Novel compound and use thereof

Abstract

The present invention relates to a novel compound and the use thereof. With excellent binding affinity for cerebron, the novel compound of the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof can effectively degrade GSPT1 through E3 ubiquitin ligase activity of the cereblon complex and thus can effectively treat proliferative diseases and the like.

Description

Novel compounds and their uses

[0001] The present invention relates to a novel compound and its use.

[0002] Typically, drugs exert their effects by binding to specific sites on a specific protein and inhibiting its function. In other words, whether a druggable target for new therapeutics is determined by the potential to target a specific active site or binding pocket of a disease-related protein.

[0003] According to a 2016 report, approximately 400 proteins are targeted by drugs approved by the U.S. Food and Drug Administration (FDA), most of which are enzymes, receptors, transporters, various channels, and membrane proteins. However, currently, approximately 3,000 proteins are known to cause human diseases, and only 13% of these are being developed as target proteins. This is because current drug development methods are unable to target and inhibit the function of most disease-causing proteins. For example, c-Myc, a well-known target of anticancer drugs, is a transcription factor and lacks a hydrophobic pocket structure for drug binding. Furthermore, protein aggregates that cause neurodegenerative diseases, such as Tau tangles, are intractable to remove using current technology. Therefore, new attempts to target "undruggable" target proteins are continuously being conducted.

[0004] For example, a method for selectively removing target proteins using the ubiquitin-proteasome pathway has recently been proposed. Recently, it has been reported that ubiquitin-mediated protein degradation is related to various diseases, particularly neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as genetic diseases. Abnormalities in the protein degradation pathway are believed to be the cause of various diseases, including cancer. Accordingly, therapeutics based on proteolysis-targeting chimaeras (PROTACs) are being researched and developed as a treatment that removes disease-causing proteins by activating the ubiquitin-proteasome pathway. PROTACs are bifunctional small organic molecules consisting of a ligand that binds to the target protein, a ligand that binds to an E3 ubiquitin ligase, and a linker. By binding the target protein to the E3 ubiquitin ligase, which can initiate the protein degradation system, the PROTAC has a structure that facilitates the degradation of the target protein. This is expected to achieve the desired therapeutic effect by positioning the desired disease-related protein near the E3 ubiquitin ligase, thereby degrading the target protein. However, PROTACs have the disadvantage of low cell penetration efficiency due to their relatively large molecular size. On the other hand, molecular adhesives induce the formation of a complex between the E3 ubiquitin ligase and the target protein without a linker, thereby degrading the target protein. Therefore, compared to PROTACs, they have a lower molecular weight, facilitating the development of therapeutics with superior pharmacokinetic properties.

[0005] GSPT1 (G1 to S phase transition 1) is a translation termination factor that regulates the final step of protein translation and is involved in cell cycle regulation and apoptosis. Therefore, GSPT1 is primarily studied in proliferative diseases where protein translation is active, and is known to be overexpressed in various cancers, including acute myeloid leukemia (AML), gastric cancer, colon cancer, liver cancer, and breast cancer. Furthermore, since MYC-induced protein translation in cancer cells is known to be dependent on GSPT1, it is expected to exhibit anti-tumor effects in MYC-driven cancers.

[0006] Accordingly, the inventors of the present invention developed a novel compound and its use as a molecular adhesive, thereby completing the present invention.

[0007] One aspect provides a compound represented by chemical formula 78, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0008] Another aspect provides a pharmaceutical composition for preventing or treating a proliferative disease comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0009] Another aspect provides a pharmaceutical composition for preventing or treating a GSPT1-related disease comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0010] Another aspect provides a method for preventing or treating a proliferative disease or a GSPT1-associated disease, comprising administering to a subject the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a composition comprising the same.

[0011] Another aspect provides a use of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof for the prevention or treatment of a proliferative disease or a GSPT1-associated disease.

[0012] Another aspect provides the use of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof in the manufacture of a medicament for preventing or treating a proliferative disease or a GSPT1-associated disease.

[0013] Another aspect provides a pharmaceutical composition comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0014] Another aspect provides a GSPT1 degrader comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0015] One aspect is to provide a compound according to the following chemical formula 78, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:

[0016] [Chemical Formula 78]

[0017]

[0018] In the above chemical formula 78,

[0019] One or more R 1 are each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylamino group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, -CH2R 3 , -OR 3 , -OCH2R 3 , -NR 3 R 4 , -NH(C=O)R 3 , -(C=O)R 3 , -(C=O)OR 3 , -(C=O)NR 3 R 4 , -SO2NHR 3, -CN, -NO2, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0020] R 2 is selected from the group consisting of hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl group and a substituted or unsubstituted C1-C6 haloalkyl group,

[0021] R 3 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl group, amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C3 haloalkyl group, substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, substituted or unsubstituted C3-C12 aryl group and substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0022] R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl group, amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C3 haloalkyl group, substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, substituted or unsubstituted C3-C12 aryl group and substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0023] m is an integer in the range 0 to 2,

[0024] n is an integer in the range 0 to 2,

[0025] X is C=O or CH2,

[0026] Y is CH or N,

[0027] Z is selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group.

[0028] The definitions of substituted substituents used in chemical formulas in this specification are as follows.

[0029] The term "alkyl" as used in chemical formulas refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon group. Non-limiting examples of such "alkyl" groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, and the like.

[0030] The term "halogen" as used in chemical formulas includes fluorine, bromine, chlorine, iodine, etc.

[0031] The term "halogen-substituted alkyl group (haloalkyl)" as used in chemical formulas refers to an alkyl group substituted with one or more halo groups, including, but not limited to, polyhaloalkyl containing monohaloalkyl, dihaloalkyl, or perhaloalkyl. Monohaloalkyl refers to an alkyl group having one iodine, bromine, chlorine, or fluorine, while dihaloalkyl and polyhaloalkyl refer to an alkyl group having two or more identical or different halo atoms.

[0032] The term "alkoxy" as used in chemical formulas refers to alkyl-O-, wherein the alkyl is as described above. Non-limiting examples of the alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclohexyloxy, and the like.

[0033] The term "alkenyl" as used in chemical formulas refers to a branched or unbranched hydrocarbon having at least one carbon-carbon double bond. Non-limiting examples of alkenyls include vinyl, allyl, butenyl, isopropenyl, and isobutenyl.

[0034] The term "alkynyl" as used in chemical formulas refers to a branched or unbranched hydrocarbon having at least one carbon-carbon triple bond. Non-limiting examples of such alkynyls include ethynyl, butynyl, isobutynyl, and isopropynyl.

[0035] The term "cycloalkyl" as used in chemical formulas refers to an alkyl group that forms a ring, as described above. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In addition, "cycloalkenyl" refers to an alkenyl group that forms a ring, as described above.

[0036] The term "heterocycloalkyl" as used in chemical formulas refers to a cyclic hydrocarbon that contains one or more heteroatoms selected from N, O, P or S as a reducing group and is entirely saturated. In addition, "heterocycloalkenyl" refers to a cyclic hydrocarbon that contains one or more heteroatoms selected from N, O, P or S as a reducing group and has at least one double bond.

[0037] The term "aryl" as used in chemical formulas, alone or in combination, refers to an aromatic hydrocarbon group containing one or more rings. The term "aryl" also includes groups in which an aromatic ring is fused to one or more cycloalkyl rings. Non-limiting examples of "aryl" include phenyl, naphthyl, and tetrahydronaphthyl.

[0038] The term "arylalkyl" as used in chemical formulas refers to an alkyl substituted with an aryl. Examples of arylalkyl include benzyl or phenyl-CH2CH2-. Additionally, "aryloxy" refers to O-aryl, and examples of aryloxy include phenoxy.

[0039] The term "heteroaryl" as used in chemical formulas refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from N, O, P or S, with the remaining ring atoms being carbon. The heteroaryl group may contain, for example, 1-5 heteroatoms and 3-12 ring members. The S or N may be oxidized to have various oxidation states.

[0040] The term "heteroarylalkyl" as used in chemical formulas means an alkyl substituted with a heteroaryl. Additionally, the term "heteroaryloxy" means an -O-heteroaryl moiety.

[0041] The term "amino group" as used in chemical formulas refers to a nitrogen atom covalently bonded to at least one carbon or heteroatom. Amino groups include, for example, -NH2 and substituted moieties. The term "amino group" may include alkylamino groups in which the nitrogen is bonded to at least one additional alkyl group, arylamino groups in which the nitrogen is bonded to at least one or more independently selected aryl groups, and diarylamino groups.

[0042] The '*' used in chemical formulas represents a bonding site with a neighboring atom.

[0043] The term "substituted" or "substituted" as used herein means a group in which one or more hydrogen atoms are replaced by one or more non-hydrogen atoms, provided that valence requirements are satisfied and a chemically stable compound results from the substitution. As used herein, all substituents should be interpreted as being either substituted or unsubstituted, unless explicitly stated as "unsubstituted."

[0044] For example, the 'substitution' in 'substituted' used in the alkyl group, haloalkyl group, alkoxy group, alkylamino group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group and heteroaryl group used above means a C1-C10 alkyl group in which one or more hydrogen atoms are substituted with halogen, halogen (e.g., CCF3, CHCF2, CH2) F , CCl3, etc.), alkoxy group, hydroxy group, nitro group, cyano group, amino group, amide group, sulfonamide group, ketone group, ester group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group, arylalkyl, aryloxy, heteroaryl group, heteroarylalkyl, and heteroaryloxy, etc.

[0045] In one embodiment, the substitution comprises one or more R a may be substituted with one or more of the R a are each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, -CH2R 3 -OR 3 , -OCH2R 3 , -NR 3R 4 , -NH(C=O)R 3 , -NHSO2R 3 , -(C=O)R 3 , -(C=O)OR 3 , -(C=O)NR 3 R 4 , -SO2NHR 3 , -CN, -NO2, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group.

[0046] The term "pharmaceutically acceptable salt" as used herein refers to a salt that can be used pharmaceutically among salts, which are substances in which cations and anions are bound by electrostatic attraction, and can typically be a metal salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. For example, the metal salt can be an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt, etc.; the salt with an organic base can be a salt with triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.; the salt with an inorganic acid can be a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; salts with basic amino acids include salts with arginine, lysine, ornithine, etc.; salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Particularly preferred salts include, when the compound has an acidic functional group therein, inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), and organic salts such as ammonium salts; and, when the compound has a basic functional group therein, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

[0047] The term "isomer" as used herein refers to a compound or salt thereof that has the same chemical formula or molecular formula but is optically or sterically different. Specifically, the isomer may include at least one selected from the group consisting of enantiomers, stereoisomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, racemates, and pharmaceutically acceptable salts thereof.

[0048] The term "solvate" as used herein refers to a compound solvated in an organic or inorganic solvent. The solvate may be, for example, a hydrate.

[0049] The compound may be one in the chemical formula 78, wherein X is CH2 and Y is CH. Specifically, the compound may be one represented by the following chemical formula 79.

[0050] [Chemical Formula 79]

[0051]

[0052] The compound is a compound having the chemical formula 78, wherein m is 0, n is 1, and R 2 may be hydrogen. Specifically, the compound may be represented by the following chemical formula 80.

[0053] [Chemical Formula 80]

[0054]

[0055] The compound is a compound having the chemical formula 78, wherein X is CH2, Y is CH, m is 0, n is 1, and R 2 may be hydrogen. Specifically, the compound may be represented by the following chemical formula 81.

[0056] [Chemical Formula 81]

[0057]

[0058] In one embodiment, the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may be a compound according to the above chemical formula 81, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0059] The compound has one or more chemical formulas among the chemical formulas 78 to 81 (specifically, chemical formula 81),

[0060] The above Z is selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0061] When the above Z is a substituted functional group, one or more R a It has been replaced with,

[0062] One or more of the above R a are each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, -CH2R 3 -OR 3 , -OCH2R 3 , -NR 3 R 4 , -NH(C=O)R 3 , -NHSO2R 3 , -(C=O)R 3 , -(C=O)OR 3 , -(C=O)NR 3 R 4 , -SO2NHR 3, -CN, -NO2, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0063] R 3 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl group, amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C3 haloalkyl group, substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, substituted or unsubstituted C3-C12 aryl group and substituted or unsubstituted 3 to 12 membered heteroaryl group, and

[0064] R 4 may be independently selected from the group consisting of hydrogen, halogen, hydroxyl group, amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C3 haloalkyl group, substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, substituted or unsubstituted C3-C12 aryl group, and substituted or unsubstituted 3 to 12 membered heteroaryl group.

[0065] In one embodiment, the Z may be bonded to a carbon (C) atom of a ketone group of any one or more of the chemical formulae 78 to 81, and specifically, any carbon (C) atom in the Z may be bonded to a carbon (C) atom of a ketone group of the chemical formulae.

[0066] The compound may be one having at least one of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises at least one selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12-membered heteroaryl group, and a group represented by the following chemical formulas 82-1 to 82-52:

[0067]

[0068]

[0069] .

[0070] In any one or more of the above chemical formulas 82-1 to 82-52,

[0071] R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylamino group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, -CH2R 3 -OR 3 , -OCH2R 3 , -NR 3 R 4 , -NH(C=O)R 3 , -NHSO2R 3 , -(C=O)R 3 , -(C=O)OR 3 , -(C=O)NR 3 R 4 , -SO2NHR 3, -CN, -NO2, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0072] R 10 , R 11 and R 12 are each independently hydrogen, halogen, -OR 3 , -NR 3 R 4 , selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted benzyl group,

[0073] R 3 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl group, amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C3 haloalkyl group, substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, substituted or unsubstituted C3-C12 aryl group and substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0074] R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl group, amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C3 haloalkyl group, substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, substituted or unsubstituted C3-C12 aryl group and substituted or unsubstituted 3 to 12 membered heteroaryl group,

[0075] o is an integer in the range 0 to 2,

[0076] p is an integer in the range 1 to 3, and

[0077] * is a bonding site with a neighboring atom.

[0078] In one embodiment, the compound may be one having at least one of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises at least one selected from the group represented by the following chemical formulas 82-1 to 82-5, 82-8 to 82-10, 82-14, 82-15, 82-18, 82-19, 82-28, 82-30, 82-31, 82-33, 82-34, 82-37 to 82-39, 82-44, and 82-49 to 82-52:

[0079]

[0080]

[0081] In one embodiment, in any one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), Z may include at least one selected from the group represented by the following chemical formulas 82-1, 82-14, 82-28, 82-30, 82-31, 82-33, 82-34, 82-49, and 82-52:

[0082]

[0083] In the above chemical formula 82-1, R 5 , R 8 , and R 9 is hydrogen.

[0084] In one embodiment, the compound may be a compound having one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises at least one selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12-membered heteroaryl group, and a group represented by the following chemical formulas 82-1 to 82-52, and R of the chemical formulas 82-1 to 82-52 6 and R 7 are each independently hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C3 haloalkyl group, -CH2R 3 -OR 3 , -NR 3 R 4 , is selected from the group consisting of a C3-C8 cycloalkyl group, a 3 to 8 membered heterocycloalkyl group, a C6-C10 aryl group, and a 5 to 10 membered heteroaryl group, wherein o may be 0 or 1.

[0085] In one embodiment, the compound may be a compound having one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z includes at least one selected from the group consisting of groups represented by chemical formulas 82-1, 82-14, 82-28, 82-30, 82-31, 82-33, 82-34, 82-49 and 82-52, and in chemical formulas 82-1, 82-14, 82-28, 82-30, 82-31, 82-33, 82-34, 82-49 and 82-52, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 can be as follows:

[0086] 1) R 5 , R 8 , and R9 is hydrogen,

[0087] 2) R 6 and R 7 are each independently hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C3 haloalkyl group, -CH2R 3 -OR 3 , -NR 3 R 4 , a C3-C8 cycloalkyl group, a 3 to 8 membered heterocycloalkyl group, a C6-C10 aryl group and a 5 to 10 membered heteroaryl group, and specifically, may be selected from the group consisting of hydrogen, halogen, hydroxyl group, methyl, tert-butyl, cyclohexyl, -NH(C6H5), and -N(CH3)2,

[0088] 3) R 10 Silver hydrogen, halogen, -OR 3 , -NR 3 R 4 , may be selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted benzyl group, and may be specifically selected from the group consisting of hydrogen, halogen, phenyl group, and -NHCH3,

[0089] 4) R 11 Silver hydrogen, halogen, -OR 3 , -NR 3 R 4 , may be selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted phenyl group and a substituted or unsubstituted benzyl group, and may be specifically selected from the group consisting of hydrogen, a methyl group and a phenyl group,

[0090] 5) R 12 is hydrogen, halogen, -OR 3 , -NR 3 R 4, may be selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted phenyl group and a substituted or unsubstituted benzyl group, and may be specifically hydrogen,

[0091] 6) o can be 0, 1 or 2, specifically 0 or 1, and

[0092] 7) p can be 1 or 2, specifically 1.

[0093] In one embodiment, the compound may be one having one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises a substituted or unsubstituted 6-membered heteroaryl, and the 6-membered heteroamine may comprise one or two nitrogen (N) atoms as a reducing group.

[0094] In one embodiment, the compound may be one having one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises a substituted or unsubstituted 5-membered heteroaryl, and the 5-membered heteroamine may comprise one or more, specifically one or two, selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S) as a reducing agent.

[0095] In one embodiment, the compound may be one having one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises a substituted or unsubstituted 9-membered heteroaryl, and the 9-membered heteroamine may comprise one or more, specifically one or two, selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S) as a reducing agent.

[0096] In one embodiment, the compound may be one having one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises a substituted or unsubstituted 10-membered heteroaryl, and the 10-membered heteroamine may comprise one or two nitrogen (N) atoms as a reducing group.

[0097] In one embodiment, the compound may be one having one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises a substituted or unsubstituted C6 to C10 aryl.

[0098] In one embodiment, the Z may be bonded to a carbon (C) atom of a ketone group of any one or more of the chemical formulae 78 to 81, and specifically, any nitrogen (N) atom in the Z may be bonded to a carbon (C) atom of the ketone group of the chemical formulae.

[0099] The compound may be one having at least one of the chemical formulas 78 to 81 (specifically, chemical formula 81), wherein Z comprises at least one selected from the group consisting of groups represented by chemical formulas 83-1 to 83-11:

[0100]

[0101] In the above chemical formula,

[0102] R 13 and R 14 are each independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl group, CF3, NHR 15 , OR 15 , and is selected from the group consisting of substituted or unsubstituted C3-C12 aryl groups,

[0103] R 15are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C2 haloalkyl group, and a substituted or unsubstituted C3-C12 aryl group,

[0104] * is a bonding site with a neighboring atom.

[0105] In one embodiment, in any one or more of the chemical formulas 78 to 81 (specifically, chemical formula 81), Z may include at least one selected from the group represented by the following chemical formulas 83-1, 83-2, 83-5, 83-6, and 83-8:

[0106] .

[0107] In one embodiment, the compound may include one or more compounds selected from the group consisting of compounds 1 to 77 described in Tables 1 to 8. Specifically, compounds 1 to 77 may be represented by chemical formulas 1 to 77, respectively, and the chemical formulas of compounds 1 to 77 are described below.

[0108]

[0109]

[0110]

[0111]

[0112]

[0113] Accordingly, the compound, its isomer, its pharmaceutically acceptable salt or its solvate may include at least one selected from the group consisting of one or more compounds selected from the chemical formulae 1 to 77, its isomer, its pharmaceutically acceptable salt and its solvate.

[0114] The compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may be capable of binding to a Cereblon (CRBN) protein, and may specifically have binding affinity for the Cereblon protein, and more specifically may have excellent binding affinity for the Cereblon protein.

[0115] The term "cereblon (CRBN)" as used herein refers to the protein encoded by the human CRBN gene located at cytogenetic location 3p26.2 and molecular location between base pairs 3,148,489 and 3,179,716 of chromosome 3 (UCSC Genome Browser for Human, December 2013 (GRCh38 / hg38) assembly). CRBN is the substrate recognition component of the DCX (DDB1-CUL4-X-box) E3 protein ligase complex, which mediates ubiquitination and subsequent proteasomal degradation of target proteins. The DCX (DDB1-CUL4-X-box) E3 protein ligase complex can be composed of at least CRBN, CUL4A, DDB1, and RBX1. The CRBN protein has two isoforms generated by alternative splicing: isoform 1 has 442 amino acids and a molecular weight of 50,546 Da; and isoform 2 has 441 amino acids and a molecular weight of 50,475 Da.

[0116] The compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may be for modulating the activity of a cereblon protein or a complex comprising the cereblon protein, and specifically may be for enhancing the activity.

[0117] The complex including the above-mentioned CRBN protein is an E3 ubiquitin ligase complex, and may include a complex including a CRBN protein and DDB1 (DNA damage-binding protein 1) (CRBN-DDB1 complex), specifically, a complex including a CRBN protein, DBB1, and Cullin-4 (CUL4) (CRBN-DDB1-CUL4 complex), and more specifically, a complex including a CRBN protein, DBB1, CUL4, and Rbx1 (RING-box protein 1) (CRBN-DDB1-CUL4-Rbx1 complex).

[0118] The activity of the above-mentioned Cereblon protein or a complex comprising the above-mentioned Cereblon protein may include E3 ubiquitin ligase activity, and specifically, may include a degrading activity of the Cereblon protein or a complex comprising the same toward a target protein.

[0119] In one embodiment, the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may bind to a cereblon protein and enhance the degradative activity against the target protein.

[0120] The compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof can modulate the activity or degradation level of the GSPT1 (Eukaryotic peptide chain release factor GTP-binding subunit ERF3A) protein, and specifically, can induce degradation of the GSPT1 protein to reduce the activity and / or reduce the expressed level.

[0121] The term "GSPT1 (Eukaryotic peptide chain release factor GTP-binding subunit ERF3A)" in this specification is a translation termination factor that binds to eRF1 and mediates stop codon recognition and release of nascent proteins from the ribosome. Ubiquitination and degradation of GSPT1 are known to induce suppression of the expression levels of translationally addicted oncoproteins (e.g., c-MYC, N-MYC, L-MYC, BCL-2, MCL-1, etc.) whose expression levels are maintained at high levels depending on protein translation in cancer cells. In addition, GSPT1 degradation is known to activate a cell death mechanism called the "integrated stress response."

[0122] In one embodiment, the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may have molecular adhesive properties, specifically capable of binding to a cereblon protein and inducing degradation of the GSPT1 protein.

[0123] In one embodiment, the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may have a GSPT1 degrading agent use, and specifically, may bind to the cereblon protein to induce degradation of the GSPT1 protein.

[0124] In one embodiment, the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may have a preventive or therapeutic effect on a proliferative disease.

[0125] In one embodiment, the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may have a preventive or therapeutic effect on a GSPT1-related disease.

[0126]

[0127] Another aspect provides a pharmaceutical composition for the prevention or treatment of proliferative diseases, comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The same parts as described above also apply to the composition.

[0128] The proliferative disease may include cancer.

[0129] In one embodiment, the proliferative disease is adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen dependent and independent breast cancer, Burkitt's lymphoma, corpus cancer, carcinoma of unknown primary tumor (CUP-syndrome), colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, Endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose, and throat tumors,Hematologic tumors, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumors, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumors, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose, and throat), colon carcinoma, craniopharyngiomas, oral cancer, cancer of the central nervous system, liver cancer, liver metastases, Leukemia, eyelid tumor, lung cancer, lymphoma, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors of the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's / Non-Hodgkin's lymphomas, mycosis fungoides, nasal cancer,neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic and osteoplastic carcinomas, osteosarcomas, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, esophageal cancer, T-cell lymphoma, thymoma, tube carcinoma, eye tumors, Urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, nephroblastoma, cervical carcinoma, tongue cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ,Small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brain stem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumors, sarcoma of the uterus, salivary gland cancers, anal gland adenocarcinomas, mast cell tumors, pelvis tumor, ureter tumor, hereditary papillary renal cancers, renal papillary sporadic papillary renal cancers, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cavity cancer,It may include squamous cell cancer, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, lymphoma of the central nervous system, malignant fibrous histiocytoma, lymph sarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma, and feline mammary carcinoma, and combinations thereof.

[0130] The above proliferative disease may include a GSPT1-related disease.

[0131] The above GSPT1-related disease may include a disease that is caused or may be caused by the expression and / or activity of the GSPT1 protein, and specifically may include a disease that is caused or may be caused by the overexpression and / or overactivity of the GSPT1 protein.

[0132] In one embodiment, the GSPT1-related disease may include acute myeloid leukemia, gastric cancer, colon cancer, liver cancer, breast cancer, and MYC-driven cancers.

[0133] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" may refer to a carrier or diluent that does not stimulate a living organism and does not inhibit the biological activity or properties of the injected compound. Here, "pharmaceutically acceptable" means that the carrier does not inhibit the activity of the active ingredient and does not exhibit toxicity exceeding the adaptability of the subject of application (prescription). Any carrier commonly used in the art and pharmaceutically acceptable for the pharmaceutical composition may be used. Non-limiting examples of the above carriers include lactose, dextrose, maltodextrin, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, glycerol, ethanol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. These may be used alone or in combination of two or more. The pharmaceutical composition may be prepared as an oral formulation or a parenteral formulation according to the route of administration by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. The above pharmaceutical composition can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions, each according to a conventional method.

[0134] The above pharmaceutical composition may be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods. When formulating the above pharmaceutical composition, it may be prepared by adding diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, or surfactants that are commonly used.

[0135] When the above pharmaceutical composition is manufactured into an oral dosage form, it can be manufactured into a dosage form such as powder, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers, etc., using a suitable carrier according to a method known in the art. At this time, examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, etc.; starches such as corn starch, potato starch, and wheat starch; celluloses such as cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyols, and vegetable oils. In case of formulation, the formulation may include diluents and / or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants, as needed.

[0136] When the above pharmaceutical composition is prepared as a parenteral dosage form, it can be formulated in the form of injections, transdermal administration, nasal inhalation, and suppositories using a suitable carrier according to a method known in the art. When formulated as an injection, suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof, and preferably, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, sterile water for injection, and isotonic solutions such as 5% dextrose can be used. When formulated as a transdermal dosage form, it can be formulated in the form of ointments, creams, lotions, gels, external solutions, pastes, liniments, aerosols, etc. In the case of nasal inhalation, it can be formulated in the form of an aerosol spray using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, or carbon dioxide, and in the case of formulating it as a suppository, the base can be witepsol, tween 61, polyethylene glycol, cacao butter, laurin butter, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sorbitan fatty acid ester, etc.

[0137] The pharmaceutical composition may be administered in a pharmaceutically effective amount, wherein the term "pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention, and the effective dosage level may be determined according to the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the treatment period, the drug used in combination or concurrently with the composition of the present invention used, and other factors well known in the medical field. The pharmaceutical composition may be administered alone or in combination with a component known to exhibit a therapeutic effect on a known proliferative disease or a GSPT1-related disease. It is important to take all of the above factors into consideration and administer an amount that can achieve the maximum effect with the minimum amount without side effects.

[0138] The dosage of the pharmaceutical composition may be determined by a person skilled in the art in consideration of the intended use, the degree of toxicity of the disease, the patient's age, weight, sex, medical history, or the type of substance used as the active ingredient. For example, the pharmaceutical composition of the present invention may be administered at about 0.1 ng to about 1,000 mg / kg, preferably 1 ng to about 100 mg / kg, per adult, and the frequency of administration of the composition of the present invention is not particularly limited thereto, but may be administered once a day or administered in divided doses several times. The dosage or frequency of administration does not limit the scope of the present invention in any way.

[0139]

[0140] Another aspect is a pharmaceutical composition for preventing or treating a GSPT1-related disease, comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The same parts as described above also apply to the composition.

[0141] The above GSPT1-related disease may include a disease that is caused or may be caused by the expression and / or activity of the GSPT1 protein, and specifically may include a disease that is caused or may be caused by the overexpression and / or overactivity of the GSPT1 protein.

[0142] In one embodiment, the GSPT1-related disease may include acute myeloid leukemia, gastric cancer, colon cancer, liver cancer, breast cancer, and MYC-driven cancers.

[0143]

[0144] Another aspect provides a method for preventing or treating a proliferative disease or a GSPT1-associated disease, comprising administering to a subject the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a composition comprising the compound. The same portions described above also apply to the method.

[0145] The term "subject" as used herein may include, without limitation, mammals, birds, reptiles, farmed fish, etc., including dogs, cats, mice, livestock, and humans, that are or are at risk of developing a proliferative disease or a GSPT1-related disease. The subject may exclude humans.

[0146] The pharmaceutical composition may be administered in single or multiple doses in a pharmaceutically effective amount. The composition may be formulated and administered in the form of a liquid, powder, aerosol, injection, infusion (Ringel), capsule, pill, tablet, suppository, or patch. The pharmaceutical composition may be administered via any conventional route as long as it can reach the target tissue.

[0147] The pharmaceutical composition may be administered, but is not particularly limited thereto, via routes such as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, intranasal administration, intrapulmonary administration, and rectal administration, depending on the intended purpose. However, when administered orally, it may be administered in an unformulated form, and since the active ingredient of the pharmaceutical composition may be denatured or decomposed by gastric acid, the oral composition may be administered orally in a form that coats the active agent or is formulated to protect it from decomposition in the stomach, or in the form of an oral patch. In addition, the composition may be administered by any device that allows the active ingredient to move to the target cell.

[0148]

[0149] Another aspect provides a use of the compound, its isomer, its pharmaceutically acceptable salt, or its solvate for the prevention or treatment of a proliferative disease or a GSPT1-associated disease. The same portions described above also apply to the above use.

[0150]

[0151] Another aspect provides the use of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof in the manufacture of a medicament for preventing or treating a proliferative disease or a GSPT1-associated disease. The same portions described above also apply to the above use.

[0152]

[0153] Another aspect provides a pharmaceutical composition comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The same aspects described above also apply to the composition.

[0154]

[0155] Another aspect provides a GSPT1 degrader comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The same principles as described above also apply to the degrader.

[0156] In one embodiment, the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may modulate the activity of the cereblon protein or a complex comprising the same, thereby degrading or reducing the expression level of the GSPT1 protein.

[0157] The novel compound of the present invention, its isomer, its pharmaceutically acceptable salt, or its solvate has excellent binding affinity to cereblon, and can effectively degrade GSPT1 through the E3 ubiquitin ligase activity of the cereblon complex, thereby effectively treating diseases such as proliferative diseases.

[0158] Figure 1 is a drawing showing the results of confirming the GSPT1 decomposition activity of the novel compound of the present invention through Western blotting analysis.

[0159] The present invention will be described in more detail through the following examples. However, these examples are provided for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0160]

[0161] Manufacturing Example 1: Synthesis of Compound 1

[0162] 1.1: Synthesis of compound A2

[0163] [Reaction Formula 1-1]

[0164]

[0165] 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (A1, 4 g, 0.014 mol) was dissolved in DCM (100 mL) and sodium benzenethiolate (1.84 g, 0.014 mol), DIPEA (3.59 g, 0.028 mol) and 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tributyl-2,4,6-trioxide (T4P, 50% mass ratio / EtOAc, 30.05 g, 0.042 mol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. This was purified by flash chromatography (DCM / MeOH = 100: 0 to 90: 10) to obtain A2 (3.8 g, yield 64%) as a white solid.

[0166]

[0167] 1.2: Synthesis of compound 1

[0168] [Reaction Formula 1-2]

[0169]

[0170] A mixture of compound A2 (50 mg, 0.1314 mmol), phenylboronic acid (19 mg, 0.16 mmol), Pd2(dba)3-chloroform complex (13 mg, 0.013 mmol), tri(2-furyl)phosphine (TFP, 6.1 mg, 0.026 mmol), and copper(I)thiophene-2-carboxylate (CuTC, 38 mg, 0.20 mmol) in THF (3 mL) was stirred at 50 °C under N2 atmosphere for 18 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. This was purified by silica gel chromatography (DCM: MeOH = 97%: 3%) and washed with MeOH to give compound 1 (18 mg, yield 39%) as a white solid.

[0171]

[0172] Manufacturing Example 2: Synthesis of Compound 2

[0173] [Reaction Formula 2]

[0174]

[0175] 2-1: Synthesis of compound 2-1

[0176] To a solution of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (A1, 100 mg, 0.35 mmol), tert-butyl(S)-methyl(pyrrolidin-3-yl)carbamate (104 mg, 0.52 mmol), 1-hydroxybenzotrizole (56 mg, 0.42 mmol), and NEt3 (88 mg, 0.42 mmol) in DCM (5 mL) was slowly added a solution of EDCI (80 mg, 0.42 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 18 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. This was purified by silica gel chromatography (DCM: MeOH = 97%: 3%) and washed with MeOH to obtain compound 2-1 (100 mg, yield 55%) as a white solid.

[0177]

[0178] 2-2: Synthesis of compound 2

[0179] Compound 2-1 (100 mg, 0.2125 mmol) was dissolved in MeOH (2 mL) and HCl (2 mL, 4N in dioxane) was stirred at 25 °C for 1 h. The mixture was dried under a nitrogen atmosphere. The resulting solid was purified by prep-HPLC (column: Phenomenex luna C18 250 mm Х 100 mm Х 10 μm; mobile phase: [H2O (0.1% HCl) / MeCN = 0% - 50%]) to give compound 2 (12 mg, yield 14%) as a white solid.

[0180]

[0181] Manufacturing Example 3: Synthesis of Compound 3

[0182] [Reaction Formula 3]

[0183]

[0184] 3-1: Synthesis of compound 3-2

[0185] (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (3-1, 38 mg, 0.14 mmol) was synthesized in the same manner as compound 1 to obtain compound 3-2 (20 mg, yield 28%) as a brown solid.

[0186]

[0187] 3-2: Synthesis of compound 3

[0188] TFA (1 mL) was added to a DCM (1 mL) solution containing compound 3-2 (20 mg, 0.04 mmol) at 25 o C for 1 h. The solution was removed under a nitrogen atmosphere, and the pH of the mixture was adjusted to 7 with saturated aqueous NaHCO3 solution. The aqueous solution was extracted with DCM (5 mL x 3), and the organic layer was concentrated to obtain the crude product. Then, it was washed with MeOH, and the solid was collected by centrifugation to obtain compound 3 (12 mg, yield 71%) as a pale white solid.

[0189]

[0190] Manufacturing Example 4: Synthesis of Compound 4

[0191] [Reaction Formula 4]

[0192]

[0193] 4-1: Synthesis of compound 4-2

[0194] (1-(tert-butoxycarbonyl)-1H-indol-3-yl)boronic acid (4-1, 76 mg, 0.29 mmol) was synthesized using the same process as compound 1 to obtain 4-2 (60 mg, yield 42%) as a white solid.

[0195]

[0196] 4-2: Synthesis of compound 4

[0197] Compound 4-2 (49 mg, 0.10 mmol) was synthesized in the same manner as compound 3 to obtain compound 4 (20 mg, yield 49%) as a white solid.

[0198]

[0199] Manufacturing Example 5: Synthesis of Compound 5

[0200] [Reaction Formula 5]

[0201]

[0202] 5-1: Synthesis of compound 5-1

[0203] NaI (2.43 g, 0.016 mol) and TMSCl (0.59 g, 0.005 mol) were added to a solution of methyl 6-chloro-2-methylnicotinate (1 g, 0.005 mol) in MeCN (15 mL) at 25 °C under N2 atmosphere. ℃ was added. The mixture was stirred at 75 ℃ for 4.5 hours. After the reaction was completed, the solution was cooled to room temperature, dissolved in water (20 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. This was purified by silica gel column chromatography (EtOAc / PE, 5% to 10%) to obtain methyl 6-iodo-2-methylnicotinate (compound 5-1, 1 g, yield 59%) as a yellow solid.

[0204]

[0205] 5-2: Synthesis of compound 5-2

[0206] Benzoic acid (340 mg, 2.78 mmol) was dissolved in THF (10 mL) and iPrMgBr (431 mg, 2.92 mmol), compound 5-1 (849 mg, 3.06 mmol), and isopropyl magnesium chloride-lithium chloride complex (485 mg, 3.34 mmol) were added at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction was quenched with NH4Cl(aq.) (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE, from 0% to 10%) to give compound 5-2 (160 mg, yield 20%) as a yellow solid.

[0207]

[0208] 5-3: Synthesis of compound 5-3

[0209] Compound 5-2 (200 mg, 0.78 mmol) was dissolved in CCl4 (10 mL), to which NBS (167 mg, 0.94 mmol) and AIBN (64 mg, 0.39 mmol) were added at room temperature under a N2 atmosphere. The mixture was stirred at 60 °C for 18 h. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. This was purified by silica gel column chromatography (EtOAc / PE, 5% to 10%) to obtain compound 5-3 (110 mg, yield 43%) as a yellow solid.

[0210]

[0211] 5-4: Synthesis of compound 5

[0212] 3-Aminopiperidine-2,6-dione hydrochloride (108 mg, 0.65 mmol) was dissolved in DMF (5 mL) and DIPEA (213 mg, 1.64 mmol) was added at room temperature under a N2 atmosphere. The mixture was stirred at room temperature for 30 minutes. Then, compound 5-3 (110 mg, 0.33 mmol) was added to the solution and stirred at 80 °C for 12 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (MeOH / DCM, 5% to 10%). This was washed with MeOH to obtain compound 5 (11.95 mg, yield 10%) as a white solid.

[0213]

[0214] Manufacturing Example 6: Synthesis of Compound 6

[0215] [Reaction Formula 6]

[0216]

[0217] 6-1: Synthesis of compound 6-1

[0218] A solution of tert-butyl 6-bromo-1H-indazole-1-carboxylate (0.5 g, 1.69 mmol), Pd(PPh3)4 (0.14 g, 0.17 mmol), and (Bu3Sn)2 (1.18 g, 2.03 mmol) in toluene (5 mL) was stirred at 110 ℃ for 7 h under N2 atmosphere. After completion of the reaction, the mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. This was purified by silica gel chromatography (EtOAc / PE = 5%) to obtain compound 6-1 (0.4 g, yield 41%) as a yellow liquid.

[0219]

[0220] 6-2: Synthesis of compound 6

[0221] 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonyl chloride (100 mg, 0.33 mmol) was added to a solution of compound 6-1 (167 mg, 0.33 mmol) and 1,8-bis(dimethylamino)naphthalene (35 mg, 0.16 mmol) in THF (5 mL). After 15 min, allylpalladium chloride dimer (allyl2PdCl2, 10 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 5 min and then at 70 °C for 2 h. After the reaction was confirmed by LCMS, the mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. This was purified by silica gel chromatography (MeOH / DCM = 5%) to obtain a crude product. This crude product was purified by prep-HPLC (column: Phenomenex luna C18 250 mm x 100 mm x 10 um; mobile phase: [H2O (0.05% FA)-ACN]; B%: 20% - 55%, 35 min) to obtain compound 6 (10.08 mg, yield 7.6%) as a white solid.

[0222]

[0223] Manufacturing Example 7: Synthesis of Compound 7

[0224] [Reaction Formula 7]

[0225]

[0226] A solution of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (compound A1, 50 mg, 0.17 mmol), pyrrolidine (20 mg, 0.28 mmol), DIPEA (112 mg, 0.87 mmol), and 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (T4P, 50 wt% in EtOAc, 250 mg, 0.35 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (15 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. This was purified by silica gel chromatography (DCM: MeOH = 100: 0 to 97: 3) and triturated with methyl tert-butyl ether (MTBE) to obtain compound 7 (22.47 mg, yield 37%) as a white solid.

[0227]

[0228] Manufacturing Example 8: Synthesis of Compound 8

[0229] [Reaction Formula 8]

[0230]

[0231] 8-1: Synthesis of compound 8-2

[0232] To a solution of tert-butyl 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (compound 8-1, 280 mg, 0.74 mmol) in THF / H2O (1:1, 30 mL) were added NaIO4 (475 mg, 2.22 mmol) and NH4OAc (171 mg, 2.22 mmol). The mixture was stirred at room temperature for 12 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine (100 mL X 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. This was purified by flash column chromatography (PE / EtOAc = 100: 0 to 50: 50) to obtain compound 8-2 (180 mg, yield 73%) as a white solid.

[0233]

[0234] 8-2: Synthesis of compound 8-3

[0235] Compound 8-2 (180 mg, 0.61 mmol) was synthesized in the same manner as compound 1 to obtain compound 8-3 (80 mg, yield 17%) as a yellow liquid.

[0236]

[0237] 8-3: Synthesis of compound 8

[0238] Compound 8-3 (80 mg, 0.15 mmol) was synthesized in the same manner as compound 3 to obtain compound 8 (28.13 mg, yield 43%) as a white solid.

[0239]

[0240] Manufacturing Example 9: Synthesis of Compound 9

[0241] [Reaction Formula 9]

[0242]

[0243] 9-1: Synthesis of compound 9-2

[0244] (1-(tert-butoxycarbonyl)-5-fluoro-1H-indol-2-yl)boronic acid (compound 9-1, 97 mg, 0.35 mmol) was synthesized using the same process as compound 1 to obtain compound 9-2 (25 mg, yield 16%) as a white solid.

[0245]

[0246] 9-2: Synthesis of compound 9

[0247] Compound 9-2 (25 mg, 0.050 mmol) was synthesized in the same manner as compound 3 to obtain compound 9 (10.65 mg, yield 53%) as a white solid.

[0248]

[0249] Manufacturing Example 10: Synthesis of Compound 10

[0250] [Reaction Formula 10]

[0251]

[0252] 10-1: Synthesis of compound 10-2

[0253] 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid (compound 10-1, 520 mg, 1.72 mmol) was synthesized using the same process as compound A2 to obtain compound 10-2 (360 mg, yield 74%) as a yellow solid.

[0254]

[0255] 10-2: Synthesis of compound 10-3

[0256] Compound 10-2 (220 mg, 0.56 mmol) and (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (219 mg, 0.84 mmol) were synthesized using the same process as for compound 1 to obtain compound 10-3 (180 mg, yield 44%) as a brown solid.

[0257]

[0258] 10-3: Synthesis of compound 10

[0259] Compound 10-3 (180 mg, 0.36 mmol) was synthesized in the same manner as compound 3 to obtain compound 10 (15.24 mg, yield 10%) as a yellow solid.

[0260]

[0261] Manufacturing Example 11: Synthesis of Compound 11

[0262] [Reaction Formula 11]

[0263]

[0264] 11-1: Synthesis of compound 11-2

[0265] (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (compound 11-1, 252 mg, 1.10 mmol) was synthesized using the same process as compound 1 to obtain compound 11-2 (180 mg, yield 64%) as a yellow solid.

[0266]

[0267] 11-2: Synthesis of compound 11-3

[0268] Compound 11-2 (180 mg, 0.40 mmol) was dissolved in EtOAc (10 mL) and PtO2 (18 mg) was added. The mixture was evacuated and replenished with hydrogen three times, followed by replenished with hydrogen again. The mixture was stirred at room temperature for 3 hours. The mixture was then filtered through Celite, concentrated, and purified by flash chromatography (DCM / MeOH = 100:0 to 97:3) to obtain compound 11-3 (120 mg, yield 59%) as a yellow solid.

[0269]

[0270] 11-3: Synthesis of compound 11-4

[0271] Compound 11-3 (120 mg, 0.26 mmol) was dissolved in HCl dioxane solution (4 N, 5 mL) and stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure to obtain compound 11-4 (100 mg, yield 77%) as a yellow solid.

[0272]

[0273] 11-4: Synthesis of compound 11

[0274] Benzaldehyde (81 mg, 0.77 mmol) and NaBH(OAc)3 (108 mg, 0.51 mmol) were added to a solution of compound 11-4 (100 mg, 0.26 mmol) in ACN (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 min. The mixture was quenched with water and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH = 100: 0 to 97: 3) and prep-HPLC (Gemini 5 μm C18 150 Х 21.2 mm, mobile phase: ACN - H2O (0.1% FA), 40-60%), and triturated with MeOH to give compound 11 (10.54 mg, yield 8%) as a white solid.

[0275]

[0276] Manufacturing Example 12: Synthesis of Compound 12

[0277] [Reaction Formula 12]

[0278]

[0279] To a THF (10 mL) solution of 2-(tributylstannyl)pyridine (145 mg, 0.39 mmol) and compound A2 (100 mg, 0.26 mmol) were added Pd2(dba)3 (24 mg, 0.026 mmol), tri(2-furyl)phosphine (TFP, 12 mg, 0.052 mmol), and copper(I) diphenylphosphinate (CuDPP, 163 mg, 0.58 mmol). The reaction mixture was stirred at 50 °C for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. This was purified by flash chromatography (DCM / MeOH = 100: 0 to 97: 3) and prep-HPLC (Gemini 5 μm C18 150 Х 21.2 mm, mobile phase: ACN - H2O (0.1% FA), 30 - 50%) to obtain compound 12 (14.17 mg, yield 15%) as a white solid.

[0280]

[0281] Manufacturing Example 13: Synthesis of Compound 13

[0282] [Reaction Formula 13]

[0283]

[0284] (4-(morpholinomethyl)phenyl)boronic acid (105 mg, 0.47 mmol) was synthesized using the same process as for compound 1 to obtain compound 13 (10.45 mg, yield 9%) as a pale yellow solid.

[0285]

[0286] Manufacturing Example 14: Synthesis of Compound 14

[0287] [Reaction Formula 14]

[0288]

[0289] (3-(morpholinomethyl)phenyl)boronic acid (203 mg, 0.92 mmol) was synthesized using the same process as for compound 1 to obtain compound 14 (10.97 mg, yield 6%) as a white solid.

[0290]

[0291] Manufacturing Example 15: Synthesis of Compound 15

[0292] [Reaction Formula 15]

[0293]

[0294] (4-(phenylamino)phenyl)boronic acid (180 mg, 0.84 mmol) was synthesized in the same manner as compound 1 to obtain compound 15 (13.07 mg, yield 7%) as a yellow solid.

[0295]

[0296] Manufacturing Example 16: Synthesis of Compound 16

[0297] [Reaction Formula 16]

[0298]

[0299] (3-(phenylamino)phenyl)boronic acid (92 mg, 0.43 mmol) was synthesized using the same process as compound 1 to obtain compound 16 (10.9 mg, yield 8%) as a yellow solid.

[0300]

[0301] Manufacturing Example 17: Synthesis of Compound 17

[0302] [Reaction Formula 17]

[0303]

[0304] 17-1: Synthesis of compound 17-2

[0305] p-TsOH·H2O (39 mg, 0.20 mmol) was added to a DCM (20 mL) solution of 3-iodo-1H-indazole (17-1, 500 mg, 2.05 mmol) and 3,4-dihydro-2H-pyran (207 mg, 2.46 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by flash column chromatography (PE / EtOAc = 100: 0 to 60: 40) to obtain compound 17-2 (600 mg, yield 80%) as a white solid.

[0306]

[0307] 17-2: Synthesis of compound 17-3

[0308] Compound 17-2 (600 mg, 1.83 mmol) and 1,1,1,2,2,2-hexabutyldistannane (1.6 g, 2.74 mmol) were dissolved in a dioxane (15 mL) solution. Pd(PPh3)4 (211 mg, 0.18 mmol) and LiCl (155 mg, 3.66 mmol) were added at room temperature. The reaction mixture was stirred at 90 °C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EtOAc = 100: 0 to 90: 10) to obtain compound 17-3 (380 mg, yield 38%) as a yellow solid.

[0309]

[0310] 17-3: Synthesis of compound 17-4

[0311] Compound 17-3 (336 mg, 0.68 mmol) was synthesized in the same manner as compound 13 to obtain compound 17-4 (150 mg, yield 51%) as a brown solid.

[0312]

[0313] 17-4: Synthesis of compound 17

[0314] Compound 17-4 (150 mg, 0.32 mmol) was synthesized in the same manner as compound 3 to obtain compound 17 (19.93 mg, yield 15%) as a white solid.

[0315]

[0316] Manufacturing Example 18: Synthesis of Compound 18

[0317] [Reaction Formula 18]

[0318]

[0319] 18-1: Synthesis of compound 18-1

[0320] (1-(tert-butoxycarbonyl)-6-chloro-1H-indol-3-yl)boronic acid (100 mg, 0.34 mmol) was synthesized in the same manner as compound 1 to obtain compound 18-1 (100 mg, yield 51%) as a white solid.

[0321]

[0322] 18-2: Synthesis of compound 18

[0323] Compound 18-1 (100 mg, 0.19 mmol) was synthesized in the same manner as compound 3 to obtain compound 18 (15.16 mg, 18%) as a white solid.

[0324]

[0325] Manufacturing Example 19: Synthesis of Compound 19

[0326] [Reaction Formula 19]

[0327]

[0328] 19-1: Synthesis of compound 19-1

[0329] (1-(tert-butoxycarbonyl)-6-fluoro-1H-indol-2-yl)boronic acid (110 mg, 0.39 mmol) was synthesized using the same process as for compound 1 to obtain compound 19-1 (40 mg, yield 27%) as a white solid.

[0330]

[0331] 19-2: Synthesis of compound 19

[0332] Compound 19-1 (40 mg, 0.079 mmol) was synthesized in the same manner as compound 3 to obtain compound 19 (9.49 mg, yield 29%) as a yellow solid.

[0333]

[0334] Manufacturing Example 20: Synthesis of Compound 20

[0335] [Reaction Formula 20]

[0336]

[0337] 20-1: Synthesis of compound 20-1

[0338] (1-(tert-butoxycarbonyl)-6-chloro-1H-indol-2-yl)boronic acid (468 mg, 1.58 mmol) was synthesized in the same manner as compound 1 to obtain compound 20-1 (310 mg, yield 52%) as a pale brown solid.

[0339]

[0340] 20-2: Synthesis of compound 20

[0341] Compound 20-1 (310 mg, 0.41 mmol) was synthesized in the same manner as compound 3 to obtain compound 20 (81.17 mg, yield 45%) as a white solid.

[0342]

[0343] Manufacturing Example 21: Synthesis of Compound 21

[0344] [Reaction Formula 21]

[0345]

[0346] 21-1: Synthesis of compound 21-1

[0347] To a THF (40 mL) solution of 6-bromo-1H-indazole (3 g, 15 mmol) was added NaH (60%, 0.91 g, 22.8 mmol) at 0 °C under N2 atmosphere. The solution was stirred at 0 °C for 30 min, and then SEMCl (3.04 g, 18.2 mmol) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for another 2 h. After the reaction was completed, the mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. This was purified by silica gel chromatography (PE / EtOAc = 0-10%) to obtain compound 21-1 (3 g, yield 54%) as a colorless liquid.

[0348]

[0349] 21-2: Synthesis of compound 21-2

[0350] Hexabutylditin (Sn2Bu6, 2.09 g, 3.6 mmol) and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 350 mg, 0.3 mmol) were added to a toluene (20 mL) solution containing compound 21-1 (1 g, 3 mmol). The reaction mixture was stirred at 100 °C for 16 h under a N2 atmosphere. After the reaction was completed, the mixture was concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 0-10%) to obtain compound 21-2 (950 mg, yield 57%) as a colorless liquid.

[0351]

[0352] 21-3: Synthesis of compound 21-3

[0353] 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonyl chloride (210 mg, 0.69 mmol) was dissolved in THF (10 mL) and proton sponge (298 mg, 1.39 mmol), compound 23-2 (748 mg, 1.39 mmol), and allylpalladium chloride dimer (76 mg, 0.21 mmol) were added. The reaction mixture was stirred at 60 °C for 4 h under N2 atmosphere. After completion of the reaction, the mixture was concentrated. This was purified by silica gel chromatography (PE / EtOAc = 0-10%) to obtain compound 21-3 (170 mg, yield 33%) as a yellow solid.

[0354]

[0355] 21-4: Synthesis of compound 21

[0356] TFA (1 mL) was added to a DCM (10 mL) solution containing compound 21-3 (170 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water (10 mL), and the pH of the mixture was adjusted to 8 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with DCM (30 mL x 2), and the organic layer was concentrated to obtain the crude product. The crude product was purified by prep-HPLC to obtain compound 21 (11.02 mg, yield 8.6%) as a white solid.

[0357]

[0358] Manufacturing Example 22: Synthesis of Compound 22

[0359] [Reaction Formula 22]

[0360]

[0361] 22-1: Synthesis of compound 22-1

[0362] To a solution of tert-butyl 6-bromo-1H-indole-1-carboxylate (3.00 g, 0.010 mol) and tert-butyl carbamate (2.39 g, 0.020 mol) in dioxane (100 mL) were added K2CO3 (4.18 g, 0.030 mol), X-Phos (0.96 g, 0.0020 mol), and Pd2(dba)3 (1.85 g, 0.0020 mol) at room temperature. The mixture was stirred at 110 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. This was purified by flash column chromatography (PE / EtOAc = 100: 0 to 0: 100) to obtain compound 22-1 (2.10 g, yield 56%) as a yellow liquid.

[0363]

[0364] 22-2: Synthesis of compound 22-2

[0365] Compound 22-1 (2.10 g, 0.006 mol) was dissolved in DMF (35 mL) and NaH (60% mass ratio / mineral oil, 0.38 g, 0.009 mol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. Then, CH3I (1.34 g, 0.009 mol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. This was purified by flash column chromatography (PE / EtOAc = 100: 0 to 20: 80) to obtain compound 22-2 (1.6 g, yield 65%) as a yellow liquid.

[0366]

[0367] 22-3: Synthesis of compound 22-3

[0368] LDA (1 M / THF solution, 6.9 mL, 0.007 mol) was added to a THF (40 mL) solution containing compound 22-2 (1.6 g, 0.005 mol) at -78 °C. The mixture was stirred at -78 °C for 30 min. Then, triisopropyl borate (1.3 g, 0.007 mol) was added at the same temperature and stirred at -78 °C for 30 min. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. This was purified by flash column chromatography (PE / EtOAc = 100: 0 to 10: 90) to obtain compound 22-3 (1.0 g, yield 50%) as a yellow liquid.

[0369]

[0370] 22-4: Synthesis of compound 22-4

[0371] Compound 22-3 (200 mg, 0.526 mmol) was synthesized in the same manner as compound 1 to obtain compound 22-4 (40 mg, yield 11%) as a white solid.

[0372]

[0373] 22-5: Synthesis of compound 22

[0374] Compound 22-4 (40 mg, 0.065 mmol) was synthesized in the same manner as compound 3 to obtain compound 22 (13.38 mg, yield 48%) as an orange solid.

[0375]

[0376] Manufacturing Example 23: Synthesis of Compound 23

[0377] [Reaction Formula 23]

[0378]

[0379] (3,5-Diphenylphenyl)boronic acid (48 mg, 0.17 mmol) was synthesized in the same manner as compound 1 to obtain compound 23 (21.0 mg, yield 25%) as a white solid.

[0380]

[0381] Manufacturing Example 24: Synthesis of Compound 24

[0382] [Reaction Formula 24]

[0383]

[0384] 24-1: Synthesis of compound 24-1

[0385] A solution of 5-bromo-1H-indole (5.0 g, 25.5 mmol), phenylboronic acid (4.66 g, 38.2 mmol), Pd(dppf)Cl2 (1.04 g, 1.2 mmol), and K2CO3 (7.08 g, 51 mmol) in dioxane (40 mL) and water (10 mL) was stirred at 90 °C for 4 h under N2 atmosphere. The mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel chromatography (EtOAc / PE, 0-10%) to obtain compound 24-1 (2.8 g, yield 61%) as a white solid.

[0386]

[0387] 24-2: Synthesis of compound 24-2

[0388] Compound 24-1 (1.1 g, 5.7 mmol) was dissolved in THF (20 mL), and (Boc)2O (2.5 g, 11.4 mmol) and 4-dimethylaminopyridine (70 mg, 0.57 mmol) were slowly added at 0 °C. The mixture was stirred at 20 °C for 1 h. Then, the resulting mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel column chromatography (EtOAc / PE, 0-3%) to obtain compound 24-2 (1.5 g, yield 90%) as a white solid.

[0389]

[0390] 24-3: Synthesis of compound 24-3

[0391] Compound 24-2 (1.3 g, 4.4 mmol) was dissolved in THF (5 mL) and NBS (0.8 g, 4.6 mmol) was added at 20 °C. The mixture was stirred at 20 °C for 2 hours. The resulting mixture was then diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel column chromatography (EtOAc / PE, 0-5%) to obtain compound 24-3 (1.3 g, yield 79%) as a white solid.

[0392]

[0393] 24-4: Synthesis of compound 24-4

[0394] Compound 24-3 (500 mg, 1.34 mmol) was synthesized in the same manner as compound 22-3 to obtain compound 24-4 (200 mg, yield 44%) as a white solid.

[0395]

[0396] 24-5: Synthesis of compound 24-5

[0397] Compound 24-4 (185 mg, 0.55 mmol) was synthesized in the same manner as compound 1 to obtain compound 24-5 (230 mg, yield 97%) as a white solid.

[0398]

[0399] 24-6: Synthesis of compound 24

[0400] Compound 24-5 (230 mg, 0.40 mmol) was synthesized in the same manner as compound 3 to obtain compound 24 (23 mg, yield 12%) as a white solid.

[0401]

[0402] Manufacturing Example 25: Synthesis of Compound 25

[0403] [Reaction Formula 25]

[0404]

[0405] 25-1: Synthesis of compound 25-1

[0406] A solution of 5-bromo-1H-indole (5.0 g, 25.7 mmol), CuI (0.7 g, 3.6 mmol), iodobenzene (3.7 g, 18.4 mmol), and Cs2CO3 (11.9 g, 36.8 mmol) in DMF (30 mL) was stirred at 120°C for 16 h under N2 atmosphere. The mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mLХ3). The combined organic layers were washed with water (100 mL), dried over Na2SO4, and concentrated. This was purified by silica gel chromatography (PE) to obtain compound 25-1 (3.0 g, yield 53.8%) as a colorless liquid.

[0407]

[0408] 25-2: Synthesis of compound 25-2

[0409] Compound 25-1 (3.0 g, 11 mmol) was synthesized in the same manner as compound 24-1 to obtain compound 25-2 (1.9 g, yield 57%) as a white solid.

[0410]

[0411] 25-3: Synthesis of compound 25-3

[0412] Compound 25-2 (1.9 g, 7.1 mmol) was synthesized in the same manner as compound 24-3 to obtain compound 25-3 (2.5 g, yield 80%) as a white solid.

[0413]

[0414] 25-4: Synthesis of compound 25-4

[0415] Compound 25-3 (200 mg, 0.57 mmol) was synthesized in the same manner as compound 22-3 to obtain compound 25-4 (200 mg, yield 78%) as a white solid.

[0416]

[0417] 25-5: Synthesis of compound 25

[0418] Compound 25-4 (86 mg, 0.27 mmol) was synthesized in the same manner as compound 1 to obtain compound 25 (23.76 mg, yield 23%) as a white solid.

[0419]

[0420] Manufacturing Example 26: Synthesis of Compound 26

[0421] [Reaction Formula 26]

[0422]

[0423] Biphenyl-3-boronic acid (50 mg, 0.25 mmol) was synthesized in the same manner as compound 1 to obtain compound 26 (36.42 mg, yield 41%) as a white solid.

[0424]

[0425] Manufacturing Example 27: Synthesis of Compound 27

[0426]

[0427] 27-1: Synthesis of compound A4

[0428] [Reaction Formula 27-1]

[0429]

[0430] 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (A3, 1.0 g, 3.10 mmol) and hexabutylditin (Sn2Bu6, 2.7 g, 4.65 mmol) were dissolved in dioxane (30 mL) to which Pd(PPh3)4 (360 mg, 0.31 mmol) was added at room temperature. The reaction mixture was stirred at 90 °C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (PE / EtOAc = 100:0 to 65:35) to obtain compound A4 (700 mg, yield 38%) as a yellow solid.

[0431]

[0432] [Reaction Formula 27-2]

[0433]

[0434] 27-2: Synthesis of compound 27-1

[0435] 4-Phenyl-1H-pyrrole-2-carboxylic acid (2 g, 0.011 mol) was synthesized in the same manner as compound A2 to obtain compound 27-1 (0.25 g, yield 8.1%) as a yellow solid.

[0436]

[0437] 27-3: Synthesis of compound 27

[0438] To a THF (5 mL) solution of compound 27-1 (250 mg, 0.895 mmol) and compound A4 (477 mg, 0.895 mmol) were added Pd2(dba)3 (82 mg, 0.089 mmol), tri(2-furyl)phosphine (TFP, 104 mg, 0.447 mmol), and copper(I) diphenylphosphinate (CuDPP, 504 mg, 1.79 mmol) at room temperature. The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting yellow solid was purified by pre-TLC (MeOH / DCM=10 / 1) and prep-HPLC to obtain compound 27 (10 mg, yield 2.7%).

[0439]

[0440] Manufacturing Example 28: Synthesis of Compound 28

[0441] [Reaction Formula 28]

[0442]

[0443] 2-Phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (50 mg, 0.186 mmol) was synthesized using the same procedure as for compound 1 to obtain compound 28 (4 mg, yield 6.5%) as a yellow solid.

[0444]

[0445] Manufacturing Example 29: Synthesis of Compound 29

[0446] [Reaction Formula 29]

[0447]

[0448] 29-1: Synthesis of compound 29-1

[0449] Ethyl 4-bromo-3H-imidazole-2-carboxylate (4.5 g, 0.021 mol) was synthesized using the same process as for compound 21-1 to obtain compound 29-1 (4.0 g, yield 56%) as a yellow liquid.

[0450]

[0451] 29-2: Synthesis of compound 29-2

[0452] Compound 29-1 (4.5 g, 0.013 mol) was synthesized in the same manner as compound 24-1 to obtain compound 29-2 (4 g, yield 90%) as a yellow solid.

[0453]

[0454] 29-3: Synthesis of compound 29-3

[0455] Compound 29-2 (4 g, 0.012 mol) was dissolved in a H2O / THF (1 / 4, 40 mL) mixture, and NaOH (1.38 g, 0.035 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 4 hours. The mixture was poured into water (50 mL), the pH was adjusted to 8-9 with HCl (4 N), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated to obtain compound 29-3 (3.7 g, yield 86%) as a yellow solid.

[0456]

[0457] 29-4: Synthesis of compound 29-4

[0458] Compound 29-3 (1.4 g, 4.4 mmol) was synthesized in the same manner as compound A2 to obtain compound 29-4 (500 mg, yield 28%) as a yellow solid.

[0459]

[0460] 29-5: Synthesis of compound 29-5

[0461] Compound 29-4 (500 mg, 0.94 mmol) was synthesized in the same manner as compound 27 to obtain compound 29-5 (100 mg, yield 15%) as a yellow solid.

[0462]

[0463] 29-6: Synthesis of compound 29

[0464] Compound 29-5 (100 mg, 0.18 mmol) was dissolved in HCl / EA (4 mL, 2.5 N) and stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The resulting mixture was purified by prep-HPLC to obtain compound 29 (15.85 mg, yield 21%) as a yellow solid.

[0465]

[0466] Manufacturing Example 30: Synthesis of Compound 30

[0467] [Reaction Formula 30]

[0468]

[0469] (4-Phenylthiophen-2-yl)boronic acid (200 mg, 0.98 mmol) was synthesized in the same manner as compound 1 to obtain compound 30 (14.68 mg, yield 3.5%) as an orange solid.

[0470]

[0471] Manufacturing Example 31: Synthesis of Compound 31

[0472] [Reaction Formula 31]

[0473]

[0474] 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (A1, 200 mg, 0.70 mmol), 1,2-dihydrobenzo[cd]indole (108 mg, 0.70 mmol), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH, 292 mg, 1.04 mmol) were dissolved in ACN (6 mL). N-Methylimidazole (NMI, 171 mg, 2.08 mmol) was added at 25°C. The mixture was stirred at 25°C for 2 h. The mixture was concentrated, and it was purified by prep-HPLC to obtain compound 31 (15.01 mg, yield 5.1%) as a yellow solid.

[0475]

[0476] Manufacturing Example 32: Synthesis of Compound 32

[0477] [Reaction Formula 32]

[0478]

[0479] 32-1: Synthesis of compound 32-1

[0480] 1-Benzyl-1H-indole-3-carboxylic acid (800 mg, 3.18 mmol) was synthesized in the same manner as compound A2 to obtain compound 32-1 (150 mg, yield 14%) as a white solid.

[0481]

[0482] 32-2: Synthesis of compound 32

[0483] Compound 32-1 (150 mg, 0.44 mmol) was synthesized in the same manner as compound 27 to obtain compound 32 (20.15 mg, yield 9.7%) as a white solid.

[0484]

[0485] Manufacturing Example 33: Synthesis of Compound 33

[0486] [Reaction Formula 33]

[0487]

[0488] Biphenyl-4-boronic acid (100 mg, 0.51 mmol) was synthesized in the same manner as compound 1 to obtain compound 33 (12.65 mg, yield 5.6%) as a white solid.

[0489]

[0490] Manufacturing Example 34: Synthesis of Compound 34

[0491] [Reaction Formula 34]

[0492]

[0493] 34-1: Synthesis of compound 34-1

[0494] Benzofuran-2-carboxylic acid (600 mg, 3.70 mmol) was synthesized in the same manner as compound A2 to obtain compound 34-1 (600 mg, yield 74%) as a white solid.

[0495]

[0496] 34-2: Synthesis of compound 34

[0497] Compound 34-1 (200 mg, 0.79 mmol) was synthesized in the same manner as compound 27 to obtain compound 39 (13.51 mg, yield 4.3%) as a white solid.

[0498]

[0499] Manufacturing Example 35: Synthesis of Compound 35

[0500] [Reaction Formula 35]

[0501]

[0502] 35-1: Synthesis of compound 35-1

[0503] To a DCM (30 ml) solution of 1-phenyl-1H-indole-3-carboxylic acid (1.3 g, 5.5 mmol) and 4-methylbenzenethiol (1.03 g, 8.25 mmol) were added DMAP (67 mg, 0.55 mmol) and DCC (1.25 g, 6.05 mmol). The mixture was stirred at room temperature under N2 atmosphere for 16 h. The reaction was quenched with aqueous ammonium chloride solution, and the mixture was extracted with DCM (50 ml x 3). The combined organic extracts were washed with brine and dried over Na2SO4. The mixture was purified by silica gel chromatography (PE / EtOAc=1 / 3) to obtain compound 35-1 (1.9 g, yield 100%) as a colorless liquid.

[0504]

[0505] 35-2: Synthesis of compound 35

[0506] To a solution of compound 35-1 (300 mg, 0.875 mmol) and (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)boronic acid (A5, 200 mg, 0.7 mmol) in THF (10 ml) were added Pd2(dba)2 (160 mg, 0.175 mmol), CuTC (285 mg, 1.3 mmol), and TFP (47 mg, 0.2 mmol). The mixture was stirred at 50 °C for 16 h under N2 atmosphere. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with DCM (30 ml x 3). The combined organic extracts were washed with brine and dried over Na2SO4. The mixture was purified by silica gel chromatography (DCM / MeOH = 1 / 10) and concentrated. This was purified by PREP-HPLC (FA) (column: Wepure Prep C18 10μm 21.2*250mm; mobile phase A: water (0.2%FA) B: acetonitrile; B: 33-63%) to obtain compound 35 (20 mg, yield 4.9%) as a white solid.

[0507]

[0508] Manufacturing Example 36: Synthesis of Compound 36

[0509] [Reaction Formula 36]

[0510]

[0511] To a solution of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (A1, 95 mg, 0.33 mmol) in DCM (5 mL) was added isoindoline (47 mg, 0.395 mmol), HATU (187.8 mg, 0.494 mmol), and DIPEA (127.8 mg, 0.989 mmol) at 0 °C. The mixture was stirred from 0 °C to room temperature for 3 h, after which H2O (5 mL) was added. The mixture was extracted with DCM (3 x 5 mL). The combined organic extracts were dried, filtered, and concentrated. This was purified by PREP-HPLC (FA) (column: Boston Prep C18 10μm 21.2Х250mm; mobile phase A: water (0.2%FA) B: acetonitrile; B: 13-43%) to obtain compound 36 (55 mg, yield 43%) as a white solid.

[0512]

[0513] Manufacturing Example 37: Synthesis of Compound 37

[0514] [Reaction Formula 37]

[0515]

[0516] 37-1: Synthesis of compound A6

[0517] To a solution of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (A1, 500 mg, 1.74 mmol) and 4-methylbenzenethiol (260 mg, 2.1 mmol) in DCM (20 mL) were added DMAP (21 mg, 0.174 mol) and DCC (394 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. This was purified by silica gel chromatography (PE / EA = 1 / 3) to obtain compound A6 (440 mg, yield 64%) as a white solid.

[0518]

[0519] 37-2: Synthesis of compound 37

[0520] Compound 37 (160 mg, yield 54%) as a white solid was obtained through the same synthetic process as for compound 1 from benzofuran-3-ylboronic acid (136 mg, 0.836 mmol) and compound A6 (300 mg, 0.76 mmol).

[0521]

[0522] Manufacturing Example 38: Synthesis of Compound 38

[0523] [Reaction Formula 38]

[0524]

[0525] 38-1: Synthesis of compound 38-1

[0526] 4-Methylbenzenethiol (0.5 g, 4 mmol) was dissolved in DCM (20 mL) under nitrogen atmosphere at 0 oIsobutyryl chloride (0.5 g, 4.9 mmol) and pyridine (0.5 g, 6.3 mmol) were added to C. The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into water (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. This was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain 38-1 (0.8 g, yield 99%) as a colorless liquid.

[0527]

[0528] 38-2: Synthesis of compound 38

[0529] To a solution of compound A4 (160 mg, 0.3 mmol), compound 38-1 (60 mg, 0.3 mmol), CuDPP (105 mg, 0.37 mmol), and Pd(OAc)2 (3 mg, 0.01 mmol) in DMF (5 mL) was added triethylphosphite (10 mg, 0.06 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. Potassium fluoride (60 mg, 1 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 h. The mixture was poured into water (30 mL) and extracted with EA (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. This was purified by prep-hplc (Xtimate Prep C18 10μm 21.2Х250mm. A: water (0.2%FA) B: acetonitrile 12-42%B 8 min, stopped at 16 min) to obtain compound 38 (17.2 mg, yield 18%) as a white solid.

[0530]

[0531] Manufacturing Example 39: Synthesis of Compound 39

[0532] [Reaction Formula 39]

[0533]

[0534] 39-1: Synthesis of compound 39-1

[0535] To a solution of cyclopentanecarboxylic acid (720 mg, 6.3 mmol) in DCM (20 ml) were added DMAP (77 mg, 0.63 mmol) and EDCI (1.81 g, 9.45 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 minutes, and then 4-methylbenzenethiol (859 mg, 6.93 mmol) was added. The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. Water (50 mL) was added to the reaction mixture, and extracted with DCM (30 ml x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. This was purified by silica gel chromatography (PE / EA = 1 / 3) to obtain compound 39-1 (400 mg, yield 29%) as a colorless liquid.

[0536]

[0537] 39-2: Synthesis of compound 39

[0538] Compound 39-1 (62 mg, 0.28 mmol) was synthesized in the same manner as compound 38 to obtain compound 39 (22.9 mg, yield 24%) as a white solid.

[0539]

[0540] Manufacturing Example 40: Synthesis of Compound 40

[0541] [Reaction Formula 40]

[0542]

[0543] (4-Fluorophenyl)boronic acid (25.4 mg, 0.18 mmol) and compound A6 (65 mg, 0.16 mmol) were synthesized using the same process as for compound 1 to obtain compound 40 (20.1 mg, yield 33%) as a white solid.

[0544]

[0545] Manufacturing Example 41: Synthesis of Compound 41

[0546] [Reaction Formula 41]

[0547]

[0548] (4-(piperidin-1-yl)phenyl)boronic acid (40 mg, 0.20 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 41 (15.0 mg, yield 20%) as a yellow solid.

[0549]

[0550] Manufacturing Example 42: Synthesis of Compound 42

[0551] [Reaction Formula 42]

[0552]

[0553] Compound 42 (19.1 mg, yield 27%) as a white solid was obtained through the same synthetic process as for compound 1 from benzo[d][1,3]dioxol-5-ylboronic acid (33 mg, 0.20 mmol) and compound A6 (70 mg, 0.18 mmol).

[0554]

[0555] Manufacturing Example 43: Synthesis of Compound 43

[0556] [Reaction Formula 43]

[0557]

[0558] Naphthalen-1-ylboronic acid (34 mg, 0.20 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 43 (23.7 mg, yield 33%) as a white solid.

[0559]

[0560] Manufacturing Example 44: Synthesis of Compound 44

[0561] [Reaction Formula 44]

[0562]

[0563] Naphthalen-2-ylboronic acid (34 mg, 0.20 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 44 (31.6 mg, yield 43%) as a white solid.

[0564]

[0565] Manufacturing Example 45: Synthesis of Compound 45

[0566] [Reaction Formula 45]

[0567]

[0568] (4-(Trifluoromethoxy)phenyl)boronic acid (37.3 mg, 0.18 mmol) and compound A6 (65 mg, 0.16 mmol) were synthesized using the same process as for compound 1 to obtain compound 45 (21.5 mg, yield 30%) as a white solid.

[0569]

[0570] Manufacturing Example 46: Synthesis of Compound 46

[0571] [Reaction Formula 46]

[0572]

[0573] (4-(Dimethylamino)phenyl)boronic acid (34 mg, 0.20 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 46 (19.6 mg, yield 28%) as a yellow solid.

[0574]

[0575] Manufacturing Example 47: Synthesis of Compound 47

[0576] [Reaction Formula 47]

[0577]

[0578] (4-(Dimethylcarbamoyl)phenyl)boronic acid (39 mg, 0.20 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 47 (21.8 mg, yield 29%) as a white solid.

[0579]

[0580] Manufacturing Example 48: Synthesis of Compound 48

[0581] [Reaction Formula 48]

[0582]

[0583] (4-Chlorophenyl)boronic acid (47.5 mg, 0.304 mmol) and compound A6 (100 mg, 0.254 mmol) were synthesized using the same process as for compound 1 to obtain compound 48 (52.1 mg, yield 54%) as a white solid.

[0584]

[0585] Manufacturing Example 49: Synthesis of Compound 49

[0586] [Reaction Formula 49]

[0587]

[0588] (4-Bromophenyl)boronic acid (39.4 mg, 0.223 mmol) and compound A6 (80 mg, 0.203 mmol) were synthesized using the same process as for compound 1 to obtain compound 49 (25.2 mg, yield 29%) as a white solid.

[0589]

[0590] Manufacturing Example 50: Synthesis of Compound 50

[0591] [Reaction Formula 50]

[0592]

[0593] (4-(Trifluoromethyl)phenyl)boronic acid (42.4 mg, 0.223 mmol) and compound A6 (80 mg, 0.203 mmol) were synthesized in the same manner as compound 1 to obtain compound 50 (21.4 mg, yield 28%) as a white solid.

[0594]

[0595] Manufacturing Example 51: Synthesis of Compound 51

[0596] [Reaction Formula 51]

[0597]

[0598] (4-Methoxyphenyl)boronic acid (36.9 mg, 0.223 mmol) and compound A6 (80 mg, 0.203 mmol) were synthesized using the same process as for compound 1 to obtain compound 51 (36.9 mg, yield 48%) as a white solid.

[0599]

[0600] Manufacturing Example 52: Synthesis of Compound 52

[0601] [Reaction Formula 52]

[0602]

[0603] (4-Hydroxyphenyl)boronic acid (33.5 mg, 0.223 mmol) and compound A6 (80 mg, 0.203 mmol) were synthesized using the same process as for compound 1 to obtain compound 52 (19.6 mg, yield 27%) as a white solid.

[0604]

[0605] Manufacturing Example 53: Synthesis of Compound 53

[0606] [Reaction Formula 53]

[0607]

[0608] (4-(Benzyloxy)phenyl)boronic acid (55.4 mg, 0.223 mmol) and compound A6 (80 mg, 0.203 mmol) were synthesized using the same process as for compound 1 to obtain compound 53 (25.5 mg, yield 28%) as a white solid.

[0609]

[0610] Manufacturing Example 54: Synthesis of Compound 54

[0611] [Reaction Formula 54]

[0612]

[0613] Compound 54 (13.5 mg, yield 15%) as a white solid was obtained through the same synthetic process as for compound 1 from p-tolylboronic acid (40 mg, 0.3 mmol) and compound A6 (100 mg, 0.25 mmol).

[0614]

[0615] Manufacturing Example 55: Synthesis of Compound 55

[0616] [Reaction Formula 55]

[0617]

[0618] (4-Cyclohexylphenyl)boronic acid (43 mg, 0.21 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 55 (15 mg, yield 20%) as a white solid.

[0619]

[0620] Manufacturing Example 56: Synthesis of Compound 56

[0621] [Reaction Formula 56]

[0622]

[0623] (4-(Ethoxycarbonyl)phenyl)boronic acid (42 mg, 0.21 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 56 (16 mg, yield 21%) as a white solid.

[0624]

[0625] Manufacturing Example 57: Synthesis of Compound 57

[0626] [Reaction Formula 57]

[0627]

[0628] (4-Nitrophenyl)boronic acid (34 mg, 0.20 mmol) and compound A6 (70 mg, 0.18 mmol) were synthesized using the same process as for compound 1 to obtain compound 57 (13.5 mg, yield 19%) as a white solid.

[0629]

[0630] Manufacturing Example 58: Synthesis of Compound 58

[0631] [Reaction Formula 58]

[0632]

[0633] Furan-2-ylboronic acid (18 mg, 0.16 mmol) and compound A6 (60 mg, 0.15 mmol) were synthesized using the same process as for compound 1 to obtain compound 58 (17.6 mg, yield 35%) as a white solid.

[0634]

[0635] Manufacturing Example 59: Synthesis of Compound 59

[0636] [Reaction Formula 59]

[0637]

[0638] (1-Methyl-1H-indol-2-yl)boronic acid (48.8 mg, 0.28 mmol) and compound A6 (100 mg, 0.25 mmol) were synthesized using the same process as for compound 1 to obtain compound 59 (40 mg, yield 40%) as a white solid.

[0639]

[0640] Manufacturing Example 60: Synthesis of Compound 60

[0641] [Reaction Formula 60]

[0642]

[0643] 60-1: Synthesis of compound 60-1

[0644] 4-Methylbenzenethiol (1 g, 8.05 mmol), oxalyl chloride (1.02 g, 8.05 mmol), and TBAI (0.3 g, 0.8 mmol) were dissolved in acetonitrile (30 mL). 2-Aminobenzenethiol (1 g, 8.05 mmol) was added dropwise to the solution in acetonitrile (5 mL) at room temperature, and the mixture was stirred at 60 °C for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (40 mL), and extracted with EA (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting yellow solid compound 60-1 (0.65 g, yield 28%) was purified by silica gel column chromatography (PE / EA = 1 / 10-1 / 5).

[0645]

[0646] 60-2: Synthesis of compound 60

[0647] Compound 60-1 (120 mg, 0.42 mmol) was synthesized in the same manner as compound 38 to obtain compound 60 (56 mg, yield 33%) as a white solid.

[0648]

[0649] Manufacturing Example 61: Synthesis of Compound 61

[0650] [Reaction Formula 61]

[0651]

[0652] Compound 61 (40 mg, yield 36%) as a white solid was obtained through the same synthetic process as for compound 1 from m-tolylboronic acid (49 mg, 0.36 mmol) and compound A6 (120 mg, 0.30 mmol).

[0653]

[0654] Manufacturing Example 62: Synthesis of Compound 62

[0655] [Reaction Formula 62]

[0656]

[0657] Compound 62 (6.5 mg, yield 5.9%) as a white solid was obtained through the same synthetic process as for compound 1 from o-tolylboronic acid (49 mg, 0.36 mmol) and compound A6 (120 mg, 0.30 mmol).

[0658]

[0659] Manufacturing Example 63: Synthesis of Compound 63

[0660] [Reaction Formula 63]

[0661]

[0662] (4-(tert-butyl)phenyl)boronic acid (64 mg, 0.36 mmol) and compound A6 (120 mg, 0.30 mmol) were synthesized using the same process as for compound 1 to obtain compound 63 (18 mg, yield 15%) as a white solid.

[0663]

[0664] Manufacturing Example 64: Synthesis of Compound 64

[0665] [Reaction Formula 64]

[0666]

[0667] 64-1: Synthesis of compound 64-1

[0668] (4-(((benzyloxy)carbonyl)amino)phenyl)boronic acid (78 mg, 0.40 mmol) and compound A6 (140 mg, 0.36 mmol) were synthesized using the same process as for compound 1 to obtain compound 64-1 (60 mg, yield 34%) as a white solid.

[0669]

[0670] 64-2: Synthesis of compound 64

[0671] TMSI (240 mg, 1.2 mmol) was added to a DCM (10 mL) solution of compound 64-1 (60 mg, 0.12 mmol) at 0°C. The mixture was stirred at 0°C for 30 min and then at room temperature for 1 h. The reaction was quenched by pouring ice water and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. This was purified by prep-HPLC to obtain compound 64 (14.2 mg, yield 33%) as a white solid.

[0672]

[0673] Manufacturing Example 65: Synthesis of Compound 65

[0674] [Reaction Formula 65]

[0675]

[0676] To a solution of compound A6 (123 mg, 0.312 mmol) in DMF (8 mL) were added 3-(tributylstannyl)pyridine (115 mg, 0.312 mmol), Pd(OAc)2 (1.4 mg, 0.00624 mmol), CuDPP (105 mg, 0.374 mmol), and P(OEt)3 (10 mg, 0.0624 mmol). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. KF (60 mg dissolved in an aqueous solution) was added to the mixture, stirred for 1 h at room temperature, and filtered. The filtrate was extracted with EA (30 mL x 1). The organic layer was washed with brine (30 mL x 1), dried over Na2SO4, and concentrated. This was purified by prep-hplc (A: water (0.2% FA) B: acetonitrile, 10-40%) to obtain compound 65 (15.7 mg, yield 14%) as a white solid.

[0677]

[0678] Manufacturing Example 66: Synthesis of Compound 66

[0679] [Reaction Formula 66]

[0680]

[0681] 66-1: Synthesis of compound 66-1

[0682] Isonicotinic acid (1.0 g, 8.1 mmol) was synthesized in the same manner as compound 39-1 to obtain compound 66-1 (80 mg, yield 4.3%) as a white solid.

[0683]

[0684] 66-2: Synthesis of compound 66

[0685] Compound 66-1 (80 mg, 0.35 mmol) was synthesized in the same manner as compound 38 to obtain compound 66 (9.82 mg, yield 8.1%) as a white solid.

[0686]

[0687] Manufacturing Example 67: Synthesis of Compound 67

[0688] [Reaction Formula 67]

[0689]

[0690] 5-(Tributylstannyl)pyrimidine (140 mg, 0.38 mmol) was synthesized in the same manner as compound 65 to obtain compound 67 (6.2 mg, yield 4.6%) as a white solid.

[0691]

[0692] Manufacturing Example 68: Synthesis of Compound 68

[0693] [Reaction Formula 68]

[0694]

[0695] 68-1: Synthesis of compound 68-1

[0696] Pyrazine-2-carboxylic acid (1.0 g, 8.1 mmol) was synthesized in the same manner as compound 39-1 to obtain compound 68-1 (70 mg, yield 3.8%) as a white solid.

[0697]

[0698] 68-2: Synthesis of compound 68

[0699] Compound 68-1 (62 mg, 0.28 mmol) was synthesized in the same manner as compound 38 to obtain compound 68 (34 mg, yield 34%) as a white solid.

[0700]

[0701] Manufacturing Example 69: Synthesis of Compound 69

[0702] [Reaction Formula 69]

[0703]

[0704] 69-1: Synthesis of compound 69-1

[0705] 2-Methylisonicotinic acid (1.0 g, 7.3 mmol) was synthesized in the same manner as compound 39-1 to obtain compound 69-1 (650 mg, yield 37%) as a white solid.

[0706]

[0707] 69-2: Synthesis of compound 69

[0708] Compound 69-1 (70 mg, 0.29 mmol) was synthesized in the same manner as compound 38 to obtain compound 69 (19.7 mg, yield 19%) as a white solid.

[0709]

[0710] Manufacturing Example 70: Synthesis of Compound 70

[0711] [Reaction Formula 70]

[0712]

[0713] 70-1: Synthesis of compound 70-1

[0714] Quinoline-2-carboxylic acid (1.0 g, 5.8 mmol) was synthesized in the same manner as compound 39-1 to obtain compound 70-1 (60 mg, yield 3.7%) as a white solid.

[0715]

[0716] 70-2: Synthesis of compound 70

[0717] Compound 70-1 (95 mg, 0.34 mmol) was synthesized in the same manner as compound 38 to obtain compound 70 (14.7 mg, yield 11%) as a white solid.

[0718]

[0719] Manufacturing Example 71: Synthesis of Compound 71

[0720] [Reaction Formula 71]

[0721]

[0722] 71-1: Synthesis of compound 71-1

[0723] Isoquinoline-1-carboxylic acid (500 mg, 2.9 mmol) was synthesized in the same manner as compound 39-1 to obtain compound 71-1 (130 mg, yield 16%) as a white solid.

[0724]

[0725] 71-2: Synthesis of compound 71

[0726] Compound 71-1 (90 mg, 0.32 mmol) was synthesized in the same manner as compound 38 to obtain compound 71 (15 mg, yield 12%) as a white solid.

[0727]

[0728] Manufacturing Example 72: Synthesis of Compound 72

[0729] [Reaction Formula 72]

[0730]

[0731] 72-1: Synthesis of compound 72-1

[0732] Oxazole-2-carboxylic acid (250 mg, 2.2 mmol) was synthesized in the same manner as compound 39-1 to obtain compound 72-1 (45 mg, yield 9.3%) as a white solid.

[0733]

[0734] 72-2: Synthesis of compound 72

[0735] Compound 72-1 (45 mg, 0.21 mmol) was synthesized in the same manner as compound 38 to obtain compound 72 (8.8 mg, yield 13%) as a white solid.

[0736]

[0737] Manufacturing Example 73: Synthesis of Compound 73

[0738] [Reaction Formula 73]

[0739]

[0740] 73-1: Synthesis of compound 73-1

[0741] (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (76 mg, 0.36 mmol) and compound A6 (120 mg, 0.30 mmol) were synthesized using the same process as for compound 1 to obtain compound 73-1 (50 mg, yield 37%) as a white solid.

[0742]

[0743] 73-2: Synthesis of compound 73

[0744] Compound 73-1 (50 mg, 0.11 mmol) was synthesized in the same manner as compound 2 to obtain compound 73 (16 mg, yield 39%) as a white solid.

[0745]

[0746] Manufacturing Example 74: Synthesis of Compound 74

[0747] [Reaction Formula 74]

[0748]

[0749] (4-Cyanophenyl)boronic acid (88 mg, 0.60 mmol) and compound A6 (200 mg, 0.51 mmol) were synthesized using the same process as for compound 1 to obtain compound 74 (9.3 mg, yield 4.9%) as a white solid.

[0750]

[0751] Manufacturing Example 75: Synthesis of Compound 75

[0752] [Reaction Formula 75]

[0753]

[0754] 2-(Tributylstannyl)thiazole (95 mg, 0.25 mmol) was synthesized in the same manner as compound 65 to obtain compound 75 (8.8 mg, yield 9.7%) as a white solid.

[0755]

[0756] Manufacturing Example 76: Synthesis of Compound 76

[0757] [Reaction Formula 76]

[0758]

[0759] Benzo[d]thiazol-6-ylboronic acid (102 mg, 0.57 mmol) and compound A6 (205 mg, 0.52 mmol) were synthesized using the same process as for compound 1 to obtain compound 76 (10.3 mg, yield 5.3%) as a white solid.

[0760]

[0761] Manufacturing Example 77: Synthesis of Compound 77

[0762] [Reaction Formula 77]

[0763]

[0764] (4-(hydroxymethyl)phenyl)boronic acid (139 mg, 0.91 mmol) and compound A6 (300 mg, 0.76 mmol) were synthesized using the same process as for compound 1 to obtain compound 77 (6.7 mg, yield 2.3%) as a white solid.

[0765]

[0766] Example 1: Analysis of synthesized compounds

[0767] To analyze the characteristics of the compound synthesized in the above manufacturing example, LC-MS and NMR analyses were performed.

[0768] As a result, the structures and IUPAC names of the compounds are described in Tables 1 to 8, and the analysis results (LC-MS and NMR) of the compounds are described in Tables 9 to 16 below.

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785] 화합물특성 데이터화합물1White solid; 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.80 - 7.78 (m, 2H), 7.74 - 7.70 (m, 1H), 7.61 - 7.57 (m, 2H), 5.19 - 5.15 (m, 1H), 4.59 - 4.42 (m, 2H), 2.98 - 2.88 (m, 1H), 2.67 - 2.59 (m, 1H), 2.46 - 2.36 (m, 1H), 2.06 - 2.02 (m, 1H).;LC-MS (ESI): m / z 349.15 [M+H]+.화합물2White solid; 1H NMR (400 MHz, MeOD): δ 7.90 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 5.20 - 5.16 (m, 1H), 4.62 - 4.51 (m, 2H), 4.03 - 3.85 (m, 3H), 3.78 - 3.62 (m, 2H), 2.97 - 2.87 (m, 1H), 2.81 - 2.70 (m, 4H), 2.56 - 2.40 (m, 2H), 2.21 - 2.18 (m, 2H).;LC-MS (ESI): m / z 371.25 [M+H]+.화합물3White solid ; 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 11.03 (s, 1H), 8.16 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.36 - 7.32 (m, 1H), 7.22 (s, 1H), 7.13 - 7.10 (m, 1H), 5.21-5.18 (m, 1H), 4.63 - 4.46 (m, 2H), 2.98-2.90 (m, 1H), 2.66-2.56 (m, 1H), 2.46-2.33 (m, 1H), 2.08-2.04 (m, 1H).;LC-MS (ESI): m / z 388.25 [M+H]+.화합물4White solid; 1H NMR (400 MHz, DMSO-d6): δ 12.16 (s, 1H), 11.02 (s, 1H), 8.29 - 8.27 (m, 1H), 8.05 - 8.01 (m, 2H), 7.89 - 7.86 (m, 2H), 7.54 - 7.53 (m, 1H), 7.30 - 7.25 (m, 2H), 5.20 - 5.16 (m, 1H), 4.60 - 4.43 (m, 2H), 2.95 - 2.90 (m, 1H), 2.64 - 2.60 (m, 1H), 2.46 - 2.39 (m, 1H), 2.06 - 2.04 (m, 1H).;LC-MS (ESI): m / z 388.10 [M+H]+.화합물5White solid; 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.98 (m, 2H), 7.73 - 7.69 (m, 1H), 7.58 - 7.54 (m, 2H), 5.26 - 5.21 (m, 1H), 4.65-4.44 (m, 2H), 2.99 - 2.89 (m, 1H), 2.65 - 2.58 (m, 1H), 2.46 - 2.40 (m, 1H), 2.07 - 2.04 (m, 1H).;LC-MS (ESI): m / z 350.20 [M+H]+.화합물6White solid; 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.57 (s, 1H), 8.48 (d, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 7.99 (d, 1H), 7.90 (d, 1H), 7.73 (t, 1H), 7.52 (t, 1H), 5.20-5.16 (m, 1H), 4.62 - 4.43 (m, 2H), 2.97 - 2.89 (m, 1H), 2.65 - 2.60 (m, 1H), 2.48 - 2.41 (m, 1H), 2.09 - 2.03 (m, 1H).;LC-MS (ESI): m / z 389.00 [M+H]+.화합물7White solid; 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.78-7.74 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 5.16 - 5.12 (m, 1H), 4.52-4.35 (m, 2H), 3.51 - 3.46 (m, 2H), 3.39 - 3.34 (m, 2H), 2.98 - 2.90 (m, 1H), 2.69 - 2.56 (m, 1H), 2.46 - 2.36 (m, 1H), 2.04 - 2.00 (m, 1H), 1.90 - 1.78 (m, 4H).;LC-MS (ESI): m / z 342.05 [M + H] +.화합물8White solid; 1H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H), 11.03 (s, 1H), 8.27 (s, 1H), 8.12 (d, 1H), 8.01 (s, 1H), 7.91 - 7.86 (m, 2H), 7.56 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8, 1H), 5.20-5.15 (m, 1H), 4.59 - 4.43 (m, 2H), 2.98 - 2.89 (m, 1H), 2.67 - 2.58 (m, 1H), 2.48 - 2.45 (m, 1H), 2.08 - 2.03 (m, 1H).;LC-MS (ESI): m / z 422.10 [M + H] +.화합물9White solid; 1H NMR (400 MHz, DMSO-d6): 12.17 (s, 1H), 11.04 (s, 1H), 8.16 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.56 - 7.46 (m, 2H), 7.24 - 7.19 (m, 2H), 5.21-5.16 (m, 1H), 4.62 - 4.45 (m, 2H), 2.98 - 2.89 (m, 1H), 2.66 - 2.60 (m, 1H), 2.48 - 2.42 (m, 1H), 2.08 - 2.04 (m, 1H).;LC-MS (ESI): m / z 405.90 [M + H] +.화합물10Yellow solid; 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 11.17 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.74 (d, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.13 (t, J =7.6 Hz, 1H), 5.26 - 5.21 (m, 1H), 2.97 - 2.88 (m, 1H), 2.69 - 2.54 (m, 2H), 2.14 - 2.07 (m, 1H). ;LC-MS (ESI): m / z 402.05 [M+H]+.

[0786]

[0787] 화합물특성 데이터화합물 11White solid; 1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.34 - 7.23 (m, 5H), 5.17 - 5.12 (m, 1H), 4.56 - 4.39 (m, 2H), 3.52 - 3.40 (m, 3H), 2.95 - 2.84 (m, 3H), 2.65 - 2.56 (m, 1H), 2.44 - 2.36 (m, 1H), 2.20 - 1.96 (m, 3H), 1.81 - 1.75 (m, 2H), 1.63 - 1.55 (m, 2H).;LC-MS (ESI): m / z 446.10 [M+H]+.화합물 12White solid; 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.19 (s, 1H), 8.15 - 8.06 (m, 3H), 7.88 (d, 1H), 7.73 - 7.70 (m, 1H), 5.19 - 5.15 (m, 1H), 4.59 - 4.41 (m, 2H), 2.97 - 2.89 (m, 1H), 2.68 - 2.56 (m, 1H), 2.45 - 2.36 (m, 1H), 2.08 - 2.03 (m, 1H).;LC-MS (ESI): m / z 350.05 [M+H]+.화합물 13Light yellow solid ; 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 5.19-5.14 (m, 1H), 4.58-4.41 (m, 2H), 3.61-3.58 (m, 6H), 2.98-2.88 (m, 1H), 2.68-2.59 (m, 1H), 2.46-2.39 (m, 5H), 2.07-2.03 (m, 1H).;LC-MS (ESI): m / z 448.20 [M+H]+.화합물 14White solid; 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.68 - 7.64 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 5.19 - 5.15 (m, 1H), 4.59 - 4.42 (m, 2H), 3.58 - 3.55 (m, 6H), 2.96 - 2.86 (m, 1H), 2.65 - 2.57 (m, 1H), 2.46 - 2.37 (m, 5H), 2.09 - 2.02 (m, 1H).;LC-MS (ESI): m / z 448.05 [M+H]+.화합물 15yellow solid; 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1 H), 8.97 (s, 1 H), 7.88-7.85 (m, 2 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 2 H), 7.37-7.33 (m, 2 H), 7.24-7.22 (m, 2 H), 7.11 (d, J = 8.8 Hz, 2 H), 7.03 (t, J = 7.6 Hz, 1 H), 5.19-5.15 (m, 1 H), 4.58-4.41 (m, 2 H), 2.96-2.89 (m, 1 H), 2.66-2.58 (m, 1 H), 2.46-2.38 (m, 1 H), 2.07-2.02 (m, 1 H).; LC-MS (ESI): m / z 440.15 [M+H]+.화합물 16yellow solid; 1H NMR (400 MHz, DMSO-d6): 11.03 (s, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.91 - 7.84 (m, 2H), 7.45 - 7.35 (m, 3H), 7.29 - 7.24 (m, 2H), 7.22-7.19 (m, 1H), 7.15-7.12 (m, 2H), 6.90-6.87 (t, 1H), 5.20 - 5.15 (m, 1H), 4.58 - 4.42 (m, 2H), 2.97 - 2.88 (m, 1H), 2.65 - 2.60 (m, 1H), 2.46 - 2.40 (m, 1H), 2.08 - 2.03 (m, 1H).;LC-MS (ESI): m / z 440.15 [M+H]+.화합물 17White solid; 1H NMR (400 MHz, DMSO-d6): δ 14.11 (s, 1H), 11.04 (s, 1H), 8.43 (s, 1H), 8.37-8.32 (m, 2H), 7.92 (d, 1H), 7.76 (d, 1H), 7.53 (t, 1H), 7.41 (t, 1H), 5.21 - 5.16 (m, 1H), 4.63 - 4.45 (m, 2H), 2.97 - 2.89 (m, 1H), 2.68 - 2.58 (m, 1H), 2.47 - 2.42 (m, 1H), 2.08 - 2.02 (m, 1H).; LC-MS (ESI): m / z 388.95 [M]+.화합물 18White solid; 1H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 11.04 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.91 - 7.86 (m, 2H), 7.58 (s, 1H), 7.30 (d, 1H), 5.21-5.16 (m, 1H), 4.60 - 4.43 (m, 2H), 2.95 - 2.89 (m, 1H), 2.66 - 2.59 (m, 1H), 2.46 - 2.41 (m, 1H), 2.08 - 2.03 (m, 1H).; LC-MS (ESI): m / z 422.10 [M+H]+.화합물 19Yellow solid; 1H NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 11.03 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.25 - 7.20 (m, 2H), 7.03 - 6.99 (m, 1H), 5.21-5.16 (m, 1H), 4.62 - 4.45 (m, 2H), 2.98 - 2.89 (m, 1H), 2.64 - 2.59 (m, 1H), 2.46 - 2.40 (m, 1H), 2.07 - 2.04 (m, 1H).; LC-MS (ESI): m / z 406.10 [M+H]+.화합물 20Light brown solid; 1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 11.04 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.26 (s, 1H), 7.15 (d, J = 8.8, 1H), 5.22 - 5.17 (m, 1H), 4.62 - 4.46 (m, 2H), 2.95 - 2.90 (m, 1H), 2.68 - 2.58 (m, 1H), 2.47 - 2.42 (m, 1H), 2.08 - 2.04 (m, 1H).; LC-MS (ESI): m / z 422.05 [M+H]+.

[0788]

[0789] 화합물특성 데이터화합물 21White solid; 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 11.03 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.96 - 7.88 (m, 4H), 7.58 - 7.56 (m, 1H), 5.21 - 5.16 (m, 1H), 4.59 - 4.42 (m, 2H), 2.98 - 2.89 (m, 1H), 2.68 - 2.60 (m, 1H), 2.46 - 2.40 (m, 1H), 2.07 - 2.03 (m, 1H).;LC-MS (ESI): m / z 388.90 [M+H]+.화합물 22Orange solid; 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1 H), 11.03 (s, 1 H), 8.07 (s, 1 H), 7.95 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.01 (s, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 6.39 (s, 1 H), 6.16 (br s, 1 H), 5.20 - 5.15 (m, 1H), 4.60 - 4.43 (m, 2H), 2.98 - 2.89 (m, 1 H), 2.74 (s, 3 H), 2.66 - 2.58 (m, 1 H), 2.44 - 2.40 (m, 1 H), 2.10 - 2.00 (m, 1 H).;LC-MS (ESI): m / z 417.15 [M + H] +.화합물 23white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.98 - 7.91 (m, 4H), 7.85 - 7.83 (m, 4H), 7.54 - 7.50 (m, 4H), 7.46 - 7.42 (m, 2H), 5.19 - 5.15 (m, 1H), 4.61 - 4.44 (m, 2H), 2.97 - 2.88 (m, 1H), 2.64 - 2.59 (m, 1H), 2.44 - 2.40 (m, 1H), 2.08 - 2.03 (m, 1H).;LC-MS (ESI): m / z 501.2 [M + H] +.화합물 24white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 11.03 (s, 1H), 8.54 (s, 1H), 8.07 (d, J = 3.2 Hz, 1H), 8.02 (s, 1H), 7.92 - 7.87 (m, 2H), 7.70 - 7.68 (m, 2H), 7.64 - 7.58 (m, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 5.21 - 5.16 (m, 1H), 4.61 - 4.44 (m, 2H), 2.99 - 2.90 (m, 1H), 2.65 - 2.61 (m, 1H), 2.47 - 2.43 (m, 1H), 2.08 - 2.04 (m, 1H).;LC-MS (ESI): m / z 463.75 [M]+, 464.80 [M + H] +.화합물 25white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 - 7.72 (m, 4H), 7.67 - 7.63 (m, 4H), 7.56 - 7.50 (m, 3H), 7.41 - 7.37 (m, 1H), 5.20 - 5.15 (m, 1H), 4.61 - 4.45 (m, 2H), 2.98 - 2.89 (m, 1H), 2.65 - 2.60 (m, 1H), 2.45 - 2.40 (m, 1H), 2.05 - 2.03 (m, 1H).;LC-MS (ESI): m / z 540.2 [M + H] +.화합물 26white solid; 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.03 - 8.00 (m, 3H), 7.91 (m, 2H), 7.78 - 7.75 (m, 1H), 7.74 - 7.67 (m, 3H), 7.51 - 7.48 (m, 2H), 7.43 - 7.39 (m, 1H), 5.19 - 5.15 (m, 1H), 4.60 - 4.42 (m, 2H), 2.96 - 2.88 (m, 1H), 2.63 - 2.59 (m, 1H), 2.46 - 2.36 (m, 1H), 2.07 - 2.02 (m, 1H).;MS (ESI): m / z 425.1 [M + H] +.화합물 27Yellow solid; 1H NMR (400 MHz, DMSO-d6): δ 12.34 (s, 1H), 11.04 (s, 1H), 8.10 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.33 (t, 2H), 7.26 (s, 1H), 7.20 - 7.16 (m, 1H), 5.18 (dd, J = 4.8, 8.4 Hz, 1H), 4.61 - 4.57 (m, 1H), 4.49 - 4.45 (m, 1H), 2.97 - 2.89 (m, 1H), 2.64 - 2.60 (m, 1H), 2.46 - 2.39 (m, 1H), 2.08 - 2.03 (m, 1H).; LC-MS (ESI): m / z 414.1 [M + H] +.화합물 28Yellow solid; 1H NMR (400 MHz, DMSO-d6): δ 12.40 (s, 1H), 11.04 (s, 1H), 8.05 (s, 1H), 7.98 - 7.92 (m, 3H), 7.88 - 7.86 (m, 1H), 7.46 - 7.42 (m, 2H), 7.36 - 7.32 (m, 1H), 6.93 - 6.92 (m, 1H), 6.82 - 6.80 (m, 1H), 5.20 - 5.16 (m, 1H), 4.60 - 4.56 (m, 1H), 4.83 - 4.39 (m, 1H), 2.95 - 2.94 (m, 1H), 2.64 - 2.60 (m, 1H), 2.46 - 2.40 (m, 1H), 2.08 - 2.05 (m, 1H).;LC-MS (ESI): m / z 414.1 [M + H] +.화합물 29Yellow solid; 1H NMR (400 MHz, DMSO-d6): δ 13.29 (s, 1H), 10.73 (s, 1H), 8.75 (s, 1H), 8.64 (d, J = 7.6 Hz, 1H), 7.93 (t, J = 7.6 Hz, 4H), 7.50 - 7.28 (m, 3H), 5.13 (dd, J = 13.2, 5.2 Hz, 1H), 4.59 (dd, J = 40.0, 17.2 Hz, 2H), 2.97 - 2.88 (m, 1H), 2.71 - 2.63 (m, 1H), 2.46 - 2.40 (m, 1H), 2.18-2.06 (m, 1H).;LC-MS (ESI): m / z 415.2 [M + H] +.화합물 30Orange solid; 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 8.50 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 1.6 Hz, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 5.19 (dd, J = 13.2, 5.2 Hz, 1H), 4.54 (dd, J = 48.4, 18.0 Hz, 2H), 3.01 - 2.87 (m, 1H), 2.62 (d, J = 19.2 Hz, 1H), 2.47 - 2.38 (m, 1H), 2.08-2.01 (m, 1H).;LC-MS (ESI): m / z 431.0 [M + H] +.

[0790]

[0791] 화합물특성 데이터화합물 31Yellow solid; 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.10 - 7.76 (m, 4H), 7.72 (d, J = 8.4 Hz, 1H), 7.64-7.37 (m, 3H), 7.31 (s, 1H), 5.32 (s, 2H), 5.18 (dd, J =13.2 Hz, 4.8 Hz, 1H), 4.51 (dd, J = 51.2, 17.6 Hz, 2H), 3.01 - 2.88 (m, 1H), 2.63 (d, J = 16.4 Hz, 1H), 2.48 - 2.39 (m, 1H), 2.10 - 2.00 (m, 1H).;LC-MS (ESI): m / z 426.0 [M + H] +.화합물 32white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.33 (s, 1H), 8.31 - 8.29 (m, 1H), 8.02 (s, 1H), 7.92 - 7.88 (m, 2H), 7.56 - 7.54 (m, 1H), 7.34 - 7.26 (m, 7H), 5.54 (s, 2H), 5.21 - 5.17 (m, 1H), 4.58 (d, J = 17.6 Hz, 1H), 4.47 (d, J = 17.6 Hz, 1H), 2.99 - 2.90 (m, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.44 - 2.36 (m, 1H), 2.06 - 2.03 (m, 1H).;LC-MS (ESI): m / z 478.2 [M + H] +.화합물 33white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.01 (s, 1H), 7.93 - 7.88 (m, 6H), 7.79 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 5.20 - 5.16 (m, 1H), 4.58 (d, J = 18.0 Hz, 1H), 4.45 (d, J = 17.6 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.67 - 2.60 (m, 1H), 2.46 - 2.33 (m, 1H), 2.08 - 1.96 (m, 1H).;LC-MS (ESI): m / z 425.3 [M + H] +.화합물 34white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.23 (s, 1H), 8.11 - 8.07 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.90 - 7.87 (m, 2H), 7.82 - 7.79 (m, 1H), 7.63 - 7.59 (m, 1H), 7.44 - 7.40 (m, 1H), 5.22 - 5.17 (m, 1H), 4.60 (d, J = 17.6 Hz, 1H), 4.48 (d, J = 17.6 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.68 - 2.65 (m, 1H), 2.34 - 2.32 (m, 1H), 2.08 - 2.03 (m, 1H).;LC-MS (ESI): m / z 389.1 [M + H] +.화합물 35white solid; 1H NMR(400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.41 (dd, J = 5.7, 3.2 Hz, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.64 - 7.55 (m, 3H), 7.51 (t, J = 7.4 Hz, 1H), 7.38 (p, J = 7.2 Hz, 2H), 5.16 (dd, J = 13.2, 5.0 Hz, 1H), 4.50 (dd, J = 47.0, 17.6 Hz, 2H), 2.98 - 2.85 (m, 1H), 2.60 (d, J = 17.6 Hz, 1H), 2.41 (dd, J = 13.1, 4.2 Hz, 1H), 2.09 - 1.96 (m, 1H). ;LC-MS (ESI): m / z 463.9 [M + H] +.화합물 36white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.85-7.82 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.34-7.24 (m, 3H), 5.16 (dd, J1 = 13.2 Hz, J2 = 4.8 Hz, 1H), 4.90 (S, 2H), 4.79-4.72 (m, 2H), 4.53 (d, J = 17.6 Hz, 1H), 4.40 (d, J = 17.6 Hz, 1H), 2.98-2.89 (m, 1H), 2.64-2.59 (m, 1H), 2.45-2.38 (m, 1H), 2.06-2.01 (m, 1H). ;LC-MS (ESI): m / z 390.0 [M + H] +.화합물 37white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.79 (s, 1H), 8.20 - 8.16 (m, 1H), 8.14 (s, 1H), 8.03 - 7.97 (m, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.77 (dd, J = 6.8, 1.8 Hz, 1H), 7.51 - 7.43 (m, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 (dd, J = 42.9, 17.7 Hz, 2H), 2.99 - 2.87 (m, 1H), 2.61 (dd, J = 15.2, 2.1 Hz, 1H), 2.44 (dd, J = 13.2, 4.5 Hz, 1H), 2.08 - 2.01 (m, 1H).;MS (ESI): m / z 389.0 [M + H] +.화합물 38white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (d, J = 17.7 Hz, 1H), 4.42 (d, J = 17.7 Hz, 1H), 3.77 - 3.65 (m, 1H), 2.99 - 2.85 (m, 1H), 2.63-2.59 (m, 1H), 2.45-2.34 (m, 1H), 2.09 - 1.96 (m, 1H), 1.13 (d, J = 6.8 Hz, 6H).;MS (ESI): m / z 315.1 [M + H] +.화합물 39white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 5.16-5.14 (m, 1H), 4.56-4.39 (m, 2H), 3.92-3.88 (m, 1H), 2.95-2.87 (m, 1H), 2.65-2.59 (m, 1H), 2.44-2.39 (m, 1H), 2.03-1.90 (m, 3H), 1.75-1.77 (m, 2H), 1.60-1.64 (m, 4H);MS (ESI): m / z 341.1 [M + H] +.화합물 40white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.96 (s, 1H), 7.92-7.83 (m, 4H), 7.45-7.40 (m, 2H), 5.18 (dd, J = 13.2, 5.2 Hz, 1H), 4.57 (d, J = 5.2 Hz, 1H), 4.44 (d, J = 18.0 Hz, 1H), 2.98-2.89 (m, 1H), 2.65-2.59 (m, 1H), 2.45-2.38 (m, 1H), 2.08-2.01 (m, 1H).;MS (ESI): m / z 367.1 [M + H] +.

[0792]

[0793] 화합물특성 데이터화합물 41yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.86-7.84 (m, 2H), 7.73 (d, J = 8.8 Hz,1H), 7.66 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 9.2 Hz, 2H), 5.17-5.15 (m, 1H), 4.57-4.39 (m, 2H), 3.43 - 3.42 (m, 4H), 2.95-2.91 (m, 1H), 2.66-2.60 (m, 1H), 2.44 - 2.39 (m, 1H), 2.05 - 2.01 (m, 1H), 1.62-1.58 (m, 6H).;MS (ESI): m / z 432.2 [M + H] +.화합물 42white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.91-7.87 (m, 2H), 7.80-7.77 (m, 1H), 7.35-7.33 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.18 (s, 2H), 5.17-5.15 (m, 1H), 4.58-4.40 (m, 2H), 2.95 - 2.86 (m, 1H), 2.63-2.59 (m, 1H), 2.42-2.39 (m, 1H), 2.04 - 2.01 (m, 1H). ;MS (ESI): m / z 393.1 [M + H] +.화합물 43white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H) 7.88 (s, 2H), 7.67-7.58 (m, 4H), 5.17-5.15 (m, 1H), 4.55-4.43 (m, 2H), 2.92 - 286 (m, 1H), 2.63-2.59 (m, 1H), 2.40-2.37 (m, 1H), 2.03 - 2.01 (m, 1H).;MS (ESI): m / z 399.0 [M + H] +.화합물 44white solid; 1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.37 (s, 1H), 8.14 - 8.10 (m, 2H), 8.04-8.03 (m, 2H), 7.94-7.91 (m, 3H), 7.73-7.69 (m, 1H), 7.65-7.61 (m, 1H), 5.20-5.16 (m, 1H), 4.60-4.43 (m, 2H), 2.93- 2.90 (m, 1H), 2.63-2.59 (m, 1H), 2.45-2.41 (m, 1H), 2.07 - 2.03 (m, 1H). ;MS (ESI): m / z 399.1 [M + H] +.화합물 45white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.00 (s, 1H), 7.95-7.86 (m, 4H), 7.58 (d, J = 8.0 Hz, 2H), 5.18 (dd, J = 12.8, 5.2 Hz, 1H), 4.50 (dd, J = 49.0, 17.6 Hz, 2H), 2.98-2.89 (m, 1H), 2.64-2.59 (m, 1H), 2.51-2.41 (m, 1H), 2.07-2.01 (m, 1H). ;MS (ESI): m / z 433.0 [M + H] +.화합물 46yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.86-7.83 (m, 2H), 7.73-7.67 (m, 3H), 6.78 (d, J = 8.8 Hz, 2H), 5.20-5.15 (m, 1H), 4.57-4.39 (m, 2H), 3.05 (s, 6H), 2.97-2.89 (m, 1H), 2.63-2.59 (m, 1H), 2.43-2.38 (m, 1H), 2.06-2.02 (m, 1H). ;MS (ESI): m / z 392.2 [M + H] +.화합물 47white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.99 (s, 1H), 7.90-7.87 (m, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 5.18-5.15 (m, 1H), 4.58-4.40 (m, 2H), 3.02 (s, 3H), 2.96-2.87 (m, 4H), 2.64-2.59 (m, 1H), 2.42-2.38 (m, 1H), 2.04-2.01 (m, 1H). ;MS (ESI): m / z 420.1 [M + H] +.화합물 48white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.97 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.83-7.80 (m, 2H), 7.68-7.65 (m, 2H), 5.18 (dd, J = 13.6, 5.2 Hz, 1H), 4.50 (dd, J = 48.6, 17.6 Hz, 2H), 2.98-2.89 (m, 1H), 2.64-2.59 (m, 1H), 2.45-2.38 (m, 1H) , 2.08-2.01 (m, 1H). ;MS (ESI): m / z 383.0, 385.0 [M + H] +.화합물 49white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.96 (s, 1H), 7.91-7.89 (m, 1H), 7.86-7.84 (m, 1H), 7.81-7.79 (m, 2H), 7.74-7.71 (m, 2H), 5.17 (dd, J = 13.2, 5.2 Hz, 1H), 4.49 (dd, J = 48.0, 17.6 Hz, 2H), 2.97-2.88 (m, 1H), 2.64-2.63 (m, 1H), 2.60-2.49 (m, 1H), 2.45-2.37 (m, 1H).;MS (ESI): m / z 427.0 429.0 [M + H] +.화합물 50white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.01 (s, 1H), 7.99-7.88 (m, 6H), 5.17 (dd, J = 13.2, 5.2 Hz, 1H), 4.58-4.54 (m, 1H), 4.46-4.42 (m, 1H), 2.97-2.88 (m, 1H), 2.63-2.59 (m, 1H), 2.45-2.37 (m, 1H), 2.07-2.02 (m, 1H).;MS (ESI): m / z 417.0 [M + H] +.

[0794]

[0795] 화합물특성 데이터화합물 51white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.92-7.88 (m, 2H), 7.82-7.79 (m, 3H), 7.14-7.10 (m, 2H), 5.18 (dd, J = 13.2, 5.2 Hz, 1H), 4.50 (dd, J = 50.0, 17.6 Hz, 2H), 3.88 (s, 3H), 2.98-2.89 (m, 1H), 2.65-2.60 (m, 1H), 2.45-2.39 (m, 1H), 2.08-2.02 (m, 1H).;MS (ESI): m / z 379.0 [M + H] +.화합물 52white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.54 (s, 1H), 7.89-7.87 (m, 2H), 7.77 (dd, J = 7.6, 1.6 Hz, 1H), 7.73-7.69 (m, 2H), 6.93-6.90 (m, 2H), 5.17 (dd, J = 13.2, 5.2 Hz, 1H), 4.49 (dd, J = 50.2, 17.6 Hz, 2H), 2.98-2.89 (m, 1H), 2.64-2.60 (m, 1H), 2.45-2.37 (m, 1H), 2.08-2.01 (m, 1H).;MS (ESI): m / z 365.1 [M + H] +.화합물 53white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.92-7.88 (m, 2H), 7.81-7.79 (m, 3H), 7.50-7.48 (m, 2H), 7.44-7.41 (m, 2H), 7.38-7.34 (m, 1H), 7.21-7.18 (m, 2H), 5.25 (s, 2H), 5.17 (dd, J = 13.2, 5.2 Hz, 1H), 4.50 (dd, J = 50.6, 17.6 Hz, 2H), 2.98-2.89 (m, 1H), 2.64-2.58 (m, 1H), 2.45-2.37 (m, 1H), 2.08-2.01 (m, 1H).;MS (ESI): m / z 455.2 [M + H] +.화합물 54white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.98-7.76 (m, 3H), 7.70 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (dd, J = 49.9, 17.7 Hz, 2H), 3.00-2.86 (m, 1H), 2.68-2.60 (m, 1H), 2.45-2.31 (m, 4H), 2.11-1.99 (m, 1H). ;MS (ESI): m / z 363.2 [M + H] +.화합물 55white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.94 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.7 Hz, 1H), 4.43 (d, J = 17.7 Hz, 1H), 3.00-2.84 (m, 1H), 2.66-2.60 (m, 1H), 2.44-2.36 (m, 1H), 2.08-1.99 (m, 1H), 1.82 (d, J = 7.9 Hz, 4H), 1.72 (d, J = 13.1 Hz, 1H), 1.50-1.35 (m, 4H), 1.29-1.22 (m, 2H).;MS (ESI): m / z 431.3 [M + H] +.화합물 56white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.98 (s, 1H), 7.95-7.80 (m, 4H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.8 Hz, 1H), 4.44 (d, J = 17.7 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.99-2.83 (m, 1H), 2.64-2.60 (m, 1H), 2.45-2.34 (m, 1H), 2.06-2.03 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H);MS (ESI): m / z 421.2 [M + H] +.화합물 57white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.40-8.38 (m, 2H), 8.03-8.00 (m, 3H), 7.94-7.90 (m, 2H), 5.19-5.15 (m, 1H), 4.58-4.20 (m, 2H), 2.95-2.88 (m, 1H), 2.64-2.59 (m, 1H), 2.49-2.39 (m, 1H), 2.07-2.02 (m, 1H).;MS (ESI): m / z 394.0 [M + H] +.화합물 58white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.17 (dd, J = 1.7, 0.7 Hz, 1H), 8.12 (s, 1H), 8.00 (dd, J = 7.9, 1.3 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 3.6, 0.6 Hz, 1H), 6.83 (dd, J = 3.6, 1.7 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (dd, J = 48.3, 17.7 Hz, 2H), 2.99-2.87 (m, 1H), 2.65-2.59 (m, 1H), 2.48-2.41 (m, 1H), 2.07-1.91 (m, 1H). ;MS (ESI): m / z 339.0 [M + H] +.화합물 59white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.09 (s, 1H), 7.98 (dd, J = 7.9, 1.3 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.6, 0.7 Hz, 1H), 7.43 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 7.20 - 7.13 (m, 1H), 7.09 (d, J = 0.7 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 17.7 Hz, 1H), 4.46 (d, J = 17.6 Hz, 1H), 4.09 (s, 3H), 3.00 - 2.86 (m, 1H), 2.64-2.61 (m, 1H), 2.46-2.40 (m, 1H), 2.06 (dd, J = 9.5, 4.2 Hz, 1H).;MS (ESI): m / z 402.1 [M + H] +.화합물 60white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.63 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.34-8.31 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.72-7.67 (m, 2H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 17.7 Hz, 1H), 4.50 (d, J = 17.7 Hz, 1H), 3.04 - 2.85 (m, 1H), 2.67 - 2.60 (m, 1H), 2.46-2.41 (m, 1H), 2.08-2.05 (m, 1H).; MS (ESI): m / z 406.0 [M + H] +.

[0796]

[0797] 화합물특성 데이터화합물 61white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 8.0 Hz 1H), 7.84-7.82 (m, 1H), 7.60-7.45 (m, 4H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.7 Hz, 1H), 4.44 (d, J = 17.7 Hz, 1H), 3.02-2.85 (m, 1H), 2.67-2.64 (m, 1H), 2.45-2.34 (m, 4H), 2.12 - 1.97 (m, 1H). ;MS (ESI): m / z 363.1 [M + H] +.화합물 62white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53-7.46 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.37-7.29 (m, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 17.8 Hz, 1H), 4.42 (d, J = 17.8 Hz, 1H), 3.00-2.81 (m, 1H), 2.63-2.59 (m, 1H), 2.41-2.35 (m, 1H), 2.26 (s, 3H), 2.08-1.97 (m, 1H).;MS (ESI): m / z 363.3 [M + H] +.화합물 63white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.96 (s, 1H), 7.92-7.80 (m, 2H), 7.79-7.70 (m, 2H), 7.66-7.55 (m, 2H), 5.17 (dd, J = 13.3, 5.0 Hz, 1H), 4.56 (d, J = 17.7 Hz, 1H), 4.43 (d, J = 17.8 Hz, 1H), 2.99-2.84 (m, 1H), 2.67-2.59 (m, 1H), 2.44-2.35 (m, 1H), 2.11-1.98 (m, 1H), 1.34 (s, 9H).;MS (ESI): m / z 405.1 [M + H] +.화합물 64white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.84-7.80 (m, 2H), 7.70-7.67 (m, 1H), 7.56-7.53 (m, 2H), 6.62-6.59 (m, 2H), 6.25 (s, 2H), 5.18-5.14 (m, 1H), 4.56-4.39 (m, 2H), 2.92 - 2.89 (m, 1H), 2.67-2.54 (m, 1H), 2.49-2.32 (m, 1H), 2.05 - 2.02 (m, 1H). ;MS (ESI): m / z 364.1 [M + H] +.화합물 65white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.87 (dd, J = 5.0, 1.5 Hz, 1H), 8.17 (dd, J = 8.0, 2.0 Hz, 1H), 8.02 (s, 1H), 7.94-7.88 (m, 2H), 7.63 (dd, J = 8.0, 5.0 Hz, 1H), 5.17 (dd, J = 13.5, 5.0 Hz, 1H), 4.57 (d, J = 18.0 Hz, 1H), 4.45 (d, J = 18.0 Hz, 1H), 2.97-2.88 (m, 1H), 2.65-2.58 (m, 1H), 2.45-2.36 (m, 1H), 2.08-2.01 (m, 1H);MS (ESI): m / z 350.0 [M + H] +.화합물 66white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.84 (dd, J = 4.4, 1.6 Hz, 2H), 8.03 (s, 1H), 7.92-7.91 (m, 2H), 7.68 (dd, J = 4.4, 1.6 Hz, 2H), 5.17 (dd, J = 13.2, 5.2 Hz, 1H), 4.50 (dd, J = 50, 18 Hz, 2H), 2.99 - 2.85 (m, 1H), 2.67-2.59 (m, 1H), 2.43-2.33 (m, 1H), 2.09 - 1.99 (m, 1H). ;MS (ESI): m / z 350.1 [M + H] +.화합물 67white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.46 (s, 1H), 9.15 (s, 2H), 8.09 (s, 1H), 7.99 - 7.92 (m, 2H), 5.18 (dd, J = 13.2, 5.2 Hz, 1H), 4.58 (d, J = 18.0 Hz, 1H), 4.46 (d, J = 18.0 Hz, 1H), 2.97 - 2.87 (m, 1H), 2.65 - 2.58 (m, 1H), 2.46 - 2.37 (m, 1H), 2.07 - 2.00 (m, 1H).;MS (ESI): m / z 351.0 [M + H] +.화합물 68white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.24 (d, J = 1.5 Hz, 1H), 8.96 (d, J = 2.5 Hz, 1H), 8.83 (dd, J = 2.5, 1.5 Hz, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (dd, J = 54.5, 17.7 Hz, 2H), 3.00 - 2.83 (m, 1H), 2.72 - 2.58 (m, 1H), 2.46 - 2.37 (m, 1H), 2.10 - 1.96 (m, 1H).;MS (ESI): m / z 351.1 [M + H] +.화합물 69white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.70 (d, J = 4.5 Hz, 1H), 8.00 (s, 1H), 7.93-7.89 (m, 2H), 7.53 (s, 1H), 7.46 (d, J = 5.0 Hz, 1H), 5.19 (dd, J = 13.5, 5.5 Hz, 1H), 4.58 (d, J = 18.0 Hz, 1H), 4.46 (d, J = 18.0 Hz, 1H), 2.96-2.89 (m, 1H), 2.64-2.58 (m, 4H), 2.47-2.36 (m, 1H), 2.06-2.02 (m, 1H). ; MS (ESI): m / z 364.0 [M + H] +.화합물 70white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H), 8.20-8.11 (m, 4H), 7.92-7.87 (m, 2H), 7.79 (t, J = 7.5 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 (dd, J = 64.5, 17.7 Hz, 2H), 3.00-2.88 (m, 1H), 2.64-2.61 (m, 1H), 2.45-2.34 (m, 1H), 2.09 - 2.01 (m, 1H). ;MS (ESI): m / z 400.0 [M + H] +.

[0798]

[0799] 화합물특성 데이터화합물 71white solid; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.17-8.13 (m, 3H), 8.09 (s, 1H), 7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.92 - 7.88 (m, 2H), 7.77 - 7.73 (m, 1H), 5.16 (dd, J = 13.2, 4.8 Hz, 1H), 4.47 (dd, J = 53.2, 17.6 Hz, 2H), 2.96 - 2.87 (m, 1H), 2.68 - 2.58 (m, 1H), 2.44 - 2.32 (m, 1H), 2.08 - 1.99 (m, 1H).;MS (ESI): m / z 400.0 [M + H] +.화합물 721H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.56 (s, 2H), 8.48 (dd, J = 8.0, 0.8 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 5.18 (dd, J = 13.2, 5.2 Hz, 1H), 4.61 (d, J = 17.6 Hz, 1H), 4.47 (d, J = 17.6 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.68 - 2.60 (m, 1H), 2.45 - 2.33 (m, 1H), 2.08 - 2.03 (m, 1H).화합물 731H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 11.02 (s, 1H), 8.02 (s, 1H), 7.96-7.79 (m, 2H), 7.28-7.26 (m, 1H), 6.87-6.85 (m, 1H), 6.48-6.19 (m, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.6 Hz, 1H), 4.44 (d, J = 17.7 Hz, 1H), 3.01-2.84 (m, 1H), 2.69-2.62 (m, 1H), 2.43-2.32 (m, 1H), 2.10-1.98 (m, 1H).화합물 741H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.99 (s, 1H), 7.94-7.87 (m, 4H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 17.8 Hz, 1H), 4.44 (d, J = 17.9 Hz, 1H), 2.99-2.85 (m, 1H), 2.67-2.59 (m, 1H), 2.45-2.33 (m, 1H), 2.10-1.97 (m, 1H).화합물 751H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.58 (s, 1H), 8.50 (d, J = 9.2 Hz, 1H), 8.35 (d, J = 3.2 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 5.18 (dd, J = 13.2, 4.8 Hz, 1H), 4.54 (dd, J = 55.2, 18 Hz, 2H), 2.98-2.89 (m, 1H), 2.64-2.60 (m, 1H), 2.49-2.38 (m, 1H), 2.08-2.04 (m, 1H).화합물 761H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.64 (s, 1H), 8.67 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.99-7.89 (m, 3H), 5.17 (dd, J = 13.2, 5.2 Hz, 1H), 4.51 (dd, J = 48.0, 17.6 Hz, 2H), 2.97-2.88 (m, 1H), 2.64-2.59 (m, 1H), 2.45-2.34 (m, 1H), 2.07-2.03 (m, 1H).화합물 771H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.94 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 5.41 (t, J = 5.7 Hz, 1H), 5.17 (dd, J = 13.4, 5.1 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 4.56 (d, J = 17.7 Hz, 1H), 4.44 (d, J = 17.7 Hz, 1H), 3.00-2.87 (m, 1H), 2.64-2.60 (m, 1H), 2.44-2.35 (m, 1H), 2.12-1.96 (m, 1H).

[0800]

[0801] Example 2: Evaluation of binding affinity of synthesized compounds to cereblon

[0802] To confirm the binding affinity of the compound synthesized in the above manufacturing example to the Cereblon (CRBN) protein, Eurofins' E3scan TM The following experiments were performed using .

[0803] Specifically, CRBN was produced using HEK-293 cells and labeled with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to generate an affinity resin for E3scan analysis. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and prevent nonspecific binding. Binding reactions were performed by mixing CRBN, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). The compounds were prepared as 100x stocks in 100% DMSO and diluted directly into the experimental solution. All reactions were performed in polypropylene 384-well plates with a final volume of 0.02 ml of the reaction solution. The experimental plates were incubated for 1 hour at room temperature with shaking, and the affinity beads were washed with washing buffer (1x PBS, 0.05% Tween 20). The beads were then redispersed in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. The CRBN concentration in the eluate was measured by qPCR. The compounds and the control (lenalidomide) were analyzed at a concentration of 5 μM, and the binding affinity was calculated as the relative binding affinity, '% Ctrl', using the following formula. A lower '% Ctrl' indicates a stronger binding affinity. Meanwhile, DMSO was used as a negative control (100% Ctrl), and the control compound (Lenalidomide) was used as a positive control (0% Ctrl).

[0804] [Mathematical Formula 1]

[0805]

[0806] The results of analyzing the binding affinity of the compounds synthesized in the above manufacturing examples for CRBN are shown in the table below.

[0807] Compound CRBN Binding Affinity (% Ctrl @ 5uM) Lenalidomide A Compound 1 C Compound 3 A Compound 4 B Compound 5 C Compound 6 A Compound 7 A Compound 10 C Compound 11 A Compound 12 A Compound 15 A Compound 16 A Compound 17 A Compound 21 A Compound 22 A Compound 24 D Compound 25 D Compound 26 A Compound 27 A Compound 28 C Compound 30 A Compound 31 A Compound 34 A Compound 35 A Compound 36 A Compound 37 C Binding affinity range: A: 0 ≤ '% Ctrl' < 0.1, B: 0.1 ≤ '% Ctrl' < 1, C: 1≤'%Ctrl'<10, D: 10≤'%Ctrl'<35, E '%Ctrl'≥35

[0808]

[0809] As confirmed in Table 17 above, it can be seen that the compounds according to the present invention exhibit strong binding affinity for CRBN.

[0810]

[0811] Example 3: Evaluation of the decomposition activity of the synthesized compound against GSPT1

[0812] To confirm the GSPT1 protein decomposition activity of the compound synthesized in the above manufacturing example, the amount of GSPT1 protein present in the cells was measured after treatment with Jurkat cells. The amount of GSPT1 protein was measured using a Western blotting detection method.

[0813]

[0814] 3-1: Cell line culture

[0815] The culture medium for the Jurkat cell line used RPMI medium containing 10% heat-inactivated FBS and 1% penicillin / streptomycin antibiotics (P / S). The culture medium was stored in a refrigerator and warmed in a 37°C water bath before use. The Jurkat cell line (manufacturer: KCLB, Cat. No.: 40152) was used for testing after a stabilization period of more than 2 weeks after thawing, and the thawing and subculture conditions were performed based on the information provided by the cell line manufacturer.

[0816]

[0817] 3-2: Western blotting analysis

[0818] Jurkat cell line was seeded in 6-well plates at 3X10 6 After seeding under the conditions of cells / well, the test substances were treated at various concentrations in the Jurkat cell line and cultured in a CO2 incubator at 37°C for 24 hours. The drug-treated cell line for 24 hours was washed with DPBS and lysed by adding RIPA buffer. Then, the supernatant was collected after centrifugation at 12,000 rpm for 10 minutes at 4°C to obtain proteins. The obtained proteins were quantified using a BCA protein assay kit (Thermo, 23225), and samples containing the same protein concentration were prepared by adding 4x loading buffer (Gendepot, L1100-001). The prepared samples were loaded onto 4-12% Bis-Tris Midi Protein Gels (Invitrogen, WG1403BOX), SureLock TMAfter electrophoresis using a Tandem Midi Gel Tank (Invitrogen, STM1001), the membrane was blotted onto a PVDF membrane (Thermo, IB24001) using a Transfer device (Thermo, IB21001). The membrane was blocked with TBS-T (T&I, BTT-9110) buffer containing 5% BSA (Gendepot, A0100-010) and washed with 1x TBS-T. After washing, the membrane was treated with primary antibodies prepared in TBS-T buffer containing 5% BSA (GSTP1 1:1000, β-actin 1:3000) and incubated overnight at 4°C. Afterwards, the membrane was washed with 1x TBS-T and treated with secondary antibodies prepared using TBS-T buffer containing 5% skim milk powder (GSTP1 1:3000, β-actin 1:5000) and reacted at room temperature for 1 hour. After washing the membrane with 1x TBS-T, Amersham ECL Western blotting detection reagent (Cytiva, RPN2235) was treated and protein bands were confirmed using Amersham Imager 680 (Cytiva, #29270769) equipment. The confirmed protein bands were analyzed for changes in protein expression using the ImageQuant TL program. The results for the target protein obtained through the Western blot test were normalized using the results for β-actin, which was the loading control group. And the target protein degradation activity of the test substance was analyzed by taking the normalized result of the target protein in the group treated with only vehicle (DMSO) as 100%.

[0819] The results of analyzing the GSPT1 protein degradation activity of the compounds synthesized in the above manufacturing examples are shown in the table below. In addition, the Western blotting results for some of the compounds are shown in Figure 1.

[0820] Compound GSPT1 Degradation (%) 0.1 μM 1 μM 10 μM Compound 1 DCB Compound 3 AAA Compound 4 BAA Compound 6 DBB Compound 7 CBB Compound 8 AAA Compound 9 AAA Compound 10 DCA Compound 14 DCC Compound 15 BAA Compound 16 CBA Compound 17 CBB Compound 18 DBA Compound 19 AAA Compound 20 AAA Compound 21 BAA Compound 22 AAA Compound 26 CCB Compound 27 AAA Compound 28 BAA Compound 30 DBB Compound 31 BAA Compound 32 BAA Compound 33 AAA Compound 34 BAA Compound 35 AAA Compound 36 AAA Compound 37 BAA Compound 39DDC Compound 40DBB Compound 41BBA Compound 42AAA Compound 43DDC Compound 44AAA Compound 45CAA Compound 46AAA Compound 48BBB Compound 49BBB Compound 50BBA Compound 51BBB Compound 52BAA Compound 53BAA Compound 54BAA Compound 55BAA Compound 57EDB Compound 59BAA Compound 60DDC Compound 61AAA Compound 63AAA Compound 64CAA Compound 69EDB Compound 70EDC Compound 73AAA Compound 74EEC Compound 76AAA Decomposition activity range: A: 90<%≤100, B: 70<%≤90, C: 50<%≤70, D: 30<%≤50, E: %≤30

[0821]

[0822] As confirmed in Table 18 above, it can be seen that the compounds according to the present invention exhibit excellent activity in decomposing GSPT1.

[0823]

[0824] Example 4: Evaluation of cancer cell toxicity of synthesized compounds

[0825] To evaluate the toxicity of the compound synthesized in the above manufacturing example to cancer cells, a cell viability analysis experiment was performed according to treatment with the synthesized compound using the T cell leukemia cell line Jurkat (KCLB, Cat# 40152), the human acute monocytic leukemia cell line MV-4-11 (ATCC, Cat# CRL9591), and the human multiple myeloma cell line MM.1S (ATCC, Cat# CRL-2974).

[0826]

[0827] 4-1: Cell culture

[0828] The culture medium for the cell line used RPMI medium containing 10% heat-inactivated FBS and 1% penicillin / streptomycin antibiotics (P / S). The culture medium was stored in a refrigerator and warmed in a 37°C water bath before use. Each cell line was used for testing after a stabilization period of more than 2 weeks after thawing, and the thawing and subculture conditions were performed based on the information provided by the cell line manufacturer.

[0829]

[0830] 4-2: Cell viability assessment

[0831] Jurkat, MV4-11 or MM.1S cell lines were seeded at 1x10 in a 96-well plate. 4After seeding under the conditions of cells / well, the cells were cultured overnight in a CO2 incubator at 37°C. After culture, the prepared test substances were treated to each cell line and cultured in a CO2 incubator at 37°C for 72 hours. After 72 hours of culture, the cell counting kit-8 (Dojindo, Cat# CK04-20) reagent was added and incubated in a CO2 incubator at 37°C. The absorbance was measured at 450 nm using SpectraMax M3 Microplate Readers (N=2, duplicate measurements). The concentrations for evaluating the cytotoxicity of the above compounds were 100 uM, 20 uM, 4 uM, 0.8 uM, 0.16 uM, 0.032 uM, 0.0064 uM, 0.00128 uM, 0.000256 uM, and 0 uM, with 10 points, and the test was conducted with 2 wells / concentration point (n=2). The GI was measured using the GraphPad Prism program. 50 was derived.

[0832] The cytotoxicity of the compounds synthesized in the above manufacturing examples against each cell line is shown in the table below (activity range: A: GI 50 ≤0.1μM, B: 0.1 <GI 50 ≤1μM, C: 1 <GI 50 ≤10μM, D: GI 50 ≤10μM).

[0833] Compound Jurkat cell line - Cell viability (GI50) Compound 1B Compound 3A Compound 4B Compound 8A Compound 9A Compound 10C Compound 15B Compound 16C Compound 17B Compound 18B Compound 19A Compound 20A Compound 21B Compound 22A Compound 26C Compound 27A Compound 28B Compound 30B Compound 31B Compound 32B Compound 33A Compound 34A Compound 35A Compound 36A Compound 37B Compound 39C Compound 40B Compound 41B Compound 42A Compound 43C Compound 44A Compound 45B Compound Compound 46A Compound 48B Compound 49A Compound 50B Compound 51B Compound 52B Compound 53B Compound 54B Compound 55A Compound 59B Compound 61A Compound 63A Compound 64B Compound 70C Compound 73A Compound 76A

[0834]

[0835] Compound MV-4-11 cell line - Cell viability (GI50) Compound 3A Compound 15A Compound 17A Compound 18A Compound 21D Compound 22A

[0836]

[0837] Compound MM.1S cell line - Cell viability (GI50) Compound 3A Compound 4A Compound 9A Compound 15A Compound 17A Compound 18A Compound 19A Compound 20A Compound 21C Compound 22A Compound 27A Compound 31A Compound 33A Compound 34A Compound 35A Compound 37A Compound 42A Compound 44D Compound 46A Compound 49C Compound 52A Compound 55A Compound 59A Compound 63A Compound 70D

[0838]

[0839] As confirmed in Tables 19 to 21 above, it can be seen that the compounds according to the present invention exhibit cytotoxicity against various types of cancer cells.

[0840]

[0841] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A compound according to the following chemical formula 78, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof: [Chemical formula 78] In the above chemical formula 78, One or more R 1 are each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylamino group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, -CH 2 R 3 , -OR 3 , -OCH 2 R 3 , -NR 3 R 4 , -NH(C=O)R 3 , -(C=O)R 3 , -(C=O)OR 3 , -(C=O)NR 3 R 4 , -SO 2 NHR 3 , -CN, -NO 2 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group, R 2 is selected from the group consisting of hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl group and a substituted or unsubstituted C1-C6 haloalkyl group, R 3 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, an amine group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C3 haloalkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 aryl group and a substituted or unsubstituted 3 to 12 membered heteroaryl group, R 4 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, an amine group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C3 haloalkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 aryl group and a substituted or unsubstituted 3 to 12 membered heteroaryl group, m is an integer in the range 0 to 2, n is an integer in the range 0 to 2, X is C=O or CH 2 And, Y is CH or N, Z is selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group.

2. In claim 1, in the chemical formula 78 The above X is CH 2 And, The above Y is CH, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. In claim 1, in the chemical formula 78 The above m is 0, The above n is 1, Above R 2 is hydrogen, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. In claim 1, in the chemical formula 78, The above Z is selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group, When the above Z is a substituted functional group, one or more R a has been replaced by , One or more of the above R a are each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, -CH 2 R 3 -OR 3 , -OCH 2 R 3 , -NR 3 R 4 , -NH(C=O)R 3 , -NHSO 2 R 3 , -(C=O)R 3 , -(C=O)OR 3 , -(C=O)NR 3 R 4 , -SO 2 NHR 3 , -CN, -NO 2 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group, R 3 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, an amine group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C3 haloalkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group, and R 4 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, an amine group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C3 haloalkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 aryl group and a substituted or unsubstituted 3 to 12 membered heteroaryl group. A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. In claim 1, in the chemical formula 78, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z comprises at least one selected from the group consisting of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12-membered heteroaryl group, and groups represented by the following chemical formulae 82-1 to 82-52: In the above chemical formula, R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylamino group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, -CH 2 R 3 -OR 3 , -OCH 2 R 3 , -NR 3 R 4 , -NH(C=O)R 3 , -NHSO 2 R 3 , -(C=O)R 3 , -(C=O)OR 3 , -(C=O)NR 3 R 4 , -SO 2 NHR 3 , -CN, -NO 2 , a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C3-C12 cycloalkenyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkenyl group, a substituted or unsubstituted C3-C12 aryl group, and a substituted or unsubstituted 3 to 12 membered heteroaryl group, R 10 , R 11 and R 12 are each independently hydrogen, halogen, -OR 3 , -NR 3 R 4 , selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted benzyl group, R 3 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, an amine group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C3 haloalkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 aryl group and a substituted or unsubstituted 3 to 12 membered heteroaryl group, R 4 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, an amine group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C3 haloalkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3 to 12 membered heterocycloalkyl group, a substituted or unsubstituted C3-C12 aryl group and a substituted or unsubstituted 3 to 12 membered heteroaryl group, o is an integer in the range 0 to 2, p is an integer in the range 1 to 3, and * is a bonding site with a neighboring atom.

6. In claim 5, in the chemical formula 78, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z comprises at least one selected from the group consisting of groups represented by the following chemical formulas: .

7. In claim 5, in the chemical formula 78, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z comprises at least one selected from the group consisting of groups represented by the following chemical formulas: In the above chemical formula 82-1, R 5 , R 8 , and R 9 is hydrogen.

8. In any one of claims 5 to 7, Above R 6 and R 7 are each independently hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C3 haloalkyl group, -CH 2 R 3 -OR 3 , -NR 3 R 4 , selected from the group consisting of a C3-C8 cycloalkyl group, a 3 to 8 membered 8-heterocycloalkyl group, a C6-C10 aryl group and a 5 to 10 membered heteroaryl group, Wherein o is 0 or 1, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

9. In claim 1, in the chemical formula 78, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z comprises at least one selected from the group consisting of groups represented by the following chemical formulae 83-1 to 83-11: In the above chemical formula, R 13 and R 14 are each independently hydrogen, halogen, a substituted or unsubstituted C1-C4 alkyl group, CF 3 , NHR 15 , OR 15 , and is selected from the group consisting of substituted or unsubstituted C3-C12 aryl groups, R 15 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C2 haloalkyl group, and a substituted or unsubstituted C3-C12 aryl group, * is a bonding site with a neighboring atom.

10. In claim 9, in the chemical formula 78, A compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z comprises at least one selected from the group consisting of groups represented by the following chemical formulas: .

11. A compound according to claim 1, wherein the compound comprises at least one compound selected from the group consisting of compounds 1 to 77 described in Tables 1 to 8 of the specification, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

12. In claim 1, the compound is a compound capable of binding to Cereblon (CRBN) protein, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. In claim 1, the compound is a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is for regulating the activity of a cereblon protein or a complex comprising the cereblon protein.

14. In claim 1, the compound is a compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, which modulates the activity or degradation of GSPT1 protein.

15. A pharmaceutical composition for preventing or treating a proliferative disease, comprising a compound of any one of claims 1 to 14, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

16. A pharmaceutical composition according to claim 15, wherein the proliferative disease is a GSPT1-related disease.

17. In claim 15, the proliferative disease is cancer, preferably adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen dependent and independent breast cancer, Burkitt's lymphoma, corpus cancer, carcinoma unknown primary tumor (CUP-syndrome), colorectal cancer, small intestine cancer, small intestinal tumors, Ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose, and throat tumors.nose and throat tumors, hematologic tumor, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose, and throat), colon carcinoma, craniopharyngiomas, oral cancer, cancer of the central nervous system, liver cancer, Liver metastases, leukemia, eyelid tumor, lung cancer, lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors of the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's / Non-Hodgkin's lymphomas,Mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, esophageal cancer, T-cell lymphoma, Thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, nephroblastoma, cervical carcinoma, tongue cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,Lobular carcinoma in situ, small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brain stem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumors, sarcoma of the uterus, salivary gland cancers, anal gland adenocarcinomas, mast cell tumors, pelvis tumor, ureter tumor, hereditary papillary Hereditary papillary renal cancers, sporadic papillary renal cancers, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer,oropharyngeal cancer, oral cavity cancer, squamous cell cancer, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, lymphoma of the central nervous system, malignant fibrous histiocytoma, lymph sarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma, and feline mammary carcinoma, and combinations thereof. Pharmaceutical composition., 18. A GSPT1 degrader comprising a compound of any one of claims 1 to 14, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Images