Halogen-substituted isoindoline compounds and uses thereof

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 from a prior application bearing patent application number 2022104939244 and entitled "Halogen-Substituted Isoindoline Compounds and Uses Thereof," filed with the State Intellectual Property Office of China on April 29, 2022, the entire text of which is incorporated herein by reference.

[0002] [Technical field] The present invention relates to the pharmaceutical technical field, specifically to halogen-substituted isoindoline compounds and their uses.

[0003] [Background technology] Protein mutations, expression imbalances, allostery and functional abnormalities cause many diseases. Protein synthesis or degradation is a process that is tightly controlled spatially and temporally during cell growth and proliferation. Abnormal regulation of these processes can cause uncontrolled cell growth, proliferation and migration, leading to the development of diseases such as cancer, aging and viral infection.

[0004] Translation termination factor GSPT1 (eRF3a) is closely associated with diseases such as cancer, where it can mediate the recognition of stop codons and promote the release of nascent peptides from ribosomes. In addition to having translation termination function, GSPT1 is also involved in several other important cellular processes, including cell cycle regulation, cytoskeleton organization, and apoptosis. GSPT1 is an oncogenic driver in multiple types of cancer, including hematoma, breast cancer, liver cancer, gastric cancer, and prostate cancer. In addition, GSPT1 is obviously 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, depletion of GSPT1 effectively inhibits cancer cell proliferation and migration in vitro, induces apoptosis of invasive colon cancer cells, and inhibits the tumorigenicity of HCT116 colon cancer cells in vivo. Moreover, 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 is a regulator of 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 related to cancer progression was first found in hematopoietic malignancies, where dysfunction of Ikaros was associated with the development of chronic lymphocytic leukemia. Recently, Ikaros has been found to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia and also involved in the differentiation and function of individual helper T cells. Aiolos plays a key role in the maturation of B and T cells, and in chronic lymphocytic leukemia, enhanced Aiolos expression can promote cell survival by regulating Bcl2 family proteins. Increased expression of Aiolos has been detected in follicular center cell lymphoma. Aiolos cooperates with Blimp-1 to regulate the survival of multiple myeloma cells. Moreover, in solid tumors, overexpression of Aiolos can also promote epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells.

[0006] At present, there are no commercially available drugs based on protein regulation such as GSPT1, and no reports of halogen-substituted isoindoline compounds as small molecules of protein regulators such as GSPT1 have been found in the prior art. At present, the protein regulator with the most advanced research and development progress is CC-90009 from Celegen, which is administered intravenously and is undergoing phase I clinical studies. Oral administration is the most commonly used administration method because it is simple, safe and economical compared to injection administration. In addition, small changes in the molecular structure of the protein regulator will cause large changes in drug metabolism activity and biological activity. For example, a change in one atom in a molecular glue or PROTAC molecule may cause the compound to lose its decomposition activity against a certain protein and its biological activity against tumors. Therefore, regulators with different chemical structures may improve the efficacy and safety of drugs.

[0007] [Summary of the Invention] [Means for solving the problem] 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 pharma- ceutically acceptable salt thereof.

[0008] [ka]

[0009] (R 1 is hydrogen, deuterium, C 1~12 Alkyl,

[0010] [ka]

[0011] is selected from R 2 are identical or different and independently represent hydrogen, unsubstituted or optionally substituted by one or more Ra, C 1~12 Alkyl, C 6~20 Aryl, 5-20 membered heteroaryl, C 3~20 cycloalkyl, and 3- to 20-membered heterocyclyl; R' and R 3 are identical or different and independently represent hydrogen, unsubstituted or optionally substituted by one or more Rb, C 1~12 Alkyl, C 1~12 Alkoxy, C 6~20 Aryl, 5-20 membered heteroaryl, C 3~20 cycloalkyl, and 3- to 20-membered heterocyclyl; R 4 and R 5 are the same or different and are independently selected from hydrogen, deuterium, halogen, m is 1, 2 or 3; R 6is hydrogen, deuterium, halogen, unsubstituted or optionally substituted by one or more Rc, C 1~12 Alkyl, C 1~12 alkoxy; Q 1 -CH 2 -, -CD 2 -, -C(O)- or -C(S)-; R 7 , R 8 , R 9 , and R 10 are the same or different and are independently hydrogen, halogen, deuterium, CN, C 1~12 Alkyl, -CH 2 -NHBoc, -CH 2 -NH 2 , -CH 2 -NHCO-CF 2 -R 11 , -CH 2 -NHCO-R 12 , -CH 2 -NHCO-YR 13 , -CH 2 -NH-YR 14 , -CH 2 -NHCONH-R 12 and wherein the -CH 2 -NHBoc, -CH 2 -NH 2 , -CH 2 -NHCO-CF 2 -R 11 , -CH 2 -NHCO-R 12 , -CH 2 -NHCONH-R 12 , -CH 2 -NHCO-YR 13 , -CH 2 -NH-YR 14 The hydrogen on the methylene is optionally replaced by one or two deuterium atoms; R 11 , R 12 , R 13 , and R 14 are identical or different and, independently of each other, unsubstituted or optionally substituted by one or more Rs, C6~20 Aryl, 5-20 membered heteroaryl, C 3~20 Cycloalkyl, 3-20 membered heterocyclyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 1~12 Alkyl, -P(C 6~20 Aryl) 2 , -N(C 1~12 Alkyl) 2 , -COC 1~12 Alkyl, -C 1~12 AlkylN(C 1~12 Alkyl) 2 , C 6~20 Aryl C 3~20 Cycloalkyl, C 3~20 Cycloalkyl and C 3~20 spiro groups consisting of cycloalkyl; Y is C 1~12 Alkylene, C 3~20 Cycloalkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, -CH 2 NH-, -CH 2 NHCO-, -CH 2 NHCO-, -CH 2 O-, -C 2 H 4 O-, -CH 2 S-,

[0012] [ka]

[0013] is selected from Ra, Rb, Rc, and Rs are the same or different and each independently represents halogen, amino, hydroxy, C 1~12 Alkyl, C 1~12 Alkoxy, HaloC 1~12 Alkyl, CN, C 3~20 Cycloalkyl, -N(C 1~12 Alkyl) 2 , deuterated group, C 2~12 Alkenyl, C 2~12 Alkynyl, -COC 1~12 Alkyl, -COC6~20 Aryl, C 1~12 Alkylthio, mercapto, =O, -C 1~12 Alkylhydroxy, 3-20 membered heterocyclyl, -SO 2 C 1~12 Alkyl, -SO 2 NH 2 , C 6~20 Aryl, -OC 6~20 Aryl, -C 1~12 Alkyl C 6~20 Aryl, -C 1~12 Alkylamino, -C 6~20 Aryl C 1~12 Alkylamino, -C 6~20 Arylamino, -OC 1~12 Alkyl C 6~20 Aryl, -C 6~20 Arylhydroxy, -C 6~20 Aryl C 1~12 alkylhydroxy. According to an embodiment of the present invention, R 1 is hydrogen, C 1~6 Alkyl, -C 1~6 Alkyl COOC 1~6 Alkyl, -COOC 1~6 Alkyl or -C 1~6 Alkyl OCOOC 1~6 alkyl, R 4 , R 5 , and R 6 is selected from hydrogen, m is 1, 2 or 3, and Q 1 -CH 2 - or -C(O)-, R 7 , R 8 , R 9 , and R 10 are the same or different and independently represent hydrogen, deuterated radicals, halogen, CN, C 1~6 Alkyl, -CH 2 -NHBoc, -CH 2 -NH 2 , -CH 2 -NHCO-CF 2 -R 11 , -CH 2-NHCO-R 12 , -CH 2 -NHCONH-R 12 , -CH 2 -NHCO-YR 13 , -CH 2 -NH-YR 14 and wherein the -CH 2 -NHBoc, -CH 2 -NH 2 , -CH 2 -NHCO-CF 2 -R 11 , -CH 2 -NHCO-R 12 , -CH 2 -NHCONH-R 12 , -CH 2 -NHCO-YR 13 , -CH 2 -NH-YR 14 CH 2 wherein the hydrogen is optionally replaced by one or two deuterium atoms; R 11 , R 12 , R 13 , and R 14 are identical or different and, independently of each other, unsubstituted or optionally substituted by one or more Rs, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 Cycloalkyl, 3-12 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 Aryl C 3~12 Cycloalkyl, C 3~12 Cycloalkyl and C 3~12 spiro groups consisting of cycloalkyl; Y is C 1~6 Alkylene, C 3~12Cycloalkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -CH 2 NH-, -CH 2 NHCO-, -CH 2 NHCO-, -CH 2 O-, -C 2 H 4 O-, -CH 2 S-,

[0014] [ka]

[0015] is selected from Rs are the same or different and are independently selected from halogen, amino, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, CN, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl) 2 , deuterated group, C 2~6 Alkenyl, C 2~6 Alkynyl, -COC 1~6 Alkyl, -COC 6~12 Aryl, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, 3-12 membered heterocyclyl, -SO 2 C 1~6 Alkyl, -SO 2 NH 2 , C 6~12 Aryl, -OC 6~12 Aryl, -C 1~6 Alkyl C 6~12 Aryl, -C 1~6 Alkylamino, -C 6~12 Aryl C 1~6 Alkylamino, -C 6~12 Arylamino, -OC 1~6 Alkyl C 6~12 Aryl, -C 6~12 Arylhydroxy, -C 6~12 Aryl C 1~6alkylhydroxy.

[0016] In one embodiment, Formula I has the structure shown in Formula I-1 below:

[0017] [ka]

[0018] (In the formula, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Q 1 has the above definition.) In one embodiment, Formula I has the structure shown in Formula I-2 below:

[0019] [ka]

[0020] (In the formula, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Q 1 has the above definition.) In one embodiment, Formula I has the structure shown in Formula I-3 below:

[0021] [ka]

[0022] (In the formula, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Q1 has the above definition.) According to an embodiment of the present invention, formula I is selected from the structure shown in formula Ia below:

[0023] [ka]

[0024] (In formula Ia, R 1 is hydrogen, C 1~6 Alkyl, -C 1~6 Alkyl COOC 1~6 Alkyl, -COOC 1~6 Alkyl or -C 1~6 Alkyl OCOOC 1~6 alkyl, R 4 , R 5 , and R 6 is selected from hydrogen or deuterium; m is 1, 2 or 3; Q 1 -CH 2 -, -CD 2 - or -C(O)-, R 7 ' is selected from hydrogen, deuterium, and halogen, and p is 1, 2, or 3, provided that at least one R 7 ' is selected from halogens, R 8 ',CN,-CH 2 -NHBoc, -CH 2 -NH 2 , -CH 2 -NHCO-CF 2 -R 11 , -CH 2 -NHCO-R 12 , -CH 2 -NHCONH-R 12 , -CH 2 -NHCO-YR 13 , -CH 2 -NH-YR 14 and wherein the -CH 2 -NHBoc, -CH 2 -NH 2, -CH 2 -NHCO-CF 2 -R 11 , -CH 2 -NHCO-R 12 , -CH 2 -NHCONH-R 12 , -CH 2 -NHCO-YR 13 , -CH 2 -NH-YR 14 CH 2 where H is optionally replaced by one or two deuterium atoms; R 11 , R 12 , R 13 , and R 14 are identical or different and, independently of each other, unsubstituted or optionally substituted by one or more Rs, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 Cycloalkyl, 3-12 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 Aryl C 3~12 Cycloalkyl, C 3~12 Cycloalkyl and C 3~12 spiro groups consisting of cycloalkyl; Y is C 1~6 Alkylene, C 3~12 Cycloalkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -CH 2 NH-, -CH 2 NHCO-, -CH 2 NHCO-, -CH 2 O-, -C 2 H 4 O-, -CH 2 S-,

[0025] [ka]

[0026] Selected from Rs are the same or different and are independently selected from halogen, amino, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, CN, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl) 2 , deuterated group, C 2~6 Alkenyl, C 2~6 Alkynyl, -COC 1~6 Alkyl, -COC 6~12 Aryl, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, 3-12 membered heterocyclyl, -SO 2 C 1~6 Alkyl, -SO 2 NH 2 , C 6~12 Aryl, -OC 6~12 Aryl, -C 1~6 Alkyl C 6~12 Aryl, -C 1~6 Alkylamino, -C 6~12 Aryl C 1~6 Alkylamino, -C 6~12 Arylamino, -OC 1~6 Alkyl C 6~12 Aryl, -C 6~12 Arylhydroxy, -C 6~12 Aryl C 1~6 alkylhydroxy. According to an embodiment of the present invention, R 7 , R 8 , R 9 and R 10 At least one of R is halogen. 7 , R 8 , R 9 and R 10one of which is halogen, or two of which are halogen, or three of which are halogen.

[0027] In one embodiment of the present invention, R 7 , R 8 , R 9 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 shown in formula Ib below:

[0029] [ka]

[0030] (In formula Ib, R 15 , R 16 , R 17 , and R 18 are identical or different and independently represent hydrogen, deuterium, halogen, amino, hydroxy, cyano, unsubstituted or optionally substituted by one or more Rx, C 1~6 Alkyl, -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, 3-12 membered heterocyclyl, -SO 2 NH 2 is selected from Rx are the same or different and independently represent halogen, amino, hydroxy, C 1~6 Alkyl, C 1~6Alkoxy, HaloC 1~6 Alkyl, CN, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl) 2 , deuterated group, C 2~6 Alkenyl, C 2~6 Alkynyl, -COC 1~6 Alkyl, -COC 6~12 Aryl, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, -C 1~6 Alkylamino, 3-12 membered heterocyclyl, -SO 2 C 1~6 Alkyl, -SO 2 NH 2 , C 6~12 Aryl, -OC 6~12 Aryl, -C 1~6 Alkyl C 6~12 aryl. In one embodiment of the present invention, in formula Ib, R 15 , R 16 , R 17 , and R 18 are the same or different and are each independently 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,

[0031] [ka]

[0032] is selected from.

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

[0034] [ka]

[0035] (In the formula, R 15 , R 16 , R 17 , and R 18 has the above definition.) Compound Im undergoes a condensation reaction with compound In to give a compound of 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 are identical or different and independently represent hydrogen, deuterium, halogen, amino, hydroxy, cyano, unsubstituted or optionally substituted by one or more Rx, C 1~6 Alkyl, -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, 3-12 membered heterocyclyl, -SO 2 NH 2 is selected from Rx are the same or different and independently represent halogen, amino, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, CN, C 3~12 Cycloalkyl, -N(C 1~6 Alkyl) 2 , deuterated group, C 2~6 Alkenyl, C 2~6 Alkynyl, -COC 1~6 Alkyl, -COC 6~12 Aryl, C 1~6 Alkylthio, mercapto, =O, -C 1~6 Alkylhydroxy, -C 1~6 Alkylamino, 3-12 membered heterocyclyl, -SO 2 C 1~6 Alkyl, -SO 2 NH 2 , C 6~12 Aryl, -OC 6~12 Aryl, -C 1~6 Alkyl C 6~12 aryl, and R 19 is not H.) In one embodiment of the present invention, the compound of formula Ic is prepared by the following method:

[0039] [ka]

[0040] (In the formula, R 15 , R 16 , R 17 , R 18 and R 19 has the above definition.) Compound Ip undergoes a condensation reaction with compound Iq to give a compound of 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 Alkynyl, C 2~12 Alkenyl, NH, oxygen, sulfur or C 1~12 alkyl, 1~12 The alkyl is optionally substituted with hydroxy, amino, R 20 is unsubstituted or optionally substituted by one or more Ry; 6~12 aryl, 3- to 12-membered cycloalkyl, 5- to 12-membered heterocyclyl, or 5- to 12-membered heteroaromatic ring group; Ry is a deuterated group, halogen, hydroxy, amino, carboxy, CN, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 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, 3-12 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. In a preferred embodiment, in Id, L is a chemical bond, C 2~12 Alkynyl, C2~12 Alkenyl, NH, or C 1~6 alkyl, 1~6 The alkyl is optionally substituted with hydroxy, amino, R 20 is unsubstituted or optionally substituted by one or more Ry; 6~12 aryl or 5-12 heteroaromatic ring group; Ry is hydroxy, amino, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~12 Aryl, -OC 1~3 Alkyl C 6~12 Aryl, -C 1~3 Alkyl C 6~12 Aryl, -C 1~6 Alkyl-NH 2 , -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 arylhydroxy.

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

[0045] [ka]

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

[0047] [ka]

[0048] is selected from.

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

[0050] [ka]

[0051] (In the formula, R 20 , L has the above definition. Compound Ix undergoes a condensation reaction with compound Iy to give a compound of formula Id.

[0052] By way of example, the compound of formula I is selected from:

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] According to an embodiment of the invention, the pharma- ceutically acceptable salt is selected from the salts defined below, for example the salts include, but are not limited to, hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate, or meglumine salts, preferably hydrochloride.

[0061] The present invention also provides the use of a compound represented by the above formula I, or a tautomer, stereoisomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease, illness, or condition associated with mutation, imbalance in expression, allostery, and abnormal function of a protein such as GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC.

[0062] According to an embodiment of the present invention, the disease, illness or condition is myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, papillary and follicular thyroid cancer, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary body melanoma and chronic melanoma, iris melanoma, recurrent Includes interocular melanoma, extraocular melanoma, solid tumors, T-cell lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia, myeloid leukemia (e.g. acute myeloid leukemia), central nervous system lymphoma, brain tumor, meningioma, spinal cord tumor, 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, viral infections.

[0063] The present invention also provides a pharmaceutical composition comprising a compound of formula I above, a tautomer, stereoisomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof.

[0064] According to an embodiment of the present invention, the pharmaceutical composition further comprises, in addition to the compound represented by formula I as an active ingredient, another therapeutic agent, and the other therapeutic agent is a PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab), 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, gemcitabine, dacarbazine, cladribine ... Rithromycin, vincristine, docetaxel, clofarabine injection, HDAC inhibitors (e.g., panobinostat, romidepsin, vorinostat, belinostat, chidamide), 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, orelabrutinib), palbociclib, erythroid growth hormone, eltrombopag, minocycline, and CAR-T.

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

[0066] According to an embodiment of the present invention, the pharmaceutical composition is used for treating or preventing diseases, disorders or symptoms associated with mutations, imbalance in expression, allostery and abnormal function of proteins such as GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC or C-MYC.

[0067] According to an embodiment of the present invention, the disease, illness or condition is myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, papillary and follicular thyroid cancer, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary body melanoma and chronic melanoma, iris melanoma, recurrent Includes interocular melanoma, extraocular melanoma, solid tumors, T-cell lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia, myeloid leukemia (e.g. acute myeloid leukemia), central nervous system lymphoma, brain tumor, meningioma, spinal cord tumor, 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, viral infections.

[0068] According to an embodiment of the present invention, the compound of formula I or pharmaceutical composition may be administered by oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous and transdermal administration. In one embodiment, the pharmaceutical composition is administered orally.

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

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

[0071] 1. The present inventors have unexpectedly found that the halogen-substituted compounds of the present invention have significantly improved antitumor cell proliferation activity and also significantly improved decomposition effects on proteins such as GSPT1, compared with their non-substituted counterparts. For example, the halogen-substituted compound FDAB-48 of the present invention has anti-MV-4-11 cell proliferation activity IC 50 The compound with no halogen substitution had a GSPT1 protein degradation rate of 88% after 6 hours of co-incubation with NB-4 cells.

[0072] [ka]

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

[0074] 2. The compounds of the present invention have hERG channel inhibitory activity that is barely observable at a concentration of 3 μM (9-25% inhibition), whereas the conventional compound CC-90009 undergoing clinical research has clear hERG channel inhibitory activity (66% inhibition).

[0075] 3. Compound CC-90009 in conventional clinical research is an injection. The compound of the present invention has significant tumor inhibitory activity in mouse transplanted tumor model, but compound CC-90009 does not have tumor inhibitory activity at the same dose administered orally. This shows that the compound of the present invention can be made into an oral dosage form that is more convenient, safe and economical to administer, compared with compound CC-90009 (injection).

[0076] As described above, the compounds of the present invention have obvious excellent antitumor activity, and can be made into oral dosage forms that are more convenient, safe and economical for administration, and therefore have a significantly improved utility value compared with conventional compounds.

[0077] (Definition and explanation of terms) Unless otherwise stated, the definitions of groups and terms in the specification and claims of this application include exemplary definitions, exemplary definitions, preferred definitions, definitions given in the tables, and definitions of specific compounds in the examples, which may be combined or combined in any manner, and such combinations and combined group definitions and compound structures are to be considered as falling within the scope described in the specification of this application.

[0078] As used herein, the terms "comprise", "include", and / or "contain" are open-ended, i.e., they include the subject matter specified in the present invention but do not exclude the subject matter in other embodiments.

[0079] As used herein, when describing one / one type, two / two types, or multiple / multiple types, "multiple / multiple types" should be taken to mean more than two, for example, an integer equal to or greater than 3, such as 3, 4, 5, 6, 7, 8, 9, or 10 pieces / types.

[0080] In this specification, the term "optionally" refers to the two cases where the described feature is present or absent, which means that the event described later may occur but does not necessarily occur, and thus includes the two cases where this event occurs or does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl may be present but does not necessarily exist, and thus includes the cases of heterocyclyl substituted with alkyl and the cases of heterocyclyl not substituted with alkyl.

[0081] In this application, the term "

[0082] [ka]

[0083] " and "*" are linking sites.

[0084] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and / or iodine. Thus, the term "halo" refers to fluoro, chloro, bromo and / or iodo. Within the scope of this specification, when an atom, residue, group or moiety is halogenated, the atom at the halogenated position may be mono-, di-, poly- or even completely substituted by halogen atoms.

[0085] "C 1~12 The term "alkyl" should be understood to mean linear or branched saturated monovalent hydrocarbyl having from 1 to 12 carbon atoms, preferably C 1~6 It is an alkyl group. 1~6 "Alkyl" is to be understood to mean a linear or branched saturated monovalent hydrocarbyl, preferably 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, etc., or an isomer thereof. In particular, the group is an alkyl group having 1, 2 or 3 carbon atoms ("C 1~3 alkyl), such as methyl, ethyl, n-propyl, or isopropyl.

[0086] "C 2~12 The term "alkenyl" should be understood to mean a straight or branched chain monovalent hydrocarbyl containing one or more double bonds and having 2 to 12 carbon atoms, preferably "C 2~6 alkenyl". 2~6Alkenyl preferably contains one or more double bonds and has 2, 3, 4, 5, 6 carbon atoms, especially 2 or 3 carbon atoms ("C 2~3 It should be understood that the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbyl having a double bond ("alkenyl"), and it should be understood that when said alkenyl contains more than one double bond, said double bonds can be separate from each other or conjugated to each other. The alkenyl can be, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl nyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0087] "C 2~12The term "alkynyl" should be understood to mean a straight or branched chain monovalent hydrocarbyl containing one or more triple bonds and having 2 to 12 carbon atoms, preferably "C 2 ~C 6 alkynyl. 2 ~C 6 The term "alkynyl" preferably includes one or more triple bonds and has 2, 3, 4, 5, 6 carbon atoms, in particular 2 or 3 carbon atoms ("C 2 ~C 3 "alkynyl" should be understood to mean straight or branched monovalent hydrocarbyl, such as, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-2-ynyl, 2-methylpent-3-ynyl, 2-methylpent-4-ynyl, 2-methylpent-5-ynyl, 2-methylpent-1-ynyl, 2-methylpent-2-ynyl, 2-methylpent-2-ynyl, 2-methylpent-4-ynyl, 2-methylpent-5 ... Alkynyl is ethynyl, propynyl, propynyl, eth ...

[0088] "C 3~20 The term "cycloalkyl" is to be understood as meaning a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3~12"Cycloalkyl". 3~12 The 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 Cycloalkyl 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- to 20-membered heterocyclyl" denotes a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5 heteroatoms independently selected from N, O and S, preferably "3- to 12-membered heterocyclyl". The term "3- to 12-membered heterocyclyl" denotes a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3, heteroatoms selected from N, O and S. The heterocyclyl may be linked to the remainder of the molecule via any of the carbon atoms or via the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to, a 4-membered ring such as azetidinyl or oxetanyl, a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or pyrrolinyl, a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclyl may be, but is not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., contain one or more double bonds, including but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or may be benzo-fused, including but not limited to dihydroisoquinolinyl. According to the present invention, said 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 aryl". 6~12The term "aryl" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring, preferably having 6, 7, 8, 9, 10, 11 or 12 carbon atoms ("C 6~12 aryl"), particularly a ring having six carbon atoms, such as phenyl or biphenyl ("C 6 aryl"), or a ring having nine carbon atoms, such as indanyl or indenyl ("C 9 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 rings with 14 carbon atoms, such as anthracenyl ("C 14 It should be understood that the term is an aryl group.

[0091] The term "5-20 membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5-12 membered heteroaryl". The term "5-12 membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms, in particular 5, 6, 9 or 10 carbon atoms, containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, which may further be benzo-fused in each case. In particular, heteroaryl is thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl; or pyridinyl. , pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and benzo derivatives thereof, such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl.

[0092] Unless otherwise stated, heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, including their positional isomers. Thus, as some illustrative non-limiting examples, pyridinyl or pyridylene includes pyridin-2-yl, pyridylene-2-yl, pyridin-3-yl, pyridylene-3-yl, pyridin-4-yl and pyridylene-4-yl, and thienyl or thienylene includes thiophen-2-yl, thienylene-2-yl, thiophen-3-yl and thienylene-3-yl.

[0093] "C 1~12 The above definition of the term "alkyl" includes "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 alkyl hydroxy", "-N(C 1~6 Alkyl) 2 ", -C 1~6 "C" such as "alkylhydroxy" 1~12 In other words, the term "C alkyl" is also applicable to other terms that include "C 1~6 If the reference is to a group containing an "alkyl" substituent, the C 1~6 The definition of alkyl is the same as that defined above. 6~12 Aryl, C 3~20 The terms "cycloalkyl", "5- to 20-membered heteroaryl", "3- to 20-membered heterocyclyl", and the like have the same definition throughout this specification.

[0094] "C 1~12 Haloalkyl" and "HaloC 1~12 The terms "alkyl" and "alkyl" are synonymous and are the same as those in the above "C 1~12 "Alkyl" refers to a substituent substituted by halogen.

[0095] "C 6~20 Aryl C 3~20 The term "cycloalkyl" refers to the C 6~20 Aryl and C 3~20 Cycloalkyl refers to a group formed by sharing at least two carbon atoms.

[0096] "C3~20 Cycloalkyl and C 3~20 C in the term "cycloalkyl spiro group" 3~20 The definition of cycloalkyl is the same as above, with two C 3~20 Cycloalkyl means a spiro group formed by sharing one carbon atom.

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

[0098] The term "Boc" is tert-butoxycarbonyl.

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

[0100] Pharmaceutically acceptable salts include the fully basic acid addition salts of the compounds of the present invention that have nitrogen atoms in a chain or ring.Basic nitrogen-containing groups can also 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; aralkyl halides, such as benzyl bromide and phenethyl bromide.By way of example, physiologically / pharmacologically acceptable salts include, but are not limited to, hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate or meglumine salts.

[0101] Since the compound of the present invention may have multiple salt-forming sites, the physiological / pharmacologically acceptable salt includes not only salts formed at one salt-forming site of the compound of the present invention, but also salts formed at two, three or all of the salt-forming sites. Therefore, in the physiological / pharmacologically acceptable salt, the molar ratio of the compound of formula (I) to the acid radical ion (anion) or base cation required for salt formation may 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 solutions of the present invention are described in further detail below with reference to specific embodiments. It should be understood that the following embodiments 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 is intended to protect.

[0103] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. The structures of the compounds are 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 liquid chromatography-mass spectrometry (LC-MS) instrument using an ESI ion source.

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

[0105] [ka]

[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 mixture was heated and stirred at 60° C. for about 30 minutes to react, after which 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 stirring at 60° C. for about 1 hour, the reaction was detected by LCMS, which showed that the raw material 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, and then ethyl acetate (2×100 ml) was added, extracted, and separated. The organic phase was combined and repeatedly washed with saturated saline, 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 to 1 / 10) gave 4.5 g (yield 43%) of a pale yellow oily liquid T1-1.

[0107] Synthesis of T1-2: Intermediate T1-1 (4.5 g, 21.0 mmol) and aqueous sodium hydroxide solution (5 M, 50 ml) were mixed. The mixed liquid system was heated to 100° C. and stirred for about 16 hours to react, and the results of detection by LCMS showed that T1-1 had reacted completely. The reaction liquid was cooled to room temperature, and 6 M hydrochloric acid solution was added dropwise to the reaction liquid in an ice bath to adjust the acidity to about 1. A large amount of solid generated from the reaction liquid during the acidity adjustment 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 at room temperature for about 1 hour, and the reaction was detected by LCMS, which showed that the raw material T1-2 had disappeared. The reaction solution was quenched by adding ice water, and ethyl acetate (2 x 100 ml) was added, extracted, and separated. The organic phase was combined and repeatedly washed with saturated saline, and 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 to 1 / 20) gave 4.3 g (yield 90%) of pale yellow oily liquid T1-3.

[0109] Synthesis of T1-4: Intermediate T1-3 (9.8g, 39.7mmol) and cuprous cyanide (5.34g, 59.7mmol) were dissolved in 60ml of N-methylpyrrolidone, the mixture was heated to 180°C, and stirred and reacted at this temperature for about 2 hours. The result of detection by LCMS showed that the raw material disappeared. The mixture was cooled to room temperature and filtered, and the filtrate was diluted with 100ml of water, and ethyl acetate (2x100ml) was added, extracted and separated. The organic phase was combined and repeatedly washed with saturated saline, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. Column chromatography (ethyl acetate / petroleum ether = 1 / 20-1 / 10) gave 4.6g of 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 catalytic amount of azobisisobutyronitrile (0.1 g) was added, and the reaction was continued by stirring at this temperature for about 4 hours, and the result of detection by LCMS showed that the raw material disappeared. It was cooled to room temperature, filtered by suction, the filter cake was washed with 30 ml of dichloromethane, the filtrate was diluted by adding 30 ml of water, and dichloromethane (2 × 30 ml) was added, extracted and separated. The organic phase was combined and washed repeatedly with saturated saline, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. Column chromatography (ethyl acetate / petroleum ether = 1 / 20 ~ 1 / 10) gave 3.3 g (yield 60%) of pale yellow liquid T1-5.

[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, stirred at this temperature for about 4 hours, and detected by LCMS, which showed that T1-5 had completely reacted. The reaction solution was diluted with 100 ml of water, and a mixture of methanol / dichloromethane = 1:10 (3 x 100 ml) was added, extracted, and separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30) was used to obtain 3.5 g of 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 tetrahydrofuran / N,N-dimethylformamide=10:1 mixed solvent, and Raney-nickel (0.6 g) was added at room temperature. The mixture was replaced with hydrogen gas three times, and a constant hydrogen pressure system was maintained. The temperature was raised to 40 °C, and the reaction was stirred at this temperature for about 4 hours. The result of detection by LCMS showed that FDAB-1 was completely reacted. After cooling the reaction solution, it was suction filtered, and the filter cake was washed three times with 50 ml of dichloromethane / methanol (10 / 1), and the filtrate was combined and concentrated under reduced pressure. Then, 100 ml of water was added to the concentrated solution, and it was extracted with ethyl acetate (3 × 100 ml) and separated. The organic phase was combined and washed repeatedly with saturated saline, and the organic phase was 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) gave 6.3 g (yield 81%) of a white solid of FDAB-2.

[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 of hydrochloric acid (1 M, 5 ml) was added at room temperature, and the temperature was raised to 40 ° C. to react. After about 1 hour of reaction, the result of detection by LCMS showed that the raw material FDAB-2 had disappeared. The mixture was concentrated under reduced pressure to remove excess hydrochloric acid solution and solvent, and the concentrated dichloromethane was adjusted to about 7 with aqueous ammonia, concentrated again, and column chromatography (methanol: dichloromethane = 1 / 100 to 1 / 10) was used to obtain about 2.8 g (yield about 86%) of a nearly white solid product FDAB-3.

[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 was based on the raw material 4-bromo-5-fluoro-2-methylaniline, and was performed by referring to the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in the above Examples 1 to 3. 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] [ka]

[0119] The synthesis of compounds FDAB-7, FDAB-8, and FDAB-9 was based on the raw material 4-bromo-2-fluoro-6-methylaniline, and was performed by referring to the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in the above Examples 1 to 3. 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] [ka]

[0122] The synthesis of compounds FDAB-10, FDAB-11, and FDAB-12 was based on the raw material 4-bromo-3-chloro-2-methylaniline, and was performed by referring to the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in the above Examples 1 to 3. 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] [ka]

[0125] The synthesis of compounds FDAB-13, FDAB-14, and FDAB-15 was based on the raw material 4-bromo-5-chloro-2-methylaniline, and was performed by referring to the synthesis methods of FDAB-1, FDAB-2, and FDAB-3 in the above Examples 1 to 3. The characteristic evaluation data of 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 based on the raw material 3-bromo-5-fluoro-2-methylaniline, and was based on the synthesis methods of FDAB-2 and FDAB-3 in the above Examples 2 and 3. The characterization data of 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, and 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 added slowly in a batchwise manner. After reacting for about 2 h, the result of detection by LCMS showed that the raw material FDAB-3 had disappeared. The reaction solution was quenched by adding 50 ml of water, extracted by adding ethyl acetate and separated, and the extraction was repeated three times until complete extraction. The organic phase was combined and washed repeatedly with saturated saline, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow concentrate crude product. Approximately 210 mg (yield 71%) of a white solid product FDAB-48 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, and 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 added slowly in a batchwise manner. After reacting for about 2 h, the result of detection by LCMS showed that the raw material FDAB-3 had disappeared. The reaction solution was quenched by adding 50 ml of water, extracted by adding ethyl acetate and separated, and the extraction was repeated three times until complete extraction. The organic phase was combined and washed repeatedly with saturated saline, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow concentrate crude product. Approximately 191 mg (yield 65%) of a white solid product FDAB-121 was obtained by column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 30).

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

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

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

[0138] [ka]

[0139] Chloromethyl isopropyl carbonate (34 mg, 0.22 mmol) was slowly added dropwise 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) at 0°C, and the mixture was slowly warmed to room temperature and stirred for about 3 hours to continue the reaction. After that, the detection by LCMS showed that the raw material FDAB-48 had disappeared. The reaction solution was quenched by adding 20 ml of water, and ethyl acetate was added to extract and separate the liquids. The extraction was repeated three times until complete extraction. The organic phase was combined and repeatedly washed with saturated saline, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a pale yellow concentrate crude product. Column chromatography (methanol / dichloromethane = 1 / 100-1 / 50) gave about 49 mg of white solid product FDAB-128 (yield 45%).

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

[0141] [ka]

[0142] Chloromethyl isopropyl carbonate (34 mg, 0.22 mmol) was slowly added dropwise 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) at 0°C, and the temperature was slowly raised to room temperature. After stirring and reacting for about 3 hours, the result of detection by LCMS showed that the raw material FDAB-121 had disappeared. The reaction solution was quenched by adding 20 ml of water, and ethyl acetate was added to extract and separate the liquids. The extraction was repeated three times until complete extraction. The organic phase was combined and repeatedly washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow concentrate crude product. Column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 50) gave about 38 mg of white solid product FDAB-130 (yield 35%).

[0143] In the present invention, some compounds, such as FDAB-128 and FDAB-130, which are substituted on the N of the glutarimide ring as mentioned above, are prepared by referring to the synthesis process of FDAB-128 and FDAB-130 mentioned above, and for the sake of brevity, are not described in detail here.The characterization data of 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 about 1 hour. Sodium cyanoborohydride (5.8 mg, 0.09 mmol) was then added to the reaction solution, and the reaction was continued with stirring at 50 ° C for about 1 hour. 20 ml of water was added to the reaction solution for quenching, and ethyl acetate (10 ml) was added for extraction and separation, and extraction was repeated three times until complete extraction. The organic phase was combined and repeatedly washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a brown concentrate crude product. 15 mg (yield 52%) of white solid FDAB-166 product was obtained by column chromatography (methanol / dichloromethane = 1 / 100-1 / 30).

[0147] With reference to the synthesis method of FDAB-166, FDAB-3 was used to react with the corresponding aldehyde to obtain compounds FDAB-165, FDAB-167, and FDAB-168. For brevity, they are not described in detail here. The characterization data of these compounds are shown in Table 1 below.

[0148] Characterization data for some of the above compounds are 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 compounds MV411 cells in logarithmic growth phase were diluted with medium (RPMI + 10% FBS) and plated at 5000 cells / well, 50 μl / well in a 96-well plate with black walls and black bottom (WHB). After plating, the cells were incubated at 4°C for 1 h at 5% CO 2 After 24 hours, the compounds were cultured in a 37°C incubator, and the drugs were added. Compounds were prepared in 10 mM stock solution with DMSO, and diluted with culture medium to the required concentration (final DMSO concentration was 0.2%). 50 μl was then added to the 96-well plate containing the cells so that the final compound concentrations were 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0 nM. Ten concentration gradients were set for each compound, and two duplicate wells were set up for each concentration. After the drugs were added, the wells were incubated in 5% CO 2The plates were then placed in a 37°C incubator and cultured 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 and shaken on a microplate shaker for 12 minutes. Luminescence values ​​were measured at room temperature using a GloMax navigator (Promega GM2010). IC values ​​were calculated using GraphPad Prism 7 software, with 0 nM control group as 0% inhibition. 50 values ​​were calculated.

[0175] The anti-MV-4-11 cell proliferation activity of the compounds is shown in Table 2, where A is the 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 ≧1000nM.

[0176] [Table 2-1]

[0177] [Table 2-2]

[0178] [Table 2-3]

[0179] Example 15: Antiproliferative activity of compounds against various tumor cells Logarithmic growth phase U937, NCI-H929, AML-2, and MOLM-13 cells were diluted with medium (RPMI + 10% FBS), (RPMI + 10% FBS), (MEMα + 20% FBS), and (RPMI + 20% FBS), respectively, and plated at 4000 cells / well, 50 μl / well in a 96-well plate with black walls and black bottom (WHB). After plating, the cells were incubated at 37 °C for 2 h at 5% CO 2After 24 hours, the compounds were cultured in a 37°C incubator, and the drugs were added. The compounds were prepared in 10 mM stock solution with DMSO, and diluted with culture medium to the required concentration (final DMSO concentration was 0.2%). Then, 50 μl of the compounds were added to the 96-well plate containing the cells so that the final compound concentrations were 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0 nM. Ten concentration gradients were set for each compound, and two duplicate wells were set up for each concentration. After the drugs were added, the wells were incubated in 5% CO 2 The plates were then placed in a 37°C incubator and cultured 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 and shaken on a microplate shaker for 12 minutes. Luminescence values ​​were measured at room temperature using a GloMax navigator (Promega GM2010). IC values ​​were calculated using GraphPad Prism 7 software, with 0 nM control group as 0% inhibition. 50 values ​​were calculated.

[0180] The antitumor cell proliferation activity of the compounds is shown in Table 3, where A is the 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 ≧1000nM.

[0181] [Table 3]

[0182] Example 16: Effect of compounds on apoptosis of AML cells MV-4-11 cells in logarithmic growth phase were diluted with growth medium and plated in 6-well plates at 600,000 cells / well, 2 mL / well, and treated with drugs. Cells were harvested, washed twice with pre-chilled PBS, resuspended in 100 μl of 1X annexin-binding buffer, and incubated at room temperature for 15 min in the dark with 5 μl of FITC and 1 μl of 100 μg / mL PI. After incubation, 400 μl of 1X annexin-binding buffer was added on ice, mixed gently, and detected by flow cytometry.

[0183] As a result, when the compounds FDAB-46 and FDAB-65 were added to the cells and treated for 7 hours, none of the compounds at concentrations of 10 μM, 1 μM, and 100 nM were able to induce apoptosis in MV-4-11 cells, whereas when the compounds FDAB-46 and FDAB-65 were added to the cells and treated for 16 hours, none of the compounds at concentrations of 1 μM and 100 nM were able to induce apoptosis in the cells.

[0184] Example 17: Modulation effect of compounds on GSPT1 protein NB-4 cells were grown in RPMI 1640 (containing 10% FBS) medium, and after centrifugation and counting, the cell concentration was adjusted to 106 cells / well and plated in a 12-well plate at 1350 μl / well. 150 μl of DMSO and compounds at a concentration of 1 μM were added and incubated in 5% CO 2 The cells were then placed in a 37°C incubator and cultured for 6 hours. The cells were centrifuged to discard the medium, and PBS was added and washed and discarded. Whole cell lysates were prepared with RIPA lysis solution containing a protease inhibitor mixture and phosphatase inhibitors, and left on ice for 30 minutes. The cell debris precipitate was discarded by centrifugation, and the whole cell lysate, which was the supernatant, was collected and transferred to a new EP tube. After measuring BCA protein, samples were prepared using loading buffer. The samples were treated in a metal bath at 100°C for 10 minutes.

[0185] Samples were electrophoresed on 4-20% precast gels (SDS-PAGE gels) to separate proteins, then transferred to PVDF membranes, which were then blocked with 5% NFDM / TBST for 1 h at room temperature, incubated with primary antibodies overnight at 4 °C, and incubated with secondary antibodies the next day for 2 h at room temperature. Signals were detected using a 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 The degradation effect of GSPT1 protein is shown in Table 4, where A means that the degradation percentage of GSPT1 protein is 80% or more, B means that the degradation percentage is less than 80% and 50% or more, C means that the degradation percentage is less than 50% and 25% or more, 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, the results showed that compound FDAB-48 had anti-MV-4-11 cell proliferation activity IC 50The compound had a 10.8 nM concentration and achieved 88% degradation of GSPT1 protein after 6 h incubation in NB-4 cells, whereas the corresponding compound without halogen substitution

[0192] [ka]

[0193] Anti-MV-4-11 cell proliferation activity IC 50 The concentration of GSPT1 in the NB-4 cells was 102.6 nM, and after incubation for 6 hours in NB-4 cells, the degradation effect of GSPT1 protein was only 65%.

[0194] Example 18: Modulation effects of compounds on IKZF1, IKZF3, CK1α, and c-MYC proteins HL-60 cells were grown in IMDM (containing 20% ​​FBS) medium, and after centrifugation and counting, the cell concentration was adjusted to 1.26 cells / well and plated in a 12-well plate at 1350 μl / well. 150 μl of DMSO and compounds were added and incubated in 5% CO 2 The cells were then centrifuged to discard the medium, and washed with PBS and discarded. Whole cell lysates were prepared with RIPA lysis solution containing a protease inhibitor mixture and phosphatase inhibitors, and left on ice for 30 minutes. The cell debris precipitate was discarded by centrifugation, and the supernatant whole cell lysate was collected and transferred to a new EP tube. After measuring BCA protein, samples were prepared using loading buffer. The samples were treated at 100°C for 10 minutes in a metal bath. The samples were electrophoresed on a 4-20% precast gel (SDS-PAGE gel) to separate proteins, and then transferred to a PVDF membrane, which was then blocked with 5% NFDM / TBST at room temperature for 1 hour, incubated with primary antibodies at 4°C overnight, and incubated with secondary antibodies at room temperature the next day for 2 hours. Signals were detected using a 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 decomposition ability of each concentration of the compound on IKZF1, IKZF3, CK1α and c-Myc protein in HL-60 cells, where A means that the decomposition percentage of GSPT1 protein is 80% or more, B means that the decomposition percentage is less than 80% and 50% or more, C means that the decomposition percentage is less than 50% and 25% or more, and D means that the decomposition percentage is less than 25%.

[0197] [Table 5]

[0198] Example 19: Anti-cell proliferation effects of compounds in combination with other drugs Logarithmic growth phase MOLM-13 cells were diluted in medium (RPMI + 20% FBS), and NCI-H929 cells were diluted in medium (RPMI + 10% FBS) and plated at 4000 cells / well, 50 μl / well in a 96-well plate with black walls and black bottom (WHB). After plating, incubation at 5% CO 2After 24 hours, the compounds were added to a 37°C incubator. Compounds were prepared in 10 mM stock solution with DMSO and diluted with culture medium to the required concentration (final DMSO concentration was 0.2%). 50 μl was then added to the 96 well plate containing the cells so that the final compound concentrations 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 set for each compound, and two duplicate wells were placed for each concentration. After the drug was added, the wells were incubated in 5% CO 2 The plates were then placed in a 37°C incubator and cultured for 72 hours. When drugs were used in combination, the concentrations of azacytidine and dexamethasone were kept at 200nM and 500nM, respectively, and the compounds were diluted in a 3-fold concentration gradient starting from 10,000nM. After the culture was completed, the plates were equilibrated at room temperature for 30 minutes, and 100μl of CellTiter-Glo® Reagent (Promega G7573) was added to each well and shaken for 12 minutes on a microplate shaker. Luminescence values ​​were measured at room temperature using a GloMax navigator (Promega GM2010). The IC was calculated using GraphPad Prism 7 software, with the 0nM control group as 0% inhibition. 50 values ​​were calculated.

[0199] [Table 6]

[0200] [Table 7]

[0201] The test results are shown in Table 6. From Table 6, the IC 50 The IC value of FDAB-121 was 751.1 nM, indicating that azacytidine at a concentration of 200 nM had no obvious anti-MOLM-13 cell proliferation activity. However, when FDAB-121 was combined with 200 nM azacytidine, the IC value of FDAB-121 increased to 751.1 nM. 50The activity increased from 247.9 nM to 9.675 nM, a roughly 25-fold increase in activity. When used alone or in combination with azacytidine, FDAB-121 was roughly 5-fold more active than CC-90009.

[0202] As shown in Table 7, the anti-NCI-H929 cell proliferation activity IC of dexamethasone 50 IC of FDAB-48 exceeds 10,000 nM, and 500 nM dexamethasone has no obvious anti-NCI-H929 cell proliferation activity. However, when FDAB-48 is combined with 500 nM dexamethasone, the anti-NCI-H929 cell proliferation activity IC of FDAB-48 is increased. 50 The IgG antibody titer increased from 14.26 nM to 2.447 nM, improving activity by approximately 6-fold. Furthermore, the anti-NCI-H929 cell proliferation activity of the FDAB-48 compound, either alone or in combination with dexamethasone, was much higher than that of CC-90009 and the first-line myeloma drugs lenalidomide and pomalidomide.

[0203] Example 20: Measurement of hERG inhibition The rapidly activating potassium channel encoded by the human ether-a-go-go-related gene (hERG) is a key ion channel involved in the formation of phase 3 repolarization of the myocardial action potential. Drugs that block the hERG channel can prolong cardiac repolarization, which is shown by the prolongation of the QT interval on the electrocardiogram, which is called long QT syndrome. Drug-induced delayed ventricular repolarization can cause torsades de pointes, a potentially fatal arrhythmia.

[0204] This assay is used to measure the effect of compounds on cloned hERG potassium channel expressed in human embryonic kidney cells (HEK293). The assay method is as follows: Cells were placed in HEPES-buffered saline in a glass-lined 96-well plate, and appropriate amounts of test solutions at each concentration and control solutions were loaded with an exposure duration of 3 minutes. The compounds to be tested were diluted in 0.3% DMSO. The compound's inhibition rate against hERG was tested under a concentration of 3 μM using an automated parallel patch clamp system QPatch 48 X (Sophion).

[0205] Results: The inhibition rates of compounds FDAB-48, FDAB-65, FDAB-120 and FDAB-121 against hERG at 3μM were 25%, 11%, 13% and 9%, respectively, which indicates that compounds FDAB-65, FDAB-120 and FDAB-121 have almost unobservable hERG inhibitory activity (<20% inhibition) at 3μM, and compound FDAB-48 has only slight hERG inhibitory activity (25% inhibition). Meanwhile, compound CC-90009 significantly inhibited hERG by 66% at 3μM. From this, it was found that the compounds of the present invention unexpectedly reduced the inhibitory activity against hERG channel.

[0206] Example 21: Efficacy study in acute myeloid leukemia xenograft mouse model For in vivo efficacy studies, immunocompromised 6-8 week old female NSG mice were used. Mice were housed in a laboratory environment for 7 days after arrival and before starting the experiment. Animals were housed in IVC (independently ventilated system) cages in an SPF grade animal room, with 6 mice per cage. Mice were inoculated via tail vein injection with luciferase expressing human MV-4-11 acute myeloid leukemia cells MV-4-11-luc (5 × 10 6Cells / animal). Seven days after inoculation of cells, mice were imaged using an IVIS Lumina III small animal imager, dosed in groups, and tumor-bearing mice were randomly assigned to vehicle control or compound treatment groups (6 per group). Animals in each treatment group were gavaged with compound (10 mg / kg twice daily). Body weights were measured daily, and mean luminescence was measured after initiation of treatment with compound or vehicle.

[0207] Experimental endpoints: Experimental endpoints 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 signal is determined as the number of exposed photons per second. The tumor inhibition effect of the compounds was evaluated by the tumor growth rate T / C (%). T / C%=T RTV / C RTV *100%(T RTV : RTV in the treatment group, C RTV : Negative control group RTV, RTV=V t / V 0 where V 0 is the tumor signal measured when drugs were administered separately in cages (i.e., day 0), V t (The tumor signal at each measurement is shown.) According to the guiding principles of the National Center for Drug Evaluation, T / C (%)>40% is considered as ineffective, and T / C≦40% and P<0.05 by statistical processing are considered as effective.

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

[0209] [Table 8]

[0210] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound represented by formula I below, a tautomer, stereoisomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (R １ is hydrogen, deuterium, C １～１２ Alkyl, 【Chemistry 2】 is selected from R ２ are identical or different and independently represent hydrogen, unsubstituted or optionally substituted by one or more R a , C １～１２ Alkyl, C ６～２０ Aryl, 5-20 membered heteroaryl, C ３～２０ cycloalkyl, 3- to 20-membered heterocyclyl; R′ and R ３ are identical or different and independently represent hydrogen, unsubstituted or optionally substituted by one or more Rb, C １～１２ Alkyl, C １～１２ Alkoxy, C ６～２０ Aryl, 5-20 membered heteroaryl, C ３～２０ cycloalkyl, 3- to 20-membered heterocyclyl; R ４ and R ５ are the same or different and are independently selected from hydrogen, deuterium, halogen, m is 1, 2 or 3; R ６ is hydrogen, deuterium, halogen, unsubstituted or optionally substituted by one or more Rc, C １～１２ Alkyl, C １～１２ alkoxy; Q １ is -CH ２ --, --CD ２ -, -C(O)-, or -C(S)-; R ７ , R ８ , R ９ , and R １０ are the same or different and are independently hydrogen, halogen, deuterium, CN, C １～１２ Alkyl, -CH ２ -NHBoc, -CH ２ -NH ２ , -CH ２ -NHCO-CF ２ -R １１ , -CH ２ -NHCO-R １２ , -CH ２ -NHCO-Y-R １３ , -CH ２ -NH-Y-R １４ , -CH ２ -NHCONH-R １２ and said -CH ２ -NHBoc, -CH ２ -NH ２ , -CH ２ -NHCO-CF ２ -R １１ , -CH ２ -NHCO-R １２ , -CH ２ -NHCONH-R １２ , -CH ２ -NHCO-Y-R １３ , -CH ２ -NH-Y-R １４ The hydrogen on the methylene is optionally replaced by one or two deuterium atoms; R １１ , R １２ , R １３ , and R １４ are identical or different and, independently of each other, unsubstituted or optionally substituted by one or more Rs; ６～２０ Aryl, 5-20 membered heteroaryl, C ３～２０ Cycloalkyl, 3- to 20-membered heterocyclyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C １～１２ Alkyl, -P(C ６～２０ Aryl) ２ , -N(C １～１２ Alkyl) ２ , -COC １～１２ Alkyl, -C １～１２ AlkylN(C １～１２ Alkyl) ２ , C ６～２０ Aryl C ３～２０ Cycloalkyl, C ３～２０ Cycloalkyl and C ３～２０ spiro groups consisting of cycloalkyl; Y is C １～１２ Alkylene, C ３～２０ Cycloalkylene, C ２～１２ Alkenylene, C ２～１２ Alkynylene, -CH ２ NH-, -CH ２ NHCO-, -CH ２ NHCO-, -CH ２ O-, -C ２ H ４ O-, -CH ２ S-, 【Chemistry 3】 is selected from Ra, Rb, Rc, and Rs are the same or different and each independently represent halogen, amino, hydroxy, C １～１２ Alkyl, C １～１２ Alkoxy, HaloC １～１２ Alkyl, C, N ３～２０ Cycloalkyl, -N(C １～１２ Alkyl) ２ , deuterated group, C ２～１２ Alkenyl, C ２～１２ Alkynyl, -COC １～１２ Alkyl, -COC ６～２０ Aryl, C １～１２ Alkylthio, mercapto, =O, -C １～１２ Alkylhydroxy, 3- to 20-membered heterocyclyl, -SO ２ C １～１２ Alkyl, -SO ２ N.H. ２ , C ６～２０ Aryl, -OC ６～２０ Aryl, -C １～１２ Alkyl C ６～２０ Aryl, -C １～１２ Alkylamino, -C ６～２０ Aryl C １～１２ Alkylamino, -C ６～２０ Arylamino, -OC １～１２ Alkyl C ６～２０ Aryl, -C ６～２０ Arylhydroxy, -C ６～２０ Aryl C １～１２ alkylhydroxy.

2. R １ is hydrogen, C １～６ Alkyl, -C １～６ Alkyl COOC １～６ Alkyl, -COOC １～６ Alkyl, or -C １～６ Alkyl OCOOC １～６ alkyl, R ４ , R ５ , and R ６ is selected from hydrogen, m is 1, 2 or 3, and Q １ is -CH ２ - or -C(O)-, R ７ , R ８ , R ９ , and R １０ are the same or different and independently represent hydrogen, a deuterated group, a halogen, CN, C １～６ Alkyl, -CH ２ -NHBoc, -CH ２ -NH ２ , -CH ２ -NHCO-CF ２ -R １１ , -CH ２ -NHCO-R １２ , -CH ２ -NHCONH-R １２ , -CH ２ -NHCO-Y-R １３ , -CH ２ -NH-Y-R １４ and said -CH ２ -NHBoc, -CH ２ -NH ２ , -CH ２ -NHCO-CF ２ -R １１ , -CH ２ -NHCO-R １２ , -CH ２ -NHCONH-R １２ , -CH ２ -NHCO-Y-R １３ , -CH ２ -NH-Y-R １４ CH ２ wherein the hydrogen is optionally replaced by one or two deuterium atoms; R １１ , R １２ , R １３ , and R １４ are identical or different and, independently of each other, unsubstituted or optionally substituted by one or more Rs; ６～１２ Aryl, 5-12 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 Aryl C ３～１２ Cycloalkyl, C ３～１２ Cycloalkyl and C ３～１２ spiro groups consisting of cycloalkyl; Y is C １～６ Alkylene, C ３～１２ Cycloalkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, -CH ２ NH-, -CH ２ NHCO-, -CH ２ NHCO-, -CH ２ O-, -C ２ H ４ O-, -CH ２ S-, 【Chemistry 4】 is selected from Rs are the same or different and are independently selected from halogen, amino, hydroxy, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, C, N ３～１２ Cycloalkyl, -N(C １～６ Alkyl) ２ , deuterated group, C ２～６ Alkenyl, C ２～６ Alkynyl, -COC １～６ Alkyl, -COC ６～１２ Aryl, C １～６ Alkylthio, mercapto, =O, -C １～６ Alkylhydroxy, 3- to 12-membered heterocyclyl, -SO ２ C １～６ Alkyl, -SO ２ N.H. ２ , C ６～１２ Aryl, -OC ６～１２ Aryl, -C １～６ Alkyl C ６～１２ Aryl, -C １～６ Alkylamino, -C ６～１２ Aryl C １～６ Alkylamino, -C ６～１２ Arylamino, -OC １～６ Alkyl C ６～１２ Aryl, -C ６～１２ Arylhydroxy, -C ６～１２ Aryl C １～６ 2. The compound of claim 1, wherein the aryl group is selected from alkyl, alkylhydroxy.

3. 3. The compound according to claim 1, wherein formula I is selected from the structures of formula Ia: 【Chemistry 5】 (In formula Ia, R １ is hydrogen, C １～６ Alkyl, -C １～６ Alkyl COOC １～６ Alkyl, -COOC １～６ Alkyl, or -C １～６ Alkyl OCOOC １～６ alkyl, R ４ , R ５ , and R ６ is selected from hydrogen or deuterium, m is 1, 2 or 3, and Q １ is -CH ２ --, --CD ２ - or -C(O)-, R ７ ' is selected from hydrogen, deuterium, halogen, and p is 1, 2, or 3, provided that at least one R ７ ' is selected from halogens, R ８ ' is CN, -CH ２ -NHBoc, -CH ２ -NH ２ , -CH ２ -NHCO-CF ２ -R １１ , -CH ２ -NHCO-R １２ , -CH ２ -NHCONH-R １２ , -CH ２ -NHCO-Y-R １３ , -CH ２ -NH-Y-R １４ and said -CH ２ -NHBoc, -CH ２ -NH ２ , -CH ２ -NHCO-CF ２ -R １１ , -CH ２ -NHCO-R １２ , -CH ２ -NHCONH-R １２ , -CH ２ -NHCO-Y-R １３ , -CH ２ -NH-Y-R １４ CH ２ wherein H is optionally replaced by one or two deuterium atoms; R １１ , R １２ , R １３ , and R １４ are identical or different and, independently of each other, unsubstituted or optionally substituted by one or more Rs; ６～１２ Aryl, 5-12 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 Aryl C ３～１２ Cycloalkyl, C ３～１２ Cycloalkyl and C ３～１２ spiro groups consisting of cycloalkyl; Y is C １～６ Alkylene, C ３～１２ Cycloalkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, -CH ２ NH-, -CH ２ NHCO-, -CH ２ NHCO-, -CH ２ O-, -C ２ H ４ O-, -CH ２ S-, 【Chemistry 6】 is selected from Rs are the same or different and are independently selected from halogen, amino, hydroxy, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, C, N ３～１２ Cycloalkyl, -N(C １～６ Alkyl) ２ , deuterated group, C ２～６ Alkenyl, C ２～６ Alkynyl, -COC １～６ Alkyl, -COC ６～１２ Aryl, C １～６ Alkylthio, mercapto, =O, -C １～６ Alkylhydroxy, 3- to 12-membered heterocyclyl, -SO ２ C １～６ Alkyl, -SO ２ N.H. ２ , C ６～１２ Aryl, -OC ６～１２ Aryl, -C １～６ Alkyl C ６～１２ Aryl, -C １～６ Alkylamino, -C ６～１２ Aryl C １～６ Alkylamino, -C ６～１２ Arylamino, -OC １～６ Alkyl C ６～１２ Aryl, -C ６～１２ Arylhydroxy, -C ６～１２ Aryl C １～６ alkylhydroxy.

4. Formula I is selected from the structures shown in formula Ib below: Alternatively, formula I is selected from the structure shown in formula Ic: Alternatively, the compound according to claim 1 or 2, characterized in that formula I is selected from the structure shown in formula Id: 【Chemistry 7】 (In formula Ib, R １５ , R １６ , R １７ , and R １８ are the same or different and independently represent hydrogen, deuterium, halogen, amino, hydroxy, cyano, unsubstituted or optionally substituted by one or more Rx, C １～６ Alkyl, -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 N.H. ２ is selected from Rx are the same or different and are independently selected from halogen, amino, hydroxy, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, C, N ３～１２ Cycloalkyl, -N(C １～６ Alkyl) ２ , deuterated group, C ２～６ Alkenyl, C ２～６ Alkynyl, -COC １～６ Alkyl, -COC ６～１２ Aryl, C １～６ Alkylthio, mercapto, =O, -C １～６ Alkylhydroxy, -C １～６ Alkylamino, 3- to 12-membered heterocyclyl, -SO ２ C １～６ Alkyl, -SO ２ N.H. ２ , C ６～１２ Aryl, -OC ６～１２ Aryl, -C １～６ Alkyl C ６～１２ aryl.) 【Chemistry 8】 (In formula Ic, R １５ , R １６ , R １７ , R １８ , and R １９ are the same or different and independently represent hydrogen, deuterium, halogen, amino, hydroxy, cyano, unsubstituted or optionally substituted by one or more Rx, C １～６ Alkyl, -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 N.H. ２ is selected from Rx are the same or different and are independently selected from halogen, amino, hydroxy, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, C, N ３～１２ Cycloalkyl, -N(C １～６ Alkyl) ２ , deuterated group, C ２～６ Alkenyl, C ２～６ Alkynyl, -COC １～６ Alkyl, -COC ６～１２ Aryl, C １～６ Alkylthio, mercapto, =O, -C １～６ Alkylhydroxy, -C １～６ Alkylamino, 3- to 12-membered heterocyclyl, -SO ２ C １～６ Alkyl, -SO ２ N.H. ２ , C ６～１２ Aryl, -OC ６～１２ Aryl, -C １～６ Alkyl C ６～１２ aryl, and R １９ is not H.) 【Chemistry 9】 (In Id, L is a chemical bond, C ２～１２ Alkynyl, C ２～１２ Alkenyl, NH, oxygen, sulfur or C １～１２ alkyl, １～１２ The alkyl is optionally substituted with hydroxy, amino, R ２０ is unsubstituted or optionally substituted by one or more Ry; ６～１２ aryl, 3- to 12-membered cycloalkyl, 5- to 12-membered heterocyclyl, or 5- to 12-membered heteroaromatic ring group; Ry is a deuterated group, halogen, hydroxy, amino, carboxy, CN, C １～６ Alkyl, C １～６ Alkoxy, HaloC 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, 3- to 12-membered heterocyclyl, -SO ２ C １～６ Alkyl, -SO ２ N.H. 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.

5. In formula Ib, R １５ , R １６ , R １７ , and R １８ are the same or different and are each independently 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 N.H. ２ , hydroxymethyl, N-tetrahydropyrrolyl, -SO ２ CH ２ , p-aminophenyl, 【Chemistry 10】 is selected from Preferably, in Id, L is a chemical bond, alkynyl, NH, 【Chemistry 11】 and R ２０ is phenyl, Ry is Cl, hydroxy, amino, tert-butyl, phenyl, p-aminophenyl, p-hydroxyphenyl, ethylamino, hydroxyethyl, p-hydroxyethylphenyl, p-ethylaminophenyl, 【Chemistry 12】 5. The compound according to claim 4, wherein said compound is selected from the group consisting of:

6. The compound according to any one of claims 1 to 5, characterized in that the compound of formula I is selected from: 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 【Chemistry 13-4】 【Chemistry 13-5】 【Chemistry 13-6】 【Chemistry 13-7】

7. Use of a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 6, in the manufacture of a medicament for treating or preventing a disease, illness, or condition associated with mutations, imbalances in expression, allostery, and abnormalities in function of proteins such as GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC.

8. The diseases, conditions or symptoms include myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, papillary and follicular thyroid cancer, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary body melanoma and chronic melanoma, iris melanoma, recurrent interocular melanoma, ocular 8. The use according to claim 7, characterized in that the cancer includes: extracellular melanoma, solid tumors, T-cell lymphoma, erythrocytic lymphoma, monoblastic and monocytic leukemia, myeloid leukemia, central nervous system lymphoma, brain tumor, meningioma, spinal tumor, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, Burkitt's lymphoma, Hodgkin's lymphoma, large cell lymphoma, diffuse large B-cell lymphoma, astrocytoma, hepatocellular carcinoma or primary macroglobulinemia, viral infections.

9. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 6, or a tautomer, stereoisomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof.

10. In addition to the compound of formula I which is the active ingredient, other therapeutic agents may be included, and the other therapeutic agents may be PD-1 inhibitors, PD-L1 inhibitors, rituximab, trastuzumab, elotuzumab, utuximab, daratumumab, atlizumab, ibritumomab, alemtuzumab, brentuximab, cytarabine, azacitidine, anthracycline drugs, prednisone, dexamethasone, melphalan, cladribine, fludarabine, mitoxantrone, etoposide, methotrexate, tetracycline ... at least one selected from among treoxat, pemetrexed, topotecan, doxorubicin, cyclophosphamide, gemcitabine, dacarbazine, clarithromycin, vincristine, docetaxel, clofarabine injection, HDAC inhibitors, FLT3 inhibitors, IDH1 / 2 inhibitors, BCL-2 inhibitors, proteasome inhibitors, PI3K inhibitors, BTK inhibitors, palbociclib, erythrocyte growth hormone, eltrombopag, minocycline, and CAR-T; Preferably, in addition to the compound of formula I as an active ingredient, it further contains azacitidine or dexamethasone, 10. The pharmaceutical composition according to claim 9, characterized in that it is preferably administered by oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous and transdermal administration.

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