Isoindolinone derivatives having a quinoline amide structure and uses thereof

Abstract

The present invention relates to an isoindolinone derivative compound having a quinoline-substituted glutarimide core and its applications, and more particularly to an isoindolinone derivative compound having a quinoline-substituted glutarimide core with a thalidomide analogue structure. The compound of the present invention, represented by Formula 1, specifically binds to CRBN protein and participates in its function. Therefore, the compound of the present invention can be useful for the prevention or treatment of leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancers mediated by the CRBN protein.

Description

[Technical Field]

[0001] The present invention relates to an isoindolinone derivative having a quinoline amide structure and uses thereof, and more particularly to an isoindolinone derivative compound having a quinoline amide structure that exhibits the effect of preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancer. [Background technology]

[0002] Thalidomide is a racemic compound sold under the trade name THALOMID® and the chemical names α-(N-phthalimido)glutarimide or 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione. Thalidomide was originally developed to treat morning sickness but was discontinued due to its teratogenic effects. Thalidomide is currently approved in the United States for the treatment of erythema nodosum in humans (Patent Document 1: Korean Patent Registered Publication No. 10-0671366).

[0003] Thalidomide has also been reported to be used in patients with leprosy, chronic graft-versus-host disease, rheumatoid arthritis, sarcoidosis, some inflammatory skin diseases, and inflammatory bowel disease, and it has also been reported that thalidomide can be combined with other drugs to treat ischemia / reperfusion associated with cardiac and cerebral artery occlusion (Patent Document 2: U.S. Patent No. 05643915).

[0004] In recent years, thalidomide has been used to treat certain types of cancer, including refractory multiple myeloma, brain, melanoma, breast, colon, mesothelioma, and renal cell carcinoma. Thalidomide has also been reported to be used to prevent the development of doxorubicin-induced chronic cardiomyopathy in rats. Other reports of the use of thalidomide in the treatment of certain cancers include its use in combination with carboplatin in the treatment of glioblastoma multiforme. Thalidomide has also been reported to be used as an analgesic in the treatment of astrocytoma (Non-Patent Document 1: Costa, PT et al., Blood, 92 (Suppl 1, Pt 2), 235b, 1998; Marx, GM 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] Thalidomide is also used for various purposes, including the prevention and treatment of lupus nephritis, fibromyalgia, schizophrenia, central nervous system diseases, diabetes, and inflammatory diseases. However, it has a history of causing fatal side effects in pregnant women who take it, including birth defects, and was removed from the market at the end of 1961.

[0006] Research is being actively conducted to develop derivatives of thalidomide that retain the various physiological benefits of thalidomide while eliminating the serious side effects.

[0007] Intracellular protein degradation is primarily mediated by the ubiquitin-proteasome system (UPS). Proteins called E1, E2, and E3 ligases transfer ubiquitin (Ub), a 76-amino acid chain, to the substrate to be degraded, resulting in polyubiquitination. The 26S proteasome then recognizes the polyubiquitin and degrades the protein.

[0008] Lenalidomide and pomalidomide, derivatives of thalidomide known as immunomodulatory drugs (IMiDs), are used as treatments for multiple myeloma by binding to the E3 ligase cerebron (CRBN) and inducing the degradation of the zinc finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Lenalidomide, in particular, is used as a treatment for 5q-del-MDS patients by degrading CK-1α, and is one of the best-selling anticancer drugs worldwide.

[0009] GSPT1 is a GTPase that forms a complex with eRF1 under GTP-bound conditions and binds to the stop codon of mRNA. When GTP is converted to GDP, GSPT1 is separated from eRF1, thereby participating in protein cleavage by eRF1 (Non-Patent Document 2: Cell Reports, 2014, 8, 59-65).

[0010] It is known that GSPT1 knockdown reduces the phosphorylation of 4E-BP1 and the kinase S6K1, thereby suppressing mTOR activity and inducing G1 arrest (Non-Patent Document 3: Molecular and Cellular Biology, 2007, 27, 5619).

[0011] GSPT1 is overexpressed in a colon cancer cell line (HCT116) and is involved in cell growth and migration. It has been confirmed that knocking down GSPT1 induces cell death by suppressing the expression of c-myc, survivin, and Bcl2L15 (Non-patent document 4: Biomed. Pharmacother. 2015, 74, 138-144).

[0012] In addition, Celgene has reported that the CC-885 compound, derived from lenalidomide, degrades the new protein GSPT1 and exhibits high cytotoxicity in various blood cancer cells. Through optimization research, they have derived the CC-90009 substance, which is currently undergoing clinical trials in patients with R and R-AML (Non-patent document 5: Nature, 2016, 14, 252; Blood, 2021).

[0013] We have developed novel piperidine-2,6-dione-based thalidomide derivatives that retain the physiological activity of thalidomide but lack its side effects, and have confirmed that these compounds promote the proteolysis of GSPT1 and Aiolos. Furthermore, we have confirmed that the developed compounds have sufficient cytotoxicity in cancer cells, and that compounds substituted with urea derivatives and triazine derivative compounds in particular have superior cytotoxic activity against cancer cells (Patent Document 3: Korean Patent Publication No. 10-2020-0054046).

[0014] Furthermore, it has been reported that 5-substituted isoindoline compounds exhibit antiproliferative effects against various cancer cells, including those of prostate, colon, pancreas, and breast, in addition to TNF-α inhibitory effects and IL-2 production effects (Patent Document 4: Korean Patent Publication No. 10-2011-0019761), and that isoindoline compounds are effective against various diseases, including cancer, by controlling angiogenesis, inhibiting the production of specific cytokines such as TNF-α, and stimulating the production of specific cytokines such as IL-10 (Patent Document 5: Korean Patent Registration No. 10-1696938).

[0015] In addition, a method for predicting and treating various diseases, including cancer, by administering a compound having isoindolinone and glutarimide has been reported (Patent Document 6: Korean Patent Publication No. 10-2018-0095094), and it has been reported that a compound having an aminoamide linker acts as a regulator of the activity of various proteins, such as cytokines, TNF-α, and GSPT1, and is effective in treating various diseases, such as inflammatory diseases and cancer (Patent Document 7: Australian Patent Publication No. 2019284608).

[0016] The present inventors have confirmed that the compound represented by Chemical Formula 1 of the present invention, which has a quinoline amide structure, exhibits superior physiological activity against cancer cells compared to the compounds developed in the existing prior patents, and have thus completed the present invention. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] Korean Patent Registration No. 10-0671366 [Patent Document 2] U.S. Patent No. 05643915 [Patent Document 3] Republic of Korea Patent No. 10-2020-0054046 [Patent Document 4] Republic of Korea Publication Patent No. 10-2011-0019761 [Patent Document 5] Republic of Korea Patent No. 10-1696938 [Patent Document 6] Republic of Korea Publication Patent No. 10-2018-0095094 [Patent Document 7] Australian Patent Publication No. 2019284608 [Patent Document 8] Republic of Korea Patent Application Publication No. 10-2010-7029476 [Non-patent literature]

[0018] [Non-Patent Document 1] Costa,PTet al.,Blood,92(Suppl 1,Pt 2), 235b,1998;Marx,GMet 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 [Non-patent document 2] Cell Reports,2014,8,59-65 [Non-patent document 3] Molecular and cellular biology,2007,27,5619 [Non-patent document 4] Biomed.Pharmacother.2015,74,138-144 [Non-patent document 5] Nature, 2016, 14, 252; Blood, 2021 Summary of the Invention [Problem to be solved by the invention]

[0019] The present inventors have developed isoindolinone derivative compounds having a quinoline-substituted glutarimide core, which exhibit preventive or therapeutic effects against leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancer, and have evaluated their activity, thereby completing the present invention.

[0020] Accordingly, an object of the present invention is to provide a compound represented by the following Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

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

[0022] [ka]

[0023] During the ceremony,

[0024] m is 1 or 2;

[0025] n is 0 or 1;

[0026] p is an integer from 1 to 3;

[0027] R1 is substituted with hydrogen or deuterium (D);

[0028] R2 independently represents hydrogen, halogen, hydroxy, carboxylic acid, C 1-5 Alkyl carboxyl group, amino, acetamino, sulfonic acid, C 1-5 Alkyl sulfonic acid, nitro, mono or di(C 1-5 Alkyl)amino, C 1-5 Alkyl, C 1-3 Alkoxy, HaloC 1-3 Alkyl, HaloC 1-3 substituted with one or more substituents selected from the group consisting of alkoxy;

[0029] R3 is hydrogen, halogen, hydroxy, amino, acetamino, mono- or di(C 1-5 Alkyl)amino, C 1-5 Alkyl, C 1-3 Alkoxy, HaloC 1-3 Alkyl, HaloC 1-3 Alkoxy, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted C 6-10 substituted with one substituent selected from the group consisting of heteroaryl;

[0030] wherein the substituted aryl or heteroaryl is selected from the group consisting of hydrogen, halogen, C 1-5 Alkyl, C 1-3 Alkoxy, HaloC 1-3 Alkyl, HaloC 1-3substituted with one or more substituents selected from the group consisting of alkoxy;

[0031] R4 is hydrogen, halogen, C 1-5 Alkyl, C 1-3 Alkoxy, HaloC 1-3 Alkyl or haloC 1-3 substituted with alkoxy;

[0032] The present invention also relates to a compound represented by the following chemical formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0033] [ka]

[0034] During the ceremony,

[0035] m is 1 or 2;

[0036] n is 0 or 1;

[0037] p is an integer from 1 to 3;

[0038] X1, X2 are independently N, CH, or C;

[0039] R1 is substituted with hydrogen or deuterium (D);

[0040] R2 independently represents hydrogen, halogen, hydroxy, carboxylic acid, C 1-5 Alkyl carboxyl group, amino, acetamino, sulfonic acid, C 1-5 Alkyl sulfonic acid, nitro, mono or di(C 1-5 Alkyl)amino, C 1-5 Alkyl, C 1-3 Alkoxy, HaloC 1-3 Alkyl, HaloC 1-3 substituted with one or more substituents selected from the group consisting of alkoxy;

[0041] R4 is hydrogen, halogen, C 1-5 Alkyl, C 1-3 Alkoxy, HaloC 1-3 Alkyl or haloC 1-3 Substituted with alkoxy.

[0042] More specifically, the compound of the present invention represented by the above formula 1 is

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

[0044] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-isopropylphenyl)quinoline-4-carboxamide (compound 2);

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

[0046] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-phenylquinoline-4-carboxamide (compound 4);

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

[0048] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(p-tolyl)quinoline-4-carboxamide (compound 6);

[0049] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(pyridin-4-yl)quinoline-4-carboxamide (compound 7);

[0050] 2-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide (compound 8);

[0051] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide (compound 9);

[0052] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-(pyridin-3-yl)quinoline-4-carboxamide (Compound 10) ;

[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] The compound of the present invention represented by the above Chemical Formula 1 can be prepared by the following Reaction Schemes 1 and 2.

[0058] [ka]

[0059] [ka]

[0060] In the above reaction scheme 1, the methods for producing intermediates 2 to 5 are as follows.

[0061] Reaction Scheme 2 is produced by the method disclosed in Patent Document 7: Korean Patent Application Publication No. 10-2010-7029476.

[0062] The method for producing the compound represented by Chemical Formula 1 according to the present invention, disclosed in the above preparation section, is only one example of a method for producing the compound of the present invention, and any method capable of producing the compound represented by Chemical Formula 1 according to the present invention is included in the present invention. In addition, the methods presented in the present specification and preparation methods that can be easily modified and altered by a skilled artisan are also included in the scope of the present invention, and these are obvious to a skilled artisan.

[0063] As used herein, the following terms have the following meanings unless otherwise specified: Any term not defined has its art-understood meaning.

[0064] As used herein, "halo" or "halogen" refers to fluoro (F), chlorine (Cl), bromine (Br), and iodo (I).

[0065] As used herein, the term "alkyl" refers to a single-bonded straight or branched chain hydrocarbon group, including but not limited to methyl, ethyl, propyl, and the like.

[0066] The term "alkoxy" as used herein means a single bonded straight or branched chain saturated hydrocarbon attached oxygen radical, including but not limited to methoxy, ethoxy, propoxy, etc.

[0067] As used herein, the term "haloalkyl" refers to a substituted alkyl group as defined above, wherein one or more hydrogen atoms on the alkyl group have been replaced with a halo group, including, but not limited to, trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0068] As used herein, the term "haloalkoxy" refers to the group alkyl-O-, where one or more hydrogen atoms on the alkyl group are replaced with a halo group, including, but not limited to, trifluoromethoxy.

[0069] As used herein, the term "aryl" refers to aromatic ring compounds, including, but not limited to, phenyl, naphthalene, anthracene, and the like.

[0070] The term "heteroaryl" as used herein refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, naphthofuranyl, quinolinyl, isoquinolinyl, quinoxanyl, etc., depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms.

[0071] The compounds of Chemical Formula 1 of the present invention may include pharmaceutically acceptable salts, as well as any salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods. Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and partial stereoisomers are within the scope of the present invention.

[0072] The term "pharmaceutically acceptable salt" as used herein refers to a salt or complex of Formula 1 that possesses the desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as with 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. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, including, among others, chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

[0073] The acid addition salt according to the present invention can be prepared by a conventional method. For example, the acid addition salt can be prepared by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and excess acid under reduced pressure, drying the resulting precipitate, and crystallizing it in an organic solvent.

[0074] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in a solution of an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide, filtering the undissolved compound salt, and evaporating the filtrate to dryness. In this case, sodium, potassium, or calcium salts are pharmaceutically suitable as metal salts. The corresponding salts can also be obtained by reacting alkali metal or alkaline earth metal salts with an appropriate silver salt (e.g., silver nitrate).

[0075] The present invention also relates to a pharmaceutical composition for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancer, comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0076] In one test example of the present invention, it was confirmed that CRBN (celebron) protein binds to CRBN protein and degrades Ikaros / Aiolos and GSPT1. CRBN protein is a type of E3 ubiquitin ligase, and is known to have the activity of binding to thalidomide and its analogs, pomalidomide and lenalidomide, and attaching ubiquitin to substrate proteins, such as Ikaros / Aiolos and GSPT1.

[0077] The cancer may be selected from the group consisting of breast cancer, colon cancer, lung cancer, small cell carcinoma, 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, trumpet cancer, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma, but is not limited thereto.

[0078] The pharmaceutical composition of the present invention may be formulated into an appropriate form with a commonly used pharmaceutically acceptable carrier. A "pharmaceutically acceptable composition" refers to a composition that is physiologically acceptable and does not normally cause allergic or similar reactions, such as gastrointestinal disorders or dizziness, when administered to humans. In addition, the compositions may be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, topical preparations, suppositories, and sterile injection solutions by conventional methods.

[0079] Carriers, excipients, and diluents that can be included in the composition include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl parahydroxybenzoate, propyl parahydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, commonly used diluents or excipients such as fillers, stabilizers, binders, disintegrants, and surfactants are used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and are prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid formulations include suspensions, oral solutions, emulsions, syrups, etc., and may contain various excipients, such as wetting agents, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cocoa butter, lauric butter, glycerol, gelatin, etc. To prepare a dosage form for parenteral administration, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is sterilized and / or mixed with auxiliary agents such as preservatives, stabilizers, hydrating agents or emulsifying agents, salts for adjusting osmotic pressure and / or buffers, and other therapeutically useful substances in water to prepare a solution or suspension, which can be packaged in a unit dosage form such as ampoules or vials.

[0080] The pharmaceutical composition includes the compound of Formula 1 and an excipient. The compound may be added in an amount of preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight, based on the total weight of the entire composition.

[0081] Pharmaceutical compositions containing the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals, such as rodents, livestock, and humans, via various routes. Any administration route is contemplated, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebrovascular administration. The dosage may vary depending on the age, sex, and 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 prescriber's discretion. Determining the dosage based on these factors is within the skill of one of ordinary skill in the art. Generally, the dosage ranges from 0.01 mg / kg / day to 2000 mg / kg / day. A more preferred dosage is 1 mg / kg / day to 500 mg / kg / day. The dosage may be administered once a day or in multiple divided doses. The dosages listed above are not intended to limit the scope of the present invention in any way. [Effects of the Invention]

[0082] The compound of Chemical Formula 1 according to the present invention specifically binds to CRBN protein and participates in its function, and therefore can be useful for the prevention or treatment of leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancers caused by the action of CRBN protein. [Brief explanation of the drawings]

[0083] [Figure 1] 1 shows the measurement of the degradation activity of Compound 1 of the present invention against GSPT1 and beta-actin (b-actin) in KG-1 cells treated for 6 hours. [Figure 2] The compounds of the present invention were treated with NCI-H1155 cancer cells for 72 hours, and the inhibitory effect on cancer cell growth was measured. DETAILED DESCRIPTION OF THE INVENTION

[0084] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail below with reference to preferred embodiments thereof. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, this description is provided so that this disclosure will be thorough and complete, and will fully convey the concept of the present invention to those skilled in the art.

[0085] Example 1: Synthesis of isoindolinone derivative compounds having a quinoline-substituted glutarimide core and confirmation of their physicochemical properties

[0086] The compound of the present invention represented by the above Chemical Formula 1 can be prepared by the following Reaction Schemes 1 and 2.

[0087] [ka]

[0088] [ka]

[0089] In the above reaction scheme 1, the methods for producing intermediates 2 to 5 are as follows.

[0090] 1) Synthesis of methyl 4-cyano-2-methylbenzoate (intermediate 2)

[0091] Methyl 4-bromo-2-methylbenzoate (3 g, 13.10 mmol) was dissolved in DMF (40 mL), followed by the addition of Pd2(dba)3 (0.480 g, 0.524 mmol), dppf (0.436 g, 0.786 mmol), and zinc cyanide (1.692 g, 14.41 mmol). The mixture was stirred under nitrogen for 30 minutes. The temperature was then raised to 130 °C and the mixture was stirred for 3 hours. After the reaction was complete, the mixture was filtered through Celite® and washed multiple times with DMF. The filtrate was extracted with EtOAc (50 mL × 2) and washed with water and brine. The combined organic layer was then concentrated under reduced pressure to remove the solvent after removing water with anhydrous magnesium sulfate. The mixture was purified by column chromatography (hexane: EtOAc = 9:1) to give Intermediate 2 (1.96 g, 11.19 mmol, 85%) as a light yellow solid in 85% yield.

[0092] 2) Synthesis of methyl 2-(bromomethyl)-4-cyanobenzoate (Intermediate 3)

[0093] Intermediate 2 (1.96 g, 11.19 mmol) was dissolved in DCE (30 mL), N-bromosuccinimide (2.64 g, 22.38 mmol) and benzoyl peroxide (0.271 g, 1.119 mmol) were added, and the mixture was heated under reflux and stirred for 8 hours. After the reaction was complete, the temperature was cooled to room temperature. The mixture was concentrated under reduced pressure to remove the solvent, and the mixture was purified by column chromatography (hexane: EtOAc = 9:1) to give intermediate 3 (2.29 g, 9.03 mmol, 81%) as a yellow solid in 81% yield.

[0094] 3) Synthesis of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (Intermediate 4)

[0095] 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 at 80°C overnight. After the reaction was completed, the temperature was lowered to room temperature and the mixture was 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 water was completely removed from the solid under reduced pressure to give Intermediate 4 (6.28 g, 23.32 mmol, 81%) as a dark blue solid in 81% yield.

[0096] 4) Synthesis of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate 5)

[0097] Intermediate 4 (1.7 g, 6.31 mmol) was dissolved in DMA (20 ml), and 10% Pd / C (2.32 g, 6.31 mmol) and methanesulfonic acid (0.451 ml, 6.94 mmol) were added. The mixture was stirred overnight at 40°C under hydrogen gas. After the reaction was completed, the mixture 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 mixture of methanol and ethyl ether (5 ml / 30 ml). The precipitate was filtered to give intermediate 5 (0.99 g, 2.69 mmol, 43%) as a gray solid in 43% yield.

[0098] 1H NMR (500 MHz, DMSO-d6) 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).

[0099] Compounds 1 to 15 of the present invention were prepared by referring to the method disclosed in Patent Document 7: Korean Patent Application No. 10-2010-7029476, and their physicochemical properties are as follows.

[0100] Compound 1. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-phenylquinoline-4-carboxamide

[0101] [ka]

[0102] 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate (15 mg, 0.00406 mmol) was dissolved in DMF (1 mL). 2-Phenylquinoline-4-carboxylic acid (9.5 mg, 0.0487 mmol), EDCl·HCl (8.5 mg, 0.0446 mmol), HOBt·HO (6.0 mg, 0.0446 mmol), and DIPEA (28 μL, 0.162 mmol) were added and stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the desired compound 1 (5.0 mg, 28%) as a white solid.

[0103] 1 H 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).

[0104] Compound 2. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-isopropylphenyl)quinoline-4-carboxamide

[0105] [ka]

[0106] Compound 2 was synthesized by the same method as that for compound 1, except that 2-(4-isopropylphenyl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0107] 1 H 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).

[0108] Compound 3. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methyl-2-phenylquinoline-4-carboxamide

[0109] [ka]

[0110] Compound 3 was synthesized by the same method as that for compound 1, except that 6-methyl-2-phenylquinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0111] 1 H NMR (500 MHz, DMSO-d6) 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).

[0112] Compound 4. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-phenylquinoline-4-carboxamide

[0113] [ka]

[0114] Compound 4 was synthesized by the same method as that for compound 1, except that 8-methyl-2-phenylquinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0115] 1H NMR (500 MHz, DMSO-d6) 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).

[0116] Compound 5. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(m-tolyl)quinoline-4-carboxamide

[0117] [ka]

[0118] Compound 5 was synthesized by the same method as that for compound 1, except that 2-(m-tolyl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0119] 1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.53 (t, J = 6.0 Hz, 1H), 8.22-8.08 (m, 5H), 7.83 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.69-7.57 (m, 3H), 7.47 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 5.12 (dd, J = 13.2, 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), 2.98-2.83 (m, 1H), 2.63 (d, J = 3.4 Hz, 1H), 2.46 (s, 3H), 2.41-2.32 (m, 1H), 2.07-1.93 (m, 1H).

[0120] Compound 6. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(p-tolyl)quinoline-4-carboxamide

[0121] [ka]

[0122] Compound 6 was synthesized by the same method as that for compound 1, except that 2-(p-tolyl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0123] 1H NMR (300 MHz, DMSO-d6) 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).

[0124] Compound 7. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(pyridin-4-yl)quinoline-4-carboxamide

[0125] [ka]

[0126] Compound 7 was synthesized by the same method as that for compound 1, except that 2-(pyridin-4-yl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0127] 1H 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).

[0128] Compound 8. 2-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide

[0129] [ka]

[0130] Compound 8 was synthesized by the same method as that for compound 1, except that 2-chloroquinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0131] 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.55 (t, J = 5.9 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.89 (m, 1H), 7.77 - 7.70 (m, 3H), 7.65 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 5.13 (dd, J = 13.3, 5.0 Hz, 1H), 4.68 (d, J = 6.0 Hz, 2H), 4.49 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.93 (m, 1H), 2.65 - 2.57 (m, 1H), 2.47 - 2.34 (m, 1H), 2.08 - 1.95 (m, 1H).

[0132] Compound 9. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-4-carboxamide

[0133] [ka]

[0134] Compound 9 was synthesized by the same method as that for compound 1, except that quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0135] 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.45 (t, J = 5.9 Hz, 1H), 9.00 (d, J = 4.3 Hz, 1H), 8.16 (d, J = 1.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.83 (m, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.70 - 7.61 (m, 3H), 7.56 (d, J = 7.9 Hz, 1H), 5.13 (dd, J = 13.4, 5.0 Hz, 1H), 4.69 (d, J = 6.0 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4.35 (d, J = 17.3 Hz, 1H), 2.93 (m, 1H), 2.64 - 2.56 (m, 1H), 2.46 - 2.32 (m, 1H), 2.06 - 1.97 (m, 1H).

[0136] Compound 10. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-8-methyl-2-(pyridin-3-yl)quinoline-4-carboxamide

[0137] [ka]

[0138] Compound 10 was synthesized by the same method as that for compound 1, except that 8-methyl-2-(pyridin-3-yl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0139] 1H 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) .

[0140] transformation Compound 12. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methyl-2-phenylquinoline-4-carboxamide

[0141] [ka]

[0142] Compound 12 was synthesized by the same method as that for compound 1, except that 3-methyl-2-phenylquinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0143] 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).

[0144] Compound 13. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(o-tolyl)quinoline-4-carboxamide

[0145] [ka]

[0146] Compound 13 was synthesized by the same method as that for compound 1, except that 2-(o-tolyl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0147] 1H 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).

[0148] Compound 14. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-fluorophenyl)quinoline-4-carboxamide

[0149] [ka]

[0150] Compound 14 was synthesized by the same method as that for compound 1, except that 2-(4-fluorophenyl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0151] 1H 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).

[0152] Compound 15. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-fluorophenyl)quinoline-4-carboxamide

[0153] [ka]

[0154] Compound 15 was synthesized by the same method as that for compound 1, except that 2-(2-fluorophenyl)quinoline-4-carboxylic acid was used instead of 2-phenylquinoline-4-carboxylic acid.

[0155] 1H 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).

[0156] Comparative Example 1: Synthesis of comparative isoindolinone derivative compounds having a glutarimide core and confirmation of their physicochemical properties

[0157] The physicochemical properties of the comparative compounds 1 to 3 are as follows.

[0158] Comparative Compound 1. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoquinoline-3-carboxamide

[0159] [ka]

[0160] Comparative compound 1 was synthesized by the same method as that for compound 1, except that isoquinoline-3-carboxylic acid was used instead of 6-chloro-1H-indazole-3-carboxylic acid.

[0161] 1H NMR (500 MHz, DMSO-d6) 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, 5.1Hz, 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).

[0162] Comparative Compound 2: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoxaline-2-carboxamide

[0163] [ka]

[0164] Comparative compound 2 was synthesized by the same method as that for compound 1, except that quinoxaline-2-carboxylic acid was used instead of 6-chloro-1H-indazole-3-carboxylic acid.

[0165] 1H NMR (500 MHz, DMSO-d6) 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).

[0166] Comparative Compound 3. 6-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-2-carboxamide

[0167] [ka]

[0168] Comparative compound 3 was synthesized by the same method as that for compound 1, except that 6-chloroquinoline-2-carboxylic acid was used instead of 6-chloro-1H-indazole-3-carboxylic acid.

[0169] 1H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 9.65 (t, J = 6.4 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.90 (dd, J = 9.0, 2.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (dd, J = 7.8, 1.4 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.69 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.59 (m, 1H), 2.35 (m, 1H), 2.06 - 1.94 (m, 1H).

[0170] <Experimental Example 1. Evaluation of substrate proteolytic activity against CRBN>

[0171] To confirm whether the compounds of the present invention can specifically bind to CRBN (celebron) and inhibit its function, we investigated the effect of the compounds on the degradation activity of Ikaros (IKZF1) protein (Chamberlain, PP et al., 2014) or GSPT1 protein (Matyskiela, ME et al., 2016), which are degraded by CRBN protein when bound to thalidomide and its analogs.

[0172] In order to evaluate the activity of the compounds according to the present invention to degrade Ikaros (IKZF1) protein or GSPT1 protein, the following experiment was carried out.

[0173] 5 × 10 KG-1 cells in a 12-well plate 5After seeding, cells were treated with each compound at a designated concentration in each well. After 6 hours, cell lysates were collected using TBSN buffer. Ikaros proteolytic activity was assessed by Western blot analysis using antibodies against Ikaros protein and GSPT1 protein. Equal amounts of protein were loaded into each well of a 4-15% gradient gel. After electrophoresis, the proteins were transferred to a PVDF membrane and bound to the primary antibodies against each protein. Subsequently, a secondary antibody conjugated with HRP was added and developed using HRP substrate.

[0174] As a result, as shown in FIG. 1, it was confirmed that the compounds of the present invention selectively promote the degradation of GSPT1 protein when treated with KG-1 cell line for 6 hours.

[0175] <Experimental Example 2. Cytotoxicity Experiment>

[0176] In order to confirm the effect of the example compounds of the present invention on cancer cells, a cytotoxicity experiment was carried out as follows.

[0177] Cancer cells (KG-1) were dispensed into a 96-well plate at 10,000 cells per well and treated with the example compounds of the present invention and comparative compounds (Comparative Compounds 1, 2, and 3) at predetermined concentrations. After 72 hours, WST-1 reagent was added, and the degree of cancer cell death was measured by measuring absorbance at 450 nm using a Spectramax spectrophotometer one hour later. The IC was calculated using the measured values ​​in the GraphPad Prism program. 50 The (μM) values ​​were calculated and are shown in Table 1.

[0178] The viability of NCI-H1155 (lung cancer cells) was measured using a CytoX cell viability assay kit (LPS solution, #CYT3000). NCI-H1155 cells were seeded into 12-well plates and then treated with each of the compounds of the present invention and the comparative compound (CC-90009) at 10 nM and 500 nM concentrations for 72 hours. After adding CytoX solution to the cells and incubating for 1 hour, the absorbance of each well was measured at 450 nm using a microplate reader, and the % viability was calculated and shown in Table 1.

[0179] As a result, as shown in FIG. 2, it was confirmed that the example compounds of the present invention had an excellent growth inhibitory effect on NCI-H1155 lung cancer cells.

[0180] [Table 1]

[0181] As shown in Table 1, it was confirmed that the isoindolinone derivative compounds having a quinoline amide structure of the present invention have superior cytotoxic activity against KG-1 cancer cells compared to the comparative compounds. Furthermore, the compounds substituted with an aryl at the 2-position of the quinoline (compounds 7, 10, 11 to 15) showed superior cytotoxicity in NCI-H1155 cancer cells compared to the compounds without an aryl substituent (compounds 8 and 9).

[0182] As a result, as shown in FIG. 2, the cytotoxicity of the compound of the present invention to NCI-H1155 cancer cells was confirmed.

[0183] <Formulation Example 1. Manufacture of powder>

[0184] 12 g of the compound of the present invention and 1 g of lactose were mixed and filled into an airtight pack to produce a powder.

[0185] <Formulation Example 2. Tablet manufacturing>

[0186] 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 compressed into tablets by a conventional tablet manufacturing method.

[0187] <Formulation Example 3. Production of Capsules>

[0188] 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 ingredients were mixed and filled into gelatin capsules according to a conventional capsule manufacturing method to prepare capsules.

[0189] <Formulation Example 4. Manufacture of pills>

[0190] 190 mg of the compound of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and small amounts of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives to inhibit hygroscopicity were mixed, and then 100 mg pills were prepared by a conventional method.

[0191] <Formulation Example 5. Manufacture of injections>

[0192] 110 mg of the compound of the present invention, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster were mixed, and then prepared into an ampoule (2 ml) containing the above ingredients according to a conventional method for preparing an injection.

Claims

1. The following chemical formula 1: 【Chemistry 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 substituted with hydrogen or deuterium (D); R ２ are independently hydrogen, halogen, hydroxy, carboxylic acid, C １－５ Alkyl carboxyl group, amino, acetamino, sulfonic acid, C １－５ Alkyl sulfonic acid, nitro, mono or di (C １－５ alkyl)amino, C １－５ Alkyl, C １－３ Alkoxy, HaloC １－３ Alkyl, haloC １－３ substituted with one or more substituents selected from the group consisting of alkoxy; R ３ is hydrogen, halogen, hydroxy, amino, acetamino, mono- or di-(C １－５ alkyl)amino, C １－５ Alkyl, C １－３ Alkoxy, HaloC １－３ Alkyl, haloC １－３ Alkoxy, substituted or unsubstituted C ６－１０ Aryl, or substituted or unsubstituted C ６－１０ substituted with one substituent selected from the group consisting of heteroaryl; wherein the substituted aryl or heteroaryl is selected from hydrogen, halogen, C １－５ Alkyl, C １－３ Alkoxy, HaloC １－３ Alkyl, haloC １－３ substituted with one or more substituents selected from the group consisting of alkoxy; R ４ is hydrogen, halogen, C １－５ Alkyl, C １－３ Alkoxy, HaloC １－３ Alkyl or haloC １－３ substituted with alkoxy; It is displayed as A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

2. The above chemical formula 1 can be converted to the following chemical formula 2: 【Chemistry 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 is independently N, CH, or C; R １ is substituted with hydrogen or deuterium (D); R ２ are independently hydrogen, halogen, hydroxy, carboxylic acid, C １－５ Alkyl carboxyl group, amino, acetamino, sulfonic acid, C １－５ Alkyl sulfonic acid, nitro, mono or di (C １－５ alkyl)amino, C １－５ Alkyl, C １－３ Alkoxy, HaloC １－３ Alkyl, haloC １－３ substituted with one or more substituents selected from the group consisting of alkoxy; R ４ is hydrogen, halogen, C １－５ Alkyl, C １－３ Alkoxy, HaloC １－３ Alkyl or haloC １－３ Substituted with alkoxy. It is displayed as 2. The compound of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of formula 1 above is 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); Selected from the group consisting of 2. The compound of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

4. A composition comprising the compound represented by Chemical Formula 1 according to claim 1, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

1. A pharmaceutical composition for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases or cancer, comprising:

5. The cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, small cell carcinoma, 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, perianal cancer, colon cancer, breast cancer, trumpet cancer, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumors, primary CNS lymphomas, spinal cord tumors, brainstem glioma, and pituitary adenoma. The pharmaceutical composition according to claim 4 for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases or cancer.

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