KR101663662B1 - Novel aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists - Google Patents

Abstract

The present invention relates to an aryl isoxazole derivative showing activities as an antagonist against metabolic glutamate receptor 1. The present invention further relates to a method for producing the compound, and to a pharmaceutical composition containing the compound as an active ingredient.

Description

[0001] Novel aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists having activity at metabotropic glutamate receptor 1 [

The present invention relates to an arylisoxazole derivative exhibiting activity as an antagonist for metabotropic glutamate receptor 1, a process for preparing the compound, and a pharmaceutical composition comprising the compound as an active ingredient.

The metabotropic glutamate receptor (mGluR) is a type of G-protein-associated receptor and is divided into three groups, Group I, II and III, according to their specific properties. Group I, consisting of mGluR1 and mGluR5, acts as a post-synaptic receptor involved in increasing neuronal excitability and activates phospholipase C (PLC) via the Gq protein. Group Ⅱ (mGluR2 and mGluR3) and Group Ⅲ (mGluR4, mGluR6, mGluR7 and mGluR8) inhibit the activity of adenylyl cyclase activated by the Gi protein as a synaptic receptor. Such Group I mGluR related disorders include, for example, neurodegenerative diseases such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis; Mental disorders such as schizophrenia and anxiety; Depression, pain, and drug dependence. Among them, mGluR1 is involved in neuropathic pain, and antagonist has been reported to be effective in relieving neuropathic pain. [Non-Patent Documents 1 to 3]

Further, triazole derivatives, pyrimidone derivatives, tetracyclic compounds, and the like have been reported as compounds having antagonistic activity against mGluR1. [Non-Patent Documents 4 to 7] However, there is still a need for a pharmaceutical composition which is excellent in selectivity to mGluR1, has a good pharmacokinetic profile, good ADME (absorption, distribution, metabolism and release) Addiction, schizophrenia, fragile X syndrome, epilepsy; cancer; Heart disease such as hypertensive, deep arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; There is a need for new antagonists effective in the treatment of pain disorders such as neuropathic pain, chronic and acute pain.

 Jeffrey M. Schkeryantz et al., J. Med. Chem. 2007, 50, 2563-2568  Chad J. Swanson et al., Nat Rev Drug Discov., 2005, 4, 131-144  S. Ito et al., Bioorg. Med. Chem. Lett. 2009, 19, 5310-5313  Satoru Ito et al., Bioorganic & Medicinal Chemistry, 2008, 16, 9817-9829  T. K. Sasikumar et al., Bioorganic & Medicinal Chemistry Letters, 2009, 19, 3199-3203  Wen-Lian Wu et al., J. Med. Chem. 2007, 50, 5550-5553  Kim SH, Chung JM, Pain, 1992, 50, 355-363

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and has the object of the following invention.

That is, the present invention aims at providing novel compounds selected from arylisoxazole derivatives of the novel structure and pharmaceutically acceptable salts thereof.

It is another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of diseases mediated by mGluR1 containing the novel compound as an active ingredient.

Another object of the present invention is to provide a process for producing the novel compound.

In order to achieve the above object, the present invention provides an arylisoxazole compound represented by the following formula (1), which exhibits an activity as a control substance for mGluR1, a process for producing the compound, and a pharmaceutical composition comprising the compound do.

In Formula 1,

Z is

; or

ego,

R ¹ is a hydrogen atom; Or a C ₁ -C ₁₀ alkyl group;

R ² is a C ₆ -C ₁₀ aryl group unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₁₀ alkyl and C ₁ -C ₁₀ alkoxy; Which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy and (C ₁ -C ₁₀ alkoxy) -C ₁ -C ₁₀ alkoxy, And is a pentagonal to hexagonal heteroaryl group containing one or two heteroatoms.

As described above, the aryl isoxazole compound represented by Formula 1 according to the present invention exhibits excellent activity as an antagonist of mGluR1.

Accordingly, the compounds according to the present invention are useful for the treatment of brain diseases selected from the group consisting of dementia, depression, schizophrenia, Parkinson's disease, fragile X syndrome, drug addiction, epilepsy; cancer; Hypertension, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Neuropathic pain, chronic and acute pain. ≪ RTI ID = 0.0 > [0002] < / RTI >

Figure 1 is a graph showing the withdrawal threshold as a result of comparing the mechanical allodynia treatment effects of the compounds 12 and 15 with gabapentin and DFMTI drugs, respectively, as compounds of the present invention.

 The substituents used to define the arylisoxazole compound represented by Formula 1 according to the present invention will be described in more detail as follows.

The term "alkyl group" includes both straight, branched and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups include methyl, ethyl, a tert -butyl group, a cyclopentyl group, and a cyclohexyl group. "Alkoxy group" means an alkyl group of carbon linked to an oxygen, wherein alkyl is as defined above. "Aryl group" means an aromatic ring group, wherein aryl refers to a ring having at least six atoms, or two rings having at least 15 atoms, or a double bond to an adjacent carbon atom, The group may include a phenyl group, a naphthyl group, and the like, and the aryl group may be substituted with one or more substituents selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, and the like. The "heteroaryl group" may be a 5- to 7-membered ring group containing one or two N atoms, and may specifically include pyridyl, pyrimidyl, pyrrole, pyrazole, and the like. The substituent selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, (C ₁ -C ₁₀ alkoxy) -C ₁ -C ₁₀ alkoxy and the like may be substituted with one or more.

The aryl isoxazole compound represented by the formula (1) may be represented by the following formula (1a) or (1b) according to the kind of Z.

[Formula 1a]

(Wherein R ₁ and R ₂ are the same as defined in Formula 1, respectively)

[Chemical Formula 1b]

(In the above formula (1b), R < _{1 >} And R < ₂ > are the same as defined in the above formula (1)

Preferably, in the compound represented by Formula 1a or Formula 1b, R ¹ is a hydrogen atom; Or a C ₁ -C ₁₀ alkyl group, R ² is a phenyl group substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₁₀ alkyl and C ₁ -C ₁₀ alkoxy; Or pyridyl substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy and (C ₁ -C ₁₀ alkoxy) -C ₁ -C ₁₀ alkoxy, Lt; / RTI >

Particularly preferred examples of the aryl isoxazole compound represented by the above formula (1) are as follows.

Compound 1: 5- [3- (2,4-Difluorophenyl) -4-methylisooxazol-5-yl] -2-isopropylisoindolin-

Compound 2: 5- [3- (4-Fluorophenyl) -4-methylisooxazol-5-yl] -2-isopropylisoindolin-

Compound 3: 5- [3- (4-Chlorophenyl) -4-methylisooxazol-5-yl] -2-isopropylisoindolin-

Compound 4: 5- [3- (2,4-Difluorophenyl) isooxazol-5-yl] -2-isopropylisoindolin-

Compound 5: 2-Isopropyl-5- (3-p-tolyloisoxazol-5-yl) isoindolin-

Compound 6: 2-Isopropyl-5- [3- (4-methoxyphenyl) isooxazol-5-yl] isoindolin-

Compound 7: 5- [3- (2-Fluorophenyl) isooxazol-5-yl] -2-isopropylisoindolin-

Compound 8: 5- [3- (6-Chloropyridin-3-yl) -4-methylisooxazol-5-yl] -2-isopropylisoindolin-

Compound 9: 2-Isopropyl-5- [3- (6-methoxypyridin-3-yl) -4-methylisooxazol-5-yl] isoindolin-

Compound 10: 5- [3- (6-Chloropyridin-3-yl) isooxazol-5-yl] -2-isopropylisoindolin-

Compound 11: 2-Isopropyl-5- [3- (6-methylpyridin-3-yl) isooxazol-5-yl] isoindolin-

Compound 12: 2-Isopropyl-5- [3- (6-methoxypyridin-3-yl) isooxazol-5-yl] isoindolin-

Compound 13: 2-Isopropyl-5- (3- (6- (2-methoxyethoxy) pyridin-3- yl) isooxazol-

Compound 14: 4- [3- (4-Chlorophenyl) -4-methylisoxazole-5-yl] -N-isopropylbenzamide

Compound 15: N-isopropyl-4- [3- (4-methoxyphenyl) -4-methylisooxazol-5-yl] benzamide

Compound 16: 4- [3- (2,4-Difluorophenyl) isooxazol-5-yl] -N-isopropylbenzamide

Compound 17: 4- [3- (4-Fluorophenyl) isooxazol-5-yl] -N-isopropylbenzamide

Compound 18: 4- [3- (4-Chlorophenyl) isooxazol-5-yl] -N-isopropylbenzamide

Compound 19: 4- [3- (2-Fluorophenyl) isooxazol-5-yl] -N-isopropylbenzamide

Compound 20: N-isopropyl-4- (3- (4-methoxyphenyl) isooxazol-5-yl)

Compound 21: 4- [3- (6-Chloropyridin-3-yl) isooxazol-5-yl] -N-isopropylbenzamide

Compound 22: N-isopropyl-4- [3- (6-methoxypyridin-3-yl) isooxazol-

Compound 23: 4- (3- (2-Fluoropyridin-3-yl) isooxazol-5-yl) -N-isopropylbenzamide.

The present invention also relates to a process for preparing an isoxazole compound represented by the formula (1), wherein the process according to the present invention can be represented by the following reaction formula (1).

[Reaction Scheme 1]

(In the above Reaction Scheme 1, Z, R < _{1 >} and R < ₂ > are each as defined in the above formula (1), and X is a halogen atom)

According to the production method of Reaction Scheme 1, the 5- (tributylstannyl) isoxazole compound represented by Formula 2 and the halide compound represented by Formula 3 are subjected to a coupling reaction in the presence of a palladium catalyst, 1 < / RTI > In the above coupling reaction, palladium is used as a catalyst. Specifically, tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) may be used and 0.01 to 0.2 equivalent based on the reactant may be used. As the reaction solvent, a conventional organic solvent can be used. Specifically, toluene, dimethylformamide, 1,4-dioxane and the like are used, and toluene was mainly used in the examples of the present invention. The reaction temperature is a temperature at which the used solvent can be refluxed, specifically, a temperature range of 110 to 150 ° C is maintained. The reaction time is about 15 to 48 hours, preferably 18 to 24 hours. The progress of the reaction is tracked using thin layer chromatography (TLC). After completion of the reaction, filtration under reduced pressure using celite, and methylene chloride, ethyl acetate, chloroform, ethanol and the like can be used as a solvent for filtration. The most suitable solvent is chloroform.

As another manufacturing method, the present invention provides an arylisoxazole compound represented by the above formula (1) by reacting an oxime compound represented by the following formula (4) with an acetylene compound represented by the following formula (5) .

[Reaction Scheme 2]

(In the above Reaction Scheme 2, Z, R < _{1 >} and R < ₂ > are the same as defined in the above formula (1)

According to the process of Reaction Scheme 1, N-chlorosuccinimide (NCS) is added to the oxime compound represented by Chemical Formula 4 and reacted. Then, KHCO ₃ , which is a base, and an acetylene compound represented by Chemical Formula 5 are added, To thereby produce an aryl isoxazole compound represented by the above formula (1).

The acetylene compound represented by the formula (5) used as a starting material in the preparation method according to the reaction scheme 2 may be prepared by using an ordinary organic synthesis method or may be purchased as a commercially available product .

The acetylenic compound represented by Formula 5 may be synthesized through a reaction pathway as shown in Reaction Scheme 3 below.

[Reaction Scheme 3]

(Wherein Z is as defined in the above formula (1), R ₁ is a hydrogen atom, and TMS is a trimethylsilyl group)

According to Reaction Scheme 3, the halide compound represented by Formula 3 is reacted with ethynyltrimethylsilane, a Pd catalyst and CuI, and the reaction is carried out using diisopropylamine, triethylamine or the like as a base and a solvent, To produce a trimethylsilylacetylene compound. Then, the acetylene compound (R ₁ = H) represented by Formula 5 may be prepared by reacting the compound represented by Formula 6 with potassium carbonate.

Meanwhile, the compound represented by the formula (2) and the compound represented by the formula (3) as the reactant used in the production method according to the reaction scheme 1 may be prepared and used by a conventional organic synthesis method, It can also be purchased as a product.

 In the case of the 5- (tributylstannyl) isoxazole compound represented by the above formula (2), it can be synthesized through a reaction pathway as shown in the following reaction formula (4).

[Reaction Scheme 4]

(In the above Reaction Scheme 4, R ₁ and R < ₂ > are the same as defined in the above formula (1)

According to Reaction Scheme 4, an aldehyde compound represented by Formula 7 is added to a solution of a hydroxyamine salt (NH ₂ OH-HCl) dissolved in an organic solvent such as ethanol and then a base such as sodium carbonate is dissolved in distilled water, To prepare an oxime compound represented by the above formula (4). Then, the oxime compound represented by Chemical Formula 4 and N-chlorosuccinimide (NCS) were dissolved in an organic solvent such as ethyl acetate and reacted. Then, an acetylene-substituted tributylstannane, potassium hydrogen carbonate, The same base is added and the reaction is carried out at room temperature to synthesize 5- (tributylstannyl) isoxazole compound represented by Formula 2 above.

The aldehyde compound represented by the formula (7) used as a starting material in the preparation method according to the reaction scheme 2 is a known compound and can be purchased as a commercially available product.

In addition, the halide compound represented by Formula 3 may be synthesized through a reaction path as shown in the following Reaction Schemes 5 to 7 according to the structure of Z.

For example, when Z is an isoindolinone group (

) Can be synthesized by using the benzoic acid compound represented by the following formula (8) as a starting material and the route shown in the following reaction formula (5).

[Reaction Scheme 5]

(In the above Reaction Scheme 5, X is a halogen atom)

According to Reaction Scheme 5, the benzoic acid compound represented by Formula 8 is dissolved in methanol under a sulfuric acid catalyst and reacted to prepare a methylbenzoate compound represented by Formula 9. Then, the methylbenzoate compound represented by the above formula (9) is reacted with N-bromosuccinimide (NBS) in the presence of benzoyl peroxide to obtain a bromine-introduced methylbenzoate represented by the above formula (10) Acetate. Then, the brominated methylbenzoate compound represented by Formula 10 is cyclized using isopropylamine and a triethylamine base to obtain an isoindolinone-bonded halide represented by Formula 3a Compounds can be prepared.

The benzoic acid compound represented by the formula (9) used as a starting material in the process according to the reaction formula (5) is a known compound and can be readily prepared by using the known compound.

Also, when Z is a benzamide group (

) Can be synthesized through the route shown in Scheme 6 below.

[Reaction Scheme 6]

(In the above Scheme 6, X is a halogen atom)

According to Scheme 6, the halide-benzoic acid compound represented by Formula 11 is reacted with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt) Methylmorpholine (NMM), and the like, to prepare a halide compound to which the benzamide group represented by Formula 3b is bonded.

The benzoic acid compound represented by the formula (11) used as a starting material in the preparation method according to the reaction formula (6) is a known compound and can be readily prepared by using the known compound.

Meanwhile, the present invention includes a pharmaceutical composition comprising the arylisoxazole compound represented by Formula 1 as an active ingredient for the prevention and treatment of diseases.

The pharmaceutical composition of the present invention may be formulated by a conventional formulation method, including an arylisoxazole compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof, together with other conventional carriers, adjuvants or diluents, May be prepared in a form suitable for oral administration. In the case of oral administration, it can be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc. In the case of parenteral administration, it can be prepared in the form of injections for peritoneal, subcutaneous, muscular and transdermal administration.

In administering the pharmaceutical composition of the present invention as a metabotropic glutamate antagonist, the effective daily dose is 0.01 to 1000 mg / day on an adult basis, but the administration dose varies depending on the age, body weight, sex, dosage form, And may be administered once or several times a day at a predetermined time interval according to the judgment of a doctor or a pharmacist.

Accordingly, the present invention provides a pharmaceutical use of the arylisoxazole compound represented by Formula 1 or the pharmaceutical composition containing the same, for the purpose of prevention and treatment of diseases.

That is, the present invention is based on the finding that the aryl isoxazole compound represented by formula (I) has activity against mGluR1, and thus can be used for the treatment of central nervous system diseases such as dementia, depression, schizophrenia, Parkinson's disease, fragile X syndrome, drug poisoning, A brain disorder selected from the group consisting of; cancer; Hypertension, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Neuropathic pain, chronic and acute pain. ≪ Desc / Clms Page number 2 >

The present invention will now be described in more detail with reference to the following examples, preparation examples and experimental examples. However, the following examples, preparation examples and experimental examples are merely illustrative of the present invention, The present invention is not limited thereto.

[Example]

Example 1. Methyl 4-bromo-2-methylbenzoate

4-Bromo-2-methylbenzoic acid (500 mg, 2.32 mmol) was dissolved in methanol (10 mL). Concentrated sulfuric acid (0.4 mL) was added and stirred at 80 < 0 > C for 18 h. The progress and completion of the reaction were confirmed by thin layer chromatography (Hex: EA = 2: 1). The reaction was terminated with saturated sodium bicarbonate solution and the solvent was removed under reduced pressure. After extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure, followed by vacuum drying to obtain a compound.

Yield 95%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 2.61 (3H, s), 3.89 (3H, s), 7.38 (1H, d, J = 8.4 Hz), 7.42 (1H, s), 7.78 (1H, d, J = 8.4 Hz); ^{13 C NMR (75 MHz, CDCl} 3) δ ppm 167.30, 142.43, 134.56, 132.15, 128.96, 128.38, 126.69, 51.97, 21.57.

Example 2. Methyl 4-bromo-2- (bromomethyl) benzoate

N -Bromosuccinimide (23.3 g, 130.91 mmol) and benzoyl peroxide (2.2 g, 9.29 mmol) were added to carbon tetrachloride in which methyl 4-bromo-2-methylbenzoate (26.6 g, 116.12 mmol) Then, the mixture was stirred at 80 ° C. The reaction progress and completion were confirmed by TLC (Hex: EA = 5: 1). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure.

Yield 100%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 3.94 (3H, s), 4.90 (2H, s), 7.51 (1H, d, J = 8.2 Hz), 7.64 (1H, s), 7.85 (1H, d, J = 8.4 Hz)

Example 3. 5-Bromo-2-isopropylisoindolin-1-one

Using a pressure flask, methyl 4-bromo-2- (bromomethyl) benzoate was dissolved in toluene. Was added isopropylamine (12 mL, 139.10 mmol) and triethylamine (21 mL, 150.17 mmol), followed by stirring at 110 ° C. The progress and completion of the reaction were confirmed by thin layer chromatography (Hex: EA = 10: 1). After completion of the reaction, the reaction product was filtered with a reduced pressure filter to obtain a pure target compound as a solid. The filtrate was concentrated under reduced pressure and then separated by liquid chromatography to obtain the desired compound.

Yield 80%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.29 (6H, d, J = 6.8 Hz), 4.32 (1H, s), 4.66 (1H, m), 7.59 (1H, d, J = 8.0 Hz), 7.61 (1H, s), 7.70 (1H, d, J = 8.0 Hz); ^{13 C NMR (75 MHz, CDCl} 3) δ ppm 20.79, 42.80, 44.64, 125.00, 125.67, 126.15, 131.45, 132.37, 142.88, 166.92.

Example 4. (Z, E) -2,4-Difluorobenzaldehyde oxime

2,4-difluorobenzaldehyde (21.1 mmol), hydroxyamine salt (27.4 mmol) and sodium carbonate (27.4 mmol) were dissolved in ethanol and distilled water, and the mixture was stirred at room temperature. The reaction progress and completion were confirmed by thin layer chromatography (Hex: EA = 5: 1). After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Extracted with ethyl acetate, and the organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound.

Yield 100%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 6.83-6.94 (2H, m), 7.63 (1H, s), 7.75 (1H, q, J = 6.5 Hz), 8.32 (1 H, s)

Example 5. (Z, E) -4-Fluorobenzaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 93%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 7.08 (2H, m), 7.54-7.58 (2H, m), 8.13 (1H, s), 8.35 (1H, brs)

Example 6. Synthesis of (Z, E) -4-chlorobenzaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 100%; ¹ H NMR (400 MHz, CDCl ₃ + DMSO)? Ppm 7.36 (2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.9 Hz), 8.10 (1H, s)

Example 7. (Z, E) -4-methylbenzaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 95%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 2.37 (3H, s), 7.19 (2H, d, J = 8.0 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.94 (1H, br s), 8.12 (1H, s)

Example 8. Synthesis of (Z, E) -4-methoxybenzaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 98%; (1H, d, J = 8.3 Hz, 1H) 8.9 Hz), 7.91 (1H, d, J = 8.9 Hz), 8.08 (1H, s), 8.23 (1H, s), 10.63

Example 9. (Z, E) -2-Fluorobenzaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 100%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 7.07-7.18 (2H, m), 7.34-7.39 (1H, m), 7.73 (1H, t, J = 7.6 Hz), 8.38 (1 H, s)

Example 10. Synthesis of 3- (2,4-difluorophenyl) -4-methyl-5- (tributylstannanyl) isooxazole

(Z, E) -2,4-difluorobenzaldehyde oxime (620 mg, 3.95 mmol) and N-chlorosuccinimide (1 eq) were dissolved in ethyl acetate and stirred at room temperature. The reaction progress and completion were confirmed by thin layer chromatography (Hex: EA = 5: 1). Propene-1-yl tributylstannane (1.3 eq) was added and KHCO ₃ dissolved in a small amount of H ₂ O was added dropwise. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (Hex: EA = 30: 1) to obtain the desired compound.

Yield 36%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.82-2.04 (27H, m), 2.47 (3H, s), 6.41-6.98 (2H, m), 7.45 (1H, q, J = 6.4 Hz)

Example 11 3- (4-fluorophenyl) -4-methyl-5- (tributylstannyl) isooxazole

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 39%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.81-1.39 (27H, m), 2.46 (3H, s), 7.12 (2H, m), 7.44-7.48 (2H, m)

Example 12. Preparation of 3- (4-chlorophenyl) -4-methyl-5- (tributylstannyl) isooxazole

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 38%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.82-1.62 (27H, m), 2.74 (3H, s), 7.42 (2H, d, J = 8.5 Hz), 7.72 (2H, d, J = 8.5 Hz)

Example 13. Synthesis of 4-methyl-3-p-tolyl-5- (tributylstannyl) isooxazole

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 49%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.81-1.36 (27H, m), 2.41 (3H, s), 2.45 (3H, s), 7.22 (2H, d, J = 7.8 Hz), 7.36 (2H, d, J = 7.8 Hz)

Example 14. Synthesis of 3- (4-methoxyphenyl) -4-methyl-5- (tributylstannyl) isooxazole

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 39%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.81-1.39 (27H, m), 2.45 (3H, s), 3.85 (3H, s), 6.94 (2H, d, J = 8.9 Hz), 7.41 (2H, d, J = 8.9 Hz)

Example 15 3- (2-fluorophenyl) -4-methyl-5- (tributylstannyl) isoxazole

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 36%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 0.81 - 1.37 (27 H, m), 2.48 (3 H, s), 7.13-7.23 (2H, m), 7.41-7.48

Example 16. Preparation of (3- (2,4-difluorophenyl) -4-methylisooxazol-5-yl) -2-isopropylisoindolin-

To a mixture of 5-bromo-2-isopropylisoindolin-1-one (630 mg, 2.48 mmol) and 3- (2,4- difluorophenyl) carbonyl) was added dropwise and then the isoxazole-(1 g, 2.06 mmol) was dissolved in _{toluene, Pd (PPh 3) 4 (} 476 mg, 0.41 mmol). Stir overnight at 110 < 0 > C. The progress and completion of the reaction were confirmed by thin layer chromatography. After completion of the reaction, the mixture was filtered using a celite filter and concentrated under reduced pressure. The concentrate was separated by liquid chromatography (Hex: EA: MC = 2: 1: 1) to obtain the target compound.

Yield 52%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.29 (6H, d, J = (1H, d, J = 6.8 Hz), 2.53 (3H, s), 4.31 6.9 Hz), 7.20 (1H, s), 7.46 (1H, m), 7.79 (1H, d, J = 6.9 Hz); ^{13 C NMR (100 MHz, CDCl} 3) δ ppm 11.79, 20.85, 42.69, 44.95, 104.76, 105.02, 111.87, 112.11, 116.62, 122.90, 123.91, 128.67, 132.25, 132.81, 133.16, 141.70, 157.06, 166.79, 167.23

Example 17. Synthesis of 5- (3- (4-fluorophenyl) -4-methylisooxazol-5-yl) -2-isopropylisoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 56%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.30 (6H, d, J = (2H, t, J = 6.8 Hz), 2.47 (3H, s), 4.33 8.8 Hz), 7.23 (1H, s), 7.27 (1H, d, J = 8.0 Hz), 7.38-7.41 (2H, m), 7.86 (1H, d , J = 7.8 Hz); ¹³ C NMR (100 MHz, CDCl 3) 11.68, 20.86, 42.76, 44.96, 115.27, 115.69, 115.91, 124.65, 124.91, 129.73, 130.32, 130.40, 133.00, 133.29, 141.78, 160.22, 162.29, 164.78, 167.14, 167.22

Example 18. Preparation of 5- (3- (4-chlorophenyl) -4-methylisooxazol-5-yl) -2-isopropylisoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 61%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.31 (6H, d, J = (1H, d, J = 6.8 Hz), 2.47 (3H, s), 4.33 8.6 Hz)

Example 19. Synthesis of 2-isopropyl-5- (3- (4-methoxyphenyl) -4-methylisooxazol-5-yl) isoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 53%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.30 (6H, d, J = (2H, d, J = 6.8 Hz), 2.45 (3H, s), 3.81 (3H, s), 4.32 8.9 Hz), 7.25-7.30 (2H, m), 7.34 (2H, d, J = 8.9 Hz), 7.85 (1H, d, J = 7.8 Hz); ^{13 C NMR (100 MHz, CDCl} 3) δ ppm 11.68, 20.86, 42.72, 44.97, 55.28, 114.05, 115.17, 121.07, 123.91, 124.08, 129.78, 132.80, 133.75, 141.68, 160.61, 160.71, 166.76, 167.33

Example 20. Preparation of 3- (2,4-difluorophenyl) -5- (tributylstannyl) isooxazole

(Z, E) -2,4-difluorobenzaldehyde oxime (2.21 g, 14.0 mmol) and N-chlorosuccinimide (1.87 g, 14.0 mmol) were dissolved in ethyl acetate and stirred at room temperature. The reaction progress and completion were confirmed by TLC (Hex: EA = 5: 1). Ethyl tributylstannane (2.9 mL, 10.0 mmol) was added to the reaction mixture, and KHCO ₃ (2.8 g, 28.0 mmol) dissolved in a small amount of H ₂ O was added dropwise. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (Hex: EA = 30: 1) to obtain the desired compound.

Yield 60%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 0.84-1.62 (27H, m), 6.77 (1H, d, J = 1.8 Hz), 6.90-7.00 (2H, m), 7.99 (1H, q, J = 6.6 Hz)

Example 21. Synthesis of 3- (4-fluorophenyl) -5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 76%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.89-1.62 (27H, m), 6.64 (1H, s), 7.13 (2H, t, J = 8.7 Hz), 7.81-7.84 (2H, m)

Example 22. Preparation of 3- (4-chlorophenyl) -5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 73%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.89-1.62 (27H, m), 6.65 (1H, s), 7.42 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.7 Hz)

Example 23. Synthesis of 3-p-tolyl-5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 46%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.89 (27H, m), 2.39 (3H, s), 6.65 (1H, s), 7.25 (2H, d, J = 7.7 Hz), 7.73 (2H, d, J = 8.0 Hz)

Example 24. Synthesis of 3- (4-methoxyphenyl) -5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 65%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.84-1.62 (27H, m), 3.84 (3H, s), 6.63 (1H, s), 6.96 (2H, d, J = 8.8 Hz), 7.77 (2H, d, J = 8.8 Hz)

Example 25. Preparation of 3- (2-fluorophenyl) -5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 56%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 0.89-1.63 (27H, m), 6.83 (1H, d, J = 3.7 Hz), 7.20-7.25 (3H, m), 7.55 (1H, m), 8.00

Example 26. Preparation of 5- (3- (2,4-difluorophenyl) isooxazol-5-yl) -2-isopropylisoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 56%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.33 (6H, d, J = (2H, s), 7.94-7.97 (3H, m), 6.98-7.04 (2H, 8.06 (1H, q, J = 6.4 Hz)

Example 27. 2-isopropyl-5- (3-p-tolylisooxazol-5-yl) isoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 49%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.33 (6H, d, J = (2H, d, J = 6.8 Hz), 2.43 (3H, s), 4.43 7.9 Hz), 7.76 (2H, d, J = 8.0 Hz), 7.89-7.91 (3H, m); ^{13 C NMR (100 MHz, CDCl} 3) δ ppm 169.97, 161.13, 141.94, 140.42, 134.87, 129.91, 129.71, 126.72, 125.90, 124.25, 120.09, 98.62, 45.11, 42.89, 21.47, 20.84

Example 28. 2-isopropyl-5- (3- (4-methoxyphenyl) isooxazol-5-yl) isoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 42%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.34 (6H, d, J = (1H, d, J = 6.8 Hz), 3.89 (3H, s), 4.44 (2H, s), 4.61-4.82 8.3 Hz), 7.82 (2H, d, J = 8.3 Hz), 7.87-8.00 (3H, m); ¹³ C NMR (100 MHz, CDCl ₃ ) ppm 169.33, 166.97, 162.78, 141.94, 128.22, 125.89, 124.24, 120.08, 114.42, 98.45, 55.39, 45.11, 42.90, 22.82

Example 29. 5- (3- (2-fluorophenyl) isooxazol-5-yl) -2-isopropylisoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 54%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.33 (6H, d, J = 6.8 Hz), 4.44 (2H, s), 4.71 (1H, m), 7.08 (1H, d, J = (1H, d, J = 8.4 Hz), 7.22-7.03 (3H, m), 7.46-7.48 (1H, m), 7.94-7.97 8.4 Hz), 8.06 (1 H, m); ¹³ C NMR (100 MHz, CDCl ₃ )? Ppm 168.69, 165.84, 161.75, 141.36, 135.40, 128.11, 125.94, 124.30, 120.12, 116.45, 97.66, 85.12, 45.10, 42.89, 20.85;

Example 30. (Z, E) -6-chloronicotinaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 98%; ¹ H NMR (400 MHz, CDCl ₃ + DMSO-d ₆ )? Ppm 7.33 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 8.3 Hz), 8.51 (1H, s), 11.06 (1H, s)

Example 31. Synthesis of (Z, E) -6-methylnitotinaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 94%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 2.60 (3H, s), 7.25 (1H, d, J = 8.1 Hz), 7.86 (1H, dd, J = 8.0, 2.3 Hz), 8.15 (1H, s), 8.69 (1H, s), 9.97

Example 32. (Z, E) -6-methoxynicotinaldehyde oxime

Was synthesized in the same manner as in Example 4 to obtain the target compound.

Yield 100%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 3.95 (3H, s), 6.74 (1H, d, J = 8.6 Hz), 7.91 (1H, d, J = 8.7 Hz), 8.08 (1H, s), 10.63 (1H, s)

Example 33. 3- (6-Chloropyridin-3-yl) -4-methyl-5- (tributylstannyl)

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 60%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.82-1.40 (27H, m), 2.49 (3H, s), 7.42 (1H, d, J = 8.2 Hz), 7.82 (1H, d, J = 8.2 Hz), 8.51 (1 H, s)

Example 34. Preparation of 4-methyl-3- (6-methylpyridin-3-yl) -5- (tributylstannyl)

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 54%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.81-1.39 (27H, m), 2.47 (3H, s), 2.62 (3H, s), 7.23 (1H, d, J = 8.0 Hz), 7.73 (1H, dd, J = 8.0, 2.3 Hz), 8.61 (1H, s)

Example 35. Preparation of 3- (6-methoxypyridin-3-yl) -4-methyl-5- (tributylstannyl)

Synthesis was conducted in the same manner as in Example 10 to obtain the desired compound.

Yield 56%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 0.82-1.66 (27H, m), 2.47 (3H, s). 3.99 (3 H, s), 6.80 (1 H, d, J = 8.6 Hz), 7.70 (1 H, d, J = 8.5 Hz), 8.27 (1H, s)

Example 36. Preparation of 5- (3- (6-chloropyridin-3-yl) -4-methylisooxazol-5-yl) -2-isopropylisoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 45%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.33 (6H, d, J = (1H, d, J = 6.8 Hz), 2.48 (3H, s), 4.34 (2H, s), 4.72 (1H, m), 7.23 8.3 Hz), 7.89 (1H, d, J = 8.1 Hz), 8.41 (1 H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) 11.60, 20.86, 42.80, 44.96, 115.42, 124.01, 124.38, 124.44, 129.63, 132.41, 133.49, 138.16, 142.09, 148.94, 157.52, 166.98, 167.90

Example 37. 2-isopropyl-5- (4-methyl-3- (6-methylpyridin-3- yl) isooxazol-

The target compound was synthesized by the same method as in Example 16.

Yield 55%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.30 (6H, d, J = (1H, d, J = 6.8 Hz), 2.50 (3H, s), 2.61 (3H, s), 4.34 8.2 Hz), 7.52 (1H, m), 7.84 (1H, d, J = 8.2 Hz), 8.02 (1H, d, J = 8.1 Hz), 8.86 (1H, s)

Example 38. 2-Isopropyl-5- (3- (6-methoxypyridin-3-yl) -4-methylisooxazol-

The target compound was synthesized by the same method as in Example 16.

Yield 37%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.31 (6H, d, J = (1H, d, J = 6.8 Hz), 2.46 (3H, s), 3.92 8.1 Hz), 7.27 (2H, m), 7.67 (1H, d, J = 8.7 Hz), 7.87 (1H, d, J = 7.8 Hz), 8.16 (1H, s)

Example 39. 3- (6-Chloropyridin-3-yl) -5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 68%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 0.95 (t, J = 7.2 Hz, 9H), 1.23-1.29 (m, 6H), 1.33-1.40 (m, 6H), 1.60-1.66 , 6.72 (s, 1H), 7.46 (dd, J = 6.0, 2.4 Hz, 1H), 8.17 (ddd, J = 8.4, 2.4, 0.6 Hz, 1H), 8.84 (d, J = 2.4 Hz, 1H); ^{13 C NMR (75 MHz, CDCl} 3) δ ppm 181.81, 156.71, 152.36, 147.97, 137.01, 124.86, 124.53, 111.52, 28.81, 27.12, 13.58, 10.66.

Example 40. 3- (6-Methylpyridin-3-yl) -5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 41%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 0.91 (9H, t, J = (1H, s), 7.25 (1H, d, J = 8.3 Hz), 1.19-1.63 8.0 Hz), 8.05 (1H, dd, J = 8.0, 2.3 Hz), 8.92 (1H, s)

Example 41. 3- (6-methoxypyridin-3-yl) -5- (tributylstannyl) isooxazole

The target compound was synthesized by the same method as in Example 20.

Yield 66%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 0.89-1.60 (27H, m), 3.99 (3H, s), 6.63 (1H, s), 6.82 (1H, d, J = 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.58 (1 H, s); ^{13 C NMR (100 MHz, CDCl} 3) δ ppm 180.58, 164.89, 157.61, 145.58, 137.23, 119.15, 111.41, 111.21, 53.68, 28.82, 27.14, 13.62, 10.57.

Example 42. 5- (3- (6-Chloropyridin-3-yl) isooxazol-5-yl) -2-isopropylisoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 57%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.26 (6H, d, J = 6.8 Hz), 4.44 (1H, m), 4.56 (2H, s), 7.76 (1H, d, J = 8.4 Hz), 7.89 (1H, s), 7.86 (1H, d, J = 8.1 Hz), 8.02 (1H, d, J = 8.1 Hz), 8.14 (1H, s), 8.38 (1H, dd, J = 8.2, 2.4 Hz), 8.99 (1H, s); ¹³ C NMR (75 MHz, CDCl ₃ ) ? Ppm 170.58, 166.80, 159.67, 153.13, 147.76, 142.06, 136.70, 135.38, 129.27, 126.04, 124.79, 124.46, 124.10, 120.25, 98.14, 45.15, 43.00, 20.82; mp 181.8 [deg.] C; HPLC purity 95.1%, retention time = 14.66 min, HRMS (ESI +): m / z: calcd for C 21 H 17 ClN 2 O 2: 354.0979, [M + H] +; found: 354.1004.

Example 43. 2-isopropyl-5- (3- (6-methylpyridin-3-yl) isooxazol-5-yl) isoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 46%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.33 (6H, d, J = (1H, d, J = 6.8 Hz), 2.65 (3H, s), 4.44 8.0 Hz), 7.91-7.97 (3H, m), 8.10 (1H, dd, J = 8.0, 2.3 Hz), 8.95 (1H, s)

Example 44. 2-isopropyl-5- (3- (4-methoxyphenyl) isooxazol-5-yl) isoindolin-

The target compound was synthesized by the same method as in Example 16.

Yield 32%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.31 (6H, d, J = 6.8 Hz), 3.97 (3H, s), 4.52 (2H, s), 4.53 (1H, m), 6.92 (1H, d, J = 8.6 Hz), 7.51 (1H, s), 7.84 (1H, d, J = 7.9 Hz), 7.99 (1H, d, J = 7.9 Hz), 8.08 (2H, s), 8.17 (1H, d, J = 8.6 Hz), 8.71 (1H, s)

Example 45. 4-Bromobenzoic acid

 Methyl 6-bromobenzoate (100 mg, 0.44 mmol) was dissolved in ethanol, and 1N sodium hydroxide (1.31 mL) was added dropwise thereto, followed by stirring at room temperature. Reaction progress and completion were confirmed by thin layer chromatography (Hex: EA = 5: 1). After completion of the reaction, the reaction product was filtered under reduced pressure with ethanol to obtain the target compound as a white solid.

Yield 100%; ¹ H NMR (400 MHz, CD ₃ OD)? Ppm 7.61 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.5 Hz)

Example 46. 4-Iodo-N-isopropylbenzamide

 (500 mg, 2.02 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI, 720 mg, 3.64 mmol), 1-hydroxybenzotriazole mg, 3.43 mmol) and N-methylmorpholine (NMM; 387 uL, 3.43 mmol) were dissolved in methylene chloride, and the mixture was stirred at room temperature for 2 hours. After confirmation by TLC, isopropylamine (208 uL, 2.42 mmol) was added dropwise. Reaction progress and completion were confirmed by thin layer chromatography (MC: MeOH = 20: 1). When the reaction was complete, it was extracted with water and dichloromethane and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the target compound as a white solid.

Yield 70%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.26 (6H, d, J = 6.5 Hz), 4.26 (1H, m), 6.00 (1H, brs), 7.47 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8.5 Hz)

Example 47. 4-Bromo-N-isopropylbenzamide

The target compound was obtained in the same manner as in Example 46.

Yield 88%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.26 (6H, d, J = 6.8 Hz), 4.28 (1H, m), 5.89 (1H, brs), 7.55 (2H, d, J = 6.7 Hz), 7.63 (2H, d, J = 6.8 Hz)

Example 48. 4- (3- (2,4-difluorophenyl) -4-methylisoxazole-5-yl) -N-

(55 mg, 0.23 mmol) and 3- (2,4-difluorophenyl) -4-methyl-5- (tributylstannyl) isooxazole was added dropwise a _{Pd (PPh 3) 4 (46} mg, 0.04 mmol) was dissolved in a (100 mg, 0.21 mmol) in toluene. The mixture was stirred at 110 < 0 > C. Reaction progress and completion were confirmed by thin layer chromatography (Hex: EA = 2: 1). After completion of the reaction, the mixture was subjected to vacuum filtration with a celite filter and distillation under reduced pressure. The target compound was isolated by liquid chromatography.

Yield 40%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.28 (6H, d, J = 6.8 Hz), 2.62 (3H, s), 4.29 (1H, m), 5.89 (1H, brs), 6.86-7.07 (2H, m), 7.15 (2H, d, J = 8.4 Hz), 7.44 (1H, m), 7.67 (2H, d, J = 8.5 Hz)

Example 49. 4- (3- (4-Chlorophenyl) -4-methylisoxazole-5-yl) -N-isopropylbenzamide

The target compound was obtained in the same manner as in Example 48.

Yield 32%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.29 (6H, d, J = (1H, d, J = 6.8 Hz), 2.46 (3H, s), 4.32 8.5 Hz), 7.32 (4H, m), 7.77 (2H, d, J = 8.3 Hz)

Example 50. N-isopropyl-4- (3- (4-methoxyphenyl) -4-methylisooxazol-5-yl)

The target compound was obtained in the same manner as in Example 48.

Yield 33%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.30 (6H, d, J = 6.8 (2H, d, J = 6.8 Hz), 2.44 (3H, s), 4.10 6.8 Hz), 7.25 (2H, d, J = 8.2 Hz), 7.33 (2H, d, J = 6.8 Hz), 7.76 (2H, d, J = 8.3 Hz)

Example 51. 4- (3- (2,4-Difluorophenyl) isooxazol-5-yl) -N-isopropylbenzamide

The target compound was obtained in the same manner as in Example 48.

Yield 22%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.27 (6H, d, J = (2H, d, J = 6.8 Hz), 4.31 (1H, m), 5.92 (1H, brs), 7.38-7.60 6.7 Hz)

Example 52. 4- (3- (4-Fluorophenyl) isooxazol-5-yl) -N-isopropylbenzamide

The target compound was obtained in the same manner as in Example 48.

Yield 31%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.30 (6H, d, J = 6.8 Hz), 4.33 (1H, m), 5.96 (1H, br s), 6.87

Example 53. 4- (3- (4-chlorophenyl) isooxazol-5-yl) -N-isopropylbenzamide

 The target compound was obtained in the same manner as in Example 48.

Yield 97%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.29 (6H, d, J = 6.6 Hz), 4.27 (3H, s), 4.33 (1H, m), 5.95 (1H, d, J = 7.4 Hz), 6.86 (1H, s), 7.01 (2H, d, J = 8.8 Hz), 7.80 (2H, d, J = 8.8 Hz), 7.85-7.91 (4 H, m)

Example 54. 4- (3- (2-fluorophenyl) isooxazol-5-yl) -N-isopropylbenzamide

The target compound was obtained in the same manner as in Example 48.

Yield 68%; 1 H NMR (600 MHz, CDCl 3)? Ppm 1.30 (6H, d, J = M), 7.46 (1H, m), 7.88 (2H, s), 7.28 (1H, d, J = 6.4 Hz), 7.91 (2H, d, J = 6.4 Hz)

Example 55. N-isopropyl-4- (3- (6-methoxypyridin-3-yl) -4-methylisooxazol-

The target compound was obtained in the same manner as in Example 48.

Yield 55%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.29 (6H, d, J = 6.8 Hz), 2.44 (3H, s), 3.92 (3H, s), 4.35 (1H, m), 6.03 (1H, brs), 6.70 (1H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.46 (1H, m), 7.66 (1H, m), 7.78 (2H, d, J = 8.4 Hz)

Example 56. 4- (3- (6-Chloropyridin-3-yl) isooxazol-5-yl) -N-isopropylbenzamide

 The target compound was obtained in the same manner as in Example 48.

Yield 45%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.30 (6H, d , J = (1H, d, J = 6.8 Hz), 4.33 (1H, s), 5.94 8.2 Hz), 7.90 (4H, s), 8.19 (1H, d, J = 8.2 Hz), 8.85 (1H, s)

Example 57. N-isopropyl-4- (3- (6-methoxypyridin-3-yl) isooxazol-

The target compound was obtained in the same manner as in Example 48.

Yield 27%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.29 (6H, d, J = 6.8 Hz), 4.00 (2H, s), 4.31 (1H, m), 5.96 (1H, brs), 6.86 (1H, d, J = 6.8 Hz), 6.88 (1H, s), 7.90 (4H, m), 8.01 (1H, d, J = 6.7 Hz), 8.62 (1H, s)

Example 58. Synthesis of 2-isopropyl-5 - ((trimethylsilyl) ethynyl) isoindolin-1-

(300 mg, 1.18 mmol) and ethynyltrimethylsilane (167 [mu] l, 2.36 mmol) were dissolved in 10 mL of dipropylamine under nitrogen, and PdCl ₂ (PPh ₃ ) ₂ (41 mg, 0.06 mmol) and CuI (11 mg, 0.06 mmol) were added dropwise. The mixture was stirred at room temperature. Reaction progress and completion were confirmed by thin layer chromatography (Hex: EA = 9: 1). After completion of the reaction, the reaction mixture was extracted with water and dichloromethane, dried over sodium sulfate, and distilled under reduced pressure. The target compound was isolated by liquid chromatography.

Yield 61%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 0.30 (9H, s), 1.31 (6H, d, J = M), 7.82 (1H, d, J = 6.8 Hz), 4.36 8.1 Hz)

Example 59. 5-Ethynyl-2-isopropylisoindolin-1-one

1-one (71 mg, 0.27 mmol) synthesized in Example 58 was dissolved in 1 mL of ethanol and 0.4 mL of water. Potassium hydroxide (7.8 mg, 0.03 mmol) was added dropwise thereto, followed by stirring at room temperature for one hour. Extracted with ethyl acetate and water, dried over sodium sulfate and concentrated.

Yield 100%; ¹ H NMR (300 MHz, CDCl ₃ )? Ppm 1.33 (6H, d, J = (1H, d, J = 6.8 Hz), 3.22 (1H, s), 4.36 8.1 Hz)

Example 60. (E) -6- (2-methoxyethoxy) nicotinic aldehyde oxime

1) 6- (2-methoxyethoxy) nicotinic acid

(500 mg, 3.17 mmol) and methoxyethanol (300 μl, 3.81 mmol) were dissolved in 10 mL of toluene, and sodium hydroxide (760 mg, 19.04 mmol) and tetrabutylammonium bromide (102 mg, 0.32 mmol) mmol) was added dropwise. And the mixture was stirred at 120 ° C for 15 hours. After cooling to room temperature, it was acidified with 1N HCl and filtered under reduced pressure with hexane to obtain 6- (2-methoxyethoxy) nicotinic acid as a yellow solid.

Yield 67%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 3.45 (3H, s), 3.77 (2H, m), 4.57 (2H, d, J = 5.37 Hz, 2 H), 6.86 (1 H, d, J = 8.7 Hz), 8.20 (1H, d, J = 8.8 Hz), 8.88 (1H, d, J = 2.1 Hz)

2) [6- (methoxyethoxy) pyridin-3-yl] methanol

6- (2-Methoxyethoxy) nicotinic acid (100 mg, 0.51 mmol) was dissolved in anhydrous THF and stirred at 0 ° C. From _{0 ℃ 1.0M BH 3 (2.03 mL} , 2.03 mmol) and then slowly added dropwise thereto and the mixture was stirred at room temperature for 1 hour. The organic layer was extracted with ethyl acetate and water and dried over sodium sulfate.

Yield 100%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 3.48 (3H, s), 3.79 (2H, m), 4.52 (2H, m), 4.66 (2H, s), 6.86 (1H, m), 7.66 (1H , < / RTI > m), 8.14 (1H, s)

3) 6- (2-methoxyethoxy) nicotinic aldehyde

3-yl] methanol (195 mg, 1.06 mmol), PCC (460 mg, 2.13 mmol) and silica gel (460 mg) were dissolved in dichloromethane and stirred at room temperature. Purification via column chromatography.

Yield 57%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 3.48 (3H, s), 3.80 (2H, m), 4.62 (2H, m), 6.94 (1H, m), 8.10 (1H, d, J = 8.7 Hz), 8.64 (1H, s), 9.98 (1H, s)

3) (Z, E) -6- (2-methoxyethoxy) nicotinaldehyde oxime

(55 mg, 0.79 mmol) and sodium carbonate (84 mg, 0.79 mmol) were dissolved in 1 mL of ethanol and 1 mL of water, and the mixture was stirred at room temperature Lt; / RTI > Extracted with ethyl acetate and water, dried over sodium sulfate, and then distilled under reduced pressure.

Yield 92%; ^{1 H NMR (400 MHz, CDCl} 3) δ ppm 3.48 (3H, s), 3.79 (2H, m), 4.54 (2H, m), 6.85 (1H, d, J = 8.5 Hz), 7.45 (1H, s), 7.92 (1H, d, J = 8.4 Hz), 8.12 (1H, s), 8.23 (1H, s)

Example 61. 2-isopropyl-5- (3- (6- (2-methoxyethoxy) pyridin-3- yl) isooxazol-

(75 mg, 0.56 mmol) and (Z, E) -6- (2-methoxyethoxy) nicotinaldehyde oxime (110 mg, 0.56 mmol) were dissolved in ethyl acetate, Lt; / RTI > The reaction progress and completion were confirmed by TLC (Hex: EA = 4: 1). Ethynyl-2-isopropylisoindolin-1-one (123 mg, 0.62 mmol) synthesized in Example 59 was added to the reaction solution, and KHCO ₃ dissolved in a small amount of H ₂ O (67 mg, 0.67 mmol) was added dropwise. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then filtered under reduced pressure with diethyl ether to obtain the desired compound.

Yield 54%; ¹ H NMR (400 MHz, CDCl ₃ )? Ppm 1.36 (6H, d, J = (2H, m), 4.74 (2H, m), 4.74 (1H, s), 6.98 m), 7.87-8.06 (3H, m), 8.15 (1H, d, J = 8.7 Hz), 8.63 (1H, s);

[Formulation Example]

Meanwhile, the novel compounds represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1: Tablets (direct pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation 2: Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation 3: Powder and Capsule

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation 4: Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water were added to prepare an injection.

[Experimental Example]

On the other hand, the novel compounds represented by Formula 1 according to the present invention were tested for antagonism to metabotropic glutamate receptor 1 (mGluR1) by the method shown in the following Experimental Examples. As a result of the experiment, the percent inhibition of mGluR1 was determined using FDSS6000, and the IC ₅₀ was determined using an automatic patch clamp mainly on some compounds showing excellent activity.

Experimental Example 1: Detection of metabolic glutamate activity using FDSS6000

Chem3 cell line with m-GluR1 in 96-well plates are stably expressed (HTS145C: Millipore) to stabilize for one hour the cells at 2 x 10 ⁶ / ㎖ made of a density by dividing by _{50 ㎕ 5% CO 2, 37} ℃ of . Were incubated in HBSS buffer solution containing 5% CO ₂ and 37 ° C for 30 min with a Ca ²⁺ fluorescent dye (FLIPR Calcium 5 assay kit: Molecular Devices) and labeled with fluorescent dye. Separate from the cell-prepared 96-well plate, a 96-well drug plate containing L-glutamate (final concentration of 10 [mu] M) and a blocking agent to activate m-GluR1 was prepared. Most cell-based HTS devices have a liquid application system for drug injection, but since there is no liquid suction system, 25 μL of the blocking agent and L-glutamate to be searched are prepared in HBSS buffer at a high concentration of 6 times, And diluted to 1/6 at the final volume of 150 μL. Specific FDSS6000 measurement conditions were a change in intracellular calcium concentration, which was changed by administration of L-glutamate after 75 seconds of drug pretreatment after recording the reference value of 20 seconds, in which the ratio of 480/520 ratio value The area was set at 100%, and the inhibitory effect of the test substance on the inhibitory effect (%) was obtained. As a control drug, 10 μM of 5- [1- (2,4-difluorophenyl) -5-methyl- 1H -1,2,3-triazol- 2- (1-methylethyl) -1 H - the isoindole-1-one (DFMTI) was used.

Detailed calcium imaging techniques were used to selectively expose excitation wavelengths (340 nm and 380 nm) to a cell by means of a computer-controlled filter wheel illuminating four light sources of a xenon lamp mounted on a FDSS6000. Data were collected every 1.23 seconds and the emitter fluorescence light passing through a 515 nm long-pass filter passed through a cooled CCD camera embedded in the instrument and passed through a 96-well Lt; RTI ID = 0.0 > 340/380 < / RTI > All image data and analysis were performed using a program dedicated to FDSS6000 provided by Hamamatsu Photonics.

The% inhibition results for the m-GluR1 of the novel compounds according to the invention are shown in Table 1 below.

Experimental compound FDSS% inhibition rate
(10 [mu] M) Experimental compound FDSS% inhibition rate
(10 [mu] M) Compound 1 87.58 Compound 11 62.65 Compound 2 62.80 Compound 12 59.44 Compound 3 61.64 Compound 14 49.08 Compound 4 36.51 Compound 15 43.65 Compound 6 35.13 Compound 17 50.44 Compound 7 88.56 Compound 18 33.89 Compound 8 56.85 Compound 19 91.07 Compound 9 46.46 Compound 23 42.28 Compound 10 47.12 Control drug (DFMTI) 93.13

 [Control Drug _DFMTI]

Experimental Example 2: Experimental animal model of neuropathic pain (SNL model)

1. Preparation of experimental animals

Male rats SD (Rat Sprague Dawley) weighing 300-320 g were anesthetized with a mixture gas of 2% isoflurane and 95% oxygen. Anesthesia was maintained with a mixture of 1.5% isoflurane and 95% oxygen throughout the entire procedure. After removal of the transverse process of the left L6 vertebrae of the rat, the L4 to L5 spinal nerve connections were separated from the left side of the L5 spinal nerve and the L5 spinal nerve was firmly fixed to the 6-0 silk thread to cause neuropathic pain, (SNL Model). [Non-Patent Document 7]

2. Drug experiment

All behavioral tests were performed by a blind study by a researcher who did not know whether the drug was administered.

(A) Mechanical allodynia

The rats were placed in a round acrylic vat (5.5 ", 15", 6.5 ", 18 cm, depending on body size), pulled out of the tail only, and placed on the plate. Measurement of mechanical allodynia was performed using an up-down method (Chaplan et al, 1994) using various von-Fry hairs (0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g) ) Was performed by calculating the gram (g) of von-Frey hair showing a 50% avoidance response with a tail. It was judged that mechanical allodynia occurred when the avoidance response threshold decreased statistically compared to before nerve injury.

(B) cold allodynia

The mice were placed in a round acrylic vial, taken out of the tail only, draped, and placed in 4 ° C water to measure the time until the tail was evaded. Experimental results were obtained by the mean of five measurements at intervals of 5 minutes. When not escaping by 15 seconds, the tail was removed in water to prevent sensitization of the tail, resulting in 15 seconds. In cases of significant early avoidance than before surgery, it was estimated to be the result of cold allodynia. The results of the above-mentioned behavior test showed that when the significant avoidance reaction was observed after the nerve injury compared to before the nerve injury, the pain was induced.

The experimental results of animal models of neuropathic pain according to Experimental Example 2 are shown in Fig. According to the experimental results shown in Fig. 1, compounds 12 and 15 as compounds according to the present invention exhibit equivalent or superior activities as those of gabapentin, which is commercially available as a pain relieving agent. In addition, DFMTI used as a reference drug in Experimental Example 1 showed little efficacy in an experimental model of neuropathic pain.

Claims (8)

delete delete delete A compound selected from the group consisting of a compound represented by the following formula (1b) and a pharmaceutically acceptable salt thereof:
[Chemical Formula 1b]

In the above formula (1b)
R ¹ is a hydrogen atom; Or a C ₁ -C ₁₀ alkyl group;
R ² is a phenyl group substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₁₀ alkyl and C ₁ -C ₁₀ alkoxy; Or a pyridyl group substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy and (C ₁ -C ₁₀ alkoxy) -C ₁ -C ₁₀ alkoxy to be.
5. A compound according to claim 4 selected from:
Compound 14: 4- [3- (4-Chlorophenyl) -4-methylisoxazole-5-yl] -N-isopropylbenzamide
Compound 15: N-isopropyl-4- [3- (4-methoxyphenyl) -4-methylisooxazol-5-yl] benzamide
Compound 16: 4- [3- (2,4-Difluorophenyl) isooxazol-5-yl] -N-isopropylbenzamide
Compound 17: 4- [3- (4-Fluorophenyl) isooxazol-5-yl] -N-isopropylbenzamide
Compound 18: 4- [3- (4-Chlorophenyl) isooxazol-5-yl] -N-isopropylbenzamide
Compound 19: 4- [3- (2-Fluorophenyl) isooxazol-5-yl] -N-isopropylbenzamide
Compound 20: N-isopropyl-4- (3- (4-methoxyphenyl) isooxazol-5-yl)
Compound 21: 4- [3- (6-Chloropyridin-3-yl) isooxazol-5-yl] -N-isopropylbenzamide
Compound 22: N-isopropyl-4- [3- (6-methoxypyridin-3-yl) isooxazol-
Compound 23: 4- (3- (2-Fluoropyridin-3-yl) isooxazol-5-yl) -N-isopropylbenzamide.
A brain disorder selected from the group consisting of dementia, depression, schizophrenia, Parkinson's disease, fragile X syndrome, drug addiction, and epilepsy, including a compound selected from the group consisting of 4 or 5; And neuropathic pain, chronic and acute pain. ≪ Desc / Clms Page number 19 >
delete delete

Images