KR20220026168A - Novel benaodiazepin-3-one derivatives and phamarceutical composition for treating or preventing of diabetic peripheral neuropathy - Google Patents

Abstract

The present invention relates to a novel benzodiazepin-3-one derivative and a pharmaceutical composition for the treatment or prevention of diabetic neuropathy comprising the same. The novel benzodiazepin-3-one derivative compound of the present invention acts on semi-cells and inhibits the neuroaxon degeneration of Schwann cells and the dedifferentiation of Schwann cells to prevent the degeneration of peripheral nerves, thereby being able to be effectively used for preventing or treating diabetic neuropathy diseases. In addition, a method for manufacturing the compound according to the present invention enables eco-friendly production of a 7-membered benzodiazepin-3-one derivative at low cost.

Description

Novel benzodiazepin-3-one derivatives and a pharmaceutical composition for treating or preventing diabetic neuropathy comprising the same

The present invention relates to a benzodiazepin-3-one derivative compound or a pharmaceutically acceptable salt thereof; a method for preparing the compound; And it relates to a pharmaceutical composition for preventing or treating diabetic neuropathy comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Diabetic peripheral neuropathy is one of the complications of neuropathy in diabetic patients. It is a disease that is urgently needed because symptoms appear due to nerve damage and cause great inconvenience to the patient and further severe disability. . However, until now, the root cause treatment and prevention methods for suppressing the onset are not known, and only symptomatic treatment methods exist. There are 420 million people with diabetes worldwide, and most of them have complications such as diabetic neuropathy. Diabetic peripheral neuropathy varies from asymptomatic to severe pain that makes daily life impossible depending on the patient. The main goals of the treatment of diabetic peripheral neuropathy are to prevent nerve degeneration, help regeneration, improve the quality of life, and prevent serious complications, thereby reducing the burden on the patient's own health and family. The current treatment strategies for diabetic peripheral neuropathy are divided into three main categories. ① Treatment to control blood sugar and manage risk factors that are the root cause of diabetic neuropathy. ② Treatment based on etiological studies of the pathogenesis of diabetic neuropathy. ③ Treatment of symptoms related to pain caused by diabetic peripheral neuropathy. Until now, only symptomatic treatment for symptom improvement has been mainly used, and existing etiological treatments caused by peripheral nerve degeneration are insignificant. In addition, prevention of diabetic neuropathy by blood sugar control has its limits, and once degenerated peripheral nerves are damaged, regeneration is impossible due to damage to the nerve cell bodies. Therefore, there is an urgent need to develop a new therapeutic agent to effectively inhibit neurodegeneration during the prevalence of diabetes and to prevent the progression to neuropathy by maintaining nerve function damage.

Korean Patent Registration No. 10-1695207 discloses a composition for preventing or treating anticancer drug-induced peripheral neuropathy containing an extract of Phytolaccae Radix as an active ingredient.

Korean Patent Application No. 10-2018-0012940 (filed on Feb. 01, 2018) discloses a composition for preventing or treating neuropathic pain containing trimethobenzamide.

International Publication No. WO2018047175 (published on March 15, 2018) discloses a composition comprising a triterpenoid and its use for treating optic neuropathy.

The sulfamate functional group is an important component found in natural products of various biological activities and therapeutic agents exhibiting pharmacological activity. Molecules containing sulfamate functional groups exhibit a wide range of biological activities such as antibacterial, antifungal, anticonvulsant, anticancer and cardiovascular activities. For example, estriol sulfamate is a steroid-based enzyme inhibitor under development for the treatment of endometriosis, and nucleocidin, a fluorine-containing nucleoside isolated from Streptomyces calcus, inhibits t-RNA synthetase. showing activity. Topiramate is a broad-spectrum anticonvulsant for epilepsy treatment and migraine prevention, and Pevonedistat is a NEDD8 inhibitor being studied as an anticancer treatment for mantle cell lymphoma.

Accordingly, the present inventors have made intensive research efforts to develop small molecules capable of inhibiting diabetic neuropathy. As a result, a benzodiazepine-3-one derivative compound having a variety of novel substituents was synthesized in high yield by an environmentally friendly method. It was confirmed that neurodegeneration can be effectively suppressed, and the present invention was completed.

An object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

An object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In order to solve the above problems, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

wherein R ₁ is hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy; R ₂ is hydrogen, straight or branched chain C1 to C6 alkyl, aryl or C1 to C6 alkoxy; R ₃ is C1 to C6 alkyl, R ₄ and R ₅ are hydrogen, straight or branched C1 to C6 alkyl.

Preferably, wherein R ₁ can be hydrogen, bromine, chlorine, methyl, or methoxy, R ₂ can be methyl, ethyl, isopropyl or benzyl, substituted phenyl, and R ₃ can be methyl, ethyl, butyl , aryl or benzyl. R ₄ and R ₅ may be branched-chain C1 to C6 alkyl or C7 to C12 alkyl. In this case, R ₁ may be located at any bondable position on the benzene ring.

Preferably, the compound represented by Formula 1 is

1) 4-(benzyloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

2) 4-(benzyloxy)-2,2,7-trimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

3) 4-(benzyloxy)-7-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

4) 4-(benzyloxy)-7-chloro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

5) 4-(benzyloxy)-7-bromo-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

6) 4-(benzyloxy)-8-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

7) 4-(benzyloxy)-2,2-dimethyl-5-[( p -toluoyl)methyl]-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

8) 5-[( p -anisoyl)methyl]-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

9) 4-(benzyloxy)-5-[( p -fluorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

10) 4-(benzyloxy)-5-[( p -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

11) 4-(benzyloxy)-5-[( m -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

12) 4-(benzyloxy)-5-[( o -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

13) 4-(benzyloxy)-5-[( p -bromobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

14) 4-(benzyloxy)-5-[(2-furoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

15) 4-(benzyloxy)-5-[(2-thenoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

16) 5-acetonyl-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

17) 4-methoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

18) 4-ethoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

19) 4-(aryloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

20) 2,2-dimethyl-5-phenacyl-4- tert -butoxy-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

21) 4-(benzyloxy)-5-phenacyl-2,2-dipropyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one,

22) 4-(benzyloxy)-5-phenacyl-4,5-dihydro- 1H -spiro[1,4-benzodiazepin-2,1′-cyclopentan]-3-one;

23) methyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

24) ethyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

25) tert -butyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

26) methyl [4-(benzyloxy)-2,2,7-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

27) methyl [4-(benzyloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

28) methyl [4-(benzyloxy)-7-chloro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate,

29) methyl [4-(benzyloxy)-7-bromo-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

30) methyl [4-(benzyloxy)-8-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

31) methyl (7-fluoro-4-methoxy-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl)acetate;

32) methyl [4-(aryloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

33) methyl [4-(benzyloxy)-2,2-diethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

34) methyl [4-(benzyloxy)-2-methyl-3-oxo-2-propyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate,

35) methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1 H -spiro[1,4-benzodiazepine 2,1′-cyclopentan]-5-yl}acetate, or

36) methyl {4-(benzyloxy)-3-oxo-4,5-dihydro- 1H -spiro[1,4-benzodiazepine 2,1′-cyclobutan]-5-yl}acetate.

Compounds 1 to 36 according to the present invention have the following chemical structures, respectively.

[Compound 1]

[Compound 2]

[Compound 3]

[Compound 4]

[Compound 5]

[Compound 6]

[Compound 7]

[Compound 8]

[Compound 9]

[Compound 10]

[Compound 11]

[Compound 12]

[Compound 13]

[Compound 14]

[Compound 15]

[Compound 16]

[Compound 17]

[Compound 18]

[Compound 19]

[Compound 20]

[Compound 21]

[Compound 22]

[Compound 23]

[Compound 24]

[Compound 25]

[Compound 26]

[Compound 27]

[Compound 28]

[Compound 29]

[Compound 30]

[Compound 31]

[Compound 32]

[Compound 33]

[Compound 34]

[Compound 35]

[Compound 36]

In the above chemical formula, Me is a methyl group, and Bn is a benzyl group.

In another aspect, the present invention provides a method for preparing a compound of Formula 1, comprising reacting a compound represented by Formula 2 with a compound represented by Formula 3 below:

[Formula 1]

In the above formula, R ₁ to R ₅ are as defined for Formula 1, and X is halogen.

In the method for preparing the compound according to the present invention, a base is used as a catalyst, preferably Et ₃ N, DBU, DABCO, K ₂ HPO ₄ , Na ₂ CO ₃ , K ₂ CO ₃ , and Cs ₂ CO ₃ am:

The concentration of the base to be added can be arbitrarily adjusted by those skilled in the art, but preferably at a concentration of 1 to 5 equivalents, more preferably 2 equivalents, based on the amount of the 2-aminophenyl α,β-unsaturated carbonyl derivative compound used as a reactant. may be added at a concentration of When added at a concentration lower than the concentration range, the yield may decrease, and when added at a concentration exceeding the above range, side reactions may be accompanied.

Preferably, the molar ratio of the 2-aminophenyl α,β-unsaturated carbonyl derivative compound represented by Formula 2 to the hydroxamate derivative compound represented by Formula 3 is 1:1.5. When the molar ratio of the reactants is lower than 1:1.5, the reaction does not occur properly and the yield is lowered, and when the molar ratio of the reactants is higher than 1:1.5, there is no significant improvement in the yield.

The reaction is preferably carried out at 0 to 80 ℃ for 4 to 72 hours. It is also preferably carried out using benzene, toluene, xylene, trifluorotoluene, acetonitrile, tetrahydrofuran or a mixture thereof as a solvent. More preferably, toluene or a trifluorotoluene solvent may be used, but is not limited thereto. In the reaction, if the concentration of the reactant is less than 0.05 M, the reaction rate may be slow, and if it is more than 1.0 M, the reactant may not be completely dissolved in the solvent. It is preferred to determine the amount of solvent to remain in the range of to 1.0 M.

When the reaction is carried out at a low temperature of less than 0 ° C, the reaction rate is slowed and the reaction time is prolonged, and when the reaction is carried out at a high temperature of more than 100 ° C, the reaction is quickly terminated or a side reaction occurs, thereby reducing the reaction yield. More preferably, the reaction may vary depending on the type of the carbonyl functional group of the 2-aminophenyl α,β-unsaturated carbonyl derivative, and when carbonyl is a ketone, it is at 20 to 30° C., most preferably at 25° C. In the case of carbonyl as an ester, it may be carried out at 60 to 100 °C, most preferably at 80 °C.

The reaction time may be appropriately selected by those skilled in the art according to the type of reactant. However, if the reaction time is shorter than 4 hours, the reaction may not be completed, and if it is longer than 72 hours, the reaction may result in continuation of the reaction conditions even after the reaction is already completed.

Furthermore, the yield may be further improved by performing the reaction by additionally including hexafluoroisopropanol. The amount of hexafluoroisopropanol to be added can be arbitrarily adjusted by those skilled in the art, but preferably at a concentration of 1 to 3 equivalents based on the amount of the reactant used, the 2-aminophenyl α,β-unsaturated carbonyl derivative compound, more preferably may be added at a concentration of 1.2 equivalents.

As another aspect, the present invention provides a pharmaceutical composition for preventing or treating diabetic neuropathy, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, the compound is 1) 4-(benzyloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

2) 4-(benzyloxy)-2,2,7-trimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

3) 4-(benzyloxy)-7-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

4) 4-(benzyloxy)-7-chloro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

5) 4-(benzyloxy)-7-bromo-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

6) 4-(benzyloxy)-8-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

7) 4-(benzyloxy)-2,2-dimethyl-5-[( p -toluoyl)methyl]-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

8) 5-[( p -Anisoyl)methyl]-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

9) 4-(benzyloxy)-5-[( p -fluorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

10) 4-(benzyloxy)-5-[( p -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

11) 4-(benzyloxy)-5-[( m -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

12) 4-(benzyloxy)-5-[( o -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

13) 4-(benzyloxy)-5-[( p -bromobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

14) 4-(benzyloxy)-5-[(2-furoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

15) 4-(benzyloxy)-5-[(2-thenoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

16) 5-acetonyl-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

17) 4-methoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

18) 4-ethoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

19) 4-(aryloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

20) 2,2-dimethyl-5-phenacyl-4- tert -butoxy-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

21) 4-(benzyloxy)-5-phenacyl-2,2-dipropyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;

22) 4-(benzyloxy)-5-phenacyl-4,5-dihydro-1 H -spiro[1,4-benzodiazepin-2,1′-cyclopentan]-3-one;

23) methyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

24) ethyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

25) tert -butyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

26) methyl [4-(benzyloxy)-2,2,7-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

27) methyl [4-(benzyloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

28) methyl [4-(benzyloxy)-7-chloro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

29) methyl [4-(benzyloxy)-7-bromo-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

30) methyl [4-(benzyloxy)-8-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

31) methyl (7-fluoro-4-methoxy-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl)acetate;

32) methyl [4-(aryloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

33) methyl [4-(benzyloxy)-2,2-diethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

34) methyl [4-(benzyloxy)-2-methyl-3-oxo-2-propyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;

35) methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1 H -spiro[1,4-benzodiazepine 2,1′-cyclopentan]-5-yl}acetate; and

36) from the group consisting of methyl {4-(benzyloxy)-3-oxo-4,5-dihydro- 1H -spiro[1,4-benzodiazepine 2,1′-cyclobutan]-5-yl}acetate It may be any one selected compound.

of the present invention The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof acts on Schwann cells when neurodegeneration begins to inhibit the neuroaxon degeneration of Schwann cells and dedifferentiation of Schwann cells, thereby preventing the degeneration of peripheral nerves and improving nerve conduction function. keep

The term "prevention" of the present invention means any action that inhibits or delays the occurrence, spread, and recurrence of diabetic disease by administration of the composition of the present invention, and "treatment" refers to any action of the disease by administration of the composition of the present invention. It refers to any action that improves or changes to a favorable condition.

Accordingly, the present invention provides a pharmaceutical composition for inhibiting diabetic neuropathy comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention may contain the active ingredient, the compound of Formula 1, in an amount of 0.1 to 75% by weight, preferably 1 to 50% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention may be formulated in various oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its It may contain disintegrating or boiling mixtures and/or absorbents, such as sodium salts, coloring, flavoring, and sweetening agents. In addition, a representative formulation for parenteral administration is an injection formulation, preferably an isotonic aqueous solution or suspension.

The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts and/or buffers for regulating osmotic pressure and other therapeutically useful substances, and may contain conventional mixing, granulating or coating It can be formulated according to the method.

As an active ingredient, the compound of Formula 1 is administered orally or parenterally in an amount of 2.5 to 100 mg/kg body weight per day, preferably 5 to 60 mg/kg body weight, once a day or divided into human and mammalian subjects. It can be administered via route.

The composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field. can The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 100 mg per kg of body weight, preferably 5 to 60 mg, is administered daily or every other day, or 1 It can be administered in divided doses 1 to 3 times a day. However, the dosage is not intended to limit the scope of the present invention in any way since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, and the like.

The novel benzodiazepin-3-one derivative compound of the present invention acts on semi-cells to inhibit the degeneration of Schwann cells and the dedifferentiation of Schwann cells, thereby preventing the degeneration of peripheral nerves and effectively preventing or treating diabetic neuropathy. could be used for In addition, the method for preparing the compound according to the present invention enables eco-friendly production of a 7-membered benzodiazepin-3-one derivative at low cost.

Figure 1shows a change in the horizontal streaks seen in sciatic nerve explants for primary drug screening. Con shows that there are many transverse streaks in the explants. 3DIV is a negative control treated with DMSO solution, and the horizontal stripes disappear after 3 days. NEM isN-Ethyl maleimide (N-ethyl-maleimide) was used as a positive control, and horizontal streaks were maintained even after 3 days. K-04, as compound 16, inhibited the disappearance of horizontal stripes.
Figure 2show the effect on the generation of ovoid structures in the stretched sciatic nerve fibers for secondary drug screening (size bars = 50 μm). Con is a control group, and 3DIV shows the appearance of an ovoid structure after 3 days of treatment with DMSO, a negative control, in vitro. NEM is N-ethylmyleimide as a positive control. K-01 is compound 1, K-04 is compound 16, and K-06 is compound 24.
Fig. 3shows a quantitative drug effect on the formation of ovoid structures for secondary screening (n = 4 mice, ***P <0.0001). K-01 is a compoundOne, K-02 is a compound3, K-03 is a compound6, K-04 is a compound16, K-05 is a compound17, K-06 is a compound24am.
.

Hereinafter, an embodiment of the present invention will be described in more detail. However, the following examples only illustrate the present invention, and the content of the present invention is not limited by the following examples.

Example 1: Synthesis of benzodiazepin-3-one derivative compound

1.1. 4-(Benzyloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)-2,2-dimethyl Synthesis of-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;1a)

( E ) ^-3- (2-aminophenyl)-1-phenylprop-2-en-1-one ( 2a ; 0.10 mmol), N- (benzyloxy)-2-bromo-2-methylpropanamide ( 3a ; Toluene (1 mL) was added to 0.15 mmol) and hexafluoroisopropanol (0.12 mmol), and Cs ₂ CO ₃ (0.20 mmol) was added as a base, followed by stirring at room temperature for 24 hours. The solid in the reaction product was removed by filtration, and the solution was concentrated under reduced pressure and purified by silica gel column chromatography in ethyl acetate/hexane to obtain the target compound as a colorless gum ( 1a ; 84% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 7.3 Hz, 2H), 7.57-7.29 (m, 8H), 7.11 (td, J = 7.6, 1.4 Hz, 1H), 6.98 (d, J = 6.5 Hz, 1H), 6.89 (t, J = 7.1 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.06 (dd, J = 9.9, 3.1 Hz, 1H), 4.96 (q, J = 10.5 Hz, 2H), 4.31 (dd, J = 16.8, 9.9 Hz, 1H), 3.50 (dd, J = 16.8, 3.1 Hz, 1H), 3.11 (s, 1H), 1.69 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.6, 173.2, 144.1, 136.7, 135.4, 133.2, 130.6 (two peaks overlapping), 130.1, 129.3, 128.8, 128.6, 128.5, 128.1, 123.1, 122.9, 76.0, 64.6, 62.9, 41.9, 29.8, 28.1;

IR (neat) 3314, 3031, 2967, 2927, 1681, 1644, 1597, 1490, 1449, 1409, 1356, 1323, 1284, 1230, 1200, 1177, 1111, 1080 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₆ N ₂ O ₃ : 414.1943 Found: 414.1920.

1.2. 4-(Benzyloxy)-2,2,7-trimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)-2,2 Synthesis of ,7-trimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1b))

( E )-3-(2-amino-5-methylphenyl)-1-phenylprop- in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1b (69% yield) was obtained in the same manner as in Example 1, except that 2-en-1-one 2b was used.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 7.5 Hz, 2H), 7.57-7.29 (m, 8H), 6.90 (d, J = 7.3 Hz, 1H), 6.73 (s, 1H) , 6.62 (d, J = 7.7 Hz, 1H), 5.06-4.86 (m, 3H), 4.33 (dd, J = 16.8, 9.7 Hz, 1H), 3.50 (dd, J = 16.7, 2.1 Hz, 1H), 3.07 (s, 1H), 2.21 (s, 3H), 1.67 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.7, 173.2, 141.5, 136.8, 135.4, 133.1, 132.6, 131.1, 130.6, 130.2, 129.7, 128.7, 128.6, 128.5, 128.1, 122.9, 76.0, 64.7, 62.9, 42.1 , 29.8, 28.0, 20.7;

IR (neat) 3316, 2969, 2924, 2870, 1735, 1681, 1639, 1598, 1509, 1449, 1373, 1318, 1244, 1210, 1128, 1045 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₇ H ₂₈ N ₂ O ₃ : 428.2100 Found: 428.2116.

1.3. 4-(Benzyloxy)-7-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)- Synthesis of 7-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1c)))

( E )-3-(2-amino-5-fluorophenyl)-1-phenylprop- in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1c (62% yield) was obtained in the same manner as in Example 1, except that 2-en-1-one 2c was used.

m.p. 155-157 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 7.3 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.42-7.33 (m, 7H), 6.81 (td, J = 8.3, 2.8 Hz, 1H), 6.66 (dt, J = 8.7, 4.2 Hz, 2H), 5.06-4.88 (m, 3H), 4.33 (dd, J = 17.1, 10.0 Hz, 1H), 3.49 (dd, J ) = 17.1, 3.0 Hz, 1H), 3.04 (s, 1H), 1.67 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ )δ 197.4, 173.2, 158.6 (d, J ¹ = 242.3 Hz), 140.0 (d, J ⁴ = 2.6 Hz), 136.6, 135.3, 133.3, 132.5 (d, J ³ = 7.8 Hz), 130.3, 129.0, 128.7 (two peaks overlapping), 128.1, 124.1 (d, J ³ = 8.0 Hz), 117.5 (d, J ² = 23.2 Hz), 115.8 (d, J ² = 22.3 Hz), 76.2, 64.3, 63.0, 41.8, 29.8, 28.0;

IR (neat) 3318, 2965, 2919, 2852, 1672, 1651, 1496, 1448, 1401, 1352, 1319, 1261, 1207, 1150, 1061 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₅ FN ₂ O ₃ : 432.1849 Found: 432.1838.

1.4. 4-(Benzyloxy)-7-chloro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)-7 Synthesis of -chloro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1d)))

( E )-3-(2-amino-5-chlorophenyl)-1-phenylprop- in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1d (75% yield) was obtained in the same manner as in Example 1, except that 2-en-1-one 2d was used.

m.p. 126-128 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.76 (m, 2H), 7.55-7.47 (m, 1H), 7.42-7.31 (m, 7H), 7.07 (dd, J = 8.2, 2.4 Hz, 1H ), 6.84 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 4.93 (ddd, J = 11.4, 9.9, 6.9 Hz, 3H), 4.28 (dd, J = 17.1, 9.9 Hz, 1H), 3.50 (dd, J = 17.1, 3.1 Hz, 1H), 3.07 (s, 1H), 1.68 (s, 3H), 1.24 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.2, 172.9, 142.7, 136.6, 135.2, 133.3, 132.2, 130.5, 130.3, 129.1, 129.1, 128.8, 128.6, 128.1 (two peaks overlapping), 124.1, 76.2, 64.2, 63.0, 41.6, 29.7, 28.2;

IR (neat) 3317, 2980, 2919, 2864, 1672, 1650, 1595, 1489, 1449, 1396, 1355, 1309, 1259, 1195, 1180, 1126, 1057 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₅ ClN ₂ O ₃ : 448.1554 Found: 448.1532.

1.5. 4-(Benzyloxy)-7-bromo-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)- Synthesis of 7-bromo-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1e))

( E )-3-(2-amino-5-bromophenyl)-1-phenylprop- in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1e (82% yield) was obtained in the same manner as in Example 1, except that 2-en-1-one 2e was used.

m.p. 58-61 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.74 (m, 2H), 7.50 (dd, J = 10.5, 4.2 Hz, 1H), 7.41-7.31 (m, 7H), 7.20 (dd, J = 8.2) , 2.3 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 4.92 (ddd, J = 13.3, 11.5, 7.0 Hz, 3H), 4.26 (dd , J = 17.1, 9.8 Hz, 1H), 3.50 (dd, J = 17.1, 3.2 Hz, 1H), 3.14 (d, J = 23.4 Hz, 1H), 1.67 (s, 3H), 1.24 (s, 3H) ;

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.2, 172.8, 143.2, 136.6, 135.2, 133.3 (two peaks overlapping), 132.5, 132.1, 130.3, 129.1, 128.7, 128.6, 128.0, 124.4, 115.6, 76.2, 64.1, 62.9, 41.6, 29.7, 28.3;

IR (neat) 3309, 2967, 2926, 2873, 1681, 1643, 1634, 1597, 1487, 1448, 1393, 1393, 1302, 1283, 1259, 1196, 1176, 1051 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₅ BrN ₂ O ₃ : 492.1049 Found: 492.1032.

1.6. 4-(Benzyloxy)-8-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)- Synthesis of 8-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1f)))

( E )-3-(2-amino-4-fluorophenyl)-1-phenylprop- in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1f (77% yield) was obtained in the same manner as in Example 1, except that 2-en-1-one 2f was used.

m.p. 127-129 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84-7.72 (m, 2H), 7.50 (ddd, J = 6.9, 4.0, 1.3 Hz, 1H), 7.44-7.31 (m, 7H), 6.88 (dd, J ) = 8.4, 6.2 Hz, 1H), 6.57 (td, J = 8.4, 2.5 Hz, 1H), 6.45 (dd, J = 9.2, 2.5 Hz, 1H), 5.01-4.86 (m, 3H), 4.26 (dd, J = 16.9, 10.1 Hz, 1H), 3.47 (dd, J = 16.9, 3.0 Hz, 1H), 1.68 (s, 3H), 1.25 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.6, 173.0, 163.0 (d, J ¹ = 248.1 Hz), 145.8 (d, J ² =9.2 Hz), 136.7, 135.4, 133.3, 132.2 (d, J ² = 9.7 Hz), 130.2, 128.9, 128.7, 128.6, 128.1, 126.4 (d, J ³ = 3.0 Hz), 109.9 (d, J ⁴ = 1.8 Hz), 109.7, 76.1, 64.0, 63.1, 41.7, 29.7, 28.2;

IR (neat) 3309, 3029, 2923, 2850, 1680, 1634, 1610, 1503, 1493, 1450, 1378, 1254, 1275, 1233, 1180, 1110, 1047 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₁₅ FN ₂ O ₃ : 432.1849 Found: 432.1852.

1.7. 4-(benzyloxy)-2,2-dimethyl-5-[( p -Toluoyl)methyl]-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)-2,2-dimethyl-5-[( p -toluoyl)methyl]-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1g))

( E )-3-(2-aminophenyl)-1-p-tolylprop-2- in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material 1g (78% yield) of the target compound was obtained in the same manner as in Example 1, except that 2g of en-1-one was used.

m.p. 117-119 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (d, J = 8.2 Hz, 2H), 7.46-7.31 (m, 5H), 7.16 (d, J = 8.0 Hz, 2H), 7.11 (td, J = 7.6, 1.6 Hz, 1H), 6.98 (dd, J = 7.5, 1.4 Hz, 1H), 6.89 (td, J = 7.5, 1.1 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 5.06 ( dd, J = 9.9, 3.1 Hz, 1H), 4.96 (q, J = 10.4 Hz, 2H), 4.28 (dd, J = 16.8, 9.9 Hz, 1H), 3.49 (dd, J = 16.7, 3.2 Hz, 1H) ), 3.11 (s, 1H), 2.36 (s, 3H), 1.69 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.3, 173.2, 144.1, 144.0, 135.4, 134.4, 130.7, 130.6, 130.1, 129.3, 129.2, 128.8, 128.6, 128.2, 123.1, 122.9, 76.0, 64.7, 62.9, 41.8 , 29.9, 28.1, 21.7;

IR (neat) 3322, 2965, 2922, 2865, 1681, 1667, 1645, 11602, 1493, 1455, 1407, 1325, 1292, 1232, 1199, 1179, 1112, 1059, 1038 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₇ H ₂₈ N ₂ O ₃ : 428.2100 Found: 428.2093.

1.8. 5-[( p -Anisoyl)methyl]-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (5-[( p -Anisoyl)methyl]-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1h))

( E )-3-(2-aminophenyl)-1-(4-methoxyphenyl)prop in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1h (80% yield) was obtained in the same manner as in Example 1, except that -2-en-1-one 2h was used.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.9 Hz, 2H), 7.48-7.30 (m, 5H), 7.10 (td, J = 7.6, 1.4 Hz, 1H), 6.98 (dd, J = 7.5, 1.2 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 6.83 (d, J = 8.9 Hz, 2H), 6.73 (d, J = 7.6 Hz, 1H), 5.05 (dd, J = 9.9, 3.1 Hz, 1H), 4.96 (q, J = 10.4 Hz, 2H), 4.26 (dd, J = 16.5, 9.9 Hz, 1H), 3.82 (s, 3H), 3.46 (dd, J = 16.5) , 3.2 Hz, 1H), 3.19 (s, 1H), 1.69 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 196.2, 173.2, 163.5, 144.1, 135.4, 130.7, 130.6, 130.4, 130.1, 130.0, 129.3, 128.8, 128.6, 123.1, 122.9, 113.7, 76.0, 64.8, 62.9, 55.5 , 41.6, 29.9, 28.1;

IR (neat) 3316, 2965, 2926, 2855, 1644, 1597, 1574, 1510, 1492, 1456, 1417, 1356, 1318, 1257, 1202, 1166, 1112, 1026 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₇ H ₂₈ N ₂ O ₄ : 444.2049 Found: 444.2043.

1.9. 4-(benzyloxy)-5-[( p -Fluorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)-5-[( p -fluorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1i))

( E )-3-(2-aminophenyl)-1-(4-fluorophenyl)prop in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1h (97% yield) was obtained in the same manner as in Example 1, except that -2-en-1-one 2i was used.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86-7.75 (m, 2H), 7.48-.29 (m, 5H), 7.12 (td, J = 7.5, 1.5 Hz, 1H), 7.02 (t, J = 8.6 Hz, 2H), 6.95 (dd, J = 7.5, 1.3 Hz, 1H), 6.89 (td, J = 7.4, 0.9 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.03-4.92 ( m, 3H), 4.27 (dd, J = 16.6, 9.8 Hz, 1H), 3.46 (dd, J = 16.6, 3.1 Hz, 1H), 3.13 (s, 1H), 1.69 (s, 3H), 1.22 (s) , 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 196.1, 173.2, 165.8 (d, J ¹ = 254.9 Hz), 144.1, 135.4, 133.3 (d, J ⁴ = 3.0 Hz), 130.8, 130.7, 130.6, 130.4, 130.1 , 129.4, 128.9, 128.7, 123.0 (d, J ² = 27.6 Hz), 115.6 (d, J ³ = 21.9 Hz), 76.1, 64.8, 62.9, 41.8, 29.8, 28.1;

IR (neat) 1725, 1681, 1642, 1597, 1508, 1457, 1408, 1323, 1285, 1230, 1177, 1112 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₁₈ H ₂₂ N ₂ O ₂ : C ₂₆ H ₂₅ FN ₂ O ₃ : 432.1849 Found: 432.1855.

1.10. 4-(benzyloxy)-5-[( p -Chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4- (Benzyloxy)-5-[( p -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1j))

( E )-3-(2-aminophenyl)-1-(4-chlorophenyl)prop in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1j (84% yield) was obtained in the same manner as in Example 1, except that -2-en-1-one 2j was used.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75-7.66 (m, 2H), 7.46-7.30 (m, 7H), 7.12 (td, J = 7.5, 1.7 Hz, 1H), 6.94 (dd, J = 7.5) , 1.5 Hz, 1H), 6.89 (td, J = 7.4, 0.9 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.00-4.91 (m, 3H), 4.25 (dd, J = 16.6, 9.8 Hz, 1H), 3.45 (dd, J = 16.6, 3.2 Hz, 1H), 3.15 (s, 1H), 1.69 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 196.5, 173.2, 144.1, 139.6, 135.4, 135.1, 130.6, 130.4, 130.1, 129.5, 129.4, 128.9, (two peaks overlapping), 128.7, 123.2, 122.9, 76.1, 64.8 , 63.0, 41.9, 29.9, 28.1;

IR (neat) 3316, 2967, 2926, 2871, 1682, 1642, 1588, 1488, 1456, 1399, 1323, 1286, 1200, 1176, 1112, 1096 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₅ ClN ₂ O ₃ : 448.1554 Found: 448.1526.

1.11. 4-(benzyloxy)-5-[( m -Chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4- (Benzyloxy)-5-[( m -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1k))

( E )-3-(2-aminophenyl)-1-(3-chlorophenyl)prop in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1k (75% yield) was obtained in the same manner as in Example 1, except that -2-en-1-one 2k was used.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (t, J = 1.8 Hz, 1H), 7.68-7.60 (m, 1H), 7.54-7.28 (m, 7H), 7.12 (td, J = 7.6, 1.8) Hz, 1H), 6.99-6.83 (m, 2H), 6.74 (d, J = 7.5 Hz, 1H), 5.04-4.88 (m, 3H), 4.23 (dd, J = 16.6, 9.8 Hz, 1H), 3.45 (dd, J = 16.6, 3.3 Hz, 1H), 3.13 (s, 1H), 1.69 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 196.5, 173.2, 144.1, 138.3, 135.4, 134.9, 133.1, 130.6, 130.3, 130.2, 129.9, 129.5, 128.9, 128.7, 128.3, 126.2, 123.2, 122.9, 76.1, 64.8 , 63.0, 42.0, 29.8, 28.1;

IR (neat) 1682, 1644, 1598, 1571, 1488, 1456, 1415, 1321, 1288, 1199, 1177, 1112 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₅ ClN ₂ O ₃ : 448.1554 Found: 448.1532.

1.12. 4-(benzyloxy)-5-[( o -Chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4- (Benzyloxy)-5-[( o -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1l))

( E )-3-(2-aminophenyl)-1-(2-chlorophenyl)prop in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 11 (77% yield) was obtained in the same manner as in Example 1, except that -2-en-1-one 2l was used.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (dt, J = 6.3, 3.7 Hz, 2H), 7.39-7.28 (m, 5H), 7.21-7.05 (m, 3H), 6.90 (d, J = 4.3) Hz, 2H), 6.72 (d, J = 7.7 Hz, 1H), 5.01-4.95 (m, 3H), 4.25 (dd, J = 16.7, 9.8 Hz, 1H), 3.49 (dd, J = 16.7, 3.7 Hz) , 1H), 3.10 (s, 1H), 1.63 (s, 3H), 1.21 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 200.6, 173.1, 144.3, 138.9, 135.3, 131.8, 131.0, 130.5, 130.4, 130.3, 130.2, 129.4, 129.0, 128.9, 128.7, 126.8, 123.1, 122.8, 76.1, 64.6 , 62.9, 46.0, 29.8, 28.1;

IR (neat) 3316, 2968, 2926, 2872, 1693, 1640, 1591, 1490, 1457, 1433, 1408, 1318, 1229, 1200, 1131, 1111, 1072 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₅ ClN ₂ O ₃ : 448.1554 Found: 448.1564.

1.13. 4-(benzyloxy)-5-[( p -Bromobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)-5-[( p -bromobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1m))

( E )-3-(2-aminophenyl)-1-(4-bromophenyl)prop in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material The target compound 1m (80% yield) was obtained in the same manner as in Example 1, except that -2-en-1-one 2m was used.

m.p. 109-111 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66-7.58 (m, 2H), 7.53-7.46 (m, 2H), 7.38 (ddd, J = 31.3, 5.7, 3.3 Hz, 5H), 7.12 (td, J ) = 7.5, 1.7 Hz, 1H), 6.91 (dtd, J = 8.4, 7.5, 1.2 Hz, 2H), 6.73 (d, J = 7.5 Hz, 1H), 5.04-4.89 (m, 3H), 4.24 (dd, J = 16.6, 9.8 Hz, 1H), 3.45 (dd, J = 16.6, 3.2 Hz, 1H), 3.17 (s, 1H), 1.68 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 196.7, 173.2, 144.1, 135.5, 135.3, 131.8, 130.5, 130.4, 130.1, 129.6, 129.4, 128.9 128.7 128.3, 123.2 122.9, 76.1 64.7, 62.9 41.8, 29.8, 28.1;

IR (neat) 3329, 2922, 2851, 1677, 1495, 1454, 1380, 1359, 1291, 1273, 1260, 1190, 1113, 1030 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₆ H ₂₅ BrN ₂ O ₃ : 492. 1049 Found: 492.1046.

1.14. 4-(Benzyloxy)-5-[(2-furoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy Synthesis of )-5-[(2-furoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1n))

As a starting material ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a instead of ( E )-3-(2-aminophenyl)-1-(furan-2-yl ) The target compound 1n (80% yield) was obtained in the same manner as in Example 1, except that prop-2-en-1-one 2n was used.

m.p. 124-126 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (dd, J = 1.7, 0.7 Hz, 1H), 7.46-7.39 (m, 2H), 7.37-7.31 (m, 3H), 7.11 (ddd, J = 7.7) , 6.9, 2.1 Hz, 1H), 7.02 (dd, J = 3.6, 0.7 Hz, 1H), 6.89 (dt, J = 6.9, 3.2 Hz, 2H), 6.74 (d, J = 7.4 Hz, 1H), 6.41 (dd, J = 3.6, 1.7 Hz, 1H), 5.05-4.90 (m, 3H), 4.03 (dd, J = 16.0, 9.5 Hz, 1H), 3.43 (dd, J = 16.0, 3.9 Hz, 1H), 3.16 (s, 1H), 1.67 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 186.4, 173.1, 152.6, 146.5, 144.2, 135.3, 130.4, 130.3, 130.1, 129.4, 128.8, 128.6, 123.2, 122.9, 117.5, 112.2, 76.0, 64.5, 62.9, 42.0 , 29.8, 28.1;

IR (neat) 3317, 2967, 2927, 2871, 1666, 1660, 1644, 1599, 1567, 1492, 1464, 1409, 1392, 1320, 1295, 1261, 1202, 1176, 1112, 1058 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₂₄ N ₂ O ₄ : 404.1736 Found: 404.1748.

1.15. 4-(Benzyloxy)-5-[(2-thenoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy Synthesis of )-5-[(2-thenoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1o))

( E )-3-(2-aminophenyl)-1-(then-2-yl in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material ) The target compound 1o (78% yield) was obtained in the same manner as in Example 1, except that prop-2-en-1-one 2o was used.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59-7.50 (m, 2H), 7.47-7.40 (m, 2H), 7.39-7.31 (m, 3H), 7.11 (td, J = 7.6, 1.9 Hz, 1H ), 7.01 (dd, J = 4.9, 3.8 Hz, 1H), 6.94-6.84 (m, 2H), 6.73 (d, J = 7.5 Hz, 1H), 5.01-4.92 (m, 3H), 4.18 (dd, J = 16.0, 9.8 Hz, 1H), 3.48 (dd, J = 16.0, 3.6 Hz, 1H), 3.12 (s, 1H), 1.68 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 190.5, 173.2, 144.3, 144.2, 135.3, 133.9, 132.2, 130.5, 130.3, 130.1, 129.4, 128.9, 128.7, 128.1, 123.2, 122.9, 76.1, 64.9, 62.9, 42.5 , 29.8, 28.1;

IR (neat) 3317, 2967, 2926, 2859, 1643, 1598, 1518, 1491, 1456, 1412, 1357, 1318, 1289, 1235, 1201, 176, 1125, 1082 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₂₄ N ₂ O ₃ S: 420.1508 Found: 420.1534.

1.16. 5-Acetonyl-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (5-Acetonyl-4-(benzyloxy)-2 Synthesis of ,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1p))

( E )-4-(2-aminophenyl)but-3-en-2-one in place of ( E )-3-(2-aminophenyl)-1-phenylprop-2-en-1-one 2a as a starting material A target compound 1p (62% yield) was obtained in the same manner as in Example 1, except that 2p was used.

m.p. 58-61 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.32 (m, 5H), 7.16 (ddd, J = 7.7, 6.7, 2.3 Hz, 1H), 6.98-6.89 (m, 2H), 6.76 (d, J ) = 7.4 Hz, 1H), 4.92 (q, J = 10.4 Hz, 2H), 4.84 (dd, J = 9.6, 3.5 Hz, 1H), 3.64 (dd, J = 16.8, 9.6 Hz, 1H), 3.06 (s) , 1H), 3.04 (dd, J = 16.9, 3.4 Hz, 1H), 1.90 (s, 3H), 1.64 (s, 3H), 1.20 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 206.3, 173.0, 144.1, 135.4, 130.7, 130.4, 130.1, 129.4, 128.9, 128.7, 123.2, 122.9, 76.0, 64.0, 62.9, 46.8, 30.6, 29.8, 28.1;

IR (neat) 3316, 2968, 2927, 2873, 1709, 1637, 1598, 1490, 1456, 1409, 1358, 1259, 1202, 1158, 1113, 1022 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₄ N ₂ O ₃ : 352.1787 Found: 352.1783.

1.17. 4-Methoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-Methoxy-2,2-dimethyl-5-phenacyl Synthesis of -1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1q))

As a starting material, the target compound 1q ( 51% yield) was obtained.

m.p. 154-156 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.46-7.34 (m, 3H), 7.15 (td, J = 7.4, 0.9 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.29 (dd, J = 9.7, 3.1 Hz, 1H), 4.39 (dd, J = 16.9, 9.7 Hz, 1H), 3.79 (s, 3H), 3.60 (dd, J = 16.8, 3.2 Hz, 1H), 3.15 (s, 1H), 1.67 (s, 3H), 1.22 (s, 3H) );

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.8, 172.8, 144.2, 136.9, 133.3, 131.0, 130.5, 129.5, 128.6, 128.1, 123.4, 123.1, 63.1, 62.8, 61.5, 42.2, 30.0, 28.0;

IR (neat) 3316, 2963, 2921, 2852, 1669, 1647, 1597, 1494, 1449, 1409, 1357, 1324, 1262, 1197, 1160, 1130, 1058, 1025 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₀ H ₂₂ N ₂ O ₃ : 338.1630 Found: 338.1632.

1.18. 4-Ethoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-Ethoxy-2,2-dimethyl-5-phenacyl Synthesis of -1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;1r))

As a starting material, the target compound 1r ( 64% yield) was obtained.

m.p. 136-138 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.45-7.34 (m, 3H), 7.15 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.26 (dd, J = 9.7, 2.9 Hz, 1H), 4.42 (dd, J = 16.8, 9.8 Hz, 1H), 4.12-3.93 (m, 2H), 3.62 (dd, J = 16.8, 3.0 Hz, 1H), 3.18 (s, 1H), 1.67 (s, 3H), 1.28 (t, J ) = 7.0 Hz, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.8, 173.0, 144.3, 136.8, 133.3, 130.9, 130.6, 129.4, 128.6, 128.1, 123.3, 123.1, 69.4, 63.9, 62.8, 42.1, 29.9, 28.2, 13.7;

IR (neat) 3319, 2957, 2921, 2851, 1650, 1596, 1578, 1494, 1449, 1415, 1377, 1358, 1309, 1289, 1230, 1160, 1112, 1058 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₄ N ₂ O ₃ : 352.1787 Found: 352.1768.

1.19. 4-(Aryloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Allyloxy)-2,2-dimethyl Synthesis of -5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1s))

The target compound in the same manner as in Example 1, except that N -(allyloxy)-2-bromo-2-methylpropanamide 3d was used instead of N- (benzyloxy)-2-bromo-2-methylpropanamide 3a as a starting material. 1s (71% yield) was obtained.

m.p. 117-119 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 9 7.84 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.43-7.35 (m, 3H), 7.15 (td, J ) = 7.6, 1.3 Hz, 1H), 7.05-6.94 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.11-5.99 (m, 1H), 5.36-5.20 (m, 3H), 4.56- 4.34 (m, 3H), 3.62 (dd, J = 16.9, 3.1 Hz, 1H), 3.21 (s, 1H), 1.67 (s, 3H), 1.21 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.8, 173.2, 144.3, 136.8, 133.3, 132.3, 130.7, 130.7, 129.4, 128.6, 128.1, 123.3, 123.0, 120.9, 75.2, 64.3, 62.9, 42.0, 29.8, 28.2 ;

IR (neat) 3312, 2968, 2926, 2865, 1736, 1689, 1639, 1597, 1491, 1449, 1374, 1357, 1324, 1232, 1200, 1179, 1111, 1039 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₂ H ₂₄ N ₂ O ₃ : 364.1787 Found: 364.1780.

1.20. 2,2-dimethyl-5-phenacyl-4- tert -Butoxy-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (2,2-Dimethyl-5-phenacyl-4- tert -butoxy-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; Synthesis of 1t))

The target compound in the same manner as in Example 1, except that N-tert -butoxy-2-bromo-2-methylpropanamide 3e was used instead of N- (benzyloxy)-2-bromo-2-methylpropanamide 3a as a starting material. 1t (69% yield) was obtained.

m.p. 143-146 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.45-7.31 (m, 3H), 7.16 (dd, J = 11.0, 4.1 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.19 (dd, J = 10.2, 2.4 Hz, 1H), 4.45 (dd, J = 16.7, 10.4 Hz, 1H), 3.60 (dd, J = 16.8, 2.5 Hz, 1H), 3.24 (s, 1H), 1.67 (s, 3H), 1.31 (s, 9H), 1.25 (s, 3H) );

¹³ C NMR (100 MHz, CDCl ₃ ) δ 198.1, 177.3, 144.5, 136.8, 133.2, 131.3 (two peaks overlapping), 129.3, 128.6, 128.1, 122.9, 122.4, 83.1, 77.5, 77.2, 76.8, 66.6, 62.8, 40.7, 29.2 (two peaks overlapping), 27.3;

IR (neat) 3341, 2967, 2923, 2853, 1672, 1596, 1579, 1493, 1450, 1379, 1264, 1320, 1305, 1226, 1179, 1112, 1101, 1058 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₃ H ₂₈ N ₂ O ₃ : 380.2100 Found: 380.2108.

1.21. 4-(Benzyloxy)-5-phenacyl-2,2-dipropyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (4-(Benzyloxy)-5-phenacyl- Synthesis of 2,2-dipropyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one; 1u))

In the same manner as in Example 1, except that N -(benzyloxy)-2-bromo-2-propylpentanamide 3f was used instead of N -(benzyloxy)-2-bromo-2-methylpropanamide 3a as a starting material, the target compound 1u (79% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80-7.73 (m, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.45-7.31 (m, 7H), 7.09 (td, J = 7.6, 1.5) Hz, 1H), 6.93 (dd, J = 7.5, 1.3 Hz, 1H), 6.84 (dd, J = 10.8, 4.1 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 5.05 (dd, J ) = 10.0, 3.0 Hz, 1H), 4.97 (q, J = 10.5 Hz, 2H), 4.34 (dd, J = 16.6, 10.0 Hz, 1H), 3.50 (dd, J = 16.6, 3.0 Hz, 1H), 3.25 (s, 1H), 2.33-2.23 (m, 1H), 1.89-1.75 (m, 1H), 1.63-1.40 (m, 4H), 1.32-1.19 (m, 2H), 1.03 (t, J = 7.1 Hz) , 3H), 0.76 (t, J = 7.2 Hz, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.5, 172.4, 144.2, 136.7, 135.2, 133.1, 130.5, 130.0 (two peaks overlapping), 129.2, 128.7, 128.6, 128.5, 127.9, 122.5, 122.3, 76.2, 69.2, 64.5, 42.4, 42.3, 42.2, 18.1, 16.4, 14.7, 14.3;

IR (neat) 3314, 2958, 2927, 2871, 1682, 1633, 1597, 1488, 1448, 1410, 1352, 1326, 1281, 1260, 1218, 1202, 1158, 1080, 1036 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₃₀ H ₃₄ N ₂ O ₃ : 470.2569 Found: 470.2549.

1.22. 4-(Benzyloxy)-5-phenacyl-4,5-dihydro-1 H -spiro[1,4-benzodiazepine-2,1′-cyclopentan]-3-one (4-(Benzyloxy)-5-phenacyl-4,5-dihydro-1 H -spiro[1,4-benzodiazepine-2,1'-cyclopentan]-3-one; Synthesis of 1v))

As a starting material, the target compound 1v ( 38 % yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.45-7.32 (m, 7H), 7.11 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 6.7 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.06 (dd, J = 9.8, 3.1 Hz, 1H), 4.95 (dt, J = 19.6, 9.8 Hz, 2H), 4.28 (dd, J = 16.8, 9.8 Hz, 1H), 3.56 (dd, J = 16.8, 3.1 Hz, 1H), 3.20 ( s, 1H), 2.92-2.82 (m, 1H), 2.04-1.93 (m, 1H), 1.91-1.77 (m, 3H), 1.75-1.49 (m, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 197.6, 173.2, 144.0, 136.7, 135.3, 133.1, 130.7, 130.5, 130.0, 129.2, 128.7, 128.5, (two peaks overlapping), 128.0, 122.9, 122.5, 75.9, 73.2 , 64.5, 42.0, 39.6, 37.6, 24.1, 24.0;

IR (neat) 3327, 2955, 2924, 2872, 1681, 1634, 1597, 1485, 1449, 1408, 1328, 1260, 1180, 1118, 1017 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₈ H ₂₈ N ₂ O ₃ : 440.2100 Found: 440.2081.

1.23. Methyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (Methyl [4-(benzyloxy)- Synthesis of 2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1w)))

( E )-methyl 3-(2-aminophenyl)acrylate ( 2q ; 0.10 mmol), N- (benzyloxy)-2-bromo-2-methylpropanamide ( 3a ; 0.15 mmol) and hexafluoroisopropanol (0.12 mmol) at 0 ^o C After trifluorotoluene (1 mL) was added, Cs ₂ CO ₃ (0.20 mmol) was added as a base, followed by stirring at room temperature for 1 hour. Then, the reactant was stirred at 80 ^o C for 24 hours, the solid in the reactant was removed by filtration, the solution was concentrated under reduced pressure, and purified by silica gel column chromatography in ethyl acetate/hexane to obtain the target compound as a white solid ( 1w ; 71% yield).

m.p. 115-117 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.33 (m, 5H), 7.17 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.95 (q, J = 10.4 Hz, 2H), 4.77 (dd, J = 9.7, 4.4 Hz, 1H), 3.47 (d, J = 11.5 Hz, 3H), 3.43 (dd, J = 15.3, 9.8 Hz, 1H), 3.10 (s, 1H), 3.07 (dd, J = 15.3, 4.3 Hz, 1H), 1.63 (s, 3H), 1.20 ( s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.9, 171.3, 144.3, 135.3, 130.1 (two peaks overlapped), 130.0, 129.6, 128.9, 128.7, 123.1, 123.0, 76.1, 65.3, 62.9, 51.7, 37.7, 29.8, 28.1;

IR (neat) 1733, 1641, 1599, 1492, 1456, 1436, 1413, 1376, 1357, 1288, 1229, 1200, 1157, 1111, 1082 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₄ N ₂ O ₄ : 368.1736 Found: 368.1722.

1.24. Ethyl [4- (benzyloxy) -2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl] acetate (Ethyl [4- (benzyloxy) - Synthesis of 2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1x)))

The target compound in the same manner as in Example 23, except that ( E )-ethyl 3-(2-aminophenyl)acrylate 2r was used instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material 1x (71% yield) was obtained.

m.p. 115-117 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.33 (m, 5H), 7.17 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.95 (q, J = 10.4 Hz, 2H), 4.77 (dd, J = 9.7, 4.4 Hz, 1H), 3.47 (d, J = 11.5 Hz, 3H), 3.43 (dd, J = 15.3, 9.8 Hz, 1H), 3.10 (s, 1H), 3.07 (dd, J = 15.3, 4.3 Hz, 1H), 1.63 (s, 3H), 1.20 ( s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.9, 171.3, 144.3, 135.3, 130.1 (two peaks overlapped), 130.0, 129.6, 128.9, 128.7, 123.1, 123.0, 76.1, 65.3, 62.9, 51.7, 37.7, 29.8, 28.1;

IR (neat) 1733, 1641, 1599, 1492, 1456, 1436, 1413, 1376, 1357, 1288, 1229, 1200, 1157, 1111, 1082 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₄ N ₂ O ₄ : 368.1736 Found: 368.1722.

1.25. tert -Butyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate ( tert -Butyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; Synthesis of 1y))

In the same manner as in Example 23, except that ( E ) -tert -butyl 3-(2-aminophenyl)acrylate 2s was used instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material The target compound 1y (69% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.30 (m, 5H), 7.16 (dd, J = 7.4, 6.7 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 4.95 (q, J = 10.5 Hz, 2H), 4.70 (dd, J = 10.1, 4.4 Hz, 1H), 3.35 (dd, J = 14.5, 10.2 Hz, 1H), 3.08 (s, 1H), 2.97 (dd, J = 14.5, 4.4 Hz, 1H), 1.63 (s, 3H), 1.25 (s, 9H), 1.20 (s, 3H) );

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.8, 169.9, 144.5, 135.5, 130.1 (three peaks overlapped), 129.4, 128.8, 128.6, 122.9, 122.8, 80.7, 76.1, 65.6, 62.9, 39.2, 29.8, 28.1, 28.0;

IR (neat) 3318, 2951, 2927, 2872, 1733, 1641, 1599, 1492, 1456, 1436, 1376, 1357, 1320, 1288, 1229, 1200, 1157, 1111, 1048 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₄ H ₃₀ N ₂ O ₄ : 410.2206 Found: 410.2212.

1.26. Methyl [4- (benzyloxy) -2,2,7-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl] acetate (Methyl [4- (benzyloxy Synthesis of )-2,2,7-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1z))

The same as in Example 23, except that ( E )-methyl 3-(2-amino-5-methylphenyl)acrylate 2t was used instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material By the method, the target compound 1z (61% yield) was obtained.

m.p. 154-156 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.32 (m, 5H), 6.97 (dd, J = 7.8, 1.3 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.94 (q, J = 10.4 Hz, 2H), 4.71 (dd, J = 9.5, 4.6 Hz, 1H), 3.51 (s, 3H), 3.42 (dd, J = 15.3, 9.5) Hz, 1H), 3.08 (dd, J = 15.3, 4.6 Hz, 1H), 2.94 (s, 1H), 2.23 (s, 3H), 1.61 (s, 3H), 1.20 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.9, 171.3, 141.5, 135.3, 132.5, 130.4, 130.0 (two peaks overlapped), 129.9, 128.7, 128.5, 122.9, 75.9, 65.3, 62.8, 51.6, 37.8, 29.7, 27.9, 20.6;

IR (neat) 3305, 2954, 2923, 2852, 1734, 1626, 1509, 1495, 1456, 1437, 1403, 1353, 1321, 1289, 1254, 1200, 1159, 1130, 1040 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₂ H ₂₆ N ₂ O ₄ : 382.1893 Found: 382.1880.

1.27. Methyl [4-(benzyloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (Methyl [4 Synthesis of -(benzyloxy)-7-fluoro-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1za))

The same as in Example 23, except that ( E )-methyl 3-(2-amino-5-fluorophenyl)acrylate 2u was used instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material By the method, the target compound 1za (72% yield) was obtained.

m.p. 164-166 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.31 (m, 5H), 6.87 (td, J = 8.4, 2.9 Hz, 1H), 6.71 (dd, J = 8.5, 4.8 Hz, 1H), 6.49 ( dd, J = 8.6, 2.9 Hz, 1H), 5.03-4.85 (m, 2H), 4.65 (dd, J = 9.9, 4.4 Hz, 1H), 3.53 (s, 3H), 3.46 (dd, J = 15.6, 9.9 Hz, 1H), 3.05 (dd, J = 15.6, 4.4 Hz, 1H), 2.99 (s, 1H), 1.61 (s, 3H), 1.21 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.8, 171.018, 158.4 (d, J ¹ = 242.4 Hz), 140.1 (d, J ⁴ = 2.6 Hz), 135.1, 131.8 (d, J ³ = 7.7 Hz), 130.1, 128.9, 128.6, 124.1 (d, J ³ = 8.0 Hz), 116.6 (d, J ² = 23.3 Hz), 115.9 (d, J ² = 22.2 Hz), 76.1, 64.9, 64.8, 62.8, 51.7, 37.3 , 29.5, 27.8;

IR (neat) 3309, 2955, 2922, 2851, 1730, 1627, 1506, 1495, 1454, 1438, 1419, 1373, 1354, 1319, 1288, 1247, 1204, 1165, 1150, 1112, 1084 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₃ FN ₂ O ₄ : 386.1642 Found: 386.1633.

1.28. Methyl [4- (benzyloxy) -7-chloro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl] acetate (Methyl [Methyl [ Synthesis of 4-(benzyloxy)-7-chloro-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1zb))

The same as in Example 23, except that ( E )-methyl 3-(2-amino-5-chlorophenyl)acrylate 2v was used instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material By the method, the target compound 1zb (65% yield) was obtained.

m.p. 181-183 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.31 (m, 5H), 7.13 (dd, J = 8.3, 2.4 Hz, 1H), 6.69 (t, J = 5.7 Hz, 2H), 4.93 (q, J = 10.7 Hz, 2H), 4.62 (dd, J = 9.8, 4.5 Hz, 1H), 3.53 (s, 3H), 3.40 (dd, J = 15.5, 9.8 Hz, 1H), 3.05 (dd, J = 15.5) , 4.4 Hz, 2H), 1.62 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.5, 170.925, 142.755, 135.1, 131.5, 130.2, 129.7, 129.3, 129.0, 128.6, 127.9, 124.1, 76.1, 64.8, 62.9, 51.7, 37.2, 29.5, 28.1;

IR (neat) 3303, 2953, 2925, 2854, 1731, 1627, 1491, 1454, 1416, 1398, 1354, 1319, 1288, 1324, 1197, 1168, 1125, 1092, 1064 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₃ ClN ₂ O ₄ : 402.1346 Found: 402.1364.

1.29. Methyl [4-(benzyloxy)-7-bromo-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (Methyl [Methyl Synthesis of [4-(benzyloxy)-7-bromo-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1zc))

The same as in Example 23, except that ( E )-methyl 3-(2-amino-5-bromophenyl)acrylate 2w was used instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material By this method, the target compound 1zc (60% yield) was obtained.

m.p. 167-169 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.34 (m, 5H), 7.31-7.24 (m, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 5.01-4.84 (m, 2H), 4.60 (dd, J = 9.7, 4.5 Hz, 1H), 3.53 (s, 3H), 3.38 (dd, J = 15.5, 9.7 Hz, 1H), 3.14-2.96 (m, 2H), 1.62 (s, 3H), 1.22 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.4, 170.9, 143.2, 135.1, 132.6, 132.2, 131.9, 130.2, 129.0, 128.7, 124.4, 115.4, 76.1, 64.7, 62.9, 51.7, 37.2, 29.5, 28.2;

IR (neat) 3301, 2954, 2925, 2852, 1730, 1626, 1586, 1488, 1451, 1415, 1397, 1374, 1318, 1257, 1222, 1266 1138, 1083, 1061 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₃ BrN ₂ O ₄ : 446.0841 Found: 446.0863.

1.30. Methyl [4-(benzyloxy)-8-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (Methyl [4 Synthesis of -(benzyloxy)-8-fluoro-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1zd))

The same as in Example 23, except that ( E )-methyl 3-(2-amino-4-fluorophenyl)acrylate 2x was used instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material By the method, the target compound 1zd (51% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.32 (m, 5H), 6.74 (dd, J = 8.3, 6.2 Hz, 1H), 6.59 (td, J = 8.4, 2.5 Hz, 1H), 6.50 ( dd, J = 9.2, 2.4 Hz, 1H), 4.94 (q, J = 10.6 Hz, 2H), 4.69 (dd, J = 10.0, 4.3 Hz, 1H), 3.50 (s, 3H), 3.39 (dd, J = 15.4, 10.0 Hz, 1H), 3.13 (s, 1H), 3.02 (dd, J = 15.4, 4.3 Hz, 1H), 1.62 (s, 3H), 1.23 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.5, 171.1, 163.0 (d, J = 248.3 Hz), 146.0 (d, J = 9.2 Hz), 135.2, 131.4 (d, J = 9.7 Hz), 130.0, 128.8 , 128.6, 125.8 (d, J = 3.0 Hz), 109.9 (d, J = 22.3 Hz), 109.6 (d, J = 21.4 Hz), 76.1, 64.5, 63.0, 51.6, 37.4, 29.5, 28.1;

IR (neat) 3315, 2922, 2852, 1737, 1630, 1518, 1484, 1428, 1408, 1374, 1327, 1293, 1253, 1220, 1164, 1133, 1105, 1058 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₁ H ₂₃ FN ₂ O ₄ : 386.1642 Found: 386.1646.

1.31. Methyl (7-fluoro-4-methoxy-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl) acetate (Methyl [Methyl (7 Synthesis of -fluoro-4-methoxy-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl)acetate; 1ze))

Using ( E )-methyl 3-(2-amino-5-fluorophenyl)acrylate 2u instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material and N- (benzyloxy) as a starting material A target compound 1ze (56% yield) was obtained in the same manner as in Example 23, except for 2-bromo- N -methoxy-2-methylpropanamide 3b instead of -2-bromo-2-methylpropanamide 3a .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (dd, J = 8.5, 2.9 Hz, 1H), 6.93 (td, J = 8.4, 2.9 Hz, 1H), 6.77 (dd, J = 8.5, 4.8 Hz, 1H), 4.94 (dd, J = 9.7, 4.4 Hz, 1H), 3.77 (s, 3H), 3.59 (s, 3H), 3.54 (dd, J = 15.5, 9.8 Hz, 1H), 3.16 (dd, J ) = 15.5, 4.4 Hz, 1H), 3.03 (s, 1H), 1.60 (s, 3H), 1.21 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.5, 171.0, 158.6 (d, J ¹ = 242.8 Hz), 140.2 (d, J ⁴ = 2.7 Hz), 132.3 (d, J ³ = 7.5 Hz), 124.5 ( d, J ³ = 8.0 Hz), 116.5 (d, J ² = 23.2 Hz), 116.1 (d, J ² = 22.2 Hz), 63.3, 62.8, 61.6, 51.8, 37.7, 29.7, 27.6;

IR (neat) 3309, 2951, 2925, 2854, 1731, 1627, 1507, 1496, 1438, 1403, 1354, 1320, 1248, 1205, 1166, 1113, 1087, 1048 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₁₅ H ₁₉ FN ₂ O ₄ : 310.1329 Found: 310.1306.

1.32. Methyl [4-(aryloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (Methyl [4 Synthesis of -(allyloxy)-7-fluoro-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1zf))

Using ( E )-methyl 3-(2-amino-5-fluorophenyl)acrylate 2u instead of ( E )-methyl 3-(2-aminophenyl)acrylate 2q as a starting material and N- (benzyloxy) as a starting material A target compound 1zf (66% yield) was obtained in the same manner as in Example 23, except for N -(allyloxy)-2-bromo-2-methylpropanamide 3d instead of -2-bromo-2-methylpropanamide 3a .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.00 (dd, J = 8.5, 2.9 Hz, 1H), 6.92 (td, J = 8.4, 2.9 Hz, 1H), 6.76 (dd, J = 8.5, 4.8 Hz, 1H), 6.04 (ddt, J = 17.0, 10.2, 6.6 Hz, 1H), 5.38-5.24 (m, 2H), 4.91 (dd, J = 9.9, 4.3 Hz, 1H), 4.53-4.33 (m, 2H) , 3.64-3.49 (m, 4H), 3.17 (dd, J = 15.6, 4.3 Hz, 1H), 3.01 (s, 1H), 1.59 (s, 3H), 1.19 (s, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.8, 171.0, 158.6 (d, J ¹ = 242.6 Hz), 140.3 (d, J ⁴ = 2.7 Hz), 132.1, 132.0 (d, J ³ = 7.6 Hz), 124.3 (d, J ³ = 8.0 Hz), 121.0, 116.7 (d, J ² = 23.2 Hz), 116.0 (d, J ² = 22.2 Hz), 75.2, 64.5, 62.8, 51.7, 37.4, 29.5, 27.8;

IR (neat) 3318, 2970, 2954, 2920, 2870, 1733, 1641, 1502, 1453, 1437, 1406, 1376, 1357, 1306, 1292, 1245, 1207, 1150, 1106, 1044 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₁₇ H ₂₁ FN ₂ O ₄ : 336.1485 Found: 336.1495.

1.33. Methyl [4- (benzyloxy) -2,2-diethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl] acetate (Methyl [4- (benzyloxy) Synthesis of -2,2-diethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1zg)))

In the same manner as in Example 23, except for 3g of N-(benzyloxy)-2-bromo-2-ethylbutanamide instead of N- ( benzyloxy)-2-bromo-2-methylpropanamide 3a as a starting material, 1zg of the target compound (64 % yield) was obtained.

m.p. 136-138 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.32 (m, 5H), 7.15 (td, J = 7.6, 1.5 Hz, 1H), 6.86 (td, J = 7.4, 1.1 Hz, 1H), 6.82 6.74 (m, 2H), 4.96 (q, J = 10.6 Hz, 2H), 4.75 (dd, J = 9.7, 4.4 Hz, 1H), 3.38 (dd, J = 15.2, 9.8 Hz, 1H), 3.21 (s) , 1H), 3.09 (dd, J = 15.2, 4.4 Hz, 1H), 2.27 (dq, J = 14.6, 7.4 Hz, 1H), 1.65 (dd, J = 14.1, 7.5 Hz, 1H), 1.58-1.41 ( m, 2H), 1.11 (t, J = 7.3 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H);

¹³ C NMR (100 MHz, CDCl ₃ )δ 172.0, 171.2, 144.4, 135.3, 130.0, 129.9, 129.6, 129.4, 128.7, 128.6, 122.5, 122.3, 76.3, 69.4, 65.2, 51.6, 38.2, 32.3, 32.2, 9.0 , 7.6;

IR (neat) 3317, 2954, 2914, 2855, 1734, 1621, 1597, 1486, 1455, 1439, 1373, 1349, 1303, 1273, 1260, 1219, 1166, 1114, 1104, 1037 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₃ H ₂₈ N ₂ O ₄ : 396.2049 Found: 396.2044.

1.34. Methyl [4-(benzyloxy)-2-methyl-3-oxo-2-propyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (Methyl [Methyl [4- Synthesis of (benzyloxy)-2-methyl-3-oxo-2-propyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate; 1zh))

The target compound 1zh ( 32 % yield) was obtained.

m.p. 117-119 °C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.42 (m, 2H), 7.40 - 7.32 (m, 3H), 7.17 (td, J = 7.5, 1.7 Hz, 1H), 6.88 (dtd, J = 9.1) , 7.5, 1.3 Hz, 2H), 6.76 (d, J = 7.0 Hz, 1H), 4.93 (dd, J = 33.5, 10.5 Hz, 2H), 4.78 (dd, J = 9.7, 4.5 Hz, 1H), 3.48 (s, 3H), 3.36 (dd, J = 15.2, 9.8 Hz, 1H), 3.30 (s, 1H), 3.08 (dd, J = 15.2, 4.5 Hz, 1H), 1.54 (s, 3H), 1.40- 1.21 (m, 4H), 0.77 (t, J = 7.1 Hz, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.2, 171.2, 144.0, 135.3, 129.9, 129.8, 129.7, 129.4, 128.7, 128.5, 122.6, 122.4, 76.16, 65.4, 65.0, 51.6, 41.6, 37.4, 26.1, 16.5 , 14.2;

IR (neat) 3324, 3065, 2958, 2930, 2874, 1734, 1650, 1626, 1487, 1454, 1436, 1405, 1358, 1327, 1281, 1257, 1192, 1162, 1114, 1025 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₃ H ₂₈ N ₂ O ₄ : 396.2049 Found: 396.2036.

1.35. methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1 H -spiro[1,4-benzodiazepine 2,1′-cyclopentan]-5-yl}acetate (Methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1 H -spiro[1,4-benzodiazepine-2,1'-cyclopentan]-5-yl}acetate; Synthesis of 1zi))

As a starting material, the target compound 1zi (40% yield) was prepared in the same manner as in Example 23, except for N-(benzyloxy)-1-bromocyclopentanecarboxamide 3f instead of N- (benzyloxy)-2-bromo-2-methylpropanamide 3a as a starting material. got it

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.40 (m, 2H), 7.39-7.31 (m, 3H), 7.17 (td, J = 7.6, 1.5 Hz, 1H), 6.91 (t, J = 7.4) Hz, 1H), 6.88-6.81 (m, 1H), 6.73 (d, J = 7.7 Hz, 1H), 4.95 (dd, J = 24.7, 10.5 Hz, 2H), 4.77 (dd, J = 9.8, 4.4 Hz) , 1H), 3.48 (s, 3H), 3.41 (dd, J = 15.2, 9.8 Hz, 1H), 3.15 (s, 1H), 3.09 (dd, J = 15.2, 4.4 Hz, 1H), 2.78 (ddd, J = 17.4, 10.9, 6.8 Hz, 1H), 1.95 (dd, J = 13.2, 4.5 Hz, 1H), 1.87-1.73 (m, 3H), 1.64 (dt, J = 12.8, 7.0 Hz, 3H); ^One

³ C NMR (100 MHz, CDCl ₃ ) δ 172.9, 171.3, 144.1, 135.3, 130.01(two peaks overlapped), 129.98, 129.4, 128.7, 128.5, 122.8, 122.6, 76.0, 73.3, 65.1, 51.6, 39.6, 37.8, 37.5, 24.1, 23.9;

IR (neat) 3328, 3031, 2951, 2874, 1735, 1635, 1598, 1485, 1454, 1436, 1411, 1352, 1327, 1284, 1251, 1229, 1198, 1158, 1188, 1028, 1015 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₃ H ₂₆ N ₂ O ₄ : 394.1893 Found: 394.1909.

1.36. Methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1 H -spiro[1,4-benzodiazepine 2,1′-cyclobutan]-5-yl}acetate (Methyl {4-( Synthesis of benzyloxy)-3-oxo-4,5-dihydro- 1H -spiro[1,4-benzodiazepine-2,1'-cyclobutan]-5-yl}acetate; 1zj)))

As a starting material, the target compound 1zi (28% yield) was prepared in the same manner as in Example 23, except for N -(benzyloxy)-1-bromocyclobutanecarboxamide 3i instead of N -(benzyloxy)-2-bromo-2-methylpropanamide 3a as a starting material. got it

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (dd, J = 6.6, 3.0 Hz, 2H), 7.40-7.31 (m, 3H), 7.14 (td, J = 7.7, 1.6 Hz, 1H), 6.94- 6.86 (m, 1H), 6.82 (td, J = 7.5, 1.0 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.01 (t, J = 7.1 Hz, 1H), 4.91 (dd, J ) = 45.4, 10.1 Hz, 2H), 3.74 (s, 1H), 3.58 (s, 3H), 3.32-3.10 (m, 3H), 2.39-2.29 (m, 1H), 2.18 (dd, J = 17.5, 12.7) Hz, 1H), 2.03-1.90 (m, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.2, 170.9, 144.4, 135.2, 129.8, 129.3, 128.7, 128.5, 128.2, 126.8, 121.2, 120.6, 64.1, 61.2, 51.8, 36.0, 35.0, 34.0, 29.7, 13.8 ;

IR (neat) 3339, 3031, 2950, 2876, 1736, 1656, 1606, 1482, 1454, 1437, 1355, 1322, 1287, 1258, 1195, 1166, 1117, 1081 cm ^-1 ;

HRMS (EI) m/z calcd for [M] ⁺ C ₂₂ H ₂₄ N ₂ O ₄ : 380.1736 Found: 380.1717.

Example 2: Analysis of diabetic neuropathy inhibitory activity using sciatic nerve ex vivo culture

Sciatic nerve explant culture

The sciatic nerve is one of the largest peripheral nerves in the nervous system. In peripheral neurodegenerative diseases such as diabetic neuropathy, the most common complication of diabetes, peripheral nerves degenerate and appear with multiple morphological phenotypes such as annihilation of transverse stripes and ovarian segmentation. A sciatic nerve explant culture system was used to establish an in vitro peripheral neurodegenerative environment. Five-week-old adult male wild-type C57BL/6 mice were purchased from Samtako. After asphyxiation with carbon dioxide, the sciatic nerve was removed from the male mouse and cut into three parts with a length of about 3 to 4 mm. The explants were cultured in free-floating condition in Dulbecco's Modified Eagle's Medium (DMEM) at 37° C. under an atmosphere containing 5% CO ₂ . The medium was supplemented with 10% fetal bovine serum and 100 units/ml of penicillin and streptomycin. The explant cultures were maintained for 3 days. Controls were freshly extracted sciatic nerves, not nerve segments cultured in DMEM medium. The obtained ischial explants were washed with phosphate buffered saline (PBS) and fixed in 4% paraformaldehyde (PFA) for 8 h.

Teased nerve technique

A portion of the fixed nerve segment was mounted on a gelatin-coated slide, and using fine forceps, it was torn a short distance from the slide to straighten it. Single nerve fibers were placed side by side in close proximity (about 0.2 mm apart). Pulled fibers mounted on slides were stored at -80 °C until use.

Preparation of compound solutions

A dimethyl sulfoxide (DMSO) solution of the compound (1 mM) was prepared and passed through a 0.22 μm sterile polyvinylidene fluoride (PVDF) filter. Mouse sciatic nerve explants (3DIV) were cultured in vitro for 3 days. DMSO solvent itself (maximum concentration: 30 µL/mL culture medium) did not affect the degeneration of the extracted sciatic nerve. Cultures treated with solvent alone were represented by 3DIV.

Quantitative drug effect calculating myelin ovoid number

The oocyte number (oocyte index) of the sciatic nerve fibers is expressed as the number of ovoid structures counted from sciatic nerve fibers teasing 200 μm in length under a Zeiss Axioimager vertical microscope using differential interference contrast (DIC). In quantitative data, all data are presented as ± SEM.

result

Based on the notion that the transverse streaks of the sciatic nerve disappear during peripheral nerve degeneration, bisindorylmethane Sulfamate compounds (1, 19 and 20) (1 mM solutions) were screened. The results are shown in FIGS. 1 to 3 .

They significantly inhibited the disappearance of transverse streaks within 3 days of in vitro (3DIV) during ex vivo peripheral neurodegeneration ( Fig. 1 ). DMSO is a negative control and N -ethyl maleimide (NEM) is a positive control. 1 shows statistical significance similar to that of the positive control. Segmentation into ovoid structures is one of the phenotypic forms of peripheral neurodegenerative processes. To specify the inhibitory effect following primary screening of these benzodiazepin-3-one compounds on neurodegeneration, we used a morphological approach under differential interference contrast (DIC) as a secondary drug to count ovoid structures in sciatic nerve fibers. Screening was performed. DIC microscopy analysis specifically showed that compound 16 effectively inhibited the appearance of ovoid-like fragments in 3DIV (after 3 days) ( FIG. 2 ). To quantify the inhibitory effect of the benzodiazepin-3-one compound, a morphological analysis of oocyte formation was performed, showing that it statistically reduced the number of oocytes at 3DIV (after 3 days) in elongated sciatic nerve fibers ( Fig. 3 ). Therefore, the results of the present invention indicate that benzodiazepin-3-one compounds, especially compound 16, have bioactivity to prevent peripheral neurodegeneration.

Claims (18)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

In the above formula,
R ₁ is hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy;
R ₂ is hydrogen, straight or branched chain C1 to C6 alkyl, aryl or C1 to C6 alkoxy;
R ₃ is C1 to C6 alkyl;
R ₄ and R ₅ are each independently hydrogen, straight-chain or branched C1 to C6 alkyl, or R ₄ and R ₅ are C3 to C7 cyclic alkyl. According to claim 1,
R ₁ is hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy; or a pharmaceutically acceptable salt thereof. According to claim 1,
R ₂ is hydrogen, straight-chain or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy; or a pharmaceutically acceptable salt thereof. According to claim 1,
R ₃ is C1 to C6 alkyl, or a pharmaceutically acceptable salt thereof. According to claim 1,
R ₄ and R ₅ are each independently hydrogen, straight-chain or branched C1 to C6 alkyl, or a pharmaceutically acceptable salt thereof. According to claim 1,
R ₄ and R ₅ are C3 to C7 cyclic alkyl, or a pharmaceutically acceptable salt thereof. According to claim 1,
The compound is
1) 4-(benzyloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
2) 4-(benzyloxy)-2,2,7-trimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
3) 4-(benzyloxy)-7-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
4) 4-(benzyloxy)-7-chloro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
5) 4-(benzyloxy)-7-bromo-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
6) 4-(benzyloxy)-8-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
7) 4-(benzyloxy)-2,2-dimethyl-5-[( p -toluoyl)methyl]-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
8) 5-[( p -Anisoyl)methyl]-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
9) 4-(benzyloxy)-5-[( p -fluorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
10) 4-(benzyloxy)-5-[( p -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
11) 4-(benzyloxy)-5-[( m -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
12) 4-(benzyloxy)-5-[( o -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
13) 4-(benzyloxy)-5-[( p -bromobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
14) 4-(benzyloxy)-5-[(2-furoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
15) 4-(benzyloxy)-5-[(2-thenoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
16) 5-acetonyl-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
17) 4-methoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
18) 4-ethoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
19) 4-(aryloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
20) 2,2-dimethyl-5-phenacyl-4- tert -butoxy-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
21) 4-(benzyloxy)-5-phenacyl-2,2-dipropyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
22) 4-(benzyloxy)-5-phenacyl-4,5-dihydro-1 H -spiro[1,4-benzodiazepin-2,1′-cyclopentan]-3-one;
23) methyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
24) ethyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
25) tert -butyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
26) methyl [4-(benzyloxy)-2,2,7-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
27) methyl [4-(benzyloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
28) methyl [4-(benzyloxy)-7-chloro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
29) methyl [4-(benzyloxy)-7-bromo-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
30) methyl [4-(benzyloxy)-8-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
31) methyl (7-fluoro-4-methoxy-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl)acetate;
32) methyl [4-(aryloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
33) methyl [4-(benzyloxy)-2,2-diethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
34) methyl [4-(benzyloxy)-2-methyl-3-oxo-2-propyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
35) methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1 H -spiro[1,4-benzodiazepine 2,1′-cyclopentan]-5-yl}acetate; and
36) from the group consisting of methyl {4-(benzyloxy)-3-oxo-4,5-dihydro- 1H -spiro[1,4-benzodiazepine 2,1′-cyclobutan]-5-yl}acetate Any one selected compound or a pharmaceutically acceptable salt thereof. A method for preparing a compound represented by Formula 1, comprising reacting a compound represented by Formula 2 with a compound represented by Formula 3 below:
[Formula 1]

[Formula 2]

[Formula 3]

wherein R ₁ is hydrogen, halogen or straight or branched C1 to C6 alkyl, aryl or C1 to C6 alkoxy;
R ₂ is hydrogen, straight or branched chain C1 to C6 alkyl, aryl or C1 to C6 alkoxy;
R ₃ is C1 to C6 alkyl;
R ₄ and R ₅ are each independently hydrogen, straight-chain or branched C1 to C6 alkyl, or R ₄ and R ₅ are C3 to C7 cyclic alkyl. The method of claim 8, wherein the reaction uses any one catalyst selected from the group consisting of Et ₃ N, DBU, DABCO, K ₂ HPO ₄ , Na ₂ CO ₃ , K ₂ CO ₃ , and Cs ₂ CO ₃ A method for producing a compound represented by the formula (1), characterized in that. The method according to claim 8, wherein the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 is 1:1.5. [Claim 9] The method of claim 8, wherein the amount of the compound represented by the formula (2) and the chokmaeng is in a concentration of 1 to 5 equivalents. According to claim 8, wherein the reaction is represented by Formula 1, characterized in that it is carried out in a solvent selected from the group consisting of benzene, toluene, xylene, trifluorotoluene, acetonitrile, tetrahydrofuran, and mixtures thereof. A method for producing a compound to be The method according to claim 8, wherein the reaction is performed by further comprising hexafluoroisopropanol. The method according to claim 8, wherein the amount of the compound represented by Formula 2 and hexafluoroisopropanol is in an amount of 1 to 3 equivalents. A pharmaceutical composition for preventing or treating diabetic neuropathy, comprising the compound according to claim 1. 16. The compound of claim 15, wherein the compound is 1) 4-(benzyloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
2) 4-(benzyloxy)-2,2,7-trimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
3) 4-(benzyloxy)-7-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
4) 4-(benzyloxy)-7-chloro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
5) 4-(benzyloxy)-7-bromo-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
6) 4-(benzyloxy)-8-fluoro-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
7) 4-(benzyloxy)-2,2-dimethyl-5-[( p -toluoyl)methyl]-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
8) 5-[( p -Anisoyl)methyl]-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
9) 4-(benzyloxy)-5-[( p -fluorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
10) 4-(benzyloxy)-5-[( p -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
11) 4-(benzyloxy)-5-[( m -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
12) 4-(benzyloxy)-5-[( o -chlorobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
13) 4-(benzyloxy)-5-[( p -bromobenzoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
14) 4-(benzyloxy)-5-[(2-furoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
15) 4-(benzyloxy)-5-[(2-thenoyl)methyl]-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
16) 5-acetonyl-4-(benzyloxy)-2,2-dimethyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
17) 4-methoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
18) 4-ethoxy-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
19) 4-(aryloxy)-2,2-dimethyl-5-phenacyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
20) 2,2-dimethyl-5-phenacyl-4- tert -butoxy-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
21) 4-(benzyloxy)-5-phenacyl-2,2-dipropyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one;
22) 4-(benzyloxy)-5-phenacyl-4,5-dihydro-1 H -spiro[1,4-benzodiazepin-2,1′-cyclopentan]-3-one;
23) methyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
24) ethyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
25) tert -butyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
26) methyl [4-(benzyloxy)-2,2,7-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
27) methyl [4-(benzyloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
28) methyl [4-(benzyloxy)-7-chloro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
29) methyl [4-(benzyloxy)-7-bromo-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
30) methyl [4-(benzyloxy)-8-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
31) methyl (7-fluoro-4-methoxy-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl)acetate;
32) methyl [4-(aryloxy)-7-fluoro-2,2-trimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
33) methyl [4-(benzyloxy)-2,2-diethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
34) methyl [4-(benzyloxy)-2-methyl-3-oxo-2-propyl-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate;
35) methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1 H -spiro[1,4-benzodiazepine 2,1′-cyclopentan]-5-yl}acetate; and
36) from the group consisting of methyl {4-(benzyloxy)-3-oxo-4,5-dihydro- 1H -spiro[1,4-benzodiazepine 2,1′-cyclobutan]-5-yl}acetate A pharmaceutical composition for preventing or treating diabetic neuropathy, characterized in that it is any one selected compound. The pharmaceutical composition for preventing or treating diabetic neuropathy according to any one of claims 15 to 16, wherein the composition further comprises a pharmaceutically acceptable carrier. [Claim 17] The pharmaceutical composition for preventing or treating diabetic neuropathy according to any one of claims 15 and 16, wherein the compound acts on Schwann cells to inhibit neuronal axon degeneration or dedifferentiation of Schwann cells.

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