WO2023207241A1 - 卤素取代异吲哚啉化合物及其应用 - Google Patents

卤素取代异吲哚啉化合物及其应用 Download PDF

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WO2023207241A1
WO2023207241A1 PCT/CN2023/074286 CN2023074286W WO2023207241A1 WO 2023207241 A1 WO2023207241 A1 WO 2023207241A1 CN 2023074286 W CN2023074286 W CN 2023074286W WO 2023207241 A1 WO2023207241 A1 WO 2023207241A1
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alkyl
aryl
group
nhco
cycloalkyl
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French (fr)
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胡伟
王力强
蔡鑫
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成都分迪药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to halogen-substituted isoindoline compounds and their applications.
  • Protein mutations, expression imbalance, allostery and functional abnormalities can cause many diseases. Protein synthesis or degradation is a strictly regulated process in space and time during cell growth and proliferation. Abnormal regulation of these processes may lead to uncontrolled growth, proliferation, and migration of cells, leading to the occurrence of diseases such as cancer, aging, and viral infection.
  • the translation termination factor GSPT1 (eRF3a) is closely related to diseases such as cancer. It can mediate stop codon recognition and promote the release of nascent peptides from ribosomes. In addition to its function in translation termination, GSPT1 is involved in several other key cellular processes, such as cell cycle regulation, cytoskeletal organization, and apoptosis. GSPT1 is an oncogenic driver in multiple cancer types, including hematoma, breast, liver, gastric, and prostate cancers. In addition, GSPT1 is significantly upregulated in cancer tissues and cell lines, its high expression is positively correlated with tumor size, and its overexpression can promote cancer cell proliferation and migration.
  • GSPT1 depletion can effectively inhibit the proliferation and migration of cancer cells and induce apoptosis of invasive colon cancer cells in vitro, and inhibit the tumorigenicity of HCT116 colon cancer cells in vivo.
  • recent studies have shown that downregulation of GSPT1 is also effective in treating cystic fibrosis, Lassa virus, and Ebola virus infections.
  • the Ikaros zinc finger (IKZF) family of transcription factors is a regulator of hematopoietic cell development and differentiation 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).
  • Ikaros encoded by the gene IKZF1
  • IKZF2 Helios
  • IKZF3 Aiolos
  • Eos IKZF4
  • Pegasus IKZF5
  • Aiolos plays an important role in the maturation of B and T cells. Increased Aiolos expression can promote cell survival by regulating Bcl2 family proteins in chronic lymphocytic leukemia. Increased Aiolos expression has been detected in follicular center cell lymphoma. Aiolos cooperates with Blimp-1 to regulate multiple myeloma cell survival. In addition, in solid tumors, overexpression of Aiolos can also promote epithelial-mesenchymal transition and cancer stem cell-like properties of lung cancer cells.
  • the present invention provides a compound represented by the following formula I, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt:
  • R 1 is selected from hydrogen, deuterium, C 1-12 alkyl,
  • R 2 is the same or different, independently selected from hydrogen, the following groups that are unsubstituted or optionally substituted by one, two or more Ra: C 1-12 alkyl, C 6 - 20 aryl, 5-20 3-20-membered heteroaryl, C 3-20 cycloalkyl, 3-20-membered heterocyclyl;
  • R' and R 3 are the same or different, and are independently selected from the following groups: hydrogen, unsubstituted or optionally substituted by one, two or more Rb: C 1-12 alkyl, C 1-12 alkoxy , C 6-20 aryl group, 5-20 membered heteroaryl group, C 3-20 cycloalkyl group, 3-20 membered heterocyclyl group;
  • R 4 and R 5 are the same or different, and are independently selected from hydrogen, deuterium and halogen;
  • n 1, 2 or 3;
  • R 6 is selected from hydrogen, deuterium, halogen, unsubstituted or the following groups optionally substituted by one, two 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 selected from 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 ; 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 , - The hydrogen on the methylene group of CH 2 -NH-YR 14 is optionally replaced by 1 or 2 deuterons;
  • R 11 , R 12 , R 13 , and R 14 are the same or different, and are independently selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rs: C 6 - 20 aryl, 5-20 Heteroaryl, C 3-20 cycloalkyl, 3-20 heterocyclyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkyl, -P(C 6 - 20 aryl base) 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 and C A spirocyclic group composed of 3-20 cycloalkyl, C 3-20 cycloalkyl and C 3-20 cycloalkyl;
  • Y is selected from 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-,
  • R 1 is selected from hydrogen, C 1-6 alkyl, -C 1-6 alkylCOOC 1-6 alkyl, -COOC 1-6 alkyl or -C 1-6 alkyl OCOOC 1-6 alkyl;
  • R 4 , R 5 and R 6 are selected from hydrogen; m is 1, 2 or 3; Q 1 is -CH 2 - or -C(O)-;
  • R 7 , R 8 , R 9 , R 10 are the same or different, and are independently selected from hydrogen, deuterated, 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 ; 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 ,
  • the hydrogen on CH 2 of -CH 2 -NH-YR 14 is optionally replaced by 1 or 2 deuterons;
  • R 11 , R 12 , R 13 , and R 14 are the same or different, and are independently selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rs: C 6 - 12 aryl, 5-12 Heteroaryl, C 3-12 cycloalkyl, 3-12 heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, -P(C 6 - 20 aryl base) 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 and C A spirocyclic group composed of 3-12 cycloalkyl, C 3-12 cycloalkyl and C 3-12 cycloalkyl;
  • Y is selected from 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-,
  • Formula I has the structure shown in Formula I-1 below:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and Q 1 have the above definitions.
  • Formula I has the structure shown in Formula I-2 below:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and Q 1 have the above definitions.
  • Formula I has the structure shown in Formula I-3 below:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and Q 1 have the above definitions.
  • Formula I is selected from the following structures represented by Formula Ia:
  • R 1 is selected from hydrogen, C 1-6 alkyl, -C 1-6 alkylCOOC 1-6 alkyl, -COOC 1-6 alkyl or -C 1-6 alkylOCOOC 1-6 alkyl;
  • R 4 , R 5 , R 6 are selected from hydrogen or deuterium
  • n 1, 2 or 3;
  • Q 1 is -CH 2 -, -CD 2 - or -C(O)-;
  • R 7 ' is selected from hydrogen, deuterium and halogen; p is 1, 2 or 3, provided that at least one R 7 ' is selected from halogen;
  • R 8 ' is selected from 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 ; the -CH 2 -NHBoc, -CH 2 -NH 2 , -CH 2 -NHCO-CF 2 -R 11 , -CH 2 -NHCO
  • the H on CH 2 of -R 12 , -CH 2 -NHCONH-R 12 , -CH 2 -NHCO-YR 13 , -CH 2 -NH-YR 14 is optionally replaced by 1 or 2 deuteriums;
  • R 11 , R 12 , R 13 , and R 14 are the same or different, and are independently selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rs: C 6 - 12 aryl, 5-12 Heteroaryl, C 3-12 cycloalkyl, 3-12 heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, -P(C 6 - 20 aryl base) 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 and C A spirocyclic group composed of 3-12 cycloalkyl, C 3-12 cycloalkyl and C 3-12 cycloalkyl;
  • Y is selected from 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-,
  • At least one of R 7 , R 8 , R 9 , and R 10 is halogen.
  • one of R 7 , R 8 , R 9 and R 10 is halogen, or two is halogen, or three is halogen.
  • one of R 7 , R 8 , R 9 and R 10 is F.
  • formula I is selected from the structure represented by the following formula Ib:
  • R 15 , R 16 , R 17 , and R 18 are the same or different, and are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and cyano, and are unsubstituted or optionally substituted by one, two or more The following groups substituted by 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 - 12aryl , -OC 6 - 12aryl , -C 1-6 alkyl-hydroxy, 3-12 membered heterocyclyl, -SO 2 NH 2 ;
  • R 15 , R 16 , R 17 , and R 18 are the same or different, and are independently selected from hydrogen, deuterium, F, Cl, methyl, amino, hydroxyl, and methoxy. , trifluoromethyl, cyano, phenyl, dimethylamino, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, ethynyl, cyclopropyl, carbonylmethyl, carbonylphenyl, benzene Oxygen, tert-butoxy group, alkylthio group, -SO 2 NH 2 , hydroxymethyl group, N-tetrahydropyrrolyl group, -SO 2 CH 2 , p-aminophenyl group,
  • formula Ib is prepared by the following method:
  • R 15 , R 16 , R 17 , and R 18 have the above definitions;
  • formula I is selected from the following structures represented by formula Ic:
  • R 15 , R 16 , R 17 , R 18 , and R 19 are the same or different, and are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and cyano, and are unsubstituted or optionally substituted by one, two or More Rx substituted groups as follows: 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 ;
  • formula Ic is prepared by the following method:
  • R 15 , R 16 , R 17 , R 18 , and R 19 have the above definitions;
  • formula I is selected from the following structures represented by formula Id:
  • L is a chemical bond, C 2-12 alkynyl group, C 2-12 alkenyl group, NH, oxygen, sulfur or C 1-12 alkyl group, and the C 1-12 alkyl group is optionally substituted by the following group: Hydroxy, amino;
  • R 20 is the following group that is unsubstituted or optionally substituted by one, two or more Ry: C 6 - 12 aryl, 3-12 membered cycloalkyl, 5-12 membered heterocyclyl or 5-12 One-membered heteroaromatic ring group;
  • L is a chemical bond, C 2-12 alkynyl, C 2-12 alkenyl, NH or C 1-6 alkyl; the C 1-6 alkyl is optionally represented by the following Group substitution: hydroxyl, amino;
  • R 20 is the following group that is unsubstituted or optionally substituted by one, two or more Ry: C 6 - 12 aryl group or 5-12 membered heteroaromatic ring group;
  • Ry is selected from hydroxyl, 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 alkyl hydroxyl, -C 1-6 alkyl -COOH, -C 6 - 12 aryl -C 1-3 alkyl hydroxylamino group, -C 6 - 12 aryl -C 1-3 alkyl hydroxyl group, -C 6 - 12 arylamino group or -C 6 - 12 aryl hydroxyl group.
  • L is a chemical bond, alkynyl group, NH,
  • R 20 is phenyl
  • Ry is selected from Cl, hydroxyl, amino, tert-butyl, phenyl, p-aminophenyl, p-hydroxyphenyl, ethylamino, hydroxyethyl, p-hydroxyethylphenyl, p-ethylaminophenyl,
  • the compound represented by formula Id is prepared by the following method:
  • R 20 and L have the above definitions
  • the compound of formula I is selected from the following:
  • the pharmaceutically acceptable salt is selected from the group consisting of salts as defined below, for example salts include but are not limited to hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, esters Acid, oxalate, citrate, methanesulfonate, formate or meglumine salt, preferably hydrochloride.
  • the present invention also provides compounds represented by formula I as mentioned above, and their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts are used in the preparation of treatments or prevention of GSPT1, IKZF1, IKZF2, Use in drugs for diseases, disorders or conditions related to protein mutations, expression imbalance, allostery and functional abnormalities such as IKZF3, CK1 ⁇ , N-MYC or C-MYC.
  • the disease, disorder or condition includes: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin 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 and chronic melanoma, iris melanoma, recurrent interocular melanoma, extraocular extension melanoma, solid tumors, T Cellular lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia, myeloid leukemia (such as acute mye
  • the present invention also provides a pharmaceutical composition, which includes the compound represented by Formula I as above, its tautomers, stereoisomers isomers, hydrates, solvates, or pharmaceutically acceptable salts.
  • the pharmaceutical composition in addition to the compound represented by the active ingredient Formula I, further contains other therapeutic agents, and the other therapeutic agents include but are not limited to: PD-1 inhibitors (such as sodium Volumab, pembrolizumab, cimepilimab), PD-L1 inhibitors (such as atezolizumab, avelumab, durvalumab), rituximab anti, trastuzumab, elotuzumab, utuximab, daratumumab, atolizumab, itumolizumab, alemtuzumab, brentuximab, Cytarabine, azacitidine, anthracyclines, prednisone, dexamethasone, melphalan, cladribine, fludarabine, mitoxantrone, etoposide, methotrexate, Pemetrexed, topotecan, doxorubicin,
  • PD-1 inhibitors such as
  • BCL-2 inhibitors e.g. venetoclax
  • proteasome inhibitors e.g. bortezomib, carfilzomib, ixazomib
  • PI3K inhibitors e.g. bortezomib, carfilzomib, ixazomib
  • BTK Inhibitors such as zanubrutinib, acalabrutinib, ibrutinib, tiragrutinib, orelabrutinib
  • palbociclib erythrocyte growth hormone, eltrombopag, minocycline, CAR -At least one of T.
  • the pharmaceutical composition in addition to the compound represented by Formula I as an active ingredient, also includes azacitidine or dexamethasone.
  • the pharmaceutical composition is used to treat or prevent diseases related to protein mutations, expression imbalance, allostery and functional abnormalities such as GSPT1, IKZF1, IKZF2, IKZF3, CK1 ⁇ , N-MYC or C-MYC. , disease or condition.
  • the disease, disorder or condition includes: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin 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 and chronic melanoma, iris melanoma, recurrent interocular melanoma, extraocular extension melanoma, solid tumors, T Cellular lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia, myeloid leukemia (such as acute mye
  • the compound or pharmaceutical composition represented by Formula I can be administered in the following ways: oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous and transdermal administration. .
  • the pharmaceutical composition is administered orally.
  • the compound of the present invention has regulatory effects on proteins such as GSPT1, IKZF1, IKZF2, IKZF3, CK1 ⁇ , N-MYC or C-MYC, and has anti-tumor and anti-cancer activities, especially strong effects on acute myeloid leukemia and myeloma cells. inhibition active.
  • the active advantages of the compound of the present invention are mainly reflected in:
  • the inventor unexpectedly discovered that the anti-tumor cell proliferation activity of the halogen-substituted compound of the present invention was greatly improved compared to its unsubstituted compound, and at the same time, the degradation effect on proteins such as GSPT1 was significantly improved.
  • the anti-MV-4-11 cell proliferation activity IC 50 of the halogen-substituted compound FDAB-48 of the present invention is 10.8 nM, and it can degrade GSPT1 protein by 88% when co-incubated in NB-4 cells for 6 hours, while the compound without halogen substitution compound
  • the IC 50 of anti-MV-4-11 cell proliferation activity is 102.6nM, and its degradation effect on GSPT1 protein after co-incubation in NB-4 cells for 6 hours is only 65%.
  • the compound of the present invention has almost no observable hERG channel inhibitory activity (9-25% inhibition) at a concentration of 3 ⁇ M, while the existing clinical compound CC-90009 has obvious hERG channel inhibitory activity (66% inhibition) .
  • the existing compound under clinical development, CC-90009 is an injection.
  • the compound of the present invention has significant tumor-inhibiting activity in mouse transplanted tumor models, while the compound CC-90009 has no tumor-inhibiting activity at the same dose orally. It shows that compared with compound CC-90009 (injection), the compound of the present invention can be made into an oral dosage form that is more convenient, safe and economical for administration.
  • the compound of the present invention has significantly better anti-tumor activity, and can be made into an oral dosage form that is more convenient, safe and economical for administration. Therefore, its utilization value is significantly improved compared with existing compounds.
  • “more/kind” shall refer to the situation greater than 2, for example, indicating the situation of an integer greater than or equal to 3, such as 3, 4 , 5, 6, 7, 8, 9 or 10 pieces/species.
  • a heterocyclic group optionally substituted by an alkyl group means that the alkyl group may but does not necessarily exist, thus including heterocyclic groups substituted by an alkyl group and heterocyclic groups not substituted by an alkyl group.
  • halogen means fluorine, chlorine, bromine and/or iodine. Accordingly, the term “halo” means fluoro, chloro, bromo and/or iodo.
  • halogen means fluorine, chlorine, bromine and/or iodine.
  • halo means fluoro, chloro, bromo and/or iodo.
  • the atoms at the halogenated position may be mono-, di- or multi-substituted up to fully substituted by halogen atoms.
  • C 1-12 alkyl is understood to preferably mean a linear or branched saturated monovalent hydrocarbon radical having 1 to 12 carbon atoms, preferably Choose C 1-6 alkyl.
  • C 1-6 alkyl is understood to mean preferably a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group 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 base, 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 their isomers.
  • said groups have 1, 2 or 3 carbon atoms ("C 1-3 alkyl
  • C 2-12 alkenyl is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 12 carbon atoms, preferably "C 2-6 alkenyl".
  • C 2-6 alkenyl is understood to mean preferably a linear or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6 carbon atoms, in particular 2 or 3 carbon atoms ("C 2-3 alkenyl”), it being understood that where the alkenyl group contains more than one double bond, the double bonds may be isolated from each other or conjugated.
  • the alkenyl group is, 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, (Z)-pent-1-enyl base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-en
  • C 2-12 alkynyl is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2 to 12 carbon atoms, preferably "C 2 -C 6 alkynyl” .
  • C 2 -C 6 alkynyl is understood to mean preferably a linear or branched monovalent hydrocarbon radical which contains 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").
  • the alkynyl group is, 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-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-ynyl, 1-
  • C 3-20 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably “C 3-12 cycloalkyl”.
  • C 3-12 cycloalkyl is 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.
  • the C 3-12 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecanyl, or a bicyclic hydrocarbon group such as a decalin ring.
  • 3-20-membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably “3-12-membered heterocyclyl” ".
  • 3-12 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclyl group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclyl group may include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl Or trithialkyl; or 7-membered ring, such as diazacycloheptyl.
  • 4-membered rings such as azetidinyl, oxetanyl
  • 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl
  • the heterocyclyl group may be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing nitrogen atoms may be partially unsaturated, i.e.
  • the heterocyclyl group is nonaromatic.
  • C 6-20 aryl is 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”.
  • C 6-12 aryl is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12 carbon atoms.
  • C 6-12 aryl especially a ring with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C 6 aryl”) 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring with 13 A ring having 14 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • 5-20 membered heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 independently selected from N, O and S heteroatoms, such as "5-12 membered heteroaryl".
  • the term “5-12 membered heteroaryl” is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms , in particular 5 or 6 or 9 or 10 carbon atoms, and which contains 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in addition in each case, benzene and fused.
  • the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl, thi-4H-pyrazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene Triazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinoline base, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridinyl or pyridylene includes pyridin-2-yl, pyridinylene- 2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl and pyridin-4-yl;
  • thienyl or thienylene includes thiophen-2-yl, thiophenylene-2-yl, Thiophen-3-yl and thiophene-3-yl.
  • C 1-12 alkyl is also applicable to other terms containing “C 1-12 alkyl", such as the terms “C 1-12 alkoxy”, “halogenated 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-C 1-6 alkyl hydroxy", “-N( C 1-6 alkyl) 2 ”, “-C 1-6 alkyl hydroxyl” and so on.
  • C 1-6 alkyl in this group is the same as that defined above.
  • C 6-12 aryl “C 3-20 cycloalkyl”, “5-20 membered heteroaryl”, “3-20 membered heterocyclyl” , etc. have the same definitions throughout the text.
  • C 1-12 haloalkyl and “halo C 1-12 alkyl” have the same meaning, and both refer to the substituent formed by replacing the above-mentioned "C 1-12 alkyl” with halogen.
  • C 6-20 aryl and C 3-20 cycloalkyl refers to the above-mentioned C 6-20 aryl and C 3-20 cycloalkyl groups composed of at least 2 carbon atoms in common .
  • C 3-20 cycloalkyl in the term "spirocyclic group composed of C 3-20 cycloalkyl and C 3-20 cycloalkyl" is the same as above, which refers to two C 3-20 cycloalkyl groups sharing A spirocyclic group composed of 1 carbon atom.
  • C 1-12 alkylthio refers to -SC 1-12 alkyl, wherein C 1-12 alkyl is as defined above.
  • Boc is tert-butoxycarbonyl.
  • pharmaceutically acceptable salts refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and have appropriate biological activity.
  • Pharmaceutically acceptable salts include sufficiently basic acid addition salts of compounds of the invention having nitrogen atoms in the chain or ring.
  • basic nitrogen-containing groups 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 sulfuric acid Dimethyl, diethyl, dibutyl and dipyl sulfate; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Halides such as benzyl and phenethyl bromide, etc.
  • physiologically/pharmaceutically acceptable salts include, but are not limited to, hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, methanesulfonic acid Salt, formate or meglumine salt, etc.
  • the physiologically/pharmaceutically acceptable salts include not only the salt formed at one salt-forming site of the compound of the present invention, but also 2 and 3 of them. Or salt formed at all salt-forming sites.
  • the molar ratio of the compound of formula (I) to the acid radical ion (anion) or base cation required for salt formation can vary within a wide range, For example, it can be 4:1-1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
  • 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 was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • the NMR spectrum was obtained by a Bruker Avance-400 instrument, and the mass spectrum was obtained by a liquid chromatography-mass spectrometry (LC-MS) coupled instrument Agilent Technologies 6110. Use ESI ion source.
  • T1-1 Dissolve cuprous cyanide (5.28g, 59.0mmol) and tert-butyl nitrite (14g, 136.1mmol) in 100 ml of dimethyl sulfoxide, raise the temperature and maintain the temperature at 60°C, stir and react for about 30 minutes, and then a solution of 4-bromo-3-fluoro-2-methylaniline (10 g, 49.0 mmol) in dimethyl sulfoxide (20 ml) was slowly added dropwise for about 30 minutes. After continuing to stir the reaction at 60°C for about 1 hour, LCMS detection showed that the raw materials had disappeared.
  • reaction solution was lowered to room temperature, 6M hydrochloric acid solution was added dropwise to the reaction solution to quench the reaction, and then ethyl acetate (2 x 100 ml) was added for extraction and liquid separation.
  • the organic phases were combined and backwashed with saturated brine.
  • T1-2 Synthesis of T1-2: Mix intermediate T1-1 (4.5g, 21.0mmol) and aqueous sodium hydroxide solution (5M, 50ml). The mixed liquid system was heated to 100°C and stirred for about 16 hours. LCMS detection showed that the T1-1 reaction was complete. Lower the reaction solution to room temperature and add 6M hydrochloric acid solution dropwise to the reaction solution in an ice bath to adjust the acidity to ⁇ 1. A large amount of solids will be produced in the reaction solution during the acid adjustment process. Filter and rinse the filter cake twice with distilled water. After drying the filter cake, a light yellow solid T1-22.4g was obtained, with a yield of 50%.
  • T1-5 Dissolve intermediate T1-4 (3.9g, 20.0mmol) and N-bromosuccinimide (5.4g, 30.0mmol) in 50 ml of chloroform and raise the temperature to 65°C, then add A catalytic amount of azobisisobutyronitrile (0.1g) was added and the reaction was continued to stir at this temperature for about 4 hours. LCMS detection showed that the raw material had disappeared. Cool to room temperature, suction filter, wash the filter cake with 30 ml of methylene chloride, add 30 ml of water to the filtrate to dilute and add methylene chloride (2x 30 ml) for extraction and separation. The organic phases were combined and backwashed with saturated brine.
  • FDAB-4, FDAB-5 and FDAB-6 starts from the raw material 4-bromo-5-fluoro-2-methylaniline, with reference to the methods of FDAB-1, FDAB-2 and FDAB-3 in Examples 1 to 3 above. resolve resolution.
  • the characterization data of the obtained compounds FDAB-4, FDAB-5 and FDAB-6 are shown in Table 1 below.
  • FDAB-120 was prepared by replacing the above raw material 2-fluoro-4-methylbenzoic acid with 3-fluoro-4-methylbenzoic acid.
  • FDAB-3 is used to react with the corresponding aldehydes to obtain compounds FDAB-165, FDAB-167, and FDAB-168. To save space, no details will be given here.
  • the characterization data of these compounds are shown in Table 1 below.
  • Example 14 Anti-proliferative activity of compounds against MV-4-11 cells
  • MV411 cells in the logarithmic growth phase were diluted with culture medium (RPMI+10% FBS), and plated at 5000 cells/well in a 96-well plate with black wall and black bottom (WHB), 50 ⁇ l per well. After plating, place it in 5% CO 2 and incubate at 37°C, and add medicine after 24 hours.
  • the final concentration of the compound is 10000, 3333.33, 1111.11 , 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0nM.
  • the anti-proliferation activity of compounds against MV-4-11 cells is shown in Table 2, where A represents IC 50 ⁇ 1nM, B represents 1 ⁇ IC 50 ⁇ 10nM, C represents 10nM ⁇ IC 50 ⁇ 100nM, D represents 100nM ⁇ IC 50 ⁇ 1000nM, E Indicates IC 50 ⁇ 1000nM.
  • Example 15 Compounds have anti-proliferative activity against various tumor cells
  • U937, NCI-H929, AML-2, and MOLM-13 cells in the logarithmic growth phase were cultured in culture media (RPMI+10%FBS), (RPMI+10%FBS), (MEM ⁇ +20%FBS), ( RPMI + 20% FBS), and plated in a black wall and black bottom 96-well plate (WHB) at 4000 cells/well, 50 ⁇ l per well. After plating, place it in 5% CO 2 and incubate at 37°C, and add medicine after 24 hours.
  • Use DMSO to prepare the compound into a 10mM stock solution dilute it with culture medium to the required concentration (the final concentration of DMSO is 0.2%), then add 50 microliters to a 96-well plate containing cells.
  • the final concentration of the compound is 10000, 3333.33, 1111.11 , 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0nM.
  • the anti-tumor cell proliferation activity of the compounds is shown in Table 3, where A represents IC 50 ⁇ 1nM, B represents 1 ⁇ IC 50 ⁇ 10nM, C represents 10nM ⁇ IC 50 ⁇ 100nM, D represents 100nM ⁇ IC 50 ⁇ 1000nM, and E represents IC 50 ⁇ 1000nM.
  • Example 16 Effect of compounds on AML cell apoptosis
  • MV-4-11 cells in the logarithmic growth phase were diluted with growth medium, plated in a 6-well plate at 600,000 cells/well, 2 mL per well, and treated with drug. Collect the cells and wash them twice with pre-cooled PBS. Resuspend the cells with 100 ⁇ l of 1X annexin-binding buffer. Add 5 ⁇ l of FITC and 1 ⁇ l of 100 ⁇ g/mL PI and incubate at room temperature for 15 min in the dark. Add 400 ⁇ l of 1X annexin-bindingbuffer on ice and mix gently for flow cytometry detection.
  • Example 17 Modulating effect of compounds on GSPT1 protein
  • NB-4 cells were grown in RPMI 1640 (containing 10% FBS) medium. After centrifugation and counting, the cell concentration was adjusted to 106 cells/well and plated on a 12-well plate, 1350 ⁇ l per well. Add 150 ⁇ l of DMSO and compound in 5% CO 2 , the compound concentration is 1 ⁇ M, and incubate in a 37°C incubator for 6 hours. Centrifuge the cells to discard the culture medium, add PBS to wash and discard. Prepare whole cell lysates in RIPA lysis buffer containing protease inhibitor cocktail and phosphatase inhibitors and place on ice for 30 minutes. Centrifuge to discard the cell debris pellet, collect the supernatant whole cell lysate and transfer it to a new EP tube. After measuring BCA protein, use loading buffer to configure the sample. Metal bath 100°C for 10 minutes.
  • the samples were electrophoresed in a 4-20% precast gel (SDS-PAGE gel) to separate proteins, then transferred to a PVDF membrane and blocked with 5% NFDM/TBST at room temperature for 1 hour.
  • the primary antibody was incubated overnight at 4°C, and the next day Incubate with secondary antibody for 2 hours at room temperature. Signals were detected using the MINICHEMITM imaging system.
  • the GSPT1 protein degradation effect is shown in Table 4, where A means that the GSPT1 protein degradation percentage is not less than 80%, B means that the degradation percentage is less than 80% but not less than 50%, C means that the degradation percentage is less than 50% but not less than 25%, and D means The degradation percentage is less than 25%.
  • the IC 50 of the tested compound FDAB-48 against MV-4-11 cell proliferation activity was 10.8 nM. It degraded GSPT1 protein by 88% after co-incubation in NB-4 cells for 6 hours, and it did not contain the corresponding halogen substitution.
  • compound The IC 50 of anti-MV-4-11 cell proliferation activity is 102.6nM, and its degradation effect on GSPT1 protein after co-incubation in NB-4 cells for 6 hours is only 65%.
  • Example 18 Regulatory effects of compounds on IKZF1, IKZF3, CK1 ⁇ , and c-MYC proteins
  • HL-60 cells were grown in IMDM (containing 20% FBS) medium. After centrifugation and counting, the cell concentration was adjusted to 1.26 cells/well and plated on a 12-well plate, 1350 ⁇ l per well. Add 150 ⁇ l of DMSO and compound and place in 5% CO 2 in a 37°C incubator for 4 hours. Centrifuge the cells to discard the culture medium, add PBS to wash and discard. Prepare whole cell lysates in RIPA lysis buffer containing protease inhibitor cocktail and phosphatase inhibitors and place on ice for 30 minutes. Centrifuge to discard the cell debris pellet, collect the supernatant whole cell lysate and transfer it to a new EP tube. After measuring BCA protein, use loading buffer to configure the sample.
  • Table 5 shows the degradation ability of different concentrations of compounds on IKZF1, IKZF3, CK1 ⁇ and c-Myc proteins in HL-60 cells.
  • A indicates that the degradation percentage of GSPT1 protein is not less than 80%
  • B indicates that the degradation percentage is less than 80% but not less than 50%
  • C indicates that the degradation percentage is less than 50% but not less than 25%
  • D indicates that the degradation percentage is less than 25%.
  • MOLM-13 cells in the logarithmic growth phase were diluted with culture medium (RPMI+20% FBS), NCI-H929 cells were diluted with culture medium (RPMI+10% FBS), and 4000 cells/well were plated on black walls and black bottoms.
  • the final concentration of the compound is 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0nM, 10 concentration gradients were set for each compound, and there were 2 duplicate wells for each concentration. After adding the drug, it was placed in 5% CO 2 and cultured in a 37°C incubator for 72 hours. When using drugs in combination, keep the concentrations of azacitidine and dexamethasone at 200nM and 500nM respectively, and dilute the compounds in three-fold concentration gradients from 10,000nM. After incubation, equilibrate at room temperature for 30 minutes, and add 100 ⁇ l to each well. Reagent (Promega G7573), shake with microplate shaker for 12 minutes. The luminescence value was measured using GloMax navigator (Promega GM2010) at room temperature. Taking 0 nM control group as 0% inhibition, the IC 50 value was calculated using GraphPad Prism 7 software.
  • the test results are shown in Table 6. It can be seen from Table 6 that the IC 50 of azacitidine's anti-MOLM-13 cell proliferation activity is 751.1 nM, and azacitidine at a concentration of 200 nM has no obvious anti-MOLM-13 cell proliferation activity. But when FDAB-121 was combined with 200 nM azacitabine After the combination of glycosides, the anti-MOLM-13 cell proliferation activity IC 50 of FDAB-121 increased from 247.9nM to 9.675nM, and the activity increased by about 25 times. Whether the compound is used alone or in combination with azacitidine, the activity of FDAB-121 is approximately 5 times higher than that of CC-90009.
  • the IC 50 of dexamethasone's anti-NCI-H929 cell proliferation activity is greater than 10000 nM, and 500 nM dexamethasone has no obvious anti-NCI-H929 cell proliferation activity.
  • the IC 50 of FDAB-48's anti-NCI-H929 cell proliferation activity increased from 14.26nM to 2.447nM, and the activity increased by about 6 times.
  • the rapidly activated potassium channel encoded by the human ether-a-go-go-related gene is an important ion channel involved in the formation of the third phase repolarization of myocardial action potential.
  • Drugs that block hERG channels can lead to prolonged cardiac repolarization, and the electrocardiogram shows a prolonged QT interval, which is called long QT syndrome.
  • Drug-induced delayed ventricular repolarization may in some cases trigger a fatal arrhythmia - torsades de pointes.
  • This assay is used to measure the effect of compounds on cloned hERG potassium channels expressed in human embryonic kidney cells (HEK293).
  • the assay was performed by placing cells in HEPES-buffered saline solution in glass-lined 96-well plates and loading with appropriate amounts of test and control solutions at each concentration for a 3-minute exposure time. Dilute test compounds in 0.3% DMSO.
  • the automated parallel patch clamp system QPatch 48 X (Sophion) was used to test the inhibitory rate of hERG by the compound at a concentration of 3 ⁇ M.
  • Example 21 Effectiveness study in acute myeloid leukemia xenograft mouse model
  • mice Immunocompromised 6- to 8-week-old female NSG mice were used in the in vivo effectiveness study. After the animals arrived, they were raised in the experimental environment for 7 days before starting the experiment. The animals were kept in IVC (independent ventilation system) cages in SPF-level animal rooms, with 6 mice per cage. Human MV-4-11 acute myeloid leukemia cells expressing luciferase, MV-4-11-luc, were injected into mice through the tail vein (5 ⁇ 10 6 cells/animal). Seven days after the cells were inoculated, the mice were imaged using an IVIS Lumina III small animal imager and drug administration began. Tumor-bearing mice were randomly assigned to the vehicle control group or the compound treatment group (6 animals/group). Animals in each treatment group were administered compound (10 mg/kg twice daily) via oral gavage. Body weights were measured daily, while mean luminescence was measured after initiation of treatment with compound or vehicle.
  • IVC independent ventilation system
  • Table 8 shows the tumor proliferation rate T/C (%) of each compound at different time points. Among them, compound CC-9000910mg/kg was taken orally twice a day and did not show tumor inhibitory effect within 14 days.
  • the T/C (%) of the compounds of the present invention FDAB-48, FDAB-65, FDAB-120 and FDAB-121 at 10 mg/kg orally twice a day on the 14th day are respectively: 0.05%, 0.78%, 2.12% and 0.005 %. It can be seen that all administration groups of the compound of the present invention showed obvious anti-tumor effects. Unexpectedly, the compound of the present invention has been detected to have obvious tumor inhibitory effect on the third day of administration.
  • FDAB-48, FDAB-65, FDAB-120 and FDAB-121 were orally administered at 10 mg/kg twice a day at the T/C on the third day. (%) are: 0.95%, 4.58%, 6.69% and 0.32% respectively.

Abstract

本发明涉及如下式I所示卤素取代异吲哚啉化合物及其应用。本发明的化合物具有明显更优异的抗肿瘤活性，且可制成给药更方便、安全和经济的口服剂型。因此，其利用价值相对于现有化合物显著提高。

Description

卤素取代异吲哚啉化合物及其应用
本申请要求2022年4月29日向中国国家知识产权局提交的，专利申请号为2022104939244，发明名称为“卤素取代异吲哚啉化合物及其应用”在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药技术领域，具体涉及卤素取代异吲哚啉化合物及其应用。
背景技术
蛋白突变、表达失衡、变构与功能异常会引起许多的疾病。蛋白合成或降解在细胞生长、增殖过程中在空间和时间上都是严格调控的过程。这些过程的调控异常可能导致细胞不受控制的生长、增殖和迁移，从而导致癌症、衰老、病毒感染等疾病的发生。
翻译终止因子GSPT1(eRF3a)与癌症等疾病密切相关，它能介导终止密码子识别并促进新生肽从核糖体的释放。除了具有翻译终止的功能外，GSPT1还参与其他几个关键的细胞过程，例如细胞周期调节，细胞骨架组织和细胞凋亡。GSPT1是多种癌症类型的致癌驱动因素，包括血液瘤、乳腺癌、肝癌、胃癌和前列腺癌等。此外，GSPT1在癌症组织和细胞系中被显著上调，其高表达与肿瘤大小正相关，且其过表达可促进癌细胞增殖和迁移。如GSPT1耗竭在体外能有效抑制癌细胞的增殖、迁移和诱导侵袭的结肠癌细胞凋亡，并在体内抑制HCT116结肠癌细胞的致瘤性。此外，近期研究表明GSPT1的下调在治疗囊性纤维化、拉沙病毒和埃博拉病毒感染方面也具有疗效。
Ikaros锌指(IKZF)转录因子家族是造血细胞发育分化和包括CD4+T细胞在内的许多免疫细胞的调节因子。IKZF家族由五个成员组成：Ikaros(由基因IKZF1编码)、Helios(IKZF2)、Aiolos(IKZF3)、Eos(IKZF4)和Pegasus(IKZF5)。Ikaros家族与癌症进展相关的证据最初是在造血系统恶性肿瘤中发现的，Ikaros的功能障碍与慢性淋巴细胞白血病的发展有关。近年来发现Ikaros是参与人类B细胞急性淋巴细胞白血病的主要肿瘤抑制因子并且它还参与个体T辅助细胞的分化和功能细胞。而Aiolos在B和T细胞的成熟中发挥重要作用，Aiolos表达升高可通过调节慢性淋巴细胞白血病中的Bcl2家族蛋白来促进细胞存活，在滤泡中心细胞淋巴瘤中检测到Aiolos表达升高。Aiolos与Blimp-1协同调节多发性骨髓瘤细胞的存活。此外，在实体瘤中，Aiolos的过表达还可以促进肺癌细胞的上皮间质转化和癌症干细胞样特性。
目前暂无上市的基于GSPT1等蛋白调节药物，且现有技术中还未出现卤素取代异吲哚啉 化合物作为GSPT1等蛋白调节剂小分子的报道。目前此类蛋白调节药物研发进度最领先的最领先的为Celegen的CC-90009，该药物为静脉注射给药，正在进行临床一期研究。相较于注射给药方式，口服给药方便、安全和经济，因此是最常用的给药方式。此外，蛋白调节剂较小的分子结构变化会造成药物代谢活性和生物活性的巨大改变，如分子胶或PROTACs分子中一个原子的变化可能会导致化合物丧失对特定蛋白的降解活性以及对肿瘤的生物活性，因此不同化学结构的调节剂可能会提高药物的有效性和安全性。
发明内容
为解决上述技术问题，本发明提供如下式I所示的化合物，其互变异构体、立体异构体、水合物、溶剂化物、或药学上可接受的盐：
R1选自氢、氘、C1-12烷基、
R2相同或不同，彼此独立选自氢，无取代或任选被一个、两个或更多个Ra取代的如下基团：C1-12烷基、C6-20芳基、5-20元杂芳基、C3-20环烷基、3-20元杂环基；
R’、R3相同或不同，彼此独立选自氢，无取代或任选被一个、两个或更多个Rb取代的如下基团：C1-12烷基、C1-12烷氧基、C6-20芳基、5-20元杂芳基、C3-20环烷基、3-20元杂环基；
R4、R5相同或不同，彼此独立选自氢、氘、卤素；
m为1、2或3；
R6选自氢、氘、卤素、无取代或任选被一个、两个或更多个Rc取代的如下基团：C1-12烷基、C1-12烷氧基；
Q1为-CH2-、-CD2-、-C(O)-或-C(S)-；
R7、R8、R9、R10相同或不同，彼此独立选自氢、卤素、氘、CN、C1-12烷基、-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14、-CH2-NHCONH-R12；所述-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14的亚甲基上的氢任选被1或2个氘取代；
R11、R12、R13、R14相同或不同，彼此独立选自无取代或任选被一个、两个或更多个Rs取代的如下基团：C6-20芳基、5-20元杂芳基、C3-20环烷基、3-20元杂环基、C2-12烯基、C2-12炔基、C1-12烷基、-P(C6-20芳基)2、-N(C1-12烷基)2、-COC1-12烷基、-C1-12烷基N(C1-12烷基)2、C6-20芳基并C3-20环烷基、C3-20环烷基与C3-20环烷基构成的螺环基；
Y选自C1-12亚烷基、C3-20亚环烷基、C2-12亚烯基、C2-12亚炔基、-CH2NH-、-CH2NHCO-、-CH2NHCO-、-CH2O-、-C2H4O-、-CH2S-、
Ra、Rb、Rc、Rs相同或不同，彼此独立选自卤素、氨基、羟基、C1-12烷基、C1-12烷氧基、卤代C1-12烷基、CN、C3-20环烷基、-N(C1-12烷基)2、氘代、C2-12烯基、C2-12炔基、-COC1- 12烷基、-COC6-20芳基、C1-12烷硫基、巯基、＝O、-C1-12烷基羟基、3-20元杂环基、-SO2C1-12烷基、-SO2NH2、C6-20芳基、-OC6-20芳基、-C1-12烷基C6-20芳基、-C1-12烷基氨基、-C6-20芳基C1-12烷基氨基、-C6-20芳基氨基、-OC1-12烷基C6-20芳基、-C6-20芳基羟基、-C6-20芳基C1-12烷基羟基。
根据本发明的实施方案，R1选自氢、C1-6烷基、-C1-6烷基COOC1-6烷基、-COOC1-6烷基或-C1-6烷基OCOOC1-6烷基；
R4、R5、R6选自氢；m为1、2或3；Q1为-CH2-或-C(O)-；
R7、R8、R9、R10相同或不同，彼此独立选自氢、氘代、卤素、CN、C1-6烷基、-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14；所述-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14的CH2上的氢任选被1或2个氘取代；
R11、R12、R13、R14相同或不同，彼此独立选自无取代或任选被一个、两个或更多个Rs取代的如下基团：C6-12芳基、5-12元杂芳基、C3-12环烷基、3-12元杂环基、C2-6烯基、C2-6炔基、C1-6烷基、-P(C6-20芳基)2、-N(C1-6烷基)2、-COC1-6烷基、-C1-6烷基N(C1-6烷基)2、C6-12芳基并C3-12环烷基、C3-12环烷基与C3-12环烷基构成的螺环基；
Y选自C1-6亚烷基、C3-12亚环烷基、C2-6亚烯基、C2-6亚炔基、-CH2NH-、-CH2NHCO-、- CH2NHCO-、-CH2O-、-C2H4O-、-CH2S-、
Rs相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基、-C1-6烷基氨基、-C6-12芳基C1-6烷基氨基、-C6-12芳基氨基、-OC1-6烷基C6-12芳基、-C6-12芳基羟基、-C6-12芳基C1-6烷基羟基。
在一个实施方案中，式I具有如下式I-1所示结构：
其中，R1、R4、R5、R6、R7、R8、R9、R10、Q1具有如上所述定义。
在一个实施方案中，式I具有如下式I-2所示结构：
其中，R1、R4、R5、R6、R7、R8、R9、R10、Q1具有如上所述定义。
在一个实施方案中，式I具有如下式I-3所示结构：
其中，R1、R4、R5、R6、R7、R8、R9、R10、Q1具有如上所述定义。
根据本发明的实施方案，式I选自如下式Ia所示结构：
式Ia中，
R1选自氢、C1-6烷基、-C1-6烷基COOC1-6烷基、-COOC1-6烷基或-C1-6烷基OCOOC1-6烷基；
R4、R5、R6选自氢或氘；
m为1、2或3；
Q1为-CH2-、-CD2-或-C(O)-；
R7’选自氢、氘、卤素；p为1、2或3，条件是至少一个R7’选自卤素；
R8’选自CN、-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14；所述-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14的CH2上的H任选被1或2个氘取代；
R11、R12、R13、R14相同或不同，彼此独立选自无取代或任选被一个、两个或更多个Rs取代的如下基团：C6-12芳基、5-12元杂芳基、C3-12环烷基、3-12元杂环基、C2-6烯基、C2-6炔基、C1-6烷基、-P(C6-20芳基)2、-N(C1-6烷基)2、-COC1-6烷基、-C1-6烷基N(C1-6烷基)2、C6-12芳基并C3-12环烷基、C3-12环烷基与C3-12环烷基构成的螺环基；
Y选自C1-6亚烷基、C3-12亚环烷基、C2-6亚烯基、C2-6亚炔基、-CH2NH-、-CH2NHCO-、- CH2NHCO-、-CH2O-、-C2H4O-、-CH2S-、
Rs相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基、-C1-6烷基氨基、-C6-12芳基C1-6烷基氨基、-C6-12芳基氨基、-OC1-6烷基C6-12芳基、-C6-12芳基羟基、-C6-12芳基C1-6烷基羟基。
根据本发明的实施方案，R7、R8、R9、R10中至少一个为卤素。优选地，R7、R8、R9、R10中一个为卤素，或者两个为卤素，或者三个为卤素。
在本发明的一个实施方案中，R7、R8、R9、R10中一个为F。
根据本发明优选的实施方案，式I选自如下式Ib所示结构：
式Ib中，R15、R16、R17、R18相同或不同，彼此独立选自氢、氘、卤素、氨基、羟基、氰基，无取代或任选被一个、两个或更多个Rx取代的如下基团：C1-6烷基、-SO2C1-6烷基、C1-6卤代烷基、C6-12芳基、C1-6烷氧基、-N(C1-6烷基)2、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷硫基、-COC1-6烷基、-COC6-12芳基、-OC6-12芳基、-C1-6烷基-羟基、3-12元杂环基、-SO2NH2；
Rx相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、-C1-6烷基氨基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基。
在本发明的一个实施方案中，式Ib中，R15、R16、R17、R18相同或不同，彼此独立选自氢、氘、F、Cl、甲基、氨基、羟基、甲氧基、三氟甲基、氰基、苯基、二甲氨基、乙基、正丙基、异丙基、叔丁基、乙烯基、乙炔基、环丙基、羰甲基、羰苯基、苯氧基、叔丁氧 基、烷硫基、-SO2NH2、羟甲基、N-四氢吡咯基、-SO2CH2、对氨基苯基、
在本发明的一个实施方案中，式Ib采用如下方法制备：
其中，R15、R16、R17、R18具有如上所述定义；
化合物Im与化合物In发生缩合反应得到式Ib所示的化合物。
在一个优选的实施方案中，式I选自如下式Ic所示结构：
式Ic中，R15、R16、R17、R18、R19相同或不同，彼此独立选自氢、氘、卤素、氨基、羟基、氰基，无取代或任选被一个、两个或更多个Rx取代的如下基团：C1-6烷基、-SO2C1-6烷基、C1-6卤代烷基、C6-12芳基、C1-6烷氧基、-N(C1-6烷基)2、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷硫基、-COC1-6烷基、-COC6-12芳基、-OC6-12芳基、-C1-6烷基-羟基、3-12元杂环基、-SO2NH2；
Rx相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、-C1-6烷基氨基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基，且R19不为H。
在本发明的一个实施方案中，式Ic采用如下方法制备：
其中，R15、R16、R17、R18、R19具有如上所述定义；
化合物Ip与化合物Iq发生缩合反应得到式Ic所示的化合物。
在一个优选的实施方案中，式I选自如下式Id所示结构：
Id中，L为化学键、C2-12炔基、C2-12烯基、NH、氧、硫或C1-12烷基，所述C1-12烷基任选被如下基团取代：羟基、氨基；
R20为无取代或任选被一个、两个或更多个Ry取代的如下基团：C6-12芳基、3-12元环烷基、5-12元杂环基或5-12元杂芳环基；
Ry选自氘代、卤素、羟基、氨基、羧基、CN、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-12环烷基、-N(C1-6烷基)2、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、-C1-6烷基氨基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-OC1-6烷基C6-12芳基、-C1-6烷基C6-12芳基、-C1-6烷基-COOH、-C6-12芳基-C1-6烷基氨基、-C6-12芳基-C1-6烷基羟基、-C6-12芳基氨基、-C6-12芳基羟基。
在一个优选的实施方案中，Id中，L为化学键、C2-12炔基、C2-12烯基、NH或C1-6烷基；所述C1-6烷基任选被如下基团取代：羟基、氨基；
R20为无取代或任选被一个、两个或更多个Ry取代的如下基团：C6-12芳基或5-12元杂芳环基；
Ry选自羟基、氨基、C1-6烷基、C1-6烷氧基、C6-12芳基、-OC1-3烷基C6-12芳基、-C1-3烷基C6-12芳基、-C1-6烷基-NH2、-C1-6烷基羟基、-C1-6烷基-COOH、-C6-12芳基-C1-3烷基氨基、-C6-12芳基-C1-3烷基羟基、-C6-12芳基氨基或-C6-12芳基羟基。
在一个更优选的实施方案中，Id中，L为化学键、炔基、NH、
R20为苯基；
Ry选自Cl、羟基、氨基、叔丁基、苯基、对氨基苯基、对羟基苯基、乙基氨、羟乙基、对羟乙基苯基、对乙基氨苯基、
在一个实施方案中，式Id所示的化合物采用如下方法制备：
其中，R20、L具有如上所述定义；
化合物Ix与化合物Iy发生缩合反应得到式Id所示的化合物。
作为示例，所述式I化合物选自如下：






根据本发明的实施方案，所述药学上可接受的盐选自如下文所定义的盐，例如盐包括但不限于盐酸盐、硫酸盐、硝酸盐、硫酸氢盐、氢溴酸盐、醋酸盐、草酸盐、柠檬酸盐、甲磺酸盐、甲酸盐或葡甲胺盐，优选为盐酸盐。
本发明还提供如上所述式I所示化合物，其互变异构体、立体异构体、水合物、溶剂化物、或药学上可接受的盐在制备治疗或预防由GSPT1、IKZF1、IKZF2、IKZF3、CK1α、N-MYC或C-MYC等蛋白突变、表达失衡、变构与功能异常相关的疾病、病症或病况的药物中的用途。
根据本发明的实施方案，所述的疾病、病症或病况包括：骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、慢性粒单核细胞白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、眼外延伸黑色素瘤、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病(例如急性髓系白血病)、中枢神经系统淋巴瘤、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤、弥漫性大B细胞淋巴瘤、星状细胞瘤、肝细胞癌或原发性巨球蛋白血症、病毒感染。
本发明还提供一种药物组合物，其包括如上所述式I所示化合物，其互变异构体、立体 异构体、水合物、溶剂化物、或药学上可接受的盐。
根据本发明的实施方案，所述药物组合物中，除活性成分式I所示化合物外，还进一步包含其他治疗剂，所述的其他治疗剂包括但不限于：PD-1抑制剂(例如纳武单抗、帕博利珠单抗、西米普利单抗)、PD-L1抑制剂(例如阿替利珠单抗、阿维鲁单抗、度伐利尤单抗)、利妥昔单抗、曲妥珠单抗、埃罗妥珠单抗、乌妥昔单抗、达雷木单抗、阿托珠单抗、替伊莫单抗、阿仑单抗、本妥昔单抗、阿糖胞苷、阿扎胞苷、蒽环类药物、泼尼松、地塞米松、美法仑、克拉屈滨、氟达拉滨、米托蒽醌、依托泊苷、甲氨蝶呤、培美曲塞、托泊替康、阿霉素、环磷酰胺、吉西他滨、达卡巴嗪、克拉霉素、长春新碱、多西他赛、氯法拉滨注射液、HDAC抑制剂(例如帕比司他、罗米地辛、伏立诺他、贝利司他、西达本胺)、FLT3抑制剂(例如米哚妥林、吉瑞替尼、奎扎替尼)、IDH1/2抑制剂(例如艾伏尼布、恩西地平)、BCL-2抑制剂(例如维奈克拉)、蛋白酶体抑制剂(例如硼替佐米、卡非佐米、伊沙佐米)、PI3K抑制剂、BTK抑制剂(例如泽布替尼、阿卡替尼、伊布替尼、替拉鲁替尼、奥布替尼)、帕博西尼、红血球生长激素、艾曲波帕、米诺四环素、CAR-T中的至少一种。
根据本发明优选的实施方案，所述药物组合物中，除活性成分式I所示化合物外，还包括阿扎胞苷或地塞米松。
根据本发明的实施方案，所述药物组合物用于治疗或预防由GSPT1、IKZF1、IKZF2、IKZF3、CK1α、N-MYC或C-MYC等蛋白突变、表达失衡、变构与功能异常相关的疾病、病症或病况。
根据本发明的实施方案，所述的疾病、病症或病况包括：骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、慢性粒单核细胞白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、眼外延伸黑色素瘤、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓系白血病(例如急性髓系白血病)、中枢神经系统淋巴瘤、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤、弥漫性大B细胞淋巴瘤、星状细胞瘤、肝细胞癌或原发性巨球蛋白血症、病毒感染。
根据本发明的实施方案，所述式I所示化合物或药物组合物可通过如下方式进行给药：口服、直肠、局部、口腔、肠胃外、肌内、真皮内、静脉内和透皮给药。在一个实施方案中，所述药物组合物为口服给药。
有益效果：
本发明的化合物对GSPT1、IKZF1、IKZF2、IKZF3、CK1α、N-MYC或C-MYC等蛋白具有调节作用，具有抗肿瘤、抗癌活性，尤其是对急性髓系白血病和骨髓瘤细胞有很强的抑制 活性。本发明化合物的活性优势主要体现在：
1.发明人出乎意料地发现本发明卤素取代化合物相比其未取代化合物抗肿瘤细胞增殖活性大大提高，同时对GSPT1等蛋白降解效果显著提高。例如本发明卤素取代化合物FDAB-48的抗MV-4-11细胞增殖活性IC50为10.8nM，其在NB-4细胞中共孵6小时对GSPT1蛋白的降解达88％，而不含卤素取代的化合物抗MV-4-11细胞增殖活性IC50为102.6nM，其在NB-4细胞中共孵6小时对GSPT1蛋白的降解效果只有65％。
2.本发明化合物在3μM浓度下具有几乎不可观察到的hERG通道的抑制活性(9～25％抑制)，而现有临床在研化合物CC-90009具有明显hERG通道的抑制活性(66％抑制)。
3.现有的临床在研化合物CC-90009为注射剂。本发明化合物在小鼠移植肿瘤模型中具有显著抑制肿瘤活性，而口服同等剂量化合物CC-90009无抑制肿瘤活性。说明本发明化合物相对于化合物CC-90009(注射剂)可以制成给药更方便、安全和经济的口服剂型。
综上可知，本发明的化合物具有明显更优异的抗肿瘤活性，且可制成给药更方便、安全和经济的口服剂型。因此，其利用价值相对于现有化合物显著提高。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
在本文中，术语“包括”、“包含”和/或“含有”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本文中，在描述一个/种、两个/种或更多个/种时，“更多个/种”应当是指大于2的情形，例如表示大于等于3的整数情形，例如3、4、5、6、7、8、9或10个/种。
在本文中，术语“任选(的/地)”表示所述特征存在或不存在这两种情形，这意味着随后所描述的事件可以但不必然发生，因此包括该事件发生或不发生的两类情形。例如，“任选被烷基取代的杂环基团”意味着该烷基可以但不必然存在，因此包括被烷基取代的杂环基团和没有被烷基取代的杂环基团的情形。
本申请中部分取代基的“|”和“*”处为连接位点。
在本文中，术语“卤素”表示氟、氯、溴和/或碘。相应地，术语“卤代”是指氟代、氯代、溴代和/或碘代。在本文的范围内，在原子、残基、基团或部分被卤代时，卤代位置的原子可以被卤素原子单取代、二取代或多取代直至全取代。
术语“C1-12烷基”应理解为优选表示具有1～12个碳原子的直链或支链饱和一价烃基，优 选为C1-6烷基。“C1-6烷基”应理解为优选表示具有1、2、3、4、5、或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C1-3烷基”)，例如甲基、乙基、正丙基或异丙基。
术语“C2-12烯基”应理解为表示直链或支链的一价烃基，其包含一个或多个双键并且具有2～12个碳原子，优选“C2-6烯基”。“C2-6烯基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6个碳原子，特别是2或3个碳原子(“C2-3烯基”)，应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-12炔基”应理解为表示直链或支链的一价烃基，其包含一个或多个三键并且具有2～12个碳原子，优选“C2-C6炔基”。术语“C2-C6炔基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6个碳原子，特别是2或3个碳原子(“C2-C3-炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C3-20环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～20个碳原子，优选“C3-12环烷基”。术语“C3-12环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6、7、8、9、10、11或12个碳原子。所述C3-12环烷基可以是单环烃基，如环丙基、 环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个独立选自N、O和S的杂原子，优选“3-12元杂环基”。术语“3-12元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。
术语“C6-20芳基”应理解为表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C6-12芳基”。术语“C6-12芳基”应理解为优选表示具有6、7、8、9、10、11、12个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-12芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5～20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-12元杂芳基”。术语“5-12元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明，杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶- 2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
上述对术语“C1-12烷基”的定义同样适用于含有“C1-12烷基”的其他术语，例如术语“C1-12烷氧基”、“卤代C1-12烷基”、“-C1-12烷基COOC1-12烷基”、“-COOC1-12烷基”或“-C1-12烷基OCOOC1-12烷基”，“-C1-6烷基C6-12芳基”、“-C6-12芳基-C1-6烷基氨基”、“-C6-12芳基-C1-6烷基羟基”、“-N(C1-6烷基)2”、“-C1-6烷基羟基”等等。换句话说，本申请只要涉及含“C1-6烷基”取代基的基团，该基团中C1-6烷基的定义与上文所定义相同。同理，“C6-12芳基”、“C3-20环烷基”、“5-20元杂芳基”、“3-20元杂环基”等在全文中的定义均相同。
术语“C1-12卤代烷基”与“卤代C1-12烷基”含义相同，均是指上述“C1-12烷基”被卤素取代的形成的取代基。
术语“C6-20芳基并C3-20环烷基”指上文所述C6-20芳基与C3-20环烷基以共用至少2个碳原子的方式所构成的基团。
术语“C3-20环烷基与C3-20环烷基构成的螺环基”中C3-20环烷基的定义同上文，其是指2个C3-20环烷基以共用1个碳原子的方式所构成的螺环基。
术语“C1-12烷硫基”指-SC1-12烷基，其中C1-12烷基的定义同上。
术语“Boc”为叔丁氧羰基。
在本文中，“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
药学上可接受的盐包括在链或环中具有氮原子的具有足够碱性的本发明的化合物的酸加成盐。另外，碱性含氮基团可用如下试剂季铵化：低级烷基卤化物，例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；硫酸二烷基酯，例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯；长链卤化物，例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。作为实例，生理学上/药学上可接受的盐包括但不限于盐酸盐、硫酸盐、硝酸盐、硫酸氢盐、氢溴酸盐、醋酸盐、草酸盐、柠檬酸盐、甲磺酸盐、甲酸盐或葡甲胺盐等。
由于本发明的化合物可存在多个成盐位点，所述生理学上/药学上可接受的盐，不仅包括本发明化合物其中1个成盐位点上形成的盐，而且还包括其中2、3或全部成盐位点上形成的盐。为此，所述生理学上/药学上可接受的盐中，式(I)的化合物与成盐所需的酸的根离子(阴离子)或碱的阳离子摩尔比可以在较大的范围内变化，例如可以是4:1-1:4，如3:1、2:1、1:1、1:2、1:3等。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。化合物的结构由核磁共振(NMR)或质谱(MS)来确定，核磁共振谱是通过Bruker Avance-400仪器获得，质谱是由液相色谱-质谱(LC-MS)联用仪Agilent Technologies 6110获得，采用ESI离子源。
实施例1：化合物FDAB-1的合成
T1-1的合成：将氰化亚铜(5.28g,59.0mmol)和亚硝酸叔丁酯(14g,136.1mmol)溶于100毫升二甲基亚砜中，升温并保持温度60℃搅拌反应约30分钟，然后缓慢滴加4-溴-3-氟-2-甲基苯胺(10g,49.0mmol)的二甲基亚砜(20毫升)溶液约30分钟。在60℃继续搅拌反应约1小时后，LCMS检测显示原料已消失。将反应液降至室温，向反应液中滴加入6M盐酸溶液淬灭反应，然后加入乙酸乙酯(2 x 100毫升)进行萃取分液。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。经过柱层析(乙酸乙酯/石油醚＝1/20-1/10)得到淡黄色油状液体T1-14.5g，收率为43％。
T1-2的合成：将中间体T1-1(4.5g,21.0mmol)和氢氧化钠水溶液(5M，50毫升)混合。混合液体系升温至100℃并搅拌反应约16小时，LCMS检测显示T1-1反应完全。将反应液降至室温并在冰浴下向反应液中滴加入6M盐酸溶液调至酸性～1，调酸过程中反应液中会产生大量固体，过滤并用蒸馏水冲洗滤饼两次。将滤饼干燥后得到淡黄色固体T1-22.4g，收率为50％。
T1-3的合成：将中间体T1-2(4.5g,19.3mmol)和碳酸钾(5.3g,38.6mmol)溶于50毫升N,N-二甲基甲酰胺中，室温下缓慢加入碘甲烷(4.1g,29.0mmol)。在室温下搅拌反应约1小时，LCMS检测显示原料T1-2已消失。向反应液中加入冰水淬灭，加入乙酸乙酯(2 x 100毫升)萃取分液。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。经过柱层析(乙酸乙酯/石油醚＝1/50-1/20)得到淡黄色油状液体T1-34.3g，收率为90％。
T1-4的合成：将中间体T1-3(9.8g,39.7mmol)和氰化亚铜(5.34g,59.7mmol)溶于60毫升N-甲基吡咯烷酮中，混合体系升温至180℃并在此温度下搅拌反应约2小时，LCMS检测显示原料已消失。待混合体系冷却至室温后过滤，向滤液中加入100毫升水稀释，加入乙酸乙酯(2 x 100毫升)萃取分液。合并有机相并用饱和食盐水进行反洗，有机 相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。经过柱层析(乙酸乙酯/石油醚＝1/20-1/10)得到类白色固体T1-44.6g，收率为60％。
T1-5的合成：将中间体T1-4(3.9g,20.0mmol)和N-溴代丁二酰亚胺(5.4g,30.0mmol)溶于50毫升氯仿中并升温至65℃，然后加入催化量偶氮二异丁腈(0.1g)并在此温度下继续搅拌反应约4小时，LCMS检测显示原料已消失。冷却至室温，抽滤，滤饼用30毫升二氯甲烷洗涤，向滤液中加入30毫升水进行稀释并加入二氯甲烷(2x 30毫升)进行萃取分液。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。经过柱层析(乙酸乙酯/石油醚＝1/20-1/10)得到淡黄色液体T1-53.3g，收率为60％。
将中间体T1-5(5.4g,20.0mmol)和3-氨基哌啶-2,6-二酮盐酸盐(3.3g,20.0mmol)溶于60毫升N,N-二甲基甲酰胺中，室温下加入二异丙基乙胺(7.7g,60.0mmol)。混合体系升温至75℃并在此温度下搅拌反应约4小时，LCMS检测显示T1-5反应完全。向反应液中加入100毫升水稀释并加入甲醇/二氯甲烷＝1:10混合液(3x 100毫升)进行萃取分液。合并有机相，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。经过柱层析(甲醇/二氯甲烷＝1/100-1/30)得到类白色固体FDAB-13.5g，收率为60％。
实施例2：化合物FDAB-2的合成
将FDAB-1(5.7g,20.0mmol)和二碳酸二叔丁酯(6.5g,30.0mmol)溶于60毫升四氢呋喃/N,N-二甲基甲酰胺＝10：1混合溶剂中,室温下加入雷尼镍(0.6g)。混合体系经氢气置换三次并保持一定的氢气压力体系，升温至40℃并在此温度下搅拌反应约4小时，LCMS检测显示FDAB-1反应完全。反应液冷却后抽滤，滤饼用50毫升二氯甲烷/甲醇(10/1)洗涤三次,合并滤液并减压浓缩。然后，向浓缩液中加入100毫升水，用乙酸乙酯(3x 100毫升)萃取分液。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。经过柱层析(甲醇/二氯甲烷＝1/100-1/50)得到FDAB-2白色固体6.3g，收率为81％。
实施例3：化合物FDAB-3的合成
将中间体FDAB-2(3.9g,10mmol)溶于30毫升二氯甲烷中，室温下加入盐酸的1，4-二氧六环溶液(1M，5毫升)并升温至40℃反应。反应约1小时后LCMS检测显示原料FDAB-2消失。减压浓缩除去多余的盐酸溶液和溶剂,将浓缩物二氯甲烷并用氨水调节酸性～7，再次浓缩并柱层析(甲醇：二氯甲烷＝1/100–1/10)得到类白色固体产物FDAB-3约2.8g，收率约为86％。
实施例4：化合物FDAB-4，FDAB-5和FDAB-6的合成
FDAB-4，FDAB-5和FDAB-6的合成从原料4-溴-5-氟-2-甲基苯胺开始，参照如上实施例1～3中FDAB-1、FDAB-2、FDAB-3的合成方法。所得化合物FDAB-4，FDAB-5和FDAB-6的表征数据如下表1所示。
实施例5：FDAB-7，FDAB-8和FDAB-9的合成
化合物FDAB-7，FDAB-8和FDAB-9的合成从原料4-溴-2-氟-6-甲基苯胺开始，参照如上实施例1～3中FDAB-1、FDAB-2、FDAB-3的合成方法。所得化合物FDAB-7，FDAB-8和FDAB-9的表征数据如下表1所示。
实施例6：FDAB-10，FDAB-11和FDAB-12的合成
化合物FDAB-10，FDAB-11和FDAB-12的合成从原料4-溴-3-氯-2-甲基苯胺开始，参照如上实施例1～3中FDAB-1、FDAB-2、FDAB-3的合成方法。所得化合物FDAB-10，FDAB-11和FDAB-12的表征数据如下表1所示。
实施例7：化合物FDAB-13，FDAB-14和FDAB-15的合成
化合物FDAB-13，FDAB-14和FDAB-15的合成从原料4-溴-5-氯-2-甲基苯胺开始，参照如上实施例1～3中FDAB-1、FDAB-2、FDAB-3的合成方法。所得化合物FDAB-13，FDAB-14和FDAB-15的表征数据如下表1所示。
实施例8：化合物FDAB-16和FDAB-17
化合物FDAB-16和FDAB-17的合成从原料3-溴-5-氟-2-甲基苯胺开始，参照如上实施例2、3中FDAB-2、FDAB-3的合成方法。所得化合物FDAB-16和FDAB-17的表征数据如下表1所示。
实施例9：化合物FDAB-48的合成
将FDAB-3(226mg,0.69mmol)和对氯苯甲酸(107mg，0.69mmol)溶于10毫升N,N-二甲基甲酰胺中，搅拌下加入三乙胺(139mg,1.37mmol)，并分批缓慢加入N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(310mg,0.83mmol)。反应约2h后 LCMS检测显示原料FDAB-3已消失。向反应液中加入50毫升水进行淬灭并加入乙酸乙酯进行萃取分液，重复萃取三次至萃取完全。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥浓缩得到淡黄色浓缩物粗品。经过柱层析(甲醇/二氯甲烷＝1/100-1/30)得到白色固体产物FDAB-48约210mg，产率为71％。
实施例10：化合物FDAB-121的合成
将FDAB-3(226mg,0.69mmol)和2-氟-4-甲基苯甲酸(106mg，0.69mmol)溶于10毫升N,N-二甲基甲酰胺中，搅拌下加入三乙胺(139mg,1.38mmol)，并分批缓慢加入N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(310mg,0.83mmol)。反应约2h后LCMS检测显示原料FDAB-3已消失。向反应液中加入50毫升水进行淬灭并加入乙酸乙酯进行萃取分液，重复萃取三次至萃取完全。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥浓缩得到淡黄色浓缩物粗品。经过柱层析(甲醇/二氯甲烷＝1/100-1/30)得到白色固体产物FDAB-121约191mg，产率为65％。
将上述原料2-氟-4-甲基苯甲酸替换为3-氟-4-甲基苯甲酸制备了FDAB-120。
本发明中前文所列举的含有酰胺基如FDAB-48和FDAB-121的部分化合物参考上述FDAB-48和FDAB-121的合成过程来制备，为节约篇幅，此处不再详述，这些化合物的表征数据如下表1所示。
实施例11：化合物FDAB-128的合成
将氯甲基碳酸异丙酯(34mg,0.22mmol)在0℃下缓慢滴加入FDAB-48(86mg,0.2mmol)和碳酸钾(41mg，0.3mmol)的N,N-二甲基甲酰胺(10毫升)溶液中，缓慢升至室温并继续搅拌反应约3小时后LCMS检测显示原料FDAB-48已消失。向反应液中加入20毫升水进行淬灭并加入乙酸乙酯进行萃取分液，重复萃取三次至萃取完全。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥浓缩得到淡黄色浓缩物粗品。经过柱层 析(甲醇/二氯甲烷＝1/100-1/50)得到白色固体产物FDAB-128约49mg，产率为45％。
实施例12：化合物FDAB-130的合成
将氯甲基碳酸异丙酯(34mg,0.22mmol)在0℃下缓慢滴加入FDAB-121(85mg,0.2mmol)和碳酸钾(41mg，0.3mmol)的N,N-二甲基甲酰胺(10毫升)溶液中，缓慢升至室温并继续搅拌反应约3小时后LCMS检测显示原料FDAB-121已消失。向反应液中加入20毫升水进行淬灭并加入乙酸乙酯进行萃取分液，重复萃取三次至萃取完全。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥浓缩得到淡黄色浓缩物粗品。经过柱层析(甲醇/二氯甲烷＝1/100-1/50)得到白色固体产物FDAB-130约38mg，产率为35％。
本发明中前文所列举的戊二酰亚胺环上N被取代的如FDAB-128和FDAB-130的部分化合物参考上述FDAB-128和FDAB-130的合成过程来制备，为节约篇幅，此处不再详述，这些化合物的表征数据如下表1所示。
实施例13：化合物FDAB-166的合成
将FDAB-3(20mg,0.06mmol)和4-苯氧基苯甲醛(14mg，0.07mmol)溶于5毫升四氢呋喃中，搅拌下加入碳酸氢钠(10mg,0.12mmol)，升温至50℃反应约1小时。然后向反应液中加入氰基硼氢化钠(5.8mg,0.09mmol),继续在50℃下搅拌反应约1小时。向反应液中加入20毫升水进行淬灭并加入乙酸乙酯(10毫升)进行萃取分液，重复萃取三次至萃取完全。合并有机相并用饱和食盐水进行反洗，有机相用无水硫酸钠干燥浓缩得到棕色浓缩物粗品。经过柱层析(甲醇/二氯甲烷＝1/100-1/30)得到白色固体FDAB-166产物15mg，产率为52％。
参照FDAB-166的合成方法，使用FDAB-3和对应的醛反应，得到化合物FDAB-165、FDAB-167、FDAB-168。为节约篇幅，此处不再详述，这些化合物的表征数据如下表1所示。
上文所述部分化合物的表征数据如下表1所示。
表1






















实施例14：化合物抗MV-4-11细胞增殖活性
将对数生长期的MV411细胞用培养基(RPMI+10％FBS)稀释，以5000个细胞/孔铺板于黑壁黑底96孔板(WHB)，每孔50微升。铺板后置于5％CO2，37℃培养箱培养，24小时后加药。将化合物用DMSO配置成10mM母液，用培养基稀释至所需浓度(DMSO终浓度为0.2％)后取50微升加到含细胞的96孔板中，化合物的终浓度为10000、3333.33、1111.11、370.37、123.46、41.15、13.72、4.57、1.52、0nM，每个化合物设置10个浓度梯度，每个浓度2个复孔，加药后置于5％CO2，37℃培养箱培养72小时。培养结束后，室温平衡30分钟，每孔加入100微升Reagent(Promega G7573)，微孔板振荡器振荡12分钟。室温GloMax navigator(Promega GM2010)测定发光值。以0nM对照组作为0％抑制，用GraphPad Prism 7软件计算IC50值。
化合物抗MV-4-11细胞增殖活性见表2，其中A表示IC50<1nM，B表示1≤IC50＜10nM，C表示10nM≤IC50＜100nM，D表示100nM≤IC50＜1000nM，E表示IC50≥1000nM。
表2抗增殖活性


实施例15：化合物对多种肿瘤细胞具有抗增殖活性
将对数生长期的U937、NCI-H929、AML-2、MOLM-13细胞分别于用培养基(RPMI+10％FBS)、(RPMI+10％FBS)、(MEMα+20％FBS)、(RPMI+20％FBS)稀释，以4000个细胞/孔铺板于黑壁黑底96孔板(WHB)，每孔50微升。铺板后置于5％CO2，37℃培养箱培养，24小时后加药。将化合物用DMSO配置成10mM母液，用培养基稀释至所需浓度(DMSO终浓度为0.2％)后取50微升加到含细胞的96孔板中，化合物的终浓度为10000、3333.33、1111.11、370.37、123.46、41.15、13.72、4.57、1.52、0nM，每个化合物设置10个浓度梯度，每个浓度2个复孔，加药后置于5％CO2，37℃培养箱培养72小时。培养结束后，室温平衡30分钟，每孔加入100微升Reagent(Promega G7573)，微孔板振荡器振荡12分钟。室温GloMax navigator(Promega GM2010)测定发光值。以0nM对照组作为0％抑制，用GraphPad Prism 7软件计算IC50值。
化合物抗肿瘤细胞增殖活性见表3，其中A表示IC50<1nM，B表示1≤IC50＜10nM，C表示10nM≤IC50＜100nM，D表示100nM≤IC50＜1000nM，E表示IC50≥1000nM。
表3抗增殖活性IC50

实施例16：化合物对AML细胞凋亡效果
将对数生长期的MV-4-11细胞用生长培养基稀释，以60万个细胞/孔铺板于6孔板，每孔2mL，加药处理。收集细胞并用预冷的PBS清洗细胞两次，用100微升的1X annexin-binding buffer重悬细胞，加入5微升的FITC和1微升的100μg/mL的PI避光室温孵育15min，结束后于冰上加入400微升的1X annexin-bindingbuffer，轻柔混匀进行流式检测。
结果：细胞中加入化合物FDAB-46、FDAB-65处理7小时后，浓度为10μM、1μM、100nM的化合物均未能诱导MV-4-11细胞凋亡。而在加入化合物FDAB-46、FDAB-65处理16小时后，浓度1μM和100nM的化合物均能诱导细胞发生凋亡。
实施例17：化合物对GSPT1蛋白的调节效果
NB-4细胞在RPMI 1640(含10％FBS)的培养基中生长，离心计数后调整细胞浓度以106个细胞/孔铺板于12孔板，每孔1350微升。加入150微升DMSO和化合物置于5％CO2，化合物浓度为1μM，37℃培养箱培养6小时。将细胞离心弃去培养液，加入PBS清洗后弃去。用含有蛋白酶抑制剂混合液和磷酸酶抑制剂的RIPA裂解液制备全细胞裂解物，置于冰上30分钟。离心弃去细胞碎片沉淀，收集上清全细胞溶解产物并将其转移至新的EP管中。进行BCA蛋白测定后使用loading buffer配置样品。金属浴100℃10分钟。
将样品在4-20％的预制胶(SDS-PAGE凝胶)中进行电泳分离蛋白，再转至PVDF膜后用5％NFDM/TBST进行室温封闭1小时，一抗4℃孵育过夜，次日二抗室温2小时孵育。使用MINICHEMITM成像系统检测信号。
以下是本实施例所用抗体：
Anti-eRF3/GSPT1:Cell Signaling Technology#14980s
Anti-GAPDH：Huabio ET601-4
Goatanti-Rabbit IgG-HRP antibody：Huabio HA1001
GSPT1蛋白降解效果如表4所示，其中A表示GSPT1蛋白降解百分数不小于80％，B表示降解百分数小于80％但不小于50％，C表示降解百分数小于50％但不小于25％，D表示降解百分数小于25％。
表4：化合物对GSPT1蛋白的降解

此外，经测试化合物FDAB-48抗MV-4-11细胞增殖活性IC50为10.8nM，其在NB-4细胞中共孵6小时对GSPT1蛋白的降解达88％，而其不含卤素取代对应的化合物抗MV-4-11细胞增殖活性IC50为102.6nM，其在NB-4细胞中共孵6小时对GSPT1蛋白的降解效果只有65％。
实施例18：化合物对IKZF1、IKZF3、CK1α、c-MYC蛋白的调节效果
HL-60细胞在IMDM(含20％FBS)的培养基中生长，离心计数后调整细胞浓度以1.26个细胞/孔铺板于12孔板，每孔1350微升。加入150微升DMSO和化合物置于5％CO2，37℃培养箱培养4小时。将细胞离心弃去培养液，加入PBS清洗后弃去。用含有蛋白酶抑制剂混合液和磷酸酶抑制剂的RIPA裂解液制备全细胞裂解物，置于冰上30分钟。离心弃去细胞碎片沉淀，收集上清全细胞溶解产物并将其转移至新的EP管中。进行BCA蛋白测定后使用loading buffer配置样品。金属浴100℃10分钟。将样品在4-20％的预制胶(SDS-PAGE凝胶)中进行电泳分离蛋白，再转至PVDF膜后用5％NFDM/TBST进行室温封闭1小时，一抗4℃孵育过夜，次日二抗室温2小时孵育。使用MINICHEMITM成像系统检测信号。
以下是本实施例所用抗体：
Anti-eRF3/GSPT1:Cell Signaling Technology#14980s
Anti-c-Myc:Cell Signaling Technology#9402s
Anti-Casein Kinase 1alpha:Abcam ab206652
Anti-ikaros(IKZF1):Abcam ab191394
Anti-IKZF3:Abcam 139408
Anti-beta Tubulin：Huabio SR25-04
Goatanti-Rabbit IgG-HRP：Huabio HA1001
表5表示在HL-60细胞中不同浓度的化合物对IKZF1、IKZF3、CK1α和c-Myc蛋白的降解能力。其中A表示GSPT1蛋白降解百分数不小于80％，B表示降解百分数小于80％但不小于50％，C表示降解百分数小于50％但不小于25％，D表示降解百分数小于25％。
表5：化合物对IKZF1、IKZF3、CK1α、c-MYC蛋白的选择性降解

注：“/”表示未测试。
实施例19：化合物联用其他药物的抗细胞增殖效果
将对数生长期的MOLM-13细胞用培养基(RPMI+20％FBS)稀释，NCI-H929细胞用培养基(RPMI+10％FBS)稀释，以4000个细胞/孔铺板于黑壁黑底96孔板(WHB)，每孔50微升。铺板后置于5％CO2，37℃培养箱培养，24h后加药。将化合物用DMSO配置成10mM母液，用培养基稀释至所需浓度(DMSO终浓度为0.2％)后取50微升加到含细胞的96板中，化合物的终浓度为10000、3333.33、1111.11、370.37、123.46、41.15、13.72、4.57、1.52、0nM，每个化合物设置10个浓度梯度，每个浓度2个复孔，加药后置于5％CO2，37℃培养箱培养72小时。药物联用时，保持联阿扎胞苷和地塞米松的浓度分别为200nM和500nM，化合物从10000nM依次三倍浓度梯度稀释。培养结束后，室温平衡30分钟，每孔加入100微升Reagent(Promega G7573)，微孔板振荡器振荡12分钟。室温GloMax navigator(Promega GM2010)测定发光值。以0nM对照组作为0％抑制，用GraphPad Prism 7软件计算IC50值。
表6：化合物与阿扎胞苷联用抗MOLM-13细胞增殖
表7：化合物与地塞米松联用抗NCI-H929细胞增殖
测试结果如表6所示。由表6可知，阿扎胞苷抗MOLM-13细胞增殖活性IC50为751.1nM，浓度200nM的阿扎胞苷无明显抗MOLM-13细胞增殖活性。但当FDAB-121与200nM阿扎胞 苷联用后，FDAB-121的抗MOLM-13细胞增殖活性IC50从247.9nM增高到9.675nM，活性提高约25倍。无论是化合物单用还是与阿扎胞苷联用，FDAB-121活性相对于CC-90009提高约5倍。
如表7所示，地塞米松抗NCI-H929细胞增殖活性IC50大于10000nM，500nM的地塞米松无明显抗NCI-H929细胞增殖活性。但当FDAB-48与500nM地塞米松联用后，FDAB-48抗NCI-H929细胞增殖活性IC50从14.26nM增高到2.447nM，活性提高约6倍。此外，无论是FDAB-48化合物单用还是与地塞米松联用，其抗NCI-H929细胞增殖活性都远高于CC-90009和临床一线治疗骨髓瘤药物来那度胺、泊马度胺。
实施例20：hERG抑制测定
人类ether-a-go-go-related基因(hERG)编码的快速激活钾通道是参与心肌动作电位3期复极的形成的重要离子通道。药物阻断hERG通道能够导致心脏复极延长，心电图表现为QT间期延长，称为长QT间期综合征。药物引起的心室延迟复极在某些情况下可能引发致命性心律失常-尖端扭转型室性心动过速。
此测定用于测量化合物对人胚肾细胞(HEK293)中表达的克隆的hERG钾通道的作用。测定方法为：将细胞置于玻璃衬里的96孔板中的HEPES缓冲的生理盐水溶液中并且在各浓度下用适量的测试和对照溶液加载持续3分钟暴露时间。在0.3％DMSO中稀释待测化合物。将自动平行膜片钳系统QPatch 48 X(Sophion)用于测试化合物在3μM浓度下对hERG的抑制率。
结果：化合物FDAB-48、FDAB-65、FDAB-120以及FDAB-121在3μM下对hERG的抑制率分别为25％、11％、13％以及9％，表明化合物FDAB-65、FDAB-120以及FDAB-121在3μM下具有几乎不可观察到的hERG抑制活性(<20％抑制)，化合物FDAB-48只有较小的hERG抑制活性(25％抑制)。而化合物CC-90009在3μM对hERG产生66％的明显抑制。可见，本发明化合物具有出乎意料地减小针对hERG通道的抑制活性。
实施例21：急性髓系白血病异种移植小鼠模型中的有效性研究
在体内有效性研究中使用免疫受损之6～8周龄雌性NSG小鼠，动物到达后在实验环境饲养7天后方开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养，每笼6只小鼠。将表达荧光素酶的人MV-4-11急性髓系白血病细胞MV-4-11-luc通过尾部静脉注射(5×106个细胞/动物)给小鼠接种。细胞接种7天后，小鼠用IVIS Lumina III小动物成像仪进行成像开始分组给药，将具肿瘤小鼠随机分配至媒介物对照组或化合物治疗组中(6只动物/组)。通过口服胃管灌食向每一治疗组中的动物给予化合物(10mg/kg，每天两次)。每天量测体重，同时在开始使用化合物或媒介物进行治疗之后量测平均发光。
实验指标：实验指标是考察肿瘤生长是否可以被抑制、延缓或治愈。每周两次用IVIS Lumina III小动物成像仪测量肿瘤大小。肿瘤信号以每秒的曝光光子数来判断。化合物的抑 瘤疗效用肿瘤增殖率T/C(％)评价。T/C％＝TRTV/CRTV*100％。(TRTV：治疗组RTV；CRTV：阴性对照组RTV；RTV＝Vt/V0。其中V0为分笼给药时(即day0)测量所得肿瘤信号，Vt为每一次测量时的肿瘤信号)。根据国家药审中心指导原则T/C(％)＞40％为无效；T/C≤40％，并经统计学处理P<0.05为有效。
结果：表8中显示了各化合物不同时间点的肿瘤增殖率T/C(％)。其中化合物CC-9000910mg/kg每天口服两次在14天内未表现出抑瘤效果。而本发明化合物FDAB-48、FDAB-65、FDAB-120以及FDAB-121每天10mg/kg口服两次在第14天的T/C(％)分别为：0.05％，0.78％，2.12％和0.005％。可见，本发明化合物所有给药组均表现出明显的抗肿瘤效果。意外地，本发明化合物给药第三天检测已发生明显的肿瘤抑制效果，FDAB-48、FDAB-65、FDAB-120以及FDAB-121每天10mg/kg口服两次在第3天的T/C(％)分别为：0.95％，4.58％，6.69％和0.32％。
表8化合物在MV-4-11-Luc异种移植模型中的抗肿瘤活性
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 如下式I所示的化合物，其互变异构体、立体异构体、水合物、溶剂化物、或药学上可接受的盐：
    R1选自氢、氘、C1-12烷基、
    R2相同或不同，彼此独立选自氢，无取代或任选被一个、两个或更多个Ra取代的如下基团：C1-12烷基、C6-20芳基、5-20元杂芳基、C3-20环烷基、3-20元杂环基；
    R’、R3相同或不同，彼此独立选自氢，无取代或任选被一个、两个或更多个Rb取代的如下基团：C1-12烷基、C1-12烷氧基、C6-20芳基、5-20元杂芳基、C3-20环烷基、3-20元杂环基；
    R4、R5相同或不同，彼此独立选自氢、氘、卤素；
    m为1、2或3；
    R6选自氢、氘、卤素、无取代或任选被一个、两个或更多个Rc取代的如下基团：C1-12烷基、C1-12烷氧基；
    Q1为-CH2-、-CD2-、-C(O)-或-C(S)-；
    R7、R8、R9、R10相同或不同，彼此独立选自氢、卤素、氘、CN、C1-12烷基、-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14、-CH2-NHCONH-R12；所述-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14的亚甲基上的氢任选被1或2个氘取代；
    R11、R12、R13、R14相同或不同，彼此独立选自无取代或任选被一个、两个或更多个Rs取代的如下基团：C6-20芳基、5-20元杂芳基、C3-20环烷基、3-20元杂环基、C2-12烯基、C2-12炔基、C1-12烷基、-P(C6-20芳基)2、-N(C1-12烷基)2、-COC1-12烷基、-C1-12烷基N(C1-12烷基)2、 C6-20芳基并C3-20环烷基、C3-20环烷基与C3-20环烷基构成的螺环基；
    Y选自C1-12亚烷基、C3-20亚环烷基、C2-12亚烯基、C2-12亚炔基、-CH2NH-、-CH2NHCO-、-CH2NHCO-、-CH2O-、-C2H4O-、-CH2S-、
    Ra、Rb、Rc、Rs相同或不同，彼此独立选自卤素、氨基、羟基、C1-12烷基、C1-12烷氧基、卤代C1-12烷基、CN、C3-20环烷基、-N(C1-12烷基)2、氘代、C2-12烯基、C2-12炔基、-COC1- 12烷基、-COC6-20芳基、C1-12烷硫基、巯基、＝O、-C1-12烷基羟基、3-20元杂环基、-SO2C1-12烷基、-SO2NH2、C6-20芳基、-OC6-20芳基、-C1-12烷基C6-20芳基、-C1-12烷基氨基、-C6-20芳基C1-12烷基氨基、-C6-20芳基氨基、-OC1-12烷基C6-20芳基、-C6-20芳基羟基、-C6-20芳基C1-12烷基羟基。
  2. 根据权利要求1所述的化合物，其特征在于，R1选自氢、C1-6烷基、-C1-6烷基COOC1-6烷基、-COOC1-6烷基或-C1-6烷基OCOOC1-6烷基；
    R4、R5、R6选自氢；m为1、2或3；Q1为-CH2-或-C(O)-；
    R7、R8、R9、R10相同或不同，彼此独立选自氢、氘代、卤素、CN、C1-6烷基、-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14；所述-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14的CH2上的氢任选被1或2个氘取代；
    R11、R12、R13、R14相同或不同，彼此独立选自无取代或任选被一个、两个或更多个Rs取代的如下基团：C6-12芳基、5-12元杂芳基、C3-12环烷基、3-12元杂环基、C2-6烯基、C2-6炔基、C1-6烷基、-P(C6-20芳基)2、-N(C1-6烷基)2、-COC1-6烷基、-C1-6烷基N(C1-6烷基)2、C6-12芳基并C3-12环烷基、C3-12环烷基与C3-12环烷基构成的螺环基；
    Y选自C1-6亚烷基、C3-12亚环烷基、C2-6亚烯基、C2-6亚炔基、-CH2NH-、-CH2NHCO-、-CH2NHCO-、-CH2O-、-C2H4O-、-CH2S-、
    Rs相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳 基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基、-C1-6烷基氨基、-C6-12芳基C1-6烷基氨基、-C6-12芳基氨基、-OC1-6烷基C6-12芳基、-C6-12芳基羟基、-C6-12芳基C1-6烷基羟基。
  3. 根据权利要求1或2所述的化合物，其特征在于，式I选自如下式Ia所示结构：
    式Ia中，R1选自氢、C1-6烷基、-C1-6烷基COOC1-6烷基、-COOC1-6烷基或-C1-6烷基OCOOC1-6烷基；
    R4、R5、R6选自氢或氘；m为1、2或3；Q1为-CH2-、-CD2-或-C(O)-；
    R7’选自氢、氘、卤素；p为1、2或3，条件是至少一个R7’选自卤素；
    R8’选自CN、-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14；所述-CH2-NHBoc、-CH2-NH2、-CH2-NHCO-CF2-R11、-CH2-NHCO-R12、-CH2-NHCONH-R12、-CH2-NHCO-Y-R13、-CH2-NH-Y-R14的CH2上的H任选被1或2个氘取代；
    R11、R12、R13、R14相同或不同，彼此独立选自无取代或任选被一个、两个或更多个Rs取代的如下基团：C6-12芳基、5-12元杂芳基、C3-12环烷基、3-12元杂环基、C2-6烯基、C2-6炔基、C1-6烷基、-P(C6-20芳基)2、-N(C1-6烷基)2、-COC1-6烷基、-C1-6烷基N(C1-6烷基)2、C6-12芳基并C3-12环烷基、C3-12环烷基与C3-12环烷基构成的螺环基；
    Y选自C1-6亚烷基、C3-12亚环烷基、C2-6亚烯基、C2-6亚炔基、-CH2NH-、-CH2NHCO-、-CH2NHCO-、-CH2O-、-C2H4O-、-CH2S-、
    Rs相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳 基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基、-C1-6烷基氨基、-C6-12芳基C1-6烷基氨基、-C6-12芳基氨基、-OC1-6烷基C6-12芳基、-C6-12芳基羟基、-C6-12芳基C1-6烷基羟基。
  4. 根据权利要求1或2所述的化合物，其特征在于，式I选自如下式Ib所示结构：
    式Ib中，R15、R16、R17、R18相同或不同，彼此独立选自氢、氘、卤素、氨基、羟基、氰基，无取代或任选被一个、两个或更多个Rx取代的如下基团：C1-6烷基、-SO2C1-6烷基、C1-6卤代烷基、C6-12芳基、C1-6烷氧基、-N(C1-6烷基)2、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷硫基、-COC1-6烷基、-COC6-12芳基、-OC6-12芳基、-C1-6烷基-羟基、3-12元杂环基、-SO2NH2；
    Rx相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、-C1-6烷基氨基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基；
    或者，式I选自如下式Ic所示结构：
    式Ic中，R15、R16、R17、R18、R19相同或不同，彼此独立选自氢、氘、卤素、氨基、羟基、氰基，无取代或任选被一个、两个或更多个Rx取代的如下基团：C1-6烷基、-SO2C1-6烷基、C1-6卤代烷基、C6-12芳基、C1-6烷氧基、-N(C1-6烷基)2、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷硫基、-COC1-6烷基、-COC6-12芳基、-OC6-12芳基、-C1-6烷基-羟基、3-12元杂环基、-SO2NH2；
    Rx相同或不同，彼此独立选自卤素、氨基、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、CN、C3-12环烷基、-N(C1-6烷基)2、氘代、C2-6烯基、C2-6炔基、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、-C1-6烷基氨基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-C1-6烷基C6-12芳基，且R19不为H；
    又或者，式I选自如下式Id所示结构：
    Id中，L为化学键、C2-12炔基、C2-12烯基、NH、氧、硫或C1-12烷基，所述C1-12烷基任选被如下基团取代：羟基、氨基；
    R20为无取代或任选被一个、两个或更多个Ry取代的如下基团：C6-12芳基、3-12元环烷基、5-12元杂环基或5-12元杂芳环基；
    Ry选自氘代、卤素、羟基、氨基、羧基、CN、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、C3-12环烷基、-N(C1-6烷基)2、-COC1-6烷基、-COC6-12芳基、C1-6烷硫基、巯基、＝O、-C1-6烷基羟基、-C1-6烷基氨基、3-12元杂环基、-SO2C1-6烷基、-SO2NH2、C6-12芳基、-OC6-12芳基、-OC1-6烷基C6-12芳基、-C1-6烷基C6-12芳基、-C1-6烷基-COOH、-C6-12芳基-C1-6烷基氨基、-C6-12芳基-C1-6烷基羟基、-C6-12芳基氨基、-C6-12芳基羟基。
  5. 根据权利要求4所述的化合物，其特征在于，式Ib中，R15、R16、R17、R18相同或不同，彼此独立选自氢、氘、F、Cl、甲基、氨基、羟基、甲氧基、三氟甲基、氰基、苯基、二甲氨基、乙基、正丙基、异丙基、叔丁基、乙烯基、乙炔基、环丙基、羰甲基、羰苯基、苯氧基、叔丁氧基、烷硫基、-SO2NH2、羟甲基、N-四氢吡咯基、-SO2CH2、对氨基苯基、
    优选地，Id中，L为化学键、炔基、NH、
    R20为苯基；
    Ry选自Cl、羟基、氨基、叔丁基、苯基、对氨基苯基、对羟基苯基、乙基氨、羟乙基、对羟乙基苯基、对乙基氨苯基、
  6. 根据权利要求1-5任一项所述的化合物，其特征在于，所述式I化合物选自如下：






  7. 权利要求1-6任一项所述式I所示化合物，其互变异构体、立体异构体、水合物、溶剂化物、或药学上可接受的盐在制备治疗或预防由GSPT1、IKZF1、IKZF2、IKZF3、CK1α、N-MYC或C-MYC等蛋白突变、表达失衡、变构与功能异常相关的疾病、病症或病况的药物中的用途。
  8. 根据权利要求7所述的用途，其特征在于，所述的疾病、病症或病况包括：骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、慢性粒单核细胞白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、眼外延伸黑色素瘤、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓系白血病、中枢神经系统淋巴瘤、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状 腺癌、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤、弥漫性大B细胞淋巴瘤、星状细胞瘤、肝细胞癌或原发性巨球蛋白血症、病毒感染。
  9. 一种药物组合物，其特征在于，包括权利要求1-6任一项所述式I所示化合物，其互变异构体、立体异构体、水合物、溶剂化物、或药学上可接受的盐。
  10. 根据权利要求9所述的药物组合物，其特征在于，所述药物组合物中，除活性成分式I所示化合物外，还进一步包含其他治疗剂，所述的其它治疗剂选自如下中的至少一种：PD-1抑制剂、PD-L1抑制剂、利妥昔单抗、曲妥珠单抗、埃罗妥珠单抗、乌妥昔单抗、达雷木单抗、阿托珠单抗、替伊莫单抗、阿仑单抗、本妥昔单抗、阿糖胞苷、阿扎胞苷、蒽环类药物、泼尼松、地塞米松、美法仑、克拉屈滨、氟达拉滨、米托蒽醌、依托泊苷、甲氨蝶呤、培美曲塞、托泊替康、阿霉素、环磷酰胺、吉西他滨、达卡巴嗪、克拉霉素、长春新碱、多西他赛、氯法拉滨注射液、HDAC抑制剂、FLT3抑制剂、IDH1/2抑制剂、BCL-2抑制剂、蛋白酶体抑制剂、PI3K抑制剂、BTK抑制剂、帕博西尼、红血球生长激素、艾曲波帕、米诺四环素、CAR-T中的至少一种；
    优选地，所述药物组合物中，除活性成分式I所示化合物外，还包括阿扎胞苷或地塞米松。
    优选地，所述药物组合物通过如下方式进行给药：口服、直肠、局部、口腔、肠胃外、肌内、真皮内、静脉内和透皮给药。
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