Halogen-substituted isoindoline compounds and their use

Abstract

The present invention relates to a halogen-substituted isoindoline compound represented by the following formula I and its use. The compound of the present invention has obviously excellent antitumor activity, and can also be made into an oral dosage form that is more convenient, safe and economical for administration. Therefore, its utility is greatly improved compared with that of conventional compounds. [Formula 1] JPEG2025514398000096.jpg59169

Description

Detailed description of the invention

[0001] This application claims priority to a prior application filed with the China National Intellectual Property Administration on April 29, 2022, with patent application number 2022104939244, titled "Halogen-substituted isoindoline compounds and their use." The entire text of said application is incorporated into this application by reference.

[0002] [Technical field] This invention belongs to the field of pharmaceutical technology and, more specifically, relates to halogen-substituted isoindoline compounds and their use.

[0003] [Background technology] Protein mutations, expression imbalances, allosteria, and functional abnormalities can cause many diseases. Protein synthesis or degradation are processes that are strictly controlled spatially and temporally during cell growth and proliferation. Abnormal control of these processes can lead to uncontrolled cell growth, proliferation, and migration, potentially resulting in the development of diseases such as cancer, aging, and viral infections.

[0004] The translation termination factor GSPT1 (eRF3a) is closely associated with diseases such as cancer, mediating the recognition of stop codons and facilitating the release of nascent peptides from ribosomes. In addition to its translation termination function, GSPT1 is involved in several other important cellular processes, including cell cycle regulation, cytoskeletal organization, and apoptosis. GSPT1 is a carcinogenic driver in several types of cancer, including hematoma, breast cancer, liver cancer, gastric cancer, and prostate cancer. Furthermore, GSPT1 is clearly upregulated in cancer tissues and cancer cell lines; its high expression is positively correlated with tumor size, and its overexpression may promote cancer cell proliferation and migration. For example, GSPT1 depletion effectively inhibits cancer cell proliferation and migration in vitro, induces apoptosis in invasive colon cancer cells, and inhibits the tumorigenicity of HCT116 colon cancer cells in vivo. Furthermore, recent studies have shown that downregulation of GSPT1 is also effective in treating cystic fibrosis, Lassa virus infection, and Ebola virus infection.

[0005] The Ikaros zinc finger (IKZF) transcription factor family regulates the development and differentiation of hematopoietic cells and many immune cells, including CD4+ T cells. The IKZF family consists of five members: Ikaros (encoded by the gene IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). Evidence that the Ikaros family is associated with cancer progression was first found in hematopoietic malignancies, and Ikaros dysfunction was associated with the development of chronic lymphocytic leukemia. More recently, Ikaros has been found to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia and is also involved in the differentiation and function of individual helper T cells. Aiolos plays a crucial role in the maturation of B cells and T cells, and in chronic lymphocytic leukemia, increased Aiolos expression can promote cell survival by regulating Bcl2 family proteins. Increased Aiolos expression has been detected in follicular central cell lymphoma. Aiolos works with Blimp-1 to regulate the survival of multiple myeloma cells. Furthermore, in solid tumors, overexpression of Aiolos may promote epithelial-mesenchymal transition and cancer stem cell-like characteristics in lung cancer cells.

[0006] Currently, there are no commercially available drugs based on protein modulation such as GSPT1, and there are no reports of halogen-substituted isoindoline compounds as small molecules of protein modulators such as GSPT1 using conventional technology. Currently, the most advanced such protein modulator in research and development is CC-90009 from Celegen, which is administered intravenously and is undergoing Phase I clinical trials. Oral administration is the most commonly used method of administration because it is simpler, safer, and more economical than injection. Furthermore, even small changes in the molecular structure of protein modulators can lead to significant changes in drug metabolic activity and biological activity. For example, if one atom in a molecular glue or PROTAC molecule changes, the compound may lose its degrading activity against specific proteins and its biological activity against tumors. Therefore, modulators with different chemical structures can improve the efficacy and safety of drugs.

[0007] [Summary of the Invention] [Means for Solving the Problems] In order to solve the above technical problems, the present invention provides a compound represented by the following formula I, a tautomer, a stereoisomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

[0008] [Chemical Formula]

[0009] (R1 is hydrogen, deuterium, C 1~12 alkyl,

[0010] [Chemical Formula]

[0011] selected from R2 is the same or different and independently of one another is hydrogen, C 1~12 alkyl, C 6~20 aryl, 5-20 member heteroaryl, C 3~20 cycloalkyl, 3-20 member heterocyclyl, selected from R' and R3 are the same or different and independently of one another are hydrogen, C 1~12 alkyl, C 1~12 alkoxy, C 6~20 aryl, 5-20 member heteroaryl, C 3~20 cycloalkyl, 3-20 member heterocyclyl, selected from R4 and R5 are the same or different and independently of one another are selected from hydrogen, deuterium, halogen, m is 1, 2 or 3, R6 is hydrogen, deuterium, halogen, C 1~12 alkyl, C 1~12Selected from alkoxy, Q1 is -CH2-, -CD2-, -C(O)-, or -C(S)-. R7, R8, R9, and R 10 They are either the same or different, and independently of each other, hydrogen, halogen, deuterium, CN, C 1~12 Alkyl, -CH2-NHBoc, -CH2-NH2, -CH2-NHCO-CF2-R 11 -CH2-NHCO-R 12 -CH2-NHCO-YR 13 -CH2-NH-YR 14 -CH2-NHCONH-R 12 Selected from -CH2-NHBoc, -CH2-NH2, -CH2-NHCO-CF2-R 11 -CH2-NHCO-R 12 -CH2-NHCONH-R 12 -CH2-NHCO-YR 13 -CH2-NH-YR 14 The hydrogen atoms on the methylene group are optionally substituted by one or two deuterium atoms. R 11 , R 12 , R 13 , and R 14 C is either identical or different, independently of each other, unsubstituted or arbitrarily substituted by one or more Rs. 6~20 Aryl, 5-20 member heteroaryl, C 3~20 Cycloalkyl, 3-20 membered heterocyclyl, C 2~12 Alkenil, C 2~12 Alkinyl, C 1~12 Alkyl, -P(C 6~20 aryl)2, -N(C 1~12 Alkyl)2,-COC 1~12 Alkyl, -C 1~12 Alkyl N(C) 1~12 Alkyl)2, C 6~20 Aryl C 3~20 Cycloalkyl, C 3~20 Cycloalkyl and C 3~20 Selected from spiro groups consisting of cycloalkyl groups, Y is C 1~12Alkilen, C 3~20 Cycloalkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, -CH2NH-, -CH2NHCO-, -CH2NHCO-, -CH2O-, -C2H4O-, -CH2S-,

[0012] [ka]

[0013] Selected from, Ra, Rb, Rc, and Rs are either identical or different, and independently of each other, they are halogen, amino, hydroxy, and C. 1~12 Alkyl, C 1~12 Alkoxy, Halo C 1~12 Alkyl, CN, C 3~20 Cycloalkyl, -N(C 1~12 Alkyl)2, deuterated group, C 2~12 Alkenil, C 2~12 Alkinyl, -COC 1~12 Alkyl, -COC 6~20 Ariel, C 1~12 Alkylthio, mercapto, =O, -C 1~12 Alkylhydroxy, 3-20 membered heterocyclyl, -SO2C 1~12 Alkyl, -SO2NH2, C 6~20 Ariel, -OC 6~20 Ariel, -C 1~12 Alkyl C 6~20 Ariel, -C 1~12 Alkylamino, -C 6~20 Aryl C 1~12 Alkylamino, -C 6~20 Arylamino, -OC 1~12 Alkyl C 6~20 Ariel, -C 6~20 Arylhydroxy, -C 6~20 Aryl C 1~12 Selected from alkylhydroxy compounds. According to embodiments of the present invention, R1 is hydrogen, C 1~6 Alkyl, -C 1~6 Alkyl COOC 1~6 Alkyl, -COOC1~6 alkyl, or -C 1~6 alkylOCOOC 1~6 selected from alkyl, R4, R5, and R6 are selected from hydrogen, m is 1, 2 or 3, Q1 is -CH2- or -C(O)-, R7, R8, R9, and R 10 are the same or different and independently of one another are hydrogen, a deuterated group, halogen, CN, C 1~6 alkyl, -CH2-NHBoc, -CH2-NH2, -CH2-NHCO-CF2-R 11 -CH2-NHCO-R 12 -CH2-NHCONH-R 12 -CH2-NHCO-Y-R 13 -CH2-NH-Y-R 14 selected from, and the hydrogen on the CH2 of said -CH2-NHBoc, -CH2-NH2, -CH2-NHCO-CF2-R 11 -CH2-NHCO-R 12 -CH2-NHCONH-R 12 -CH2-NHCO-Y-R 13 -CH2-NH-Y-R 14 is optionally substituted by one or two deuteriums, R 11 R 12 R 13 and R 14 are the same or different and independently of one another are unsubstituted or optionally substituted by one or more Rs, C 6~12 aryl, 5- to 12-membered heteroaryl, C 3~12 cycloalkyl, 3- to 12-membered heterocyclyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkyl, -P(C 6~20 aryl)2, -N(C 1~6 alkyl)2, -COC 1~6 alkyl, -C 1~6 alkylN(C 1~6 alkyl)2, C 6~12 arylC 3~12 cycloalkyl, C 3~12Cycloalkyl and C 3~12 Selected from spiro groups consisting of cycloalkyl groups, Y is C 1~6 Alkilen, C 3~12 Cycloalkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -CH2NH-, -CH2NHCO-, -CH2NHCO-, -CH2O-, -C2H4O-, -CH2S-,

[0014] [ka]

[0015] Selected from, Rs are either identical or different, and independently of each other, they are halogen, amino, hydroxy, and C. 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkyl, CN, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl)2, deuterated group, C 2~6 Alkenil, C 2~6 Alkinyl, -COC 1~6 Alkyl, -COC 6~12 Ariel, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, 3-12 membered heterocyclyl, -SO2C 1~6 Alkyl, -SO2NH2, C 6~12 Ariel, -OC 6~12 Ariel, -C 1~6 Alkyl C 6~12 Ariel, -C 1~6 Alkylamino, -C 6~12 Aryl C 1~6 Alkylamino, -C 6~12 Arylamino, -OC 1~6 Alkyl C 6~12 Ariel, -C 6~12 Arylhydroxy, -C 6~12 Aryl C 1~6 Selected from alkylhydroxy.

[0016] In one embodiment, formula I has the structure shown by formula I-1 below.

[0017] [ka]

[0018] (In the formula, R1, R4, R5, R6, R7, R8, R9, R 10 Q1 has the above definition. In one embodiment, formula I has the structure shown in formula I-2 below.

[0019] [ka]

[0020] (In the formula, R1, R4, R5, R6, R7, R8, R9, R 10 Q1 has the above definition. In one embodiment, formula I has the structure shown in formula I-3 below.

[0021] [ka]

[0022] (In the formula, R1, R4, R5, R6, R7, R8, R9, R 10 Q1 has the above definition. According to embodiments of the present invention, formula I is selected from the structures represented by the following formula Ia.

[0023] [ka]

[0024] (In equation Ia, R1 is hydrogen, C 1~6 Alkyl, -C 1~6 Alkyl COOC 1~6 Alkyl, -COOC 1~6 Alkyl, or -C 1~6 Alkyl OCOOC1~6 Selected from alkyl groups, R4, R5, and R6 are selected from hydrogen or deuterium. m is 1, 2, or 3. Q1 is -CH2-, -CD2-, or -C(O)-, R7' is selected from hydrogen, deuterium, or halogen, and p is 1, 2, or 3, provided that at least one R7' is selected from halogen. R8' is CN, -CH2-NHBoc, -CH2-NH2, -CH2-NHCO-CF2-R 11 -CH2-NHCO-R 12 -CH2-NHCONH-R 12 -CH2-NHCO-YR 13 -CH2-NH-YR 14 Selected from -CH2-NHBoc, -CH2-NH2, -CH2-NHCO-CF2-R 11 -CH2-NHCO-R 12 -CH2-NHCONH-R 12 -CH2-NHCO-YR 13 -CH2-NH-YR 14 The H atoms on CH2 are optionally substituted by one or two deuterium atoms. R 11 , R 12 , R 13 , and R 14 C is either identical or different, independently of each other, unsubstituted or arbitrarily substituted by one or more Rs. 6~12 Aryl, 5-12 member heteroaryl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl, -P(C6~ 20 aryl)2, -N(C 1~6 Alkyl)2,-COC 1~6 Alkyl, -C 1~6 Alkyl N(C) 1~6 Alkyl)2, C 6~12 Aryl C 3~12 Cycloalkyl, C 3~12 Cycloalkyl and C3~12 Selected from spiro groups consisting of cycloalkyl groups, Y is C 1~6 Alkilen, C 3~12 Cycloalkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -CH2NH-, -CH2NHCO-, -CH2NHCO-, -CH2O-, -C2H4O-, -CH2S-,

[0025] [ka]

[0026] They were selected, Rs are either identical or different, and independently of each other, they are halogen, amino, hydroxy, and C. 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkyl, CN, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl)2, deuterated group, C 2~6 Alkenil, C 2~6 Alkinyl, -COC 1~6 Alkyl, -COC 6~12 Ariel, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, 3-12 membered heterocyclyl, -SO2C 1~6 Alkyl, -SO2NH2, C 6~12 Ariel, -OC 6~12 Ariel, -C 1~6 Alkyl C 6~12 Ariel, -C 1~6 Alkylamino, -C 6~12 Aryl C 1~6 Alkylamino, -C 6~12 Arylamino, -OC 1~6 Alkyl C 6~12 Ariel, -C 6~12 Arylhydroxy, -C 6~12 Aryl C 1~6 Selected from alkylhydroxy compounds. According to embodiments of the present invention, R7, R8, R9 and R10 At least one of them is a halogen. Preferably, R7, R8, R9 and R 10 One of them is halogen, or two are halogen, or three are halogen.

[0027] In one embodiment of the present invention, R7, R8, R9 and R 10 One of them is F.

[0028] According to a preferred embodiment of the present invention, formula I is selected from the structures represented by the following formula Ib.

[0029] [ka]

[0030] (In formula Ib, R 15 , R 16 , R 17 , and R 18 C is either identical or different, and independently of each other, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, unsubstituted, or one or more Rx. 1~6 Alkyl, -SO2C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~12 Ariel, C 1~6 Alkoxy, -N(C 1~6 Alkyl)2, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Cycloalkyl, C 1~6 Alkylthio, -COC 1~6 Alkyl, -COC 6~12 Ariel, -OC 6~12 Ariel, -C 1~6 Selected from alkyl-hydroxy, 3-12 membered heterocyclyl, and -SO2NH2, Rx may be the same or different, and independently of each other, they may be halogens, aminos, hydroxyls, or C. 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkyl, CN, C3~12 Cycloalkyl, -N(C 1~6 Alkyl)2, deuterated group, C 2~6 Alkenil, C 2~6 Alkinyl, -COC 1~6 Alkyl, -COC 6~12 Ariel, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, -C 1~6 Alkylamino, 3-12 member heterocyclyl, -SO2C 1~6 Alkyl, -SO2NH2, C 6~12 Ariel, -OC 6~12 Ariel, -C 1~6 Alkyl C 6~12 (Selected from the arrow.) In one embodiment of the present invention, in formula Ib, R 15 , R 16 , R 17 , and R 18 These are either identical or different, independently of each other, hydrogen, deuterium, F, Cl, methyl, amino, hydroxy, methoxy, trifluoromethyl, cyano, phenyl, dimethylamino, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, ethynyl, cyclopropyl, carbonylmethyl, carbonylphenyl, phenoxy, tert-butoxy, alkylthio, -SO2NH2, hydroxymethyl, N-tetrahydropyrrolyl, -SO2CH2, p-aminophenyl,

[0031] [ka]

[0032] Selected from.

[0033] In one embodiment of the present invention, formula Ib is manufactured by the following method:

[0034] [ka]

[0035] (In the formula, R15 , R 16 , R 17 , and R 18 (It has the above definition.) Compound Im undergoes a condensation reaction with compound In to obtain the compound shown in formula Ib.

[0036] In a preferred embodiment, formula I is selected from the structures shown in formula Ic below.

[0037] [ka]

[0038] (In formula Ic, R 15 , R 16 , R 17 , R 18 , and R 19 C is either identical or different, and independently of each other, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, unsubstituted, or one or more Rx. 1~6 Alkyl, -SO2C 1~6 Alkyl, C 1~6 Haloalkyl, C 6~12 Ariel, C 1~6 Alkoxy, -N(C 1~6 Alkyl)2, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Cycloalkyl, C 1~6 Alkylthio, -COC 1~6 Alkyl, -COC 6~12 Ariel, -OC 6~12 Ariel, -C 1~6 Selected from alkyl-hydroxy, 3-12 membered heterocyclyl, and -SO2NH2, Rx may be the same or different, and independently of each other, they may be halogens, aminos, hydroxyls, or C. 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkyl, CN, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl)2, deuterated group, C 2~6 Alkenil, C2~6 Alkinyl, -COC 1~6 Alkyl, -COC 6~12 Ariel, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, -C 1~6 Alkylamino, 3-12 member heterocyclyl, -SO2C 1~6 Alkyl, -SO2NH2, C 6~12 Ariel, -OC 6~12 Ariel, -C 1~6 Alkyl C 6~12 Selected from the aryl, and R 19 (It's not H.) In one embodiment of the present invention, formula Ic is manufactured by the following method:

[0039] [ka]

[0040] (In the formula, R 15 , R 16 , R 17 , R 18 and R 19 (It has the above definition.) Compound Ip undergoes a condensation reaction with compound Iq to obtain the compound shown in formula Ic.

[0041] In a preferred embodiment, Formula I is selected from the structures shown in Formula Id below.

[0042] [ka]

[0043] (In Id, L is a chemical bond, C 2~12 Alkinyl, C 2~12 Alkenyl, NH, oxygen, sulfur, or C 1~12 Alkyl, and the C 1~12 Alkyl groups can be optionally substituted with hydroxyl or amino groups. R 20 C is either unsubstituted or optionally substituted by one or more Ry.6~12 The group is an aryl, a 3-12 membered cycloalkyl, a 5-12 membered heterocyclyl, or a 5-12 heteroaromatic ring group. Ry stands for deuterated group, halogen, hydroxy, amino, carboxy, CN, C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Alkyl, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl)2,-COC 1~6 Alkyl, -COC 6~12 Ariel, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, -C 1~6 Alkylamino, 3-12 member heterocyclyl, -SO2C 1~6 Alkyl, -SO2NH2, C 6~12 Ariel, -OC 6~12 Ariel, -OC 1~6 Alkyl C 6~12 Ariel, -C 1~6 Alkyl C 6~12 Ariel, -C 1~6 alkyl-COOH, -C 6~12 Aryl-C 1~6 Alkylamino, -C 6~12 Aryl-C 1~6 Alkylhydroxy, -C 6~12 Arylamino, -C 6~12 (Selected from arylhydroxy compounds.) In a preferred embodiment, in Id, L is a chemical bond, C 2~12 Alkinyl, C 2~12 Alkenyl, NH, or C 1~6 Alkyl, and the C 1~6 Alkyl groups can be optionally substituted with hydroxyl or amino groups. R 20 C is either unsubstituted or optionally substituted by one or more Ry. 6~12 It is an aryl or 5-12 heteroaromatic ring group, Ry stands for hydroxy, amino, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~12 Ariel, -OC1~3 Alkyl C 6~12 Ariel, -C 1~3 Alkyl C 6~12 Ariel, -C 1~6 Alkyl-NH2, -C 1~6 Alkylhydroxy, -C 1~6 alkyl-COOH, -C 6~12 Aryl-C 1~3 Alkylamino, -C 6~12 Aryl-C 1~3 Alkylhydroxy, -C 6~12 Arylamino or -C 6~12 Selected from arylhydroxy.

[0044] In a more preferred embodiment, in Id, L is a chemical bond, alkynyl, NH,

[0045] [ka]

[0046] And, R 20 It is phenyl, Ry is Cl, hydroxy, amino, tert-butyl, phenyl, p-aminophenyl, p-hydroxyphenyl, ethylamino, hydroxyethyl, p-hydroxyethylphenyl, p-ethylaminophenyl,

[0047] [ka]

[0048] Selected from.

[0049] In one embodiment of the present invention, formula Id is manufactured by the following method:

[0050] [ka]

[0051] (In the formula, R20 (L has the above definition.) Compound Ix undergoes a condensation reaction with compound Iy to obtain the compound shown in formula Id.

[0052] For example, the compound of formula I is selected from the following:

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] According to embodiments of the present invention, the pharmaceutically acceptable salt is selected from the following defined salts, for example, the salt includes, but is not limited to, hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate, or meglumine salts, and is preferably hydrochloride.

[0061] The present invention also provides the use of the compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts in the manufacture of drugs for treating or preventing diseases, disorders, or symptoms associated with mutations, expression imbalances, allosteria, and functional abnormalities of proteins such as GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC.

[0062] According to embodiments of the present invention, the diseases, symptoms, or conditions include myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin lymphoma, papillary thyroid carcinoma and follicular thyroid carcinoma, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, complicated regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary melanoma and chronic melanoma, iris melanoma, and recurrent This includes bilateral interocular melanoma, extraocular melanoma, solid tumors, T-cell lymphoma, erythrocyte lymphoma, monoblastic leukemia and monocytic leukemia, myeloid leukemia (e.g., acute myeloid leukemia), central nervous system lymphoma, brain tumors, meningiomas, spinal cord tumors, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, Burkitt lymphoma, Hodgkin lymphoma, large cell lymphoma, diffuse large B-cell lymphoma, astrocytoma, hepatocellular carcinoma or primary macroglobulinemia, and viral infections.

[0063] The present invention also provides pharmaceutical compositions comprising a compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

[0064] According to embodiments of the present invention, the pharmaceutical composition further comprises, in addition to the active ingredient, a compound represented by formula I, other therapeutic agents, the other therapeutic agents being PD-1 inhibitors (e.g., nivolumab, pembrolizumab, semiprimab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab), rituximab, trastuzumab, elotuzumab, utuximab, daratumumab, atrizumab, ibritumomab, alemtuzumab, brentuximab, cytarabine, azacitidine, anthracycline drugs, prednisone, dexamethasone, melphalan, cladribine, fludarabine, mitoxantrone, etoposide, methotrexate, pemetrexed, topotecan, doxorubicin, cyclophosphamide, gemcitabine, dacarbazine, cladribine This includes, but is not limited to, at least one of the following: rithromycin, vincristine, docetaxel, clofarabine injection, HDAC inhibitors (e.g., panobinostat, romidepsin, vorinostat, belinostat, tidamide), FLT3 inhibitors (e.g., midostaurin, gilteritinib, quizartinib), IDH1 / 2 inhibitors (e.g., ivosidenib, enasidenib), BCL-2 inhibitors (e.g., venetoclax), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), PI3K inhibitors, BTK inhibitors (e.g., zanubrutinib, acalabrutinib, ibrutinib, tirabrutinib, olerabrutinib), palbociclib, erythrocyte growth hormone, eltrombopag, minocycline, and CAR-T receptors.

[0065] According to a preferred embodiment of the present invention, the pharmaceutical composition further comprises azacitidine or dexamethasone in addition to the compound represented by formula I, which is the active ingredient.

[0066] According to embodiments of the present invention, the pharmaceutical composition is used to treat or prevent diseases, conditions, or symptoms related to mutations, expression imbalances, allosteria, and functional abnormalities of proteins such as GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC.

[0067] According to embodiments of the present invention, the diseases, symptoms, or conditions include myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin lymphoma, papillary thyroid carcinoma and follicular thyroid carcinoma, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, complicated regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary melanoma and chronic melanoma, iris melanoma, and recurrent This includes bilateral interocular melanoma, extraocular melanoma, solid tumors, T-cell lymphoma, erythrocyte lymphoma, monoblastic leukemia and monocytic leukemia, myeloid leukemia (e.g., acute myeloid leukemia), central nervous system lymphoma, brain tumors, meningiomas, spinal cord tumors, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, Burkitt lymphoma, Hodgkin lymphoma, large cell lymphoma, diffuse large B-cell lymphoma, astrocytoma, hepatocellular carcinoma or primary macroglobulinemia, and viral infections.

[0068] According to embodiments of the present invention, the compound or pharmaceutical composition represented by formula I may be administered orally, rectally, topically, orally, parenterally, intramuscularly, intradermally, intravenously, and transdermally. In one embodiment, the pharmaceutical composition is administered orally.

[0069] [Effects of the invention] The beneficial effects are as follows:

[0070] The compounds of the present invention have a regulatory effect on proteins such as GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC, and possess antitumor and anticancer activity, particularly strong inhibitory activity against acute myeloid leukemia and myeloma cells. The advantages of the activity of the compounds of the present invention are mainly reflected in the following points.

[0071] 1. Unexpectedly, the inventors found that the halogen-substituted compounds of the present invention exhibit significantly improved antitumor cell proliferation activity compared to their unsubstituted counterparts, and also significantly improved degradation effects on proteins such as GSPT1. For example, the halogen-substituted compound FDAB-48 of the present invention exhibits anti-MV-4-11 cell proliferation activity IC50. 50The concentration was 10.8 nM, and when co-incubated in NB-4 cells for 6 hours, 88% degradation of the GSPT1 protein was achieved, while a halogen-free compound...

[0072] [ka]

[0073] This is an anti-MV-4-11 cell proliferation activity IC 50 The concentration was 102.6 nM, and when co-incubated in NB-4 cells for 6 hours, the degradation effect of the GSPT1 protein was only 65%.

[0074] 2. The compound of the present invention has almost no hERG channel inhibitory activity (9-25% inhibition) at a concentration of 3 μM, whereas the compound CC-90009, which is currently in clinical research, has clear hERG channel inhibitory activity (66% inhibition).

[0075] 3. The compound CC-90009 used in conventional clinical studies is an injectable preparation. While the compound of the present invention exhibits significant tumor inhibitory activity in a mouse transplant tumor model, compound CC-90009 does not exhibit tumor inhibitory activity at the same oral dose. This indicates that, compared to compound CC-90009 (injectable preparation), the compound of the present invention can be made into an oral dosage form that is more convenient, safer, and more economical for administration.

[0076] As described above, the compounds of the present invention clearly possess excellent antitumor activity and can be formulated into more convenient, safe, and economical oral dosage forms. Therefore, their utility has been significantly improved compared to conventional compounds.

[0077] (Definitions and explanations of terms) Unless otherwise specified, the definitions of groups and terms in the specification and claims of this application include illustrative definitions, exemplary definitions, preferred definitions, table definitions, and definitions of specific compounds in examples, which may be combined or linked as appropriate. Such combinations and linked definitions of groups and structures of compounds should be considered to fall within the scope described in the specification of this application.

[0078] In this specification, the terms “include,” “incorporate,” and / or “contain” are open expressions, meaning they include the content specified in the present invention but do not exclude the content of other embodiments.

[0079] In this specification, when describing one / one type, two / two types, or multiple / multiple types, "multiple / multiple types" should refer to cases with more than two, for example, integers of three or more such as 3, 4, 5, 6, 7, 8, 9, or 10 / types.

[0080] In this specification, the term “optional” means that the described feature may or may not be present, meaning that the event described later may or may not occur, and therefore includes the two cases of the event occurring or not occurring. For example, “optionally substituted heterocyclil with alkyl” means that the alkyl may or may not be present, and therefore includes the case of heterocyclil with alkyl and the case of heterocyclil without alkyl substitution.

[0081] In this application, some substituents

[0082] [ka]

[0083] " and "*" are connecting points.

[0084] In this specification, the term "halogen" means fluorine, chlorine, bromine, and / or iodine. Accordingly, the term "halo" means fluoro, chloro, bromo, and / or iodine. Within the scope of this specification, when an atom, residue, group, or part is halogenated, the atom at the halogenation site may be monosubstituted, disubstituted, polysubstituted, or even completely substituted by the halogen atom.

[0085] "C 1~12 The term "alkyl" should be understood to preferably mean a linear or branched saturated monovalent hydrocarbyl having 1 to 12 carbon atoms, preferably C 1~6 It is alkyl. 1~6 "Alkyl" should preferably be understood to mean a linear or branched saturated monovalent hydrocarbyl having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2, or 3 carbon atoms ("C 1~3 It has an alkyl group, for example, methyl, ethyl, n-propyl, or isopropyl.

[0086] "C 2~12 The term "alkenyl" should be understood to mean a monovalent hydrocarbyl in a straight or branched chain having 2 to 12 carbon atoms and containing one or more double bonds, preferably "C 2~6 It is "Alkenil" "C 2~6"Alkenyl" preferably contains one or more double bonds and 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2~3 It should be understood that the term "alkenyl" refers to a monovalent hydrocarbyl in a straight or branched chain having an alkenyl, and that if the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated to each other. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-buto-2-enyl, (Z)-buto-2-enyl, (E)-buto-1-enyl, (Z)-buto-1-enyl, pento-4-enyl, (E)-pento-3-enyl, (Z)-pento-3-enyl, (E)-pento-2-enyl, (Z)-pento-2-enyl, (E)-pento-1- Enyl, (Z)-pento-1-enyl, hexa-5-enyl, (E)-hexa-4-enyl, (Z)-hexa-4-enyl, (E)-hexa-3-enyl, (Z)-hexa-3-enyl, (E)-hexa-2-enyl, (Z)-hexa-2-enyl, (E)-hexa-1-enyl, (Z)-hexa-1-enyl, isopropenyl, 2-methylpropa-2-enyl, 1-methylpropa-2-enyl Nyl, 2-methylpropa-1-enyl, (E)-1-methylpropa-1-enyl, (Z)-1-methylpropa-1-enyl, 3-methylbuto-3-enyl, 2-methylbuto-3-enyl, 1-methylbuto-3-enyl, 3-methylbuto-2-enyl, (E)-2-methylbuto-2-enyl, (Z)-2-methylbuto-2-enyl, (E)-1-methylbuto-2-enyl, (Z)-1-methyl These are buto-2-enyl, (E)-3-methylbuto-1-enyl, (Z)-3-methylbuto-1-enyl, (E)-2-methylbuto-1-enyl, (Z)-2-methylbuto-1-enyl, (E)-1-methylbuto-1-enyl, (Z)-1-methylbuto-1-enyl, 1,1-dimethylpropa-2-enyl, 1-ethylpropa-1-enyl, 1-propyl vinyl, and 1-isopropyl vinyl.

[0087] "C 2~12The term “alkynyl” should be understood to mean a monovalent hydrocarbyl in a straight or branched chain having 2 to 12 carbon atoms and containing one or more triple bonds, preferably “C2-C6 alkynyl”. The term “C2-C6 alkynyl” should preferably be understood to mean a monovalent hydrocarbyl in a straight or branched chain having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3 alkynyl”) and containing one or more triple bonds. The aforementioned alkynyls include, for example, ethinyl, propan-1-inyl, propan-2-inyl, buto-1-inyl, buto-2-inyl, buto-3-inyl, pento-1-inyl, pento-2-inyl, pento-3-inyl, pento-4-inyl, hexa-1-inyl, hexa-2-inyl, hexa-3-inyl, hexa-4-inyl, hexa-5-inyl, 1-methylpropan-2-inyl, 2-methylbuto-3-inyl, 1-methylbuto-3-inyl, 1-methylbuto-2-inyl, 3-methylbuto-1-inyl, 1-ethylpropan-2-inyl, 3-methylpento-4-inyl, 2-methylpento-inyl These are ethylpent-4-inyl, 1-methylpent-4-inyl, 2-methylpent-3-inyl, 1-methylpent-3-inyl, 4-methylpent-2-inyl, 1-methylpent-2-inyl, 4-methylpent-1-inyl, 3-methylpent-1-inyl, 2-ethylbuto-3-inyl, 1-ethylbuto-3-inyl, 1-ethylbuto-2-inyl, 1-propylpropane-2-inyl, 1-isopropylpropane-2-inyl, 2,2-dimethylbuto-3-inyl, 1,1-dimethylbuto-3-inyl, 1,1-dimethylbuto-2-inyl, or 3,3-dimethylbuto-1-inyl. In particular, the alkynyl is ethinyl, propane-1-inyl, or propane-2-inyl.

[0088] "C 3~20 The term "cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3~12 It is a cycloalkyl. 3~12The term "cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 3~12 The cycloalkyl group may be a monocyclic hydrocarbyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbyl such as a decalin ring.

[0089] The term "3-20 membered heterocyclil" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5 heteroatoms independently selected from N, O, and S, preferably a "3-12 membered heterocyclil." The term "3-12 membered heterocyclil" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3, heteroatoms selected from N, O, and S. The heterocyclil may be linked to the rest of the molecule via any of the carbon atoms or a nitrogen atom (if present). In particular, the heterocyclil may include, but is not limited to, a four-membered ring such as azetidinil or oxetanil; a five-membered ring such as tetrahydrofuranil, dioxolyl, pyrrolidinil, imidazolidinil, pyrazolidinil, or pyrrolinil; a six-membered ring such as tetrahydropyranil, piperidinil, morpholinil, dithianil, thiomorpholinil, piperazinil, or trithianil; or a seven-membered ring such as diazepanil. Optionally, the heterocyclil may be benzo-condensed. The heterocyclil may also be, but is not limited to, a five-, five-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a five-, six-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds, including but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydroxazolyl, or 4H-[1,4]thiadiinyl, or it may be benzo-condensed, including but not limited to dihydroisoquinolinyl. According to the present invention, the heterocyclyl is non-aromatic.

[0090] "C 6~20 The term "aryl" should be understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6~12 It is "Aryl". 6~12The term "aryl" preferably refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 6~12 It should be understood that this means "aryl," and in particular, a ring having 6 carbon atoms such as phenyl or biphenyl ("C6 aryl"), or a ring having 9 carbon atoms such as indanyl or indenyl ("C9 aryl"), or a ring having 10 carbon atoms such as tetrahydronaphthyl, dihydronaphthyl or naphthyl ("C 10 "aryl"), or a ring having 13 carbon atoms such as fluorenyl ("C") 13 "aryl"), or a ring having 14 carbon atoms such as anthracenyl ("C") 14 It should be understood as "Aryl".

[0091] The term “5-20 membered heteroaryl” should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5-20 ring atoms and containing 1-5 heteroatoms independently selected from N, O, and S, for example, “5-12 membered heteroaryl.” The term “5-12 membered heteroaryl” should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1-5, preferably 1-3 heteroatoms independently selected from N, O, and S, and further, in each case, which may be benzo-condensed. In particular, heteroaryls include thienyl, furanil, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl; or pyridinyl , pyridazinil, pyrimidinil, pyrazinil, triazinil and their benzo derivatives, for example, quinolinil, quinazolinil, isoquinolinil, etc.; or azosinil, indolidinil, purinil and their benzo derivatives; or selected from sinnolinil, phthalazinil, quinazolinil, quinoxalinil, naphthyridinyl, pteridinil, carbazolyl, acridinil, phenadinil, phenothiazinil, and phenoxadinil.

[0092] Unless otherwise specified, heterocyclyls, heteroaryls, or heteroarylenes include all possible isomeric forms of them, including their positional isomers. Therefore, as some descriptive non-limiting examples, pyridinyls or pyridylenes include pyridine-2-yl, pyridylene-2-yl, pyridine-3-yl, pyridylene-3-yl, pyridine-4-yl, and pyridylene-4-yl, and thienyls or thienylenes include thiophene-2-yl, thienylene-2-yl, thiophene-3-yl, and thienylene-3-yl.

[0093] "C 1~12 The above definition of the term "alkyl" is "C 1~12 "Alkoxy", "Halo C" 1~12 Alkyl, -C 1~12 Alkyl COOC 1~12 Alkyl, -COOC 1~12 "Alkyl" or "-C" 1~12 Alkyl OCOOC 1~12 Alkyl, -C 1~6 Alkyl C 6~12 "Aryl", "-C 6~12 Aryl-C 1~6 "Alkylamino", "-C 6~12 Aryl-C1~6 alkylhydroxy, -N(C 1~6 Alkyl)2", -C 1~6 "C" such as "alkylhydroxy" 1~12 This can also be applied to other terms containing "alkyl". In other words, in this application, "C 1~6 If it concerns a group containing an alkyl substituent, then the C in this group 1~6 The definition of alkyl is the same as defined above. Similarly, "C 6~12 "Aryl", "C 3~20 The terms "cycloalkyl," "5-20 membered heteroaryl," and "3-20 membered heterocyclyl" have the same definition throughout this specification.

[0094] "C 1~12 "Haloalkyl" and "Halo C 1~12 The term "alkyl" is synonymous with the above "C 1~12 "Alkyl" refers to a substituent substituted with a halogen.

[0095] "C 6~20 Aryl C 3~20 The term "cycloalkyl" refers to the above C 6~20 Aryl and C 3~20 A cycloalkyl group refers to a group that shares at least two carbon atoms.

[0096] "C 3~20 Cycloalkyl and C3~20 The term "spiro group consisting of a cycloalkyl group" is C 3~20 The definition of cycloalkyl is the same as above, with two C 3~20 This refers to a spiro group, which is composed of cycloalkyl groups sharing one carbon atom.

[0097] "C 1~12 The term "alkylthio" is -SC 1~12 It refers to alkyl, and here C 1~12 The definition of alkyl is the same as above.

[0098] The term "Boc" refers to tert-butoxycarbonyl.

[0099] In this specification, "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that has appropriate biological activity while being safe and effective when used in mammals.

[0100] Pharmaceutically acceptable salts include sufficiently basic acid addition salts of the compounds of the present invention having nitrogen atoms in the chain or ring. The basic nitrogen-containing group can be quaternized with reagents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides such as benzyl bromide and phenethyl bromide. Examples of physiologically / pharmaceutically acceptable salts include, but are not limited to, hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate, or meglumine salts.

[0101] Since the compounds of the present invention may have multiple salt-forming sites, the physiologically / pharmaceutically acceptable salts include not only salts formed at one salt-forming site of the compounds of the present invention, but also salts formed at two, three or all of the salt-forming sites among them. Therefore, in the physiologically / pharmaceutically acceptable salts, the molar ratio of the compound of formula (I) to the acid radical ion (anion) or base cation necessary for salt formation can vary within a wide range, for example, 3:1, 2:1, 1:1, 1:2, 1:3, etc., and may be 4:1 to 1:4.

[0102] [Mode for Carrying Out the Invention] The technical solution of the present invention will be further described in detail below with reference to specific examples. It should be understood that the following examples are only for illustratively describing and explaining the present invention, and do not limit the protection scope of the present invention. All technologies realized based on the above content of the present invention are included in the scope that the present invention intends to protect.

[0103] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR spectrum is obtained by a Bruker Avance-400 instrument, and the mass spectrum is obtained by an Agilent Technologies 6110, which is a liquid chromatography-mass spectrometry (LC-MS) instrument, using an ESI ion source.

[0104] Example 1: Synthesis of Compound FDAB-1

[0105] [Chemical Formula]

[0106] Synthesis of T1-1: Cuprous cyanide (5.28 g, 59.0 mmol) and tert-butyl nitrite (14 g, 136.1 mmol) were dissolved in 100 ml of dimethyl sulfoxide, and the temperature was raised and maintained at 60 °C while stirring for about 30 minutes to react. Then, a solution of 4-bromo-3-fluoro-2-methylaniline (10 g, 49.0 mmol) in dimethyl sulfoxide (20 ml) was slowly added dropwise over about 30 minutes. After continuing to stir and react at 60 °C for about 1 hour, the result detected by LCMS showed that the raw materials had disappeared. The reaction solution was cooled to room temperature, and a 6M hydrochloric acid solution was added dropwise to the reaction solution to quench the reaction. Then, ethyl acetate (2 × 100 ml) was added for extraction and liquid separation. The organic phases were combined and washed repeatedly with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Column chromatography (ethyl acetate / petroleum ether = 1 / 20 - 1 / 10) yielded 4.5 g of pale yellow oily liquid T1-1 (yield 43%).

[0107] Synthesis of T1-2: Intermediate T1-1 (4.5 g, 21.0 mmol) and an aqueous sodium hydroxide solution (5M, 50 ml) were mixed. The temperature of the mixed liquid system was raised to 100 °C and stirred for about 16 hours to react. The result detected by LCMS showed that T1-1 had completely reacted. The reaction solution was cooled to room temperature, and a 6M hydrochloric acid solution was added dropwise to the reaction solution under an ice bath to adjust the acidity to about 1. A large amount of solid generated from the reaction solution during the acidity adjustment process was filtered, and the filter cake was rinsed twice with distilled water. The filter cake was dried to obtain 2.4 g of pale yellow solid T1-2 (yield 50%).

[0108] Synthesis of T1-3: Intermediate T1-2 (4.5 g, 19.3 mmol) and potassium carbonate (5.3 g, 38.6 mmol) were dissolved in 50 ml of N,N-dimethylformamide, and methyl iodide (4.1 g, 29.0 mmol) was slowly added at room temperature. The mixture was stirred and reacted at room temperature for about 1 hour, and detection by LC-MS showed that the starting material T1-2 had disappeared. Ice water was added to the reaction mixture and quetzing was performed, and ethyl acetate (2 × 100 ml) was added for extraction and liquid-liquid separation. The organic phases were washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (ethyl acetate / petroleum ether = 1 / 50~1 / 20) yielded 4.3 g of pale yellow oily liquid T1-3 (yield 90%).

[0109] Synthesis of T1-4: Intermediate T1-3 (9.8 g, 39.7 mmol) and cuprous cyanide (5.34 g, 59.7 mmol) were dissolved in 60 ml of N-methylpyrrolidone. The mixture was heated to 180°C and stirred for approximately 2 hours to allow the reaction to proceed. LC-MS detection showed that the starting materials had disappeared. The mixture was cooled to room temperature, filtered, diluted with 100 ml of water, and extracted with ethyl acetate (2 × 100 ml). The organic phase was washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10) yielded 4.6 g of a nearly white solid T1-4 (yield 60%).

[0110] Synthesis of T1-5: Intermediate T1-4 (3.9 g, 20.0 mmol) and N-bromosuccinimide (5.4 g, 30.0 mmol) were dissolved in 50 ml of chloroform and heated to 65°C. Then, a catalytic amount of azobisisobutyronitrile (0.1 g) was added, and the reaction was continued with stirring at this temperature for about 4 hours. Detection by LC-MS showed that the starting materials had disappeared. After cooling to room temperature, the mixture was filtered by suction, and the filtered cake was washed with 30 ml of dichloromethane. The filtrate was diluted with 30 ml of water, and dichloromethane (2 × 30 ml) was added for extraction and liquid-liquid separation. The organic phase was washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10) yielded 3.3 g of pale yellow liquid T1-5 (yield 60%).

[0111] Intermediate T1-5 (5.4 g, 20.0 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (3.3 g, 20.0 mmol) were dissolved in 60 ml of N,N-dimethylformamide, and diisopropylethylamine (7.7 g, 60.0 mmol) was added at room temperature. The mixture was heated to 75°C and stirred for approximately 4 hours to allow the reaction to proceed. LC-MS detection showed that T1-5 had reacted completely. The reaction solution was diluted with 100 ml of water, and a methanol / dichloromethane = 1:10 mixture (3 × 100 ml) was added for extraction and liquid-liquid separation. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) yielded 3.5 g of a nearly white solid FDAB-1 (yield 60%).

[0112] Example 2: Synthesis of compound FDAB-2 FDAB-1 (5.7 g, 20.0 mmol) and di-tert-butyl dicarbonate (6.5 g, 30.0 mmol) were dissolved in 60 ml of a tetrahydrofuran / N,N-dimethylformamide = 10:1 mixed solvent, and rannie nickel (0.6 g) was added at room temperature. The mixture was purged three times with hydrogen gas, a constant hydrogen pressure system was maintained, and the temperature was raised to 40°C. The mixture was stirred and reacted at this temperature for approximately 4 hours. LC-MS detection showed that FDAB-1 had reacted completely. After cooling the reaction mixture, it was filtered by suction, and the filter cake was washed three times with 50 ml of dichloromethane / methanol (10 / 1). The filtrates were combined and concentrated under reduced pressure. Then, 100 ml of water was added to the concentrate, and it was extracted with ethyl acetate (3 × 100 ml) and separated. The organic phases were combined and washed repeatedly with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 50) yielded 6.3 g of FDAB-2 white solid (81% yield).

[0113] Example 3: Synthesis of compound FDAB-3 Intermediate FDAB-2 (3.9 g, 10 mmol) was dissolved in 30 ml of dichloromethane, and a 1,4-dioxane solution in hydrochloric acid (1 M, 5 ml) was added at room temperature. The mixture was heated to 40°C and the reaction was carried out. After reacting for about 1 hour, detection by LC-MS showed that the starting material FDAB-2 had disappeared. The mixture was concentrated under reduced pressure to remove excess hydrochloric acid solution and solvent. The concentrated dichloromethane was adjusted to an acidity of approximately 7 with aqueous ammonia, concentrated again, and obtained approximately 2.8 g of the nearly white solid product FDAB-3 (yield approximately 86%) by column chromatography (methanol:dichloromethane = 1 / 100 to 1 / 10).

[0114] Example 4: Synthesis of compounds FDAB-4, FDAB-5, and FDAB-6

[0115] [ka]

[0116] The synthesis of FDAB-4, FDAB-5, and FDAB-6 refers to the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in Examples 1 to 3 above, based on the raw material 4-bromo-5-fluoro-2-methylaniline. The characteristic evaluation data of the obtained compounds FDAB-4, FDAB-5, and FDAB-6 are shown in Table 1 below.

[0117] Example 5: Synthesis of FDAB-7, FDAB-8, and FDAB-9

[0118]

Chemical formula

[0119] The synthesis of compounds FDAB-7, FDAB-8, and FDAB-9 refers to the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in Examples 1 to 3 above, based on the raw material 4-bromo-2-fluoro-6-methylaniline. The characteristic evaluation data of the obtained compounds FDAB-7, FDAB-8, and FDAB-9 are shown in Table 1 below.

[0120] Example 6: Synthesis of FDAB-10, FDAB-11, and FDAB-12

[0121]

Chemical formula

[0122] The synthesis of compounds FDAB-10, FDAB-11, and FDAB-12 refers to the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in Examples 1 to 3 above, based on the raw material 4-bromo-3-chloro-2-methylaniline. The characteristic evaluation data of the obtained compounds FDAB-10, FDAB-11, and FDAB-12 are shown in Table 1 below.

[0123] Example 7: Synthesis of Compounds FDAB-13, FDAB-14, and FDAB-15

[0124]

Chemical formula

[0125] The synthesis of compounds FDAB-13, FDAB-14, and FDAB-15 was carried out using the starting material 4-bromo-5-chloro-2-methylaniline, following the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in Examples 1 to 3 above. The characterization data for the obtained compounds FDAB-13, FDAB-14, and FDAB-15 are shown in Table 1 below.

[0126] Example 8: Compounds FDAB-16 and FDAB-17

[0127] [ka]

[0128] The synthesis of compounds FDAB-16 and FDAB-17 was carried out using the starting material 3-bromo-5-fluoro-2-methylaniline, following the synthesis methods of FDAB-2 and FDAB-3 in Examples 2 and 3 above. The characterization data for the obtained compounds FDAB-16 and FDAB-17 are shown in Table 1 below.

[0129] Example 9: Synthesis of compound FDAB-48

[0130] [ka]

[0131] FDAB-3 (226 mg, 0.69 mmol) and p-chlorobenzoic acid (107 mg, 0.69 mmol) were dissolved in 10 ml of N,N-dimethylformamide. Triethylamine (139 mg, 1.37 mmol) was added while stirring, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (310 mg, 0.83 mmol) was slowly added in batch mode. After reacting for approximately 2 hours, detection by LC-MS showed that the starting material FDAB-3 had disappeared. 50 ml of water was added to the reaction mixture and quenched. Ethyl acetate was added for extraction, and the mixture was separated. Extraction was repeated three times until complete extraction was achieved. The organic phase was washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow crude concentrate. Approximately 210 mg of the white solid product FDAB-48 (yield 71%) was obtained by column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30).

[0132] Example 10: Synthesis of compound FDAB-121

[0133] [ka]

[0134] FDAB-3 (226 mg, 0.69 mmol) and 2-fluoro-4-methylbenzoic acid (106 mg, 0.69 mmol) were dissolved in 10 ml of N,N-dimethylformamide. Triethylamine (139 mg, 1.38 mmol) was added while stirring, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (310 mg, 0.83 mmol) was slowly added in batch mode. After reacting for approximately 2 hours, detection by LC-MS showed that the starting material FDAB-3 had disappeared. 50 ml of water was added to the reaction mixture and quenched. Ethyl acetate was added for extraction, and the mixture was separated. Extraction was repeated three times until complete extraction was achieved. The organic phase was washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow crude concentrate. Approximately 191 mg of the white solid product FDAB-121 (yield 65%) was obtained by column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30).

[0135] FDAB-120 was manufactured by replacing the above raw material 2-fluoro-4-methylbenzoic acid with 3-fluoro-4-methylbenzoic acid.

[0136] In this invention, some compounds containing the amide group mentioned above, such as FDAB-48 and FDAB-121, are manufactured by referring to the synthesis processes of FDAB-48 and FDAB-121 described above, and are not described in detail here for the sake of simplicity. The characterization data for these compounds are shown in Table 1 below.

[0137] Example 11: Synthesis of compound FDAB-128

[0138] [ka]

[0139] Chloromethylisopropyl carbonate (34 mg, 0.22 mmol) was slowly added dropwise at 0°C to a solution of FDAB-48 (86 mg, 0.2 mmol) and potassium carbonate (41 mg, 0.3 mmol) in N,N-dimethylformamide (10 ml). The mixture was slowly heated to room temperature and stirred for approximately 3 hours to allow the reaction to continue. LC-MS detection showed that the starting material FDAB-48 had disappeared. 20 ml of water was added to the reaction mixture for queching, and ethyl acetate was added. Extraction and liquid-liquid separation were performed, and the extraction process was repeated three times until complete extraction was achieved. The organic phases were washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated to obtain a pale yellow crude concentrate. Column chromatography (methanol / dichloromethane = 1 / 100~1 / 50) yielded approximately 49 mg of the white solid product FDAB-128 (yield 45%).

[0140] Example 12: Synthesis of compound FDAB-130

[0141] [ka]

[0142] Chloromethylisopropyl carbonate (34 mg, 0.22 mmol) was slowly added dropwise at 0°C to a solution of FDAB-121 (85 mg, 0.2 mmol) and potassium carbonate (41 mg, 0.3 mmol) in N,N-dimethylformamide (10 ml). The mixture was slowly heated to room temperature and stirred for approximately 3 hours to allow the reaction to continue. LC-MS detection showed that the starting material FDAB-121 had disappeared. 20 ml of water was added to the reaction mixture for queching, ethyl acetate was added, and the mixture was extracted and separated. This extraction process was repeated three times until complete extraction was achieved. The organic phases were washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated to obtain a pale yellow crude concentrate. Column chromatography (methanol / dichloromethane = 1 / 100~1 / 50) yielded approximately 38 mg of the white solid product FDAB-130 (yield 35%).

[0143] In this invention, some compounds such as FDAB-128 and FDAB-130, in which the N on the glutarimide ring mentioned above is substituted, are manufactured by referring to the synthesis processes of FDAB-128 and FDAB-130 described above, and are not described in detail here for the sake of simplicity. The characterization data for these compounds are shown in Table 1 below.

[0144] Example 13: Synthesis of compound FDAB-166

[0145] [ka]

[0146] FDAB-3 (20 mg, 0.06 mmol) and 4-phenoxybenzaldehyde (14 mg, 0.07 mmol) were dissolved in 5 ml of tetrahydrofuran, and sodium bicarbonate (10 mg, 0.12 mmol) was added while stirring. The mixture was heated to 50°C and reacted for approximately 1 hour. Then, sodium borohydride cyanohydride (5.8 mg, 0.09 mmol) was added to the reaction mixture, and the reaction was continued at 50°C with stirring for approximately 1 hour. 20 ml of water was added to the reaction mixture and quenched, and ethyl acetate (10 ml) was added for extraction and liquid-liquid separation. This extraction was repeated three times until complete extraction was achieved. The organic phase was washed repeatedly with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a brown crude concentrate. Column chromatography (methanol / dichloromethane = 1 / 100~1 / 30) yielded 15 mg of white solid FDAB-166 product (yield 52%).

[0147] Referring to the synthesis method for FDAB-166, FDAB-3 was reacted with the corresponding aldehyde to obtain compounds FDAB-165, FDAB-167, and FDAB-168. For simplicity, these are not described in detail here. The characterization data for these compounds are shown in Table 1 below.

[0148] The characterization data for some of the compounds mentioned above is shown in Table 1 below.

[0149] Table 1-1

[0150] Table 1-2

[0151] Table 1-3

[0152] Table 1-4

[0153] Table 1-5

[0154] Table 1-6

[0155] Table 1-7

[0156] Table 1-8

[0157] Table 1-9

[0158] Table 1-10

[0159] Table 1-11

[0160] Table 1-12

[0161] Table 1-13

[0162] Table 1-14

[0163] Table 1-15

[0164] Table 1-16

[0165] Table 1-17

[0166] Table 1-18

[0167] Table 1-19

[0168] Table 1-20

[0169] Table 1-21

[0170] [Table 1-22]

[0171] [Table 1-23]

[0172] [Table 1-24]

[0173] [Table 1-25]

[0174] Example 14: Anti-MV-4-11 cell proliferation activity of the compound Logarithmically growing MV411 cells were diluted in culture medium (RPMI + 10% FBS) and plated in 96-well plates (WHB) with black walls and black bottoms at a rate of 5000 cells / well and 50 μl / well. After plating, the plates were incubated in a 5% CO2, 37°C incubator for 24 hours, after which the drugs were added. The compounds were prepared in a 10 mM mother liquor with DMSO, diluted in culture medium to the required concentration (final DMSO concentration 0.2%), and then 50 μl was added to the 96-well plates containing cells so that the final concentrations of the compounds were 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0 nM. A concentration gradient of 10 was established for each compound, and two double wells were set up for each concentration. After adding the drugs, the plates were incubated in a 5% CO2, 37°C incubator for 72 hours. After incubation, the wells were equilibrated at room temperature for 30 minutes, and 100 μl of CellTiter-Glo® Reagent (Promega G7573) was added to each well. The wells were then shaken in a microplate shaker for 12 minutes. Luminescence values ​​were measured at room temperature using a GloMax navigator (Promega GM2010). The control group (0 nM) was defined as 0% inhibition, and IC50 was measured using GraphPad Prism 7 software. 50 The value was calculated.

[0175] Table 2 shows the anti-MV-4-11 cell proliferation activity of the compounds, where A is IC. 50 <1nM, B is 1≦IC 50 <10nM, C is 10nM≦IC 50 <100nM, D is 100nM≦IC 50 <1000nM, E is IC 50 This represents a value of ≥1000 nM.

[0176] [Table 2-1]

[0177] [Table 2-2]

[0178] [Table 2-3]

[0179] Example 15: Antiproliferative activity of compounds against various tumor cells Logarithmically growing U937, NCI-H929, AML-2, and MOLM-13 cells were diluted with the following media respectively: (RPMI + 10% FBS), (RPMI + 10% FBS), (MEMα + 20% FBS), and (RPMI + 20% FBS). These were then plated in 96-well plates (WHB) with black walls and black bottoms at a rate of 4000 cells / well and 50 μl / well. After plating, the plates were cultured in an incubator at 5% CO2 and 37°C, and drugs were added after 24 hours. The compounds were prepared in a 10 mM mother liquor with DMSO, diluted with culture medium to the required concentration (final DMSO concentration 0.2%), and then 50 μl of each compound was added to a 96-well plate containing cells so that the final concentrations of the compounds were 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0 nM. A concentration gradient of 10 was established for each compound, and two double wells were set up for each concentration. After adding the drug, the plates were incubated in a 5% CO2, 37°C incubator for 72 hours. After incubation, the plates were equilibrated at room temperature for 30 minutes, and 100 μl of CellTiter-Glo® Reagent (Promega G7573) was added to each well. The plates were shaken in a microplate shaker for 12 minutes. Luminescence values ​​were measured at room temperature using a GloMax navigator (Promega GM2010). Using GraphPad Prism 7 software, IC was analyzed with a 0nM control group as 0% inhibition. 50 The value was calculated.

[0180] Table 3 shows the antitumor cell proliferation activity of the compounds, where A is IC. 50 <1nM, B is 1≦IC 50 <10nM, C is 10nM≦IC 50 <100nM, D is 100nM≦IC 50 <1000nM, E is IC 50 This represents a value of ≥1000 nM.

[0181] [Table 3]

[0182] Example 16: Effect of compound on apoptosis of AML cells Logarithmically growing MV-4-11 cells were diluted in growth medium and plated into 6-well plates at 600,000 cells / well and 2 mL / well. The cells were then treated with drugs. The cells were collected, washed twice with pre-cooled PBS, resuspended in 100 μl of 1X annexin-binding buffer, 5 μl of FITC and 1 μl of 100 μg / mL PI were added, and the cells were incubated at room temperature in the dark for 15 minutes. After incubation, 400 μl of 1X annexin-binding buffer was added on ice and gently mixed. Flow cytometry detection was then performed.

[0183] As a result, when compounds FDAB-46 and FDAB-65 were added to cells and treated for 7 hours, none of the concentrations of the compounds (10 μM, 1 μM, and 100 nM) induced apoptosis in MV-4-11 cells. On the other hand, when compounds FDAB-46 and FDAB-65 were added and treated for 16 hours, none of the concentrations of the compounds (1 μM and 100 nM) induced apoptosis in the cells.

[0184] Example 17: Modulochemical effect of compounds on GSPT1 protein NB-4 cells were grown in RPMI 1640 medium (containing 10% FBS), centrifuged and counted, and the cell concentration was adjusted to 10⁶ cells / well. These cells were plated in 12-well plates at 1350 μl / well. 150 μl of DMSO and a 1 μM compound were added, and the cells were incubated in a 5% CO₂, 37°C incubator for 6 hours. The cells were centrifuged, the medium discarded, and the cells were washed with PBS and discarded. Whole cell lysates were prepared using a RIPA lysis solution containing a protease inhibitor mixture and a phosphatase inhibitor, and left on ice for 30 minutes. Centrifuged, the cell debris precipitate was discarded, and the supernatant, whole cell lysate, was collected and transferred to a new EP tube. After measuring BCA protein levels, samples were prepared using loading buffer. The samples were then treated in a metal bath at 100°C for 10 minutes.

[0185] The samples were separated by electrophoresis on 4-20% precast gels (SDS-PAGE gels), then transferred to a PVDF membrane, blocked with 5% NFDM / TBST at room temperature for 1 hour, incubated overnight with primary antibody at 4°C, and incubated again the following day with secondary antibody at room temperature for 2 hours. The signal was detected using the MINICHEMITM imaging system.

[0186] The antibodies used in this example are as follows:

[0187] Anti-eRF3 / GSPT1: Cell Signaling Technology #14980s Anti-GAPDH: Huabio ET601-4 Goatanti-Rabbit IgG-HRP antibody :Huabio HA1001 Table 4 shows the degradation effects of the GSPT1 protein, where A means that the degradation percentage of the GSPT1 protein is 80% or more, B means that the degradation percentage is between 50% and 80%, C means that the degradation percentage is between 25% and 50% and 50%, and D means that the degradation percentage is less than 25%.

[0188] [Table 4-1]

[0189] [Table 4-2]

[0190] [Table 4-3]

[0191] Furthermore, tests revealed that compound FDAB-48 has anti-MV-4-11 cell proliferation activity IC 50 The concentration was 10.8 nM, and when incubated in NB-4 cells for 6 hours, 88% degradation of the GSPT1 protein was achieved, while the corresponding compound without halogen substitution...

[0192] [ka]

[0193] This is an anti-MV-4-11 cell proliferation activity IC 50 The concentration was 102.6 nM, and when incubated in NB-4 cells for 6 hours, the degradation effect of the GSPT1 protein was only 65%.

[0194] Example 18: Modulochemical effects of compounds on IKZF1, IKZF3, CK1α, and c-MYC proteins HL-60 cells were grown in IMDM (containing 20% ​​FBS) medium, centrifuged and counted, and the cell concentration was adjusted to 1.26 cells / well. 1350 μl / well was plated into a 12-well plate. 150 μl of DMSO and the compound were added, and the cells were incubated in a 5% CO2, 37°C incubator for 4 hours. The cells were centrifuged, the medium was discarded, and the medium was washed with PBS and discarded. Whole cell lysates were prepared with a protease inhibitor mixture and RIPA lysis solution containing a phosphatase inhibitor, and left on ice for 30 minutes. The cells were centrifuged, the cell debris precipitate was discarded, and the supernatant whole cell lysate was collected and transferred to a new EP tube. After measuring BCA protein, the sample was prepared using loading buffer. It was treated in a metal bath at 100°C for 10 minutes. The samples were separated by electrophoresis on 4-20% precast gels (SDS-PAGE gels), then transferred to a PVDF membrane, blocked with 5% NFDM / TBST at room temperature for 1 hour, incubated overnight with primary antibody at 4°C, and incubated again the following day with secondary antibody at room temperature for 2 hours. The signal was detected using the MINICHEMITM imaging system.

[0195] The antibodies used in this example are as follows:

[0196] Anti-eRF3 / GSPT1: Cell Signaling Technology# 14980s Anti-c-Myc : Cell Signaling Technology #9402s Anti-Casein Kinase 1 alpha :Abcam ab206652 Anti-ikaros(IKZF1): Abcam ab191394 Anti-IKZF3: Abcam 139408 Anti-beta Tubulin :Huabio SR25-04 Goatanti-Rabbit IgG-HRP :Huabio HA1001 Table 5 shows the degradation capacity of each compound against IKZF1, IKZF3, CK1α, and c-Myc proteins in HL-60 cells. Here, A means that the degradation percentage of GSPT1 protein is 80% or more, B means that the degradation percentage is between 50% and 80%, C means that the degradation percentage is between 25% and 50% and 50%, and D means that the degradation percentage is less than 25%.

[0197] [Table 5]

[0198] Example 19: Anti-cell proliferation effect of the compound when used in combination with other drugs MOLM-13 cells in the logarithmic growth phase were diluted with culture medium (RPMI + 20% FBS), and NCI-H929 cells were diluted with culture medium (RPMI + 10% FBS). These were then plated in 96-well plates (WHB) with black walls and black bottoms at a rate of 4000 cells / well and 50 μl / well. After plating, the plates were cultured in an incubator at 5% CO2 and 37°C, and drugs were added after 24 hours. The compounds were prepared in a 10 mM mother liquor with DMSO, diluted in culture medium to the required concentration (final DMSO concentration 0.2%), and then 50 μl was added to a 96 plate containing cells so that the final concentrations of the compounds were 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0 nM, and 10. A concentration gradient of 10 was established for each compound, and two double wells were set up for each concentration. After adding the drug, the cells were incubated in a 5% CO2, 37°C incubator for 72 hours. When drugs were used concomitantly, the concentrations of azacitidine and dexamethasone were maintained at 200 nM and 500 nM, respectively, and the compounds were diluted in a 3x concentration gradient starting from 10000 nM. After incubation, the wells were equilibrated at room temperature for 30 minutes, and 100 μl of CellTiter-Glo® Reagent (Promega G7573) was added to each well. The wells were then shaken in a microplate shaker for 12 minutes. Luminescence values ​​were measured at room temperature using a GloMax navigator (Promega GM2010). The control group (0 nM) was defined as 0% inhibition, and IC50 was measured using GraphPad Prism 7 software. 50 The value was calculated.

[0199] [Table 6]

[0200] [Table 7]

[0201] The test results are shown in Table 6. From Table 6, the anti-MOLM-13 cell proliferation activity IC of azacitidine is shown. 50The concentration was 751.1 nM, and it was found that azacitidine at a concentration of 200 nM did not have any clear anti-MOLM-13 cell proliferation activity. However, when FDAB-121 was used in combination with 200 nM azacitidine, the anti-MOLM-13 cell proliferation activity IC of FDAB-121 was found to be low. 50 The concentration increased from 247.9 nM to 9.675 nM, and the activity improved by approximately 25 times. Whether the compound was used alone or in combination with azacitidine, FDAB-121 showed approximately 5 times higher activity compared to CC-90009.

[0202] As shown in Table 7, the anti-NCI-H929 cell proliferation activity of dexamethasone is IC2. 50 The concentration of dexamethasone exceeds 10,000 nM, and 500 nM dexamethasone does not exhibit clear anti-NCI-H929 cell proliferation activity. However, when FDAB-48 is used in combination with 500 nM dexamethasone, the anti-NCI-H929 cell proliferation activity of FDAB-48 is increased. 50 The concentration increased from 14.26 nM to 2.447 nM, representing an approximately six-fold improvement in activity. Furthermore, both when using the FDAB-48 compound alone and in combination with dexamethasone, its anti-NCI-H929 cell proliferation activity was significantly higher than that of CC-90009 and the clinically first-line myeloma drugs lenalidomide and pomalidomide.

[0203] Example 20: Measurement of hERG inhibition Rapidly activated potassium channels encoded by human ether-a-go-go-related genes (hERGs) are crucial ion channels involved in the formation of phase 3 repolarization of myocardial action potentials. Drugs that block hERG channels can delay cardiac repolarization, resulting in a prolonged QT interval on an electrocardiogram, a condition known as long QT syndrome. Drug-induced delays in ventricular repolarization can, in some cases, lead to torsades de pointes, a potentially fatal arrhythmia.

[0204] This measurement is used to assess the effect of compounds on clonal hERG potassium channels expressed in human fetal kidney cells (HEK293). The measurement procedure is as follows: Cells were placed in HEPES-buffered saline in a glass-lined 96-well plate, and appropriate amounts of test solution and control solution of each concentration were loaded with a 3-minute exposure duration. The test compound was diluted with 0.3% DMSO. The inhibition rate of the compound against hERG at a concentration of 3 μM was tested using an automated parallel patch clamp system QPatch 48 X (Sophion).

[0205] Results: At 3 μM, the inhibition rates of compounds FDAB-48, FDAB-65, FDAB-120, and FDAB-121 against hERG were 25%, 11%, 13%, and 9%, respectively. This indicates that compounds FDAB-65, FDAB-120, and FDAB-121 have almost no hERG inhibitory activity (<20% inhibition) at 3 μM, while compound FDAB-48 has only slight hERG inhibitory activity (25% inhibition). On the other hand, compound CC-90009 significantly inhibited hERG by 66% at 3 μM. From this, it was found that the compounds of the present invention unexpectedly reduced the inhibitory activity against hERG channels.

[0206] Example 21: Efficacy study in a xenograft mouse model of acute myeloid leukemia In in vivo efficacy studies, immunodeficient 6-8 week old female NSG mice were used. The mice were housed in the experimental environment for 7 days after arrival before the start of the experiment. The animals were housed in IVC (Independent Ventilation System) cages in an SPF-grade animal room, with 6 mice per cage. Human MV-4-11 acute myeloid leukemia cells expressing luciferase, MV-4-11-luc, were inoculated into the tail vein (5 × 10⁻¹⁴). 6Cells / animals). Seven days after cell inoculation, mice were imaged using an IVIS Lumina III small animal imager and administered in groups. Mice with tumors were randomly divided into either a vehicle control group or a compound treatment group (6 mice per group). Animals in each treatment group were orally administered the compound (10 mg / kg twice daily). Body weight was measured daily, and mean luminescence was measured after the start of treatment with the compound or vehicle.

[0207] Experimental metrics: Experimental metrics examine whether tumor growth can be inhibited, delayed, or cured. Tumor size was measured twice a week using an IVIS Lumina III small animal imager. Tumor signaling was determined as the number of exposure photons per second. The tumor inhibitory effect of the compound was evaluated by the tumor growth rate T / C (%). T / C% = T RTV / C RTV *100%(T RTV : RTV and C in the treatment group RTV : Negative control group RTV, RTV=V t / V0. Here, V0 is the tumor signal measured when the drug was administered separately in cages (i.e., on day 0), V t (where is the tumor signal at each measurement). According to the National Center for Drug Evaluation's guiding principles, T / C (%) > 40% is considered ineffective, and T / C ≤ 40% and statistically determined P < 0.05 is considered effective.

[0208] Results: Table 8 shows the tumor growth rate T / C (%) for each compound at different time points. Of these, compound CC-90009 did not show any tumor inhibitory effect within 14 days when administered orally at 10 mg / kg twice daily. On the other hand, when compounds FDAB-48, FDAB-65, FDAB-120, and FDAB-121 of the present invention were administered orally at 10 mg / kg twice daily, the T / C (%) on day 14 were 0.05%, 0.78%, 2.12%, and 0.005%, respectively. It was found that all dose groups of the compounds of the present invention showed clear antitumor effects. Unexpectedly, the compounds of the present invention were detected to exhibit a clear tumor inhibitory effect on the third day after oral administration. When FDAB-48, FDAB-65, FDAB-120, and FDAB-121 were administered orally at a dose of 10 mg / kg twice daily, the T / C (%) on the third day was 0.95%, 4.58%, 6.69%, and 0.32%, respectively.

[0209] [Table 8]

[0210] Embodiments of the present invention have been described above. However, the present invention is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be considered to be within the scope of protection of the present invention.

Claims

1. A structure selected from those represented by the following formula Ib, Alternatively, a structure can be selected from those shown by the following formula Ic, Alternatively, a compound, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt selected from the structures represented by the following formula Id. 【Chemistry 1】 (In formula Ib, R １５ , R １６ , R １７ , and R １８ are the same or different and, independently of one another, are hydrogen, deuterium, halogen, amino, hydroxy, cyano, C １～６ alkyl which is unsubstituted or optionally substituted by one or more Rxs, -SO ２ C １～６ alkyl, C １～６ haloalkyl, C ６～１２ aryl, C １～６ alkoxy, -N(C １～６ alkyl) ２ , C ２～６ alkenyl, C ２～６ alkynyl, C ３～１２ cycloalkyl, C １～６ alkylthio, -COC １～６ alkyl, -COC ６～１２ aryl, -OC ６～１２ aryl, -C １～６ alkyl-hydroxy, 3- to 12-membered heterocyclyl, -SO ２ NH ２ selected from, Rx may be the same or different, and independently of each other, they may be halogens, aminos, hydroxyls, or C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, CN, C ３～１２ Cycloalkyl, -N(C) １～６ Alkyl) ２ , deuterated group, C ２～６ Alkenil, C ２～６ Alkinyl, -COC １～６ Alkyl, -COC ６～１２ Ariel, C １～６ Alkylthio, mercapto, =O, -C １～６ Alkylhydroxy, -C １～６ Alkylamino, 3-12 member heterocyclyl, -SO ２ C １～６ Alkyl, -SO ２ NH ２ , C ６～１２ Ariel, -OC ６～１２ Ariel, -C １～６ Alkyl C ６～１２ (Selected from the arrow.) 【Chemistry 2】 (In formula Ic, R １５ , R １６ , R １７ , R １８ , and R １９ C is either identical or different, and independently of each other, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, unsubstituted, or one or more Rx. １～６ Alkyl, -SO ２ C １～６ Alkyl, C １～６ Haloalkyl, C ６～１２ Ariel, C １～６ Alkoxy, -N(C) １～６ Alkyl) ２ , C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Cycloalkyl, C １～６ Alkylthio, -COC １～６ Alkyl, -COC ６～１２ Ariel, -OC ６～１２ Ariel, -C １～６ Alkyl-hydroxy, 3-12 membered heterocyclyl, -SO ２ NH ２ Selected from, Rx may be the same or different, and independently of each other, they may be halogens, aminos, hydroxyls, or C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, CN, C ３～１２ Cycloalkyl, -N(C) １～６ Alkyl) ２ , deuterated group, C ２～６ Alkenil, C ２～６ Alkinyl, -COC １～６ Alkyl, -COC ６～１２ Ariel, C １～６ Alkylthio, mercapto, =O, -C １～６ Alkylhydroxy, -C １～６ Alkylamino, 3-12 member heterocyclyl, -SO ２ C １～６ Alkyl, -SO ２ NH ２ , C ６～１２ Ariel, -OC ６～１２ Ariel, -C １～６ Alkyl C ６～１２ Selected from the alphabet, and R １９ (It's not H.) 【Transformation 3】 (In Id, L is a chemical bond, C ２～１２ alkynyl, C ２～１２ alkenyl, NH, oxygen, sulfur or C １～１２ alkyl, and the C １～１２ alkyl is optionally substituted by hydroxy or amino. R ２０ C is either unsubstituted or optionally substituted by one or more Ry. ６～１２ The group is an aryl, a 3-12 membered cycloalkyl, a 5-12 membered heterocyclyl, or a 5-12 heteroaromatic ring group. Ry is selected from a deuterated group, Cl, hydroxy, amino, carboxy, CN, C １～６ alkyl, C １～６ alkoxy, halo C １～６ alkyl, C ３～１２ cycloalkyl, -N(C １～６ alkyl) ２ , -COC １～６ alkyl, -COC ６～１２ aryl, C １～６ alkylthio, mercapto, =O, -C １～６ alkylhydroxy, -C １～６ alkylamino, a 3- to 12-membered heterocyclyl, -SO ２ C １～６ alkyl, -SO ２ NH ２ , C ６～１２ aryl, -OC ６～１２ aryl, -OC １～６ alkyl C ６～１２ aryl, -C １～６ alkyl C ６～１２ aryl, -C １～６ alkyl-COOH, -C ６～１２ aryl-C １～６ alkylamino, -C ６～１２ aryl-C １～６ alkylhydroxy, -C ６～１２ arylamino, -C ６～１２ arylhydroxy.)

2. In formula Ib, R １５ , R １６ , R １７ , and R １８ These are either identical or different, and independently of each other, hydrogen, deuterium, F, Cl, methyl, amino, hydroxy, methoxy, trifluoromethyl, cyano, phenyl, dimethylamino, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, ethynyl, cyclopropyl, carbonylmethyl, carbonylphenyl, phenoxy, tert-butoxy, alkylthio, -SO ２ NH ２ Hydroxymethyl, N-tetrahydropyrrolyl, -SO ２ CH ２ p-aminophenyl, 【Chemistry 4】 A compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, selected from the above.

3. In Id, L is a chemical bond, an alkynyl, NH, 【Transformation 5】 And, R20 is phenyl, Ry is Cl, hydroxy, amino, tert-butyl, phenyl, p-aminophenyl, p-hydroxyphenyl, ethylamino, hydroxyethyl, p-hydroxyethylphenyl, p-ethylaminophenyl, 【Transformation 6】 A compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, selected from the above.

4. A compound, a tautomer, a stereoisomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, characterized by being selected from the following. 【Transformation 7】 【change】 【change】 【change】

5. Use of a compound according to any one of claims 1 to 4, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt in the manufacture of a drug for treating or preventing diseases, disorders, or symptoms associated with mutations, expression imbalances, allosteria and functional abnormalities of the proteins GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC.

6. The aforementioned diseases, conditions, or symptoms include myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin lymphoma, papillary thyroid carcinoma and follicular thyroid carcinoma, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, complicated regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary melanoma and chronic melanoma, iris melanoma, recurrent bilateral interocular melanoma, and ocular The use according to claim 5, characterized in that it includes extravasation melanoma, solid tumors, T-cell lymphoma, erythrocyte lymphoma, monoblastic leukemia and monocytic leukemia, myeloid leukemia, central nervous system lymphoma, brain tumors, meningiomas, spinal cord tumors, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, Burkitt lymphoma, Hodgkin lymphoma, large cell lymphoma, diffuse large B-cell lymphoma, astrocytoma, hepatocellular carcinoma or primary macroglobulinemia, and viral infections.

7. A pharmaceutical composition characterized by comprising a compound according to any one of claims 1 to 4, a tautomer thereof, a stereoisomer, a hydrate, a solvate thereof, or a pharmaceutically acceptable salt thereof.

8. PD-1 inhibitor, PD-L1 inhibitor, rituximab, trastuzumab, elotuzumab, utuximab, daratumumab, atlizumab, ibritumomab, alemtuzumab, brentuximab, cytarabine, azacitidine, anthracycline drugs, prednisone, dexamethasone, melphalan, cladribine, fludarabine, mitoxantrone, etoposide, methotrexate, pemetrexed, topotecan, doxorubicin, cyclophosphamide The pharmaceutical composition according to claim 7, further comprising at least one other therapeutic agent selected from gemcitabine, dacarbazine, clarithromycin, vincristine, docetaxel, clofarabine injection, HDAC inhibitor, FLT3 inhibitor, IDH1 / 2 inhibitor, BCL-2 inhibitor, proteasome inhibitor, PI3K inhibitor, BTK inhibitor, palbociclib, erythrocyte growth hormone, eltrombopag, minocycline, and CAR-T.

9. The pharmaceutical composition according to claim 8, characterized in that the other therapeutic agent is azacitidine or dexamethasone.

10. The pharmaceutical composition according to claim 7, characterized in that it is administered orally, rectally, topically, orally, parenterally, intramuscularly, intradermally, intravenously, and transdermally.

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