WO2022268066A1 - 一种蛋白降解剂 - Google Patents
一种蛋白降解剂 Download PDFInfo
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- WO2022268066A1 WO2022268066A1 PCT/CN2022/100078 CN2022100078W WO2022268066A1 WO 2022268066 A1 WO2022268066 A1 WO 2022268066A1 CN 2022100078 W CN2022100078 W CN 2022100078W WO 2022268066 A1 WO2022268066 A1 WO 2022268066A1
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- hydrogen
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/20—Antivirals for DNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- A61P35/00—Antineoplastic agents
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
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- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicines, and in particular relates to a protein degradation agent and its preparation method and application.
- c-Myc The natural disordered protein c-Myc is a well-known transcription factor that can regulate approximately 15% of human genes. c-Myc can regulate a variety of biological functions, such as cell proliferation, apoptosis, cell cycle progression, cell metabolism and embryonic development, and plays a very important role in the occurrence, development and evolution of diseases.
- c-Myc is closely related to a variety of tumor diseases, including lymphoma, breast cancer, prostate cancer, colon cancer, cervical cancer, multiple myeloma, myelogenous leukemia, melanoma, osteosarcoma, malignant glioma , small cell lung cancer, and medulloblastoma.
- c-Myc can promote the occurrence and growth of tumors in many ways (C Yu, et al. Sci Rep 6.1, 1-11).
- c-Myc is also associated with several other diseases.
- diabetes with the increase of c-Myc expression, insulin-producing ⁇ islet cells dedifferentiate or undergo apoptosis, and their insulin secretion decreases accordingly (Magid R et al. J Biol Chem, 2003, 278: 32994) .
- enhanced expression of c-Myc in vivo correlates with the development of aortic and carotid plaques, and indeed early coronary artery disease and hypercholesterolemia in the Watanabe hyperlipidemic rabbit model.
- c-Myc protein has become one of the most attractive potential anti-tumor targets.
- the transcription factor terminator (G1 to S phase transition 1, GSPT1) mediates the recognition of the stop codon and the release of the transcription-promoting peptide chain from the ribosome.
- GSPT1 is also closely related to a variety of important cellular activities such as cell cycle regulation, cytoskeleton formation, and apoptosis.
- GSPT1 is considered to be an oncogenic factor for various tumors, including breast cancer, liver cancer, gastric cancer and prostate cancer (Cui, Jian, et al. International journal of oncology, 2020, 56(4):867-878).
- Casein kinase 1 ⁇ phosphorylates p53 protein.
- p53 protein As a tumor suppressor protein, p53 protein participates in various signal transduction in cells, and plays an important role in cell cycle regulation, cell apoptosis and other processes.
- Phosphorylated p53 can bind to mouse double minigene 2 (MDM2), and then be degraded by ubiquitination (Huart, Anne-Sophie, et al. Journal of Biological Chemistry 284.47(2009): 32384-32394). Therefore, blocking the activity of CK1 ⁇ can stabilize p53, thereby exerting its tumor suppressor activity.
- MDM2 mouse double minigene 2
- Zinc finger transcription factors IKZF1/2/3 (Aiolos, Helios, Ikaros) belong to the Ikaros zinc-finger (IKZF) family, and they are essential for the survival of lymphoid cells.
- Aiolos can bind to the B lymphoma gene 2 (Bcl-2) enhancer, thereby up-regulating the effect of Bcl-2 protein on cell survival.
- Bcl-2 B lymphoma gene 2
- Abnormally activated Helios and Ikaros can up-regulate the expression of Bcl-XL and drive the occurrence and development of various hematological tumors.
- the object of the present invention is to provide a c-Myc protein degradation agent and its preparation method and application, the compound of the present invention can be used for degrading various proteins including c-Myc protein, such as N-myc, GSPT1, CK1 ⁇ , IKZF ( 1/2/3), AR and AR-V7, etc., so as to prevent, alleviate or treat diseases related to these protein imbalances.
- c-Myc protein such as N-myc, GSPT1, CK1 ⁇ , IKZF ( 1/2/3), AR and AR-V7, etc.
- the present invention provides the compound shown in formula (I) and pharmaceutically available salt, solvate, stereoisomer, isotope and prodrug thereof:
- Q is selected from: -NR 2 -, -O-;
- T, U, Z are independently selected from: chemical bond, carbonyl, C 1 -C 6 alkylene, C 3 -C 10 cycloalkylene, arylene, heteroarylene, heterocyclylene, said Alkylene, cycloalkylene, arylene, heteroarylene, heterocyclylene can be optionally substituted by one or more R9 ;
- R 6 is selected from: hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, containing 1-3 heteroatoms
- M is independently selected from: hydrogen, C 1 -C 4 alkyl
- R 11 and R 12 are independently selected from: hydrogen, C 1 -C 4 alkyl, aryl;
- R 21 is selected from: C 1 -C 4 alkyl
- R 23 is selected from: hydrogen, C 1 -C 4 alkyl, said C 1 -C 4 alkyl is optionally substituted by 1-3 groups selected from halogen, hydroxyl, amino;
- n is selected from: 0, 1, 2 or 3;
- n is selected from: 0, 1, 2, 3 or 4;
- oChoose from: 1 or 2.
- the present invention provides compounds represented by formula (I) and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- Q is selected from: -NR 2 -, -O-;
- T, U, Z are independently selected from: chemical bond, carbonyl, C 1 -C 6 alkylene, C 3 -C 10 cycloalkylene, arylene, heteroarylene, heterocyclylene, said Alkylene, cycloalkylene, arylene, heteroarylene, heterocyclylene can be optionally substituted by one or more R9 ;
- R 6 is selected from: hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, containing 1-3 heteroatoms
- the 5-6 membered heteroaryl group or the 3-10 membered heterocyclic group containing 1-3 heteroatoms, the alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group is optionally replaced by 1-3 substituted by a group respectively selected from halogen, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
- R 11 and R 12 are independently selected from: hydrogen, C 1 -C 4 alkyl, aryl;
- R 21 is selected from: C 1 -C 4 alkyl
- n is selected from: 0, 1, 2 or 3;
- n is selected from: 0, 1, 2, 3 or 4;
- oChoose from: 1 or 2.
- the R a is selected from: C 2 -C 6 alkyl, carbazolyl, 1-azacarbazolyl, 2-azacarbazolyl, 1,8-diazacarbazole yl, indolyl, phenoxazinyl, naphthyl, fluorenyl, dianilinyl, dibenzylamino, tert-butyl, quinolinyl, isoquinolyl, phenyl, 2,3-dihydroindoline Indolyl, 7-azaindolyl, 2,3-dihydro-7-azaindolyl, naphthyridinyl, tetrahydronaphthyridinyl, tetrahydroquinolinyl, pyrimidinyl or triazolyl, R a may be optionally substituted by one or more R 9 selected from hydrogen, halogen, C 1 -C 6 alkoxy, cyano, C 1 -C
- the R a is selected from: C 2 -C 6 alkyl, carbazolyl, 1-azacarbazolyl, 2-azacarbazolyl, 1,8-diazacarbazole Base, indolyl, phenoxazinyl, naphthyl, fluorenyl, diphenylamino, dibenzylamino, tert-butyl, quinolinyl, isoquinolyl or phenyl, R a can optionally be One or more R 9 are substituted, and the R 9 is selected from hydrogen, halogen, C 1 -C 6 alkoxy, cyano, C 1 -C 6 alkyl, optionally 1-3 groups selected from halogen C 1 -C 6 alkyl group substituted.
- the R a is selected from tert-butyl, carbazol-1-yl, 1-azacarbazol-9-yl, 2-azacarbazol-9-yl, 1,8-diazacarba Azol-9-yl, indol-1-yl, phenoxazin-10-yl, naphthalene-1-yl, naphthalene-2-yl, fluoren-9-yl, diphenylamino, dibenzylamino, tertiary Butyl, quinolin-4-yl, quinolin-5-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin Lin-8-yl, phenyl, 2,3-dihydro-indol-1-yl, 7-azaindolyl-1-yl, 2,3-dihydro-7-azaindolyl- 1-yl,
- the R a is selected from: tert-butyl, carbazol-1-yl, 1-azacarbazol-9-yl, 2-azacarbazol-9-yl, 1,8-diazepine Carbazol-9-yl, indol-1-yl, phenoxazin-10-yl, naphthalene-1-yl, naphthalene-2-yl, fluoren-9-yl, diphenylamino, dibenzylamino, tert-butyl, quinolin-4-yl, quinolin-5-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-5-yl, Quinolin-8-yl or phenyl, R a can optionally be substituted by one or more R 9 , said R 9 is selected from F, Cl, Br, methoxy, ethoxy, cyano,
- the R a is selected from the following groups:
- the R a is selected from the following groups:
- the Q is selected from: -NH-, -O-, -N(CH 3 )-, -N(SO 2 CH 3 )-, -N(COCH 3 )-, -N(CO -isopropyl)-, -N(CO-cyclopropyl)-, -N(isopropyl)-, -N(cyclopropyl)-, -N(2-methoxyethyl)-, - N(2-cyanoethyl)-, -N(phenyl)-, -N(benzyl)-, -N(1-naphthylmethyl)-, -N(2-naphthylethyl)-, - N(CH 2 OH)-, -N(CH 2 CH 2 OH)-, -N(CH 2 CH 2 CH 2 OH)-, -N(COCH 2 OH)-, -N(COCH 2 CH 2 OH)
- the Q is selected from: -NH-, -O-, -N(CH 3 )-, -N(SO 2 CH 3 )-, -N(COCH 3 )-, -N(CO -isopropyl)-, -N(CO-cyclopropyl)-, -N(isopropyl)-, -N(cyclopropyl)-, -N(2-methoxyethyl)-, - N(2-cyanoethyl)-, -N(phenyl)- or -N(benzyl)-.
- the T and Z are independently selected from: chemical bond, carbonyl, C 1 -C 6 alkylene or C 3 -C 10 cycloalkylene, and the C 1 -C 6 alkylene , C 3 -C 10 cycloalkylene may be optionally substituted by one or more R 9 , and said R 9 is selected from hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.
- said T and Z are independently selected from: chemical bond, carbonyl, methylene, 1,2-ethylene, 1,1-cyclopropylene or 2,2-propylene.
- the U is selected from: C 1 -C 6 alkylene, C 3 -C 10 cycloalkylene, arylene or heteroarylene, the alkylene, cycloalkylene , arylene, heteroarylene can be optionally substituted by one or more R 9 .
- said U is selected from: C 2 -C 6 alkylene, C 5 -C 6 cycloalkylene, C 6 -C 10 arylene, 5-6 membered monocyclic heteroarylene, said Alkylene, cycloalkylene, arylene, heteroarylene may be optionally substituted with one or more R 9 .
- the U is selected from: 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,3 -cyclopentylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,3-phenylene, 1,4-phenylene, 2,5-pyridinylene, 2,5- Pyrimidinyl, 2,5-thiazolyl or 2,4-thiazolyl, the 1,3-phenylene, 1,4-phenylene, 2,5-pyridinyl, 2,5- Pyrimidinylene, 2,5-thiazolylidene, 2,4-thiazolylidene can be optionally substituted by one or more R 9 .
- the R 9 is selected from: hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
- the R 9 is selected from: F, Cl, Br, methyl, methoxy or trifluoromethyl.
- said U is selected from the following groups:
- said U is selected from the following groups:
- the R 3 -R 5 are independently selected from: hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 alkylthio, C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, the alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl are optionally replaced by 1-3 two groups respectively selected from halogen, C 1 -C 3 alkyl or C 1- C 3 alkoxy; when there are multiple R 3 -R 5 , any adjacent two can be combined to form a ring.
- the R 3 -R 5 are independently selected from: hydrogen, halogen, cyano, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl.
- R 23 is selected from: hydrogen, C 1 -C 4 alkyl, all The C 1 -C 4 alkyl group is optionally substituted by 1-3 groups selected from hydroxyl and amino groups.
- R 23 is selected from: hydrogen, C 1 -C 4 alkyl, and the C 1 -C 4 alkyl is optionally substituted by 1-3 groups selected from hydroxyl and amino, respectively.
- the R 6 is selected from: hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and the alkyl and cycloalkyl are optionally selected from 1-3 respectively Halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy group substitution.
- the R 6 is selected from: hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl.
- the compound represented by the formula (I) is a compound represented by the formula (I-1) or formula (I-2):
- R 1 , R 3 -R 6 , Q, T, U, Z, Y, L, n, m are as defined above.
- the compound is a compound represented by formula (II) or formula (III) and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- R 1 , R 3 -R 6 , Q, T, U, Z, Y, L, n, m are as defined above.
- the compound is a compound represented by formula (IV) or formula (V) and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- R a , R b , L are as defined above;
- the R 91 is selected from: hydrogen, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 - C 6 alkylamino group, C 3 -C 8 cycloalkyl group, aryl group, 5-6 membered heteroaryl group containing 1-3 heteroatoms or 3-10 membered heterocyclic group containing 1-3 heteroatoms,
- the alkyl group, alkoxyl group, alkylamino group, alkylthio group, cycloalkyl group, aryl group, heteroaryl group and heterocyclyl group are optionally selected from halogen, cyano group, C 1 -C 3 alkyl or C 1- C 3 alkoxy group substitution.
- the R 92 -R 94 are independently selected from: hydrogen, C 1 -C 6 alkyl, or any adjacent two of R 92 -R 94 can be combined to form a cycloalkyl group.
- the R 92 -R 94 are independently selected from: hydrogen, methyl or ethyl, or R 92 and R 93 together form -CH 2 CH 2 -, or R 94 and R 95 together form -CH 2 CH2- .
- the compound is a compound represented by formula (IV') or formula (V') and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- R a , R b and R 91 are as defined above.
- the compound is a compound represented by formula (VI) and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- R a , R b , R 91 , and L are as defined above.
- the compound is a compound represented by formula (VI') and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- R a , R b and R 91 are as defined above.
- the compound is a compound represented by formula (VII) and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- R a , R b , R 2 , and L are as defined above.
- the R 2 is selected from: hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -SO 2 CH 3 , -CO cyclopropyl, 2-methoxyethyl, 2-cyano Ethyl, phenyl or benzyl.
- the compound is a compound represented by formula (VII') and pharmaceutically acceptable salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- R a , R b , R 2 are as defined above.
- R b in the present invention is selected from C 1 -C 4 alkyl, and the C 1 -C 4 alkyl is optionally substituted by one or more R 9 ; said R 9 is selected from: hydrogen, halogen, hydroxyl , amino, cyano, carboxyl.
- pharmaceutically acceptable salt is used to describe a salt form of one or more of the compounds described herein, provided for the purpose of increasing the solubility of the compound in the gastric juices of the gastrointestinal tract of a patient in order to facilitate the dissolution and bioactivity of the compound. Utilization.
- Pharmaceutically acceptable salts include, where applicable, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium, and many other acids and bases well known in the pharmaceutical art.
- the pharmaceutically acceptable salts of the present invention include hydrochloride, phosphate, hydrogen phosphate, dihydrogen phosphate, sulfate, nitrate, bicarbonate, carbonate, glutarate, hydrogen bromide salt, acetate, citrate, lactate, maleate, benzoate, methanesulfonate, oxalate, benzenesulfonate, p-toluenesulfonate, tartaric acid, malic acid Salt, succinate, ascorbate, gluconate, lactate, etc.
- solvate is selected from: hemihydrate, monohydrate, dihydrate, etc.
- stereoisomer is selected from: enantiomer or diastereoisomer, etc.
- prodrug is a compound A derivative of , which contains an additional moiety that is readily removed in vivo to yield the parent molecule as a pharmacologically active substance.
- An example of a prodrug is an ester, which is cleaved in vivo to yield the compound of interest.
- Another example is the N-methyl derivatives of compounds that are susceptible to oxidative metabolic mechanisms leading to N-demethylation.
- Prodrugs of a variety of compounds are known and may be adapted to the present invention, as well as materials and methods for derivatizing the parent compound to produce the prodrugs.
- Another object of the present invention is to provide a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the above compound and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof; the pharmaceutical composition MYC inhibitors, DNA methyltransferase inhibitors or Bcl-2 selective inhibitors can also be included in; the MYC inhibitors are OMO-103, APTO-253, PLX-51107, DCR-M1711, Oncomyc-NG, Any one or more of INX-3280, PU-27, GSK-3179106, cholesterol butyrate and NSC-165563; the DNA methyltransferase inhibitor is 5-azacytidine, RG108, SGI-1027 , GSK3685032, CM272, Bobcat339 hydrochloride, Decitabine (NSC 127716), Thioguanine (NSC 752), 2'-Deoxy-5-Fluorocytidine, Procainamide HCl or Zebularine (NS
- the pharmaceutical composition comprises a Bcl-2 selective inhibitor, and the Bcl-2 selective inhibitor is Venetoclax (ABT-199), Obatoclax Mesylate (GX15-070) or APG-2575 (CAS No. .2180923-05-9).
- Another object of the present invention is to provide the compounds of the present invention and their pharmaceutically available salts, solvates, stereoisomers, isotope prodrugs and the pharmaceutical composition in the preparation of c-Myc, N-myc, GSPT1, The use of any one or at least two or more of CK1 ⁇ , IKZF (1/2/3), AR and AR-V7 in protein degradation agents.
- Another object of the present invention is to provide the compounds of the present invention and their pharmaceutically available salts, solvates, stereoisomers, isotopes, prodrugs and the pharmaceutical compositions used in the preparation of therapeutic c-Myc, N-myc, Use of any one or at least two or more of GSPT1, CK1 ⁇ , IKZF (1/2/3), AR and AR-V7 in medicine for diseases related to protein imbalance.
- Another object of the present invention is to provide the compounds of the present invention and pharmaceutically available salts, solvates, stereoisomers, isotopes, prodrugs and the pharmaceutical composition in the treatment of c-Myc, N-myc, GSPT1 , CK1 ⁇ , IKZF(1/2/3), AR and AR-V7, or any one or at least two or more of protein disorders related diseases.
- said protein dysregulation is selected from protein overexpression.
- the protein disorder-related diseases are selected from: cancer, cardiovascular and cerebrovascular diseases, viral infection-related diseases, and the like.
- the cancer is selected from the group consisting of: leukemia, lymphoma, malignant glioma, medulloblastoma, melanoma, multiple myeloma, myelodysplastic syndrome, liver cancer, lung cancer, kidney cancer, pancreatic cancer, oral cancer, gastric cancer, esophageal cancer, laryngeal cancer, nasopharyngeal cancer, skin cancer, breast cancer, colon cancer, rectal cancer, cervical cancer, ovarian cancer, prostate cancer, rhabdomyosarcoma, osteosarcoma, chondrosarcoma; Disease is selected from: HIV, hepatitis B, hepatitis C, hepatitis A, influenza, Japanese encephalitis, herpes etc.; Described leukemia comprises chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) , acute non-lymphocytic
- the present invention provides the compounds of the present invention and their pharmaceutically available salts, solvates, stereoisomers, isotopes, prodrugs and the pharmaceutical composition in the preparation of drugs for the treatment of acute myeloid leukemia (AML) the use of.
- the pharmaceutical composition comprises a Bcl-2 selective inhibitor, and the Bcl-2 selective inhibitor is Venetoclax (ABT-199), Obatoclax Mesylate (GX15-070) or APG-2575 (CAS No. .2180923-05-9).
- the compounds of the present invention and their pharmaceutically available salts, solvates, stereoisomers, isotopes, and prodrugs are used in combination or in combination with Bcl-2 selective inhibitors; for example, compounds A1-A236 of the present invention and Bcl-2
- Bcl-2 selective inhibitors for example, compounds A1-A236 of the present invention and Bcl-2
- ABT-199 can solve the problem of drug resistance in the treatment of acute myeloid leukemia (AML) by simply using the Bcl-2 selective inhibitor venetoclax (ABT-199).
- Another object of the present invention is to provide the compounds of the present invention and pharmaceutically available salts, solvates, stereoisomers, isotopes and prodrugs thereof for the preparation of proteolysis targeting chimera (proteolysis targeting chimera, PROTAC) Or use in antibody-drug conjugate (ADC).
- proteolysis targeting chimera proteolysis targeting chimera, PROTAC
- ADC antibody-drug conjugate
- the compounds provided by the present invention have excellent degradation effects on any one or more proteins including c-Myc, N-myc, GSPT1, CK1 ⁇ , IKZF (1/2/3), AR and AR-V7, etc. , so that it can be used to prevent, alleviate or treat any one of the above (such as c-Myc) or diseases related to high expression of multiple proteins, such as the prevention and treatment of various diseases such as cancer, cardiovascular and cerebrovascular diseases, and viral infections.
- the compound The synthesis method of the invention is simple and convenient, and the protein degradation effects of c-Myc, N-myc, GSPT1, CK1 ⁇ , IKZF(1/2/3), AR and AR-V7 are exact and remarkable.
- connection point representing a connected part.
- unsubstituted shall mean substituted by hydrogen atoms only.
- substituted or “optionally substituted” refers to the presence of one or more substituents independently at any carbon (or nitrogen) position in the molecule, preferably 1-5 substituents, most preferably 1-3 Substituents, which can be: hydroxyl, mercapto, carboxyl, cyano, nitro, halogen (preferably 1, 2 or 3 halogen, especially on alkyl, especially methyl, for example trifluoromethyl), Alkyl (preferably C 1 -C 10 , more preferably C 1 -C 6 ), haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl (especially phenyl), heteroaryl, heterocyclyl, Alkoxy (preferably C 1 -C 6 alkoxy), aryloxy (preferably phenoxy), thioether (C 1 -C 6 alkylthio or arylthio such as phenylthio), acyl (preferably C 1 -C 6 acyl
- alkyl refers to a straight chain, branched fully saturated hydrocarbon group or alkyl group which may be optionally substituted, preferably C 1 -C 10 , more preferably C 1 -C 6 , or C 1 -C 4 alkyl.
- alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl base, n-decyl, etc.
- alkylene refers to a divalent group formed by further removing a hydrogen atom from an alkyl group.
- cycloalkyl refers to a cyclic hydrocarbon group or alkyl group which may be optionally substituted, preferably C 3 -C 20 , more preferably C 3 -C 15 , or C 3 -C 8 alkyl.
- Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cycloheptyl and the like.
- cycloalkylene refers to a divalent group formed by further removing a hydrogen atom from a cycloalkyl group.
- bridged ring group refers to a ring structure formed by two or more ring structures that may be optionally substituted and share two non-adjacent carbon atoms with each other, preferably C 5 -C 15 , more preferably C 6 -C 12 , or C 7 -C 10 bridged ring group.
- Examples of bridged ring groups are norbornyl, adamantyl and the like.
- alkenyl refers to a straight chain, branched chain or cyclic C 2 -C 10 (preferably C 2 -C 8 ) hydrocarbon group containing at least one C ⁇ C bond.
- alkynyl refers to a straight chain, branched chain or cyclic C 2 -C 10 (preferably C 2 -C 8 ) hydrocarbon group containing at least one C ⁇ C bond.
- aryl refers to a C6-C16 aromatic group having a single ring (such as phenyl) or a condensed ring (such as naphthyl, anthracenyl, phenanthrenyl, fluorenyl, etc.) that can be optionally substituted, preferably C6-C10 aromatic group.
- arylene refers to a divalent group formed by further removing a hydrogen atom from an aryl group.
- heteroaryl refers to an optionally substituted 5-16 membered aromatic group containing one or more heteroatoms selected from N, O, S or P, preferably a 5-10 membered aromatic group
- heteroaryl groups include imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl , pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, benzopyrazolyl, benzofuryl, benzothienyl, benzothiazolyl, dibenzofuryl, diphenyl Thienyl, quinolinyl, isoquinolyl, naphthyridinyl, carbazolyl, azacarbazolyl (such as 1-azacarbazo
- heteroarylene refers to a divalent group formed by removing a hydrogen atom from a heteroaryl group.
- heterocyclyl refers to a partially or fully unsaturated 3-20 membered optionally substituted containing one or more heteroatoms selected from N, O, S, SO, SO or P Cyclic group, preferably 3-10 membered cyclic group, more preferably 3-6 membered cyclic group; said heterocyclic group contains 1-19 carbon atoms, preferably contains 2-10 carbon atoms, more preferably contains 3-5 carbon atoms atom.
- heterocyclyl groups include: aziridinyl, oxiranyl, azetidinyl, oxetanyl, 1,4-benzodioxanyl, 1,3-benzo Dioxolyl, dihydroimidazolyl, dihydropyranyl, dihydrofuryl, dioxanyl, ethyleneureido, 1,3-dioxolyl, 1, 3-dioxanyl, 1,4-dioxanyl, imidazolinyl, indolinyl, morpholinyl, pyridone, 2-pyrrolidone, piperazinyl, homopiperazinyl, piperidinyl, homo Piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydr
- heterocyclylene refers to a divalent group formed by further removing a hydrogen atom from a heterocyclic group.
- heterocycloalkyl refers to a fully saturated heterocyclyl group.
- fused arylcycloalkyl refers to a group in which the above-mentioned aryl is fused with a cycloalkyl.
- fused heteroarylheterocyclic group refers to a group in which the above-mentioned heteroaryl group and heterocyclic group are fused.
- halogen refers to F, Cl, Br, I.
- pharmaceutically acceptable carrier may mean any and all solvents, dispersion media, coatings, antibacterial and antibiotics, etc., compatible with pharmaceutical administration.
- the term “compound” refers to any specific compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (for enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof.
- the term compound generally refers not only to a single compound, but may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures), as well as the disclosed compounds A specific enantiomer or an enantiomerically enriched mixture.
- the term also in this context refers to prodrug forms of the compound which have been modified to facilitate administration and delivery of the compound to the active site.
- protein proteolysis targeting chimeras is a hybrid bifunctional small molecule compound (Sakamoto KM. et al. Proc Natl Acad Sci U S A, 2001, 98:8554-8559), It includes a small molecular compound that can bind to the target protein (protein of interst, POI), connect the group at its proper position, and then connect with a small molecular compound that can bind to E3 ubiquitin ligase.
- ADC antibody-drug conjugate
- Fig. 1 is the degradation result of the compound of the present invention to various proteins in HL60 cells
- Fig. 2 is the degradation result of the compound of the present invention to c-Myc and n-Myc protein in H69 cells;
- Fig. 3 is the result of degradation of c-Myc protein in Ramos and MM1S cells by the compound of the present invention.
- PE petroleum ether EA ethyl acetate; THF tetrahydrofuran; MTBE methyl tert-butyl ether; TFA trifluoroacetic acid; DCM dichloromethane; HATU 2-(7-azabenzotriazole)-N,N,N ',N'-Tetramethylurea hexafluorophosphate; TEA triethylamine; DMF N,N-dimethylformamide; LDA lithium diisopropylamide; DEAD diethyl azodicarboxylate; DCE dichloro Ethane; Selectfluor selective fluorine reagent; DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone; DIPEAN, N-diisopropylethylamine; DPPA diphenylphosphoryl azide; DBU 1,8 -Diazabicycloundec-7-ene; NBS N-bromosuccinimide
- Carbazole (200mg, 1.20mmol) was dissolved in anhydrous THF (6mL), and sodium hydride (69mg, 60%, 1.73mmol) was added slowly under ice-cooling. After the reaction at room temperature for 30 min, the compound 3-bromopropionate methyl ester (240 mg, 1.44 mmol) was added. After stirring and reacting at room temperature for 2 h, the raw materials were completely reacted as monitored by TLC thin-plate chromatography.
- Carbazole (100mg, 0.6mmol) was dissolved in DMF (4mL), and sodium hydride (96mg, 60%, 2.4mmol) was added in batches under ice-cooling until the bubbles completely disappeared, and reacted at room temperature for 1h.
- Methyl 2-bromoisobutyrate 140 mg, 0.77 mmol was further added thereto. After reacting at room temperature for 1 h, it was refluxed at 100°C for 2 h. The completion of the reaction was monitored by a TLC plate. After cooling to room temperature, dilute hydrochloric acid was added to adjust the pH to neutral, extracted with ethyl acetate (30 mL*3), and the organic phases were combined.
- A214-1 (72.2 g, 404.2 mmol) was dissolved in 620 mL of ethanol, and 25% aqueous sodium hydroxide solution (320 mL) was added thereto under ice cooling. After reacting at 100° C. for 4 h, TLC showed that the reaction was complete. After cooling to room temperature, 6N hydrochloric acid was added thereto to adjust the pH to 4. The aqueous phase was extracted with dichloromethane (300 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, and spin-dried to obtain compound A214-2 (73.6 g, yield 92%).
- A214-2 (22.6 g, 114.4 mmol) was dissolved in toluene (225 mL), and triethylamine (11.57 g, 114.4 mmol) and DPPA (31.5 g, 114.4 mmol) were added thereto. After reacting at 100° C. for 1 h, 12N hydrochloric acid (38 mL) was added thereto and the reaction was continued for 1 h. After cooling to room temperature, ice water (50 mL) was added to quench the reaction. After adding solid sodium bicarbonate thereto to adjust the pH to 8, (Boc) 2 O (37.42 g, 171.54 mmol) was added. After overnight reaction at room temperature, 400 mL of water was added thereto.
- the aqueous phase was extracted with ethyl acetate (200 mL*2).
- the organic phases were combined and dried over anhydrous sodium sulfate and spin-dried.
- A214-4 (10.5 g, 40.5 mmol) was dissolved in 50 mL of ethyl acetate, to which was added HCl/EtOAc (4M, 160 mL). After reacting at room temperature for half an hour, TLC showed that the reaction was complete. The solvent was spin-dried to obtain compound A214-5 (10.3 g, crude product).
- A1-5 (430 mg, 1.42 mmol) was dissolved in 5 mL of DMF, and HATU (650 mg, 1.70 mmol) was added thereto. After reacting at room temperature for 30 min, A103-4 (360 mg, 1.42 mmol) and DIPEA (275 mg, 2.13 mmol) were added thereto. After reacting at room temperature for 1 h, TLC showed that the reaction was complete. Ethyl acetate (30 mL) was added thereto for dilution. The organic phase was washed with saturated brine (10 mL*3), dried and spin-dried.
- A1-5 (1.17 g, 3.89 mmol) was dissolved in 30 mL of DMF, and HATU (1.77 g, 4.67 mmol) was added thereto. After reacting at room temperature for 30 min, compound A111-5 (1.03 g, 3.89 mmol) and DIPEA (760 mg, 5.84 mmol) were added thereto. After reacting at room temperature for 1 h, TLC showed that the reaction was complete. After dilution with water (50 mL), the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (10 mL*3), dried and spin-dried.
- A124-2 (4.69 g, 14.0 mmol) was dissolved in 25 mL HCl/dioxane (4M). After reacting at room temperature for 1 h, TLC showed that the reaction was complete. The solvent was spin-dried to obtain compound A124-3 (2.50 g, crude product).
- A124-3 (1.72g, 12.9mmol), A1-5 (3.06g, 12.9mmol), N-methylimidazole (2.58g, 80.2mmol) were dissolved in 30mL of acetonitrile, and TCFH (3.42g, 20.7 mmol). After reacting at room temperature for 1 h, TLC showed that the reaction was complete. 20 mL of ethyl acetate/water (1:1) was added to the reaction solution, and the precipitated solid was suction-filtered to obtain compound A124-4 (1.55 g, yield 32%).
- A133-1 (5.0 g, 21.2 mmol) was dissolved in 50 mL of DMF, and sodium azide (4.82 g, 74.1 mmol) was added thereto. After reacting at room temperature for 1 h, TLC showed that the reaction was complete. Add water (100 mL) to dilute, and extract the aqueous phase with ethyl acetate (150 mL*2). The combined organic phases were washed with saturated brine (100 mL), dried and spin-dried to obtain compound A133-2 (4.5 g, crude product).
- Methyl 4-bromo-2-methylbenzoate (30.0 g, 131 mmol) was dissolved in 300 mL of carbon tetrachloride, and NBS (28 g, 131 mmol) and AIBN (6.4 g, 40 mmol) were added thereto. After reacting at 80° C. for 1 h, TLC showed that the reaction was complete. After adding 150mL of MTBE to dilute, filter. The filtrate was washed with saturated aqueous sodium bicarbonate (30 mL*3). The organic phase was dried and spin-dried to obtain compound A153-1 (48 g, crude product).
- A153-1 (48 g, 131 mmol) was dissolved in 450 mL of DMF, to which 3-aminopiperidine-2,6-dione hydrochloride (28 g, 172 mmol) and potassium carbonate (65 g, 469 mmol) were added. After reacting at 70° C. for 1 h, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was spun to remove most of the solvent. Slurry with 200mL dichloromethane/water (1:1), and filter with suction. The filter cake was dried to obtain compound A152-2 (19 g, yield 38%).
- the compound 2-fluoro-5-methylaniline (24.34g, 0.195mol) was dissolved in DMF (240ml), and NBS (34.62g, 0.195mol) was added in batches under ice cooling. After the addition was completed, after half an hour of reaction at room temperature, TLC showed that the reaction was complete. The reaction was quenched by adding 450 mL of ice water. The aqueous phase was extracted with ethyl acetate (500ml*3). The organic phases were combined and washed with saturated brine (100 mL*3). Add anhydrous sodium sulfate to dry, spin dry. Add methyl tert-butyl ether and beat to obtain A222-1 (32.11g, yield 81%).
- Tetramethylpiperidine (27.73 mL, 0.163 mol) was dissolved in anhydrous THF (110 ml), and n-butyllithium solution (2.5M, 63.1 mL, 0.157 mol) was added dropwise thereto at 0°C. After reacting for 30 minutes, the temperature was lowered to -45°C, and a THF solution (50 mL) of 4-bromo-3-fluorobenzoic acid (14.33 g, 0.065 mol) was added dropwise to the reaction solution. After reacting for 2.5 h, DMF (7.6 mL) was added dropwise thereto. After the addition was completed, it was raised to room temperature to continue the reaction for 1h.
- A223-1 (16.6g, 0.065mol) and 3-amino-2,6-piperidinedione hydrochloride (16.65g, 0.101mol) were dissolved in DMF (165mL), and three Sodium acetoxyborohydride (35.73 g, 0.168 mol). After the addition was completed, the reaction was continued at room temperature for 2 h, and TLC showed that the reaction was complete. Ice water (400 mL) was added thereto under ice cooling to quench the reaction. The mixture was filtered, and the filter cake was rinsed with methyl tert-butyl ether and dried to obtain compound A223-2 (9.8 g, yield 43%).
- Embodiment 3 is a diagrammatic representation of Embodiment 3
- Embodiment 4 is a diagrammatic representation of Embodiment 4:
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Abstract
Description
Claims (42)
- 式(I)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药:其中,R 1选自:R aC(=O)-、R aCH 2C(=O)-、R aCH 2CH 2C(=O)-、R a-、R aCH 2-、R aCH 2CH 2-、R aNHC(=O)-、R aCH 2NHC(=O)-、R aCH 2CH 2NHC(=O)-、R aOC(=O)-、R aCH 2OC(=O)-、R aCH 2CH 2OC(=O)-、R aS(=O) 2-、R aCH 2S(=O) 2-或R aCH 2CH 2S(=O) 2-,所述“CH 2”任选被一个或更多个C 1-C 4烷基取代,或者任选被-CH 2CH 2-取代,所述“NH”任选被R b-、R bC(=O)-或者R bS(=O) 2-取代;Q选自:-NR 2-、-O-;R 2选自:氢、R b-、R bC(=O)-、R bS(=O) 2-;R a、R b分别独立地选自:C 1-C 8烷基、C 3-C 10环烷基、C 3-C 10桥环基、-NR 11R 12、C 3-C 10任含O、S、SO 2、N或NHC(=O)R 22的杂环基、芳基、杂芳基、稠合芳基环烷基、稠合杂芳基杂环基、芳基-环烷基、芳基-杂环基、环烷基-杂环基、杂环基-杂环基,所述C 1-C 8烷基中的任意两个C-C之间可以插入选自-O-、-S-、-C(=O)-、-S(=O)-、-S(=O) 2-、-NH-、-NHC(=O)-、-NHC(=O)NH-、-NHS(=O) 2-中的一种的基团,R a、R b可任选的被一个或多个R 9取代;T、U、Z分别独立地选自:化学键、羰基、C 1-C 6亚烷基、C 3-C 10亚环烷基、亚芳基、亚杂芳基、亚杂环基,所述亚烷基、亚环烷基、亚芳基、亚杂芳基、亚杂环基可任选的被一个或多个R 9取代;Y选自:化学键、-NHC(=O)-、-C(=O)NH-、-C(=O)NHCH 2-、-NHC(=O)CH 2-、-O-、-OCH 2-、-OCH 2CH 2-、-NH-、-NHCH 2-、-NHCH 2CH 2-,所述“CH 2”任选被一个或更多个C 1-C 4烷基取代,或者任选被-CH 2CH 2-取代,所述“NH”任选被R b-、R bC(=O)-或者R bS(=O) 2-取代;L选自:-(CR 7R 8) o-、-C(=O)-;R 3-R 5、R 7-R 9分别独立地选自:氢、卤素、羟基、氰基、氨基、硝基、-R 21NHC(=O)R 22、-R 21C(=O)OR 22、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 6烷胺基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基,所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、氰基、C 1-C 3烷基或C 1-C 3烷氧基的基团取代;当R 3-R 5、R 7-R 9为多个的情况下,任意相邻两个可结合形成环;R 6选自:氢、C 1-C 6烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基,所述烷基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、羟基、氰基、氨基、硝基、-C(=O)OR 23、-OC(=O)R 23、-NHC(=O)R 23、-C(=O)NHR 23、C 1-C 3烷基、C 1-C 3烷氧基或-OP(=O)(OM) 2的基团取代;M独立地选自:氢、C 1-C 4烷基;R 11、R 12分别独立地选自:氢、C 1-C 4烷基、芳基;R 21选自:C 1-C 4烷基;R 22选自:氢、氨基、C 1-C 4烷基、C 1-C 4烷氧基、烯丙基或苄基,所述C 1-C 4烷基、C 1-C 4烷氧基、烯丙基或苄基任选的被芳基、-C(=O)OR 21所取代;R 23选自:氢、C 1-C 4烷基,所述C 1-C 4烷基任选被1-3个分别选自卤素、羟基、氨基的基团取代;n选自:0、1、2或3;m选自:0、1、2、3或4;o选自:1或2。
- 式(I)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药:其中,R 1选自:R aC(=O)-、R aCH 2C(=O)-、R aCH 2CH 2C(=O)-、R a-、R aCH 2-、R aCH 2CH 2-、R aNHC(=O)-、R aCH 2NHC(=O)-、R aCH 2CH 2NHC(=O)-、R aOC(=O)-、R aCH 2OC(=O)-、R aCH 2CH 2OC(=O)-、R aS(=O) 2-、R aCH 2S(=O) 2-或R aCH 2CH 2S(=O) 2-,所述“CH 2”任选被一个或更多个C 1-C 4烷基取代,或者任选被-CH 2CH 2-取代,所述“NH”任选被C 1-C 4烷基取代;Q选自:-NR 2-、-O-;R 2选自:氢、R b-、R bC(=O)-、R bS(=O) 2-;R a、R b分别独立地选自:C 1-C 8烷基、C 3-C 10环烷基、C 3-C 10桥环基、-NR 11R 12、C 3-C 10任含O、S、SO 2、N或NHC(=O)R 22的杂环基、芳基、杂芳基、稠合芳基环烷基、稠合杂芳基杂环基、芳基-环烷基、芳基-杂环基、环烷基-杂环基、杂环基-杂环基,R a、R b可任选的被一个或多个R 9取代;T、U、Z分别独立地选自:化学键、羰基、C 1-C 6亚烷基、C 3-C 10亚环烷基、亚芳基、亚杂芳基、亚杂环基,所述亚烷基、亚环烷基、亚芳基、亚杂芳基、亚杂环基可任选的被一个或多个R 9取代;Y选自:化学键、-NHC(=O)-、-C(=O)NH-、-C(=O)NHCH 2-、-NHC(=O)CH 2-、-O-、-OCH 2-、-OCH 2CH 2-、-NH-、-NHCH 2-、-NHCH 2CH 2-,所述“CH 2”任选被一个或更多个C 1-C 4烷基取代,或者任选被-CH 2CH 2-取代,所述“NH”任选被C 1-C 4烷基取代;L选自:-(CR 7R 8) o-、-C(=O)-;R 3-R 5、R 7-R 9分别独立地选自:氢、卤素、羟基、氰基、氨基、-R 21NHC(=O)R 22、-R 21C(=O)OR 22、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 6烷胺基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基,所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、氰基、C 1-C 3烷基或C 1-C 3烷氧基的基团取代;当R 3-R 5、R 7-R 9为多个的情况下,任意相邻两个可结合形成环;R 6选自:氢、C 1-C 6烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基,所述烷基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、氰基、C 1-C 3烷基或C 1-C 3烷氧基的基团取代;R 11、R 12分别独立地选自:氢、C 1-C 4烷基、芳基;R 21选自:C 1-C 4烷基;R 22选自:氢、氨基、C 1-C 4烷基、C 1-C 4烷氧基、烯丙基或苄基,所述C 1-C 4烷基、C 1-C 4烷氧基、烯丙基或苄基任选的被芳基、-C(=O)OR 21所取代;n选自:0、1、2或3;m选自:0、1、2、3或4;o选自:1或2。
- 权利要求1或2所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R 1选自:R aC(=O)-、R aCH 2C(=O)-、R aCH 2CH 2C(=O)-、R a-、R aCH 2-、R aCH 2CH 2-、R aNHC(=O)-、R aCH 2NHC(=O)-、R aCH 2CH 2NHC(=O)-、R aOC(=O)-或R aCH 2OC(=O)-、R aCH 2CH 2OC(=O)-,所述“CH 2”任选被一个或更多个C 1-C 4烷基取代,或者任选被-CH 2CH 2-取代,所述“NH”任选被R b-、R bC(=O)-或者R bS(=O) 2-取代,所述R b选自C 1-C 4烷基,该C 1-C 4烷基任选被一个或多个R 9取代,所述R a选自:C 1-C 8烷基、-NR 11R 12、芳基、杂芳基,R a可任选的被一个或多个R 9取代;优选的,所述R 1选自:R aC(=O)-、R aCH 2C(=O)-、R aCH 2CH 2C(=O)-、R a-、R aCH 2-、R aCH 2CH 2-、R aNHC(=O)-、R aCH 2NHC(=O)-、R aCH 2CH 2NHC(=O)-、R aOC(=O)-或R aCH 2OC(=O)-、R aCH 2CH 2OC(=O)-,所述“CH 2”任选被一个或更多个C 1-C 4烷基取代,或者任选被-CH 2CH 2-取代,所述“NH”任选被C 1-C 4烷基取代,所述R a选自:C 1-C 8烷基、-NR 11R 12、芳基、杂芳基,R a可任选的被一个或多个R 9取代。
- 权利要求1-3任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R a选自:C 2-C 6烷基、咔唑基、1-氮杂咔唑基、2-氮杂咔唑基、1,8-二氮杂咔唑基、吲哚基、吩噁嗪基、萘基、芴基、二苯胺基、二苄基胺基、叔丁基、喹啉基、异喹啉基、苯基、2,3-二氢吲哚基、7-氮杂吲哚基、2,3-二氢-7-氮杂吲哚基、萘啶基、四氢萘啶基、四氢喹啉基、嘧啶基或三唑基,R a 可任选的被一个或多个R 9取代,所述R 9选自氢、卤素、C 1-C 6烷氧基、氰基、C 1-C 6烷基、任选被1-3个选自卤素或羟基的基团取代的C 1-C 6烷基、苯基、萘基;优选的,所述R a选自:C 2-C 6烷基、咔唑基、1-氮杂咔唑基、2-氮杂咔唑基、1,8-二氮杂咔唑基、吲哚基、吩噁嗪基、萘基、芴基、二苯胺基、二苄基胺基、叔丁基、喹啉基、异喹啉基或苯基,R a可任选的被一个或多个R 9取代,所述R 9选自氢、卤素、C 1-C 6烷氧基、氰基、C 1-C 6烷基、任选被1-3个选自卤素的基团取代的C 1-C 6烷基。
- 权利要求1-4任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R a选自叔丁基、咔唑-1-基、1-氮杂咔唑-9-基、2-氮杂咔唑-9-基、1,8-二氮杂咔唑-9-基、吲哚-1-基、吩噁嗪-10-基、萘-1-基、萘-2-基、芴-9-基、二苯胺基、二苄基胺基、叔丁基、喹啉-4-基、喹啉-5-基、喹啉-8-基、异喹啉-1-基、异喹啉-4-基、异喹啉-5-基、异喹啉-8-基、苯基、2,3-二氢-吲哚-1-基、7-氮杂吲哚基-1-基、2,3-二氢-7-氮杂吲哚基-1-基、1,2,3,4-四氢-1,8-萘啶-1-基、1,2,3,4-四氢喹啉-1-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、1,2,3-三唑-1-基、1,2,4-三唑-1-基或1,3,4-三唑-1-基,R a可任选的被一个或多个R 9取代,所述R 9选自F、Cl、Br、甲氧基、乙氧基、氰基、甲基、乙基、三氟甲基、羟甲基、苯基、萘-1-基、萘-2-基;优选的,所述R a选自叔丁基、咔唑-1-基、1-氮杂咔唑-9-基、2-氮杂咔唑-9-基、1,8-二氮杂咔唑-9-基、吲哚-1-基、吩噁嗪-10-基、萘-1-基、萘-2-基、芴-9-基、二苯胺基、二苄基胺基、叔丁基、喹啉-4-基、喹啉-5-基、喹啉-8-基、异喹啉-1-基、异喹啉-4-基、异喹啉-5-基、异喹啉-8-基或苯基,R a可任选的被一个或多个R 9取代,所述R 9选自F、Cl、Br、甲氧基、乙氧基、氰基、甲基、乙基、三氟甲基。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述Q选自:-NR 2-;所述R 2选自:氢、C 1-C 8烷基、C 3-C 10环烷基、芳基、C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-,所述C 1-C 8烷基、C 3-C 10环烷基、芳基以及C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-的烷基部分任选的被一个或多个R 9取代,所述R 9选自:氢、卤素、羟基、氨基、氰基、羧基、C 1-C 6烷基、C 1-C 6烷氧基或芳基;优选的,所述Q选自:-NR 2-;所述R 2选自:氢、C 1-C 8烷基、C 3-C 10环烷基、芳基、C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-,所述C 1-C 8烷基、C 3-C 10环烷基、芳基以及C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-的烷基部分任选的被一个或多个R 9取代,所述R 9选自:氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基或芳基。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述Q选自:-NH-、-O-、-N(CH 3)-、-N(SO 2CH 3)-、-N(COCH 3)-、-N(CO-异丙基)-、-N(CO-环丙基)-、-N(异丙基)-、-N(环丙基)-、-N(2-甲氧基乙基)-、-N(2-氰基乙基)-、-N(苯基)-、-N(苄基)-、-N(1-萘甲基)-、-N(2-萘乙基)-、-N(CH 2OH)-、-N(CH 2CH 2OH)-、-N(CH 2CH 2CH 2OH)-、-N(COCH 2OH)-、-N(COCH 2CH 2OH)-、-N(COCH 2CH 2CH 2OH)-、-N(CH 2NH 2)-、-N(CH 2CH 2NH 2)-、-N(COCH 2CH 2CH 2NH 2)-、-N(COCH 2NH 2)-、-N(COCH 2CH 2NH 2)-或-N(COCH 2CH 2CH 2NH 2)-;优选的,所述Q选自:-NH-、-O-、-N(CH 3)-、-N(SO 2CH 3)-、-N(COCH 3)-、-N(CO-异丙基)-、-N(CO-环丙基)-、-N(异丙基)-、-N(环丙基)-、-N(2-甲氧基乙基)-、-N(2-氰基乙基)-、-N(苯基)-或-N(苄基)-。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述T、Z分别独立地选自:化学键、羰基、C 1-C 6亚烷基或C 3-C 10亚环烷基,所述C 1-C 6亚烷基、C 3-C 10亚环烷基可任选的被一个或多个R 9取代,所述R 9选自氢、C 1-C 6烷基或C 3-C 8环烷基;优选的,所述T、Z分别独立地选自:化学键、羰基、亚甲基、1,2-亚乙基、1,1-亚环丙基或2,2-亚丙基。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述U选自:C 1-C 6亚烷基、C 3-C 10亚环烷基、亚芳基或亚杂芳基,所述亚烷基、亚环烷基、亚芳基、亚杂芳基可任选的被一个或多个R 9取代;优选的,所述U选自:C 2-C 6亚烷基、C 5-C 6亚环烷基、C 6-C 10亚芳基、5-6元单环亚杂芳基,所述亚烷基、亚环烷基、亚芳基、亚杂芳基可任选的被一个或多个R 9取代。
- 权利要求1或10所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述U选自:1,2-亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基、1,6-亚己基、1,3-亚环戊基、1,3-亚环己基、1,4-亚环己基、1,3-亚苯基、1,4-亚苯基、2,5-亚吡啶基、2,5-亚嘧啶基、2,5-亚噻唑基或2,4-亚噻唑基,所述1,3-亚苯基、1,4-亚苯基、2,5-亚吡啶基、2,5-亚嘧啶基、2,5-亚噻唑基、2,4-亚噻唑基可任选的被一个或多个R 9取代。
- 权利要求10或11所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R 9选自:氢、卤素、氰基、C 1-C 6烷基或C 1-C 6烷氧基;优选的,所述R 9选自:氢、卤素、C 1-C 6烷基或C 1-C 6烷氧基;还优选的,所述R 9选自:F、Cl、Br、氰基、甲基、甲氧基或三氟甲基;最优选的,所述R 9选自:F、Cl、Br、甲基、甲氧基或三氟甲基。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述Y选自:化学键、-NHC(=O)-、-C(=O)NH-、-C(=O)NHCH 2-、-NHC(=O)CH 2-、-O-、-OCH 2-、-OCH 2CH 2-、-NH-、-NHCH 2-、-N(CH 3)CH 2-,所述“NH”任选被R b-、R bC(=O)-或者R bS(=O) 2-取代,所述R b选自C 1-C 4烷基,该C 1-C 4烷基任选被一个或多个R 9取代;优选的,所述Y选自:化学键、-NHC(=O)-、-C(=O)NH-、-C(=O)NHCH 2-、-NHC(=O)CH 2-、-O-、-OCH 2-、-OCH 2CH 2-、-NH-、-NHCH 2-、-N(CH 3)CH 2-、-N(CH 2OH)CH 2-、-N(CH 2CH 2OH)CH 2-、-N(CH 2CH 2CH 2OH)CH 2-、-N(COCH 2OH)CH 2-、-N(COCH 2CH 2OH)CH 2-、-N(COCH 2CH 2CH 2OH)CH 2-、-N(CH 2NH 2)CH 2-、-N(CH 2CH 2NH 2)CH 2-、-N(COCH 2CH 2CH 2NH 2)CH 2-、-N(COCH 2NH 2)CH 2-、-N(COCH 2CH 2NH 2)CH 2-、-N(COCH 2CH 2CH 2NH 2)CH 2-;更优选的,所述Y选自:化学键、-NHC(=O)-、-C(=O)NH-、-C(=O)NHCH 2-、-NHC(=O)CH 2-、-O-、-OCH 2-、-OCH 2CH 2-、-NH-、-NHCH 2-、-N(CH 3)CH 2-;更优选的,所述Y选自-NHC(=O)-、-C(=O)NH-、-NHCH 2-。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述L选自:-CH 2-、-CH 2CH 2-、-C(=O)-;优选的,所述L选自:-CH 2-、-C(=O)-。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R 6选自:氢、C 1-C 6烷基、C 3-C 8环烷基,所述烷基、环烷基任选被1-3个分别选自卤素、羟基、氰基、氨基、-C(=O)OR 23、-OC(=O)R 23、-NHC(=O)R 23、-C(=O)NHR 23或-OP(=O)(OM) 2的基团取代。
- 权利要求1所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R 6选自:氢、C 1-C 4烷基、C 1-C 4卤代烷基、-CH 2OC(=O)R 23、-CH 2CH 2OC(=O)R 23、-CH 2C(=O)OR 23、-CH 2CH 2C(=O)OR 23、-CH 2OP(=O)(OH) 2、-CH 2CH 2OP(=O)(OH) 2;R 23选自:氢、C 1-C 4烷基,所述C 1-C 4烷基任选被1-3个分别选自羟基、氨基的基团取代。
- 根据前述权利要求任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述式(I)所示的化合物为式(IV)或式(V)所示的化合物:其中,所述R aCH 2C(=O)NH-、-C(R 94)(R 95)NHC(=O)-、-C(R 94)(R 95)C(=O)NH-中的“NH”任选被R b-、R bC(=O)-或者R bS(=O) 2-取代;R a、R b、L定义同前;R 91-R 95分别独立地选自:氢、卤素、羟基、氰基、氨基、-R 21NHC(=O)R 22、-R 21C(=O)OR 22、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 6烷胺基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基,所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、氰基、C 1-C 3烷基或C 1-C 3烷氧基的基团取代;当R 92-R 94中任意相邻两个可结合形成环。
- 根据权利要求21所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R 91选自:氢、卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 6烷胺基、C 3-C 8环烷基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基,所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、氰基、C 1-C 3烷基或C 1-C 3烷氧基的基团取代;所述R 92-R 94分别独立地选自:氢、C 1-C 6烷基,或者R 92-R 94中任意相邻两个可结合形成环烷基;优选地,所述R 92-R 94分别独立地选自:氢、甲基或乙基,或者R 92与R 93一起形成-CH 2CH 2-,或者R 94与R 95一起形成-CH 2CH 2-。
- 根据权利要求26所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药,其特征在于,所述R 2选自:氢、C 1-C 8烷基、C 3-C 10环烷基、芳基、C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-,所述C 1-C 8烷基、C 3-C 10环烷基、芳基以及C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-的烷基部分任选的被一个或多个R 9取代,所述R 9选自:氢、卤素、羟基、氨基、氰基、C 1-C 6烷基、C 1-C 6烷氧基或芳基;优选的,所述R 2选自:氢、甲基、乙基、异丙基、环丙基、-SO 2CH 3、-CO环丙基、2-甲氧基乙基、2-氰基乙基、2-羟基乙基、2-氨基乙基、苯基、苄基、1-萘甲基、2-萘乙基;优选的,所述R 2选自:氢、C 1-C 8烷基、C 3-C 10环烷基、芳基、C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-,所述C 1-C 8烷基、C 3-C 10环烷基、芳基以及C 1-C 8烷基C(=O)-或C 1-C 8烷基S(=O) 2-的烷基部分任选的被一个或多个R 9取代,所述R 9选自:氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基或芳基;优选的,所述R 2选自:氢、甲基、乙基、异丙基、环丙基、-SO 2CH 3、-CO环丙基、2-甲氧基乙基、2-氰基乙基、苯基或苄基。
- 一种药物组合物,其特征在于,包含药学上可接受的载体和权利要求1-29任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药。
- 根据权利要求30所述的药物组合物,其特征在于,所述药物组合物中还可以包含MYC抑制剂、DNA甲基转移酶抑制剂或Bcl-2选择性抑制剂。
- 根据权利要求31所述的药物组合物,其特征在于,所述MYC抑制剂为OMO-103、APTO-253、PLX-51107、DCR-M1711、Oncomyc-NG、INX-3280、PU-27、GSK-3179106、胆固醇丁酸酯和NSC-165563中任意一种或多种;所述DNA甲基转移酶抑制剂为5-氮杂胞苷、RG108、SGI-1027、GSK3685032、CM272、Bobcat339 hydrochloride、Decitabine(NSC 127716)、Thioguanine(NSC 752)、2'-Deoxy-5-Fluorocytidine、Procainamide HCl或Zebularine(NSC 309132)中任意一种或多种;所述Bcl-2选择性抑制剂为Venetoclax(ABT-199)、S55746、BDA-366、Obatoclax Mesylate(GX15-070)、HA14-1或APG-2575(CAS No.2180923-05-9)中任意一种或多种。
- 根据权利要求31所述的药物组合物,其特征在于,所述药物组合物中包含Bcl-2选择性抑制剂,所述Bcl-2选择性抑制剂为Venetoclax(ABT-199)、Obatoclax Mesylate(GX15-070)或APG-2575(CAS No.2180923-05-9)。
- 权利要求1-29任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素、前药以及根据权利要求30-33任一项所述的药物组合物在制备c-Myc、N-myc、GSPT1、CK1α、IKZF(1/2/3)、AR和AR-V7中任意一种或至少两种以上的蛋白降解剂中的用途。
- 权利要求1-29任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素、前药以及根据权利要求30-33任一项所述的药物组合物在制备治疗c-Myc、N-myc、GSPT1、CK1α、IKZF(1/2/3)、AR和AR-V7中任意一种或至少两种以上的蛋白失调相关疾病的药物中的用途。
- 权利要求1-29任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素、前药以及根据权利要求30-33任一项所述的药物组合物在治疗c-Myc、N-myc、GSPT1、CK1α、IKZF(1/2/3)、AR和AR-V7中任意一种或至少两种以上的蛋白失调相关疾病中的用途。
- 根据权利要求35或36所述的用途,其特征在于,所述蛋白失调选自蛋白过表达。
- 根据权利要求35或36所述的用途,其特征在于,所述蛋白失调相关疾病选自:癌症、心脑血管疾病、病毒感染相关疾病。
- 根据权利要求38所述的用途,其特征在于,所述癌症选自:白血病、淋巴瘤、恶性胶质瘤、成神经管细胞瘤、黑色素瘤、多发性骨髓瘤、骨髓增生异常综合征、肝癌、肺癌、肾癌、胰腺癌、口腔癌、胃癌、食道癌、喉癌、鼻咽癌、皮肤癌、乳腺癌、结肠癌、直肠癌、宫颈癌、卵巢癌、前列腺癌、横纹肌肉瘤、成骨肉瘤、软骨肉瘤;所述病毒感染相关疾病选自:HIV、乙肝、丙肝、甲肝、流感、流行性乙脑炎、疱疹;所述白血病包括慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、急性髓系白血病(AML)、急性非淋巴细胞性白血病(ANLL)。
- 根据权利要求1-29任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素、前药以及权利要求30-33任一项所述的药物组合物在制备治疗急性髓系白血病(AML)的药物中的用途。
- 根据权利要求40所述的用途,其特征在于,所述药物组合物中包含Bcl-2选择性抑制剂,所述Bcl-2选择性抑制剂为Venetoclax(ABT-199)、Obatoclax Mesylate(GX15-070)或APG-2575(CAS No. 2180923-05-9)。
- 权利要求1-29任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药用于制备蛋白质水解靶向嵌合体(PROTAC)或抗体偶联药物(ADC)中的用途。
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