Isoindolinone derivative with quinoline amide structure and application thereof

Abstract

The present invention relates to an isoindolinone derivative compound having a quinoline-substituted glutarimide parent nucleus and an application thereof, and more particularly, to an isoindolinone derivative compound having a thalidomide analogue structure and having a quinoline-substituted glutarimide parent nucleus. The compound of chemical formula 1 according to the present invention specifically binds to CRBN protein and participates in its function. Therefore, the compound of the present invention can be effectively used for preventing or treating leprosy, chronic graft versus host disease, inflammatory disease or cancer caused by the action of CRBN protein.

Description

Technical Field

[0001] Disclosed are an isoindolinone derivative having a quinoline amide structure and its use. More specifically, disclosed is an isoindolinone-derived compound having a quinoline amide structure, which exhibits a prophylactic or therapeutic effect on leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancer. Background Art

[0002] Thalidomide is a racemic compound, sold under the trade name THALOMID (registered trademark) and the chemical name α-(N-phthalimido) glutarimide or 2-(2,6-dioxo-3-piperidyl)-1H-isoindole-1,3(2H)-dione. Thalidomide was initially developed for the treatment of morning sickness but was withdrawn due to its teratogenic effects. Thalidomide is currently approved in the United States for the treatment of erythema nodosum leprosum in human leprosy (Korean Patent No. 10-0671366).

[0003] In addition, it has been reported that thalidomide can be used in patients with leprosy, chronic graft-versus-host disease, rheumatoid arthritis, sarcoidosis, certain inflammatory skin diseases, and inflammatory bowel disease, and that thalidomide can be used in combination with other drugs for the treatment of ischemia / reperfusion associated with cardiac and cerebral artery occlusion (U.S. Patent No. 05643915).

[0004] Recently, thalidomide has been used to treat specific types of cancer. These include refractory multiple myeloma, brain cancer, melanoma, breast cancer, colon cancer, mesothelioma, and renal cell carcinoma. It has also been reported that thalidomide is used to prevent the expression of chronic cardiomyopathy induced by doxorubicin in rats. Other reports on the use of thalidomide in the treatment of specific cancers include its combination with carboplatin for the treatment of glioblastoma multiforme. It has been reported that thalidomide can also be used as an analgesic for the treatment of astrocytoma (Costa, P.T. et al., Blood, 92 (Suppl 1, Pt 2), 235b, 1998; Marx, G.M. et al., Proc Am Soc Clin Oncol., 454a, 1999; Singhal, S. et al., N Engl J Med., 341(21), 1565-1571, 1999; Zwart, D., Arzneimittelforschung, 16(12), 1688-1689, 1966).

[0005] In addition, thalidomide has also been used for the prevention or treatment of various conditions such as lupus nephritis, fibromyalgia, schizophrenia, central nervous system diseases, diabetes, and inflammatory diseases. However, due to the fatal side effect of birth defects in infants when taken by pregnant women, it was withdrawn from the market at the end of 1961.

[0006] Currently, active research and development are underway for a derivative that can fully retain the various physiological utilities of thalidomide while also addressing its serious side effect issues.

[0007] The degradation of intracellular proteins mainly occurs through the ubiquitin-proteasome system (UPS). When proteins known as E1, E2, and E3 ligases transfer ubiquitin (Ub), which consists of 76 amino acids, to the protein to be degraded (the substrate), causing polyubiquitination, the 26S proteasome recognizes this and degrades the protein.

[0008] Lenalidomide and pomalidomide are derivatives of thalidomide and are known as immunomodulatory drugs (IMiDs). They bind to the E3 ligase called cerebron (CRBN) and induce the degradation of Ikaros (IKZF1) and aiolos (IKZF3), which are zinc finger transcription factors, and are used as therapeutic drugs for multiple myeloma. In particular, lenalidomide can degrade CK-1a and is also used as a therapeutic drug for patients with 5q-del-MDS and is one of the best-selling anti-cancer drugs globally.

[0009] GSPT1 is a GTPase that forms a complex with eRF1 upon GTP binding to bind to the stop codon of mRNA. If GTP is converted to GDP, it dissociates from eRF1, thus participating in the proteolytic cleavage of eRF1 (Cell Reports, 2014, 8, 59 - 65).

[0010] It is known that GSPT1 knockdown can reduce the phosphorylation of 4E-BP1 and kinase S6K1, thereby inhibiting the activity of mTOR and inducing G1 arrest (Molecular and cellular biology, 2007, 27, 5619).

[0011] GSPT1 is overexpressed in the colon cancer cell line (HCT116) and is involved in cell growth and migration. When GSPT1 knockdown occurs, the expression of c-myc, the apoptosis inhibitor survivin, and Bcl2L15 is confirmed to induce cell death (Biomed. Pharmacother. 2015, 74, 138 - 144).

[0012] In addition, Celgene Corporation reported that the lenalidomide-derived CC-885 compound can degrade the novel protein GSPT1, exhibits high cytotoxicity in various blood cancer cells, and through optimization research, the CC-90009 substance was derived and is currently undergoing a phase 1 clinical trial with R, R-AML patients as the subjects (Nature, 2016, 14, 252; Blood, 2021).

[0013] A novel thalidomide derivative based on piperidine-2,6-dione was developed. This novel thalidomide derivative completely retains the physiological activities exhibited by thalidomide but does not have the side effects of thalidomide, and it was confirmed that this compound can promote the protein degradation of GSPT1 and Aiolos. In addition, it was also confirmed that the developed compound has sufficient cytotoxicity in cancer cells, especially in the case of urea derivative-substituted compounds and triazine-derived compounds, and the cytotoxic activity against cancer cells is more excellent (Korean Patent Publication No. 10 - 2020 - 0054046).

[0014] In addition, it is reported that 5-substituted isoindoline compounds not only have TNF-α inhibitory effects and IL-2 generation effects, but also exhibit anti-proliferative effects on various cancer cells including prostate, colon, pancreatic, and breast tumors (Korean Patent Publication No. 10 - 2011 - 0019761), and it is reported that isoindoline compounds show effects on various diseases including cancer by controlling angiogenesis, inhibiting the generation of specific cytokines such as TNF-α, and stimulating the generation of specific cytokines such as IL-10 (Korean Patent No. 10 - 1696938).

[0015] In addition, it has been reported that a method for predicting and treating various diseases including cancer by administering a compound having isoindolinone and glutarimide (Korean Patent Publication No. 10-2018-0095094), and it has been reported that a compound having an aminoamide linker is effective in treating various diseases such as inflammatory diseases and cancer as a regulator of various protein activities such as cytokines, TNF-α, and GSPT1 (Australian Patent Publication No. 2019284608).

[0016] The present inventors have confirmed that the compound represented by Chemical Formula 1 of the present invention having a quinolineamide structure exhibits excellent physiological activity against cancer cells as compared with these existing compounds developed in prior patents, thereby completing the present invention. SUMMARY OF THE INVENTION

[0017] PROBLEM TO BE SOLVED BY THE INVENTION

[0018] The present inventors have developed an isoindolinone-derived compound having a quinoline-substituted glutarimide mother nucleus that exhibits a prophylactic or therapeutic effect against leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancer, and evaluated its activity, thereby completing the present invention.

[0019] Accordingly, an object of the present invention is to provide a compound represented by the following Chemical Formula 1, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0020] MEANS FOR SOLVING THE PROBLEM

[0021] The present invention relates to a compound represented by the following Chemical Formula 1, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0022] [Chemical Formula 1]

[0023]

[0024] In the above formula,

[0025] m is 1 or 2;

[0026] n is 0 or 1;

[0027] p is an integer from 1 to 3;

[0028] R 1 is hydrogen or deuterium (D; deuterium);

[0029] R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, carboxylic acid, C 1-5 alkyl carboxyl, amino, acetylamino, sulfuric acid, C 1-5 alkyl sulfate, nitro, mono(C 1-5 alkyl)amino or di(C 1-5(alkyl)amino, C 1-5 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, at least one substituent selected from the group consisting of

[0030] Furthermore, the present invention relates to a compound represented by the following Chemical Formula 2, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0031] [Chemical Formula 2]

[0032]

[0033] In the formula,

[0034] m is an integer from 0 to 3;

[0035] n is 0 or 1;

[0036] p is an integer from 1 to 3;

[0037] X 1 、X 2 are independently N, CH or C;

[0038] R 1 is hydrogen or deuterium (D; deuterium);

[0039] R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carboxylic acid, C 1-5 alkyl carboxyl, amino, acetylamino, sulfuric acid, C 1-5 alkyl sulfate, nitro, mono(C 1-5 alkyl)amino or di(C 1-5 alkyl)amino, C 1-5 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, at least one substituent selected from the group consisting of

[0040] R 4 is hydrogen, halogen, C 1-5 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl or halo-C 1-3 alkoxy.

[0041] More specifically, examples of the compound of Chemical Formula 1 of the present invention are selected from:

[0042] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-phenylquinoline-4-carboxamide (Compound 1),

[0043] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-isopropylphenyl)quinoline-4-carboxamide (Compound 2),

[0044] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methyl-2-phenylquinoline-4-carboxamide (Compound 3),

[0045] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-phenylquinoline-4-carboxamide (Compound 4),

[0046] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(m-tolyl)quinoline-4-carboxamide (Compound 5),

[0047] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(p-tolyl)quinoline-4-carboxamide (Compound 6),

[0048] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(pyridin-4-yl)quinoline-4-carboxamide (Compound 7),

[0049] 2-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide (Compound 8),

[0050] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide (Compound 9),

[0051] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-(pyridin-3-yl)quinoline-4-carboxamide (Compound 10),

[0052] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(m-tolyl)quinoline-4-carboxamide (Compound 11),

[0053] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methyl-2-phenylquinoline-4-carboxamide (Compound 12),

[0054] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(o-tolyl)quinoline-4-carboxamide (Compound 13),

[0055] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-fluorophenyl)quinoline-4-carboxamide (Compound 14), and

[0056] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-fluorophenyl)quinoline-4-carboxamide (Compound 15).

[0057] In addition, the compounds represented by the formula 1 of the present invention are prepared by the methods of Reaction Scheme 1 and Reaction Scheme 2 below.

[0058] [Reaction Scheme 1]

[0059]

[0060] [Reaction Scheme 2]

[0061]

[0062] In the said Reaction Scheme 1, the preparation methods of each intermediate 2 to intermediate 5 are as follows.

[0063] Reaction Scheme 2 is prepared by the method disclosed in Korean Patent Publication No. 10-2010-7029476.

[0064] The preparation method of the compound represented by the formula 1 according to the present invention shown in the said preparation method should be understood as an example of the method for preparing the compound of the present invention, and any method capable of preparing the compound represented by the formula 1 prepared by the present invention is included in the present invention without limitation. In addition, it should be understood that the methods proposed in the specification of the present invention and the preparation methods that can be easily changed, modified and tried by those of ordinary skill in the art are also included in the scope of the present invention, which can be understood as obvious to those skilled in the art.

[0065] Unless otherwise specified, the following terms in the present invention have the following meanings. Any undefined terms have the meanings understood in the art.

[0066] "Halogen" or "halogens" in the present invention means fluorine (F), chlorine (Cl), bromine (Br), iodine (I).

[0067] The term "alkyl" used in the present invention means a straight-chain or branched-chain hydrocarbon group with a single bond. For example, it includes but is not limited to methyl, ethyl, propyl, etc.

[0068] The term "alkoxy" used in the present invention refers to an oxygen group bonded to a straight-chain or branched-chain saturated hydrocarbon of a single bond. For example, it includes, but is not limited to, methoxy, ethoxy, propoxy, etc.

[0069] The term "haloalkyl" used in the present invention refers to the substituted alkyl as described above, wherein at least one hydrogen atom on the alkyl is substituted by a halogen group. For example, it includes, but is not limited to, trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0070] The term "haloalkoxy" used in the present invention refers to an alkyl-O-group, wherein at least one hydrogen atom on the alkyl is substituted by a halogen group. For example, it includes, but is not limited to, trifluoromethoxy, etc.

[0071] The term "aryl" used in the present invention refers to an aromatic ring compound, including, but not limited to, phenyl, naphthalene, anthracene, etc.

[0072] The term "heteroaryl" used in the present invention refers to an aromatic ring compound containing at least one heteroatom such as N, O or S, and includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, naphthofuranyl, quinolinyl, isoquinolinyl, quinoxalinyl, etc., according to the number, type and number of carbon atoms of the heteroatoms contained in the ring.

[0073] The compound of Formula 1 of the present invention may not only include pharmaceutically acceptable salts, but also include all salts, hydrates, solvates and prodrugs that can be prepared by conventional methods. In addition, the compounds of the present invention may contain at least one asymmetric carbon atom and can exist in racemic form and optically active form. All such compounds and diastereoisomers are included within the scope of the present invention.

[0074] In the present invention, the pharmaceutically acceptable salts refer to salts or complexes of Formula 1 having preferably biological activity. Examples of such salts are not limited thereto and include acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed from organic acids, which include acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid, etc. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those of ordinary skill in the art, in particular, including chlorides, bromides, iodides, -O-alkyls, toluene sulfates, methyl sulfates, sulfates, phosphates, or carboxylates (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamates, glycolates, and diphenylacetates).

[0075] The acid addition salts according to the present invention can be prepared by conventional methods. For example, a derivative of Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., an organic acid or an inorganic acid is added, the resulting precipitate is filtered and dried, or the solvent and the excess acid are distilled off under reduced pressure and then dried, and crystallized in an organic solvent.

[0076] In addition, an alkali can be used to prepare pharmaceutically acceptable metal salts. For the method of obtaining alkali metal or alkaline earth metal salts, for example, the compound can be dissolved in an excessive solution of alkali metal hydroxide or alkaline earth metal hydroxide, the undissolved compound salt can be filtered, and the filtrate can be evaporated and dried. At this time, as the metal salt, it is suitable for pharmaceutical use to prepare sodium salts, potassium salts or calcium salts. In addition, the corresponding salts are obtained by reacting the alkali metal salts or alkaline earth metal salts with suitable silver salts (such as silver nitrate).

[0077] In addition, the present invention relates to a pharmaceutical composition for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases or cancer, which contains the compound represented by the formula 1 or its pharmaceutically acceptable salt as an active ingredient.

[0078] According to a test example of the present invention, it was confirmed that it binds to the CRBN (celebron) protein and degrades Ikaros (IKZF1) / Aiolos and GSPT1. The CRBN protein is a kind of E3 ubiquitin ligase, and it is known to bind to pomalidomide, lenalidomide, etc., which are thalidomide and its analogs, and has the activity of attaching ubiquitin to substrate proteins such as Ikaros (IKZF1) / Aiolos protein and GSPT1 protein.

[0079] The cancer can be selected from the group consisting of breast cancer, colon cancer, lung cancer, small cell lung cancer, gastric cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, intestinal cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell cancer, renal pelvic cancer, central nervous system tumors, primary central nervous system lymphoma, spinal cord tumors, brainstem gliomas, and pituitary adenomas, but is not particularly limited thereto.

[0080] The pharmaceutical composition according to the present invention can be formulated into a suitable form together with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means a physiologically acceptable composition, and when administered to the human body, it generally does not cause allergic reactions or similar reactions, such as gastrointestinal discomfort, dizziness, etc. In addition, the composition can be made into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods for use.

[0081] As carriers, excipients and diluents included in the composition, they may include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraben, propyl paraben, talc, magnesium stearate and mineral oil. When formulating, commonly used fillers, stabilizers, binders, disintegrants, surfactants and other diluents or excipients are used for preparation. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations are prepared by mixing at least one excipient in the compound of the present invention, for example, starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. In addition, lubricants such as magnesium stearate and talc are also used in addition to simple excipients. As liquid preparations for oral use, they include suspensions, oral solutions, emulsions, syrups, etc. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients may be included, for example, wetting agents, sweeteners, flavoring agents, preservatives, etc. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), injectable esters (such as ethyl oleate), etc. can be used. As the matrix of suppositories, semi-synthetic fatty acid esters (witepsol), polyethylene glycol, tween 61, cocoa butter, glyceryl laurate, glycerin, gelatin, etc. can be used. In order to formulate a dosage form for parenteral administration, the compound of Formula 1 or its pharmaceutically acceptable salt is sterilized and mixed with auxiliaries such as preservatives, stabilizers, solubilizers or emulsifiers, salts for adjusting osmotic pressure and / or buffers, etc. and other therapeutically active substances in water to prepare a solution or suspension, and can be prepared into ampoule or vial unit dosage forms.

[0082] The pharmaceutical composition provides a pharmaceutical composition comprising the compound of Formula 1 and an excipient. The addition amount of the compound is preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight relative to the total weight of the whole composition.

[0083] A pharmaceutical composition containing the compound of Formula 1 disclosed in the present invention as an active ingredient can be administered to mammals such as mice, livestock, and humans through various routes. All administration methods are expected, for example, it can be administered orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine epidural, or intracerebrovascular injection. The dosage will vary depending on factors such as the age, sex, weight of the subject being treated, the specific disease or pathological condition being treated, the severity of the disease or pathological condition, the administration time, the administration route, the absorption, distribution, and excretion rate of the drug, the type of other drugs used, and the judgment of the prescriber. Determination of the dosage based on these factors is within the level of ordinary skill in the art, and the dosage range is generally from 0.01 mg / kg / day to about 2000 mg / kg / day. A more preferred dosage is from 1 mg / kg / day to 500 mg / kg / day. It can be administered once a day or in multiple doses. The dosage does not limit the scope of the present invention in any way.

[0084] Advantages of the Invention

[0085] The compound of Formula 1 according to the present invention specifically binds to the CRBN protein and participates in its function. Therefore, the compound of the present invention can be effectively used for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancers caused by the action of the CRBN protein. Description of the Drawings

[0086] Figure 1 It is the measurement result of the degradation activity of GSPT1 and β-actin after treating the compound 1 of the present invention in KG-1 cells for 6 hours.

[0087] Figure 2 It is the measurement result of the cancer cell growth inhibition effect after treating the compound of the present invention in NCI-H1155 cancer cells for 72 hours. Detailed Description of the Invention

[0088] Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and can also be implemented in other ways. On the contrary, these embodiments are provided to make the content introduced herein more thorough and complete, and to fully convey the idea of the present invention to those of ordinary skill in the art.

[0089] <Example 1. Synthesis of Isoindolinone Derived Compounds with a Quinoline-Substituted Glutarimide Nucleus and Confirmation of Physicochemical Properties>

[0090] The compound represented by Formula 1 of the present invention is prepared by the methods of Reaction Scheme 1 and Reaction Scheme 2 below.

[0091] [Reaction Scheme 1]

[0092]

[0093] [Reaction formula 2]

[0094]

[0095] In the said Reaction formula 1, the preparation methods of each of Intermediate 2 to Intermediate 5 are as follows.

[0096] 1) Synthesis of methyl 4-cyano-2-methylbenzoate (Intermediate 2)

[0097] Dissolve methyl 4-bromo-2-methylbenzoate (3 g, 13.10 mmol) in DMF (40 mL), then add Pd 2 (dba) 3 (0.480 g, 0.524 mmol), dppf (0.436 g, 0.786 mmol), zinc cyanide (1.692 g, 14.41 mmol), and stir under nitrogen for 30 minutes. Then, raise the temperature to 130 °C and stir for 3 hours. After the reaction is completed, filter the mixture through celite and wash it several times with DMF. Extract the filtrate with EtOAc (50 mL × 2) and wash it with water and brine. After drying the collected organic layer with anhydrous magnesium sulfate, concentrate it under reduced pressure to remove the solvent. Purify the mixture by column chromatography (Hexane:EtOAc = 9:1) to obtain Intermediate 2 (1.96 g, 11.19 mmol, 85%) as a bright yellow solid, with a yield of 85%.

[0098] 2) Synthesis of methyl 2-(bromomethyl)-4-cyanobenzoate (Intermediate 3)

[0099] Dissolve Intermediate 2 (1.96 g, 11.19 mmol) in DCE (30 mL), add N-bromosuccinimide (2.64 g, 22.38 mmol) and benzoyl peroxide (0.271 g, 1.119 mmol), and then heat under reflux and stir for 8 hours. After the reaction is completed, cool to room temperature. Concentrate the mixture under reduced pressure to remove the solvent, and purify it by column chromatography (Hexane:EtOAc = 9:1) to obtain Intermediate 3 (2.29 g, 9.03 mmol, 81%) as a yellow solid, with a yield of 81%.

[0100] 3) Synthesis of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (Intermediate 4)

[0101] Intermediate 3 (7.34 g, 28.9 mmol) was dissolved in DMF (50 mL), and 3-aminopiperidine-2,6-dione hydrochloride (4.75 g, 28.9 mmol) and TEA (12.07 mL, 87 mmol) were added at room temperature. The mixture was stirred overnight at 80 °C. After the reaction was completed, it was cooled to room temperature and then concentrated under reduced pressure to remove the solvent. Water was added to the mixture, and the resulting solid was filtered and washed with excess water. The solid was dried under reduced pressure to completely remove water, and Intermediate 4 (6.28 g, 23.32 mmol, 81%) was obtained as a dark blue solid, with a yield of 81%.

[0102] 4) Synthesis of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate 5)

[0103] Intermediate 4 (1.7 g, 6.31 mmol) was dissolved in DMA (20 mL), 10% Pd / C (2.32 g, 6.31 mmol) and methanesulfonic acid (0.451 mL, 6.94 mmol) were added, and then the mixture was stirred overnight at 40 °C under hydrogen. After the reaction was completed, it was filtered through celite and washed with 50 mL of DMA. The filtrate was concentrated under reduced pressure, and the mixture was precipitated with a methanol / ether (5 mL / 30 mL) mixed solution. The resulting precipitate was filtered, and Intermediate 5 (0.99 g, 2.69 mmol, 43%) was obtained as a gray solid, with a yield of 43%.

[0104] 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.27 (s, 3H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 4.17 (q, J = 5.9 Hz, 2H), 2.97 - 2.87 (m, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.34 (s, 6H), 2.06 - 1.97 (m, 1H).

[0105] Compounds 1 to 15 of the present invention were prepared according to the method disclosed in Korean Patent Application No. 10-2010-7029476, and their physicochemical properties are as follows.

[0106] Compound 1. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-phenylquinoline-4-carboxamide

[0107]

[0108] Dissolve 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate (15 mg, 0.00406 mmol) in DMF (1 mL), add 2-phenylquinoline-4-carboxylic acid (9.5 mg, 0.0487 mmol), EDCl·HCl (8.5 mg, 0.0446 mmol), HOBt·H 2 O (6.0 mg, 0.0446 mmol), DIPEA (28 μL, 0.162 mmol), and then stir at room temperature for 12 h. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the organic layer with brine, dry the residue over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure and purify by column chromatography to obtain the target compound 1 as a white solid (5.0 mg, 28%).

[0109] 1 1H NMR (300 MHz, DMSO) δ 11.01 (s, 1H), 9.54 (t, J = 6.0 Hz, 1H), 8.37 - 8.31 (m, 2H), 8.26 - 8.12 (m, 3H), 7.84 (m, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.70 - 7.50 (m, 6H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.73 (d, J = 5.9 Hz, 2H), 4.50 (d, J = 17.4 Hz, 1H), 4.36 (d, J = 17.4 Hz, 1H), 3.01 - 2.85 (m, 1H), 2.65 - 2.56 (m, 1H), 2.45 - 2.33 (m, 1H), 2.09 - 1.93 (m, 1H).

[0110] Compound 2. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-isopropylphenyl)quinoline-4-carboxamide

[0111]

[0112] Compound 2 was synthesized in the same manner as the synthesis method of Compound 1 using 2-(4-isopropylphenyl)quinoline-4-carboxylic acid instead of 2-phenylquinoline-4-carboxylic acid.

[0113] 1 1H NMR (500 MHz, DMSO-d6 ) δ 11.00 (s, 1H), 9.52 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 8.2 Hz, 2H), 8.18 (d, J = 11.2 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 7.82 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.63 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.99 (p, J = 6.9 Hz, 1H), 2.95 - 2.87 (m, 1H), 2.64 - 2.57 (m, 1H), 2.47 - 2.37 (m, 1H), 2.05 - 1.96 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H).

[0114] Compound 3. N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methyl-2-phenylquinoline-4-carboxamide

[0115]

[0116] Compound 3 was synthesized in the same manner as the synthesis method of Compound 1 using 6-methyl-2-phenylquinoline-4-carboxylic acid instead of 2-phenylquinoline-4-carboxylic acid.

[0117] 1 H NMR (500 MHz, DMSO-d 6) δ 11.00 (s, 1H), 9.49 (t, J = 6.0 Hz, 1H), 8.30 (d, 2H), 8.17 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.59 (dd, 1H), 7.57 (dd, 2H), 7.55 - 7.48 (m, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 17.4 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.97 - 2.86 (m, 1H), 2.64 - 2.57 (m, 1H), 2.47 - 2.35 (m, 1H), 2.05 - 1.97 (m, 1H).

[0118] Compound 4. N - ((2 - (2,6 - dioxopiperidin - 3 - yl) - 1 - oxoisoindolin - 5 - yl)methyl) - 8 - methyl - 2 - phenylquinoline - 4 - carboxamide

[0119]

[0120] Compound 4 was synthesized in the same manner as the synthesis method of Compound 1, using 8 - methyl - 2 - phenylquinoline - 4 - carboxylic acid instead of 2 - phenylquinoline - 4 - carboxylic acid.

[0121] 1 H NMR (500 MHz, DMSO - d 6 ) δ 11.00 (s, 1H), 9.49 (t, J = 5.9 Hz, 1H), 8.37 (dd, 2H), 8.22 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.67 (s, 1H), 7.62 - 7.56 (m, 3H), 7.56 - 7.49 (m, 2H), 5.12 (dd, J = 13.4, 5.1 Hz, 1H), 4.71 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.97 - 2.86 (m, 1H), 2.84 (s, 3H), 2.64 - 2.57 (m, 1H), 2.47 - 2.37 (m, 1H), 2.04 - 1.98 (m, 1H).

[0122] Compound 5. N - ((2 - (2,6 - dioxopiperidin - 3 - yl) - 1 - oxoisoindolin - 5 - yl)methyl) - 2 - (m - tolyl)quinoline - 4 - carboxamide

[0123]

[0124] Compound 5 was synthesized in the same manner as the synthesis method of Compound 1 using 2-(m-tolyl)quinoline-4-carboxylic acid in place of 2-phenylquinoline-4-carboxylic acid.

[0125] 1 H NMR(300MHz,DMSO-d 6 )δ11.00(s,1H),9.53(t,J=6.0Hz,1H),8.22-8.08(m,5H),7.83(ddd,J=8.4,6.9,1.5Hz,1H),7.76(d,J=7.8Hz,1H),7.69-7.57(m,3H),7.47(t,J=7.6Hz,1H),7.35(d,J=7.6Hz,1H),5.12(dd,J=13.2,5.1Hz,1H),4.73(d,J=5.9Hz,2H),4.50(d,J=17.4Hz,1H),4.36(d,J=17.4Hz,1H),2.98-2.83(m,1H),2.63(d,J=3.4Hz,1H),2.46(s,3H),2.41-2.32(m,1H),2.07-1.93(m,1H).

[0126] Compound 6. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(p-tolyl)quinoline-4-carboxamide

[0127]

[0128] Compound 6 was synthesized in the same manner as the synthesis method of Compound 1 using 2-(p-tolyl)quinoline-4-carboxylic acid in place of 2-phenylquinoline-4-carboxylic acid.

[0129] 1 H NMR(300MHz,DMSO-d 6)δ 11.00 (s, 1H), 9.52 (t, J = 6.0 Hz, 1H), 8.27 - 8.07 (m, 5H), 7.87 - 7.72 (m, 2H), 7.71 - 7.55 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 17.4 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.60 (d, J = 17.5 Hz, 2H), 2.40 (s, 3H), 2.07 - 1.95 (m, 1H).

[0130] Compound 7. N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(pyridin-4-yl)quinoline-4-carboxamide

[0131]

[0132] Compound 7 was synthesized in the same manner as the synthesis method of Compound 1 using 2-(pyridin-4-yl)quinoline-4-carboxylic acid in place of 2-phenylquinoline-4-carboxylic acid.

[0133] 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.55 (t, J = 5.9 Hz, 1H), 8.84 - 8.80 (m, 2H), 8.36 (s, 1H), 8.32 - 8.27 (m, 2H), 8.22 (t, J = 9.0 Hz, 2H), 7.89 (m, 1H), 7.80 - 7.71 (m, 2H), 7.68 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.74 (d, J = 5.9 Hz, 2H), 4.50 (d, J = 17.3 Hz, 1H), 4.37 (d, J = 17.3 Hz, 1H), 2.93 (m, 1H), 2.68 - 2.58 (m, 1H), 2.47 - 2.33 (m, 1H), 2.07 - 1.98 (m, 1H).

[0134] Compound 8. 2-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide

[0135]

[0136] Compound 8 was synthesized in the same manner as the synthesis method of Compound 1, using 2-chloroquinoline-4-carboxylic acid in place of 2-phenylquinoline-4-carboxylic acid.

[0137] 1 H NMR(400MHz,DMSO)δ11.00(s,1H),9.55(t,J=5.9Hz,1H),8.14(d,J=8.4Hz,1H),8.04(d,J=8.4Hz,1H),7.89(m,1H),7.77-7.70(m,3H),7.65(s,1H),7.56(d,J=7.8Hz,1H),5.13(dd,J=13.3,5.0Hz,1H),4.68(d,J=6.0Hz,2H),4.49(d,J=17.3Hz,1H),4.36(d,J=17.3Hz,1H),2.93(m,1H),2.65-2.57(m,1H),2.47-2.34(m,1H),2.08-1.95(m,1H).

[0138] Compound 9. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide

[0139]

[0140] Compound 9 was synthesized in the same manner as the synthesis method of Compound 1, using quinoline-4-carboxylic acid in place of 2-phenylquinoline-4-carboxylic acid.

[0141] 1 H NMR(400MHz,DMSO)δ11.00(s,1H),9.45(t,J=5.9Hz,1H),9.00(d,J=4.3Hz,1H),8.16(d,J=1.4Hz,1H),8.10(d,J=8.4Hz,1H),7.83(m,1H),7.75(d,J=7.8Hz,1H),7.70-7.61(m,3H),7.56(d,J=7.9Hz,1H),5.13(dd,J=13.4,5.0Hz,1H),4.69(d,J=6.0Hz,1H),4.49(d,J=17.3Hz,1H),4.35(d,J=17.3Hz,1H),2.93(m,1H),2.64-2.56(m,1H),2.46-2.32(m,1H),2.06-1.97(m,1H).

[0142] Compound 10. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-(pyridin-3-yl)quinoline-4-carboxamide

[0143]

[0144] Compound 10 was synthesized in the same manner as the synthesis method of Compound 1 using 8-methyl-2-(pyridin-3-yl)quinoline-4-carboxylic acid instead of 2-phenylquinoline-4-carboxylic acid.

[0145] 1 H NMR (500 MHz, DMSO) δ 11.02 (s, 1H), 9.50 (t, J = 6.0 Hz, 1H), 8.41 - 8.35 (m, 2H), 8.23 (s, 1H), 8.01 (dd, J = 8.3, 1.3 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.70 (m, 1H), 7.68 (s, 1H), 7.63 - 7.59 (m, 2H), 7.56 - 7.51 (m, 2H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (d, J = 5.9 Hz, 2H), 4.50 (d, J = 17.3 Hz, 1H), 4.37 (d, J = 17.4 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.85 (s, 3H), 2.65 - 2.58 (m, 1H), 2.40 (m, 1H), 2.06 - 2.00 (m, 1H).

[0146] Compound 11. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(m-tolyl)quinoline-4-carboxamide

[0147]

[0148] Compound 11 was synthesized in the same manner as the synthesis method of Compound 1 using 2-(m-tolyl)quinoline-4-carboxylic acid instead of 2-phenylquinoline-4-carboxylic acid.

[0149] 11H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 9.54 (t, J = 6.0 Hz, 1H), 8.22 (s, 1H), 8.21 - 8.19 (m, 1H), 8.18 - 8.11 (m, 3H), 7.84 (m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.66 - 7.63 (m, 1H), 7.62 - 7.59 (m, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.36 (m, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.73 (d, J = 5.9 Hz, 2H), 4.50 (d, J = 17.4 Hz, 1H), 4.37 (d, J = 17.3 Hz, 1H), 2.93 (m, 1H), 2.66 - 2.56 (m, 1H), 2.46 (s, 3H), 2.43 - 2.36 (m, 1H), 2.07 - 1.96 (m, 1H).

[0150] Compound 12. N - ((2 - (2,6 - dioxopiperidin - 3 - yl) - 1 - oxoisoindolin - 5 - yl)methyl) - 3 - methyl - 2 - phenylquinoline - 4 - carboxamide

[0151]

[0152] Compound 12 was synthesized in the same manner as the synthesis method of Compound 1, using 3 - methyl - 2 - phenylquinoline - 4 - carboxylic acid instead of 2 - phenylquinoline - 4 - carboxylic acid.

[0153] 1 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.44 (m, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.80 - 7.71 (m, 3H), 7.68 - 7.47 (m, 8H), 5.13 (dd, J = 13.4, 4.9 Hz, 1H), 4.72 (m, 2H), 4.50 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.99 - 2.85 (m, 1H), 2.61 (m, 1H), 2.42 (m, 1H), 2.32 (s, 3H), 2.02 (m, 1H).

[0154] Compound 13. N - ((2 - (2,6 - dioxopiperidin - 3 - yl) - 1 - oxoisoindolin - 5 - yl)methyl) - 2 - (o - tolyl)quinoline - 4 - carboxamide

[0155]

[0156] Compound 13 was synthesized in the same manner as the synthesis method of Compound 1, using 2-(o-tolyl)quinoline-4-carboxylic acid in place of 2-phenylquinoline-4-carboxylic acid.

[0157] 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.47 (m, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.69 (t, J = 7.7 Hz, 1H), 7.65 (s, 1H), 7.58 (t, J = 8.3 Hz, 2H), 7.45 - 7.33 (m, 3H), 5.12 (dd, J = 13.3, 5.0 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 4.48 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 17.3 Hz, 1H), 2.99 - 2.83 (m, 1H), 2.61 (m, 1H), 2.44 (s, 3H), 2.37 (m, 1H), 2.01 (m, 1H).

[0158] Compound 14. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-fluorophenyl)quinoline-4-carboxamide

[0159]

[0160] Compound 14 was synthesized in the same manner as the synthesis method of Compound 1, using 2-(4-fluorophenyl)quinoline-4-carboxylic acid in place of 2-phenylquinoline-4-carboxylic acid.

[0161] 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.52 (m, 1H), 8.40 (t, J = 7.1 Hz, 2H), 8.27 - 8.09 (m, 3H), 7.84 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.71 - 7.56 (m, 3H), 7.42 (t, J = 8.7 Hz, 2H), 5.21 - 5.05 (m, 1H), 4.73 (d, J = 5.8 Hz, 2H), 4.50 (d, J = 17.4 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.93 (m, 1H), 2.61 (m, 1H), 2.41 (m, 1H), 2.02 (m, 1H).

[0162] Compound 15. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-fluorophenyl)quinoline-4-carboxamide

[0163]

[0164] Compound 15 was synthesized in the same manner as the synthesis method of Compound 1 using 2-(2-fluorophenyl)quinoline-4-carboxylic acid instead of 2-phenylquinoline-4-carboxylic acid.

[0165] 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.58 - 9.41 (m, 1H), 8.18 (t, J = 9.1 Hz, 2H), 8.07 (m, 1H), 7.98 (m, 1H), 7.91 - 7.84 (m, 1H), 7.79 - 7.68 (m, 2H), 7.65 (s, 1H), 7.63 - 7.52 (m, 2H), 7.43 (m, 2H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.71 (d, J = 5.8 Hz, 2H), 4.49 (d, J = 17.3 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.38 (m, 1H), 2.09 - 1.95 (m, 1H).

[0166] <Comparative Example 1. Synthesis of an isoindolinone derivative comparative compound having a glutarimide nucleus and confirmation of physicochemical properties>

[0167] The physicochemical properties of Comparative Compounds 1 to 3 are as follows.

[0168] Comparative Compound 1. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoquinoline-3-carboxamide

[0169]

[0170] Comparative Compound 1 was synthesized in the same manner as the synthesis method of Compound 1 using isoquinoline-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

[0171] 1 H NMR (500 MHz, DMSO-d 6) δ 10.98 (s, 1H), 9.62 (t, J = 6.4 Hz, 1H), 9.41 (s, 1H), 8.59 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.98 - 2.84 (m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 2.03 - 1.92 (m, 1H).

[0172] Comparative Compound 2. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoxaline-2-carboxamide

[0173]

[0174] Using quinoxaline-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid, Comparative Compound 2 was synthesized in the same manner as the synthesis method of Compound 1.

[0175] 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.77 (t, J = 6.4 Hz, 1H), 9.50 (s, 1H), 8.22 (m, 2H), 8.04 - 7.98 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.59 (m, 1H), 2.43 - 2.32 (m, 1H), 2.06 - 1.95 (m, 1H).

[0176] Comparative Compound 3. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-2-carboxamide

[0177]

[0178] 6-Chloroquinoline-2-carboxylic acid was used instead of 6-chloro-1H-indazole-3-carboxylic acid to synthesize Comparative Compound 3 in the same manner as the synthesis method of Compound 1.

[0179] 1 H NMR(300MHz,DMSO)δ10.98(s,1H),9.65(t,J=6.4Hz,1H),8.57(d,J=8.5Hz,1H),8.27(d,J=2.4Hz,1H),8.23(d,J=8.6Hz,1H),8.16(d,J=9.1Hz,1H),7.90(dd,J=9.0,2.4Hz,1H),7.71(d,J=7.8Hz,1H),7.60(s,1H),7.53(dd,J=7.8,1.4Hz,1H),5.11(dd,J=13.2,5.1Hz,1H),4.69(d,J=6.3Hz,2H),4.45(d,J=17.4Hz,1H),4.31(d,J=17.4Hz,1H),2.99-2.84(m,1H),2.59(m,1H),2.35(m,1H),2.06-1.94(m,1H).

[0180] <Experimental Example 1. Evaluation of the Substrate Protein Degradation Activity of CRBN>

[0181] To confirm whether the compounds of the present invention can specifically bind to CRBN (cereblon) and inhibit the function of CRBN, the effects of the compounds of the present invention on the degradation activities of Ikaros (IKZF1) protein (Chamberlain, P.P. et al., 2014) or GSPT1 protein (Matyskiela, M.E. et al., 2016) through CRBN protein degradation were studied when binding to thalidomide and its analogs.

[0182] To evaluate the degradation activities of Ikaros (IKZF1) protein or GSPT1 protein of the compounds according to the present invention, the following experiments were conducted.

[0183] KG-1 cells were seeded at 5×10 5Cells were seeded in 12-well plates, and then each compound was treated at a predetermined concentration in each well. After 6 hours, cell lysates were collected using TBSN buffer. By Western blot, the degradation activity of Ikaros (IKZF1) protein was evaluated using an Ikaros (IKZF1) protein antibody, and the degradation activity of GSPT1 protein was evaluated using a GSPT1 protein antibody. For this purpose, an equal amount of protein was loaded into each well of a 4-15% gradient gel. After electrophoresis, the protein was transferred onto a PVDF membrane and bound to the primary antibody against each protein. Subsequently, the secondary antibody conjugated with HRP was bound, and developed using an HRP substrate.

[0184] The results are as Figure 1 shown. After treatment for 6 hours respectively in the KG-1 cell line, it was confirmed that the compounds of the present invention could selectively promote the degradation of GSPT1 protein.

[0185] <Experimental Example 2. Cytotoxicity Experiment>

[0186] To confirm the effect of the compounds of the embodiments of the present invention on cancer cells, the following cytotoxicity experiment was conducted.

[0187] Cancer cells (KG-1) were seeded in 96-well plates at a density of 10,000 cells per well, and then the compounds of the embodiments of the present invention and comparative substances (Comparative Compounds 1, 2, 3) were treated at a predetermined concentration. After 72 hours, WST-1 reagent was added. After 1 hour, the absorbance at 450 nm was measured using a spectramax spectrophotometer to determine the degree of cancer cell death. Using the measured values, the IC 50 (μM) values were calculated using the graphpad prism program and shown in Table 1.

[0188] The viability of NCI-H1155 (lung cancer cells) was determined using the CytoX cell viability assay kit (LPSsolution, #CYT3000). NCI-H1155 cells were seeded in 12-well plates, and then each compound of the present invention and the comparative substance (CC-90009) were treated at concentrations of 10 nM and 500 nM for 72 hours. Then, the CytoX solution was added to the cells and incubated for 1 hour. Subsequently, the absorbance of each well was measured at 450 nm using a microplate reader to calculate the % viability, which is shown in Table 1.

[0189] The results are as Figure 2 shown, and excellent growth inhibitory effects of the compounds of the examples of the present invention can be confirmed in NCI-H1155 lung cancer cells.

[0190] Table 1

[0191]

[0192] As can be seen from Table 1, the isoindolinone-derived compounds with a quinoline amide structure of the present invention have better cytotoxicity against KG-1 cancer cells than the comparative compound. In addition, the compounds in which the 2-position of quinoline is substituted by an aryl group (Compounds 7, 10, 11 - 15) show more excellent cytotoxicity in NCI-H1155 cancer cells than the compounds not substituted by an aryl substituent (Compounds 8, 9).

[0193] The results are as Figure 2 shown, confirming the cytotoxicity of the compounds of the present invention against NCI-H1155 cancer cells.

[0194] <Preparation Example 1. Preparation of powder>

[0195] 12 g of the compound of the present invention and 1 g of lactose were mixed and filled into a sealed bag to prepare a powder.

[0196] <Preparation Example 2. Preparation of tablets>

[0197] 1100 mg of the compound of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed, and then tableted according to the conventional tablet preparation method.

[0198] <Preparation Example 3. Preparation of capsules>

[0199] 1100 mg of the compound of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose and 2 mg of magnesium stearate were mixed, and then the above components were mixed according to the conventional preparation method of capsules and filled into gelatin capsules to prepare capsules.

[0200] <Preparation Example 4. Preparation of Pills>

[0201] 190 mg of the compound of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water and a small amount of dextrin, maltodextrin, corn starch, microcrystalline cellulose (MCC) as additives for inhibiting hygroscopicity were mixed, and then made into 100 mg pills according to the conventional method.

[0202] <Preparation Example 5. Preparation of Injection>

[0203] 110 mg of the compound of the present invention, an appropriate amount of sterile distilled water for injection and an appropriate amount of pH regulator were mixed, and then the content of the above components per ampoule (2 mL) was prepared according to the conventional preparation method of injection.

Claims

1. A compound represented by the following Chemical Formula 1, its enantiomer, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the formula, m is 1 or 2; n is 0 or 1; p is an integer from 1 to 3; R 1 is hydrogen or deuterium; R 2 independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxylic acid, C 1-5 alkyl carboxyl, amino, acetylamino, sulfuric acid, C 1-5 alkyl sulfuric acid, nitro, mono(C 1-5 alkyl)amino or di(C 1-5 alkyl)amino, C 1-5 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, and being at least one substituent selected from the group; R 3 is a substituent selected from the group consisting of hydrogen, halogen, hydroxyl, amino, acetylamino, mono(C 1-5 alkyl)amino or di(C 1-5 alkyl)amino, C 1-5 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted C 6-10 heteroaryl; wherein, The substituted aryl or heteroaryl is substituted by at least one substituent selected from the group consisting of hydrogen, halogen, C 1-5 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl, halo-C 1-3 alkoxy; R 4 is hydrogen, halogen, C 1-5 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl or halo-C 1-3 alkoxy.

2. The compound, its enantiomer, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the Chemical Formula 1 is a compound represented by the following Chemical Formula 2, its enantiomer, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the formula, m is 1 or 2; n is 0 or 1; p is an integer from 1 to 3; X 1 、X 2 independently is N, CH or C; R 1 is hydrogen or deuterium; R 2 independently selected from the group consisting of hydrogen, halogen, hydroxyl, carboxylic acid, C 1-5 alkyl carboxyl, amino, acetylamino, sulfuric acid, C 1-5 alkyl sulfate, nitro, mono(C 1-5 alkyl)amino or di(C 1-5 alkyl)amino, C 1-5 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, and being at least one substituent selected from the group; R 4 is hydrogen, halogen, C 1-5 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl or halo-C 1-3 alkoxy.

3. The compound, its enantiomer, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of Chemical Formula 1 is selected from the group consisting of the following compounds: N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-phenylquinoline-4-carboxamide (Compound 1), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-isopropylphenyl)quinoline-4-carboxamide (Compound 2), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methyl-2-phenylquinoline-4-carboxamide (Compound 3), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-phenylquinoline-4-carboxamide (Compound 4), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(m-tolyl)quinoline-4-carboxamide (Compound 5), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(p-tolyl)quinoline-4-carboxamide (Compound 6), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(pyridin-4-yl)quinoline-4-carboxamide (Compound 7), 2-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide (Compound 8), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide (Compound 9), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-(pyridin-3-yl)quinoline-4-carboxamide (Compound 10), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(m-tolyl)quinoline-4-carboxamide (Compound 11), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methyl-2-phenylquinoline-4-carboxamide (Compound 12), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(o-tolyl)quinoline-4-carboxamide (Compound 13), N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-fluorophenyl)quinoline-4-carboxamide (Compound 14), and N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-fluorophenyl)quinoline-4-carboxamide (Compound 15).

4. A pharmaceutical composition for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases or cancer, characterized in that the pharmaceutical composition contains a compound represented by Formula 1 according to Claim 1, its enantiomer or its pharmaceutically acceptable salt as an active ingredient.

5. The pharmaceutical composition according to Claim 4, characterized in that the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, small cell lung cancer, gastric cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, intestinal cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal cell cancer, renal pelvic cancer, central nervous system tumors, primary central nervous system lymphoma, spinal cord tumors, brainstem gliomas, and pituitary adenomas.

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