compound 38, 0.13 g, 0.26 mmol) in DMF (0.02 g, 0.26 mmol), and slowly dropping POCl ₃ (0.04 g, 0.26 mmol) for 6 hours While. 1 N -HCl (aq) was added to the reaction solution to adjust the pH to 4-5, stirred for 1 hour, extracted three times with methylene chloride and washed twice with brine. Drying with MgSO ₄ and distillation under reduced pressure to remove the solvent. The mixture was separated by silica gel column chromatography (hexane / ethyl acetate, 1/1) to obtain the title compound Compound 77 (0.094 g, 69.3%).

¹ H NMR (200 MHz, CDCl ₃ ) 10.48 (1H, s, -CHO), 8.83 (1H, d, J = 4.4 Hz, Ar), 8.70 (1H, m, Ar), 8.30 (1H, m, Ar ), 8.18 (1H, m, Ar), 7.97 (1H, m, Ar), 7.64-7.54 (2H, m, Ar), 7.39 (1H, m, Ar), 7.24 (1H, m, Ar), 6.78 (1H, t, J = 74.6 Hz, -CHF ₂ ), 5.29 (1H, m, -COOCH-), 4.01 (2H, d, J = 7 Hz, -OCH2-), 1.40 (6H, d, J = 6.2 Hz, -CH3), 1.26 (1H, m, -CH-), 0.65 (2H, m, -CH2-), 0.40 (2H, m, -CH2-).

[Production Example 44]

Preparation of 3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -3-formylpyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid methyl ester (Compound 78)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid methyl ester (Compound 25, 0.2 g, 0.43 mmol) was added DMF (0.03 g, 0.43 mmol) and refluxed. POCl after 40 minutes₃ (0.006 g, 0.43 mmol) was slowly dropped and refluxed for 6 hours. 1 to the reaction solutionN-HCl (aq) was added and the pH was adjusted to 4-5 and stirred for 1 hour. The reaction solution was extracted three times with methylene chloride and washed twice with brine. MgSO₄After drying over, the solvent was removed under reduced pressure. The mixture was separated by silica gel column chromatography (hexane / ethyl acetate, 1/1) to obtain the title compound 78 (0.14 g, 65.9%) was obtained.

¹ H NMR (200 MHz, CDCl 3) 10.50 (1H, s, -CHO), 8.82 (1H, d, J = 4.6 Hz, Ar), 8.70 (1H, m, Ar), 8.32 (1H, m, Ar) , 8.29 (1H, m, Ar), 8.00 (1H, m, Ar), 7.63-7.55 (2H, m, Ar), 7.38 (1H, d, J = 8.4 Hz, Ar), 7.24 (1H, m, Ar), 6.78 (1H, t, J = 74.8 Hz, -CHF ₂ ), 4.01 (2H, d, J = 7.0 Hz, -OCH _2- ), 3.96 (3H, s, -COOCH ₃ ), 1.39 (1H , m, -CH-), 0.61 ( 2H, m, -CH2-), 0.40 (2H, m, -CH 2 -).

Production Example 45

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -3-hydroxy

Preparation of methylpyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid methyl ester (Compound 79)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -3-formylpyrazolo

[1,5-a] pyrimidin-2-yl] -benzoic acid methyl ester (Compound 78, 0.1 g, 0.20 mmol) was dissolved in methanol, NaBH ₄ (0.009 g, 0.24 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. 1 N -HCl (aq) was added to the reaction solution and neutralized. Then, the mixture was extracted three times with methylene chloride and washed twice with brine. After drying over MgSO ₄ , the solvent was removed by distillation under reduced pressure. The mixture was separated by silica gel column chromatography (methylene chloride / methanol, 20/1) to obtain the title compound Compound 79 (0.048 g, 48.4%).

¹ H NMR (200 MHz, CDCl ₃ ) 8.64 (1H, s, Ar), 8.54 (1H, d, J = 4.6 Hz, Ar), 8.22 to 8.08 (3H, m, Ar), 7.63 to 7.54 (2H, m, Ar), 7.35 (1H, d, J = 8.4, Ar), 6.98 (1H, d, J = 4.6 Hz, Ar), 6.77 (1H, t, J = 74.8 Hz, -CHF ₂ ), 5.14 ( 1H, m, OH), 4.01 (2H, d, J = 7 Hz, -OCH _2- ), 3.96 (3H, s, -COOCH ₃ ), 1.40 (1H, m, -CH-), 0.65 (2H, m, -CH _2- ), 0.40 (2H, m, -CH _2- ).

Preparation Example 46

3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -3-methoxy

Preparation of methylpyrazolo [1,5-a] pyrimidin-2-yl] -benzoic acid methyl ester (Compound 80)

3- [7- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -3-formylpyrazolo

[1,5-a] pyrimidin-2-yl] -benzoic acid methyl ester (Compound 533, 0.08 g, 0.15 mmol) was dissolved in methanol, NaBH ₄ (0.015 g, 0.38 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. 1 N -HCl (aq) was added to the reaction solution and neutralized. The mixture was extracted three times with methylene chloride and washed twice with brine. After drying over MgSO ₄ , the solvent was removed by distillation under reduced pressure. The mixture was separated by silica gel column chromatography (methylene chloride / methanol, 20/1) to obtain the title compound Compound 80 (0.019 g, 24.9%).

¹ H NMR (300 MHz, CDCl ₃ ) 8.69 (1H, s, Ar), 8.58 (1H, d, J = 4.5 Hz, Ar), 8.20 (1H, m, Ar), 8.10 (2H, m, Ar) , 7.58 (2H, m, Ar), 7.35 (1H, m, Ar), 6.97 (1H, m, Ar), 6.76 (1H, t, J = 74.8 Hz, -CHF ₂ ), 4.84 (2H, s, -CH _2- ), 4.01 (2H, d, J = 6.9 Hz, -OCH _2- ), 3.96 (3H, s, -COOCH3), 3.56 (3H, s, -OCH ₃ ), 1.39 (1H, m, -CH-), 0.64 (2H, m, -CH _2- ), 0.38 (2H, m, -CH _2- ).

Production Example 47

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -2- (3-propyn

Preparation of -3-yloxyphenyl) -pyrazolo [1,5-a] pyrimidine (Compound 81)

5- (3-Propyn-3-yloxyphenyl) -2H-pyrazol-3-ylamine (3.0 g, 10.66 mmol) and 1- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -3- dimethylaminopropenone (3.169 g, 10.66) mmol) and stirred at room temperature for 12 hours. Ethyl acetate and NaHCO ₃ were added to the reaction mixture, and the organic layer was dried over MgSO ₄ and the solvent was removed under reduced pressure. The mixture was separated by silica gel column chromatography (methylene chloride / methanol, 20/1) to obtain the title compound Compound 81 (1.26 g, 26.3%).

¹ H NMR (300 MHz, CDCl ₃ ) 8.50 (d, 1H, J = 2.80 Hz, Ar), 8.09 (m, 1H, Ar), 6.84 (t, 1H, J = 75 Hz, -OCHF ₂ ), 7.67 6.91 (m, 15H, Ar), 4.76 (s, 2H, -OCH ₂ CCH), 4.02 (d, 2H, J = 6.8 Hz, -OCH _2- ), 2.55 (s, 1H, -CCH), 0.71 ~ 0.64 (m, 2H, -CH _2- ), 0.44-0.37 (m, 2H, -CH2-) MS m / z (relative intensity): 461 (M ⁺ , 23.49)

[Manufacture example 48]

7- (3 ′ , 4′-Bis difluoromethoxyphenyl) -2-phenylpyrazolo [1,5-a]

Preparation of pyrimidine (Compound 82)

Synthesis of Compound 81 using 5-amino-3-phenylpyrazol (0.1 g, 0.65 mmol) and 1- (3,4-Bis-difluoromethoxy-phenyl) -3-dimethylaminopropenone (0.2 g, 0.65 mmol) Compound 82 (0.11 g, 42%) was obtained as the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) 8.25 (d, 1H, J = 4.02 Hz, Ar), 8.33 (s, 1H, Ar), 8.07 to 7.99 (m, 3H, Ar), 7.49 to 7.31 (m, 4H, Ar), 7.10 (d, 1H, J = 2.10 Hz, Ar), 6.66 (t, 2H, -CHF ₂ ), MS m / z (relative intensity): 403.2 (M ⁺ , 65.2)

[Manufacture example 49]

Preparation of 2- (3-Benzylthiophenyl) -7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo [1,5-a] pyrimidine (Compound 83)

5- (3-Benzylthiophenyl) -2H-pyrazol-3-yl amine (3.0 g, 10.66 mmol) was used to obtain the title compound 83 (2.5 g, 45.3%) in the same manner as the synthesis of Compound 81.

¹ H NMR (300 MHz, CDCl ₃ ) 8.50 (d, 1H, J = 4.40 Hz, Ar), 8.60 (m, 1H, Ar), 6.90-7.92 (m, 15H, Ar), 6.77 (t, 1H, J = 75 Hz, -CHF ₂ ), 4.17 (s, 2H, -SH ₂ Ar), 4.01 (d, 2H, J = 7.2 Hz, OCH _2- ), 0.69-0.64 (m, 2H, -CH _2- ), 0.64 to 0.38 (m, 2H, -CH _2- ) MS m / z (relative intensity): 529.2 (M ⁺ , 23.49)

[Production Example 50]

5- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo

Preparation of [1,5-a] pyrimidin-2-yl] -2-methoxyphenol (Compound 84)

2- (3-Benzyloxy-4-methoxyphenyl) -7- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -pyrazolo [1,5-a] pyrimidine (0.1 g, 0.16 mmol) to ethanol / H ₂ O (10 / 1), and then added a small amount of Pd / C for hydrogenation for 12 hours. The reaction solution was filtered and the solvent was removed under reduced pressure. The mixture was separated by column chromatography (n-hexane / ethyl acetate, 3/1) to obtain the title compound 84 (0.025g, 35.69%).

¹ H NMR (300 MHz, CDCl ₃ ) 8.47 (d, 1H, J = 4.6 Hz, Ar), 8.10 (s, 1H, Ar), 7.60-7.14 (m, 7H, Ar), 6.77 (t, 1H, J = 75 Hz, -OCHF ₂ ), 4.03 (d, 2H, J = 6.8 Hz, -OCH _2- ), 3.95 (s, 1H, -OCH ₃ ), 0.85 to 0.71 (m, 2H, -CH _2- ), 0.67 to 0.41 (m, 2H, -CH _2- ) MS m / z (relative intensity): 453 (M ⁺ , 23.2)

2- (3-Chlorophenyl) -7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxyphenyl) -pyrazolo [1,5- a ] pyrimidine (Compound 85)

Compound 85 was prepared in the same manner as in Preparation Example 2.

Yield: 78%

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.50 (d, 1H, J = 4.0 Hz), 8.10∼6.93 (m, 9H, Ar), 6.78 (t, 1H, J = 75 Hz, —CHF ₂ ), 4.02 (d, 2H, J = 6.93 Hz, OCH _2- ), 0.69 (m, 2H, -CH _2- ), 0.41 (m, 2H, -CH _2- ).

Acetic acid 3- [7- ( 3′-cyclopropylmethoxy-4′- difluoromethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-2-yl] -phenyl ester (Compound 86)

Compound 86 was prepared in the same manner as in Preparation Example 2.

Yield: 56%

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.47 (d, 1H, J = 4.5 Hz, Ar), 8.05-6.78 (m, 9H, Ar), 6.78 (t, 1H, J = 75 Hz, -CHF ₂ ), 3.99 (d, 2H, J = 6.9 Hz, OCH _2- ), 2.34 (s, 3H, CO-CH ₃ ), 0.69 (m, 2H, -CH _2- ), 0.41 (m, 2H, -CH _2- ).

Production Example 51

7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxy-phenyl) -2- (3-tetrazol

Preparation of -1-yl-phenyl) -pyrazolo [1,5-a] pyrimidine (Compound 88)

To a solution of 43 (60 mg, 0.14 mmol) and sodium azide (28 mg, 0.43 mmol) in acetic acid (1 ml) was added triethyl orthoformate (0.070 ml, 0.43 mmol) and stirred for 3 hours. Water (2 ml) was added and extracted with EtOAc, followed by distillation under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (EtoAc / Hx = 1/2) to give compound 88 (52 mg, 77%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) 9.06 (1H, s), 8.56 (1H, d, J = 4.4 Hz), 8.37 (1H, bs), 8.16-8.11 (1H, m), 7.99 (1H, d , J = 2.0 Hz), 7.71-7.61 (3H, m), 7.38 (1H, d, J = 8.4 Hz), 7.17 (1H, s), 6.97 (1H, d, J = 4.6 Hz), 6.79 (1H , t, J = 75 Hz), 4.02 (2H, d, J = 6.8 Hz), 3.80 (2H, bs), 1.39-1.33 (1H, m), 0.72-0.62 (2H, m), 0.42-0.35 ( 2H, m).

Preparation of 1-3- [7- ( 3′-Cyclopropylmethoxy-4′- difluoromethoxyphenyl) pyrazolo [1,5-a] pyrimidin-2-yl] phenylpiperidin-1-oxide (Compound 94)

Compound 94 was prepared from compound 50 under the same conditions as in Preparation Example 29.

¹ H NMR (200 MHz, CDCl ₃ ) 8.62 (1H, bs), 8.53 (1H, d, J = 4.6 Hz), 8.07-7.95 (3H, m), 7.68-7.51 (2H, m), 7.37 (1H) , d, J = 8.2 Hz), 7.18 (1H, s), 7.93 (1H, d, J = 4.4 Hz), 6.79 (1H, t, J = 75 Hz), 4.00 (2H, d, J = 7.0 Hz ), 3.77-3.67 (4H, m), 2.83-1.63 (4H, m), 1.80-1.73 (3H, m), 1.45-1.40 (1H, m), 0.74-0.63 (2H, m), 0.45-0.38 (2H, m)

Inhibition of PDE-4 Activity

The activity inhibition activity of PDE-4d was performed by modifying the method of Kate et al. (Kate, et al., JBC , 271 : 796 (1996)). PDE-4d used human PDE-4d prepared by genetic recombination technology.

The PDE4d gene was transformed into E. coli BL21, DE3 after cloning the catalytic domain of PDE-4d into pGEX4T3 (APBiotech), a GST fusion expression vector. After incubating the strain at 37 ° C. in LB medium, the temperature was lowered to 18 ° C. when 0.3-0.5 OD was induced to induce PDE4d expression with 0.5 mM IPTG. After 15 hours of expression induction, PDE4d-expressing cells were obtained, and the cells were suspended in a buffer solution (50 mM Tris, pH 8.0, 0.4 M NaCl, 5 mM DTT), disrupted, and purified by centrifugation. The columns used for purification are Q-Sepharose (APBiotech), Glutanion-Sepharose (APBiotech), and Superdex 200 gel filtration chromatography (APBiotech) in this order.

In order to measure the ability to inhibit PDE4d activity of each compound, 1 nM of PDE4d and 250 nM of cAMP (Sigma) as a substrate were added to the reaction buffer (50 mM Tris-HCl, pH 7.5) and 4 mM MgCl ₂ , and the resultant obtained in Example 1 above. Each compound was added at a concentration of 1-50 uM and then reacted at 34 ° C. for 45 minutes. The reaction total was 60 µl. At this time, cAMP was used by mixing a ratio of [ ³ H] cAMP (Amersham, 1 μCi / μl) and cAMP (hot: cold, that is, isotope: non-isotope) at 1: 200. The reaction was then stopped by heating at 95 ° C. for 2 minutes, then cooled for 3 minutes and 30 μl of 1 mg / ml Snake Venome (sigma V0376) was added. Subsequently, after 30 minutes of reaction at 34 ° C, 30 μl of the reaction solution was poured into 250 μl of DOWEX 1 × 2-100 ion exchange resin (Aldrich, pre-mixed in distilled water at a ratio of 1 to 1) and vigorously for 2 minutes. After stirring, the resin was allowed to settle and 130 μl of the supernatant was added to 2 ml of scintillation cocktail (Packard), mixed well, and measured by a beta-counter. The concentration of each test compound that inhibited 50% of the enzyme activity compared to the enzyme activity of the control group without the addition of the compound of Formula 1 was determined as IC ₅₀ . The structure and IC ₅₀ values of the compounds are shown in the table below.

TABLE 1

PDE-4 Enzyme Selectivity Assay

In order to measure the enzyme selectivity against PDE4d, the enzyme activity inhibitory effect of each test compound against PDE-3a, PDE-5a, and PDE-7a was measured. PDE3a and PDE7a, which used cAMP as a substrate, measured the degree of activity inhibition using the Amplified Luminescent Proximity Homogeneous Assay (Alpha) Screen method. Activity inhibition efficacy was measured.

PDE3a, PDE5a and PDE7a all used human enzymes prepared by genetic recombination techniques.

     In order to measure the inhibitory activity of PDE3a and PDE7a of each test compound, first put each compound (final DMSO 1%) at the concentration to be tested in a 96 well half area white plate and follow the same conditions as the conditions for measuring PDE4d enzyme activity described above. Enzyme reaction at When measuring enzyme activity using Alpha Screen, the concentrations of PDE3a and PDE7a should be 10nM and 80nM, respectively, and were carried out according to the method proposed in the Alphascreen cAMP assay kit (Perkin Elmer life science). Briefly, after the enzymatic reaction between PDE3a and PDE7a is terminated, final 10 nM biotinylated-cAMP and 20ul / mL donor beads are added to the reaction mixture. The donor bead is sensitive to light, so be careful not to expose it to light and let it react for 30 minutes at room temperature. Then add acceptor beads to a final 20ul / ml. After reacting for 45 minutes at room temperature, the reaction was further reacted for 20 minutes in the Fusion Alpha-FP device, and the emission at 520-620 nm was measured.

In the enzymatic reaction by PDE3a and PDE7a, the signal increase and decrease is caused by the mutual competition between the remaining cAMP and the newly added biotinylated-cAMP which are not used as substrates. signal is reduced.

PDE5a, which uses cGMP as an enzyme substrate, measured the enzyme inhibitory ability of each test compound according to the experimental method presented by IMAP ^TM Phosphodiesterase Assay Kit (Molecular Device), which measures enzyme activity by fluorescence polarization (FP) method. First, add each test compound (final DMSO 5%) at the concentration to be tested in 96 well black plate, and add FL-cGMP (Fluorescence-labeled derivatives of cGMP) and final 200 nM PDE5a. After reacting for 45 minutes at 30 degrees, add the IMAP binding reagent provided by the kit. After reacting at room temperature for 60 minutes, FP obtained by 485 nm exitation and 535 nm emission was measured. The more enzyme activity of PDE5a, the higher the FP signal. The inhibition of enzyme activity of PDE5a by each test compound can be determined by measuring the decreased FP signal.

In vivo experiment

For in vivo animal experiments, 8 to 9 week old male C57BL / 6J mice weighing 20-25 g were used as experimental animals. For sensitization and challenge of airway and lung by ovalbumin (OVA), OVA mixed with Al (OH) ₃ was firstly sensitized by intraperitoneal administration to mice. 2nd sensitization. Six days after the second sensitization, 5% OVA was inhaled through the nebulizer for three days. Drug administration to sensitized mice was administered orally (po) three times each 1 hour prior to inhalation of the OVA. 0.5% CMC was administered as a control. To observe the activity and cell composition of the mouse tracheal alveolar lavage fluid, the mice were anesthetized after 62 hours, inoculated with OVA, the cervical thorax was opened, the tube was inserted into the trachea using a tube containing 0.8 ml of PBS, and then PBS was injected. After massaging the chest for about 30 seconds, a cell suspension was obtained from the lungs. The obtained cells were centrifuged at 400xg, and the supernatant was used for measuring the eosinophil peroxidase activity (EPO activity), and pellets were used for cell composition investigation. To measure the activity of basophils, 100 ul of cell suspension was reacted with 0.1 mM OPD, 0.05 M Tris-Hcl (pH 8.0), Triton X-100 and 1 mM H ₂ O _2, and the absorbance was measured at 492 nm. . For staining of basophils, cell pellets were resuspended in PBS and centrifuged at 150xg for 5 minutes to ensure that the cells adhered to the slides. The attached cells were subjected to Diff-Quick staining to observe the number of cells under a microscope. Airway hyper-responsiveness (AHR) analysis was performed using a whole body plethysmographer in living animals. 48 hours after OVA inhalation, Methacholine (Mch) was inhaled with nebulizer, and airway reactivity by Mch was measured using whole body plethysmography to compare enhanced pause (Penh) values for respiratory ability of airways.

As a result of the PDE-4 inhibitory activity test, as shown in Table 1, in the compound of the series in which R ₁ and R ₂ are substituted with methyl and cyclopentyl groups in the formula (1), the compounds in which X is substituted by meta position are substituted by ortho or para. It can be seen that the PDE-4 inhibitory activity is generally superior to the above compounds (eg, Compound 1 and Compound 11; Compound 14 and Compound 4; Compound 6 and Compound 7 or 8; Compound 16 and Compound 12). In addition, compounds having a substitution of X in the meta position of R ₁ and R ₂ substituted with difluoromethyl and cyclopropylmethyl groups, respectively, have excellent PDE-4 inhibitory activity, among which -OMe (Compound 22), -SBn (Compound 83), -OBn (Compound 23), -Br (Compound 24), -OH (Compound 89), -NO ₂ (Compound 27), -COOH (Compound 37), -CON (CH ₃ ) ₂ IC ₅₀ of (Compound 41), -OCOCH ₃ (Compound 86), -NHBn (Compound 44), -I (Compound 35), and -CONHEt (Compound 40) was 30 nM or less, which showed very good PDE-4 inhibitory activity. Able to know.

Among the compounds in which A is substituted with N or NO in Formula 1, meta-pyridine compound (Compound 58, IC ₅₀ = 20 nM) showed very good activity compared to para-pyridne compound 93 (IC ₅₀ = 180 nM), It can be seen that the meta-pyridine-based compounds have very different activities depending on the substituents of R ₁ and R ₂ (compounds 60, 62, 65, 66). In addition, in the case of R ₃ substitution, compound 67 substituted with Br was significantly increased in PDE-4 inhibitory activity than compound 19 without substitution.

Table 1 shows the results of the inhibitory activity test for PDE-3, -5, and -7 of the representative compounds having excellent activity and highly likely pharmacokinetic test results. As a result, the PDE-4 enzyme selectivity of the representative compounds tested among the synthesized compounds is 100 times or more, indicating that the selectivity for the target point of action PDE-4 is very high.

Table 2 PDE enzyme inhibitory activity IC ₅₀ (uM) of representative compounds

Representative compounds obtained from these studies were compared with the reference drug by using the OVA-sensitized C57BL / 6J mice to obtain enhanced pause (Penh) values. Compounds 87 and 94 each had a similar or superior activity when administered orally at a dose of 100 mg / kg compared to the control compound Roflumilast (30 mg / kg, orally administered).

[Figure 1] In vivo airway contraction inhibition test (Penh)

In addition, as a result of measuring eosinophil peroxidase activity (EPO activity), as shown in Fig. 2, when the oral compound 38 and 94 were orally administered at 100 mg / kg, the control compound Roflumilast (30 mg / kg, orally administered) The results were similar to that of EPO activity.

[Figure 2] Comparison of EPO activity inhibitory ability of basophils of synthetic compounds

Thus, the compounds of the present invention have new chemical structures and exhibit excellent selective activity against PDE-4 enzymes. In addition, these compounds show excellent in vivo therapeutic effects in the asthma model animal experiments used, and can be used for the treatment of inflammation-related diseases including asthma and chronic obstructive pulmonary diseases.

Claims (10)

2-aryl-7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. [Formula 1] [Wherein A is N or NO; R ₁ and R ₂ may be the same or different from each other, and each independently a hydrogen atom, a straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C _4- C ₁₀ ) cycloalkylalkyl group, phenyl, benzyl or R ₁ and R ₂ may be linked by (C ₁ -C ₃ ) alkylene; R ₃ is hydrogen atom, halogen atom, formyl, straight or branched saturated and unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkyl ketone, (C ₁ -C ₇ ) alkoxy, (C ₁ C ₇ ) alkoxyalkyl, hydroxy (C ₁ -C ₇ ) alkyl groups, carboxylic acids, carboxyl (C ₁ -C ₇ ) alkylesters, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono Or di (C ₁ -C ₇ ) alkylaminocarbonyl; X may be the same or different from each other and is a hydrogen atom, a crushed or straight chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxyalkyl , Halogen, cyano, nitro, amino, mono- or di (C ₁ -C ₇ ) alkyl amino, (C ₃ -C ₇ ) cycloalkylamine, morpholine, morpholine oxide, piperazine, piperazine oxide , Guanidine, urea, phenyl, benzyl, benzyloxy, carboxylic acid, carboxyl (C ₁ -C ₇ ) alkylester, carboxylamide, (C ₁ -C ₇ ) alkylketone, benzoyl; n is an integer from 0 to 4; Provided that the (C ₁ -C ₇ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl group, (C ₄ -C ₁₀ ) cycloalkylalkyl group, phenyl group or benzyl group of R ₁ and R ₂ and X is (C ₁ -C ₇ May be substituted with halogen, nitro, cyano, hydroxy, carboxyl or amino groups, including alkoxy, fluorine.] The method of claim 1, R ₁ and R ₂ may be the same or different from each other, and each independently a linear or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₄ -C ₈ ) Cycloalkylalkyl group, phenyl, benzyl, and the substituents of R ₁ and R ₂ may be substituted with one or more fluorine atoms, and R ₃ is a hydrogen atom, a halogen atom, formyl, straight chain or saturation and unsaturated (C ₁ −), respectively. C ₇ ) alkyl, (C ₁ -C ₇ ) alkyl ketone, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxyalkyl, hydroxy (C ₁ -C ₇ ) alkyl group, carboxylic acid, 2-aryl-characterized by carboxyl (C ₁ -C ₇ ) alkyl esters, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl 7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof. The method of claim 2, R ₁ is straight-chain or a saturated or unsaturated grinding (C ₁ - C ₇₎ alkyl or a fluorine atom is substituted by a straight chain or a saturated or unsaturated grinding - and (C ₁ C ₇₎ alkyl, R ₂ is a straight chain or a saturated or unsaturated grinding A (C ₁ -C ₇ ) alkyl, cyclopropyl methyl, cyclopropyl, cyclopentyl or allyl group, R ₃ is a hydrogen atom or a halogen, X is a hydrogen atom, hydroxy, carboxyl (C ₁ -C ₇ ) alkyl Characterized in that it is an ester, carboxyl amide, halogen, crushed or straight chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, amine group, n is a substituent of an integer from 0 to 3 2-aryl-7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof. The method of claim 2, 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof, which is represented by the following Chemical Formula 2. [Formula 2] [A is N or NO, X is hydrogen atom, hydroxy, carboxylic acid, carboxyl alkyl (C ₁ -C ₇ ) ester, carboxy amide, halogen, crushed or straight chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, an amine group, n is a compound containing a substituent which is an integer of 0-3.] The method of claim 4, wherein X is a hydrogen atom, carboxylic acid, carboxyl (C ₁ -C ₇ ) alkyl ester, n is an integer of 1 to 3, 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -Pyrazolo [1,5-a] pyrimidine compounds or pharmaceutically acceptable salts thereof. The method of claim 4, wherein 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof, which is represented by the following Chemical Formula 3. [Formula 3] [A is N or NO, X is a hydrogen atom, carboxylic acid or carboxyl (C ₁ -C ₇ ) alkyl ester, n is a compound containing a substituent of 1.] A compound of formula 1 according to claim 1 is prepared by reacting 3-amino-5- (substituted phenyl) pyrazole compound (3) with an aminopropenone compound (5) or an aminopropene compound (4). A method for preparing a 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound. Scheme 1 Scheme 2 [Wherein Ar, R ₁ and R ₂ are the same as defined in claim 1 above.] The method of claim 7, wherein A method for producing a 2-aryl-7- (3 ', 4'-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound, which is reacted in the presence of acetic acid. A 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine derivative represented by Formula 1 according to claim 1 is contained. Pharmaceutical compositions for the treatment of inflammation-related diseases, including asthma and chronic obstructive pulmonary disease. The method of claim 9, A 2-aryl-7- (3 ′, 4′-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine derivative represented by Formula 3 according to claim 4 is contained. Pharmaceutical compositions for the treatment of inflammation-related diseases, including asthma and chronic obstructive pulmonary disease.