Heterocyclic compounds and methods for their preparation and use

Abstract

The present invention provides a heterocyclic compound, and its preparation method and use. The structural formula of the heterocyclic compound is shown in Formula I. The compound has excellent bioavailability, improves cerebral blood flow level in ischemia-reperfusion animal models, reduces cerebral infarction area, and can be used to treat diseases such as stroke. JPEG2025534851000026.jpg41139

Description

[Technical Field]

[0001] The present invention belongs to the field of medicine, and specifically relates to heterocyclic compounds, and methods for their preparation and use. [Background technology]

[0002] Cerebral stroke, also known as stroke or cerebrovascular accident (CVA), is an acute cerebrovascular disease characterized by a group of conditions, including ischemic and hemorrhagic strokes, that result from sudden rupture or blockage of a blood vessel in the brain, resulting in brain tissue damage. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60% to 70% of all strokes. Blockage or stenosis of the internal carotid and vertebral arteries can cause ischemic stroke, which primarily occurs in people over 40 years of age, is more common in men than women, and can be fatal in severe cases. Hemorrhagic stroke has a high mortality rate. Research has shown that stroke is the leading cause of death in both urban and rural areas in China and the leading cause of disability among Chinese adults. Stroke is characterized by high morbidity, mortality, and disability rates. Different types of stroke require different treatments.

[0003] Currently, edaravone is primarily used to treat ischemic stroke. However, due to its confirmed free radical scavenging and antioxidant properties, various experimental studies have shown that edaravone also has protective effects against damage in many other organs. This suggests that edaravone's role is not limited to the treatment of ischemic stroke, but may also play a role in the treatment of various diseases closely related to oxidative stress. However, due to its low bioavailability, edaravone can only be used for stroke treatment via injection. Because oral dosage forms are more effective in treating end-stage stroke and amyotrophic lateral sclerosis (ALS), there is a need to find an oral medication for stroke treatment. Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide heterocyclic compounds and methods for their preparation. [Means for solving the problem]

[0005] The heterocyclic compound according to the present invention is a compound represented by Formula I or a pharmaceutically acceptable salt thereof: [ka] Formula (I) (In the formula (I), R is independently selected from the group consisting of (C1-C6) alkyl or substituted (C1-C6) alkyl, (C3-C8) carbocyclyl alkyl, (C2-C8) alkenyl or substituted (C2-C8) alkenyl, (C2-C8) alkynyl or substituted (C2-C8) alkynyl, (C6-C 20 ) aryl or substituted (C6-C 20 ) Aryl, (C2-C 20 ) Heterocyclyl or substituted (C2-C 20 ) heterocyclyl, -OR a , -NR b R c , -SO2(OR d ) is one selected from R a , R b , R c , R d are independently selected from hydrogen, (C1-C5)alkane or substituted (C1-C5)alkane, (C3-C8)carbocyclylalkyl, (C2-C8)alkenyl or substituted (C2-C8)alkenyl, (C2-C8)alkynyl or substituted (C2-C8)alkynyl, (C6-C20)aryl or substituted (C6-C20)aryl, (C2-C20)heterocyclyl or substituted (C2-C20)heterocyclyl.

[0006] Furthermore, in the formula (I), R is independently any one selected from the group consisting of (C1-C6) alkyl, halogen-substituted (C1-C6) alkyl, nitrogen- and / or oxygen-containing heterocycle, nitrogen- and / or oxygen-containing heterocycle substituted with (C1-C5) alkane or substituent-containing (C1-C5) alkane, nitrogen- and / or oxygen-containing heterocycle substituted with hydroxy or amino, nitrogen- and / or oxygen-containing heterocycle substituted with hydroxy or amino substituted with acetyl, nitrogen- and / or oxygen-containing heterocycle substituted with amino substituted with methyl or ethyl, benzene ring, benzene ring substituted with (C1-C5) alkyl or substituent (halogen)-containing (C1-C5) alkyl, hydroxy or amino, benzene ring substituted with hydroxy or amino substituted with acetyl, and benzene ring substituted with amino substituted with methyl or ethyl.

[0007] Preferably, in said formula (I), said R is independently selected from methyl, tert-butyl, trifluoromethyl, phenyl, acetoxyphenyl, pyridyl, pyrrolyl, piperidinyl, morpholinyl, and pyrazinyl.

[0008] Specifically, the compound of formula I is any one of the compounds shown below: [ka]

[0009] Pharmaceutically acceptable salts of the compounds of formula I according to the present invention refer to salts that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response or the like, and commensurate with a reasonable benefit / risk ratio.

[0010] We also found that many of the compounds could not be synthesized smoothly when R was one of several commonly used modifying groups. For example, when R was benzyl, phenethyl, or benzyl or phenethyl substituted with amino and hydroxyl, the compounds could not be synthesized smoothly. The compounds shown in the formula below are: [ka]

[0011] The present invention further provides use of the compound of formula I above or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating ischemic cerebral disease.

[0012] The ischemic brain diseases include stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and the like.

[0013] The present invention further provides a drug or pharmaceutical composition for preventing and / or treating ischemic brain disease, comprising the compound represented by the above formula I or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0014] The drug can be introduced into the body by injection, spray, penetration, absorption, physical or chemical mediation, such as into the muscle, intradermal, subcutaneous, intravenous, mucosal tissue, or can be mixed with or packaged in other substances before being taken into the body.

[0015] Preferably, the ischemic brain disease is a disease associated with the improvement of brain cells.

[0016] Preferably, the ischemic brain disease includes stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and the like.

[0017] Preferably, the dosage form of the drug or pharmaceutical composition is an oral solid formulation or liquid formulation, and preferably, the liquid formulation is an injection solution. The above-mentioned various dosage forms of drugs can all be prepared by conventional methods in the pharmaceutical field. [Effects of the Invention]

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The compound of formula I of the present invention can improve cerebral blood flow and infarct size in ischemic-reperfused animals by oral gavage administration, suggesting that it can be prepared in the form of an oral solid formulation for the treatment of diseases such as stroke, Alzheimer's disease, and ALS. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will be described in more detail below with reference to specific embodiments. The examples shown are only for illustrating the present invention and do not limit the scope of the present invention. The examples provided below can serve as a guide for further improvements by those skilled in the art and do not limit the present invention in any way.

[0021] Unless otherwise specified, all experimental methods in the following examples are conventional and are carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0022] Example 1 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-nicotinate (Test Drug 1) [ka] 1) 2,3,5-trimethylpyrazine-l-oxide [ka] 2,3,5-Trimethylpyrazine (20.0 g, 0.164 mol) was dissolved in acetic acid (100 mL), heated to 80 °C in an oil bath, and sodium perborate tetrahydrate (38.0 g, 0.247 mol) was added batchwise. The mixture was stirred for 20 h while maintaining the temperature. The insoluble matter in the reaction mixture was removed by filtration, concentrated, and purified by column chromatography to give 2,3,5-trimethylpyrazine-1-oxide (18.3 g, 80.9%) as a yellow, transparent liquid. 1 H NMR(DMSO-d6 400 MHz)δ9.24 (s,1 H), 2.45 (s,3 H), 2.34(s,6 H).ESI-MS m / z:139.1[M+H] + . 2) 2-chloro-3,5,6-trimethylpyrazine [ka] Phosphorus oxychloride (90 mL) and a catalytic amount of concentrated sulfuric acid were added to a three-necked round-bottom flask, which was then cooled to 10°C in an ice-water bath. 2,3,5-trimethylpyrazine-1-oxide (18.0 g, 0.130 mol) was added dropwise. After the addition was complete, the mixture was slowly heated to 100°C and stirred for 20 hours while maintaining the temperature. The reaction mixture was distilled under reduced pressure, and the residual liquid was poured into a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane, concentrated, and purified by column chromatography to give 2-chloro-3,5,6-trimethylpyrazine (7.5 g, 37.0%) as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ2.56 (s,3 H), 2.47(s,6 H).ESI-MS m / z:157.6[M+H] + . 3) 2-Hydrazino-3,5,6-trimethylpyrazine [ka] 2-Chloro-3,5,6-trimethylpyrazine (7.0 g, 44.9 mmol) and 80% hydrazine hydrate (100 mL) were mixed and refluxed at 100° C. for 48 hours. The reaction mixture was concentrated and purified by column chromatography to obtain 2-hydrazino-3,5,6-trimethylpyrazine (4.5 g, 65.9%) as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ7.25 (s,1 H), 4.08 (s,2 H), 2.29-2.19(m,9H).ESI-MS m / z:157.6[M+H] + . 4) 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-ol [ka] 2-Hydrazino-3,5,6-trimethylpyrazine (4.0 g, 26.3 mmol), ethyl acetoacetate (6.8 g, 52.6 mmol), and water (20 mL) were mixed and stirred for 24 hours at 100° C. The reaction mixture was concentrated and purified by column chromatography to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-ol (2.2 g, 38.4%) as a yellow oil. 1 H NMR(CDCl3400 MHz)δ3.42 (s,2 H), 2.54-2.21(m,12 H).ESI-MS m / z:219.1[M+H] + . 5) 3-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-nicotinate [ka] 3-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-ol (0.2 g, 0.92 mmol) and triethylamine (0.19 g, 1.84 mmol) were dissolved in dichloromethane (5 mL), and a solution of nicotinoyl chloride hydrochloride (0.2 g, 1.1 mmol) in dichloromethane (2 mL) was added dropwise and reacted at room temperature for 5 h. The reaction mixture was concentrated and purified by column chromatography to give 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-nicotinate (0.15 g, 50.5%) as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ9.13-7.41 (m,4 H), 6.30 (s,1 H), 2.55-2.37(m,12 H).ESI-MS m / z:324.1[M+H] + .

[0023] Example 2 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-acetate (Test Drug 2) [ka] With reference to the synthesis method of Example 1, acetic anhydride as a raw material was subjected to an esterification reaction with Intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-acetate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ6.30 (s,1 H), 2.55-2.37(m,15 H).ESI-MS m / z:261.1[M+H] + .

[0024] Example 3 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-trifluoroacetate [ka] With reference to the synthesis method of Example 1, trifluoroacetate as a raw material was subjected to an esterification reaction with Intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-trifluoroacetate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ6.30 (s,1 H), 2.55-2.37(m,12 H).ESI-MS m / z:315.1[M+H] + .

[0025] Example 4 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-pivalate (Test Drug 5) [ka] With reference to the synthesis method of Example 1, pivaloyl chloride as a raw material was subjected to an esterification reaction with Intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-pivalate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ6.03 (s,1 H), 2.55-2.37(m,12 H), 1.25(s,9 H).ESI-MS m / z:303.1[M+H] + .

[0026] Example 5 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-1H-pyrrole-2-carboxylate [ka] Referring to the synthesis method of Example 1, 1H-pyrrole-2-carboxylic acid as a raw material was subjected to an esterification reaction with Intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-1H-pyrrole-2-carboxylate as a white solid. 1H NMR(DMSO-d6 400 MHz)δ7.56-6.65(m,3 H), 6.03 (s,1 H), 2.55-2.37(m,12 H).ESI-MS m / z:312.1[M+H] + .

[0027] Example 6 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-piperidine-2-carboxylate [ka] Referring to the synthesis method of Example 1, piperidine-2-carboxylic acid as a raw material was subjected to an esterification reaction with intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazole-5-piperidine-2-carboxylate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ6.03 (s,1 H), 3.75(m,1 H), 2.75-2.37(m,14 H), 1.62-1.47(m,6 H).ESI-MS m / z:330.1 [M+H] + .

[0028] Example 7 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-morpholine-2-carboxylate [ka] Referring to the synthesis method of Example 1, morpholine-2-carboxylic acid as a raw material was subjected to an esterification reaction with intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-morpholine-2-carboxylate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ6.33 (s,1 H), 3.75-3.21(m,7 H), 2.75-2.37(m,12 H).ESI-MS m / z:332.1[M+H] + .

[0029] Example 8 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-pyrazine-2-carboxylate [ka] Referring to the synthesis method of Example 1, pyrazine-2-carboxylic acid as a raw material was subjected to an esterification reaction with intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-pyrazine-2-carboxylate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ9.36-8.78(m,3 H), 6.03 (s,1 H), 2.75-2.37(m,12 H).ESI-MS m / z:325.1[M+H] + .

[0030] Example 9 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-2-acetoxybenzoate (Test Agent 3) [ka] Referring to the synthesis method of Example 1, acetylsalicylic acid as a raw material was subjected to an esterification reaction with Intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-2-acetoxybenzoate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ8.18-7.76(m,4 H), 6.03 (s,1 H), 2.75-2.37(m,15 H).ESI-MS m / z:381.1[M+H] + .

[0031] Example 10 Synthesis of 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-benzoate (Test Agent 4) [ka] Referring to the synthesis method of Example 1, benzoic acid as a raw material was subjected to an esterification reaction with Intermediates 1 to 5 to obtain 3-methyl-1-(3,5,6-trimethylpyrazin-2-yl)-1H-pyrazol-5-yl-benzoate as a white solid. 1 H NMR(DMSO-d6 400 MHz)δ8.11-7.66(m,5 H), 6.03 (s,1 H), 2.75-2.37(m,12 H).ESI-MS m / z:323.1[M+H] + .

[0032] Example 11: Efficacy test A rat model of focal cerebral ischemia-reperfusion (tMCAO) was created using the thread embolization method, and the therapeutic effects of test substances on the tMCAO model rats were examined.

[0033] The specific modeling method for the rat focal cerebral ischemia-reperfusion (tMCAO) model was as follows: 12 hours before surgery, each rat was given approximately 30 g of food. Anesthesia was induced with 3-4% isoflurane and maintained with 1.5-2.5% isoflurane. With the patient in a supine position on a 37°C thermostatic operating table, the skin was incised along the midline of the neck, the subcutaneous tissue and muscle were bluntly separated, and the right common carotid, internal carotid, and external carotid arteries were isolated. Two ligatures were threaded through the external carotid artery and ligated at their distal ends. An arterial clamp was placed on each of the common carotid and internal carotid arteries. A small incision was made at a 45° angle approximately 4 mm from the bifurcation of the external carotid artery and the common carotid artery. An appropriate embolic thread was inserted, gently ligated at its proximal end, and the external carotid artery was severed. The direction and angle of the embolic thread were adjusted, and the embolic thread was gently pushed into the internal carotid artery. The arterial clamp was then released and the embolic thread was inserted until the black dot on the thread reached the junction of the internal carotid and common carotid arteries, approximately 18-20 mm into the embolic thread. The proximal end of the external carotid artery was tightly ligated, the embolic thread was fixed, and after confirming that there was no bleeding, the skin was sutured, the body temperature of the rat was maintained, and 1 mg / kg of meloxicam analgesic was subcutaneously injected.

[0034] Two hours after ischemia, anesthesia was induced with 3-4% isoflurane and maintained with 1.5-2.5% isoflurane. The skin sutures were cut, the ligature at the proximal end of the external carotid artery was opened, the embolic thread was removed, reperfusion was performed, and the skin was sutured after confirming the absence of bleeding. The sham-operated control group underwent the same procedure as above, except that the embolic thread was removed immediately after insertion and no reperfusion was required. After surgery, the animals were returned to their cages once they were able to lie face down.

[0035] After modeling, while the animals were awake, they were scored for their behavior according to the ZeaLonga 4-point rating scale. Animals that received a score of 1–3 were considered successful modelers, and animals that did not meet the requirements were excluded.

[0036] Methods: SPF-grade male SD rats were used to create tMCAO rat models using thread embolization. Successful modeling animals were randomly divided into six groups: model control group, test drug 1, test drug 2, test drug 3, test drug 4, and test drug 5, each containing at least six animals. A sham-operated control group of six animals was established in which the embolic thread was inserted and immediately removed during surgery. Each group was first administered the drug or vehicle 4 hours after cerebral ischemia (4 hours after the embolic thread was removed in the sham-operated group). The dose in each group was 2 × 10 -5 The dose was 3 mL / kg, with a 24-hour interval between each administration, for a total of three doses. The sham-operated and model-controlled groups received vehicle injections via a catheter inserted into the right jugular vein, while the other groups received intravenous injections containing the test substance. All doses were administered over 20 minutes. Cerebral blood flow was measured before surgery, before the first administration, and 24 hours after the final administration, and the percentage decrease, recovery, and improvement of cerebral blood flow were calculated. Approximately 24 hours after the final administration, the latency to fall in the rotarod test, behavioral scores, and percentage of cerebral infarct area were measured.

[0037] Results: All test drug groups were significantly superior to the model control group, with groups 1, 3, and 4 being superior to groups 2 and 5. Solvent: DMSO 5mL, Soluol 10mL, and sodium chloride injection (0.9%) 85mL were taken and mixed well to complete the solution. Test drug: The test substance was weighed, dissolved in a solvent and diluted to 20 ml.

[0038] 1.Cerebral blood flow Cerebral blood flow in each group was measured before surgery, before the first dose, and 24 hours after the last dose, the last detection time being after behavioral scoring.

[0039] 2. Percentage of cerebral infarction area After the final cerebral blood flow measurement, animals in each group were anesthetized and killed by decapitation. Brain tissue was quickly removed, isolated, and frozen at -80°C for approximately 5 minutes. The brains were cut into five equal slices and quickly placed in 1-2% triphenyltetrazolium chloride (TTC) phosphate buffer and incubated in the dark at 37°C. When normal tissue turned red and infarcted tissue turned white, photographs were taken and the area of ​​white tissue (infarcted area) and total brain area were analyzed using image analysis software ImageProPlus 6.0. The percentage of infarcted area was calculated according to the formula: percentage of infarcted area (%) = infarcted area / total brain area × 100%.

[0040] [Table 1]

[0041] 3. Behavioral Score As shown in Table 2, the behavioral scores of rats in the model control group were significantly increased (p<0.01) compared with those in the sham-operated control group. The behavioral scores of rats in the test drug group were significantly decreased (p<0.05 or 0.01) compared with those in the model control group.

[0042] [Table 2]

[0043] 4.Cerebral blood flow [Table 3]

[0044] 5. Percentage of cerebral infarction area [Table 4]

[0045] Each test drug group significantly improved the fall latency, behavioral score, percentage of cerebral infarction area, cerebral blood flow, percentage of recovery, and percentage of improvement in the model animals. Test drug groups 1, 3, and 4 were superior to groups 2 and 5.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof. 【Chemical 1】 Formula (I) (In the formula (I), R is independently (C 1 ~C 6 ) alkyl or substituted (C 1 ~C 6 ) alkyl, (C 3 ~C 8 ) carbocyclylalkyl, (C 2 ~C 8 ) alkenyl or substituted (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl or substituted (C 2 ~C 8 ) alkynyl, (C 6 ~C 20 ) aryl or substituted (C 6 ~C 20 ) aryl, (C 2 ~C 20 ) heterocyclyl or substituted (C 2 ~C 20 ) heterocyclyl, —OR a , -NR b R c , -SO 2 (OR d ) any one selected from The R a , R b , R c , R d are independently selected from hydrogen, (C1-C5)alkane or substituted (C1-C5)alkane, (C3-C8)carbocyclylalkyl, (C2-C8)alkenyl or substituted (C2-C8)alkenyl, (C2-C8)alkynyl or substituted (C2-C8)alkynyl, (C6-C20)aryl or substituted (C6-C20)aryl, (C2-C20)heterocyclyl or substituted (C2-C20)heterocyclyl.

2. In the formula (I), R is independently selected from the group consisting of (C 1 ~C 6 ) alkyl, halogen-substituted (C 1 ~C 6 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic ring is any one selected from the group consisting of a (C1-C5) alkyl, a nitrogen- and / or oxygen-containing heterocycle, a nitrogen- and / or oxygen-containing heterocycle substituted with a (C1-C5)alkane or a substituent-containing (C1-C5)alkane, a nitrogen- and / or oxygen-containing heterocycle substituted with a hydroxyl or amino, a nitrogen- and / or oxygen-containing heterocycle substituted with a hydroxyl or amino substituted with an acetyl, a nitrogen- and / or oxygen-containing heterocycle substituted with an amino substituted with a methyl or ethyl, a benzene ring, a benzene ring substituted with a (C1-C5)alkyl or a (C1-C5)alkyl containing a substituent (halogen), a hydroxyl or amino substituted benzene ring, a benzene ring substituted with a hydroxyl or amino substituted with an acetyl, and a benzene ring substituted with an amino substituted with a methyl or ethyl.

3. 3. The compound according to claim 2, wherein, in formula (I), R is independently selected from methyl, tert-butyl, trifluoromethyl, phenyl, acetoxyphenyl, pyridyl, pyrrolyl, piperidinyl, morpholinyl, and pyrazinyl, or a pharmaceutically acceptable salt thereof.

4. 4. The compound according to claim 3, wherein the compound represented by formula I is any of the following compounds or a pharmaceutically acceptable salt thereof: 【Chemistry 2】

5. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating an ischemic brain disease.

6. The use according to claim 5, wherein the ischemic brain disease includes stroke, Alzheimer's disease, and amyotrophic lateral sclerosis.

7. A drug or pharmaceutical composition for preventing and / or treating an ischemic brain disease, comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. The drug or pharmaceutical composition according to claim 7, characterized in that the disease is a disease associated with the improvement of brain cells.

9. The drug or pharmaceutical composition according to claim 7, wherein the ischemic brain disease includes stroke, Alzheimer's disease, and amyotrophic lateral sclerosis.

10. The drug or pharmaceutical composition according to any one of claims 7 to 9, wherein the drug or pharmaceutical composition is in the form of an oral solid or liquid formulation.

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