KR20210118297A - p38 degrader compounds, method for preparing the same, and composition for treating chronic inflammatory diseases including the same - Google Patents

Abstract

The present invention relates to a novel compound having p38 removal capability, a manufacturing method thereof, and a composition for treating chronic inflammatory disease, comprising the same. The compound represented by chemical formula A, according to the present invention, has an effect of having notably excellent p38 MAPK removal capability, and thus can be useful as a therapeutic agent for chronic inflammatory disease.

Description

A compound having p38 removal ability, a method for preparing the same, and a composition for treating chronic inflammatory diseases comprising the same {p38 degrader compounds, method for preparing the same, and composition for treating chronic inflammatory diseases including the same}

The present invention relates to a novel compound having p38 scavenging ability, a method for preparing the same, and a composition for treating chronic inflammatory diseases comprising the same.

Inflammation is known to be caused by various causes, but according to recent studies, mitogen-activated protein kinases (MAPKs) can be activated by various stress stimuli. It plays a crucial role in the production of pro-inflammatory cytokines such as -6, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, and multiple sclerosis. sclerosis), psoriasis, neuropathic pain, Alzheimer's disease, etc. are known to cause ( NATURE REVIEWS, Drug discovery (2003), Vol.2, 717-726).

Chronic inflammation is a condition in which persistent inflammation occurs, which means that the immune system continuously responds inappropriately to a specific exposure. Chronic inflammation may be caused by a single or multiple genetic factors or environmental factors such as food or fumes. Sometimes inflammation occurs and then subsides, but as it continues, sometimes the treatment becomes ineffective. Chronic inflammatory disease causes significant damage to body tissues, and various problems occur depending on the location. For example, when chronic inflammation occurs in the liver or digestive system, it causes changes in the brain, causing fatigue, personality changes, organ dysfunction, and spreading inflammation throughout the body.

Psoriasis, a representative chronic inflammatory disease, is a chronic recurrent skin disease of unknown cause, characterized by rapid proliferation of keratinocytes and accompanying skin inflammation. Lesions such as erythema, scale, papule or pustule It can appear anywhere on this skin surface. Clinically, it can be classified into plaque psoriasis, drip psoriasis, pustular psoriasis, inverse psoriasis, and erythrodermic psoriasis. Psoriasis is caused by a combination of genetic and environmental factors. The cause is still unknown, but hormonal changes, psychological aspects such as stress, trauma, infections such as tonsillitis, immunity, endocrine, inflammation, metabolism There are various causes of the disease, such as ability, climate, dry skin, drugs, and heredity. In addition, IL23, IL-17, IL-6 secreted by T immune cells differentiated by autoimmune abnormalities or hypersensitivity of the immune system due to chronic inflammatory diseases. When cytokines such as TNF-α are excessively expressed, it causes an inflammatory response in the skin, promotes hyperproliferation and division of keratinocytes, and inhibits differentiation. It occurs because the cells of the stratum corneum of the skin proliferate 6 to 7 times faster than normal cells due to these factors, and these excessive and incompletely proliferated keratinocytes are piled up in layers of white scales and fall off. Psoriasis is often referred to as a comorbidity because it is accompanied by other diseases. Psoriatic arthritis, cardiovascular disease, depression, and Crohn's disease are frequently found in psoriasis patients. Psoriatic arthritis is a chronic inflammatory disease accompanied by pain, and up to 30% of psoriasis patients show arthritis symptoms, and among them, psoriasis precedes arthritis in 85% of cases. The cause of the antecedent relationship is not yet clear. Severe psoriasis is also associated with increased mortality and metabolic syndrome such as obesity, hypertension, hyperlipidemia, and type 2 diabetes, and an increased risk of cardiovascular disease, possibly due to the effects of chronic inflammatory responses on the endocrine system. . In addition, there is a report that psoriasis skin is not aesthetically pleasing, and when it occurs on conspicuous areas such as hands or face, it causes atrophy in interpersonal relationships, and the rate of people suffering from depression or anxiety is 40% higher than that of the general public.

In addition, chronic inflammation is attracting attention as a cause of various diseases. In fact, more than 30% of patients suffering from arteriosclerosis maintain normal cholesterol levels, but due to excessive activation of the inflammatory reaction, various inflammatory cells, including white blood cells, attach to unhealthy intravascular cell walls and proliferate abnormally, thereby preventing thrombosis and arteriosclerosis. known to cause In addition, chronic inflammation is involved in the prevalence of a wide range of diseases, such as Alzheimer's disease due to brain cell damage to immune cells due to chronic inflammation, and congestive heart failure due to cardiomyocyte damage.

With the great success of monoclonal antibodies that directly neutralize TNF-α or IL-1β for the treatment of chronic inflammation, several small molecule drugs (small molecule) as inhibitors of p38 MAPK over the past few decades have been molecules) have been developed.

However, to date, the therapeutic effect is low in preclinical and clinical test results, and it has not been commercialized as a therapeutic agent due to safety issues related to hepatotoxicity and neurological side effects. This safety issue is due in part to a lack of kinase selectivity, which leads to inaccurate therapeutic effects.

Therefore, there is a need for the development of a therapeutic agent for chronic inflammation that selectively inhibits P38 MAPK and has excellent safety and efficacy.

Accordingly, the present inventors have completed the present invention by confirming that the efficacy of the compound represented by Formula A is very excellent while researching a compound that exhibits selective inhibition of P38 MAPK and has excellent safety and efficacy.

NATURE REVIEWS, Drug discovery (2003), Vol.2, 717-726

An object of the present invention is to provide a novel compound represented by the formula (A).

Another object of the present invention is to provide a method for preparing a compound represented by the above formula (A).

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating chronic inflammatory diseases comprising the compound represented by Formula A.

Another object of the present invention is to provide a health functional food composition for preventing or improving chronic inflammatory disease comprising the compound represented by Formula A.

Another object of the present invention is to provide a health food composition for preventing or improving chronic inflammatory diseases comprising the compound represented by Formula A.

In order to achieve the above object,

The present invention provides a compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof.

[Formula A]

(In the formula A,

이고;The p38 Ligand Moiety is

ego;

이고;The E3 Ligand Moiety is

ego;

,

,

,

,

또는

이고,The Linker is

,

,

,

,

or

ego,

Wherein n and m are independently integers from 1 to 10,

wherein a and b are independently integers from 1 to 10).

In addition, the present invention, as shown in Scheme 1 below,

synthesizing compound 14A by reacting compound 8A with compound 13 in an organic solvent (step 1);

synthesizing compound 19A by reacting compound 14A with 4-nitrophenylchloroformate in an organic solvent (step 2); and

It provides a method for preparing compound A1, comprising the step of reacting compound 19A and compound 5 in an organic solvent to synthesize compound A1 (step 3).

[Scheme 1]

(In Scheme 1,

L ¹ is —(CH ₂ ) _n —OH or —(CH ₂ CH ₂ —O) _n —CH ₂ CH ₂ OH, wherein n is an integer from 1 to 10;

L ² is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).

Furthermore, the present invention, as shown in Scheme 2 below,

synthesizing compound 14A by reacting compound 8A with compound 13 in an organic solvent (step 1);

synthesizing compound 27A by reacting compound 14A with p-TsCl (p-Toluenesulfonyl chloride) in an organic solvent (step 2); and

It provides a method for preparing compound A2, comprising: synthesizing compound A2 by reacting compound 27A with compound 6 in an organic solvent (step 3).

[Scheme 2]

(In Scheme 2,

L ¹ is —(CH ₂ ) _n —OH or —(CH ₂ CH ₂ —O) _n —CH ₂ CH ₂ OH, wherein n is an integer from 1 to 10;

L ² is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).

In addition, the present invention, as shown in Scheme 3 below,

synthesizing compound 37A by reacting compound 14 with compound 36A in an organic solvent (step 1);

synthesizing compound 38A by reacting compound 37A with hydrochloric acid in an organic solvent (step 2); and

It provides a method for preparing compound A3, including a step of reacting compound 38A and compound 40 in an organic solvent to synthesize compound A3 (step 3).

[Scheme 3]

(In Scheme 3,

L ³ is -(CH ₂ ) _n -OMs or -(CH ₂ CH ₂ -O) _n -CH ₂ CH ₂ OMs, wherein n is an integer from 1 to 10;

L ⁴ is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating chronic inflammatory diseases, comprising the compound represented by Formula A or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a health functional food composition for preventing or improving chronic inflammatory diseases comprising the compound represented by Formula A or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides a health food composition for preventing or improving chronic inflammatory diseases comprising the compound represented by Formula A or a pharmaceutically acceptable salt thereof.

The compound represented by Formula A according to the present invention has a remarkably excellent effect of removing p38 MAPK, and may be useful as a therapeutic agent for chronic inflammatory diseases.

1 is a view showing the chemical structural formulas of the compounds of Examples 1 to 9 and Comparative Examples 1 to 3 according to the present invention.
2 is a result of confirming the p38 MAPK removal ability of 7 types of compounds according to an embodiment of the present invention by immunoblotting method.
3 is a result confirming the removal ability of p38 (Flag) and P-p38 according to the treatment concentration of Compound 24 according to Example 2 of the present invention by immunoblotting method.
Figure 4 shows [p38 Ligand Moiety in Comparative Example 1 (Compound 43) and Example 2 (Compound 24) in which biotin was conjugated instead of [E3 Ligand Moiety (thalidomide derivative)] in Example 2 (Compound 24) of the present invention. ] is the result of evaluating the p38 MAPK binding ability of Comparative Example 2 (Compound 45) in which Biotin was bound to the Linker, respectively.
5 is a result confirming that the Example compound according to the present invention removes p38 MAPK using the intracellular proteasome system by immunoblotting method.
6 is a result of confirming that the Example compound according to the present invention removes p38 MAPK using cereblon (CRBN), one of the E3 ligase complex proteins in cells, by immunoblotting method.
7 is a result confirming that the Example compound according to the present invention removes p38 MAPK using the ubiquitination system by SDS-PAGE and immunoblotting methods.
8 is a result confirming that the compound of Example according to the present invention induces a concentration-dependent decrease in p38 MAPK and P-p38 MAPK in neurons by an immunoblotting method.
Figure 8(A): Astrocytes
Figure 8(B): Neuroblasts
Figure 8(C): Microglia
Figure 8(D): Hippocampal Neuronal cells
Figure 8 (E): After repeated experiments three or more times in microglia (Microglia), the relative values are shown numerically.
9 is a result of confirming by the ELISA method that the amount of p38 MAPK-related cytokine production due to treatment with the compound of Example of the present invention is reduced.
10 is a result confirming that the Example compound of the present invention reduces the mRNA expression level of p38 MAPK-related cytokines by qRT-PCR method.

Hereinafter, the present invention will be described in detail.

A compound represented by the formula (A)

The present invention provides a compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof.

[Formula A]

(In the formula A,

이고;The p38 Ligand Moiety is

ego;

이고;The E3 Ligand Moiety is

ego;

,

,

,

,

또는

이고,The Linker is

,

,

,

,

or

ego,

Wherein n and m are independently integers from 1 to 10,

wherein a and b are independently integers from 1 to 10).

Preferably,

Wherein n is an integer from 1 to 5,

Wherein m is an integer of 3 to 7,

wherein a is an integer from 1 to 5,

The b may be an integer of 1 to 7.

More preferably,

Wherein n is an integer of 1 to 3,

wherein m is 5,

wherein a is an integer of 1 to 2,

b may be 2 or 5.

Particularly preferably,

The compound represented by Formula A may be one selected from the following compound group.

1) 2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethyl (2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (23);

2) 2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethyl (2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (24);

3) 2-(2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy) ethoxy)ethyl(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (25);

4) 5-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)pentyl(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (26);

5) N-cyclopropyl-4'-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy) ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (31);

6) N-cyclopropyl-4'-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) )oxy)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (32);

7) N-cyclopropyl-4'-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-) 4-yl)oxy)ethoxy)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (33);

8) N-Cyclopropyl-4'-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy )pentyl)oxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (34); and

9) (S)-N-cyclopropyl-4'-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-diox) Soisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (41).

In the compound represented by Formula A according to the present invention,

The [p38 Ligand Moiety] serves to selectively target and bind p38 MAPK,

The [E3 Ligand Moiety] serves to selectively target and bind E3 (Ubiquitin Ligase).

The principle of p38 MAPK removal of the compound represented by Formula A according to the present invention is as follows. The order of steps 1 and 2 below may be reversed.

(Step 1) [p38 Ligand Moiety] binds to p38 MAPK

(Step 2) E3 binding to [E3 Ligand Moiety]

(Step 3) The bound E3 removes p38 MAPK

pharmaceutically acceptable salts

The active substance of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The expression pharmaceutically acceptable salt is a concentration having an effective action that is relatively non-toxic and harmless to a patient, and any organic or means inorganic addition salts. For these salts, inorganic acids and organic acids can be used as free acids, and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, and fumarin can be used as organic acids. Acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid Phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid may be used. Further, these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salt (calcium salt, magnesium salt, etc.) and the like. For example, acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hebenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malate ate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate Late, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, zinc salt, etc. may be included, and among these, hydrochloride or trifluoroacetate is preferable.

The acid addition salt according to the present invention is prepared by a conventional method, for example, by dissolving an active substance in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid to filter and dry the resulting precipitate. or by distilling the solvent and excess acid under reduced pressure and then drying or crystallizing in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

Furthermore, the present invention includes all possible solvates, hydrates, isomers, optical isomers and the like that can be prepared therefrom, as well as active substances and pharmaceutically acceptable salts thereof.

Manufacturing method 1

The present invention, as shown in Scheme 1 below,

synthesizing compound 14A by reacting compound 8A with compound 13 in an organic solvent (step 1);

synthesizing compound 19A by reacting compound 14A with 4-nitrophenylchloroformate in an organic solvent (step 2); and

It provides a method for preparing compound A1, comprising the step of reacting compound 19A and compound 5 in an organic solvent to synthesize compound A1 (step 3).

[Scheme 1]

(In Scheme 1,

L ¹ is —(CH ₂ ) _n —OH or —(CH ₂ CH ₂ —O) _n —CH ₂ CH ₂ OH, wherein n is an integer from 1 to 10;

L ² is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).

The organic solvent of steps 1 to 3 is independently DMF (dimethylformamide), DCM (dichloromethane), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, diisopropyl ether, diethyl ether, Dioxane, acetonitrile, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetone, chlorobenzene, etc. may be used alone or in combination.

Manufacturing method 2

The present invention is as shown in Scheme 2 below,

synthesizing compound 14A by reacting compound 8A with compound 13 in an organic solvent (step 1);

synthesizing compound 27A by reacting compound 14A with p-TsCl (p-Toluenesulfonyl chloride) in an organic solvent (step 2); and

It provides a method for preparing compound A2, comprising the step of reacting compound 27A and compound 6 in an organic solvent to synthesize compound A2 (step 3).

[Scheme 2]

(In Scheme 2,

L ¹ is —(CH ₂ ) _n —OH or —(CH ₂ CH ₂ —O) _n —CH ₂ CH ₂ OH, wherein n is an integer from 1 to 10;

L ² is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).

The organic solvent of steps 1 to 3 is independently DMF (dimethylformamide), DCM (dichloromethane), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, diisopropyl ether, diethyl ether, Dioxane, acetonitrile, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetone, chlorobenzene, etc. may be used alone or in combination.

Manufacturing method 3

The present invention, as shown in Scheme 3 below,

synthesizing compound 37A by reacting compound 14 with compound 36A in an organic solvent (step 1);

synthesizing compound 38A by reacting compound 37A with hydrochloric acid in an organic solvent (step 2); and

It provides a method for preparing compound A3, comprising the step of reacting compound 38A and compound 40 in an organic solvent to synthesize compound A3 (step 3).

[Scheme 3]

(In Scheme 3,

L ³ is -(CH ₂ ) _n -OMs or -(CH ₂ CH ₂ -O) _n -CH ₂ CH ₂ OMs, wherein n is an integer from 1 to 10;

L ⁴ is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).

The organic solvent of steps 1 to 3 is independently DMF (dimethylformamide), DCM (dichloromethane), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, diisopropyl ether, diethyl ether, Dioxane, acetonitrile, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetone, chlorobenzene, etc. may be used alone or in combination.

Pharmaceutical composition for preventing or treating chronic inflammatory disease

The present invention provides a pharmaceutical composition for the prevention or treatment of chronic inflammatory diseases comprising the compound represented by Formula A or a pharmaceutically acceptable salt thereof.

The chronic inflammatory disease is Alzheimer's, Parkinson's disease, inflammatory bowel disease, non-alcoholic chronic hepatitis, chronic hepatitis, Crohn's disease, pancreatitis, esophagitis, gastritis, colitis, ulcerative colitis, pneumonia, bronchitis, sore throat, myocardial infarction, heart failure, arthritis , psoriatic arthritis, rheumatoid arthritis, renal failure, psoriasis, anemia, diabetes, fibrosis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, periodontitis, neuropathic pain, idiopathic inflammatory myopathy, and the like.

The active substance of the present invention can be administered in various oral and parenteral dosage forms during clinical administration, and when formulating, commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. are used. is manufactured by

Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, etc., and such solid preparations include at least one or more excipients, for example, starch, calcium carbonate, It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.

In addition, the effective dosage of the active substance of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health status and disease degree, and is generally about 0.001-100 mg/kg/day, Preferably it is 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg/day, preferably 0.7-2500 mg/day, and once a day at regular time intervals according to the judgment of a doctor or pharmacist It may be administered in several divided doses.

Health functional food/health food composition for preventing or improving chronic inflammatory disease

The present invention provides a health functional food composition for preventing or improving chronic inflammatory diseases comprising the compound represented by Formula A or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a health food composition for preventing or improving chronic inflammatory diseases comprising the compound represented by Formula A or a pharmaceutically acceptable salt thereof.

The chronic inflammatory disease is Alzheimer's, Parkinson's disease, inflammatory bowel disease, non-alcoholic chronic hepatitis, chronic hepatitis, Crohn's disease, pancreatitis, esophagitis, gastritis, colitis, ulcerative colitis, pneumonia, bronchitis, sore throat, myocardial infarction, heart failure, arthritis , psoriatic arthritis, rheumatoid arthritis, renal failure, psoriasis, anemia, diabetes, fibrosis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, periodontitis, neuropathic pain, idiopathic inflammatory myopathy, and the like.

There are no special restrictions on the type of food. Examples of foods to which the active substance of the present invention can be added include drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, There are various soups, beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, and includes all health foods and health functional foods in the ordinary sense.

The health food and health functional food composition containing the active substance according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active substance may be appropriately determined depending on the purpose of its use (for prevention or improvement). In general, the amount of the composition in health food and health functional food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for health maintenance or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than or equal to the above range.

The health food and health functional food composition of the present invention is not particularly limited in other ingredients other than containing the active substance of the present invention as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates are added as additional ingredients like conventional beverages. may contain. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 nutraceuticals of the present invention.

In addition to the above, health food and health functional food composition containing the active substance of the present invention are various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.) ), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health food and health functional food composition of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage.

These components may be used independently or in combination. The proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.

<Preparation Example 1> Preparation of thalidomido derivatives (Compound 5 and Compound 6)

Preparation of tert-butyl (2,6-dioxopiperidin-3-yl)carbamate (2)

Known compounds (tert-butoxycarbonyl)glutamine (100mg, 0.406mmol), N-Hydroxysuccinimide (52mg, 0.447mmol), and DCC (92mg, 0.447mmol) were filled with Ar gas and dissolved in 3mL of DMF. The reaction was carried out at 80 °C. When it was confirmed that the starting material disappeared by TLC, DMF was removed using an evaporator and a high vacuum device. After that, the urea generated during the reaction was filtered with EtOAc and crystallized using cold ethyl ether to obtain compound 2 (92 mg. 99%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 4.17 (m, 1H) ), 2.67 (m, 1H), 2.41 (m, 1H), 1.86 (m, 2H), 1.35 (s, 9H).

Preparation of 2,2,2-trifluoroacetaldehyde, 2,6-dioxopiperidin-3-aminium salt (3)

After filling Ar gas to the synthesized compound 2 (110.7 mg, 0.485 mmol), ₂ mL of CH 2 Cl ₂ and 2 mL of TFA were added dropwise, respectively, and the reaction was carried out at room temperature (25° C.). When it was confirmed that the starting material disappeared by TLC, CH ₂ Cl ₂ was removed using an evaporator and a high vacuum device to obtain compound 3 (119.2 mg, 99%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.51 (s, 3H), 4.21 (dd, J = 13.3, 5.5 Hz, 1H), 2.70 (m, 1H), 2.59 (m, 1H), 2.13 (m, 1H), 2.04 (m, 1H).

Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (4)

After filling Ar gas to the synthesized compound 2 (100mg, 0.438mmol), 2mL of CH ₂ Cl ₂ and TFA were added dropwise each, and the reaction was carried out at room temperature (25℃). When it was confirmed by TLC that the starting material disappeared, using an evaporator and a high vacuum device, CH ₂ Cl ₂ was removed to obtain compound 3 . Immediately without purification, compound 3 , 4-nitroisobenzofuran-1,3-dione (127 mg, 0.657 mmol) and NaOAc (44 mg, 0.526 mmol) were dissolved in 3 mL of AcOH, followed by reflux reaction. When it was confirmed by TLC that the starting material disappeared, AcOH was removed using an evaporator and a high vacuum device and _{crystallized using H 2} O to obtain compound 4 (105 mg. 79%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H), 8.51 (s, 3H), 8.35 (dd, J = 8.1, 0.8 Hz, 1H), 8.24 (dd, J = 7.5, 0.7 Hz, 1H), 8.12 (t, J = 7.8 Hz, 1H), 5.20 (dd, J = 13.4, 5.3 Hz, 1H), 2.89 (m, 1H), 2.61 (m, 1H), 2.52 (m, 1H), 2.07 (m, 1H).

Preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5)

Dissolve the synthesized compound 4 (610mg, 2.012mmol) in 5mL of DMF. After that, 10% Pd/C (60mg, 0.056mmol) was added, and the reaction was carried out at room temperature (25℃) after filling _{with H 2 gas.}

When it was confirmed by TLC that the starting material disappeared, it was _{filtered with DMF to remove Pd remaining after the reaction, and crystallized using H 2} O to obtain compound 5 (512 mg, 93%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.47 (t, J = 8.2 Hz, 1H), 7.01 (t, J = 6.8 Hz, 2H), 6.53 (s, 2H) ), 5.05 (dd, J = 13.1, 5.3 Hz, 1H), 2.89 (m, 1H), 2.59 (m, 1H), 2.02 (m, 2H).

Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (6)

The synthesized compound 3 (94.5 mg, 0.39 mmol), 4-hydroxyisobenzofuran-1,3-dione (57.64 mg, 0.351 mmol) and KOAc (107.95 mg, 1.1 mmol) were dissolved in 3 mL of AcOH, followed by reflux reaction. When it was confirmed by TLC that the starting material disappeared, AcOH was removed using an evaporator and a high vacuum device, _{and crystallized using H 2} O to obtain compound 6 (54 mg. 51%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.20 (s, 1H), 11.11 (s, 1H), 7.65 (t, J = 7.7 Hz, 2H), 5.07 (m, 1H), 2.89 (m, 1H) ), 2.59 (m, 2H), 2.03 (m, 1H).

<Preparation Example 2> Preparation of compounds 9 to 12

Step 1: Preparation of compound 8

Compound 7 and pyridinium hydrochloride were reacted at 180° C. to prepare compound 8.

Step 2: Preparation of compound 9-12

Preparation of (4-bromophenyl)(4-(2-hydroxyethoxy)phenyl)methanone (9)

The synthesized compound 8 (220.2 mg, 0.794 mmol) and K ₂ CO ₃ (274.6 mg, 1.98 mmol) were dissolved in 5 mL of Acetone and 3 mL of DMF, followed by a reflux reaction for 30 minutes. Thereafter, 2-bromoethanol (0.155 mL, 2.185 mmol) was added dropwise, and the reaction was carried out overnight. When it was confirmed by TLC that the starting material disappeared, the reaction was stopped with 2N-HCl and diluted with EtOAc solvent. The organic layer was extracted by washing _{with EtOAc and H 2 O.} The extracted organic layer was _{dried over MgSO 4} and the solvent was removed using an evaporator.

The reaction mixture was purified through column chromatography to obtain compound 9 (223.4 mg, 87%) .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.8 Hz, 2H), 7.63 (s, 4H), 4.18 (t, J = 4.4 Hz, 2H), 7.80 (d, J = 8.8) Hz, 2H), 4.02 (d, J = 3.8 Hz, 2H).

Preparation of (4-bromophenyl)(4-(2-(2-hydroxyethoxy)ethoxy)phenyl)methanone (10)

The synthesized compound 8 (313.5 mg, 1.13 mmol) and K ₂ CO ₃ (468.53 mg, 3.39 mmol) were dissolved in 5 mL of Acetone and 3 mL of DMF, followed by a reflux reaction for 1 hour. Thereafter, 2-(2-chloroethoxy)ethan-1-ol (0.24 mL, 2.26 mmol) and NaI (169.37 mg, 1.13 mmol) were added dropwise, followed by overnight reaction. When it was confirmed by TLC that the starting material disappeared, the reaction was stopped with 2N-HCl and diluted with EtOAc solvent. The organic layer was extracted by washing _{with EtOAc and H 2 O.} The extracted organic layer was _{dried over MgSO 4} and the solvent was removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 10 (364.2 mg, 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.8 Hz, 2H), 7.63 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 4.24 (t, J = 4.6) Hz, 2H), 3.92 (t, J = 4.6 Hz, 2H), 3.76 (m, 2H) 3.70 (t, J = 4.4 Hz, 2H).

Preparation of (4-bromophenyl)(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)methanone (11)

Using the synthesized compound 8 (319.2mg, 1.15mmol) and 2-(2-(2-chloroethoxy)ethoxy)ethan-1-ol (0.17mL, 1.15mmol) as starting materials, use the same method as for the derivative 10 to compound 11 was obtained (447 mg, 95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 8.6 Hz, 2H), 7.62 (s, 4H), 6.98 (d, J = 8.6 Hz, 2H), 4.22 (t, J = 4.6) Hz, 2H), 3.90 (t, J = 4.5 Hz, 2H), 3.77-3.68 (m, 6H), 3.62 (t, J = 4.3 Hz, 2H).

Preparation of (4-bromophenyl)(4-((5-hydroxypentyl)oxy)phenyl)methanone (12)

Using the synthesized compound 8 (141.5 mg, 0.511 mmol) and 5-bromopentan-1-ol (0.62 mL, 0.511 mmol) as starting materials, compound 12 was obtained in the same manner as in derivative 10 (72.1 mg, 39%). ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.75 (dd, J = 7.1,5.7 Hz, 2H), 7.59 (d, J = 5.8 Hz 4H), 6.92 (t, J = 7.4 Hz, 2H), 4.02 (d, J = 6 Hz, 2H), 3.65 (t, J = 6.1 Hz, 2H), 2.90 (m, dd, J = 31.7, 5.8 Hz, 2H), 1.86 (d, J = 5.9 Hz, 2H) , 1.62 (t, J = 6.2 Hz, 2H).

<Preparation Example 3> Preparation of compound 36

Preparation of 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (36)

Dissolve commercially available tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate (220 mg, 1.072 mmol) in _{3 ml of CH 2} Cl ₂ , add Et3N (2.358 mmol) at 0° C., and slowly add MsCl (1.179 mmol) The reaction proceeds dropwise. When it is confirmed by TLC that the reaction does not proceed any further, the reaction is stopped using _{NH 4 Cl.} The organic layer was extracted by washing _{with CH 2} Cl ₂ and H _{2 O.} The extracted organic layer is _{dried with MgSO 4} and the solvent is removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 36 (297 mg, 98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.89(bs, 1H), 4.37(m, 2H), 3.73(m, 2H), 3.56(m, 2H), 3.33(m, 2H), 3.07(s) , 3H), 1.45 (s, 9H).

<Preparation Example 4> Preparation of compound 40

Step 1: Preparation of compound 39

Preparation of tert-butyl (S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate (39)

commercially available (S)-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (100 mg, 0.365 mmol), tert-butyl 2-bromoacetate (0.365 mmol), K ₂ CO ₃ (76mg, 0.548 mmol) was dissolved in 2ml of DMF to proceed with the reaction. When it was confirmed by TLC that the reaction did not proceed any further, it was diluted with EtOAc solvent. The organic layer was extracted by washing with EtOAc, brine and H _{2 O.} The extracted organic layer is _{dried with MgSO 4} and the solvent is removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 39 (118 mg, 83%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.38 (d, J) = 8.4 Hz, 1H), 5.10(m, 1H), 4.97(s, 2H), 2.95-2.83, 2.64-2.52, 2.08-1.99(m, 4H), 1.43(s, 9H).

Step 2: Preparation of compound 40

Preparation of (S)-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)oxonium 2,2,2-trifluoroacetate (40)

The synthesized compound 39 (100 mg, 0.257 mmol) _{was dissolved in 1 ml of CH 2} Cl ₂ , and TFA (0.308 mmol) was added at 0° C. and the reaction proceeded. When it was confirmed by TLC that the reaction did not proceed any further, the solvent was evaporated and washed with ether several times to obtain compound 40, which was used in the next reaction without purification (114 mg, 99%).

<Examples 1 to 4> Preparation of compounds 23 to 26

Step 1: Preparation of compounds 14 to 18

Preparation of N-cyclopropyl-4'-(4-hydroxybenzoyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide (14)

After the synthesis of compound 8 (200mg, 0.722mmol) and known boronic ester 13 (283mg, 1.083mmol) and K ₂ CO ₃ (200mg, 1.444mmol) and Pd(pph ₃ ) ₄ (75mg, 0.065mmol) were charged with Ar gas It was dissolved in 6 mL of anhydrous DMF. The reaction was carried out overnight at 90°C. When it was confirmed by TLC that the starting material disappeared, the reaction was stopped with 2N-HCl, filtered through celite, and diluted with EtOAc solvent. The organic layer was extracted by washing _{with EtOAc and H 2 O.} The extracted organic layer was _{dried over MgSO 4} and the solvent was removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 14 (135 mg, 50%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 8.44 (s, 1H), 7.77-7.71 (m, 6H ), 7.56-7.54 (m, 2H), 7.42 (m, 1H), 6.93 (m, 2H), 2.88 (m, 1H), 2.29 (s, 3H), 0.67 (m, 2H), 0.56 (m, 2H).

Preparation of N-cyclopropyl-4'-(4-(2-hydroxyethoxy)benzoyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide (15)

Using the synthesized compound 9 (223.4 mg, 0.696 mmol) and known boronic ester 13 (181.63 mg, 0.696 mmol) as starting materials, compound 15 was obtained through the same method as the derivative 14 (190 mg, 66%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.63 ( s, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.6 Hz, 2H), 6.60 (s, 1H), 4.16 ( d, J = 4.4 Hz, 2H), 4.01 (t, J = 4.1 Hz, 2H), 2.88 (m, 1H), 2.29 (s, 3H), 0.83 (d, J = 5.9 Hz, 2H), 0.61 ( s, 2H).

Preparation of N-cyclopropyl-4'-(4-(2-(2-hydroxyethoxy)ethoxy)benzoyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide (16)

Using the synthesized compound 10 (364.2 mg, 0.997 mmol) and the known boronic ester 13 (260 mg, 0.997 mmol) as starting materials, compound 16 was obtained through the same method as the derivative 14 (300 mg, 66%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.67 (dd, J = 7.9,1.8 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.35 ( s, 1H), 4.24 (t, J = 4.6 Hz, 2H), 4.24 (t, J = 4.6 Hz, 2H), 3.92 (t, J = 4.6 Hz, 2H) 3.79 (t, J = 4.5 Hz, 2H) ), 2.90 (m, 1H), 2.32 (s, 3H), 0.86 (d, J = 5.6 Hz, 2H), 0.62 (m, 2H).

Preparation of N-cyclopropyl-4'-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide (17)

Using the synthesized compound 11 (457 mg, 1.106 mmol) and the known boronic ester 13 (288.82 mg, 1.106 mmol) as starting materials, compound 17 was obtained through the same method as the derivative 14 (271.5 mg, 49%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.11 (dd, J = 8.7 Hz, 4H), 7.67 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.38 (d, J = 7.9) Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.54 (s, 1H), 4.21 (t, J = 4.4 Hz, 2H), 3.90 ( t, J = 4.3 Hz, 2H), 3.71 (t, J = 6.1 Hz, 6H), 3.61 (t, J = 4.4 Hz, 2H), 2.87 (m, 1H), 2.30 (s, 3H), 0.84 ( m, 2H), 0.57 (m, 2H).

Preparation of N-cyclopropyl-4'-(4-((5-hydroxypentyl)oxy)benzoyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide (18)

Using the synthesized compound 12 (63.2 mg, 0.174 mmol) and known boronic ester 13 (45.43 mg, 0.174 mmol) as starting materials, compound 18 was obtained in the same manner as in the derivative 14 (300 mg, 66%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (dd, J = 21.1,8.3 Hz, 3H), 7.70-7.60 (m, 3H), 7.53 (m, 1H), 7.44 (td, J = 7.4, 2.5 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 2.88 (m, 1H), 2.29 (s, 3H), 1.89-7.79 (m, 3H), 1.69-1.61 ( m, 3H), 1.60-1.50 (m, 3H), 0.82 (d, J = 5.7 Hz, 2H), 0.63-0.58 (m, 2H).

Step 2: Preparation of compounds 19 to 22

Preparation of 2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethyl (4-nitrophenyl) carbonate (19)

Dissolve 4-nitro phenyl chloroformate (225.6 mg, 1.12 mmol) in anhydrous CH ₂ Cl ₂ 3 mL in a round bottom flask. And compound 15 (93mg, 0.224mmol) and anhydrous pyridine (0.1mL, 1.12mmol) synthesized in a vial were _{dissolved in anhydrous CH 2} Cl ₂ 2mL, and this was slowly added dropwise at 0℃, and reacted at room temperature (25℃). When it was confirmed by TLC that the starting material disappeared, the reaction was stopped with 2N-HCl and diluted with EtOAc solvent. The organic layer was extracted by washing _{with EtOAc and H 2 O.} The extracted organic layer was _{dried over MgSO 4} and the solvent was removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 19 (105 mg, 81%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J = 9.0 Hz, 2H), 7.82 (dd, J = 31.5, 8.3 Hz, 4H), 7.66 (t, J = 7.3 Hz, 2H), 7.39 (d, J = 8.6 Hz, 4H ), 7.31 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 4.68 (d, J = 3.1) Hz, 2H), 4.37 (d, J = 3.4 Hz, 2H), 2.88 (m, 1H), 2.30 (s, 3H), 0.83 (d, J = 6.7 Hz, 2H), 0.61 (s, 2H).

Preparation of 2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethyl (4-nitrophenyl) carbonate (20)

Using the synthesized compound 16 (101 mg, 0.22 mmol) as a starting material, the final compound 20 was obtained in the same manner as in the derivative 19 (123 mg, 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 9.0 Hz, 2H), 7.84 (dd, J = 20.6, 8.2 Hz, 4H), 7.67 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 8.8 Hz, 3H), 7.02 (d, J = 8.6 Hz, 2H), 6.27 (s, 1H), 4.48 (d, J = 4.2 Hz, 2H), 4.26 (d, J = 4.0 Hz, 2H), 3.93 (dd, J = 17.8,3.9 Hz, 4H), 2.90 (m, 1H), 2.32 (s, 3H) ), 0.87 (d, J = 6.4 Hz, 2H), 0.62 (s, 2H).

2-(2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethoxy)ethyl (4-nitrophenyl) carbonate Preparation of (21)

Using the synthesized compound 17 (150.5 mg, 0.299 mmol) as a starting material, the final compound 21 was obtained in the same manner as in the derivative 19 (131.8 mg, 66%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J = 9.1 Hz, 2H), 7.81 (dd, J = 20.4, 8.4 Hz, 4H), 7.67 (dd, J = 7.8, 1.6 Hz, 1H) ), 7.63 (d, J = 1.4 Hz, 1H), 7.42-7.30 (m, 4H), 6.98 (d, J = 8.8 Hz, 1H), 6.49 (s, 1H), 4.46-4.41 (m, 2H) , 4.22 (t, J = 4.6 Hz, 2H), 3.91 (t, J = 4.6 Hz, 2H), 3.82 (quint, J = 2.3 Hz, 2H), 3.79-3.70 (m, 4H), 2.89 (m, 1H), 0.84 (dd, J = 12.6, 6.8 Hz, 2H), 0.63-0.58 (m, 2H).

Preparation of 5-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)pentyl (4-nitrophenyl) carbonate (22)

Using the synthesized compound 18 (61.2 mg, 0.13 mmol) as a starting material, the final compound 22 was obtained in the same manner as in the derivative 19 (77.3 mg, 93%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.7 Hz, 2H), 7.66 ( t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.3 Hz, 3H), 7.30 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.58 (s, 1H), 4.33 (t, J = 6.3 Hz, 2H), 4.08 (t, J = 5.9 Hz, 2H), 2.88 (m, 1H), 2.29 (s, 3H), 1.93-1.81 (m, 4H), 1.69-1.61 (m, 2H), 0.82 (d, J = 6.4 Hz, 2H), 0.63-0.57 (m, 2H).

Step 3: Preparation of final compounds 23 to 26

2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethyl(2-(2,6-dioxopiperidin-3-yl)-1 Preparation of ,3-dioxoisoindolin-4-yl)carbamate (23)

The synthesized compound 19 (50mg, 0.086mmol) and the synthesized compound 5 (23.53mg, 0.086mmol) were filled with Ar gas and dissolved with 3mL of anhydrous DMF. Then, NaH (3.1mg, 0.13mmol) was slowly added dropwise at 0 ℃ and reacted at room temperature (25 ℃). When it was confirmed by TLC that the starting material was gone, aq. sat. The _{reaction was stopped using NH 4} Cl and then diluted with EtOAc solvent. The organic layer was extracted by washing _{with EtOAc and H 2 O.} The extracted organic layer was _{dried over MgSO 4} and the solvent was removed using an evaporator. The reaction mixture was purified through column chromatography to obtain the final compound 23 (24.4 mg, 40%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.16 (s, 1H), 9.22 (s, 1H), 8.46 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.86 (t) , J = 7.8 Hz, 1H), 7.78 (q, J = 7.9 Hz, 5H), 7.60 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.42 (d, J) = 7.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 5.13 (dd, J = 12.5, 5.2 Hz, 1H), 4.54 (s, 1H), 4.40 (s, 1H), 2.86 (m) , 2H), 2.58 (d, J = 17.8 Hz, 2H), 2.31 (s, 3H), 2.04 (m, 1H), 1.99 (s, 1H), 0.68 (d, J = 6.7 Hz, 2H), 0.56 (s, 2H); ¹³ C-NMR (500 MHz, CDCL3) δ 195.3, 170.8, 168.9, 168.6, 167.9, 162.1, 152.8, 145.0, 141.2, 139.3, 137.8, 137.0, 136.6, 132.7(2C), 132.2, 131.5, 130.9, 130.8, 130.0(2C), 129.2(2C), 128.2, 126.3, 123.9, 118.1, 115.1, 114.4(2C), 66.2, 64.1 49.4, 31.5, 29.8, 23.3, 22.7, 20.6, 6.9

2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethyl(2-(2,6-dioxopiperidin-3 Preparation of -yl)-1,3-dioxoisoindolin-4-yl)carbamate (24)

Using the synthesized compound 20 (70 mg, 0.112 mmol) as a starting material, the final compound 24 was obtained in the same manner as in the derivative 23 (25.8 mg, 30.4%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.04 (s, 1H), 8.41 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.71 (d , J = 10.3 Hz, 6H), 7.51 (d, J = 7.8 Hz, 3H), 7.37 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 5.08 (m, 1H) ), 4.22 (d, J = 33.8 Hz, 4H), 3.76 (d, J = 27 Hz, 4H), 2.86-2.74 (m, 2H), 2.54 (d, J = 19.5 Hz, 1H), 2.26 (s) , 3H), 2.03-1.91 (m, 2H), 0.63 (d, J = 6.9 Hz, 2H), 0.51 (d, J = 1.3 Hz, 2H); ¹³ C-NMR (500 MHz, CDCL ₃ ) δ 195.2, 170.9, 168.8, 168.6, 168.0, 166.7, 162.6, 153.1, 144.9, 141.2, 138.3, 137.9, 137.1, 136.5, 132.7(2C), 132.3, 131.4, 130.9 , 130.3(2C), 129.9(2C), 129.1, 128.2, 126.3, 123.8, 118.0, 115.1, 114.4(2C), 69.8(2C), 67.5, 65.0, 49.3, 31.5, 29.7, 23.5, 22.3, 20.8, 6.6 .

2-(2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethoxy)ethyl(2-(2, Preparation of 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (25)

Using the synthesized compound 21 (74.1 mg, 0.11 mmol) as a starting material, the final compound 25 was obtained in the same manner as in the derivative 23 (48.6 mg, 54.6%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.04 (s, 1H), 8.40 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.80-7.64 (m, 6H), 7.51 (d, J = 7.2 Hz, 3H), 7.37 (d, J = 7.5 Hz, 1H), 7.04 (d, J = 7.5 Hz, 2H), 5.07 (m, 1H), 4.18 (d, J = 32.2 Hz, 4H), 3.69 (d, J = 41 Hz, 4H), 3.57 (s, 4H), 2.88-2.73 (m, 2H), 2.53 (d, J = 19.4 Hz, 1H) , 2.26 (s, 3H), 2.07-1.87 (m, 2H), 0.63 (d, J = 6.3 Hz, 2H), 0.50 (s, 2H); ¹³ C-NMR (500 MHz, CDCL ₃ ) δ 195.3, 170.8, 168.8, 168.6, 168.0, 166.8, 162.6, 153.0, 141.2, 137.9, 137.0, 136.5, 132.6(2C), 132.2, 130.8(2C), 129.9( 2C), 129.1, 128.2, 126.4, 123.8, 117.9, 115.0, 114.3 (2C), 70.9, 70.6, 69.7, 69.2, 67.7, 65.1, 60.5, 49.3, 31.5, 29.6, 23.3, 22.7, 20.6, 6.8 (2C) .

5-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)pentyl(2-(2,6-dioxopiperidin-3-yl)-1 Preparation of ,3-dioxoisoindolin-4-yl)carbamate (26)

Using the synthesized compound 22 (41.4 mg, 0.066 mmol) as a starting material, the final compound 26 was obtained in the same manner as in the derivative 23 (16 mg, 32%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 9.04 (s, 1H), 8.44 (d, J = 3.8 Hz. 1H), 8.28 (d, J = 8.4 Hz, 1H) ), 7.87-7.73 (m, 7H), 7.57 (t, J = 8.1 Hz, 3H), 7.42 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 5.13 (dd) , J = 12.7,5.4 Hz 1H), 4.20 (t, J = 5.7 Hz, 2H), 4.14-4.06 (m, 2H), 2.93-2.80 (m, 2H), 2.60 (m, 1H), 2.54 (s) , 1H) , 2.31 (s, 3H), 2.04 (m, 1H), 1.86-1.68 (m, 4H), 1.59-1.49 (m, 2H), 0.71-0.65 (m, 2H), 0.59-0.53 (m) , 2H); ¹³ C-NMR (500 MHz, DMSO-d ₆ ) δ 194.0, 172.8, 169.7, 168.0, 166.5, 162.5, 152.8, 144.4, 140.0, 138.2, 136.8, 136.5, 136.4, 132.2(2C), 132.1, 131.5, 130.5 , 129.4(2C), 129.3(2C), 129.2, 128.1, 126.7, 124.5, 117.7, 116.3, 114.2(2C), 79.2, 67.7, 65.4, 48.9, 30.9, 28.2, 27.9, 23.1, 21.9, 20.1, 5.7( 2C).

<Examples 5 to 8> Preparation of compounds 31 to 34

Step 1: Preparation of compounds 15 to 18

Step 1 and Examples 1 to 4 are the same.

Step 2: Preparation of compounds 27 to 30

Preparation of 2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethyl 4-methylbenzenesulfonate (27)

After dissolving the synthesized compound 15 (50.1 mg, 0.109 mmol) in _{3 mL of CH 2} Cl _{2 , 0.05 mL of NEt 3} is slowly added dropwise at 0°C. Thereafter, p-TsCl (25 mg, 0.131 mmol) is added dropwise at room temperature (25° C.) to react. When it is confirmed by TLC that the starting material is gone _{, the reaction is stopped with H 2} O and diluted with EtOAc solvent. The organic layer was washed with EtOAc and H ₂ O and extracted. The extracted organic layer is _{dried with MgSO 4} and the solvent is removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 27 (74.8 mg, 99%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.91-7.78 (m, 6H), 7.67 (dd, J = 7.9, 1.3 Hz, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.42 (d , J = 8.1 Hz, 2H), 7.35 (t, J = 7.1 Hz, 3H), 7.01 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.29 (s, 1H) ), 4.51-4.37 (m, 2H), 4.30-4.22 (m, 2H), 2.91 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 0.87 (d, J = 6.3 Hz, 2H), 0.65-0.58 (m, 2H).

Preparation of 2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethyl 4-methylbenzenesulfonate (28)

Using the synthesized compound 16 (50.1 mg, 0.11 mmol) as a starting material, the final compound 28 was obtained in the same manner as in the derivative 27 (47.4 mg, 71%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.89-7.75 (m, 6H), 7.67 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H) ), 7.38-7.29 (m, 3H), 6.99 (d, J = 8.6 Hz, 2H), 6.27 (s, 1H), 4.17 (dd, J = 19.4, 4.1 Hz, 4H), 3.87-3.75 (m, 4H), 2.90 (m, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 0.87 (d, J = 6.2 Hz, 2H), 0.62 (s, 2H).

2-(2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (29) manufacture of

Using the synthesized compound 17 (49.9 mg, 0.099 mmol) as a starting material, the final compound 29 was obtained in the same manner as in the derivative 27 (48 mg, 74%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.6 Hz, 2H), 7.77 (dd, J = 8.1,2.1 Hz, 4H), 7.68 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 3H), 6.98 (d, J = 8.6 Hz, 2H), 6.58 (s, 1H), 4.19 (t, J = 4.3 Hz, 2H), 4.14 (t, J = 4.7 Hz, 2H), 3.85 (t, J = 4.3 Hz, 2H), 3.71-3.64 (m, 4H), 3.63-3.59 (m) , 2H), 2.87 (m, 1H), 2.41 (s, 3H), 2.29 (s, 3H), 0.82 (d, J = 6.0 Hz, 2H), 0.63-0.57 (m, 2H).

Preparation of 5-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)pentyl 4-methylbenzenesulfonate (30)

Using the synthesized compound 18 (46.4 mg, 0.101 mmol) as a starting material, the final compound 30 was obtained in the same manner as in the derivative 27 (25.7 mg, 59%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.7 Hz, 2H), 7.78 (q, J = 3.8 Hz, 4H), 7.67 (dd, J = 7.9, 1.6 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.32 (t, J = 7.0 Hz, 3H), 6.93 (d, J = 8.7 Hz, 2H), 6.49 ( s, 1H), 4.06 (t, J = 6.3 Hz, 2H), 4.00 (t, J = 6.2 Hz, 2H), 2.88 (m, 1H), 2.43 (s, 3H), 2.30 (s, 3H), 1.81-1.67 (m, 4H), 1.57-1.46 (m, 2H), 0.87-0.80 (m, 2H), 0.64-0.58 (m, 2H).

Step 3: Preparation of final compounds 31 to 34

N-cyclopropyl-4'-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)benzoyl)-6-methyl- Preparation of [1,1'-biphenyl]-3-carboxamide (31)

Dissolve the synthesized compound 27 (63.4 mg, 0.11 mmol) and the synthesized compound 6 (15.3 mg, 0.05 mmol) and K ₂ CO ₃ (23.1 mg, 0.16 mmol) in 3 mL of Acetonitrile and proceed with a reflux reaction. When it is confirmed by TLC that the reaction does not proceed any further, the acetonitrile is removed using an evaporator device. The mixture is then diluted with CH ₂ Cl ₂ solvent. The organic layer was extracted by washing _{with CH 2} Cl ₂ and H _{2 O.} The extracted organic layer is _{dried with MgSO 4} and the solvent is removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 31 (10.3 mg, 28%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.99(s, 1H), 10.25(s, 1H), 8.60(s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.5, 1.6 Hz, 1H), 7.46 (s, 1H), 6.84 (dd, J = 6.4, 2 Hz, 4H), 6.20 (s) , 1H), 5.32 (m, 1H), 4.28 (s, 1H), 4.13 (t, J = 10.4 Hz, 2H), 3.90 (d, J = 6.3 Hz, 1H), 3.67 (d, J = 5.4 Hz, 1H), 2.67 (m, 1H), 2.05-1.93 (m, 3H) 1.40 (s, 1H); ¹³ C-NMR (500 MHz, CDCL ₃ ) δ 195.4, 170.9, 168.8, 168.6, 167.0, 165.7, 162.3, 162.1, 156.1, 145.1, 144.9, 141.2, 139.3, 137.1, 136.7, 132.7(2C), 132.2, 130.9 (2C), 129.9(2C), 129.1(2C), 128.0, 126.5, 119.9, 117.8, 116.7, 114.4, 68.4, 66.8, 64.3, 31.8, 22.9, 20.4, 14.2, 6.6(2C).

N-cyclopropyl-4'-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)benzoyl) Preparation of -6-methyl-[1,1'-biphenyl]-3-carboxamide (32)

Using the synthesized compound 28 (47.4 mg, 0.077 mmol) as a starting material, the final compound 32 was obtained in the same manner as in the derivative 31 (16.9 mg, 31%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.73 (dd, J = 7.5,2.1 Hz, 5H), 7.52 (t, J = 6.8 Hz, 3H), 7.44-7.34 (m, 2H), 7.58-7.50 (m, 2H), 7.07 (t, J = 8.4 Hz, 2H), 5.11 (m, 1H), 4.35 (s, 1H), 4.17 (dd, J = 17.9, 1.1 Hz, 2H), 3.92-3.79 (m, 3H), 3.73 (s, 1H), 3.48 (m, 1H), 3.53-3.43 (m, 1H), 2.95 (m, 1H), 2.83-2.49 (m, 2H), 2.27 (s, 1H), 2.16-1.87 (m, 2H), 0.65 (d, J = 4.8 Hz, 2H), 0.53 (s, 2H); ¹³ C-NMR (500 MHz, CDCL ₃ ) δ 195.5, 171.1, 168.7, 168.2, 167.2, 167.0, 165.8, 162.6, 156.4, 145.1, 141.2, 139.2, 137.1, 136.4, 133.8, 132.6(2C), 132.1, 130.9 (2C), 130.3, 129.8 (2C), 128.9 (2C), 128.2, 119.4, 116.3, 114.1, 70.5, 69.8, 69.6, 68.8, 67.5, 29.7, 23.5, 20.6, 14.2, 6.8 (2C).

N-cyclopropyl-4'-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy Preparation of )ethoxy)benzoyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide (33)

Using the synthesized compound 29 (38.9 mg, 0.059 mmol) as a starting material, the final compound 33 was obtained in the same manner as in the derivative 31 (7.5 mg, 34%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 7.76 (d, J = 9.4 Hz, 7H), 7.55 (d, J = 7.3 Hz, 3H), 7.41 (m, 1H) ), 7.15-7.06 (m, 2H), 5.17 (m, 1H), 4.33 (s, 1H), 4.19 (s, 2H), 3.77 (s, 2H), 3.70-3.48 (m, 5H), 3.42 (m, 1H), 2.97 (m, 1H), 2.88-2.66 (m, 1H), 2.54 (s, 1H), 2.30 (s, 1H), 2.00 (m, 1H), 0.68 (d, J = 5.2 Hz, 2H), 0.56 (s, 2H); ¹³ C-NMR (500 MHz, CDCL ₃ ) δ 195.5, 171.1, 168.4, 167.2, 165.8, 162.7, 156.4, 144.9, 141.3, 139.3, 136.9, 136.4, 133.9, 132.6(2C), 132.2, 130.9(2C), 129.8 (2C), 129.0 (2C), 128.2, 126.4, 119.6, 117.5, 116.2, 114.3 (2C), 72.7, 70.8, 70.5, 69.6, 69.2, 67.8, 61.8, 29.8, 23.4, 21.9, 20.6, 6.9 (2C) ).

N-cyclopropyl-4'-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentyl)oxy)benzoyl)-6 Preparation of -methyl-[1,1'-biphenyl]-3-carboxamide (34)

Using the synthesized compound 30 (25.7 mg, 0.042 mmol) as a starting material, the final compound 34 was obtained in the same manner as in the derivative 31 (4.1 mg, 53%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (m, 1H), 7.80-7.73 (m, 4H), 7.65-7.59 (m, 4H), 7.57-7.51 (m, 3H), 7.41 ( d, J = 8.9 Hz, 1H), 7.10 (dd, J = 8.7, 2.8 Hz, 1H), 5.24 (m, 1H), 4.24 (t, J = 5.8 Hz, 1H), 4.14-4.00 (m, 2H), 3.67 (m, 1H), 2.85 (m, 1H), 2.68 (m, 1H), 2.31 (s, 3H) ), 2.19-1.96 (m, 3H), 1.96-1.84 (m, 2H), 1.75 (m, 1H), 1.63 (m, 1H), 1.56-1.40 (m, 4H), 0.70-0.64 (m, 2H) ), 0.59-0.53 (m, 2H); ¹³ C-NMR (500 MHz, CDCL ₃ ) δ 195.3, 171.2, 168.8, 168.6, 167.2, 165.8, 162.9, 156.6, 144.7, 141.2, 139.4, 136.6, 134.0, 132.7(2C), 132.3, 130.8(2C), 129.9(2C), 129.0(2C), 128.6, 128.1, 126.3, 119.1, 117.3, 115.9, 114.1, 69.3, 68.2, 62.9, 32.4, 31.0, 29.8, 28.9, 23.2, 22.5, 20.5, 6.9(2C).

<Example 9> Preparation of compound 41

Step 1: Preparation of compound 37

Preparation of tert-butyl (2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethyl)carbamate (37)

The synthesized compounds 14 (23 mg, 0.062 mmol) and 36 (35 mg, 0.124 mmol) and K ₂ CO ₃ (26 mg, 0.186 mmol) were dissolved in 1 mL of DMF and the reaction was carried out at 90 °C. When it is confirmed by TLC that the reaction does not proceed any further, the reaction is stopped using _{NH 4 Cl.} The organic layer was washed with EtOAc and H ₂ O and extracted. The extracted organic layer is _{dried with MgSO 4} and the solvent is removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 37 (14.4 mg, 42%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.88 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.69-7.61 (m, 2H), 7.42 (d, J) = 8.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.22 (s, 1H), 4.95 (s, 1H), 4.24-4.20 (m) , 2H), 3.89-3.85(m, 2H), 3.65-3.61(m, 2H), 3.40-3.32(m, 2H), 2.92(m, 1H), 2.33(s, 3H), 1.45(s, 9H) ), 0.91-0.85 (m, 2H), 0.65-0.60 (m, 2H).

Step 2: Preparation of compound 38

Preparation of 2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethan-1-aminium chloride (38)

After dissolving the synthesized compound 37 (13.5 mg, 0.024 mmol) in CH ₂ Cl ₂ 0.8 m, HCl 4M in Dioxane (0.2 ml) is added and the reaction proceeds. When it was confirmed by TLC that the reaction did not proceed any further, the solvent was evaporated and washed several times with ether to obtain compound 38 (8.1 mg, 68%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J = 0,3 Hz, 1H), 7.93 (bs, 3H), 7.83-7.74 (m, 6H), 7.57 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 4.29-4.34 (m, 2H), 3.87-3.82 (m, 2H), 3.04- 2.98 (m, 2H), 2.85 (m, 1H), 2.32 (s, 3H), 0.71-0.66 (m, 2H), 0.59-0.54 (m, 2H).

Step 3: Preparation of final compound 41

(S)-N-cyclopropyl-4'-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy Preparation of )acetamido)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1'-biphenyl]-3-carboxamide (41)

The synthesized compound 38 (9 mg, 0.018 mmol), 40 (7 mg, 0.015 mmol), and HATU (6 mg, 0.015 mmol) were dissolved in 3 mL of DMF, and then DIPEA (0.045 mmol) was added thereto and the reaction proceeded. When it is confirmed by TLC that the reaction does not proceed any further, add brine and make pH 1 with citric acid. Again, NaHCO _{3 is} neutralized, and the organic layer is washed with CH ₂ Cl ₂ and H ₂ O and extracted. The extracted organic layer is _{dried with MgSO 4} and the solvent is removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 41 (12 mg, 89%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.44 (d, J = 4.2 Hz, 1H), 8.03 (t, J = 5.76 Hz, 1H), 7.81-7.73 (m) , 6H), 7.56 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 7.3 Hz, 1H), 7.43-7.37 (m, 2H), 7.10 (d, J = 8.9 Hz, 2H), 5.14-5.08 (m, 1H), 4.23-4.19 (m, 2H), 3.82-3.77 (m, 2H), 3.59-3.54 (m, 2H), 3.39-3.35 (m, 2H), 2.90-2.82 (m) , 2H), 2.68-2.54 (m, 1H), 2.31 (s, 3H), 2.07-1.97 (m, 2H), 0.71-0.68 (m, 2H), 0.58-0.53 (m, 2H).

<Comparative Example 1> Preparation of compound 43

The synthesized compound 38 (28 mg, 0.061 mmol) and commercially available 42 (15 mg, 0.061 mmol) were dissolved in 0.4 mL of DMF. EDC (0.073 mmol) and DMAP (0.9 mg, 0.007 mmol) were added at 0° C. and the reaction was carried out. When it is confirmed by TLC that the reaction does not proceed any further, blow off the solvent _{and wash the organic layer with CH 2} Cl ₂ and H ₂ O for extraction. The extracted organic layer is _{dried with MgSO 4} and the solvent is removed using an evaporator. The reaction mixture was purified through column chromatography to obtain compound 43 (17.2 mg, 42%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.87-7.80 (m, 4H), 7.70-7.68 (m, 2H), 7.42 (d, J = 6.9 Hz, 2H), 7.42 7.34 (d, J = 7.3) Hz, 1H), 7.01(d, J = 7.6 Hz, 2H), 6.50(s, 1H), 5.72(s, 1H), 5.17(s, 1H), 4.46(m, 1H), 4.25(d, J) = 10.1 Hz, 5H), 3.91 (m, 1H), 3.79 (m, 1H), 3.12 (s, 1H), 2.90 (m, 1H), 2.87 (m, 1H), 2.71 (d, J = 12.6 Hz) , 1H), 2.35 (s, 2H), 2.32 (s, 3H), 1.66 (m, 4H), 1.42 (s, 2H), 0.86-0.85 (m, 2H), 0.62-0.61 (m, 2H).

<Comparative Example 2> Preparation of compound 45

Using commercially available 44 (33.6 mg, 0.184 mmol) and 42 (38 mg, 0.221 mmol) as starting materials, the final compound 45 was obtained in the same manner as in the derivative 43 (33.8 mg, 45%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.30-7.28(m, 2H), 6.98-6.88(m, 3H), 5.59(s, 1H), 5.02(s, 1H), 4.48(m, 1H) , 4.31-4.21(m, 3H), 4.14-4.12(m, 2H), 3.88-3.83(m, 2H), 3.80-3.75(m, 2H), 3.12(m, 1H), 2.88(m, 1H) , 2.72 (m, 1H), 2.37 (t, J = 7.3 Hz, 2H), 1.75-1.57 (m, 4H), 1.48-1.38 (m, 2H).

<Comparative Example 3> Preparation of compound 16

In the same manner as in Step 1 of Example 1, compound 16 was prepared.

<Experimental Example 1> Evaluation of p38 MAPK (mitogen-activated protein kinases) removal ability of the compound of Examples

In order to confirm the removal of p38 MAPK, the reduction of p38 MAPK was confirmed after treatment with each compound in Huh7 cells, a hepatocellular carcinoma cell line in which p38 MAPK is constantly generated.

Specifically, Huh7 cells were cultured in Dulbecco's modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and penicillin/streptomycin (100 U/ml). In a 12-well plate, Huh7 cells were treated with 20 μM each of Examples 1 to 3 (Compounds 23-25) and Examples 5 to 8 (Compounds 31-34) according to the present invention, and _{incubated in a CO 2} incubator for 24 hours. It was confirmed how each compound had an effect on the decrease in the amount of p38 MAPK in cells through immunoblotting.

After culturing the cells according to the experimental conditions, they are washed with cold PBS. Thereafter, the cells were harvested and separated at 12000 rpm for 3 minutes. The pellet was lysed with 2X sample buffer (1M Tris-HCl pH 6.8, 50% glycerol, 10% SDS, 2-mercaptoethanol, 1% bromophenol blue) and boiled at 100°C for 10 minutes. The prepared protein sample was electrophoresed (Sodium Dodecyl sulfate poly acrylamide gel electrophoresis, SDS-PAGE) and transferred to a PVDF membrane (manufacturer: Millipore). In order to prevent non-specific binding of the antibody to the PVDF membrane, blocking was performed for 1 hour at room temperature with a 5% bovine serum albumin (BSA, manufacturer: RMbio) solution. Each target antibody was diluted in 5% bovine serum albumin (BSA, manufacturer: RMbio) solution, and the PVDF membrane was reacted overnight at 4°C. Then, the antibody-diluted BSA solution was discarded and the PVDF membrane was washed 5 times with PBST buffer (PBS, 0.5% tweene 20). Finally, PBST buffer diluted with Horse radish peroxidase (HRP)-conjugated secondary antibody (manufacturer: Cell signaling Technology) was added to the PVDF membrane and reacted at room temperature for 2 hours. After washing with PBST buffer 5 times, the amount of protein in the membrane was confirmed using HRP substrate (product name: Luminata Forte, manufacturer: Millipore).

2 is a result of confirming the p38 MAPK removal ability of 7 types of compounds according to an embodiment of the present invention by immunoblotting method.

As shown in FIG. 2 , treatment with each compound induced the removal of p38 MAPK without affecting the total protein level (β-actin; cytostatic gene). Among them, it was confirmed that compound 24 (Example 2) most effectively induced a decrease in p38 MAPK. It was confirmed that compound 24 (Example 2) was the most effective substance through three repeated experiments.

<Experimental Example 2> Concentration-dependent evaluation of p38 MAPK removal ability of compound 24 (Example 2)

In order to determine whether compound 24 according to the present invention (Example 2) induces the removal of p38 MAPK even at a low concentration, p38 MAPK-Flag was overexpressed in HEK 293T (Human Embryonic Kidney 293T) cells and then treated with compound 24 for immunity Blotting was performed.

Specifically, HEK 293T cells were cultured in Dulbecco's modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and penicillin/streptomycin (100U/ml). Then, overexpression of p38 MAPK-Flag was induced in HEK 293T cells through transfection. In a 12-well plate, HEK 293T cells were treated with compound 24 (Example 2) according to the present invention by concentration and cultured for 24 hours.

3 is a result of confirming the removal ability of p38 (Flag) and P-p38 according to the treatment concentration of Compound 24 according to Example 2 of the present invention by immunoblotting method.

As shown in FIG. 3 , treatment with compound 24 removed p38 MAPK-Flag in a concentration-dependent manner without affecting the total protein level (β-actin), and p38 MAPK phosphorylated P-p38 had a lower concentration. It was also confirmed that it was effectively removed. This indicates that compound 24 (Example 2) selectively induces and eliminates P-p38 ubiquitination.

<Experimental Example 3> Identification of a moiety that selectively binds to p38 MAPK in the example compound

The example compound of the present invention is composed of [p38 Ligand Moiety]-[Linker]-[E3 Ligand Moiety], and in order to find out which moiety is a moiety that selectively binds to p38 MAPK, the following experiment was performed.

Specifically, Compound 43 (Comparative Example 1) in which Biotin was bound instead of E3 Ligase Ligand Moiety (thalidomide derivative) of Compound 24 (Example 2) was synthesized. Thereafter, a pull-down assay was performed using Biotin. For an accurate comparison of whether p38 MAPK is detected in the pull-down assay due to the binding of [p38 Ligand Moiety] and p38 MAPK of Compound 24, Compound 45 that binds Biotin to Linker except for [p38 Ligand Moiety] in Compound 24 was used. It was used as a control.

Biotin-pull-down asaay was performed as follows. BV-2 cells were lysed using 0.1% TritonX-100. Compound 43 synthesized with Biotin and Compound 45 synthesized with Linker were treated at a concentration of 20 μM in the lysate and reacted at 37° C. overnight. Then, 40 μL of agarose beads linked to Streptavidin, which is well known for binding to biotin, were added to the lysate and reacted at 37° C. for 4 hours. Then, Streptavidin was settled by centrifugation at 4000 rpm for 1 minute and the supernatant was removed. After washing with 0.1 % Triton X-100 Lysis buffer, Streptavidin was submerged again by centrifugation at 4000 rpm for 1 minute. This process was repeated 5 times to remove the Biotin compound bound to Streptavidin and other impurities from which the protein bound to the compound was removed. After adding 2X sample buffer, the sample was prepared by boiling at 100° C. for 10 minutes. Protein samples were then analyzed by SDS-PAGE and immunoblotting.

Figure 4 shows [p38 Ligand Moiety in Comparative Example 1 (Compound 43) and Example 2 (Compound 24) in which biotin was conjugated instead of [E3 Ligand Moiety (thalidomide derivative)] in Example 2 (Compound 24) of the present invention. ] is the result of evaluating the p38 MAPK binding ability of Comparative Example 2 (Compound 45) in which Biotin was bound to the Linker, respectively.

As shown in FIG. 4 , the detection of p38 MAPK was confirmed in the group treated with Comparative Example 1 (Compound 43) containing [p38 Ligand Moiety], whereas Comparative Example 2 without [p38 Ligand Moiety] In the group treated with (Compound 45), it was confirmed that p38 MAPK was not detected (see Pull-down assay). This result proves that the [p38 Ligand Moiety] site selectively binds to p38 MAPK in the Example compound of the present invention.

<Experimental Example 4> Proteasome-dependent p38 MAPK removal confirmation of Example compound

An experiment was conducted to confirm that the Example compound of the present invention induces the removal of p38 MAPK using the intracellular proteasome system.

Specifically, in a 12-well plate, Huh7 cells were treated with 20 μM of Compound 24 (Example 2) for 24 hours, and in the last 3 hours, Lysosome Inhibitor Chloroquine (CQ) and Proteasome Inhibitor MG132 were treated with 100 μM and 10 μM, respectively. Lysosome and proteasome functions in cells were blocked through the last 3 hours. Next, evaluation was performed in the same manner as in the immunoblotting method of Experimental Example 1, and significance was confirmed through repetition of three or more times.

5 is a result confirming that the Example compound according to the present invention removes p38 MAPK using the intracellular proteasome system by immunoblotting method.

As shown in FIG. 5 , recovery of the amount of p38 MAPK protein was confirmed only in the experimental group in which the function of the proteasome was reduced (MG132 + compound 24 treatment group). This is a result confirming that the example compound reduces p38 MAPK using the intracellular proteasome system.

<Experimental Example 5> Confirmation of CRBN-dependent p38 MAPK removal of Example compounds

An experiment was conducted to confirm that the Example compound of the present invention induces the removal of p38 MAPK using cereblon (CRBN), one of the E3 ligase complex proteins in the cell.

Specifically, in a 12-well plate, BV2 cells were treated with Pomalidomide, a CRBN inhibitor, for 6 hours at each concentration to inhibit CRBN. Thereafter, the cells were separated and lysed after treatment with Compound 24 for 24 hours. Next, evaluation was performed in the same manner as in the immunoblotting method of Experimental Example 1.

6 is a result of confirming that the Example compound according to the present invention removes p38 MAPK using cereblon (CRBN), one of the E3 ligase complex proteins in cells, by immunoblotting method.

As shown in FIG. 6 , it was confirmed that the amount of P-p38 MAPK protein was recovered in the group treated with Compound 24 (Example 2) after CRBN was inhibited by treatment with Pomalidomide. This is a result confirming that Compound 24 induces a decrease in P-p38 MAPK mediated by CRBN.

<Experimental Example 6> Confirmation of ubiquitination-dependent p38 MAPK removal of Example compounds

An experiment was conducted to confirm that the Example compound induces the removal of p38 MAPK using ubiquitination.

Specifically, P38 MAPK protein was isolated by immunoprecipitation to determine whether proteasome-dependent protein reduction through ubiquitination of P38 MAPK occurred. For the immunoprecipitation method, 2 X 10 ⁷ HEK293T cells were prepared for each sample, treated with Compound 24 (Example 2) and Compound 16 (Comparative Example 3) with 10 μM and cultured for 24 hours. The cells were then lysed in 0.5% Triton X-100 lysis buffer (50 mM Tris, 150 mM NaCl, 1 mM EDTA, 0.5% triton X-100). Then, a small amount of the lysate was sampled through 5X sample buffer, and Anti-p38 rabbit antibody (manufacturer: Cell Signaling Technology) was added to the lysate and reacted at 4°C overnight. Then, Protein A / G resins (manufacturer: Sigma-Aldrich) were added and reacted at 4 °C for 4 hours. Impurities other than proteins bound to A/G resins were removed by washing with 0.5 % Triton X-100 lysis buffer. Protein samples were then analyzed by SDS-PAGE and immunoblotting.

7 is a result confirming that the Example compound according to the present invention removes p38 MAPK using the ubiquitination system by SDS-PAGE and immunoblotting methods.

As shown in Figure 7, it was confirmed that ubiquitination of p38 MAPK protein occurred in the group treated with Compound 24 (Example 2), whereas Compound 16, the compound of the step before attaching [E3 ligase Ligand Moiety] in Compound 24 ( In the group treated with Comparative Example 3), it was confirmed that ubiquitination of the p38 MAPK protein was not increased.

<Experimental Example 7> Confirmation of p38 MAPK, P-p38 MAPK reduction induction of the compound of Example in neurons

In order to confirm whether the Example compound induces a decrease in p38 MAPK in neurons, an experiment was conducted in four different mouse cell lines.

Specifically, in each experiment, as indicated in FIG. 8, compound 24 was treated at a concentration of 0.001 to 10 μM and then cultured for 24 hours. After culture, immunoblotting was performed in the same manner as in Experimental Example 1.

8 is a result confirming that the compound of Example according to the present invention induces a concentration-dependent decrease in p38 MAPK and P-p38 MAPK in neurons by immunoblotting method.

Figure 8(A): Astrocytes

Figure 8(B): Neuroblasts

Figure 8(C): Microglia

Figure 8(D): Hippocampal Neuronal cells

Figure 8 (E): After repeated experiments three or more times in microglia (Microglia), the relative values are shown numerically.

As shown in FIG. 8, as a result of treatment with Compound 24 (Example 2) in glial cells (astrocyte, FIG. 8A) and neuroblastic cells (Neuroblast, FIG. 8B) concentration-dependently decreased, P-p38 MAPK was 0.01 μM, 0.1 It was confirmed that it also decreased in μM. As a result of the same experiment in microglia (Microglia, FIG. 8C) and hippocampal neuronal cells (FIG. 8D), it was confirmed that p38 was decreased in a compound 24 concentration-dependent manner, and that P-p38 was decreased even at 0.1 μM. . 8A to 8D, it was found that Compound 24 more effectively reduced P-p38 MAPK in neurons.

<Experimental Example 8> Evaluation of reduction of p38 MAPK-related cytokine production due to treatment with Example compound

When p38 MAPK is removed by treatment with the compound of Example, it is expected that the amount of cytokine produced by p38 MAPK will decrease, and an experiment was conducted to verify this.

Specifically, microglia, BV2 cells, were cultured in a 24-well plate. In order to compare whether compound 24 (Example 2) ubiquitinates p38 MAPK in cells and removes p38 in a proteasome-dependent manner, the production of p38-related cytokines is also reduced, compound 16 (Comparative Example 3) was used as a control was treated and compared. The experimental conditions are as follows. Each compound was pre-treated with 10 μM or 20 μM for 24 hours, and then diluted with LPS (lipopolysaccharide) at 1 μg/mL in a fresh cell culture medium to induce cytokine production, and then cultured. After 24 hours, the supernatant of the cell culture medium was collected and the cytokine production was analyzed by enzyme-linked immunosorbent assay (ELISA, manufacturer: Bio-kit). The analysis method followed the protocol presented in the Bio-kit. The experiment was repeated three or more times and is shown in the graph of FIG. 9 .

9 is a result of confirming by the ELISA method that the amount of p38 MAPK-related cytokine production due to treatment with the compound of Example of the present invention is reduced.

As shown in FIG. 9 , it was confirmed that the production amount of p38 MAPK-related cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) decreased in the group treated with Compound 24 (Example 2). . It was confirmed that the decrease was more effectively compared with compound 16 (Comparative Example 3).

<Experimental Example 9> Evaluation of decrease in mRNA expression level of p38 MAPK-related cytokines due to treatment with Example compounds

When p38 MAPK is removed by treatment with the compound of Example, it is expected that the mRNA expression level of p38 MAPK-related cytokine will also decrease, and an experiment was conducted to verify this.

Specifically, microglia, BV2 cells, were cultured in a 6-well plate. Thereafter, compound 24 (Example 2) was treated at a concentration of 10 μM and 20 μM for 24 hours. In order to increase the expression of P38 MAPK-related cytokines, the last 6 hours of the 24 hour treatment of the compound was treated with LPS 1 μg/mL. Then, mRNA transcription of cytokines was analyzed by qRT-PCR (Real-Time Quantitative Reverse Transcription 　 PCR). For RNA isolation, only pure RNA was extracted using an RNA purification kit. The concentration and purity of the isolated RNA were measured with a spectrophotometer. For RNA of each sample, cDNA (complementary DNA) was synthesized using a cDNA synthesis kit, and inflammatory cytokines interleukin 6 (IL-6) and interleukin 1 beta (IL-1β) were synthesized by qRT-PCR analysis using SYBR Green. and interleukin 12 (IL-12) mRNA expression levels were measured.

10 is a result confirming that the Example compound of the present invention reduces the mRNA expression level of p38 MAPK-related cytokines by qRT-PCR method.

As shown in FIG. 10 , the mRNA levels of interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and interleukin 12 (IL-12) decreased in the group treated with compound 24 (Example 2). Confirmed. From these results, it can be seen that Compound 24 (Example 2) induces the removal of p38 MAPK, thereby also reducing the mRNA expression level of p38 MAPK-related inflammatory cytokines.

Preparation example of drug

The active substance according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods containing the active substance according to the present invention as an active ingredient, but the present invention is not limited thereto.

<Pharmaceutical Preparation Example 1> Preparation of powder

active substance 2 g

lactose 1 g

After mixing the above ingredients, the powder was prepared by filling in an airtight cloth.

<Pharmaceutical Preparation Example 2> Preparation of tablets

active substance 100 mg

corn starch 100 mg

lactose 100 mg

magnesium stearate 2 mg

After mixing the above ingredients, tablets were prepared by tableting according to a conventional method for manufacturing tablets.

<Pharmaceutical Preparation Example 3> Preparation of capsules

active substance 100 mg

corn starch 100 mg

lactose 100 mg

magnesium stearate 2 mg

After mixing the above ingredients, the capsules were prepared by filling in gelatin capsules according to a conventional manufacturing method of capsules.

<Pharmaceutical Preparation Example 4> Preparation of injection

active substance 10 μg/ml

dilute hydrochloric acid BP until pH 3.5

Sodium Chloride BP for Injection up to 1 ml

The active substance according to the present invention was dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution was adjusted to pH 3.5 using dilute hydrochloric acid BP, the volume was adjusted using sodium chloride BP for injection, and the mixture was sufficiently mixed. . The solution was filled in a 5 ml Type I ampoule made of clear glass, sealed under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120° C. for 15 minutes or more to prepare an injection solution.

<Pharmaceutical Preparation Example 5> Preparation of nasal absorbent (Nasal spray)

active substance 1.0 g

sodium acetate 0.3 g

methylparaben 0.1 g

Propylparaben 0.02 g

sodium chloride appropriate amount

HCl or NaOH pH adjustment appropriate amount

Purified water appropriate amount

According to a conventional method for preparing nasal absorbents, prepare to contain 3 mg of active substance per 1 mL of saline (0.9% NaCl, w/v, solvent is purified water), fill it in an opaque spray container, and sterilize to obtain nasal absorbent. prepared.

<Pharmaceutical Preparation Example 6> Preparation of liquid preparation

active substance 100 mg

Lee Seonghwadang 10 g

mannitol 5 g

Purified water appropriate amount

According to a conventional liquid preparation method, each component is added and dissolved in purified water, lemon flavor is added, the above components are mixed, and purified water is added to adjust the total to 100 mL, then filled in a brown bottle and sterilized to prepare a liquid preparation did.

Manufacturing example of health functional food

The active substance according to the present invention can be manufactured into various types of health functional food depending on the purpose. The following exemplifies the manufacturing method of several health functional foods containing the active ingredient according to the present invention as an active ingredient, but the present invention is not limited thereto.

<Health functional food manufacturing example 1> Manufacture of health functional food

active substance 100 mg

vitamin mixture appropriate amount

vitamin A acetate 70 μg

vitamin E 1.0 mg

vitamin B1 0.13 mg

vitamin B2 0.15 mg

vitamin B6 0.5 mg

vitamin B12 0.2 μg

vitamin C 10 mg

biotin 10 μg

Nicotinamide 1.7 mg

folic acid 50 μg

Calcium Pantothenate 0.5 mg

mineral mixture appropriate amount

ferrous sulfate 1.75 mg

zinc oxide 0.82 mg

magnesium carbonate 25.3 mg

monobasic potassium phosphate 15 mg

Dibasic Calcium Phosphate 55 mg

Potassium Citrate 90 mg

calcium carbonate 100 mg

magnesium chloride 24.8 mg

The composition ratio of the vitamin and mineral mixture is relatively suitable for health functional food, but the composition is mixed in a preferred embodiment, but the mixing ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health functional food manufacturing method. Then, the granules can be prepared and used in the preparation of a health functional food composition according to a conventional method.

<Health functional food manufacturing example 2> Manufacture of health functional beverage

active substance 100 mg

citric acid 100 mg

oligosaccharide 100 mg

Plum Concentrate 2 mg

Taurine 100 mg

Purified water is added to 500 mL

After mixing the above ingredients according to a conventional health drink manufacturing method, after stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in one sterilized container, sealed and sterilized, and then refrigerated. used in the manufacture of health beverage compositions of Although the composition ratio is a composition that is relatively suitable for a beverage of preference in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as demand class, demand country, and use purpose.

Manufacturing example of health food

The active substance according to the present invention can be manufactured into various types of health food depending on the purpose. The following exemplifies the manufacturing method of several health foods containing the active ingredient according to the present invention as an active ingredient, but the present invention is not limited thereto.

<Health food production example 1> Production of dairy products

0.01-1 parts by weight of the active substance of the present invention was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.

<Health food production example 2> Preparation of wire

Brown rice, barley, glutinous rice, and barley radish were pregelatinized by a known method and dried, and then roasted and prepared as a powder having a particle size of 60 mesh with a grinder. Black soybeans, black sesame, and perilla were also steamed and dried by a known method, and then roasted and prepared into powder having a particle size of 60 mesh with a grinder. The active material of the present invention was concentrated under reduced pressure in a vacuum concentrator to obtain a dry powder. The above-prepared grains, seeds, and dry powders of active substances were prepared by blending them in the following ratios.

Grains (34 parts by weight of brown rice, 19 parts by weight of barley, 20 parts by weight of barley),

Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame),

active substance (2 parts by weight),

Reishi (1.5 parts by weight), and

Rehmannia (1.5 parts by weight).

Claims (16)

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

(In the formula A,
The p38 Ligand Moiety is

ego;
The E3 Ligand Moiety is

ego;
The Linker is

,

,

,

,

or

ego,
Wherein n and m are independently integers from 1 to 10,
wherein a and b are independently integers from 1 to 10).
According to claim 1,
Wherein n is an integer from 1 to 5,
Wherein m is an integer of 3 to 7,
wherein a is an integer from 1 to 5,
wherein b is an integer of 1 to 7, or a pharmaceutically acceptable salt thereof.
3. The method of claim 2,
Wherein n is an integer of 1 to 3,
wherein m is 5,
wherein a is an integer of 1 to 2,
wherein b is 2 or 5, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by Formula A is a compound or a pharmaceutically acceptable salt thereof, characterized in that one selected from the following compound group.
1) 2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethyl (2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (23);
2) 2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy)ethyl (2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (24);
3) 2-(2-(2-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)ethoxy) ethoxy)ethyl(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (25);
4) 5-(4-(5'-(cyclopropylcarbamoyl)-2'-methyl-[1,1'-biphenyl]-4-carbonyl)phenoxy)pentyl(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate (26);
5) N-cyclopropyl-4'-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy) ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (31);
6) N-cyclopropyl-4'-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) )oxy)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (32);
7) N-cyclopropyl-4'-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-) 4-yl)oxy)ethoxy)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (33);
8) N-cyclopropyl-4'-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy )pentyl)oxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (34); and
9) (S)-N-cyclopropyl-4'-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-diox) Soisoindolin-4-yl)oxy)acetamido)ethoxy)ethoxy)benzoyl)-6-methyl-[1,1′-biphenyl]-3-carboxamide (41).
As shown in Scheme 1 below,
synthesizing compound 14A by reacting compound 8A with compound 13 in an organic solvent (step 1);
synthesizing compound 19A by reacting compound 14A with 4-nitrophenylchloroformate in an organic solvent (step 2); and
A method of preparing compound A1 comprising: synthesizing compound A1 by reacting compound 19A with compound 5 in an organic solvent (step 3):
[Scheme 1]

(In Scheme 1,
L ¹ is —(CH ₂ ) _n —OH or —(CH ₂ CH ₂ —O) _n —CH ₂ CH ₂ OH, wherein n is an integer from 1 to 10;
L ² is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).
6. The method of claim 5,
The organic solvent of steps 1 to 3 is independently DMF (dimethylformamide), DCM (dichloromethane), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, diisopropyl ether, diethyl ether, Dioxane, acetonitrile, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), acetone, and a manufacturing method, characterized in that at least one selected from the group consisting of chlorobenzene.
As shown in Scheme 2 below,
synthesizing compound 14A by reacting compound 8A with compound 13 in an organic solvent (step 1);
synthesizing compound 27A by reacting compound 14A with p-TsCl (p-Toluenesulfonyl chloride) in an organic solvent (step 2); and
A method of preparing compound A2 comprising: synthesizing compound A2 by reacting compound 27A with compound 6 in an organic solvent (step 3):
[Scheme 2]

(In Scheme 2,
L ¹ is —(CH ₂ ) _n —OH or —(CH ₂ CH ₂ —O) _n —CH ₂ CH ₂ OH, wherein n is an integer from 1 to 10;
L ² is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).
8. The method of claim 7,
The organic solvent of steps 1 to 3 is independently DMF (dimethylformamide), DCM (dichloromethane), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, diisopropyl ether, diethyl ether, Dioxane, acetonitrile, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), acetone, and a manufacturing method, characterized in that at least one selected from the group consisting of chlorobenzene.
As shown in Scheme 3 below,
synthesizing compound 37A by reacting compound 14 with compound 36A in an organic solvent (step 1);
synthesizing compound 38A by reacting compound 37A with hydrochloric acid in an organic solvent (step 2); and
A method of preparing compound A3 comprising: synthesizing compound A3 by reacting compound 38A with compound 40 in an organic solvent (step 3):
[Scheme 3]

(In Scheme 3,
L ³ is -(CH ₂ ) _n -OMs or -(CH ₂ CH ₂ -O) _n -CH ₂ CH ₂ OMs, wherein n is an integer from 1 to 10;
L ⁴ is -(CH ₂ ) _m -O- or -(CH ₂ CH ₂ -O) _m -, wherein m is an integer from 1 to 10).
10. The method of claim 9,
The organic solvent of steps 1 to 3 is independently DMF (dimethylformamide), DCM (dichloromethane), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, diisopropyl ether, diethyl ether, Dioxane, acetonitrile, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), acetone, and a manufacturing method, characterized in that at least one selected from the group consisting of chlorobenzene.
A pharmaceutical composition for the prevention or treatment of chronic inflammatory diseases, comprising the compound represented by Formula A of claim 1 or a pharmaceutically acceptable salt thereof.
12. The method of claim 11,
The chronic inflammatory disease is Alzheimer's, Parkinson's disease, inflammatory bowel disease, non-alcoholic chronic hepatitis, chronic hepatitis, Crohn's disease, pancreatitis, esophagitis, gastritis, colitis, ulcerative colitis, pneumonia, bronchitis, sore throat, myocardial infarction, heart failure, arthritis , psoriatic arthritis, rheumatoid arthritis, renal failure, psoriasis, anemia, diabetes, fibrosis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, periodontitis, neuropathic pain and idiopathic inflammatory myopathy. A pharmaceutical composition, characterized in that the selected disease.
A health functional food composition for the prevention or improvement of chronic inflammatory diseases comprising the compound represented by Formula A of claim 1 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13,
The chronic inflammatory disease is Alzheimer's, Parkinson's disease, inflammatory bowel disease, non-alcoholic chronic hepatitis, chronic hepatitis, Crohn's disease, pancreatitis, esophagitis, gastritis, colitis, ulcerative colitis, pneumonia, bronchitis, sore throat, myocardial infarction, heart failure, arthritis , psoriatic arthritis, rheumatoid arthritis, renal failure, psoriasis, anemia, diabetes, fibrosis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, periodontitis, neuropathic pain and idiopathic inflammatory myopathy. Health functional food composition, characterized in that the selected disease.
A health food composition for the prevention or improvement of chronic inflammatory diseases comprising the compound represented by Formula A of claim 1 or a pharmaceutically acceptable salt thereof.
16. The method of claim 15,
The chronic inflammatory disease is Alzheimer's, Parkinson's disease, inflammatory bowel disease, non-alcoholic chronic hepatitis, chronic hepatitis, Crohn's disease, pancreatitis, esophagitis, gastritis, colitis, ulcerative colitis, pneumonia, bronchitis, sore throat, myocardial infarction, heart failure, arthritis , psoriatic arthritis, rheumatoid arthritis, renal failure, psoriasis, anemia, diabetes, fibrosis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, periodontitis, neuropathic pain and idiopathic inflammatory myopathy. A health food composition, characterized in that the disease is selected.

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