WO2020007322A1 - 一种靶向降解bet蛋白的化合物及其应用 - Google Patents

一种靶向降解bet蛋白的化合物及其应用 Download PDF

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WO2020007322A1
WO2020007322A1 PCT/CN2019/094562 CN2019094562W WO2020007322A1 WO 2020007322 A1 WO2020007322 A1 WO 2020007322A1 CN 2019094562 W CN2019094562 W CN 2019094562W WO 2020007322 A1 WO2020007322 A1 WO 2020007322A1
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independently
deuterium
ring atoms
alkyl
butyl
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饶燏
李孟鸿
兰天龙
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清华大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of biomedicine, and in particular, the present invention relates to a compound for targeted degradation of BET protein and its application.
  • Bromodomain is a type of transcription co-activator containing a conserved protein domain that specifically recognizes acetylated lysine (KAc) in histones. It can recognize acetylated lysine and recruit related proteins such as transcription factors for staining.
  • KAc acetylated lysine
  • BET bromodomain and extra-terminal proteins represent a complete protein family. Its members include BRD2, BRD3, BRD4 and BRDT. Each protein contains two N-terminal Bromodomain domains BD I and BD II and C-terminal additional Extra-terminal domain.
  • BRD4 protein is currently the most studied among members of the BET protein family.
  • BRD4 is often located in the superenhancer regions upstream of some important proto-oncogenes, such as c-MYC and bcl-xL, and plays an important role in the regulation of the expression of these genes.
  • BRD4 Based on the important role played by BRD4 in the regulation of important proto-oncogene expression, BRD4 is expected to become an important target for the treatment of various tumors, such as acute myeloid leukemia, multiple myeloma, Burkit ’s lymphoma, and prostate cancer.
  • Inhibitors of BRD4 that have been developed, such as (+)-JQ-1, i-BET, and OTX-015 show great therapeutic potential in preclinical animal models of a variety of tumors, including Burkit's lymphoma.
  • (+)-JQ-1 and OTX-015 can cause a rapid multifold increase in BRD4 protein levels in a concentration-dependent manner, making inhibition of BRD4 more difficult. Even at concentrations ten times higher than the IC 50 , (+)-JQ-1 and OTX-015 cannot sufficiently inhibit c-MYC. In addition, (+)-JQ-1 caused a decrease in c-MYC in AML cells, but c-MYC levels recovered rapidly after removal of (+)-JQ-1 and were higher than before treatment. Although many small molecule inhibitors of BET including OTX-015 and I-BET726 have already entered the clinical trial stage. However, due to insufficient inhibition of c-MYC and the feedback mechanism capable of up-regulating BRD4 gene expression, the effectiveness of these drugs remains to be tested. In addition, resistance to BET inhibitors has been observed in some preclinical studies of BET inhibitors.
  • the structure is shown in Figure 1.
  • One end of this type of molecule targets E3 ligase and the other end
  • the structure is targeted to bind to the BET protein, and the structures at both ends are connected by a chain (linker) to form a complete compound molecule.
  • the compound ubiquitinates the target protein through E3 and guides the target protein into the degradation pathway, which specifically degrades the target protein Strong.
  • These compounds can efficiently degrade BET protein in a variety of cell lines at lower concentrations, and can more effectively block the expression of the proto-oncogene c-MYC; BET protein inhibitors cannot affect the abundance of BET protein.
  • PROTAC molecules for BET protein can induce the artificial ubiquitination of BET protein when the natural degradation pathway of BET protein fails, thereby overcoming the resistance of tumor cells to BET protein inhibitors.
  • the present invention proposes a compound which is a compound represented by Formula I or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs:
  • X represents a ligand of a BET protein
  • Z represents a ligand of an E3 ligase
  • Y represents a chain connecting X and Z.
  • the above compound may further include at least one of the following additional technical features:
  • X is a compound represented by Formula II-1 or II-2,
  • Cy 1 or Cy 2 are each independently a benzene ring, a C 6-12 aryl group, a heteroaryl group consisting of 5-12 ring atoms, a C 3-12 cycloalkyl group or a heterocyclic group consisting of 3-12 ring atoms ;
  • Each Cy 1 or Cy 2 is independently replaced by 1, 2 , 3, 4, 5, or 6 R h1 ;
  • Each L 1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h2 ;
  • Each R h1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-12 ring atoms Composition of heteroaryl, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w ) g- , R g
  • Each R h2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-12 ring atoms Composition of heteroaryl, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w ) g- , R g
  • Each R h1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h3 ;
  • Each R h2 is independently replaced by 1, 2, 3, 4, 5 or 6 R h4 ;
  • Each R h3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl;
  • Each R h4 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl;
  • Each R 1a is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxygen, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms The composition of heteroaryl;
  • Each R m , R w or R g is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-10 ring atoms;
  • n is independently 1, 2, 3 or 4;
  • Each g is independently 0, 1, 2, 3 or 4;
  • Each p is independently 1 or 2.
  • Cy 1 or Cy 2 are each independently a benzene ring, a C 6-10 aryl group, a heteroaryl group consisting of 5-10 ring atoms, a C 3-6 cycloalkyl group, or 3-12 A heterocyclic group consisting of ring atoms.
  • each R h1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkane , C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms , Heteroaryl consisting of 5-10 ring atoms, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w )
  • Each R h2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-10 ring atoms Composition of heteroaryl, R g- (CR m R w ) g -O- (CR m R w ) g- , R g- (CR m R w ) g -S- (CR m R w ) g- , R g- (CR m R w ) g -N (R 1a )-(CR m R w ) g- , R g- (CR m R w ) g- , R g
  • Each R h1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h3 ;
  • Each R h2 is independently replaced by 1, 2, 3, 4, 5 or 6 R h4 ;
  • Each R h3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl or C 3-6 cycloalkyl;
  • Each R h4 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl or C 3-6 cycloalkyl.
  • each R 1a is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-10 ring atoms;
  • Each R m , R w or R g is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-10 ring atoms.
  • Cy 1 or Cy 2 are each independently
  • Each R h2 is independently hydrogen, deuterium, F, Cl, Br, I, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • Each R h1 is independently replaced by 1, 2, 3, 4, 5 or 6 R h3 ;
  • Each R h2 is independently replaced by 1, 2, 3, 4, 5 or 6 R h4 ;
  • Each R h3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl;
  • Each R h4 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl.
  • each R 1a is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • Each R m , R w or R g is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • X is a compound represented by formula III-1, III-2, III-3, III-4, III-5, or III-6,
  • Z is a compound represented by Formula IV,
  • Q is N or CR 2 ;
  • M is C (R e R f ), N (R 1b ), O or S;
  • W, K are independently C (R e R f ), NH, O or S;
  • R 2 is hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each R 2a or R 2b is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, oxo, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-12 ring atoms;
  • Each R 2c is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-12 ring atoms The composition of heteroaryl;
  • Each R e and R f are independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocycle consisting of 3-12 ring atoms, or 5-10 Heteroaryl consisting of two ring atoms;
  • Each R 1b is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-12 ring atoms The composition of heteroaryl;
  • n 1 and n 2 are independently 0, 1 , 2 or 3;
  • n 3 is 0, 1, 2, 3, 4 or 5.
  • each of R e and R f is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1 -4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-12 ring atoms Heterocyclyl or heteroaryl consisting of 5-10 ring atoms;
  • Each R 1b is independently H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkane Oxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Composition of heteroaryl.
  • R 2 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • each of R 2a and R 2b is independently hydrogen, deuterium, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
  • Each R 2c is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • each of R e and R f is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
  • Each R 1b is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the Z is a compound represented by formula V-1, V-2, V-3 or V-4,
  • the Y is a group containing 1 to 30 atoms, and the atom includes at least one selected from a carbon atom, a sulfur atom, an oxygen atom, a nitrogen atom, and a selenium atom.
  • Y is optionally substituted C 1-20 alkyl, C 1-20 haloalkyl, C 1-20 alkoxy, C 2-20 alkenyl, C 2-20 alkynyl A group consisting of at least one of C 3-12 cycloalkyl, C 6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or heteroaryl consisting of 5-12 ring atoms.
  • said Y is optionally substituted Among them, x 1 -x 23 are each independently a key,
  • R 1d is H, deuterium, F, Cl, Br, I, CN, -NO 2 , OH, amino, carboxyl or C 1-4 alkyl.
  • Y is a compound represented by Formula VI-1 or VI-2,
  • Each r is an integer between 0 and 12 independently;
  • Each k is an integer between 0 and 12 independently;
  • Each j is independently an integer between 0 and 12;
  • Each t 1 or t 3 is independently a bond, Optionally substituted
  • Each t 2 or t 4 is independently a bond, Optionally substituted
  • t 5 is a bond or optionally substituted
  • R 1d is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Y is a compound represented by at least one of the following,
  • Each of t 6 , t 7 , t 8 , t 9 or t 10 is an integer between 0 and 11 independently.
  • the present invention provides a compound which is a compound represented by any one of Formulas 1 to 50 or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, Hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the invention proposes a pharmaceutical composition.
  • the pharmaceutical composition includes a compound according to any one of the above.
  • the above pharmaceutical composition may further include at least one of the following additional technical features:
  • the pharmaceutical composition further includes an excipient.
  • the pharmaceutical composition further includes other drugs for treating or preventing non-Hodgkin's lymphoma, Burkitt's lymphoma, acute myeloid leukemia, multiple myeloma, lung cancer, prostate cancer, and NUT midline cancer.
  • the other medicament for treating or preventing non-Hodgkin's lymphoma includes Ibrutinib.
  • the other medicine for treating or preventing Burkitt's lymphoma includes at least one selected from cyclophosphamide and doxorubicin.
  • the other medicament for treating or preventing acute myeloid leukemia includes at least one selected from the group consisting of cytarabine, Azacitidine, and Decitabine.
  • the other medicament for treating or preventing multiple myeloma includes at least one selected from the group consisting of carfilzomib, thalidomide, lenalidomide, and pomaridamine.
  • the other medicament for treating or preventing lung cancer includes at least one selected from the group consisting of gefitinib, erlotinib, osestatin, and afatinib.
  • the other medicament for treating or preventing prostate cancer includes at least one selected from flutamide and nirumit.
  • the present invention provides the use of the compound according to any one of the above or the pharmaceutical composition according to any one of the above to prepare a medicament, which is used to degrade the BET protein.
  • the present invention provides the use of the compound according to any one of the above or the pharmaceutical composition according to any one of the above to prepare a medicament for treating or preventing non-Hodgkin's lymph Tumor, Burkitt's Lymphoma, Acute Myeloid Leukemia, Multiple Myeloma, Lung Cancer, Prostate Cancer, and NUT Midline Cancer.
  • the present invention provides a method for degrading a BET protein.
  • the method includes: contacting a BET protein with the compound described above or the pharmaceutical composition according to any one of the above.
  • the present invention provides a method for treating or preventing non-Hodgkin's lymphoma, Burkitt's lymphoma, acute myeloid leukemia, multiple myeloma, lung cancer, prostate cancer, and NUT midline cancer.
  • the method comprises: administering to a patient the compound according to any one of the above or the pharmaceutical composition according to any one of the above.
  • HBL-1 cell line is a class of non-Hodgkin's lymphoma cells.
  • Ibrutinib is the most commonly used drug for clinical treatment of non-Hodgkin's lymphoma and has excellent therapeutic effects.
  • the target of Ibrutinib is BTK protein
  • Ibrutinib occupies the ATP-binding pocket of the BTK protein and inhibits BTK activity by covalent cross-linking of the acrylamide functional group at the molecular end with the cysteine residue at position 481 of the BTK protein.
  • the C481S mutation of the BTK protein makes cells resistant to Ibrutinib.
  • the compounds according to the embodiments of the present invention show strong degradation of BET proteins in various cell lines (DC 50 ⁇ 100 nM), and can significantly degrade the expression product c-MYC of the oncogene c-MYC downstream of BRD4. protein.
  • the compounds according to the examples of the present invention showed a very strong degradation effect on the BET protein of the HBL-1 (BTK-C481S) cell line (DC 50 ⁇ 1 nM).
  • -1 (BTK-C481S) cell line shows extremely strong killing effect (IC 50 can be as low as 0.66 nM).
  • the compounds of the embodiments of the present invention have the potential to treat non-Hodgkin's lymphoma resistant to Ibrutinib.
  • FIG. 1 is a schematic diagram of a basic technical route of PROTACs (proteolytic targeting chimeras) according to an embodiment of the present invention
  • FIG. 2 is a schematic diagram of preparing a compound of the present invention by a click reaction (click reaction) or an amide condensation reaction according to an embodiment of the present invention
  • FIG. 3 is a schematic diagram of degradation of Jurkat cell lines BRD4 and BRD2 by the compounds represented by Formula 1, Formula 9 and Formula 13 and the literature report compound ARV-825 according to an embodiment of the present invention
  • FIG. 4-1 is a schematic diagram showing the results of the degradation of BET protein of the compound represented by Formula 2 according to an example of the present invention, which is affected by other compounds such as carfilzomib (Cfz); FIG.
  • 4-2 is a schematic diagram showing the results of degradation of the BET protein of a compound represented by Formula 2 according to an example of the present invention, which are affected by other compounds such as (+)-JQ-1, ABBV-075, and Poma;
  • FIG. 5-1 is a schematic diagram of degradation of BET protein in a cell line HBL-1 by a compound represented by Formula 2, Formula 5, Formula 10, Formula 13 or Formula 15 according to an embodiment of the present invention
  • 5-2 is a schematic diagram of degradation of a BET protein in a cell line Ramos by a compound represented by Formula 2, Formula 5, Formula 10, Formula 13 or Formula 15 according to an embodiment of the present invention
  • 5-3 is a schematic diagram of degradation of BET protein by a compound of formula 2, formula 5, formula 10, formula 13 or formula 15 in a cell line according to an embodiment of the present invention
  • 5-4 is a schematic diagram of degradation of BET protein by a compound of formula 2, formula 5, formula 10, formula 13 or formula 15 in a cell line according to an embodiment of the present invention
  • Figure 6-1 shows the effect of the compound represented by formula 2 and (+)-JQ-1, ARV-825, ABBV-075, etc. on Ramos cell line for 2 hours on the proto-oncoprotein c-myc according to the embodiment of the present invention. Results diagram;
  • Figure 6-2 shows the effect of the compound represented by formula 2 and (+)-JQ-1, ARV-825, ABBV-075, etc. on Ramos cell line for 6 hours on the proto-oncoprotein c-myc according to the embodiment of the present invention. Results diagram;
  • FIG. 7 is a schematic diagram of the BET protein reduction effect of the compound represented by Formula 10 and ARV-825 on HBL-1 (BTK-C481S) cell line (incubation for 2 hours) at a low concentration according to an embodiment of the present invention
  • FIG. 8-1 is a negative control of Formula 2, a compound represented by Formula 2, Formula 10, (+)-JQ-1, ARV-825, and ABBV-075, etc. in HBL-1 (BTK-C481S) according to an embodiment of the present invention. Schematic of the cell line's killing effect on cells; and
  • FIG. 8-2 is a negative control of Formula 2, a compound represented by Formula 2, Formula 10, (+)-JQ-1, ARV-825, and ABBV-075, etc. in HBL-1 (BTK-C481S) according to an embodiment of the present invention.
  • 9-1 is a schematic diagram of the degradation of BET protein in the cell line Jurkat by the compounds represented by Formula 16, Formula 18, Formula 19, Formula 20, Formula 22, and Formula 23 according to an embodiment of the present invention
  • 9-2 is a schematic diagram of degradation of BET protein by the cell line Jurkat in the cell line Jurkat according to Formula 24, Formula 25, Formula 26, Formula 27, Formula 28, Formula 29, and Formula 30 according to an embodiment of the present invention
  • 9-3 is a schematic diagram of degradation of BET protein by a cell line Jurkat of a compound represented by Formula 16, Formula 18, Formula 19, Formula 20, Formula 21, Formula 22, and Formula 23 according to an embodiment of the present invention
  • 10-1 is a schematic diagram showing a comparison of the activities of compounds represented by Formula 2, Formula 10, Formula 21 and Formula 24 on a lung cancer K562 cell line according to an embodiment of the present invention
  • FIG. 10-2 is a schematic diagram showing a comparison of the activity of the compounds represented by Formula 2, Formula 10, Formula 21 and Formula 24 on a prostate cancer LNcap cell line according to an embodiment of the present invention.
  • the term "administers to a patient a compound or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable "Salt or prodrug or pharmaceutical composition as described above” refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner.
  • the compound of formula I, formula II, formula III, formula IV, formula V or formula VI or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate of the present invention , Metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions can be administered by any common route as long as it can reach the intended tissue.
  • Various modes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, cortical, oral, topical, nasal, lung and rectal, but the invention is not limited to these exemplary modes of administration.
  • the frequency and dosage of the pharmaceutical composition of the present invention can be determined by a number of related factors, including the type of disease to be treated, the route of administration, the age, sex, weight and severity of the disease, and the active ingredient Type of medication.
  • treatment is used to refer to obtaining the desired pharmacological and / or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing the disease and / or adverse effects caused by the disease.
  • Treatment encompasses the treatment of diseases in mammals, particularly humans, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not yet been diagnosed; (b) inhibiting the disease; or (c) Relieve disease, such as reducing symptoms associated with the disease.
  • Treatment encompasses any medication that administers a drug or compound to an individual to treat, cure, alleviate, ameliorate, alleviate or inhibit the disease of the individual, including but not limited to those containing Formula I to Formula VI or Formula 1 to 18 Compounds or pharmaceutical compositions are administered to individuals in need.
  • the excipients include pharmaceutically acceptable excipients, lubricants, fillers, diluents, disintegrants, stabilizers, preservatives, emulsifiers, solubilizers, and colorants, which are well known in the formulation field. , Sweeteners, made into tablets, pills, capsules, injections and other different dosage forms.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotomers), geometric isomers (cis / trans) isomers, atropisomers, etc. .
  • Chiral is a molecule that cannot overlap with its mirror image; “Achiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomers refer to two isomers of a compound that cannot overlap but mirror image each other.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of a molecule with respect to its one or more chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are right-handed.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, and this can occur when there is no stereoselection or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R, S) -configuration presence.
  • each asymmetric atom has at least a 50% enantiomeric excess in the (R)-or (S) -configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention may be in one of the possible isomers or mixtures thereof, such as racemic and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ).
  • Optically active (R)-or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, based on differences in the physicochemical properties of the components. And / or fractional crystallization.
  • racemates of any of the resulting end products or intermediates can be resolved into optical enantiomers by methods known to those skilled in the art using known methods, for example, by subjecting the diastereomeric salts obtained Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis ( 2nd Ed. Robert E.
  • tautomers or “tautomeric forms” refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerization is possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the compounds included in the present invention.
  • a class of compounds is understood that the term “optionally substituted” is used interchangeably with the term “substituted or unsubstituted”.
  • substituted means that one or more hydrogen atoms in a given structure are replaced with a specific substituent.
  • an optional substituent group may be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be
  • a ring system in which a substituent R 'is connected to a central ring by a bond represents that the substituent R' may be substituted at any substitutable position on the ring.
  • formula a represents any position that may be substituted on the B 'ring may be substituted by R', as shown in formula b, formula c and formula d.
  • attachment points on the ring It can be attached to the rest of the molecule at any connectable position on the loop.
  • formula i represents any position on the B ′ ring that may be connected can be used as the connection point, as shown in formulas d, e, and f.
  • two attachment points on the same ring It can be connected to the other two parts of the molecule at any two connectable positions on the ring, and the connection modes of the two ends can be interchanged.
  • formula j represents that two different positions on the D ring that may be connected can be used as connection points to connect with the other two parts of the molecule, as shown in formulas g, h, and k.
  • k is an integer between 0 and 12, which means that the number of repetitions of t 3 is k, and the structural formula of each t 3 may be the same or different.
  • connection modes at both ends can be interchanged.
  • connection modes of p -N (R 1a )-(CR m R w ) g- are interchangeable.
  • C 1 - 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • an integer between 0 and 12 includes endpoints 0 and 12, and any integer between 0 and 12, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood as the linking group.
  • the “alkyl” or “aryl” represents a linked An alkylene group or an arylene group.
  • alkyl examples include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH (CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ), tert-butyl (t-Bu, -C (CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH (CH 3 ) CH 2 CH 2 CH 3 ), 3-pentyl (-CH (CH 2 CH 3 ) 2 ), 2-methyl-2 -Butyl (-C (CH 3 ) 2
  • alkyl and its prefix “alkane” are used herein and include both straight and branched saturated carbon chains.
  • alkylene is used herein to denote a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight or branched chain saturated hydrocarbon. Examples of this include, but are not limited to, methylene, ethene , Isopropyl, and so on.
  • alkenyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-15 carbon atoms, which has at least one site of unsaturation, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group A group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl means a straight or branched monovalent hydrocarbon group containing 2-15 carbon atoms, which has at least one site of unsaturation, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like .
  • cycloalkyl refers to monovalent or polyvalent, non-aromatic, saturated or partially unsaturated And does not contain heteroatoms, including monocyclic 3-12 carbon atoms or bicyclic 7-12 carbon atoms.
  • a bicyclic carbocyclic ring having 7-12 atoms may be a bicyclic [4,5], [5,5], [5,6], or [6,6] system, and a bicyclic carbocyclic ring having 9 or 10 atoms at the same time It can be a bicyclic [5,6] or [6,6] system.
  • Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • Examples of cyclic aliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1- Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl Radical, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • heterocyclic refers to monocyclic, bicyclic or tricyclic systems in which one or more of the rings
  • the carbon atom is independently and optionally substituted with a heteroatom, which has the meaning as described herein, and the ring may be fully saturated or contain one or more degrees of unsaturation, but is by no means aromatic, and There are one or more junctions connected to other parts of the molecule.
  • Hydrogen atoms on one or more rings are independently and optionally substituted with one or more substituents described herein.
  • heterocyclic is a monocyclic ring of 3 to 7 members (1-6 carbon atoms and selected from N, 1-3 heteroatoms O, P, S, and replaced with S or P is optionally substituted by one or more oxygen atoms obtained e.g.
  • SO, SO 2, PO, PO 2 group when the When the ring is a three-membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms, obtained e.g. SO, SO 2, PO, PO 2 group).
  • heterocyclic group may be a carbon group or a heteroatom group.
  • Heterocyclyl also includes groups formed by the combination of a heterocyclic group and a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothioranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thiaxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thiocyclobutyl , Homopiperidinyl, epoxypropyl, azaheptyl, oxepanyl, thietyl, 4-
  • heterocyclic group also include 1,1-dioxothiomorpholinyl and a group in which two carbon atoms on the ring are replaced with an oxygen atom such as a pyrimidinedione group.
  • heteroatom means one or more O, S, N, P, and Si atoms, including any oxidation state of N, S, and P; forms of primary, secondary, tertiary amines, and quaternary ammonium salts; or in a heterocyclic ring A substituted form of hydrogen on a nitrogen atom, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl), or NR (e.g., N-substituted pyrrole) NR in alkyl).
  • N e.g., N in 3,4-dihydro-2H-pyrrolyl
  • NH e.g., NH in pyrrolidinyl
  • NR e.g., N-substituted pyrrole
  • aryl can be used alone or as a major part of “aralkyl”, “aralkoxy” or “aryloxyalkyl”, meaning monocyclic, bicyclic and tricyclic containing 6-14 membered rings in total
  • a carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system contains a 3-7 membered ring and has one or more attachment points connected to the rest of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring”.
  • the aromatic ring may include phenyl, naphthyl and anthracenyl.
  • heteroaryl can be used alone or as a major part of “heteroarylalkyl” or “heteroarylalkoxy”, meaning monocyclic, bicyclic and tricyclic systems containing a total of 5-14 membered rings, Wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatom has the meaning described in the present invention, wherein each ring system contains a 3-7 membered ring and has one or Multiple attachment points are connected to the rest of the molecule.
  • heteroaryl may be used interchangeably with the term “aromatic heterocycle” or "heteroaromatic compound”.
  • the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-Isoxazolyl, 4-Isoxazolyl, 5-Isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimid-5-yl, Pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazo)
  • prodrug used in the present invention represents a compound converted into a compound represented by Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI in vivo. Such transformations are influenced by the prodrug's hydrolysis in the blood or the enzyme's conversion into the parent structure in the blood or tissues.
  • the prodrug compound of the present invention may be an ester.
  • esters can be used as prodrugs such as phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylation of the hydroxy group on the parent.
  • prodrugs refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • Methodabolite refers to a product obtained by metabolizing a specific compound or a salt thereof in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention.
  • Such a product can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidolation, deamidation, esterification, degreasing, enzymatic cleavage and the like.
  • the invention includes metabolites of a compound, including metabolites produced by sufficient contact of a compound of the invention with a mammal for a period of time.
  • salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in the literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyceryl phosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pipate, pectate, persulfate, 3 -Phen
  • Salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) 4 .
  • the present invention also contemplates the formation of quaternary ammonium salts of any compound containing N groups.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • the pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations formed by anti- counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.
  • solvate of the present invention means an association formed by one or more solvent molecules and a compound of the present invention.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association formed by the solvent molecules being water.
  • any disease or disorder as used herein in some embodiments refers to ameliorating the disease or disorder (ie, slowing or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., parameters that stabilize the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / Carbonate, bisulfate / sulfate, camphor sulfonate, chloride / hydrochloride, chlorotheophylline, citrate, ethanesulfonate, fumarate, glucoheptanoate, glucose Gluconate, glucuronide, hippurate, hydroiodate / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate Acid salt, malonate, mandelate, mesylate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, stearate, oleate, oxalic acid Salt, palm
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary, and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, a basic or acidic moiety using conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K, or by These compounds are prepared by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of both.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • solvents e.g., ethanol, DMSO, etc.
  • the compounds disclosed herein may form solvates inherently or by design with pharmaceutically acceptable solvents, including water; therefore, the invention is intended to include both solvated and unsolvated forms.
  • any structural formula given in the present invention is also intended to represent the isotopically enriched form of these compounds and the isotopically enriched form.
  • Isotopically enriched compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds described herein include isotopically enriched compounds as defined in the invention, for example, those compounds in which radioisotopes are present, such as 3 H, 14 C, and 18 F, or in which non-radioactive isotopes are present, such as 2 H and 13 C.
  • This class of isotopically enriched compounds can be used in metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET), or including drugs or Single-photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in radiotherapy for patients.
  • 18 F-enriched compounds are particularly desirable for PET or SPECT studies.
  • Isotopically enriched compounds represented by Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI can use appropriate isotopes as described by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention. Labeled reagents are prepared in place of previously unlabeled reagents.
  • the substitution of heavier isotopes, especially deuterium can provide certain therapeutic advantages that result from higher metabolic stability. For example, increased half-life in the body or reduced dose requirements or improved therapeutic index. Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, especially deuterium.
  • the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation) for each specified deuterium atom, At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factors.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle, or a combination thereof.
  • the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
  • the compound of the present invention is prepared by a click reaction or an amide condensation reaction, as shown in FIG. 2.
  • the amide was dissolved and 100 microliters of acetic anhydride was added. Stir at room temperature for 2 hours. Saturated brine was added to quench the reaction, and the mixture was extracted three to five times with ethyl acetate.
  • the compounds represented by the formulae 2 to 15 and 17 can be prepared from the intermediate 3/5/7 and the CRBN terminal ligand.
  • the compounds represented by Formula 19 to Formula 23 can be synthesized from Intermediate 2.
  • the compound represented by Formula 25 to Formula 27 can be synthesized from Intermediate 8.
  • Formula 32 can be prepared by the method shown in Formula 1.
  • Formula 33 can be prepared by the method shown in Formula 1.
  • Formula 34 can be prepared by the method shown in Formula 1.
  • Formula 35 can be prepared by the method shown in Formula 1.
  • Formula 36 can be prepared by the method shown in Formula 1.
  • Formula 37 can be prepared by the method shown in Formula 1.
  • Formula 38 can be prepared by the method shown in Formula 1.
  • Formula 39 can be prepared by the method shown in Formula 1.
  • Formula 40 can be prepared by the method shown in Formula 1.
  • Formula 41 can be prepared by the method shown in Formula 1.
  • Formula 42 can be prepared by the method shown in Formula 28.
  • Formula 43 can be prepared by the method shown in Formula 28.
  • Formula 44 can be prepared by the method shown in Formula 28.
  • Formula 45 can be prepared by the method shown in Formula 28.
  • Formula 46 can be prepared by the method shown in Formula 28.
  • Formula 47 can be prepared by the method shown in Formula 28.
  • Formula 48 can be prepared by the method shown in Formula 19.
  • Formula 49 can be prepared by the method shown in Formula 19.
  • Formula 50 can be prepared by the method shown in Formula 19.
  • Collecting cells The treated cells were scraped off in the culture medium, fully suspended and centrifuged at 300g for 5 minutes to collect, washed once in PBS, and discarded.
  • Lyse cells Add 100 ⁇ L of 2 ⁇ Loading Buffer to each sample, mix thoroughly with shaking, denaturate at 100 ° C for 15 minutes, store at -20 ° C after mixing, or directly use for Western Blot detection.
  • the formula of 5 ⁇ Loading buffer is: 250mM Tris-HCl (pH 6.8), 10% (W / V) SDS, 0.5% (W / V) bromophenol blue, 50% (V / V) glycerol, 5% ( W / V) ⁇ -mercaptoethanol (2-ME). 2 ⁇ Loading buffer is prepared by adding 1.5 times the volume of dd water to 5 ⁇ Loading buffer.
  • Electrophoresis Turn on the power. The voltage of the protein sample in the concentrated gel is 80 volts. When the protein sample enters the separation gel, adjust the voltage to 120 volts and continue electrophoresis. The electrophoresis was terminated when bromophenol blue almost completely ran out of the PAGE gel.
  • Transfer film After the electrophoresis is completed, remove the gel and install the transfer device in the following order: (negative electrode), filter paper, gel, activated PVDF membrane, filter paper, and (positive electrode). Then clamp the transfer device into the transfer buffer solution, and finally put it into the ice box, put it in a 4 ° C cold storage at 100V constant voltage for 1.5 hours.
  • the concentration of ABBV-075 and Poma is 10 ⁇ M; Ramos cell line: 2 ⁇ 10 6 cells per well (6 well plate), 37 ° C 5% CO 2 , add Cfz, (+)-JQ-1, ABBV-075 and Poma was incubated for 2 hours in advance, and then the compound shown in Formula 2 was added, and incubated at 37 ° C and 5% CO 2 for 2 hours; the final concentration of DMSO was 1%); Cfz, (+ ) -JQ-1, ABBV-075 and Poma have no degradation effect on BET protein.
  • HBL-1, Ramos, IgEMM, and RPMI cell lines the compounds shown in Formula 2, Formula 5, Formula 10, Formula 13 and Formula 15 were clearly observed in the results of Western blotting (WB). 100nM) for the degradation of BET protein, as shown in Figure 5-1, Figure 5-2, Figure 5-3 and Figure 5-4 (HBL-1 cell line: 2 ⁇ 10 6 cells per well (6 well plate ), 37 ° C 5% CO 2 culture for 24 hours; DMSO final concentration is one thousandth; Ramos cell line: 2 ⁇ 10 6 cells per well (6 well plate), 37 ° C 5% CO 2 culture for 24 hours; DMSO final The concentration is one thousandth; IgEMM cell line: 2 ⁇ 10 6 cells per well (6 well plate), cultured at 37 ° C. 5% CO 2 for 24 hours; final DMSO concentration is one thousandth; RPMI cell line: 2 ⁇ 10 6 cells per well (6 well plate), cultured at 37 ° C with 5% CO 2 for 24 hours; final DMSO concentration is 1/1000).
  • HBL-1 BK-C481S
  • WB Western blotting
  • the BET protein degradation effect caused by hours is compared with the BET protein degradation effect of cells treated with the same concentration of ARV-825 for the same time, as shown in Figure 7 (HBL-1 (BTK-C481S cell line: 2 ⁇ 10 6 cells per well ( 6-well plate), 37 ° C 5% CO 2 for 2 hours: final DMSO concentration is 1/1000).
  • Reagents RPIM 1640 medium; DMEM medium; 100 ⁇ non-essential amino acids (NEAA); 100 ⁇ penicillin mixed solution; 50 mM ⁇ mercaptoethanol; fetal bovine serum (FBS, inactivated beforehand).
  • a medium 500 mL: RPIM 1640 medium (450 mL) + 100 x NEAA (5 mL) + 100 x penicillin mixed solution (5 mL) + fetal bovine serum (50 mL) + 50 mM ⁇ mercaptoethanol (0.5 mL).
  • B medium 500 mL: DMEM medium (450 mL) + 100 x NEAA (5 mL) + 100 x penicillin mixed solution (5 mL) + fetal bovine serum (50 mL) + 50 mM ⁇ mercaptoethanol (0.5 mL). .
  • FIG. 10-1 and FIG. 10-2 show the comparison of the activity of compounds of Formula 2, Formula 10, Formula 21, and Formula 24 on lung cancer K562 cell line and prostate cancer LNcap cell line. It can be seen that the cytotoxicity of formula 21 that selectively degrades BRD4 and formula 24 that does not degrade BRD2 is weaker than the non-selective formulas 2 and 10, so formulas 21 and 24 may have higher safety and therapeutic prospects.
  • Table 1 Compounds shown by Formula 1 to Formula 50 and ABBV-075, (+)-JQ-1, and ARV-825 compounds have been reported to degrade the BET protein in HBL-1 (BTK-C481S) cell line (DC 50 ) and inhibitory MTT test (IC 50 value):
  • N.D means that no inhibitory activity was detected.

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Abstract

提供一种化合物，其为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：其中，X表示BET蛋白的配体，Z表示E3连接酶的配体，Y表示连接X和Z的链。

Description

一种靶向降解BET蛋白的化合物及其应用 技术领域
本发明涉及生物医药领域，具体地，本发明涉及靶向降解BET蛋白的化合物及其应用。
背景技术
个体内部拥有共同基因序列的不同类型细胞执行不同的生物学功能，这是因为不同类型细胞之间存在不同基因转录的开放和关闭状态。这种基因表达的表观遗传调控部分程度上被组蛋白和其他蛋白上的特定赖氨酸残基的乙酰化修饰所调节。Bromodomain(BRD)是一类包含能够特异性识别组蛋白中乙酰化赖氨酸(KAc)的保守蛋白结构域的转录共激活子，可以识别乙酰化赖氨酸并招募转录因子等相关蛋白于染色质中特定的基因转录位点，改变RNA聚合酶Ⅱ的活性，促进基因转录和下游信号的传导。在一些肿瘤和炎症状态下，基因转录的表观遗传调控出现异常，导致生长促进基因和促炎因子基因的异常表达。BET(bromodomain and extra-terminal)蛋白代表了一个完整的蛋白家族，其成员包括BRD2，BRD3，BRD4和BRDT，每种蛋白都包含了N端的两个Bromodomain结构域BD I和BD II以及C端的额外末端结构域(extra-terminal domain)。
目前BET蛋白家族成员中研究最多的时BRD4蛋白。BRD4常定位于一些重要的原癌基因上游的超级增强子区域，如c-MYC和bcl-xL，并在这些基因的表达调控中发挥重要作用。基于BRD4在重要原癌基因表达调控中发挥的重要作用，BRD4有望成为多种肿瘤治疗的重要靶点，如急性髓细胞白血病、多发性骨髓瘤、Burkit’s淋巴瘤和前列腺癌等。已经开发的BRD4的抑制剂，如(+)-JQ-1、i-BET和OTX-015在包括Burkit’s淋巴瘤在内的多种肿瘤的临床前动物模型中表现出巨大的治疗潜力。
然而，新的能够有效抑制或降解BET蛋白的药物还待开发。
发明内容
本发明旨在至少在一定程度上解决现有技术的技术问题之一：
发明人发现，(+)-JQ-1和OTX-015会以浓度依赖的方式导致BRD4蛋白水平快速出现数倍的升高，使得BRD4的抑制变得更难。即使在高于IC 50十倍的浓度下，(+)-JQ-1和OTX-015仍不能充分抑制c-MYC。另外，(+)-JQ-1在AML细胞中可引起c-MYC的降低，但撤除(+)-JQ-1后c-MYC水平会迅速恢复并高于加药处理前。目前虽然已经有包括OTX-015和I-BET726在内的多个BET的小分子抑制剂已经进入了临床试验阶段。但是，由于对于c-MYC的抑制不够充分，以及反馈机制能够上调BRD4基因的表达，这些药物的有效性仍有待检验。此外，在一些BET抑制剂的临床前研究中观察到了肿瘤对BET抑制剂的耐药现象。
基于以上问题的发现，发明人提出了一种新的化合物，该化合物采用的是双靶点分子结构，结构如图1所示，该类分子一端的结构靶向结合E3连接酶，另一端的结构靶 向结合BET蛋白，两端的结构通过链(linker)相连接，形成一个完整的化合物分子，该化合物通过E3泛素化目标蛋白并引导目标蛋白进入降解通路，对目标蛋白的特异性降解作用强。该类化合物可较低浓度下在多种细胞系中高效降解BET蛋白，而且也可更加有效地阻断原癌基因c-MYC的表达；BET蛋白抑制剂并不能影响BET蛋白的丰度，一旦停药BET蛋白可以很快恢复活性，而PROTAC分子即使停药之后，BET蛋白也需要一定时间来恢复胞内的蛋白丰度。此外，设计针对BET蛋白的PROTAC分子可以在BET蛋白自然降解途径失效时诱导BET蛋白的人工泛素化降解，从而克服肿瘤细胞对BET蛋白抑制剂的耐药性。
为此，在本发明的第一方面，本发明提出了一种化合物，其为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
X-Y-Z
式I
其中，X表示BET蛋白的配体，Z表示E3连接酶的配体，Y表示连接X和Z的链。
根据本发明的实施例，上述化合物还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述X为式II-1或II-2所示化合物，
Figure PCTCN2019094562-appb-000001
Cy 1或Cy 2分别独立地为苯环，C 6-12芳基，5-12个环原子组成的杂芳基，C 3-12环烷基或3-12个环原子组成的杂环基；
L 1为-(CR mR w) g-O-(CR mR w) g-，-(CR mR w) g-S-(CR mR w) g-，-(CR mR w) g-N(R 1a)-(CR mR w) g-，-(CR mR w) n-，-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，-(CR mR w) g-(C≡C) n-(CR mR w) g-，-(CR mR w) g-S(＝O) p-(CR mR w) g-，-(CR mR w) g-C(＝O)-(CR mR w) g-，-(CR mR w) g-C(＝O)-O-(CR mR w) g-，-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-；
各Cy 1或Cy 2分别独立地被1、2、3、4、5或6个R h1所取代；
各L 1分别独立地被1、2、3、4、5或6个R h2所取代；
各R h1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基，5-12个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-，R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-， R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
各R h2分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基，5-12个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-，R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
各R h1分别独立地被1、2、3、4、5或6个R h3所取代；
各R h2分别独立地被1、2、3、4、5或6个R h4所取代；
各R h3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基或C 3-6环烷基；
各R h4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基或C 3-6环烷基；
各R 1a分别独立地为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基，C 1-6烷基，C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
各R m、R w或R g分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
各n分别独立地为1，2，3或4；
各g分别独立地为0，1，2，3或4；
各p分别独立地为1或2。
根据本发明的实施例，Cy 1或Cy 2分别独立地为苯环，C 6-10芳基，5-10个环原子组成的杂芳基，C 3-6环烷基或3-12个环原子组成的杂环基。
根据本发明的实施例，各R h1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基，5-10个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-，R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
各R h2分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基，5-10个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-，R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
各R h1分别独立地被1、2、3、4、5或6个R h3所取代；
各R h2分别独立地被1、2、3、4、5或6个R h4所取代；
各R h3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基或C 3-6环烷基；
各R h4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基或C 3-6环烷基。
根据本发明的实施例，各R 1a分别独立地为H，氘，F，Cl，Br，I，CN，NO 2，OH，氨基，羧基，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
各R m、R w或R g分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。
根据本发明的实施例，Cy 1或Cy 2分别独立地为
Figure PCTCN2019094562-appb-000002
Figure PCTCN2019094562-appb-000003
根据本发明的实施例，各R h1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，
Figure PCTCN2019094562-appb-000004
Figure PCTCN2019094562-appb-000005
Figure PCTCN2019094562-appb-000006
R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
各R h2分别独立地为氢，氘，F，Cl，Br，I，氧代，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
各R h1分别独立地被1、2、3、4、5或6个R h3所取代；
各R h2分别独立地被1、2、3、4、5或6个R h4所取代；
各R h3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
各R h4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
根据本发明的实施例，各R 1a分别独立地为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
各R m、R w或R g分别独立地为H、氘、甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
根据本发明的实施例，所述X为式III-1、III-2、III-3、III-4、III-5或III-6所示化合物，
Figure PCTCN2019094562-appb-000007
根据本发明的实施例，所述Z为式IV所示化合物，
Figure PCTCN2019094562-appb-000008
其中，Q为N或CR 2；
M为C(R eR f)，N(R 1b)，O或S；
W，K分别独立地为C(R eR f)，NH，O或S；
R 2为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基或C 2-6炔基；
各R 2a或R 2b分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，氧代，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；
各R 2c分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；
各R e、R f分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
各R 1b分别独立地为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；
W或K为NH时，所述R 2a不在所述W或K的位置进行取代；
n 1、n 2分别独立地为0、1、2或3；
n 3为0、1、2、3、4或5。
根据本发明的实施例，各R e、R f分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
各R 1b分别独立地为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。
根据本发明的实施例，R 2为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基 或叔丁基。
根据本发明的实施例，各R 2a、R 2b分别独立地为氢，氘，氧代，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
各R 2c分别独立地为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
根据本发明的实施例，各R e、R f分别独立地为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
各R 1b分别独立地为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
根据本发明的实施例，所述Z为式V-1、V-2、V-3或V-4、所示化合物，
Figure PCTCN2019094562-appb-000009
根据本发明的实施例，所述Y为含有1～30个原子的基团，所述原子包括选自碳原子、硫原子、氧原子、氮原子、硒原子的至少之一。
根据本发明的实施例，所述Y为任选取代的C 1-20烷基、C 1-20卤代烷基、C 1-20烷氧基、C 2-20烯基、C 2-20炔基、C 3-12环烷基、C 6-12芳基、3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基的至少之一构成的基团。在一些实施例中，各C 1-20烷基、C 1-20卤代烷基、C 1-20烷氧基、C 2-20烯基、C 2-20炔基、C 3-12环烷基、C 6-12芳基、3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基独立地被C 1-8烷基-C(＝O)-NH-所取代。
根据本发明的实施例，所述Y为任选取代的
Figure PCTCN2019094562-appb-000010
其中，x 1-x 23分别独立地为一个键，
Figure PCTCN2019094562-appb-000011
Figure PCTCN2019094562-appb-000012
Figure PCTCN2019094562-appb-000013
R 1d为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基或C 1-4烷基。
在一些实施例中，各x 1-x 23独立地被C 1-6烷基-C(＝O)-NH-所取代。
根据本发明的实施例，所述Y为式VI-1或VI-2所示化合物，
Figure PCTCN2019094562-appb-000014
各r分别独立地为0～12之间的整数；
各k分别独立地为0～12之间的整数；
各j分别独立地为0～12之间的整数；
各t 1或t 3分别独立地为键，
Figure PCTCN2019094562-appb-000015
任选取代的
Figure PCTCN2019094562-appb-000016
各t 2或t 4分别独立地为键，
Figure PCTCN2019094562-appb-000017
任选取代的
Figure PCTCN2019094562-appb-000018
Figure PCTCN2019094562-appb-000019
t 5为键或任选取代的
Figure PCTCN2019094562-appb-000020
R 1d为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
在一些实施例中，各t 1、t 2、t 3、t 4或t 5独立地被C 1-4烷基-C(＝O)-NH-所取代。
根据本发明的实施例，所述Y为式VI-1所示化合物时，
Figure PCTCN2019094562-appb-000021
其中：
Figure PCTCN2019094562-appb-000022
k＝k 1+2或
k＝k 2+1或
k＝k 3+1或
k＝k 4+2。
根据本发明的实施例，所述Y为下列至少之一所示化合物，
Figure PCTCN2019094562-appb-000023
Figure PCTCN2019094562-appb-000024
各t 6、t 7、t 8、t 9或t 10分别独立地为0～11之间的整数。
在本发明的第二方面，本发明提出了一种化合物，其为式1～50任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2019094562-appb-000025
Figure PCTCN2019094562-appb-000026
Figure PCTCN2019094562-appb-000027
Figure PCTCN2019094562-appb-000028
Figure PCTCN2019094562-appb-000029
Figure PCTCN2019094562-appb-000030
Figure PCTCN2019094562-appb-000031
Figure PCTCN2019094562-appb-000032
Figure PCTCN2019094562-appb-000033
Figure PCTCN2019094562-appb-000034
Figure PCTCN2019094562-appb-000035
在本发明的第三方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包括上述任一项所述的化合物。
根据本发明的实施例，上述药物组合物还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述药物组合物进一步包括辅料。
根据本发明的实施例，所述药物组合物进一步包括其他治疗或预防非霍奇金淋巴瘤、Burkitt’s淋巴瘤、急性骨髓性白血病、多发性骨髓瘤、肺癌、前列腺癌以及NUT中线癌的药物。
根据本发明的实施例，所述其他治疗或预防非霍奇金淋巴瘤的药物包括依鲁替尼。
根据本发明的实施例，所述其他治疗或预防Burkitt’s淋巴瘤的药物包括选自环磷酰胺、多柔吡星的至少之一。
根据本发明的实施例，所述其他治疗或预防急性骨髓性白血病的药物包括选自阿糖胞苷、Azacitidine、Decitabine的至少之一。
根据本发明的实施例，所述其他治疗或预防多发性骨髓瘤的药物包括选自卡非佐米、沙利度胺、来那度胺、泊马渡胺的至少之一。
根据本发明的实施例，所述其他治疗或预防肺癌的药物包括选自吉非替尼、厄洛替尼、奥司他丁、阿法替尼的至少之一。
根据本发明的实施例，所述其他治疗或预防前列腺癌的药物包括选自氟他胺、尼鲁米特的至少之一。
在本发明的第四方面，本发明提出了上述任一项所述化合物或上述任一项所述的药物组合物在制备药物中的用途，所述药物用于降解BET蛋白。
在本发明的第五方面，本发明提出了上述任一项所述化合物或上述任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防非霍奇金淋巴瘤、Burkitt’s淋巴瘤、急性骨髓性白血病、多发性骨髓瘤、肺癌、前列腺癌以及NUT中线癌。
在本发明的第六方面，本发明提出了一种降解BET蛋白的方法。根据本发明的实施例，所述方法包括：使BET蛋白与上述所述的化合物或上述任一项所述的药物组合物接触。
在本发明的第七方面，本发明提出了一种治疗或预防非霍奇金淋巴瘤、Burkitt’s淋巴瘤、急性骨髓性白血病、多发性骨髓瘤、肺癌、前列腺癌以及NUT中线癌的方法。根据本发明的实施，所述方法包括：给予患者上述任一项所述的化合物或上述任一项所述的药物组合物。
HBL-1细胞系是一类非霍奇金淋巴瘤细胞，依鲁替尼为临床治疗非霍奇金淋巴瘤的最常用药物并具有出色的治疗效果，依鲁替尼的靶点为BTK蛋白，依鲁替尼占据BTK蛋白的ATP结合口袋并通过分子末端的丙烯酰胺官能团与BTK蛋白481位的半胱氨酸残基发生共价交联而抑制BTK的活性。BTK蛋白的C481S突变使得细胞获得对依鲁替尼的耐药。一方面，根据本发明实施例的化合物对多种细胞系的BET蛋白表现出很强的降解作用(DC 50<100nM)，并且可显著降解BRD4下游原癌基因c-MYC的表达产物c-MYC蛋白。另一方面，根据本发明实施例的化合物对HBL-1(BTK-C481S)细胞系的BET蛋白表现出极强的降解作用(DC 50<1nM)，在MTT实验中本发明实施例化合物对HBL-1(BTK-C481S)细胞系表现出极强的杀伤效果(IC 50可低至0.66nM)。因而，本发明实施例化合物具有治疗依鲁替尼耐药的非霍奇金淋巴瘤的潜力。
附图说明
图1是根据本发明实施例的PROTACs(蛋白裂解靶向嵌合体)的基本技术路线示意图；
图2是根据本发明实施例的通过click反应(点击反应)或酰胺缩合反应制备本发明化合物的示意图；
图3是根据本发明实施例的式1、式9和式13所示化合物以及文献报道化合物ARV-825 对Jurkat细胞系BRD4和BRD2的降解作用示意图；
图4-1是根据本发明实施例的式2所示化合物的BET蛋白降解作用受其他化合物如卡非佐米(Cfz)的影响的结果示意图；
图4-2是根据本发明实施例的式2所示化合物的BET蛋白降解作用受其他化合物如(+)-JQ-1、ABBV-075及泊马渡胺(Poma)的影响的结果示意图；
图5-1是根据本发明实施例的式2、式5、式10、式13或式15所示化合物在细胞系HBL-1对BET蛋白的降解作用示意图；
图5-2是根据本发明实施例的式2、式5、式10、式13或式15所示化合物在细胞系Ramos对BET蛋白的降解作用示意图；
图5-3是根据本发明实施例的式2、式5、式10、式13或式15所示化合物在细胞系IgE MM对BET蛋白的降解作用示意图；
图5-4是根据本发明实施例的式2、式5、式10、式13或式15所示化合物在细胞系RPMI对BET蛋白的降解作用示意图；
图6-1是根据本发明实施例的式2所示化合物及(+)-JQ-1、ARV-825、ABBV-075等在Ramos细胞系处理2小时对原癌蛋白c-myc的影响的结果示意图；
图6-2是根据本发明实施例的式2所示化合物及(+)-JQ-1、ARV-825、ABBV-075等在Ramos细胞系处理6小时对原癌蛋白c-myc的影响的结果示意图；
图7是根据本发明实施例的式10所示化合物与ARV-825在低浓度下对HBL-1(BTK-C481S)细胞系(孵育2小时)引起的BET蛋白降作用示意图；
图8-1是根据本发明实施例的式2阴性对照、式2、式10所示化合物、(+)-JQ-1、ARV-825以及ABBV-075等在HBL-1(BTK-C481S)细胞系对细胞的杀伤作用曲线示意图；以及
图8-2是根据本发明实施例的式2阴性对照、式2、式10所示化合物、(+)-JQ-1、ARV-825以及ABBV-075等在HBL-1(BTK-C481S)细胞系对细胞的杀伤作用结果示意图；
图9-1是根据本发明实施例的式16、式18、式19、式20、式22、式23所示化合物在细胞系Jurkat对BET蛋白的降解作用示意图；
图9-2是根据本发明实施例的式24、式25、式26、式27、式28、式29、式30所示化合物在细胞系Jurkat对BET蛋白的降解作用示意图；
图9-3是根据本发明实施例的式16、式18、式19、式20、式21、式22、式23所示化合物在细胞系Jurkat对BET蛋白的降解作用示意图；
图10-1是根据本发明实施例的式2、式10、式21与式24所示化合物在肺癌K562细胞系上的活性比较示意图；
图10-2是根据本发明实施例的式2、式10、式21与式24所示化合物在前列腺癌LNcap 细胞系上的活性比较示意图。
具体实施方式
下面详细描述本发明的实施例，下面描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
在本文中所使用的术语“给予患者前面所述的化合或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药或前面所述的药物组合物”指将预定量的物质通过某种适合的方式引入病人。本发明的式I、式II、式III、式IV、式V或式VI所述化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药或者药物组合物可以通过任何常见的途径被给药，只要它可以到达预期的组织。给药的各种方式是可以预期的，包括腹膜，静脉，肌肉，皮下，皮层，口服，局部，鼻腔，肺部和直肠，但是本发明不限于这些已举例的给药方式。
本发明的药物组合物的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型，给药途径，病人年龄，性别，体重和疾病的严重程度以及作为活性成分的药物类型。
术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病的治疗，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述式I～式VI或式1～18化合物或药物组合物的给予有需要的个体。
根据本发明的实施例，所述辅料包括制剂领域公知的可药用的赋形剂、润滑剂、填充剂、稀释剂、崩解剂、稳定剂、防腐剂、乳化剂、助溶剂、着色剂、甜味剂，制成片剂、丸剂、胶囊剂、注射剂等不同剂型。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用得下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley & Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含”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。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley & Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混 合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH & Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
如本发明所描述，取代基R’由一个键连接到中心的环上形成的环体系代表取代基R’可以在该环上任何可取代的位置进行取代。例如，式a代表B’环上任何可能被取代的位置均可被R’取代，如式b，式c和式d所示。
Figure PCTCN2019094562-appb-000036
如本发明所描述，环上的附着点
Figure PCTCN2019094562-appb-000037
可以在该环上任何可连接的位置与分子其余部分连接。例如，式i代表B’环上任何可能被连接的位置均可作为连接点，如式d、e和f所示。
Figure PCTCN2019094562-appb-000038
如本发明所描述，同一个环上的两个附着点
Figure PCTCN2019094562-appb-000039
可以在该环上任何可连接的两个不同的位置与分子其余两部分分别连接，且两端的连接方式可以互换。例如，式j代表D环上任何可能被连接的两个不同的位置均可作为连接点与分子其余两部分分别连接，如式g、h和k所示。
Figure PCTCN2019094562-appb-000040
如本发明所述，在一些实施例中，所述Y为式VI-1所示化合物时，
Figure PCTCN2019094562-appb-000041
Figure PCTCN2019094562-appb-000042
为
Figure PCTCN2019094562-appb-000043
Figure PCTCN2019094562-appb-000044
且k＝k 1+2，或k＝k 2+1，或k＝k 3+1，或k＝k 4+2。
需要说明的是，所述“k＝k 1+2”、“k＝k 2+1”、“k＝k 3+1”或“k＝k 4+2”是对k 1、k 2、k 3或k 4的取值范围的限定。如前所述，式
Figure PCTCN2019094562-appb-000045
中，k为0～12之间的整数，表示的含义是，t 3的重复个数为k个，且各t 3的结构式可以相同，也可以不同。由此，式
Figure PCTCN2019094562-appb-000046
表示，当t 3为
Figure PCTCN2019094562-appb-000047
时，
Figure PCTCN2019094562-appb-000048
的重复个数为k个；式
Figure PCTCN2019094562-appb-000049
中，k＝k 1+2，表示的含义是，当t 3为
Figure PCTCN2019094562-appb-000050
Figure PCTCN2019094562-appb-000051
的组合时，
Figure PCTCN2019094562-appb-000052
的重复个数为k 1个，
Figure PCTCN2019094562-appb-000053
的重复个数为2个，重复单元总数仍保持k个，且两种重复单元具有该式所示的连接关系；式
Figure PCTCN2019094562-appb-000054
中，k＝k 2+1，表示的含义是，当t 3为
Figure PCTCN2019094562-appb-000055
的组合时，
Figure PCTCN2019094562-appb-000056
的重复个数为k 2个，
Figure PCTCN2019094562-appb-000057
的重复个数为1个，重复单元总数仍保持k个，且两种重复单元具有该式所示的连接关系；式
Figure PCTCN2019094562-appb-000058
中，k＝k 3+1，表示的含义是，当t 3为
Figure PCTCN2019094562-appb-000059
的组合时，
Figure PCTCN2019094562-appb-000060
的重复个数为1个，
Figure PCTCN2019094562-appb-000061
的重复个数为k 3个，重复单元总数仍保持k个，且两种重复单元具有该式所示的连接关系；式
Figure PCTCN2019094562-appb-000062
中，k＝k 4+2，表示的含义是，当t 3为
Figure PCTCN2019094562-appb-000063
的组合时，该式的连接关系为，重复个数为k 4个的
Figure PCTCN2019094562-appb-000064
连接重复个数为1个的
Figure PCTCN2019094562-appb-000065
再连接重复个数为1个的
Figure PCTCN2019094562-appb-000066
且重复单元总数仍保持k个。
如本发明所描述的，若链状结构上有两个连接点可与分子其余部分相连，则两端的连接方式可以互换。像本发明所描述的，例如，“-(CR mR w) g-O-C(＝O)-(CR mR w) g-”或“-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-”两端的连接方式可以互换。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，结构式“-(CR mR w) g-O-C(＝O)-(CR mR w) g-”和结构式“-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-”两者之间的R m和R w的具体选项互相之间不受影响，即使是同一个结构式中如“-(CR mR w) g-O-C(＝O)-(CR mR w) g-”，各R m的具体选项互相之间也不受影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。再例如，0～12 之间的整数包括端点0和12，以及0～12之间的任何一个整数，如1、2、3、4、5、6、7、8、9、10或11.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
除非另有说明，术语“烷基”，表示1-20个碳原子，或1-10个碳原子，或1-8个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代，取代基包括但不限于，氘、氨基、羟基、氰基、F、Cl、Br、I、巯基、硝基、氧代(＝O)等等。烷基的实例包括，但并不限于，甲基(Me，-CH 3)、乙基(Et，-CH 2CH 3)、正丙基(n-Pr，-CH 2CH 2CH 3)、异丙基(i-Pr，-CH(CH 3) 2)、正丁基(n-Bu，-CH 2CH 2CH 2CH 3)、异丁基(i-Bu，-CH 2CH(CH 3) 2)、仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)、叔丁基(t-Bu，-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)、正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)、2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)、3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)、3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)、正庚基、正辛基等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于，亚甲基、次乙基、次异丙基等等。
术语“C 1-6烷基-C(＝O)-NH-”中的“烷基”如本发明所定义的，这样的实例包括，但并不限于CH 3-C(＝O)-NH-、CH 3CH 2-C(＝O)-NH-、CH 3CH 2CH 2-C(＝O)-NH-、(CH 3) 3C-C(＝O)-NH-等等。
术语“烯基”表示含有2-15个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。
术语“炔基”表示含有2-15个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的 取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。
术语“环烷基”、“脂环族基”、“环状脂肪族基”、“碳环”、或“碳环基”是指一价或多价，非芳香族，饱和或部分不饱和的环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个原子的双环碳环可以是二环[4,5]、[5,5]、[5,6]或[6,6]体系，同时具有9或10个原子的双环碳环可以是二环[5,6]或[6,6]体系。合适的环状脂肪族基包括，但并不限于，环烷基，环烯基和环炔基。环状脂肪族基的实例包括，但绝不限于，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基等等。并且所述“环状脂肪族基”或“碳环”、“碳环基”、“环烷基”可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O) 2-、羧基取代的烷氧基等等。
术语“杂环”、“杂环基”、“杂脂环族”或“杂环的”在此处可交换使用，都是指单环、双环或三环体系，其中环上一个或多个碳原子独立且任选地被杂原子所取代，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，且有一个或多个连接点连接到分子的其他部分。一个或多个环上的氢原子独立且任选地被一个或多个本发明所描述的取代基所取代。其中一些实施方案是，“杂环”、“杂环基”、“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N、O、P、S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO、SO 2、PO、PO 2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-10元的双环(4-9个碳原子和选自N、O、P、S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO、SO 2、PO、PO 2的基团)。
杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、噻唑烷基、噁唑烷基、哌嗪基、高哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、环氧丙基、氮杂环庚基、氧杂环庚基、硫杂环庚基、4-甲氧基-哌啶-1-基、1,2,3,6-四氢吡啶-1-基、氧氮杂
Figure PCTCN2019094562-appb-000067
基、二氮杂
Figure PCTCN2019094562-appb-000068
基、硫氮杂
Figure PCTCN2019094562-appb-000069
基、吡咯啉-1-基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、1,2,6-噻二嗪烷1,1-二氧代-2-基、4-羟基-1,4-氮杂磷烷4-氧化物-1-基、2-羟基-1-(哌嗪-1-基)乙酮-4-基、2-羟基-1-(5,6-二氢-1,2,4-三嗪-1(4H)-基)乙酮-4-基、5,6-二氢-4H-1,2,4-噁二嗪-4-基、2-羟基-1-(5,6-二氢吡啶-1(2H)-基)乙酮-4-基、3-氮杂双环[3.1.0]己基、 3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、2-甲基-5,6,7,8-四氢-[1.2.4]三唑[1,5-c]嘧啶-6-基、4,5,6,7-四氢异噁唑[4,3-c]吡啶-5-基、3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基、2-氧-5-氮杂双环[2.2.2]辛烷-5-基、喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧代硫代吗啉基和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、氧代(＝O)、羟基、氨基、卤素、氰基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-、羧基取代的烷氧基等等。
术语“杂原子”表示一个或多个O、S、N、P和Si原子，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(例如3,4-二氢-2H-吡咯基中的N)、NH(例如吡咯烷基中的NH)或NR(例如N-取代的吡咯烷基中的NR)。
术语“芳基”可以单独使用或作为“芳烷基”、“芳烷氧基”或“芳氧基烷基”的一大部分，表示共含有6-14元环的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽基。并且所述芳基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O) 2-、羧基取代的烷氧基等等。
术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，表示共含有5-14元环的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中杂原子具有本发明所述的含义，其中每一个环体系包含3-7元环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O) 2-、羧基取代的烷氧基等等。
另外一些实施方案是，芳杂环包括以下的单环，但并不限于这些单环：2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、4-甲基异噁唑-5-基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、嘧啶-5-基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、1,3,4- 噻二唑-2-基、吡嗪基、吡嗪-2-基、1,3,5-三嗪基、苯并[d]噻唑-2-基、咪唑并[1,5-a]吡啶-6-基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基、3-喹啉基、4-喹啉基)和异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式I、式II、式III、式IV、式V或式VI所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通 过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
可药用的酸加成盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
可药用碱加成盐可与无机碱和有机碱形成。
可以由其衍生得到盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺，取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。 一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
另外，本发明公开的化合物，包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式I、式II、式III、式IV、式V或式VI所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物，药学上可接受的载体，赋形剂，稀释剂，辅剂，溶媒，或它们的组合。在一些实施方案，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。
下面将进一步详细描述本发明的实施例，所述实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
本发明的化合物通过click反应或酰胺缩合反应来制备，如图2所示。
一、中间体的制备
Figure PCTCN2019094562-appb-000070
向10mL圆底烧瓶中加入120mg原料1并加入3mL N,N-二甲基甲酰胺使其溶解，后依次加入70mg 2,4-二氟苯酚以及375mg K 2CO 3。保持反应液在110摄氏度搅拌约两小时至TLC监测原料1消失。将反应液恢复至室温。将反应液加入到大量水中并以乙酸乙酯萃取若干次，合并有机相并使用无水硫酸钠干燥，旋干溶剂。向残余物中加入10mL甲醇/水＝3：1的混合溶剂及稀盐酸活化并干燥的铁粉100mg和氯化铵固体50mg，此混合物在80摄氏度回流搅拌1.5小时。冷却至室温并用硅藻土过滤除去剩余铁粉，滤液中加入适量水并以乙酸乙酯萃取3次，每次20mL，合并有机相并以无水硫酸钠干燥，旋蒸除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，得90mg中间体2，产率为90％。
向10mL圆底烧瓶中依次加入33mg 5-己炔酸、120mg 2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、2mL二氯甲烷、2mL N,N-二甲基甲酰胺和100μL三乙胺，该混合物在室温下搅拌5分钟，将90mg中间体2加入到反应液中，室温反应至中间件2基本消失。将反应液加入到200mL水中并以乙酸乙酯萃取(3次，每次20mL)，合并有机相并使用无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，得95mg中间体3，产率为84％。
Figure PCTCN2019094562-appb-000071
向10mL圆底烧瓶中加入88mg原料1并加入2mL N,N-二甲基甲酰胺使其溶解，后依次加入88mg 3-(丙烷-2-炔-1-氧基)苯酚(3-(prop-2-yn-1-yloxy)phenol)以及275mg碳酸钾。保持反应液在110摄氏度搅拌约两小时至TLC监测原料1消失。将反应液恢复至室温。将反应液加入到大量水中并以乙酸乙酯萃取若干次，合并有机相并使用无水硫酸钠干燥，旋干溶剂。向残余物中加入10mL甲醇/水＝3：1的混合溶剂及稀盐酸活化并干燥的铁粉100mg和氯化铵固体50mg，反应液在80摄氏度回流搅拌1.5小时。冷却至室温并用硅藻土过滤除去剩余铁粉，滤液中加入适量水并以乙酸乙酯萃取3次，每次20mL，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，得56mg中间体4，产率为73％。
将50mg中间体4置于10mL圆底烧瓶中，加入10mL二氯甲烷使其溶解，将反应瓶置于冰水浴中，向反应液中依次加入330mg乙基磺酰氯和360微升三乙胺并在此温度下搅拌反应至原料基本消失。将反应液加入到150mL水中并以二氯甲烷萃取(3次每次20mL)，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂。将残余物转移至10mL圆底烧瓶中，后依次向反应液中加入22mg氟化钾、90mg碳酸钾及43mg 1，3-二酚，反应液在110摄氏度加热搅拌2小时。冷却至室温，将反应液加入到150mL水中并以乙酸乙酯萃取(3次，每次20mL)，合并有机相并使用无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，得45mg中间体5，产率为73％。
1H-NMR(400MHz,CDCl 3)δ(ppm)10.66(s,1H),7.50(s,1H),7.29(m,1H),7.15-7.05(m,3H),6.60(d,J＝8.60Hz,1H),6.48-6.41(m,3H),4.57(s,2H),3.56(s,3H),3.19(q,J＝6.96Hz,2H),1.42(t,J＝7.20Hz,3H)；
Figure PCTCN2019094562-appb-000072
向10mL圆底烧瓶中加入66mg原料1并加入2mL N,N-二甲基甲酰胺使其溶解，后依次加入90mg N-(3-羟基苯基)-5-炔-己酰胺、以及206mg碳酸钾。保持反应液在110摄氏度搅拌约两小时至TLC监测原料1消失。将反应液恢复至室温。将反应液加入到大量水中并以乙酸乙酯萃取若干次，合并有机相并使用无水硫酸钠干燥，旋转蒸发除去溶剂。向残余物中加入10mL甲醇/水＝3：1的混合溶剂及稀盐酸活化并干燥的铁粉100mg和氯化铵固体50mg，反应液在80摄氏度回流搅拌1.5小时。冷却至室温并用硅藻土过滤除去剩余铁粉，滤液中加入适量水并以乙酸乙酯萃取3次，每次20mL，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，得52mg中间体6，产率为79％。
将50mg中间体6置于10mL圆底烧瓶中，加入10mL二氯甲烷使其溶解，将反应瓶置于冰水浴中，向反应液中依次加入290mg乙基磺酰氯和320微升三乙胺并在此温度下搅拌反应至原料基本消失。将反应液加入到150mL水中并以二氯甲烷萃取(3次每次20mL)，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂。将残余物转移至10mL圆底烧瓶中，后依次向反应液中加入20mg氟化钾、78mg碳酸钾及38mg 1，3-二酚，反应液在110摄氏度加热搅拌2小时。冷却至室温，将反应液加入到100mL水中并以乙酸乙酯萃取(3次，每次20mL)，合并有机相并使用无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，得40mg中间体7，产率为66％。
Figure PCTCN2019094562-appb-000073
向50mL圆底烧瓶中加入300mg原料1并加入10mL N,N-二甲基甲酰胺使其溶解，然后按顺序加入300mg 4-氨基苯酚和280mg K 2CO 3。该反应液在110摄氏度搅拌两小时至TLC监测原料1消失。将反应液恢复至室温。将反应液加入到大量水中并以乙酸乙酯萃取若干次，合并有机相并使用无水硫酸钠干燥，旋干溶剂。残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，得170mg中间体8，产率为67％。
向50mL圆底烧瓶中加入300mg原料1并加入10mL N,N-二甲基甲酰胺使其溶解，然后按顺序加入300mg 4-氨基苯酚和280mg K 2CO 3。该反应液在110摄氏度搅拌两小时至TLC监测原料1消失。将反应液恢复至室温。将反应液加入到大量水中并以乙酸乙酯萃取若干次，合并有机相并使用无水硫酸钠干燥，旋干溶剂。残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，得190mg中间体9，产率为74％。
二、CRBN端配体的制备
Figure PCTCN2019094562-appb-000074
向圆底烧瓶中加入2-(2,6-二酮哌啶-3-基)-4-氟苯并恶唑啉-1,3-二酮、2.0当量的DIEA、适量N,N-二甲基甲酰胺作为溶剂及2.0当量的末端为叠氮官能团的胺原料或末端为羧酸的胺原料。反应液在80摄氏度搅拌3小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅 胶色谱柱进行分离纯化，流动相为乙酸乙酯：石油醚＝1：1至3：1，产率20-40％。
Figure PCTCN2019094562-appb-000075
式2阴性对照用到的CRBN配体端制备:向圆底烧瓶中加入2-(2,6-二酮哌啶-3-基)-4-氟苯并恶唑啉-1,3-二酮、2.0当量的碳酸钾、适量N,N-二甲基甲酰胺作为溶剂及2.0当量碘乙烷，反应在80摄氏度搅拌2小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为乙酸乙酯：石油醚＝3：1，产率90％。
向圆底烧瓶中加入2-(1-乙基-2,6-二酮哌啶-3-基)-4-氟苯并恶唑啉-1,3-二酮、2.0当量的DIEA、适量N,N-二甲基甲酰胺作为溶剂及2.0当量的末端为叠氮官能团的胺原料。反应液在80摄氏度搅拌3小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为乙酸乙酯：石油醚＝1：1至3：1，产率20-40％。
Figure PCTCN2019094562-appb-000076
向圆底烧瓶中加入原料A、5.0当量的末端炔烃原料、10％当量的1,1'-双二苯基膦二茂铁二氯化钯、20％当量的碘化亚铜并加入适量体积N,N-二甲基甲酰胺作为溶剂，烧瓶以橡胶塞密封并以氩气置换瓶内空气，用注射器向反应瓶内加入N,N-二甲基甲酰胺体积1/3的三乙胺。反应液在70摄氏度搅拌6小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1至10：1，产率约50％。
向圆底烧瓶中加入前一步中间体及3～5当量叠氮化钠及适量N,N-二甲基甲酰胺，反应液在80摄氏度搅拌6小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次， 合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1至10：1，产率为100％。
Figure PCTCN2019094562-appb-000077
向圆底烧瓶中加入300mg 2-(2,6-二酮哌啶-3-基)-4-氟苯并恶唑啉-1,3-二酮、2.0当量的DIEA、适量二甲基亚砜作为溶剂及2.0当量的Boc-L-赖氨酸。反应液在80摄氏度搅拌3小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为乙酸乙酯：石油醚＝1：1至3：1，得244mg中间体，产率为44％。取该中间体35mg置于10ml圆底烧瓶中，加入5ml二氯甲烷和200微升三氟乙酸，室温下搅拌2小时，旋干溶剂，向残余物中加入3ml N,N-二甲基甲酰胺使其溶解并加入100微升乙酸酐。室温下搅拌2小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，得24mg产品，产率为77％。
Figure PCTCN2019094562-appb-000078
向圆底烧瓶中加入2-(2,6-二酮哌啶-3-基)-3-氟苯并恶唑啉-1,3-二酮、2.0当量的DIEA、适量N,N-二甲基甲酰胺作为溶剂及2.0当量的末端为叠氮官能团的胺原料或末端为羧酸的胺原料。反应液在80摄氏度搅拌3小时。加入饱和食盐水淬灭反应，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅 胶色谱柱进行分离纯化，流动相为乙酸乙酯：石油醚＝1：1至3：1，产率20-40％。
实施例1化合物的制备
式1～17所示化合物的制备
式1所示化合物的合成：
Figure PCTCN2019094562-appb-000079
取15mg中间体3与14mg CRBN端配体置于5mL圆底烧瓶中，加入50mg抗坏血酸钠，后加入N，N-二甲基甲酰胺/水＝5：1混合溶剂2mL，最后加入2mg无水硫酸铜，室温反应6小时。向反应液中加入饱和食盐水，混合物用乙酸乙酯萃取三至五次，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂，残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1至10：1，得到13mg目标化合物，产率为56％。
1H-NMR(400MHz,CDCl 3)δ(ppm):10.15(s,1H),9.47(s,1H),8.94(s,1H),7.64(m,2H),7.47(t,J＝7.60Hz,1H),7.34(s,1H),7.21(s,1H),7.12(s,1H),7.07(d,J＝7.20Hz,1H),6.87-6.78(m,4H),6.69-6.65(m,1H),6.43(s,1H),6.19(s,1H),4.95-4.91(m,1H),4.27(t,J＝7.20Hz,2H),3.63(s,3H),3.26-3.21(m,2H),2.89-2.73(m,5H),2.47-2.44(m,2H),2.13-2.07(m,3H),1.85(m,2H),1.76(m,5H),1.64-1.61(m,2H),1.38-1.25(m,8H)；
LC-MS(ESI +):m/z calculated for C 47H 48F 2N 9O 7(M+H) +:888.36found 888.92.
按照上述制备方法可由中间体3/5/7及CRBN端配体出发制备式2～15及式17所示化合物。
Figure PCTCN2019094562-appb-000080
1H-NMR(400MHz,CDCl 3)δ(ppm)10.50(s,1H),9.48(s,1H),8.96(s,1H),7.64(s,1H),7.59(t,J＝8.80Hz,1H),7.54(s,1H),7.43(t,J＝8.00Hz,1H),7.19(s,1H),7.11(s,1H),7.05(d,J＝7.20Hz,1H),6.86-6.77(m,4H),6.66(t,J＝8.40Hz,1H),6.46(t,J＝5.20Hz,1H),6.41(s,1H),4.95-4.91(m,1H),4.43(t,J＝4.80Hz,2H),3.80(t,J＝4.80Hz,2H),3.67(t,J＝4.20Hz,2H),3.62-3.55(m,12H),3.43-3.39(m,2H),2.86-2.72(m,5H),2.44-2.41(m,2H),2.09-2.07(m,2H)；
LC-MS(ESI +):m/z calculated for C 47H 48F 2N 9O 10(M+H) +:936.34found 936.52.
Figure PCTCN2019094562-appb-000081
1H-NMR(400MHz,CDCl 3)δ(ppm)10.72(s,1H),9.70(s,1H),9.03(s,1H),7.70(d,J＝7.24Hz,1H),7.67(s,1H),7.60(d,J＝8.80Hz,1H),7.52(s,1H),7.41-7.33(m,2H),7.19(s,1H),7.11(s,1H),6.84-6.77(m,3H),6.66(t,J＝7.88Hz,1H),6.40(s,1H),5.24(dd,J＝13.08Hz,J＝4.92Hz,1H),4.43(d,J＝7.40Hz,2H),4.42(d,J＝13.36Hz,1H),4.27(d,J＝16.12Hz,1H),3.80(t,J＝4.72Hz,2H),3.64(s,3H),3.56-3.52(m,8H),3.43-3.38(m,2H),2.86-2.78(m,3H),2.67(t,J＝7.32Hz,2H),2.43(s,2H),2.38-2.28(m,1H),2.05-2.00(m,4H),1.91-1.84(m,2H)；
LC-MS(ESI +):m/z calculated for C 48H 51F 2N 8O 9(M+H) +:921.37found 921.60.
Figure PCTCN2019094562-appb-000082
1H-NMR(400MHz,CDCl 3)δ(ppm)10.68(s,1H),9.55(s,1H),8.97(s,1H),7.72(d,J＝7.08Hz,1H),7.67(s,1H),7.60(d,J＝8.88Hz,1H),7.44-7.37(m,2H),7.33(s,1H),7.23(s,1H),7.14(s,1H),6.85-6.78(m,3H),6.68(t,J＝7.72Hz,1H),6.44(s,1H),5.30-5.25(m,1H),4.46(d,J＝16.04Hz,1H),4.31-4.23(m,3H),3.64(s,3H),3.39-3.34(m,6H),2.87-2.80(m,3H),2.71(t,J＝7.40Hz,2H),2.44(t,J＝6.72Hz,2H),2.39-2.32(m,4H),2.08-1.98(m,7H),1.93-1.86(m,2H),1.65-1.59(m,2H),1.53-1.50(m,2H)；
LC-MS(ESI +):m/z calculated for C 50H 55F 2N 8O 7(M+H) +:917.41found 917.99.
Figure PCTCN2019094562-appb-000083
1H-NMR(400MHz,CDCl 3)δ(ppm)11.09(s,1H),8.87(s,1H),7.70(s,1H),7.46-7.42(m,2H),7.35(m,1H),7.20(dd,J＝8.72Hz,J＝2.68Hz,1H),7.13-7.02(m,3H),6.85(d,J＝8.52Hz,1H),6.61(dd,J＝8.28Hz,J＝1.88Hz,1H),6.44(m,2H),6.39(s,1H),5.06(s,2H),4.91(dd,J＝11.72Hz,J＝5.20Hz,1H),4.52(t,J＝4.84Hz,2H),3.85(t,J＝4.84Hz,2H),3.66(m,5H),3.61(s,4H),3.58(s,4H),3.40(t,J＝5.00Hz,2H),3.18(q,J＝7.40Hz,2H),2.88-2.70(m,3H),2.13-2.09(m,1H),1.41(t,J＝7.32Hz,3H)；
LC-MS(ESI +):m/z calculated for C 46H 50N 9O 12S(M+H) +:952.32found 952.67.
Figure PCTCN2019094562-appb-000084
1H-NMR(400MHz,CDCl 3)δ(ppm)11.43(s,1H),8.54(s,1H),7.73(s,1H),7.45-7.41(m,3H),7.20-7.17(m,2H),7.12(t,J＝8.24Hz,1H),7.06(d,J＝7.04Hz,1H),7.01(d,J＝8.72Hz,1H),6.87(s,1H),6.83(d,J＝8.52Hz,1H),6.60(d,J＝8.08Hz,1H),6.48-6.45(m,2H),6.37(s,1H),5.06(s,2H),4.89(dd,J＝11.36Hz,J＝5.00Hz,1H),4.55(t,J＝4.84Hz,2H),3.89(t,J＝4.92Hz,2H),3.70(s,3H),3.67(t,J＝5.00Hz,2H),3.62(s,4H),3.41(t,J＝5.08Hz,2H),3.18(q,J＝7.32Hz,2H),2.90-2.70(m,3H),2.05-2.00(m,1H),1.42(t,J＝7.36Hz,3H)；
LC-MS(ESI +):m/z calculated for C 44H 46N 9O 11S(M+H) +:908.30found 908.59.
Figure PCTCN2019094562-appb-000085
1H-NMR(400MHz,CDCl 3)δ(ppm)10.28(s,1H),9.74(s,1H),8.77(s,1H),.55-7.40(m,3H),7.24-7.21(m,1H),7.15-7.02(m,6H),6.86(s,1H),6.60(t,J＝6.68Hz,2H),6.34(s,1H),4.93-4.88(m,1H),4.39(t,J＝5.12Hz,2H),3.83-3.81(m,2H),3.70-3.67(m,2H),3.61-3.36(m,6H),3.49(s,3H),3.43-3.40(m,2H),3.25(q,J＝7.20Hz,2H),2.71-2.66(m,2H),2.35-2.28(m,2H),1.99-1.94(m,2H),1.44(t,J＝7.36Hz,3H)；
LC-MS(ESI +):m/z calculated for C 47H 52N 20O 11S(M+H) +:963.34found 963.78.
Figure PCTCN2019094562-appb-000086
1H-NMR(400MHz,CDCl 3)δ(ppm)10.45(s,1H),9.50(s,1H),7.65(s,1H),7.54(s,1H),7.49-7.45(m,2H),7.27-7.24(m,1H),7.21(s,1H),7.11-7.05(m,3H),7.03(m,1H),6.85(d,J＝8.60Hz,1H),6.61-6.59(m,1H),6.45-6.42(m,2H),6.38(s,1H),6.20(t,J＝5.52Hz,1H),5.06(s,2H),4.95-4.91(m,1H),4.32(t,J＝7.08Hz,2H),3.56(s,3H),3.25-3.09(m,5H),2.14-2.11(m,1H),1.89-1.85(m,2H),1.65-1.59(m,2H),1.42-1.26(m,10H)；
LC-MS(ESI +):m/z calculated for C 46H 50N 9O 9S(M+H) +:904.34found 904.88.
Figure PCTCN2019094562-appb-000087
1H-NMR(400MHz,CDCl 3)δ(ppm)10.28(s,1H),9.25(s,1H),7.54(s,1H),7.49-7.45(m,2H),7.27(s,1H),7.25-7.22(m,2H),7.13-7.04(m,4H),6.87(d,J＝8.52Hz,1H),6.63-6.60(m,1H),6.46-6.44(m,2H),6.40-6.39(m,1H),6.21(m,1H),5.06(s,2H),4.93-4.90(m,1H),4.33(t,J＝7.20Hz,1H),3.58(s,3H),3.27-3.16(m,4H),2.86-2.76(m,3H),2.12-2.11(m,1H),1.89-1.86(m,2H),1.66-1.63(m,2H),1.42(t,J＝7.36Hz,3H),1.32-1.25(m,14H)；
LC-MS(ESI +):m/z calculated for C 49H 56N 9O 9S(M+H) +:946.38found 947.35.
Figure PCTCN2019094562-appb-000088
1H-NMR(400MHz,CDCl 3)δ(ppm)10.54(s,1H),9.58(s,1H),7.77(d,J＝6.84Hz,1H),7.67-7.63(m,3H),7.55(s,1H),7.43(d,J＝2.52Hz,1H),7.24(d,J＝2.76Hz,1H),7.21(s,1H),7.07-7.04(m,2H),6.98(s,1H),6.56(dd,J＝8.0Hz,J＝1.80Hz,1H),6.39(dd,J＝8.24Hz,J＝1.92Hz,1H),6.33(m,2H),5.02(s,2H),4.99(m,1H),4.37(t,J＝7.24Hz,2H),3.54(s,3H),3.17(dd,J＝14.76Hz,J＝7.36Hz,2H),2.90-2.74(m,3H),2.50(t,J＝6.56Hz,2H),2.14-2.11(m,1H),1.99-1.92(m,2H),1.69-1.58(m,4H),(t,J＝7.32Hz,3H)；
LC-MS(ESI +):m/z calculated for C 45H 43N 8O 9S(M+H) +:871.28found 871.63.
Figure PCTCN2019094562-appb-000089
Figure PCTCN2019094562-appb-000090
1H-NMR(400MHz,CDCl 3)δ(ppm)10.33(s,1H),9.35(s,1H),8.98(s,1H),7.66-7.61(m,2H),7.50-7.46(m,1H),7.33(s,1H),7.21(t,J＝2.68Hz,1H),7.12(s,1H),7.08(d,J＝7.04Hz,1H),6.87(s,1H),6.85(s,1H),6.84-6.78(m,2H),6.70-6.66(m,1H),6.44(t,J＝2.36Hz,1H),6.21(t,J＝5.40Hz,1H),4.95-4.90(m,1H),4.28(t,J＝7.20Hz,2H),3.64(s,3H),3.24(dd,J＝12.52Hz,J＝6.60Hz,2H),2.90-2.70(m,5H),2.45(t,J＝6.76Hz,2H),2.15-2.05(m,3H),1.85(m,2H),1.63(m,2H),1.38-1.25(m,14H)；
LC-MS(ESI +):m/z calculated for C 50H 54F 2N 9O 7(M+H) +:930.40found 931.96.
Figure PCTCN2019094562-appb-000091
1H-NMR(400MHz,CDCl 3)δ(ppm)10.25(s,1H),9.66(s,1H),9.04(s,1H),7.79(dd,J＝6.32Hz,J＝2.04Hz,1H),7.71-7.66(m,3H),7.60(s,1H),7.39(s,1H),7.23(s,1H),7.15(s,1H),6.90-6.81(m,3H),6.70(m,1H),6.44(s,1H),5.03(dd,J＝12.04Hz,J＝5.36Hz,1H),4.36-4.31(m,2H),3.65(s,3H),2.92-2.76(m,5H),2.53(t,J＝6.64Hz,2H),2.47(t,J＝5.96Hz,2H),2.17-2.07(m,3H),1.96(m,2H),1.69(m,2H),1.60(m,2H)；
LC-MS(ESI +):m/z calculated for C 46H 41F 2N 8O 7(M+H) +:855.30found 855.86.
Figure PCTCN2019094562-appb-000092
1H-NMR(400MHz,CDCl 3)δ(ppm)10.45(s,1H),9.85(s,1H),9.04(s,1H),7.78(d,J＝7.36Hz,1H),7.69(dd,J＝8.76Hz,J＝2.36Hz,1H),7.58(d,J＝2.32Hz,1H),7.53(d,J＝7.48Hz,1H),7.41(t,J＝7.64Hz,1H),7.32(s,1H),7.20(t,J＝2.56Hz,3H),7.12(s,1H),6.87-6.79(m,1H),6.68(t,J＝8.80Hz,1H),6.41(s,1H),5.29(dd,J＝13.32Hz,J＝5.12Hz,1H),4.51(d,J＝12.84Hz,1H),4.32(d,J＝17.00Hz,1H),4.29(m,2H),3.63(s,3H),2.92-2.81 (m,2H),2.77(t,J＝6.36Hz,2H),2.51-2.41(m,5H),2.22-2.18(m,2H),2.09-2.01(m,2H),1.94-1.87(m,2H),1.62(m,2H),1.46(m,2H)；
LC-MS(ESI +):m/z calculated for C 46H 43F 2N 8O 6(M+H) +:841.32found 841.89.
Figure PCTCN2019094562-appb-000093
1H-NMR(400MHz,CDCl 3)δ(ppm)10.33(s,1H),9.97(s,1H),8.95(s,1H),7.83(d,J＝7.52Hz,1H),7.66-7.59(m,3H),7.45(t,J＝8.08Hz,1H),7.32(s,1H),7.21(s,1H),7.13(s,1H),6.84(m,3H),6.68(s,1H),6.43(s,1H),5.29(d,J＝10.44Hz,1H),4.53(d,J＝17.04Hz,1H),4.36-4.27(m,4H),3.65(s,3H),3.52(t,J＝5.59Hz,2H),2.88-2.81(m,4H),2.44(m,2H),2.22(m,1H),2.06(m,2H),1.88(m,2H),1.68-1.63(m,4H),1.39(m,2H)；
LC-MS(ESI +):m/z calculated for C 47H 45F 2N 8O 7(M+H) +:871.33found 871.91.
Figure PCTCN2019094562-appb-000094
将羧酸端原料与1.2当量HATU(缩合剂)溶解于DCM/DMF混合溶剂中，加入2.0当量三乙胺，并在室温下搅拌5～10分钟，将1.0当量中间体2溶于适量DCM/DMF混合溶剂中并快速滴加到上述反应液中，室温搅拌过夜。将反应液加入到50mL水中并以乙酸乙酯萃取(3次每次10mL)，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂。残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，得式16。
1H-NMR(400MHz,CDCl 3)δ(ppm)10.02(s,1H),8.60(s,1H),7.63(d,J＝2.32Hz,1H),7.57(s,1H),7.48-7.44(m,2H),7.18(t,J＝2.40Hz,1H),7.14(s,1H),7.07(d,J＝7.04Hz,1H),6.86-6.80(m,4H),6.70(t,J＝7.72Hz,1H),6.42(s,1H),6.22(t,J＝5.24Hz,1H),4.90(dd,J＝12.28Hz,J＝5.52Hz,1H),3.26(dd,J＝12.60Hz,J＝5.28Hz,1H),2.88-2.66(m,3H),2.38(t,J＝7.32Hz,2H),2.12-2.09(m,1H),1.78(m,2H),1.67(m,2H),1.49(m,2H)；
LC-MS(ESI +):m/z calculated for C 39H 35F 2N 6O 7(M+H) +:736.25found 737.96.
Figure PCTCN2019094562-appb-000095
1H-NMR(400MHz,DMSO-d6)δ(ppm)12.01(s,1H),11.11(s,1H),9.84(s,1H),8.20(s,1H),7.48(t,J＝7.64Hz,1H),7.39(d,J＝2.64Hz,1H),7.29(t,J＝2.68Hz,1H),7.27(s,1H),7.21(dd,J＝8.76Hz,J＝2.60Hz,1H),7.14(t,J＝8.20Hz,1H),7.05-6.98(m,3H),6.76(t,J＝6.12Hz,1H),6.63(dd,J＝8.16Hz,J＝1.84Hz,1H),6.48(t,J＝2.16Hz,1H),6.40(dd,J＝8.20Hz,J＝1.80Hz,1H),6.26(t,J＝2.16Hz,1H),5.06-5.01(m,1H),4.99(s,2H),4.59(t,J＝5.68Hz,2H),3.80(q,J＝6.00Hz,2H),3.11(t,J＝7.28Hz,2H),2.90-2.81(m,1H),2.59-2.45(m,2H),2.02-2.00(m,1H),1.22(t,J＝7.24Hz,3H)；
LC-MS(ESI +):m/z calculated for C 40H 38N 9O 9S(M+H) +:820.24found 820.90.
式18～50所示化合物的制备
式18所示化合物的合成：
Figure PCTCN2019094562-appb-000096
将羧酸端原料与1.2当量HATU(缩合剂)溶解于DCM/DMF混合溶剂中，加入2.0当量三乙胺，并在室温下搅拌5～10分钟，将1.0当量中间体2溶于适量DCM/DMF混合溶剂中并快速滴加到上述反应液中，室温搅拌过夜。将反应液加入到50mL水中并以乙酸乙酯萃取(3次每次10mL)，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂。残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，得式18。
1H-NMR(400MHz,CDCl 3)δ(ppm)9.86(s,1H),7.76(s,1H),7.56(d,J＝2.48Hz,1H),7.50-7.45(m,2H),7.18(t,J＝2.52Hz,1H),7.14-7.11(m,2H),7.09(d,J＝8.36Hz,1H),6.99(d,J＝8.36Hz,1H),6.87-6.81(m,3H),6.71(t,J＝7.68Hz,1H),6.50(d,J＝6.32Hz,1H),6.40(s,1H),4.89-4.85(m,1H),3.76-3.73(m,2H),3.63(s,3H),2.87-2.70(m,3H),2.08-2.05(m,1H),1.58-1.53(m,2H)；
LC-MS(ESI +):m/z calculated for C 36H 29F 2N 6O 7(M+H) +:695.20,found 695.96.
按照上述方法可由中间体2出发合成式19至式23所示化合物
Figure PCTCN2019094562-appb-000097
1H-NMR(400MHz,CDCl 3)δ(ppm)7.66(s,1H),7.47-7.42(m,2H),7.21(d,J＝1.80Hz,1H),7.14(s,1H),7.05(d,J＝5.04Hz,1H),6.92(d,J＝8.52Hz,1H),6.85-6.80(m,3H),6.68(t,J＝7.48Hz,1H),6.40(s,1H),4.88-4.84(m,1H),3.62(s,3H),3.37(t,J＝5.88Hz,2H),2.45(t,J＝7.12Hz,2H),2.10-2.03(m,3H)；
LC-MS(ESI +):m/z calculated for C 37H 31F 2N 6O 7(M+H) +:709.21,found 709.84.
Figure PCTCN2019094562-appb-000098
1H-NMR(400MHz,CDCl 3)δ(ppm)9.82(s,1H),8.29(s,1H),7.66(d,J＝2.32Hz,1H),7.52-7.43(m,3H),7.21(t,J＝2.76Hz,1H),7.15(s,1H),7.07(d,J＝7.12Hz,1H),6.89-6.81(m,4H),6.71(t,J＝7.80Hz,1H),6.44(s,1H),6.25(s,1H),4.91-4.86(m,1H),3.64(s,3H),3.32(m,2H),2.89-2.69(m,3H),2.44(t,J＝6.92Hz,2H),2.13-2.05(m,1H),1.90-1.84(m,2H),1.79-1.73(m,2H)；
LC-MS(ESI +):m/z calculated for C 38H 33F 2N 6O 7(M+H) +:723.23,found 723.42.
Figure PCTCN2019094562-appb-000099
1H-NMR(400MHz,CDCl 3)δ(ppm)9.68(d,J＝4.96Hz,1H),7.73(s,1H),7.44-7.38(m,2H),7.26-7.20(m,1H),7.18(s,1H),7.12(s,1H),7.01(d,J＝7Hz,1H),6.84-6.78(m,4H),6.68-6.67(m,1H),6.38(d,J＝2.04Hz,1H),4.87-4.84(m,1H),4.58(s,1H),3.58(s,3H),3.20(t,J＝6.4Hz,2H),2.83-2.68(m,3H),1.99(s,3H),1.87(s,1H),1.65(m,2H),1.46(m,2H),1.23(m,2H)；
LC-MS(ESI +):m/z calculated for C 41H 38F 2N 7O 8(M+H) +:794.27,found 794.77.
Figure PCTCN2019094562-appb-000100
1H-NMR(400MHz,CDCl 3)δ(ppm)9.92(s,1H),8.48(s,1H),7.66(d,J＝2.40Hz,1H),7.49-7.42(m,3H),7.20(t,J＝2.64Hz,1H),7.15(s,1H),7.07(d,J＝7.08Hz,1H),6.88-6.80(m,4H),6.70(d,J＝7.24Hz,1H),6.44(s,1H),6.21(t,J＝5.20Hz,1H),4.92-4.87(m,1H),3.64(s,3H),3.27(q,J＝6.28Hz,2H),2.89-2.66(m,3H),2.35(t,J＝7.44Hz,2H),2.14-2.10(m,1H),1.79-1.71(m,2H),1.46-1.42(m,2H),0.89-0.83(m,4H)；
LC-MS(ESI +):m/z calculated for C 40H 37F 2N 6O 7(M+H) +:751.26,found 751.92.
Figure PCTCN2019094562-appb-000101
1H-NMR(400MHz,CDCl 3)δ(ppm)9.98(s,1H),8.62(s,1H),7.69(d,J＝2.48Hz,1H),7.48(d,J＝7.56Hz,1H),7.42-7.38(m,2H),7.21(t,J＝2.64Hz,1H),7.16(s,1H),7.07(d,J＝7.08Hz,1H),6.87-6.81(m,4H),6.70(d,J＝8.68Hz,1H),6.45(s,1H),6.21(t,J＝5.40Hz,1H),4.92-4.88(m,1H),3.65(s,3H),3.25(q,J＝6.72Hz,2H),2.89-2.68(m,3H),2.36(t,J＝7.36Hz,2H),2.14-2.10(m,1H),1.75-1.71(m,2H),1.45-1.40(m,4H),0.89-0.83(m,4H)；
LC-MS(ESI +):m/z calculated for C 41H 39F 2N 6O 7(M+H) +:765.28,found 765.79.
Figure PCTCN2019094562-appb-000102
将羧酸端原料与1.0当量中间体8、1.2当量EDCI(缩合剂)、2.0当量HOBt以及0.1当量溶解于DCM/DMF混合溶剂中，加入2.0当量三乙胺，并在室温下搅拌过夜。将反应液加入到50mL水中并以乙酸乙酯萃取(3次每次10mL)，合并有机相并以无水硫酸钠干燥，旋转蒸发除去溶剂。残余物以200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，得式24。
1H-NMR(400MHz,CDCl 3)δ(ppm),8.36(d,J＝2.76Hz,1H),8.12(dd,J＝2.8Hz,J＝9.08Hz,1H),7.52-7.45(m,3H),7.12(s,1H),7.07(d,J＝7.08Hz,1H),6.97(d,J＝8.56Hz,1H),6.91(t,J＝8.12Hz,3H),6.31(d,J＝2.84Hz,1H),4.89-4.85(m,1H),3.68(t,J＝6.4Hz,2H),3.65(s,3H),2.85-2.68(m,3H),2.65(t,J＝6Hz,2H),2.11-2.06(m,1H)；
LC-MS(ESI +):m/z calculated for C 36H 30N 7O 9(M+H) +:704.20,found 704.86.
按照上述方法可由中间体8合成式25至式27所示的化合物
Figure PCTCN2019094562-appb-000103
1H-NMR(400MHz,CDCl 3:CD 3OD＝10:1)δ(ppm)8.35(d,J＝2.68Hz,1H),8.11(dd,J＝9.12Hz,J＝2.76Hz,1H),7.51(d,J＝8.84Hz,2H),7.46(t,J＝7.28Hz,1H),7.13(s,1H),7.06(d,J＝7.08Hz,1H),6.93-6.89(m,4H),6.31(d,J＝2.80Hz,1H),4.89-4.85(m,1H),3.66(s,3H),3.36(m,2H),2.84-2.66(m,3H),2.44(t,J＝7.08Hz,2H),2.07-2.03(m,3H)；
LC-MS(ESI +):m/z calculated for C 37H 32N 7O 9(M+H) +:718.22,found 718.86.
Figure PCTCN2019094562-appb-000104
1H-NMR(400MHz,CDCl 3:CD 3OD＝10:1)δ(ppm),8.36(d,J＝2.62Hz,1H),8.12(dd,d,J＝11.20Hz,d,J＝2.56Hz,1H),7.51-7.44(m,3H),7.26(s,1H),7.12(s,1H),7.05(d,J＝7.08Hz,1H),6.94-6.88(m,4H),6.32(d,J＝2.76Hz,1H),4.89-4.85(m,1H),3.66(s,3H),3.29(t,J＝6.84Hz,2H),2.86-2.73(m,5H),2.12-2.07(m,1H),1.84-1.78(m,2H),1.75-1.70(m,2H)；
LC-MS(ESI +):m/z calculated for C 38H 34N 7O 9(M+H) +:732.23,found 732.81.
Figure PCTCN2019094562-appb-000105
1H-NMR(400MHz,CDCl 3:CD 3OD＝10:1)δ(ppm)8.36(d,J＝2.92Hz,1H),8.11(dd,J＝9.04Hz,J＝2.76Hz,1H),7.51(d,J＝8.88Hz,2H),7.46(t,J＝7.56Hz,1H),7.13(s,1H),7.05(d,J＝7.12Hz,1H),6.92(d,J＝8.80Hz,2H),6.86(d,J＝8.52Hz,1H),6.32(d,J＝2.76Hz,1H),4.90-4.85(m,1H),3.66(s,3H),3.26(t,J＝6.84Hz,2H),2.86-2.68(m,3H),2.35(t,J＝7.44Hz,2H),2.09-2.07(m,1H),1.77-1.65(m,4H),1.51-1.43(m,2H)；
LC-MS(ESI +):m/z calculated for C 39H 36N 7O 9(M+H) +:746.25,found 746.79.
按照上述方法可由中间体9合成式28至式31所示的化合物
Figure PCTCN2019094562-appb-000106
1H-NMR(400MHz,CDCl 3:CD 3OD＝10:1)δ(ppm)8.38(d,J＝2.64Hz,1H),8.16(dd,J＝ 2.6Hz,J＝9.08,1H),7.51(s,1H),7.46(t,J＝7.64,1H),7.24(d,J＝2Hz,1H),7.21(t,J＝0.84Hz,1H),7.13(s,1H),7.05(q,J＝7.16Hz,3H),6.94(d,J＝8.8Hz,1H),6.67(d,J＝7.6Hz,1H),6.33(d,J＝2.48Hz,1H),4.90-4.85(m,1H),3.67(t,J＝6.08Hz,2H),3.64(s,3H),2.85-2.73(m,3H),2.65(t,J＝5.84,2H),2.10-2.02(m,1H)；
LC-MS(ESI +):m/z calculated for C 36H 30N 7O 9(M+H) +:703.20,found 703.79.
Figure PCTCN2019094562-appb-000107
1H-NMR(400MHz,CDCl 3:CD 3OD＝10:1)δ(ppm)8.35(d,J＝2.76Hz,1H),8.10(dd,J＝9.08Hz,J＝2.80Hz,1H),7.46(t,J＝1.96Hz,1H),7.41(dd,J＝8.44Hz,J＝7.20Hz,1H),7.24(d,J＝2.84Hz,1H),7.21(d,J＝8.04Hz,1H),7.13-7.11(m,2H),7.02(d,J＝7.08Hz,1H),6.96(d,J＝9.08Hz,1H),6.86(d,J＝8.56Hz,1H),6.65(dd,J＝7.92Hz,J＝1.52Hz,1H),6.31(d,J＝2.84Hz,1H),4.88-4.83(m,1H),3.64(s,3H),3.32(t,J＝6.48Hz,2H),2.83-2.69(m,3H),2.41(t,J＝7.16Hz,2H),2.08-1.97(m,3H)；
LC-MS(ESI +):m/z calculated for C 37H 32N 7O 9(M+H) +:718.22,found 718.77.
Figure PCTCN2019094562-appb-000108
1H-NMR(400MHz,CDCl 3)δ(ppm),8.38(s,1H),8.17-8.14(m,1H),7.48-7.44(m,2H),7.25-7.20(m,3H),7.13(s,1H),7.10-7.02(m,3H),6.86(d,J＝8.6Hz,1H),6.67(d,J＝7.24Hz,1H),6.33(s,1H),4.90-4.86(m,1H),3.66(s,3H),3.29(t,J＝6.44,2H),2.87-2.70(m,3H),2.37(t,J＝7.28Hz,2H),2.13-2.07(m,1H),1.82-1.78(m,2H),1.75-1.69(m,2H)；
LC-MS(ESI +):m/z calculated for C 38H 34N 7O 9(M+H) +:731.23,found 731.86.
Figure PCTCN2019094562-appb-000109
1H-NMR(400MHz,CDCl 3:CD 3OD＝10:1)δ(ppm)8.37(d,J＝2.76Hz,1H),8.13(dd,J＝9.08Hz,J＝2.80Hz,1H),7.50(s,1H),7.45(dd,J＝8.44Hz,J＝7.24Hz,1H),7.25(d,J＝2.80Hz,1H),7.22(d,J＝8.12Hz,1H),7.14(s,1H),7.11(d,J＝7.96Hz,1H),7.05(d,J＝7.08Hz,1H),6.99(d,J＝9.08Hz,1H),6.84(d,J＝8.52Hz,1H),6.67(dd,J＝7.96Hz,J＝1.64Hz,1H),6.32(d,J＝2.84Hz,1H),4.88-4.84(m,1H),3.65(s,3H),3.24(t,J＝6.80Hz,2H),2.85-2.68(m,3H),2.32(t,J＝7.36Hz,2H),2.10-2.05(m,1H),1.75-1.64(m,4H),1.48-1.41(m,2H)；
LC-MS(ESI +):m/z calculated for C 39H 36N 7O 9(M+H) +:746.25,found 746.79.
Figure PCTCN2019094562-appb-000110
式32可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 47H 48F 2N 9O 10(M+H) +:936.34,found 936.57.
Figure PCTCN2019094562-appb-000111
式33可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 43H 32F 2N 9O 8(M+H) +:848.29,found 848.95.
Figure PCTCN2019094562-appb-000112
式34可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 48H 48N 9O 11S(M+H) +:958.31,found 958.43.
Figure PCTCN2019094562-appb-000113
式35可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 46H 44N 9O 10S(M+H) +:914.29,found 914.73.
Figure PCTCN2019094562-appb-000114
式36可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 44H 41N 8O 10S(M+H) +:873.26,found 873.79.
Figure PCTCN2019094562-appb-000115
式37可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 44H 46N 9O 11S(M+H) +:908.30,found 908.49.
Figure PCTCN2019094562-appb-000116
式38可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 46H 50N 9O 12S(M+H) +:952.32,found 952.93.
Figure PCTCN2019094562-appb-000117
式39可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 43H 39N 8O 10S(M+H) +:859.24,found 859.71.
Figure PCTCN2019094562-appb-000118
式40可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 46H 43F 2N 8O 8(M+H) +:873.31,found 873.95.
Figure PCTCN2019094562-appb-000119
式41可由式1所示的方法制备。LC-MS(ESI +):m/z calculated for C 45H 47F 2N 8O 7(M+H) +:843.30,found 843.89.
Figure PCTCN2019094562-appb-000120
式42可由式28所示的方法制备。LC-MS(ESI +):m/z calculated for C 39H 36N 7O 9(M+H) +:746.25,found 746.79.
Figure PCTCN2019094562-appb-000121
式43可由式28所示的方法制备。LC-MS(ESI +):m/z calculated for C 39H 36N 7O 9(M+H) +:746.25,found 746.92.
Figure PCTCN2019094562-appb-000122
式44可由式28所示的方法制备。LC-MS(ESI +):m/z calculated for C 40H 38N 7O 9(M+H) +:760.27,found 760.73.
Figure PCTCN2019094562-appb-000123
式45可由式28所示的方法制备。LC-MS(ESI +):m/z calculated for C 40H 38N 7O 9(M+H) +:760.27,found 760.57.
Figure PCTCN2019094562-appb-000124
式46可由式28所示的方法制备。LC-MS(ESI +):m/z calculated for C 41H 40N 7O 9(M+H) +:774.28,found 774.90.
Figure PCTCN2019094562-appb-000125
式47可由式28所示的方法制备。LC-MS(ESI +):m/z calculated for C 41H 40N 7O 9(M+H) +:774.28,found 774.82.
Figure PCTCN2019094562-appb-000126
式48可由式19所示的方法制备。LC-MS(ESI +):m/z calculated for C 38H 37F 2N 6O 7(M+H) +:723.23,found 723.78.
Figure PCTCN2019094562-appb-000127
式49可由式19所示的方法制备。LC-MS(ESI +):m/z calculated for C 39H 37F 2N 6O 7(M+H) +:737.25,found 737.48.
Figure PCTCN2019094562-appb-000128
式50可由式19所示的方法制备。LC-MS(ESI +):m/z calculated for C 40H 37F 2N 6O 7(M+H) +:750.26,found 750.99.
实施例2 式1～30所示化合物在蛋白免疫印迹实验水平的生物活性测试
细胞处理：
取对数生长期的Ramos或HBL-1或IgE MM或Jurkat细胞于6孔板里，加化合物处理；孵育相应时间后收细胞。
细胞全蛋白抽提：
收集细胞：将处理后的细胞于培养基中刮下，充分混悬后300g离心5分钟收集，PBS洗一遍后，弃去PBS。
裂解细胞：每一样品加入100μL的2×Loading Buffer，充分震荡混匀，100℃变性15分钟，混匀后于-20℃保存或直接用于Western Blot检测。
5×Loading Buffer的配方为：250mM Tris-HCl(pH6.8)，10％(W/V)SDS，0.5％(W/V)溴酚蓝，50％(V/V)甘油，5％(W/V)β-巯基乙醇(2-ME)。2×Loading Buffer的制备是将1.5倍体积的dd水加入到5×Loading Buffer中即得。
蛋白免疫印迹实验(Western Blot，WB)检测的具体步骤如下：
1)配制合适浓度的SDS-PAGE胶。分离胶的浓度为8％，浓缩胶的浓度为5％。
2)制备样品。根据实验要求制备蛋白样品，95℃变性15分钟，离心、混匀并上样于SDS-PAGE胶上样孔中。根据蛋白定量结果适量调整上样体积，通常每个孔上样量为8μL。
3)电泳。接通电源，蛋白样品在浓缩胶中电压为80伏特，待蛋白样品进入分离胶时，把电压调整为120伏特继续电泳。待溴酚蓝几乎完全跑出PAGE胶时终止电泳。
4)转膜。电泳结束后取下凝胶，按下列顺序安装转膜装置：(负极)、滤纸、凝胶、活化的PVDF膜、滤纸、(正极)。然后夹紧转移装置置于转膜缓冲液中，最后放入冰盒，置于4℃冷库100V恒压通电1.5小时。
5)封闭。转膜结束后，取出PVDF膜，将膜浸没在含5％的脱脂奶粉的TBST缓冲液里，室温下摇床振荡1小时。
6)一抗孵育。封闭结束后，用TBST缓冲液荡洗3次，然后加入适度稀释比例的一抗，4℃过夜。回收一抗，将PVDF膜用TBST缓冲液荡洗3次，每次振荡10分钟。
7)二抗孵育。弃去TBST缓冲液，加入一定稀释比(通常是1：3000～1：5000)的二抗(鼠抗或者兔抗，由一抗决定)，室温下摇床振荡1小时。弃去二抗，将PVDF膜用TBST缓冲液荡洗3次，每次振荡10分钟。最后用TBST缓冲液荡洗10分钟。
8)显色并压片。将ECL显色底物均匀覆盖在PVDF膜上，室温显色0.5～15分钟。
本发明实施例的化合物对BET的降解活性如下：
在Jurkat细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到式1、式9、式13所示化合物对BET蛋白的降解作用，如图3所示(Jurkat细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2培养24小时；DMSO终浓度为千分之一)。
在Rescue实验中，在Ramos细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到式2所示化合物对BET蛋白的降解作用，受到卡非佐米(Cfz)、(+)-JQ-1、ABBV-075及泊马渡胺(Poma)的影响，结果如图4-1和图4-2所示(式2浓度为100nM；Cfz浓度为0.4μM；(+)-JQ-1、ABBV-075及Poma浓度为10μM；Ramos细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2，加入Cfz、(+)-JQ-1、ABBV-075及Poma预先孵育2小时，然后加入式2所示化合物，37℃ 5％CO 2孵育2小时；DMSO终浓度为1％)；在蛋白免疫印迹实验(WB)结果中可以明显观察到Cfz、(+)-JQ-1、ABBV-075及Poma对BET蛋白无降解作用。
在HBL-1、Ramos、IgEMM和RPMI细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到式2、式5、式10、式13及式15所示化合物(各化合物浓度均为100nM)对BET蛋白的降解作用，如图5-1、图5-2、图5-3以及图5-4所示(HBL-1细胞系：2×10 6细胞每孔(6孔板),37℃ 5％CO 2培养24小时；DMSO终浓度为千分之一；Ramos细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2培养24小时；DMSO终浓度为千分之一；IgEMM细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2培养24小时；DMSO终浓度为千分之一；RPMI细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2培养24小时；DMSO终浓度为千分之一)。
在Ramos细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到式2(浓度为100nM)所示化合物因对BET蛋白的降解作用而显现出对下游原癌基因c-MYC蛋白丰度的下降作用，如图6-1或图6-2所示。其中图6-1显示式2孵育2小时引起c-MYC的表达下调，图6-2显示式2孵育6小时引起c-MYC的表达下调作用更加显著(Ramos细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2培养24小时；DMSO终浓度为千分之一)。
在HBL-1(BTK-C481S)细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观 察到式2所示化合物在低浓度(0.1nM、0.5nM、1nM、2nM)下孵育细胞2小时引起的BET蛋白降解作用与相同浓度的ARV-825处理相同时间细胞所得的BET蛋白降解效果对比，如图7所示(HBL-1(BTK-C481S细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2培养2小时：DMSO终浓度为千分之一)。
在Jurkat细胞系中，在蛋白免疫印迹实验(WB)结果中可以明显观察到式16、式18、式19、式20、式21、式22、式23、式24、式25、式26、式27、式28、式29、式30所示化合物对BET蛋白的降解作用，其中式16、式19和式21表现出一定BRD4降解的选择性，而式24则选择性不降解BRD2，结果如图9-1、9-2和9-3所示(Jurkat细胞系：2×10 6细胞每孔(6孔板)，37℃ 5％CO 2培养24小时；DMSO终浓度为千分之一)。
实施例3 式1～50所示化合物在细胞水平的生物活性测试
MTT实验试剂：
试剂：RPIM 1640培养基；DMEM培养基；100×非必需氨基酸(NEAA)；100×青链霉素混合液；50mMβ巯基乙醇；胎牛血清(FBS，事先经过失活处理)。
A培养基(500mL)：RPIM 1640培养基(450mL)+100×NEAA(5mL)+100×青链霉素混合液(5mL)+胎牛血清(50mL)+50mMβ巯基乙醇(0.5mL)。
B培养基(500mL)：DMEM培养基(450mL)+100×NEAA(5mL)+100×青链霉素混合液(5mL)+胎牛血清(50mL)+50mMβ巯基乙醇(0.5mL)。。
CCK-8试剂盒(细胞计数Kit-8)
MTT实验流程(HBL-1(BTK-C481S))：
1)收集对数期细胞，用A培养基调节细胞悬液浓度6.6×10 4/mL。
2)用A培养基2倍梯度稀释小分子浓度为50nM至0.15nM，配置成小分子溶液。
3)将45μL的细胞悬液加入到96孔板(边缘孔用灭菌PBS填充，3000个细胞/孔)。每板设阴性对照(45μL细胞悬液和45μL的A培养基)，每组设定3复孔。
4)置37℃，5％CO 2孵育1小时后，在96孔板的每个孔中加入45μL对应的小分子溶液。然后再在37℃，5％CO 2孵育72-96小时。每孔加入10μL cck-8溶液，继续培养4h。直接酶联免疫检测仪OD490nm测量各孔的吸光值。
通过上述方法测得本发明化合物对BET蛋白降解和细胞增殖抑制结果如下表1、图8-1或图8-2所示。
另外，图10-1与图10-2展示了式2、式10、式21与式24等化合物在肺癌K562细胞系和前列腺癌LNcap细胞系上的活性比较。可以看出选择性降解BRD4的式21和不降解BRD2的式24的细胞毒性弱于非选择性的式2和式10，因而式21和式24可能具有更高的 安全性和治疗前景。
表1：式1-式50所示化合物以及文献已报道的ABBV-075，(+)-JQ-1和ARV-825等化合物对HBL-1(BTK-C481S)细胞系BET蛋白的半数降解浓度(DC 50)和抑制能力的MTT实验(IC 50值)：
Figure PCTCN2019094562-appb-000129
Figure PCTCN2019094562-appb-000130
Figure PCTCN2019094562-appb-000131
Figure PCTCN2019094562-appb-000132
Figure PCTCN2019094562-appb-000133
Figure PCTCN2019094562-appb-000134
Figure PCTCN2019094562-appb-000135
Figure PCTCN2019094562-appb-000136
备注：N.D表示未检测抑制活性。
由上表1分析可知，本发明化合物对BET蛋白降解和细胞增殖的抑制效果显著。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (32)

  1. 一种化合物，其为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    X-Y-Z
    式I
    其中，X表示BET蛋白的配体，Z表示E3连接酶的配体，Y表示连接X和Z的链。
  2. 根据权利要求1所述的化合物，其特征在于，所述X为式II-1或II-2所示化合物，
    Figure PCTCN2019094562-appb-100001
    Cy 1或Cy 2分别独立地为苯环，C 6-12芳基，5-12个环原子组成的杂芳基，C 3-12环烷基或3-12个环原子组成的杂环基；
    L 1为-(CR mR w) g-O-(CR mR w) g-，-(CR mR w) g-S-(CR mR w) g-，-(CR mR w) g-N(R 1a)-(CR mR w) g-，-(CR mR w) n-，-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，-(CR mR w) g-(C≡C) n-(CR mR w) g-，-(CR mR w) g-S(＝O) p-(CR mR w) g-，-(CR mR w) g-C(＝O)-(CR mR w) g-，-(CR mR w) g-C(＝O)-O-(CR mR w) g-，-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-；
    各Cy 1或Cy 2分别独立地被1、2、3、4、5或6个R h1所取代；
    各L 1分别独立地被1、2、3、4、5或6个R h2所取代；
    各R h1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基，5-12个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-，R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
    各R h2分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基，5-12个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-， R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
    各R h1分别独立地被1、2、3、4、5或6个R h3所取代；
    各R h2分别独立地被1、2、3、4、5或6个R h4所取代；
    各R h3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基或C 3-6环烷基；
    各R h4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基或C 3-6环烷基；
    各R 1a分别独立地为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基，C 1-6烷基，C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
    各R m、R w或R g分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
    各n分别独立地为1，2，3或4；
    各g分别独立地为0，1，2，3或4；
    各p分别独立地为1或2。
  3. 根据权利要求2所述的化合物，其特征在于，
    Cy 1或Cy 2分别独立地为苯环，C 6-10芳基，5-10个环原子组成的杂芳基，C 3-6环烷基或3-12个环原子组成的杂环基。
  4. 根据权利要求2所述的化合物，其特征在于，
    各R h1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基，5-10个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-，R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a)n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-， R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
    各R h2分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基，5-10个环原子组成的杂芳基，R g-(CR mR w) g-O-(CR mR w) g-，R g-(CR mR w) g-S-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-，R g-(CR mR w) g-(CR 1a＝CR 1a) n-(CR mR w) g-，R g-(CR mR w) g-(C≡C) n-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
    各R h1分别独立地被1、2、3、4、5或6个R h3所取代；
    各R h2分别独立地被1、2、3、4、5或6个R h4所取代；
    各R h3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基或C 3-6环烷基；
    各R h4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基或C 3-6环烷基。
  5. 根据权利要求2所述的化合物，其特征在于，
    各R 1a分别独立地为H，氘，F，Cl，Br，I，CN，NO 2，OH，氨基，羧基，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
    各R m、R w或R g分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。
  6. 根据权利要求2所述的化合物，其特征在于，
    Cy 1或Cy 2分别独立地为
    Figure PCTCN2019094562-appb-100002
    Figure PCTCN2019094562-appb-100003
  7. 根据权利要求2所述的化合物，其特征在于
    各R h1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，
    Figure PCTCN2019094562-appb-100004
    Figure PCTCN2019094562-appb-100005
    R g-(CR mR w) g-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-O-(CR mR w) g-，R g-(CR mR w) g-O-C(＝O)-(CR mR w) g-，R g-(CR mR w) g-S(＝O) p-N(R 1a)-(CR mR w) g-，R g-(CR mR w) g-N(R 1a)-S(＝O) p-(CR mR w) g-，R g-(CR mR w) g-C(＝O)-N(R 1a)-(CR mR w) g-或R g-(CR mR w) g-N(R 1a)-C(＝O)-(CR mR w) g-；
    各R h2分别独立地为氢，氘，F，Cl，Br，I，氧代，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
    各R h1分别独立地被1、2、3、4、5或6个R h3所取代；
    各R h2分别独立地被1、2、3、4、5或6个R h4所取代；
    各R h3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
    各R h4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
  8. 根据权利要求1所述的化合物，其特征在于，
    各R 1a分别独立地为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
    各R m、R w或R g分别独立地为H、氘、甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
  9. 根据权利要求1所述的化合物，其特征在于，所述X为式III-1、III-2、III-3、III-4、III-5或III-6所示化合物，
    Figure PCTCN2019094562-appb-100006
  10. 根据权利要求1所述的化合物，其特征在于，所述Z为式IV所示化合物，
    Figure PCTCN2019094562-appb-100007
    其中，Q为N或CR 2；
    M为C(R eR f)，N(R 1b)，O或S；
    W，K分别独立地为C(R eR f)，NH，O或S；
    R 2为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基或C 2-6炔基；
    各R 2a或R 2b分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，氧代，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；
    各R 2c分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；
    各R e、R f分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
    各R 1b分别独立地为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C 2-6烯基，C 2-6炔基，C 3-12环烷基，C 6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；
    W或K为NH时，所述R 2a不在所述W或K的位置进行取代；
    n 1、n 2分别独立地为0、1、2或3；
    n 3为0、1、2、3、4或5。
  11. 根据权利要求10所述的化合物，其特征在于，
    R 2为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基或C 2-4炔基。
  12. 根据权利要求10所述的化合物，其特征在于，
    各R 2a或R 2b分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，氧代，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；W或K为N，N上的取代基R 2a不为C 1-4烷基；
    各R 2c分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO 2，NH 2，COOH，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。
  13. 根据权利要求10所述的化合物，其特征在于，
    各R e、R f分别独立地为H、氘、F、Cl、Br、I、CN、-NO 2、OH、氨基、羧基、C 1-4烷 基、C 1-4卤代烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；
    各R 1b分别独立地为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基，C 1-4烷基，C 1-4卤代烷基，C 1-4烷氧基，C 2-4烯基，C 2-4炔基，C 3-6环烷基，C 6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。
  14. 根据权利要求10所述的化合物，其特征在于，
    R 2为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
  15. 根据权利要求10所述的化合物，其特征在于，
    各R 2a或R 2b分别独立地为氢，氘，氧代，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
    各R 2c分别独立地为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
  16. 根据权利要求10所述的化合物，其特征在于，
    各R e、R f分别独立地为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
    各R 1b分别独立地为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
  17. 根据权利要求10所述的化合物，其特征在于，所述Z为式V-1、V-2、V-3或V-4、所示化合物，
    Figure PCTCN2019094562-appb-100008
  18. 根据权利要求1所述的化合物，其特征在于，所述Y为含有1～30个原子的基团，所述原子包括选自碳原子、硫原子、氧原子、氮原子、硒原子的至少之一。
  19. 根据权利要求1所述的化合物，其特征在于，所述Y为任选取代的C 1-20烷基、C 1-20卤代烷基、C 1-20烷氧基、C 2-20烯基、C 2-20炔基、C 3-12环烷基、C 6-12芳基、3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基的至少之一构成的基团；
    任选地，各C 1-20烷基、C 1-20卤代烷基、C 1-20烷氧基、C 2-20烯基、C 2-20炔基、C 3-12环烷基、C 6-12芳基、3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基独立地被C 1-8烷基-C(＝O)-NH-所取代。
  20. 根据权利要求1所述的化合物，其特征在于，所述Y为任选取代的
    Figure PCTCN2019094562-appb-100009
    其中，x 1-x 23分别独立地为一个键，
    Figure PCTCN2019094562-appb-100010
    Figure PCTCN2019094562-appb-100011
    R 1d为H，氘，F，Cl，Br，I，CN，-NO 2，OH，氨基，羧基或C 1-4烷基；
    任选地，各x 1-x 23独立地被C 1-6烷基-C(＝O)-NH-所取代。
  21. 根据权利要求1所述的化合物，其特征在于，所述Y为式VI-1或VI-2所示化合物，
    Figure PCTCN2019094562-appb-100012
    各r分别独立地为0～12之间的整数；
    各k分别独立地为0～12之间的整数；
    各j分别独立地为0～12之间的整数；
    各t 1或t 3分别独立地为键，
    Figure PCTCN2019094562-appb-100013
    任选取代的
    Figure PCTCN2019094562-appb-100014
    各t 2或t 4分别独立地为键，
    Figure PCTCN2019094562-appb-100015
    任选取代的
    Figure PCTCN2019094562-appb-100016
    Figure PCTCN2019094562-appb-100017
    t 5为键或任选取代的
    Figure PCTCN2019094562-appb-100018
    R 1d为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；
    任选地，各t 1、t 2、t 3、t 4或t 5独立地被C 1-4烷基-C(＝O)-NH-所取代。
  22. 根据权利要求21所述的化合物，其特征在于，所述Y为式VI-1所示化合物，
    Figure PCTCN2019094562-appb-100019
    其中：
    Figure PCTCN2019094562-appb-100020
    为
    Figure PCTCN2019094562-appb-100021
    Figure PCTCN2019094562-appb-100022
    k＝k 1+2或
    k＝k 2+1或
    k＝k 3+1或
    k＝k 4+2。
  23. 根据权利要求1所述的化合物，其特征在于，所述Y为下列至少之一所示化合物，
    Figure PCTCN2019094562-appb-100023
    Figure PCTCN2019094562-appb-100024
    各t 6、t 7、t 8、t 9或t 10分别独立地为0～11之间的整数。
  24. 一种化合物，其为式1～50任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2019094562-appb-100025
    Figure PCTCN2019094562-appb-100026
    Figure PCTCN2019094562-appb-100027
    Figure PCTCN2019094562-appb-100028
    Figure PCTCN2019094562-appb-100029
    Figure PCTCN2019094562-appb-100030
    Figure PCTCN2019094562-appb-100031
    Figure PCTCN2019094562-appb-100032
    Figure PCTCN2019094562-appb-100033
    Figure PCTCN2019094562-appb-100034
    Figure PCTCN2019094562-appb-100035
  25. 一种药物组合物，其特征在于，包括权利要求1～24任一项所述的化合物。
  26. 根据权利要求25所述的药物组合物，其特征在于，进一步包括辅料。
  27. 根据权利要求25所述的药物组合物，其特征在于，进一步包括其他治疗或预防非霍奇金淋巴瘤、Burkitt’s淋巴瘤、急性骨髓性白血病、多发性骨髓瘤、肺癌、前列腺癌以及NUT中线癌的药物。
  28. 根据权利要求27所述的药物组合物，其特征在于，所述其他治疗或预防非霍奇金淋巴瘤的药物包括依鲁替尼；
    任选地，所述其他治疗或预防Burkitt’s淋巴瘤的药物包括选自环磷酰胺、多柔吡星的 至少之一；
    任选地，所述其他治疗或预防急性骨髓性白血病的药物包括选自阿糖胞苷、Azacitidine、Decitabine的至少之一；
    任选地，所述其他治疗或预防多发性骨髓瘤的药物包括选自卡非佐米、沙利度胺、来那度胺、泊马渡胺的至少之一；
    任选地，所述其他治疗或预防肺癌的药物包括选自吉非替尼、厄洛替尼、奥司他丁、阿法替尼的至少之一；
    任选地，所述其他治疗或预防前列腺癌的药物包括选自氟他胺、尼鲁米特的至少之一。
  29. 权利要求1-24中任一项所述化合物或权利要求25～28任一项所述的药物组合物在制备药物中的用途，所述药物用于降解BET蛋白。
  30. 权利要求1-24中任一项所述化合物或权利要求25～28任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防非霍奇金淋巴瘤、Burkitt’s淋巴瘤、急性骨髓性白血病、多发性骨髓瘤、肺癌、前列腺癌以及NUT中线癌。
  31. 一种降解BET蛋白的方法，其特征在于，包括：使BET蛋白与权利要求1-24任一项所述的化合物或权利要求25～28任一项所述的药物组合物接触。
  32. 一种治疗或预防非霍奇金淋巴瘤、Burkitt’s淋巴瘤、急性骨髓性白血病、多发性骨髓瘤、肺癌、前列腺癌以及NUT中线癌的方法，其特征在于，给予患者权利要求1-24任一项所述的化合物或权利要求25～28任一项所述的药物组合物。
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