WO2023155710A1 - Ikzf2 degradation agent, pharmaceutical composition comprising same and use thereof - Google Patents

Ikzf2 degradation agent, pharmaceutical composition comprising same and use thereof Download PDF

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WO2023155710A1
WO2023155710A1 PCT/CN2023/074793 CN2023074793W WO2023155710A1 WO 2023155710 A1 WO2023155710 A1 WO 2023155710A1 CN 2023074793 W CN2023074793 W CN 2023074793W WO 2023155710 A1 WO2023155710 A1 WO 2023155710A1
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substituted
unsubstituted
compound
group
cancer
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French (fr)
Chinese (zh)
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梅德盛
吴雄
吕仕铭
凌欣
肖程
孙高睿
刘帅帅
谭晓画
张亚茹
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苏州国匡医药科技有限公司
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    • 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
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    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • 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
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    • 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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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • 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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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
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Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a compound used as an IKAROS family zinc finger 2 (IKZF 2 ) degradation agent, a pharmaceutical composition containing the compound, and the use of the compound or the pharmaceutical composition for preventing, improving and/or Use to treat an IKZF2 dependent disease or disorder.
  • IKZF 2 IKAROS family zinc finger 2
  • IKZF 2 also known as Helios, is a member of the IKZF transcription factor family, which also includes IKZF 1 , IKZF 3 , IKZF 4 and IKZF 5 .
  • This family of transcription factors is characterized by four highly conserved N-terminal C 2 H 2 zinc fingers and two C-terminal C 2 H 2 zinc fingers involved in DNA binding, and homologous and heterologous dimerization with other family members Necessary for body protein interactions.
  • IKZF 2 is expressed in T cells, especially in FoxP3+Treg cell subsets. Forced expression of IKZF2 can promote the differentiation of immature CD4 + T cells into T helper 2 (Th2) or T follicular helper cells (Tfh), and enhance the immunosuppressive function of FoxP3+CD4 + T cells.
  • Th2 T helper 2
  • Tfh T follicular helper cells
  • IKZF2 overexpression of IKZF2 in Tregs increases the expression of Treg-associated markers such as CD103 and GITR, and cells overexpressing IKZF2 show increased suppression of responding T cells.
  • IKZF 2 binds to the promoter of FoxP3 (a limiting transcription factor of the regulatory T cell lineage), affects the expression of FoxP3, and maintains the suppressive function of Treg cells.
  • CTLA-4 antibodies are used in the clinic to target Tregs in tumors.
  • targeting CTLA-4 often causes systemic activation of T effector cells, leading to excessive toxicity and severely limiting its therapeutic utility, as shown in as many as three quarters of patients treated with anti-PD-1 and anti-CTLA-4 combinations. grade or higher adverse events. Therefore, there is a strong need to provide compounds that target Tregs in tumors without causing systemic activation of T effector cells.
  • IKZF2- specific degraders have the potential to limit the enhanced immune response only to areas within or near tumors, providing a class of potentially more tolerable and less toxic therapeutics for cancer treatment.
  • the compounds of the invention have utility as therapeutic agents, especially for cancer and related diseases.
  • the compounds of the present invention have good IKZF 2 degrading activity; on the other hand, the compounds of the present invention have selective IKZF 2 degrading activity, for example, some compounds have low or no activity on IKZF 1 .
  • the compounds of the present invention are beneficial in the treatment of cancer and other diseases based on the IKZF 2 degradation activity.
  • the inventors believe that by reducing the levels of IKZF2 in Tregs in tumors, an individual's immune system can be made more effective in treating disease.
  • the present invention provides a class of novel IKZF 2 degrading agents useful for preventing, improving and/or treating cancer and other diseases.
  • the present invention provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer,
  • X 1 , X 2 and X 3 are each independently CR 8 or N;
  • R 1 , R 2 , R 3 and R 8 are each independently hydrogen, hydroxyl, mercapto, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight-membered ring heteroalkyl, substituted or unsubstituted C 1 -C 6 ester group, substituted or unsubstituted C 1 -C 6 amide group, substituted or Unsubstituted C 1 -C 6 acyl, substituted or unsubstituted C 1 -C 6 sulfon
  • any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl, a substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted five to ten membered heteroaryl;
  • R 4 , R 5 , R 6 and R 7 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted Substituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight membered ring heteroalkyl, substituted or unsubstituted C 6 -C 10 aryl Or a substituted or unsubstituted five to ten membered heteroaryl group;
  • R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three- to eight-membered cycloheteroalkyl group;
  • cycloheteroalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl or a substituted or unsubstituted three to eight-membered cycloheteroalkenyl;
  • the number of heteroatoms in the cycloheteroalkyl group and heteroaryl group is independently 1, 2, 3 or 4, and each of the heteroatoms is independently B, N, O or S.
  • X 1 , X 2 and X 3 are each independently CR 8 , wherein R 8 is as defined in formula (I), preferably hydrogen, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy, More preferably hydrogen, C 1 -C 6 fluoroalkyl or C 1 -C 6 fluoroalkoxy, even more preferably hydrogen.
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 4 alkyl, Substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted three to six membered cycloheteroalkyl or substituted or unsubstituted C 1 -C 4 acyl, preferably hydrogen, fluorine, chlorine, bromine, iodine , azido, cyano, amino, nitro, substituted or unsubstituted methyl, substituted or unsubstituted methoxy, substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted acetyl, more preferably Hydrogen, fluorine, chlorine, bromine, cyano, amine, nitro, trifluoromethyl, trifluorometh
  • each of R 4 , R 5 , R 6 and R 7 is independently hydrogen or substituted or unsubstituted C 1 -C 4 alkyl, preferably hydrogen or substituted or unsubstituted methyl, more preferably hydrogen, or, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted three to six-membered cycloheteroalkyl, preferably substituted or unsubstituted C 3 -C 6 cycloalkyl, more preferably substituted or unsubstituted cyclopropyl.
  • It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group, preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyridyl group An azinyl group or a substituted or unsubstituted pyrimidinyl group, more preferably a substituted or unsubstituted phenyl group.
  • It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group, preferably a substituted or unsubstituted C 6 -C 10 aryl group, more preferably a substituted or unsubstituted phenyl group .
  • the number of heteroatoms in the cycloheteroalkyl and heteroaryl is independently 1, 2 or 3, preferably 1 or 2; each of the heteroatoms is independently B, N or O, N or O is preferred.
  • X 5 , X 6 , X 7 and X 8 are each independently CH or N, preferably at least one of X 5 , X 6 , X 7 and X 8 is CH, more preferably X 5 , X 6 , X 7 and X At least two of 8 are CH, even more preferably at least three of X 5 , X 6 , X 7 and X 8 are CH, further preferably X 5 , X 6 , X 7 and X 8 are all CH;
  • X 9 and X 10 are each independently CH or N, preferably at least one of X 9 and X 10 is N, more preferably X 9 and X 10 are both N;
  • R 1 , R 2 and R 3 are as defined in formula (I).
  • the present invention provides the following compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chiral pure compounds, stereoisomers or tautomers thereof.
  • the present invention provides a pharmaceutical composition, which comprises the above compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or mutual variants, and pharmaceutically acceptable carriers.
  • the pharmaceutical composition is useful in preventing, improving and/or treating IKZF2 -dependent diseases or disorders.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutically active ingredient.
  • the present invention provides a method for degrading IKZF 2 , the method comprising administering the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure Compounds, stereoisomers or tautomers, or the above-mentioned pharmaceutical compositions.
  • the present invention provides a method for regulating (preferably reducing) the protein level of IKZF 2 , the method comprising administering the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, Prodrugs, chirally pure compounds, stereoisomers or tautomers or pharmaceutical compositions of the above.
  • the present invention provides a method for preventing, improving and/or treating IKZF2- dependent diseases or disorders, the method comprising administering a preventive, improving and/or therapeutically effective amount of the above compound to an individual in need thereof Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or the above pharmaceutical composition.
  • a preventive, improving and/or therapeutically effective amount of the above compound to an individual in need thereof
  • a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or the above pharmaceutical composition preferably, said IKZF2- dependent disease or disorder is affected by a rise and fall of IKZF2 protein levels.
  • said IKZF2- dependent disease or disorder is cancer
  • said cancer is an immune response deficient cancer or an immunogenic cancer
  • said cancer is selected from lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), melanoma (such as choroidal melanoma), breast cancer (such as triple-negative breast cancer (TNBC)), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), microsatellite-invariant Stable colorectal cancer (msiCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), bladder cancer, pancreatic cancer, bone cancer, glioma, neurocytoma, esophageal cancer, lip cancer, laryngeal cancer carcinoma, hypopharyngeal carcinoma, tongue carcinoma, adenocarcinoma, choriocarcinoma, urinary carcinoma, brain tumors (such as gliom
  • the present invention provides a method for reducing and/or inhibiting cell proliferation, the method comprising administering the above-mentioned compound or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof to an individual in need thereof , a chiral pure compound, a stereoisomer or a tautomer, or the above-mentioned pharmaceutical composition.
  • the present invention provides the above compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition in the preparation of IKZF 2. Uses in degradation agents.
  • the present invention provides the above compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition in the preparation of IKZF 2.
  • protein level regulators preferably IKZF 2 protein level reducers.
  • the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition for use in the preparation of Use in medicines for preventing, improving and/or treating IKZF 2 dependent diseases or disorders.
  • said IKZF2- dependent disease or disorder is affected by a rise and fall of IKZF2 protein levels. More preferably, said IKZF2 dependent disease or disorder is cancer.
  • the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition during preparation Use in a medicament for reducing and/or inhibiting cell proliferation.
  • the above compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition which is used for Modulating (preferably reducing) IKZF2 protein levels.
  • the above compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition which is used for Prevention, improvement and/or treatment of IKZF 2 dependent diseases or disorders.
  • said IKZF2- dependent disease or disorder is affected by a rise and fall of IKZF2 protein levels. More preferably, said IKZF2 dependent disease or disorder is cancer.
  • the above compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition which is used for Reduce and/or inhibit cell proliferation.
  • the compounds of the present invention are useful as therapeutic agents, especially for the treatment of cancer and related diseases;
  • the compound of the present invention has selective IKZF 2 degradation activity, which can reduce the IKZF 2 protein level in Treg cells, thereby enabling the individual immune system to attack tumors more effectively, thereby reducing toxic and side effects;
  • the compounds of the present invention (such as compound 1, etc.) have significantly better IKZF 2 degradation activity than the prior art, such as the IKZF 2 degradation agent I-57 (P 279 ).
  • the present invention provides a class of novel IKZF 2 degrading agents beneficial to the prevention, improvement and/or treatment of cancer and/or other diseases.
  • C 1 -C 6 alkyl means an alkyl group having 1 to 6 carbon atoms group.
  • alkylaryl means a monovalent group of alkyl-aryl- group
  • arylalkyl means a monovalent aryl-alkyl-group
  • the article "a/kind/kind” means one/kind/kind or more than one/kind/kind (e.g. at least one/kind/kind) of the grammatical object of the article, e.g. "an element” means a element or more than one element.
  • an “optionally substituted” means that a given chemical moiety may (but need not) be bonded to other substituents, either "substituted” or "unsubstituted".
  • an “optionally substituted alkyl group” can be either an alkyl group that is unsubstituted by any substituent (eg, methyl) or an alkyl group substituted with at least one substituent other than hydrogen (substituted The number of groups needs to satisfy the valence bond rule) (for example, hydroxymethyl, trifluoromethyl).
  • substituents themselves may also be optionally substituted.
  • substituted means that the specified group or moiety bears one or more suitable substituents, wherein the substituents may be attached to the specified group or moiety at one or more positions.
  • an aryl group substituted with a cycloalkyl means that the cycloalkyl group is bonded to one ring-forming carbon atom of the aryl group or is fused to the aryl group through two or more common ring-forming carbon atoms.
  • unsubstituted means that the specified group or moiety does not bear any substituents.
  • aryl means a monovalent aromatic hydrocarbon group having 1 to 3 aromatic rings (including monocyclic or bicyclic groups).
  • the aromatic rings of the aryl group are optionally attached at a single point (eg, biphenyl) or fused at multiple points (eg, naphthyl).
  • An aryl group may optionally be substituted at any substitutable position with one or more substituents, for example 1 to 5 substituents.
  • an aryl group optionally has an unsaturated or partially saturated ring fused to a fully saturated ring.
  • Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzorenyl, and the like.
  • heteroaryl and/or “heteroaryl” mean a monovalent monocyclic or polycyclic (eg, bicyclic) aromatic group of 5 to 24 ring atoms containing a group selected from N , one or more ring heteroatoms of O or S, and the remaining ring atoms are C.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl , quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, indazolyl, benzimidazolyl, thieno[3,2-b]thienyl, triazolyl, triazine base, imidazo[1,2-b]pyrazolyl, imidazo[1,2-a]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl , pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,
  • a heteroaryl group as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring.
  • examples include, but are not limited to, indolinyl, indolonyl, dihydrobenzothienyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydro Benzothiazinyl, 3,4-dihydro-1H-isoquinolyl, 2,3-dihydrobenzofuryl, indolinyl, indolyl, dihydrobenzoxanyl, and the like.
  • halogen or halo means fluorine, chlorine, bromine or iodine.
  • alkyl means a monovalent straight or branched chain saturated hydrocarbon radical containing 1 to 12 carbon atoms.
  • alkyl groups include (But not limited to) methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, isohexyl, and the like.
  • alkoxy means a monovalent straight or branched chain saturated hydrocarbon radical containing 1 to 12 carbon atoms, which contains a terminal "O" in the chain.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentoxy groups, and the like.
  • alkenyl means a monovalent straight or branched chain unsaturated hydrocarbon radical containing 2 to 12 carbon atoms.
  • An “alkenyl” group contains at least one double bond in the chain. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.
  • alkynyl means a monovalent straight or branched chain unsaturated hydrocarbon radical containing 2 to 12 carbon atoms.
  • An “alkynyl” group contains at least one triple bond in the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.
  • alkylene or alkylenyl means a divalent alkyl group. Any of the above monovalent alkyl groups can become an alkylene group by removing one hydrogen atom from its structure.
  • alkylene groups include, but are not limited to, -CH2- , -CH( CH3 ) - , -C( CH3 ) 2- , -CH2CH2- , -CH2CH ( CH3 ) -, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH-, etc.
  • cycloalkyl or "carbocyclyl” means a monovalent monocyclic or polycyclic saturated hydrocarbon radical containing 3 to 18 carbon atoms. Cycloalkyl groups can be fused (eg, decahydronaphthyl) or bridged (eg, norbornyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norboranyl, bicyclo[2.2.2 ] Hinkie et al.
  • cycloheteryl or “cycloheteroalkyl” or “heterocycloalkyl” or “heterocyclyl” means a group whose ring atoms contain C atoms and at least one heteroatom selected from B, O, N or S A monovalent saturated or partially saturated monocyclic or polycyclic group that is not aromatic.
  • heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, Thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S- Oxide, thiomorpholinyl S-dioxide, piperazinyl, tropyl, oxazolidinyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxane Pentyl group, imidazolidinyl group, imidazolinyl group, 1,3-dithiolanyl group, homotropanyl group (
  • hydroxyalkyl means an alkyl group substituted with one or more hydroxy groups.
  • hydroxyalkyl groups include, but are not limited to, HO- CH2- , HO- CH2CH2- , CH2 -CH(OH)-, and the like.
  • haloalkyl means an alkyl group substituted with one or more halogen atoms.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.
  • haloalkoxy means an alkoxy group substituted with one or more halogens.
  • haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.
  • cyano means a -CN group.
  • amino means a -NH2 group.
  • alkylamino or “alkylamino” means an amino group in which one hydrogen atom is replaced by an alkyl group.
  • alkylamino groups include, but are not limited to, methylamino (-NH( CH3 )), ethylamino, propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino base amino, etc.
  • dialkylamino or "dialkylamino” means an amino group in which both hydrogen atoms are replaced by an alkyl group, which may be the same or different.
  • dialkylamino groups include, but are not limited to, dimethylamino (-N( CH3 ) 2 ), diethylamino, dipropylamino, diisopropylamino, di-n-butylamino, Di-sec-butylamino, di-tert-butylamino, methyl (ethyl) amino, methyl (butyl) amino, etc.
  • prodrug or “prodrug derivative” means a covalently bonded derivative or carrier of a parent compound or active drug substance that undergoes at least some biotransformation before exhibiting one or more of its pharmacological effects.
  • prodrugs have the ability to metabolize A cleavable group that is rapidly transformed in vivo to yield the parent compound.
  • prodrugs themselves have weak or no biological activity and are stable under normal conditions.
  • Prodrugs can be readily prepared from the parent compound using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds. ), Gordon & Breach [Gordon and Bridge Press], 1991, especially Chapter 5: "Design and Applications of Prodrugs [the design and application of prodrugs]”; Design of Prodrugs [the design of prodrugs], H.Bundgaard (Editor), Elsevier [Elsevier Group], 1985; Prodrugs: Topical and Ocular Drug Delivery [Prodrugs: Topical and Ocular Drug Delivery], KBSloan (editor), Marcel Dekker Marcel Dekker Company], 1998; Methods in Enzymology [Enzymology Methods], K.
  • Pro- Drugs as Novel Delivery Systems [prodrug as a novel delivery system], T.Higuchi and V.Stella (editors), Am.Chem.Soc.[American Chemical Society Journal], 1975; Bioreversible Carriers in Drug Design[drug design in Bioreversible Vectors], EB Roche (editor), Elsevier [Elsevier Group], 1987, each of which is herein incorporated by reference in its entirety.
  • pharmaceutically acceptable prodrug means a prodrug of a compound of the present invention which, within the scope of sound medical judgment, is suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, Anaphylaxis, etc., commensurate with a reasonable benefit/risk ratio and, where possible, valid for its intended use.
  • salt means the ionic form of the parent compound or the acid or base salt of the parent compound obtained by reacting the parent compound with a suitable acid or base.
  • Salts of the compounds of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, salts are prepared by reacting the free basic or acidic parent compound with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or different combinations of solvents.
  • pharmaceutically acceptable salt means a salt of a compound of the present invention which, within the scope of sound medical judgment, is suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction etc., commensurate with a reasonable benefit/risk ratio and, where possible, valid for their intended use.
  • the term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present invention are useful in both free base and salt forms, use of the salt form is practically equivalent to use of the base form.
  • suitable salts can be found, for example, in S.M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19.
  • pharmaceutically acceptable acid addition salt means those salts which retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, which salts may be combined with inorganic acids such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, etc.) and organic acids (such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid Acid, Benzoic Acid, 2-Acetoxybenzoic Acid, Butyric Acid, Camphoric Acid, Camphorsulfonic Acid, Cinnamic Acid, Citric Acid, Digluconic Acid, Ethylsulfonic Acid, Glutamic Acid, Glycolic Acid, Glycerophosphoric Acid, Hemisulfuric Acid, Heptanoic acid, caproic acid, formic acid, fuma
  • pharmaceutically acceptable base addition salt means those salts which retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable, which salts are formed with inorganic bases such as ammonia or hydrogen oxides, carbonates or bicarbonates) or metal cations (such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, ingot, aluminum, etc.). Particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amine compounds, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins , such as Jia Amine, Dimethylamine, Trimethylamine, Ethylamine, Diethylamine, Triethylamine, Isopropylamine, Tripropylamine, Tributylamine, Ethanolamine, Diethanolamine, 2-Dimethylaminoethanol, 2-Diethylaminoethanol , dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl glucosamine, theobromine, Pterin, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compound, tetraethylammonium compound, pyr
  • solvate means a complex of variable stoichiometry formed from a solute (eg, a compound of the invention) and a solvent (eg, water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated (eg, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). In general, such solvents are selected for the present invention so as not to interfere with the biological activity of the solute. Representative solvates include hydrates, ethanolates, methanolates, and the like. The term “hydrate” means that the solvent is a solvate of water.
  • the compounds of the invention discussed below include their free bases or acids, as well as their salts, solvates and prodrugs, and may include in their structure suitably derivatized forms such as oxidized sulfur atoms or quaternized nitrogen atoms (although not expressly stated or shown), especially in pharmaceutically acceptable forms thereof.
  • isomer means compounds that have the same number and kind of atoms, and thus the same molecular weight, but differ in the arrangement or configuration of the atoms in space.
  • the term includes stereoisomers and geometric isomers.
  • stereoisomer or “optical isomer” mean those having at least one chiral element, e.g. alkenes and spiro compounds) and are stable isomers that can rotate plane-polarized light.
  • the compounds of the present invention include asymmetric carbon atoms and can therefore be obtained as individual stereoisomers, racemates, and enantiomers and diastereoisomers. A mixture of bodies exists. Typically, such compounds will be prepared as racemic mixtures.
  • such compounds may be prepared or isolated as stereoisomers, either as individual enantiomers or diastereomers (or “chirally pure compounds"), or as stereoenriched A mixture of isomers (or “substantially chirally pure compound”).
  • individual stereoisomers of compounds are prepared either synthetically from optically active starting materials containing the desired chiral centers, or by separation or resolution after preparation of racemic mixtures. Starting compounds of particular stereochemistry are either commercially available or prepared by the methods described below and resolved by techniques well known in the art.
  • the term “enantiomer” or “enantiomer” means a pair of stereoisomers that are non-superimposable mirror images of each other.
  • racemic mixture or “racemate” means a mixture containing equal parts (usually equimolar) of a pair of enantiomers.
  • nonracemic mixture means a mixture containing unequal parts of a pair of enantiomers.
  • enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including type of activity exhibited, degree of activity, toxicity, etc.).
  • one of the enantiomers may be more active or may exhibit Beneficial effect.
  • a racemic form of a drug can be used, it is generally not as effective as administering an equivalent amount of an enantiomerically pure drug. Indeed, in some cases one enantiomer may be pharmacologically inactive and act only as a simple diluent.
  • a pair of enantiomers may even have distinctly different biological activities. Indeed, some purified single enantiomers are more dominant than their racemates. Therefore, if one enantiomer is pharmacologically more active, less toxic, or more preferred in vivo distribution than the other enantiomer, it is preferred to administer the enantiomer in the treatment of Admiral will be more helpful. In this way, the treated individual will be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer.
  • the preparation can be obtained by one or more methods known to those skilled in the art for (a) separating or resolving enantiomers or (b) selectively synthesizing enantiomers, or a combination of these methods Finish.
  • the above methods usually rely on chiral recognition, such as chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and Non-enzymatic kinetic resolution, spontaneous enantioselective crystallization, etc.
  • geometric isomer means an isomer formed from a double bond (for example, cis-2-butene and trans-2-butene) or a ring structure (for example, cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane) is a stable isomer resulting from restricted rotational freedom.
  • the specific configuration of an isomer is indicated using the cis/trans convention or using the E or Z system, where the term “E” or “E-type” means that the higher order substituents are on opposite sides of the double bond and the term “Z " or "Z type” means that the higher order substituents are on the same side of the double bond. Determination of E-form and Z-form isomers can be performed by analytical methods such as X-ray crystallography, 1 H-NMR, and 13 C-NMR.
  • tautomer refers to multiple functional isomers produced by the rapid migration of an atom in a compound molecule at at least two attachable sites, but usually in the form of one of the more stable isomers.
  • keto-enol (keto-enol) tautomer imine-enamine (imine-enamine) tautomer and the like.
  • the compounds of the present invention can exist in more than one tautomeric form and thus the compounds of the present invention include all such tautomers.
  • composition means a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, in a form suitable for oral or parenteral administration Construct, and at least one pharmaceutically acceptable carrier.
  • vector means an auxiliary material or vehicle involved in carrying or transporting a compound or composition from one tissue, organ, system or body part of a subject to another tissue, organ, system or body part of a subject , such as liquid or solid fillers (or diluents), excipients, solvents, encapsulating materials, etc.
  • the term "individual” or “subject” may be a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as Monkeys (such as rhesus monkeys), chimpanzees, baboons, etc.
  • the subject is a primate.
  • the subject is a human. If the subject will benefit biologically, medically or in quality of life after administering the drug (such as a compound or composition of the present invention), then the subject is interested in such prevention, improvement and/or treatment needed.
  • the specific amount of a compound of the invention that constitutes an effective amount will vary depending on factors such as the compound or composition used for administration and its biological properties (e.g., pharmacokinetic properties), time and frequency of administration, period of administration, administration
  • the route, the type of disease or disorder targeted and its severity, the drugs used in combination with the compound or composition of the present invention, and factors such as the age, sex, weight, general health and diet of the individual can be determined by those skilled in the art. It is determined by its professional knowledge and literature teaching.
  • inhibitor, inhibiting or inhibition means to suppress a particular disease, condition or disorder.
  • prevent, preventing or prevention mean the prophylactic treatment of a particular disease, condition or disorder, or delaying the onset or progression of a disease, condition or disorder.
  • ameliorate, ameliorating or amelioration means to progress a particular disease, condition or disorder towards a normal physiological state; or to reduce or alleviate a particular disease, condition or disorder (or to optimize at least one relevant physiological parameter or biomarker).
  • the terms “treat, treating or treatment” mean the elimination of a particular disease, condition or disorder.
  • pharmaceutically acceptable means that a substance (such as a compound or composition of the present invention, or a derivative thereof) must be chemically and/or toxicologically compatible with other compatible ingredients and/or the individual to whom it is administered.
  • administer, administering or administration means delivering a substance (such as a compound or composition of the present invention, or a derivative thereof) to a subject in need thereof, and the specific delivery method may be a method skilled in the art Well-known, for example, orally, parenterally, subcutaneously, intramuscularly, through a catheter or a cavity, and the like.
  • IKZF2- dependent disease or disorder means any disease or disorder that is directly or indirectly affected by the modulation of IKZF2 protein levels.
  • the present invention provides a class of novel compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chirally pure compounds, stereoisomers or tautomers thereof, which have Structure as shown in formula (I):
  • X 1 , X 2 and X 3 are each independently CR 8 or N;
  • R 1 , R 2 , R 3 and R 8 are each independently hydrogen, hydroxyl, mercapto, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight-membered ring heteroalkyl, substituted or unsubstituted C 1 -C 6 ester group, substituted or unsubstituted C 1 -C 6 amide group, substituted or Unsubstituted C 1 -C 6 acyl, substituted or unsubstituted C 1 -C 6 sulfon
  • any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl, a substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted five to ten membered heteroaryl;
  • R 4 , R 5 , R 6 and R 7 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted Substituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight membered ring heteroalkyl, substituted or unsubstituted C 6 -C 10 aryl Or a substituted or unsubstituted five to ten membered heteroaryl group;
  • R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three- to eight-membered cycloheteroalkyl group;
  • cycloheteroalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl or a substituted or unsubstituted three to eight-membered cycloheteroalkenyl;
  • the number of heteroatoms in the alkane group, cycloheteroalkyl group and aryl group is independently 1, 2, 3 or 4, and each of the heteroatoms is B, N, O or S independently.
  • each of X 1 , X 2 and X 3 is independently CR 8 , wherein R 8 is as defined in formula (I).
  • X 1 , X 2 and X 3 are each independently CR 8 , wherein R 8 is hydrogen, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy.
  • X 1 , X 2 and X 3 are each independently CH, C-CH 2 F, C-CHF 2 , C-CF 3 , C-OCH 2 F, C-OCHF 2 or C-OCF 3 .
  • Xi , X2 and X3 are all CH.
  • X4 is CH2 .
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, azido, cyano, substituted or unsubstituted amine, nitro, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted three to six membered cycloheteroalkyl or substituted or unsubstituted C 1 -C 4 acyl.
  • R 1 , R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, azido, cyano, amine, nitro, substituted or unsubstituted methyl , substituted or unsubstituted methoxy, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted acetyl.
  • R 1 , R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, cyano, amine, nitro, trifluoromethyl, trifluoromethoxy or acetyl base.
  • R 1 , R 2 and R 3 are each independently fluoro or cyano.
  • any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted three- to six-membered ring heteroalkyl group or a substituted or unsubstituted five- to six-membered heteroaryl group.
  • any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted three- to six-membered oxygen-containing cycloheteroalkyl group or a substituted or unsubstituted five- to six-membered Nitrogen-containing aryl group.
  • any two of R 1 , R 2 and R 3 are connected to each other to form substituted or unsubstituted 1,3-dioxolane, substituted or unsubstituted 1, 2-Oxaborolyl or substituted or unsubstituted pyrazolyl.
  • R 4 , R 5 , R 6 and R 7 are each independently hydrogen or substituted or unsubstituted C 1 -C 4 alkyl.
  • R 4 , R 5 , R 6 and R 7 are each independently hydrogen or substituted or unsubstituted methyl.
  • R4 , R5 , R6 and R7 are all hydrogen.
  • R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted three to six membered cycloheteroalkane base.
  • R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 6 cycloalkyl group.
  • R 4 and R 5 and R 6 and R 7 are each independently connected to each other to be substituted or unsubstituted Substituted cyclopropyl.
  • It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group.
  • It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group.
  • the number of heteroatoms in heterocycloalkyl and heteroaryl is independently 1, 2 or 3, preferably 1 or 2, such as pyrrolidinyl, tetrahydrofuryl, tetra Hydrothienyl, pyrrolyl, furyl, thienyl, etc., imidazolidinyl, oxazolidinyl, thiazolidinyl, imidazolyl, oxazolyl, thiazolyl, etc., containing 2 heteroatoms, containing 3 heteroatoms 1,2,4-triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, etc.
  • heterocycloalkyl and heteroaryl each independently contain at least one heteroatom
  • each heteroatom is independently B, N or O, preferably N or O, for example 1 containing 2 oxygen atoms ,3-Dioxolanyl 2-Hydroxy-1,2-oxaborolyl containing 1 oxygen atom and 1 boron atom 2-Phenyl-1,3,2-dioxaborolyl containing 2 oxygen atoms and 1 boron atom wait.
  • each substituent is independently cyano, hydroxyl, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy.
  • each substituent is independently hydroxy, fluoro, chloro, methyl or ethyl.
  • each substituent is independently hydroxy, fluoro, or methyl.
  • the compound of the present invention has a structure as shown in formula (II),
  • X 4 in formula (II) is CH 2 ; in other words, the compound of the present invention has the structure shown in formula (II'),
  • R 1 , R 2 , R 3 as defined in formula (I).
  • the compound of the present invention has a structure as shown in formula (III),
  • formula (III) represents a single bond; in other words, the compound of the present invention has a structure as shown in formula (III'),
  • R 1 , R 2 , R 3 as defined in formula (I).
  • the compounds of the present invention have the structure shown in formula (IV),
  • X 5 , X 6 , X 7 and X 8 are each independently CH or N; R 1 , R 2 , R 3 , as defined in formula (I).
  • X 5 , X 6 , X 7 and X 8 in formula (IV) are each independently CH or N, and at least one is CH.
  • X 5 , X 6 , X 7 and X 8 in formula (IV) are each independently CH or N, and at least two are CH.
  • X5 , X6 , X7 and X8 in formula (IV) are each independently CH or N, and at least three are CH.
  • X 5 , X 6 , X 7 and X 8 in formula (IV) are all CH.
  • the compound of the present invention has a structure as shown in formula (V),
  • X 9 and X 10 are each independently CH or N.
  • X 9 and X 10 in formula (V) are each independently CH or N, and at least one is N.
  • both X9 and X10 in formula (V) are N.
  • the compound of the present invention has a structure as shown in formula (VI),
  • R 1 , R 2 and R 3 are as defined in formula (I).
  • the present invention provides the following specific compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chiral pure compounds, stereoisomers or tautomers thereof.
  • the compounds of the present invention can be prepared using the methods described below, synthetic methods known in the field of synthetic organic chemistry, or methods mastered by those skilled in the art. Preferred methods include (but are not limited to) the methods described below, wherein Starting materials were either commercially available or prepared by methods disclosed in the literature.
  • Exemplary methods suitable for preparing compounds of the invention include the following steps:
  • An exemplary method suitable for preparing compound 1-8 includes the following steps:
  • the proton nuclear magnetic spectrum ( 1 H-NMR) among the present invention is collected from Bruker 400MHz nuclear magnetic resonance instrument, and the unit of chemical shift ( ⁇ ) is one millionth (ppm), and internal standard is tetramethyl Silane (TMS), the abbreviations used have the following meanings: s, singlet; d, doublet; dd, double doublet; ddd, double doublet doublet; qd, quadruplet doublet; t, triplet; dt, doublet triplet; q, quartet; qu, quintet; m, multiplet; br, broad.
  • mass spectra (MS) in the present invention were collected on a Quattro Micro TM API triple quadrupole mass spectrometer.
  • 1-(4-bromophenyl)-4-(4-(chloro Methyl) benzyl) piperazine is consistent with the synthesis of 4-(4-(4-(chloromethyl) benzyl) piperazin-1-yl)-3-fluorobenzonitrile in embodiment 1, yield is 33%.
  • the detection experiment can be carried out, and the cell viability must be greater than 90% before the experiment.
  • the complete medium was preheated to 37°C for use. Take out the cells in the logarithmic growth phase in the incubator, and when the cell density reaches above 80%, move the cell suspension to a centrifuge tube, and centrifuge at 200 g for 5 min. Discard the supernatant, add 5 mL of fresh medium to resuspend, count and divide into 12-well plates according to the passage ratio of 5 ⁇ 10 5 /well.
  • the blank control group was DMSO, while ensuring that the DMSO ratio did not exceed 0.1%.
  • the positive control group was I-57 (see patent application WO2020/128972), The concentration of the compound was 1.0 ⁇ M.
  • the cells were collected and centrifuged at 200 g for 5 minutes. The supernatant was discarded, and the cell pellet was stored in a -80°C refrigerator.
  • Step 1 Take out the cell sample in the EP tube from the -80°C freezer.
  • Step 3 centrifuge (10000g; 4°C; 10min), and collect the supernatant.
  • Step 1 Add gradient concentration protein standard solution on the microtiter plate to make a protein standard curve.
  • Step 2 Dilute the sample to be tested 10 times to make the total sample volume 25 ⁇ L.
  • Step 3 Prepare BCA working solution according to the number of samples, add 50 volumes of reagent A to 1 volume of reagent B, and mix well.
  • Step 4 Add 200 ⁇ L of BCA working solution to each well, shake and mix, place at 37°C for 30 minutes, and measure the absorbance at 562nm. Draw a standard curve with the protein content and absorbance value as the abscissa and ordinate, and then calculate the protein concentration (unit: ⁇ g/ ⁇ L) of the corresponding sample according to the absorbance value of the measured sample.
  • Step 1 According to the protein concentration test result, add loading buffer (LDS sample buffer; sample reducing agent) to adjust the sample volume, 30 ⁇ g/well sample, use precast gel, and operate electrophoresis according to standard procedures (200V; 40min).
  • loading buffer LDS sample buffer; sample reducing agent
  • Step 2 Membrane transfer: transfer protein to PVDF membrane, 350mA, 75min.
  • Step 3 Blocking: use blocking solution (TBST containing 5% skimmed milk powder) at room temperature for 1 h.
  • Step 4 Primary antibody incubation: use Antibody dilution buffer to dilute Helios Antibody and GAPDH at a ratio of 1:1000, and incubate overnight at 4°C. Wash 3 times with TBST, 10 min each time.
  • Step 5 Secondary antibody incubation: use Antibody dilution buffer to dilute the HRP secondary antibody at a ratio of 1:2000, and incubate at room temperature for 1 hour. Wash 3 times with TBST, 10 min each time.
  • Step 6 Development and fixation: Mix equal volumes of Solution A and Solution B (Tanontm High-sig ECL Western Blotting Substrate). Remove the excess washing solution on the washed blot, and add the detection mixture to the protein side of the membrane. Use Tianneng Tanon 4200 automatic chemiluminescence imaging analysis system for color development and imaging.
  • the compound of the present invention has significantly better IKZF 2 degradation activity; on the other hand, compared with IKZF 1 , the compound of the present invention has selective degradation activity against IKZF 2 .

Abstract

The present invention belongs to the field of medicinal chemistry, and relates to an IKZF2 degradation agent, a pharmaceutical composition comprising same and use thereof. Specifically, the IKZF2 degradation agent has a structure represented by formula (I), and can be used to prevent, ameliorate and/or treat IKAROS family zinc finger 2 (IKZF2)-related diseases or disorders.

Description

IKZF2降解剂及包含其的药物组合物和用途IKZF2 degradation agent and pharmaceutical composition and use comprising same
相关申请的交叉引用Cross References to Related Applications
本发明要求2022年02月16日在中国提交的，名称为“IKZF2降解剂及包含其的药物组合物和用途”、申请号为202210139879.2的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。The present invention claims the priority of the invention patent application filed in China on February 16, 2022, entitled "IKZF 2 degrading agent and its pharmaceutical composition and use", with application number 202210139879.2, which is incorporated by reference The entire content of the patent application is incorporated herein.
技术领域technical field
本发明属于药物化学领域，涉及一类用作IKAROS家族锌指2(IKZF2)降解剂的化合物，包含该化合物的药物组合物，以及将该化合物或药物组合物用于预防、改善和/或治疗IKZF2依赖性疾病或障碍的用途。The invention belongs to the field of medicinal chemistry, and relates to a compound used as an IKAROS family zinc finger 2 (IKZF 2 ) degradation agent, a pharmaceutical composition containing the compound, and the use of the compound or the pharmaceutical composition for preventing, improving and/or Use to treat an IKZF2 dependent disease or disorder.
背景技术Background technique
IKZF2又称Helios，属于IKZF转录因子家族成员，IKZF家族还包括IKZF1、IKZF3、IKZF4和IKZF5。该转录因子家族的特征是具有4个参与DNA结合的高度保守的N端C2H2锌指和2个C端C2H2锌指，是与其他家族成员发生同源和异源二聚体蛋白质相互作用所必需的。IKZF 2 , also known as Helios, is a member of the IKZF transcription factor family, which also includes IKZF 1 , IKZF 3 , IKZF 4 and IKZF 5 . This family of transcription factors is characterized by four highly conserved N-terminal C 2 H 2 zinc fingers and two C-terminal C 2 H 2 zinc fingers involved in DNA binding, and homologous and heterologous dimerization with other family members Necessary for body protein interactions.
研究表明，IKZF家族在T细胞发育和CD4+T细胞分化中起至关重要的作用。其中IKZF2在T细胞中表达，特别是在FoxP3+Treg细胞亚群中表达。IKZF2的强制表达可促进未成熟的CD4+T细胞分化为T辅助细胞2(Th2)或T滤泡辅助细胞(Tfh)，增强FoxP3+CD4+T细胞的免疫抑制功能。Studies have shown that the IKZF family plays a crucial role in T cell development and CD4 + T cell differentiation. Among them, IKZF 2 is expressed in T cells, especially in FoxP3+Treg cell subsets. Forced expression of IKZF2 can promote the differentiation of immature CD4 + T cells into T helper 2 (Th2) or T follicular helper cells (Tfh), and enhance the immunosuppressive function of FoxP3+CD4 + T cells.
同时，研究表明，IKZF2在Treg中的过表达会增加Treg相关标记如CD103和GITR的表达，并且过表达IKZF2的细胞显示出对应答T细胞的遏制增加。研究还发现，IKZF2与FoxP3的启动子(调节性T细胞谱系的限定转录因子)结合，影响FoxP3表达，存在维持Treg细胞的抑制功能。Meanwhile, studies have shown that overexpression of IKZF2 in Tregs increases the expression of Treg-associated markers such as CD103 and GITR, and cells overexpressing IKZF2 show increased suppression of responding T cells. The study also found that IKZF 2 binds to the promoter of FoxP3 (a limiting transcription factor of the regulatory T cell lineage), affects the expression of FoxP3, and maintains the suppressive function of Treg cells.
目前，CTLA-4抗体在临床中用于靶向肿瘤中的Treg。然而，靶向CTLA-4经常引起T效应细胞的全身活化，导致过度毒性并严重限制其治疗性效用，如多达3/4的患者用抗PD-1和抗CTLA-4组合治疗后产生3级或更高的不良事件。因此，强烈需要提供靶向肿瘤中的Treg而不引起T效应细胞的全身活化的化合物。Currently, CTLA-4 antibodies are used in the clinic to target Tregs in tumors. However, targeting CTLA-4 often causes systemic activation of T effector cells, leading to excessive toxicity and severely limiting its therapeutic utility, as shown in as many as three quarters of patients treated with anti-PD-1 and anti-CTLA-4 combinations. grade or higher adverse events. Therefore, there is a strong need to provide compounds that target Tregs in tumors without causing systemic activation of T effector cells.
IKZF2特异性降解剂有可能将增强的免疫应答仅仅限制在肿瘤内或肿瘤附近区域，从而为癌症治疗提供一类可能更耐受且毒性更小的治疗药物。 IKZF2- specific degraders have the potential to limit the enhanced immune response only to areas within or near tumors, providing a class of potentially more tolerable and less toxic therapeutics for cancer treatment.
发明内容Contents of the invention
本发明要解决的问题The problem to be solved by the present invention
本发明的化合物具有作为治疗剂的用途，特别是用于癌症和相关疾病。在一方面，本发明的化合物具有良好的IKZF2降解活性；在另一方面，本发明的化合物具有选择性的IKZF2降解活性，如其中的一些化合物对IKZF1低活性或无活性。本发明的化合物基于IKZF2降解活性而在治疗癌症和其他疾病等方面具备有益性。例如，虽然不旨在受任何理论的束缚，但发明人认为通过降低肿瘤中Treg中IKZF2的水平可以使个体免疫系统更有效地治疗疾病。总之，本发明提供了一类有用于预防、改善和/或治疗癌症和其他疾病的新颖的IKZF2降解剂。The compounds of the invention have utility as therapeutic agents, especially for cancer and related diseases. On the one hand, the compounds of the present invention have good IKZF 2 degrading activity; on the other hand, the compounds of the present invention have selective IKZF 2 degrading activity, for example, some compounds have low or no activity on IKZF 1 . The compounds of the present invention are beneficial in the treatment of cancer and other diseases based on the IKZF 2 degradation activity. For example, while not intending to be bound by any theory, the inventors believe that by reducing the levels of IKZF2 in Tregs in tumors, an individual's immune system can be made more effective in treating disease. In conclusion, the present invention provides a class of novel IKZF 2 degrading agents useful for preventing, improving and/or treating cancer and other diseases.
用于解决问题的方案solutions to problems
第一方面，本发明提供了具有式(I)结构的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，
In a first aspect, the present invention provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer,
其中：in:
X1、X2和X3各自独立地为CR8或N；X 1 , X 2 and X 3 are each independently CR 8 or N;
X4为CR9R10或C＝O，其中R9和R10各自独立地为氢或C1-C4烷基；X 4 is CR 9 R 10 or C=O, wherein R 9 and R 10 are each independently hydrogen or C 1 -C 4 alkyl;
R1、R2、R3和R8各自独立地为氢、羟基、巯基、卤素、叠氮基、氰基、取代或未取代的胺基、硝基、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C1-C6酯基、取代或未取代的C1-C6酰胺基、取代或未取代的C1-C6酰基、取代或未取代的C1-C6磺酰基、取代或未取代的C1-C6磺酰胺基、取代或未取代的C1-C6磺酸酯基、取代或未取代的C1-C6膦酰基、取代或未取代的C1-C6膦酰胺基或者取代或未取代的C1-C6膦酸酯基；R 1 , R 2 , R 3 and R 8 are each independently hydrogen, hydroxyl, mercapto, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight-membered ring heteroalkyl, substituted or unsubstituted C 1 -C 6 ester group, substituted or unsubstituted C 1 -C 6 amide group, substituted or Unsubstituted C 1 -C 6 acyl, substituted or unsubstituted C 1 -C 6 sulfonyl, substituted or unsubstituted C 1 -C 6 sulfonamide, substituted or unsubstituted C 1 -C 6 sulfonate substituted or unsubstituted C 1 -C 6 phosphono, substituted or unsubstituted C 1 -C 6 phosphonamido or substituted or unsubstituted C 1 -C 6 phosphonate;
或者，R1、R2和R3中的任意两个相互连接成取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基；Alternatively, any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl, a substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted five to ten membered heteroaryl;
R4、R5、R6和R7各自独立地为氢、羟基、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基；R 4 , R 5 , R 6 and R 7 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted Substituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight membered ring heteroalkyl, substituted or unsubstituted C 6 -C 10 aryl Or a substituted or unsubstituted five to ten membered heteroaryl group;
或者，R4和R5以及R6和R7各自独立地相互连接成取代或未取代的C3-C8环烷基或者取代或未取代的三至八元环杂烷基；Alternatively, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three- to eight-membered cycloheteroalkyl group;
为取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基或者取代或未取代的三至八元环杂烯基； is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl or a substituted or unsubstituted three to eight-membered cycloheteroalkenyl;
为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基； It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group;
为取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基； is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight membered heteroalkyl group, a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten Yuan Heteroaryl;
为取代或未取代的C6-C10芳基、取代或未取代的五至十元芳杂基、取代或未取代的C3-C8环烷基或者取代或未取代的三至八元环杂烷基； is a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted five to ten membered heteroaryl group, a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three to eight membered Cycloheteroalkyl;
所述环杂烷基和芳杂基中杂原子的个数各自独立地为1、2、3或4，每个所述杂原子各自独立地为B、N、O或S。The number of heteroatoms in the cycloheteroalkyl group and heteroaryl group is independently 1, 2, 3 or 4, and each of the heteroatoms is independently B, N, O or S.
优选地，X1、X2和X3各自独立地为CR8，其中R8如式(I)中所定义，优选氢、C1-C6卤代烷基或C1-C6卤代烷氧基，更优选氢、C1-C6氟代烷基或C1-C6氟代烷氧基，进一步优选氢。Preferably, X 1 , X 2 and X 3 are each independently CR 8 , wherein R 8 is as defined in formula (I), preferably hydrogen, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy, More preferably hydrogen, C 1 -C 6 fluoroalkyl or C 1 -C 6 fluoroalkoxy, even more preferably hydrogen.
优选地，X4为CH2或C＝O，优选CH2。 Preferably, X4 is CH2 or C=O, preferably CH2 .
优选地，R1、R2和R3各自独立地为氢、卤素、叠氮基、氰基、取代或未取代的胺基、硝基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的三至六元环杂烷基或者取代或未取代的C1-C4酰基，优选氢、氟、氯、溴、碘、叠氮基、氰基、胺基、硝基、取代或未取代的甲基、取代或未取代的甲氧基、取代或未取代的吡咯烷基或者取代或未取代的乙酰基，更优选氢、氟、氯、溴、氰基、胺基、硝基、三氟甲基、三氟甲氧基或乙酰基，更优选氟或氰基，或者，R1、R2和R3中的任意两个相互连接成取代或未取代的三至六元环杂烷基或者取代或未取代的五至六元芳杂基，优选取代或未取代的三至六元含氧环杂烷基或者取代或未取代的五至六元含氮芳杂基，更优选取代或未取代的1,3-二氧环杂戊基、取代或未取代的1,2-氧硼环杂戊基或者取代或未取代的吡唑基。Preferably, R 1 , R 2 and R 3 are each independently hydrogen, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 4 alkyl, Substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted three to six membered cycloheteroalkyl or substituted or unsubstituted C 1 -C 4 acyl, preferably hydrogen, fluorine, chlorine, bromine, iodine , azido, cyano, amino, nitro, substituted or unsubstituted methyl, substituted or unsubstituted methoxy, substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted acetyl, more preferably Hydrogen, fluorine, chlorine, bromine, cyano, amine, nitro, trifluoromethyl, trifluoromethoxy or acetyl, more preferably fluorine or cyano, or, in R 1 , R 2 and R 3 Any two are connected to each other to form a substituted or unsubstituted three- to six-membered cycloheteroalkyl group or a substituted or unsubstituted five- to six-membered heteroaryl group, preferably a substituted or unsubstituted three- to six-membered oxygen-containing cycloheteroalkyl group or Substituted or unsubstituted five- to six-membered nitrogen-containing heteroaryl, more preferably substituted or unsubstituted 1,3-dioxolane, substituted or unsubstituted 1,2-oxaborolyl or substituted or unsubstituted pyrazolyl.
优选地，R4、R5、R6和R7各自独立地为氢或者取代或未取代的C1-C4烷基，优选氢或者取代或未取代的甲基，更优选氢，或者，R4和R5以及R6和R7各自独立地相互连接成取代或未取代的C3-C6环烷基或者取代或未取代的三至六元环杂烷基，优选取代或未取代的C3-C6环烷基，更优选取代或未取代的环丙基。Preferably, each of R 4 , R 5 , R 6 and R 7 is independently hydrogen or substituted or unsubstituted C 1 -C 4 alkyl, preferably hydrogen or substituted or unsubstituted methyl, more preferably hydrogen, or, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted three to six-membered cycloheteroalkyl, preferably substituted or unsubstituted C 3 -C 6 cycloalkyl, more preferably substituted or unsubstituted cyclopropyl.
优选地，为取代或未取代的三至六元环杂烷基或者取代或未取代的三至六元环杂烯基，优选取代或未取代的哌啶基或者取代或未取代的四氢吡啶基。Preferably, is a substituted or unsubstituted three- to six-membered ring heteroalkyl group or a substituted or unsubstituted three- to six-membered ring heteroalkenyl group, preferably a substituted or unsubstituted piperidinyl group or a substituted or unsubstituted tetrahydropyridyl group.
优选地，为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基，优选取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的哒嗪基或者取代或未取代的嘧啶基，更优选取代或未取代的苯基。Preferably, It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group, preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyridyl group An azinyl group or a substituted or unsubstituted pyrimidinyl group, more preferably a substituted or unsubstituted phenyl group.
优选地，为取代或未取代的C3-C6环烷基或者取代或未取代的三至六元环杂烷基，优选取代或未取代的三至六元环杂烷基，更优选取代或未取代的哌嗪基或者取代或未取代的哌啶基，进一步优选取代或未取代的哌嗪基。Preferably, is a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted three to six-membered cycloheteroalkyl, preferably a substituted or unsubstituted three to six-membered cycloheteroalkyl, more preferably a substituted or unsubstituted Piperazinyl or substituted or unsubstituted piperidinyl, more preferably substituted or unsubstituted piperazinyl.
优选地，为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基，优选取代或未取代的C6-C10芳基，更优选取代或未取代的苯基。Preferably, It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group, preferably a substituted or unsubstituted C 6 -C 10 aryl group, more preferably a substituted or unsubstituted phenyl group .
优选地，所述环杂烷基和芳杂基中杂原子的个数各自独立地为1、2或3，优选1或2；每个所述杂原子各自独立地为B、N或O，优选N或O。Preferably, the number of heteroatoms in the cycloheteroalkyl and heteroaryl is independently 1, 2 or 3, preferably 1 or 2; each of the heteroatoms is independently B, N or O, N or O is preferred.
进一步地，上述式(I)化合物具有如式(II)所示的结构，
Further, the above-mentioned compound of formula (I) has the structure shown in formula (II),
其中，in,
X4、R1、R2、R3、如式(I)中所定义。 X 4 , R 1 , R 2 , R 3 , as defined in formula (I).
进一步地，上述式(I)化合物具有如式(II’)所示的结构，
Further, the above-mentioned compound of formula (I) has a structure as shown in formula (II'),
其中，in,
R1、R2、R3、如式(I)中所定义。R 1 , R 2 , R 3 , as defined in formula (I).
进一步地，上述式(I)化合物具有如式(III)所示的结构，
Further, the above-mentioned compound of formula (I) has a structure as shown in formula (III),
其中，in,
表示单键或双键，优选单键； represents a single or double bond, preferably a single bond;
R1、R2、R3、如式(I)中所定义。R 1 , R 2 , R 3 , as defined in formula (I).
进一步地，上述式(I)化合物具有如式(IV)所示的结构，
Further, the above-mentioned compound of formula (I) has a structure as shown in formula (IV),
其中，in,
X5、X6、X7和X8各自独立地为CH或N，优选X5、X6、X7和X8中的至少一个为CH，更优选X5、X6、X7和X8中的至少两个为CH，甚至更优选X5、X6、X7和X8中的至少三个为CH，进一步优选X5、X6、X7和X8均为CH；X 5 , X 6 , X 7 and X 8 are each independently CH or N, preferably at least one of X 5 , X 6 , X 7 and X 8 is CH, more preferably X 5 , X 6 , X 7 and X At least two of 8 are CH, even more preferably at least three of X 5 , X 6 , X 7 and X 8 are CH, further preferably X 5 , X 6 , X 7 and X 8 are all CH;
R1、R2、R3、如式(I)中所定义。R 1 , R 2 , R 3 , as defined in formula (I).
进一步地，上述式(I)化合物具有如式(V)所示的结构，
Further, the above-mentioned compound of formula (I) has the structure shown in formula (V),
其中，in,
X9和X10各自独立地为CH或N，优选X9和X10中的至少一个为N，更优选X9和X10均为N；X 9 and X 10 are each independently CH or N, preferably at least one of X 9 and X 10 is N, more preferably X 9 and X 10 are both N;
R1、R2、R3和如式(I)中所定义。R 1 , R 2 , R 3 and as defined in formula (I).
进一步地，上述式(I)化合物具有如式(VI)所示的结构，
Further, the above-mentioned compound of formula (I) has a structure as shown in formula (VI),
其中，R1、R2和R3如式(I)中所定义。Wherein, R 1 , R 2 and R 3 are as defined in formula (I).
第二方面，本发明提供了下列化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体。


In a second aspect, the present invention provides the following compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chiral pure compounds, stereoisomers or tautomers thereof.


第三方面，本发明提供了一种药物组合物，该药物组合物包含上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，以及药学上可接受的载体。该药物组合物在预防、改善和/或治疗IKZF2依赖性疾病或障碍中是有用的。该药物组合物可以进一步包含至少一种另外的药物活性成分。In a third aspect, the present invention provides a pharmaceutical composition, which comprises the above compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or mutual variants, and pharmaceutically acceptable carriers. The pharmaceutical composition is useful in preventing, improving and/or treating IKZF2 -dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutically active ingredient.
第四方面，本发明提供了一种降解IKZF2的方法，该方法包括向对其有需要的个体施用上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者上述药物组合物。In a fourth aspect, the present invention provides a method for degrading IKZF 2 , the method comprising administering the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure Compounds, stereoisomers or tautomers, or the above-mentioned pharmaceutical compositions.
第五方面，本发明提供了一种调节(优选降低)IKZF2蛋白水平的方法，该方法包括向对其有需要的个体施用上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者上述药物组合物。In a fifth aspect, the present invention provides a method for regulating (preferably reducing) the protein level of IKZF 2 , the method comprising administering the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, Prodrugs, chirally pure compounds, stereoisomers or tautomers or pharmaceutical compositions of the above.
第六方面，本发明提供了一种预防、改善和/或治疗IKZF2依赖性疾病或障碍的方法，该方法包括向对其有需要的个体施用预防、改善和/或治疗有效量的上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者上述药物组合物。优选地，所述IKZF2依赖性疾病或障碍受IKZF2蛋白水平升降的影响。更优选地，所述IKZF2依赖性疾病或障碍为癌症，所述癌症为免疫应答缺陷的癌症或免疫原性癌症，或者，所述癌症选自肺癌(诸如非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC))、黑色素瘤(诸如脉络膜黑色素瘤)、乳腺癌(诸如三阴性乳腺癌(TNBC))、鼻咽癌(NPC)、微卫星稳定性结直肠癌(mssCRC)、微卫星不稳定性结直肠癌(msiCRC)、胸腺瘤、类癌、胃肠道间质瘤(GIST)、膀胱癌、胰腺癌、骨癌、神经胶质瘤、神经细胞瘤、食管癌、唇癌、喉癌、下咽癌、舌癌、腺癌、绒毛膜癌、泌尿癌、脑肿瘤(诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤)、支气管癌、骨髓瘤(诸如多发性骨髓瘤)、基底细胞瘤、畸胎瘤、精原细胞瘤、颅咽管瘤、骨肉瘤、乳头状瘤、芽状神经胶质瘤、肉瘤(诸如软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤)、血管瘤、瘢痕瘤、鳞状细胞癌、淋巴瘤(诸如霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、成人T细胞白血病/淋巴瘤(ATLL)、弥漫性大B细胞淋巴瘤(DLBCL)、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤(CTCL)以及中枢神经系统淋巴瘤)、支气管腺瘤、胸膜肺母细胞瘤、头颈癌(诸如头癌、颈癌、口咽癌以及口腔癌)、乳癌(诸如浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌)、消化道癌(诸如肛门癌、食道癌、胆囊癌、胃癌、小肠癌以及唾液腺癌)、甲状腺癌(诸如甲状腺髓样癌和乳头状甲状腺癌)、副甲状腺癌及其远距离转移灶、肝癌(诸如肝细胞癌、具有或不具有纤维板层形式的肝细胞癌、胆管细胞癌以及混合型肝细胞胆管细胞癌)、白血病(诸如急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓性白血病、慢性骨髓性白血病以及绒毛细胞白血病)、脑癌(诸如脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤)、生殖器官癌(诸如前列腺癌、睾丸癌、卵巢癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌以及子宫肉瘤)、尿道癌、眼癌(诸如眼内黑素瘤和成视网膜细胞瘤)、皮肤癌(诸如卡波西肉瘤、鳞状细胞 瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌)、肾实质癌、肾癌(也称为肾细胞癌和肾腺癌)等相关癌症。In a sixth aspect, the present invention provides a method for preventing, improving and/or treating IKZF2- dependent diseases or disorders, the method comprising administering a preventive, improving and/or therapeutically effective amount of the above compound to an individual in need thereof Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or the above pharmaceutical composition. Preferably, said IKZF2- dependent disease or disorder is affected by a rise and fall of IKZF2 protein levels. More preferably, said IKZF2- dependent disease or disorder is cancer, said cancer is an immune response deficient cancer or an immunogenic cancer, or said cancer is selected from lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), melanoma (such as choroidal melanoma), breast cancer (such as triple-negative breast cancer (TNBC)), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), microsatellite-invariant Stable colorectal cancer (msiCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), bladder cancer, pancreatic cancer, bone cancer, glioma, neurocytoma, esophageal cancer, lip cancer, laryngeal cancer carcinoma, hypopharyngeal carcinoma, tongue carcinoma, adenocarcinoma, choriocarcinoma, urinary carcinoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor), Bronchial carcinoma, myeloma (such as multiple myeloma), basal cell tumor, teratoma, seminoma, craniopharyngioma, osteosarcoma, papilloma, budding glioma, sarcoma (such as chondrosarcoma , myoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmacytoma, histiosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma), hemangioma, keloid, squamous cell carcinoma, lymphoma (such as Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Burkitt Lymphoma, Adult T-Cell Leukemia/Lymphoma (ATLL), Diffuse Large B-Cell Lymphoma (DLBCL), AIDS-Related Lymphoma, Cutaneous T-Cell Lymphoma (CTCL) and central nervous system lymphoma), bronchial adenoma, pleuropulmonary blastoma, head and neck cancer (such as head, neck, oropharyngeal, and oral cavity cancers), breast cancer (such as invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ), digestive tract cancers (such as anal, esophageal, gallbladder, stomach, small intestine, and salivary glands), thyroid cancers (such as medullary thyroid and papillary thyroid ), parathyroid carcinoma and its distant metastases, liver cancer (such as hepatocellular carcinoma, hepatocellular carcinoma with or without fibrolamellar form, cholangiocarcinoma, and mixed hepatocellular cholangiocarcinoma), leukemia (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, and villous cell leukemia), brain cancers (such as brainstem and pituitary gliomas, medulloblastomas, cerebellar and cerebral astrocytomas, ventricular myringoma and neuroectodermal and pineal adenoma), reproductive organ cancers (such as prostate cancer, testicular cancer, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer and uterine sarcoma), urethral cancer, ocular Carcinomas (such as intraocular melanoma and retinoblastoma), skin cancers (such as Kaposi's sarcoma, squamous cell cancer, Merkel cell skin cancer, and non-melanoma skin cancer), renal parenchymal carcinoma, renal carcinoma (also known as renal cell carcinoma and renal adenocarcinoma) and other related cancers.
第七方面，本发明提供了一种降低和/或抑制细胞增殖的方法，该方法包括向对其有需要的个体施用上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者上述药物组合物。In a seventh aspect, the present invention provides a method for reducing and/or inhibiting cell proliferation, the method comprising administering the above-mentioned compound or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof to an individual in need thereof , a chiral pure compound, a stereoisomer or a tautomer, or the above-mentioned pharmaceutical composition.
第八方面，本发明提供了上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物在制备IKZF2降解剂中的用途。In the eighth aspect, the present invention provides the above compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition in the preparation of IKZF 2. Uses in degradation agents.
第九方面，本发明提供了上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物在制备IKZF2蛋白水平调节剂(优选IKZF2蛋白水平降低剂)中的用途。In the ninth aspect, the present invention provides the above compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition in the preparation of IKZF 2. Use in protein level regulators (preferably IKZF 2 protein level reducers).
第十方面，本发明提供了上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物在制备用于预防、改善和/或治疗IKZF2依赖性疾病或障碍的药物中的用途。优选地，所述IKZF2依赖性疾病或障碍受IKZF2蛋白水平升降的影响。更优选地，所述IKZF2依赖性疾病或障碍为癌症。In a tenth aspect, the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition for use in the preparation of Use in medicines for preventing, improving and/or treating IKZF 2 dependent diseases or disorders. Preferably, said IKZF2- dependent disease or disorder is affected by a rise and fall of IKZF2 protein levels. More preferably, said IKZF2 dependent disease or disorder is cancer.
第十一方面，本发明提供了上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物在制备用于降低和/或抑制细胞增殖的药物中的用途。In the eleventh aspect, the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition during preparation Use in a medicament for reducing and/or inhibiting cell proliferation.
第十二方面，本发明上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物，其用于降解IKZF2。In the twelfth aspect, the above-mentioned compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition, which is used for Degrades IKZF 2 .
第十三方面，本发明上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物，其用于调节(优选降低)IKZF2蛋白水平。In the thirteenth aspect, the above compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition, which is used for Modulating (preferably reducing) IKZF2 protein levels.
第十四方面，本发明上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物，其用于预防、改善和/或治疗IKZF2依赖性疾病或障碍。优选地，所述IKZF2依赖性疾病或障碍受IKZF2蛋白水平升降的影响。更优选地，所述IKZF2依赖性疾病或障碍为癌症。In the fourteenth aspect, the above compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition, which is used for Prevention, improvement and/or treatment of IKZF 2 dependent diseases or disorders. Preferably, said IKZF2- dependent disease or disorder is affected by a rise and fall of IKZF2 protein levels. More preferably, said IKZF2 dependent disease or disorder is cancer.
第十五方面，本发明上述化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者药物组合物，其用于降低和/或抑制细胞增殖。In the fifteenth aspect, the above compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or pharmaceutical composition, which is used for Reduce and/or inhibit cell proliferation.
本发明的有益效果Beneficial effects of the present invention
第一方面，本发明的化合物具有作为治疗剂的用途，特别是用于治疗癌症及其相关疾病；In the first aspect, the compounds of the present invention are useful as therapeutic agents, especially for the treatment of cancer and related diseases;
第二方面，本发明的化合物具有选择性的IKZF2降解活性，可降低Treg细胞中IKZF2蛋白水平，进而使个体免疫系统能够更有效地攻击肿瘤，从而降低毒副作用；In the second aspect, the compound of the present invention has selective IKZF 2 degradation activity, which can reduce the IKZF 2 protein level in Treg cells, thereby enabling the individual immune system to attack tumors more effectively, thereby reducing toxic and side effects;
第三方面，本发明的化合物(如化合物1等)对IKZF2降解活性显著优于现有技术如专利申请WO2020/128972中进行I/Ib期临床方案设计的IKZF2降解剂I-57(P279)。In the third aspect, the compounds of the present invention (such as compound 1, etc.) have significantly better IKZF 2 degradation activity than the prior art, such as the IKZF 2 degradation agent I-57 (P 279 ).
总之，本发明提供了一类有益于预防、改善和/或治疗癌症和(或)其他疾病的新颖IKZF2降解剂。In conclusion, the present invention provides a class of novel IKZF 2 degrading agents beneficial to the prevention, improvement and/or treatment of cancer and/or other diseases.
具体实施方式Detailed ways
术语定义和惯例Definitions of terms and conventions
在本文中，未明确定义的术语应当被理解为本领域技术人员根据上下文能够得出的含义。除非另有特别定义，否则本文中所使用的术语具有所示的含义并遵守相关惯例。Herein, terms that are not explicitly defined should be understood as meanings that can be drawn by those skilled in the art according to the context. Unless otherwise specifically defined, the terms used herein have the indicated meanings and follow relevant conventions.
化学命名法、术语和惯例Chemical Nomenclature, Terms and Conventions
在下文定义的基团(group或radical)或部分(segment)中，通常在基团之前指出碳原子数目，例如“C1-C6烷基”意指具有1至6个碳原子的烷基基团。 In a group or radical or segment as defined below, the number of carbon atoms is usually indicated before the group, for example "C 1 -C 6 alkyl" means an alkyl group having 1 to 6 carbon atoms group.
一般而言，对于包含两种或两种以上亚基团的基团，最后提及的基团为基团连接点，例如术语“烷基芳基”意指烷基-芳基-的单价基团，而术语“芳基烷基”意指芳基-烷基-的单价基团。In general, for groups containing two or more subgroups, the last-mentioned group is the point of attachment of the group, for example the term "alkylaryl" means a monovalent group of alkyl-aryl- group, while the term "arylalkyl" means a monovalent aryl-alkyl-group.
冠词“一个/种/类”是指一个/种/类或多于一个/种/类(例如，至少一个/种/类)该冠词的语法宾语，例如，“一个要素”意指一个要素或多于一个要素。The article "a/kind/kind" means one/kind/kind or more than one/kind/kind (e.g. at least one/kind/kind) of the grammatical object of the article, e.g. "an element" means a element or more than one element.
除非另有特别定义，否则术语“和/或”意指“和”或者“或”两种情况。Unless otherwise specifically defined, the term "and/or" means both "and" or "or".
术语“任选地取代的”意指给定的化学部分可以(但不是必须)与其他取代基键合，即“取代的”或者“未取代的”两种情况。例如，“任选地取代的烷基基团”既可以是未被任何取代基取代的烷基(例如，甲基)，也可以是被至少一个不同于氢的取代基取代的烷基(取代基的个数需要满足价键规则)(例如，羟甲基、三氟甲基)。当基团被取代时，合适的取代基包括(而不限于)卤素(例如，氟、氯、溴或碘)、氧代(＝O)、羟基、氰基、羧基、氰甲基、C1-C6烷基(例如，甲基、乙基、异丙基或叔丁基)、(C1-C6)烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C2-C6烯氧基、C2-C6炔氧基、C2-C6烯基、C2-C6炔基、磷酸酯基(-OP(O)(OH)2)、C1-C6酯基、C1-C6烷氧羰基、C1-C6酰基、胺基、C1-C6烷胺基、C1-C6二烷胺基、C1-C6酰胺基、C1-C6烷氨甲酰基、C1-C6烷磺酰基、C1-C6烷氨磺酰基和C1-C6二烷氨磺酰基。进一步地，上述取代基本身也可以是任选地取代的。术语“取代的”意指特定的基团或部分带有一个或多个合适的取代基，其中取代基可以在一个或多个位置处与特定的基团或部分连接。例如，被环烷基取代的芳基意指环烷基通过键与芳基的一个成环碳原子连接或通过两个或多个共同的成环碳原子与芳基稠合。术语“未取代的”意指特定的基团或部分不带任何取代基。The term "optionally substituted" means that a given chemical moiety may (but need not) be bonded to other substituents, either "substituted" or "unsubstituted". For example, an "optionally substituted alkyl group" can be either an alkyl group that is unsubstituted by any substituent (eg, methyl) or an alkyl group substituted with at least one substituent other than hydrogen (substituted The number of groups needs to satisfy the valence bond rule) (for example, hydroxymethyl, trifluoromethyl). When a group is substituted, suitable substituents include, but are not limited to, halogen (e.g., fluorine, chlorine, bromine, or iodine), oxo (=O), hydroxyl, cyano, carboxy, cyanomethyl, C -C 6 alkyl (for example, methyl, ethyl, isopropyl or tert-butyl), (C 1 -C 6 )alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy , C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phosphate (-OP(O)(OH) 2 ), C 1 -C 6 ester group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 acyl group, amino group, C 1 -C 6 alkylamino group, C 1 -C 6 dialkylamino group, C 1 -C 6 amido, C 1 -C 6 alkylcarbamoyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfamoyl and C 1 -C 6 dialkylsulfamoyl. Further, the above-mentioned substituents themselves may also be optionally substituted. The term "substituted" means that the specified group or moiety bears one or more suitable substituents, wherein the substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl means that the cycloalkyl group is bonded to one ring-forming carbon atom of the aryl group or is fused to the aryl group through two or more common ring-forming carbon atoms. The term "unsubstituted" means that the specified group or moiety does not bear any substituents.
术语“芳基”意指具有1至3个芳香族环(包括单环或二环基团)的单价芳香族烃基团。当含有两个芳香族环时，芳基基团的芳香族环任选地在单个点处连接(例如，联苯基)或在多个点处稠合(例如，萘基)。芳基基团可以在任何可取代位点任选地被一个或多个取代基取代，例如1至5个取代基。此外，当含有两个稠合环时，芳基基团任选地具有与完全饱和的环稠合的不饱和的或部分饱和的环。实例包括(但不限于)苯基、联苯基、萘基、蒽基、菲基、茚满基、茚基、四氢萘基、四氢苯并轮烯基等。The term "aryl" means a monovalent aromatic hydrocarbon group having 1 to 3 aromatic rings (including monocyclic or bicyclic groups). When containing two aromatic rings, the aromatic rings of the aryl group are optionally attached at a single point (eg, biphenyl) or fused at multiple points (eg, naphthyl). An aryl group may optionally be substituted at any substitutable position with one or more substituents, for example 1 to 5 substituents. In addition, when containing two fused rings, an aryl group optionally has an unsaturated or partially saturated ring fused to a fully saturated ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzorenyl, and the like.
术语“芳杂基”和(或)“杂芳基”意指5至24个环原子的单价单环芳香族基团或多环(例如，二环)芳香族基团，其含有选自N、O或S的一个或多个环杂原子，剩余的环原子是C。实例包括(但不限于)呋喃基、噻吩基、吡咯基、吡啶基、吡唑基、嘧啶基、咪唑基、异噁唑基、噁唑基、噁二唑基、吡嗪基、吲哚基、喹啉基、苯并吡喃基、异噻唑基、噻唑基、噻二唑基、吲唑基、苯并咪唑基、噻吩并[3,2-b]噻吩基、三唑基、三嗪基、咪唑并[1,2-b]吡唑基、咪唑并[1,2-a]吡啶基、吡咯并[2,3-c]吡啶基、吡咯并[3,2-c]吡啶基、吡唑并[3,4-c]吡啶基、噻吩并[3,2-c]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[2,3-b]吡啶基、苯并噻唑基、二氢吲哚基、吲哚酮基、二氢苯并噻吩基、二氢苯并呋喃基、苯并呋喃基、色满基、硫代色满基、四氢喹啉基、二氢苯并噻嗪基、二氢苯噁烷基、喹啉基、异喹啉基、1,6-萘啶基、噻吩并[2,3-b]吡嗪基、四唑并[1,5-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、异吲哚基、吡咯并[2,3-b]吡啶基、咪唑并[5,4-b]吡啶基、吡咯并[1,2-a]嘧啶基、四氢吡咯并[1,2-a]嘧啶基、二苯并[b,d]噻吩基、1H-吡啶并[3,4-b][1,4]噻嗪基、苯并噁唑基、苯并异噁唑基、苯并噻吩基、1,5-萘啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯并[1,2,3]三唑基、咪唑并[1,2-a]嘧啶基、[1,2,4]三唑并[4,3-b]哒嗪基、苯并[c][1,2,5]噁二唑基、3,4-二氢-2H-吡唑并[1,5-b][1,2]噁嗪基、4,5,6,7-四氢吡唑并[1,5-a]吡啶基、噻唑并[5,4d]噻唑基、噻吩并[2,3-b]吡咯基、3H-吲哚基等。此外，当含有两个稠合环时，本文定义的杂芳基基团可以具有与完全饱和的环稠合的不饱和的或部分饱和的环。实例包括(但不限于)二氢吲哚基、吲哚酮基、二氢苯并噻吩基、二氢苯并呋喃基、色满基、硫代色满基、四氢喹啉基、二氢苯并噻嗪基、3,4-二氢-1H-异喹啉基、2,3-二氢苯并呋喃基、二氢吲哚基、吲哚基、二氢苯噁烷基等。The terms "heteroaryl" and/or "heteroaryl" mean a monovalent monocyclic or polycyclic (eg, bicyclic) aromatic group of 5 to 24 ring atoms containing a group selected from N , one or more ring heteroatoms of O or S, and the remaining ring atoms are C. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl , quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, indazolyl, benzimidazolyl, thieno[3,2-b]thienyl, triazolyl, triazine base, imidazo[1,2-b]pyrazolyl, imidazo[1,2-a]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl , pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, Benzothiazolyl, indolinyl, indolinyl, dihydrobenzothienyl, dihydrobenzofuryl, benzofuryl, chromanyl, thiochromanyl, tetrahydroquinolyl , dihydrobenzothiazinyl, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, thieno[2,3-b]pyrazinyl, tetrazolo[ 1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, imidazo[5 ,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, dibenzo[b,d]thienyl, 1H-pyrido[ 3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, benzothienyl, 1,5-naphthyridinyl, [1,2,4]triazole [1,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3 -b]pyridazinyl, benzo[c][1,2,5]oxadiazolyl, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazine base, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, thiazolo[5,4d]thiazolyl, thieno[2,3-b]pyrrolyl, 3H-ind Indolyl etc. Furthermore, when containing two fused rings, a heteroaryl group as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Examples include, but are not limited to, indolinyl, indolonyl, dihydrobenzothienyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydro Benzothiazinyl, 3,4-dihydro-1H-isoquinolyl, 2,3-dihydrobenzofuryl, indolinyl, indolyl, dihydrobenzoxanyl, and the like.
术语“卤素”或“卤代”意指氟、氯、溴或碘。The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.
术语“烷基”意指含有1-12个碳原子的单价直链或支链饱和的烃基。烷基基团的实例包括 (但不限于)甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基、异己基等。The term "alkyl" means a monovalent straight or branched chain saturated hydrocarbon radical containing 1 to 12 carbon atoms. Examples of alkyl groups include (But not limited to) methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, isohexyl, and the like.
术语“烷氧基”意指含有1-12个碳原子的单价直链或支链饱和的烃基，其在链中含有末端“O”。烷氧基基团的实例包括(但不限于)甲氧基、乙氧基、丙氧基、丁氧基、叔丁氧基、戊氧基基团等。The term "alkoxy" means a monovalent straight or branched chain saturated hydrocarbon radical containing 1 to 12 carbon atoms, which contains a terminal "O" in the chain. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentoxy groups, and the like.
术语“烯基”意指含有2-12个碳原子的单价直链或支链不饱和的烃基。“烯基”基团在链中含有至少一个双键。烯基基团的实例包括(但不限于)乙烯基、丙烯基、正丁烯基、异丁烯基、戊烯基、己烯基等。The term "alkenyl" means a monovalent straight or branched chain unsaturated hydrocarbon radical containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.
术语“炔基”意指含有2-12个碳原子的单价直链或支链不饱和的烃基。“炔基”基团在链中含有至少一个三键。炔基基团的实例包括(但不限于)乙炔基、丙炔基、正丁炔基、异丁炔基、戊炔基、己炔基等。The term "alkynyl" means a monovalent straight or branched chain unsaturated hydrocarbon radical containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.
术语“亚烷基(alkylene或alkylenyl)”意指二价烷基基团。上述单价烷基基团中的任意一个可以通过从其结构中移除一个氢原子而成为亚烷基基团。亚烷基基团的实例包括(但不限于)-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH-等。The term "alkylene or alkylenyl" means a divalent alkyl group. Any of the above monovalent alkyl groups can become an alkylene group by removing one hydrogen atom from its structure. Examples of alkylene groups include, but are not limited to, -CH2- , -CH( CH3 ) - , -C( CH3 ) 2- , -CH2CH2- , -CH2CH ( CH3 ) -, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH-, etc.
术语“环烷基”或“碳环基”意指含有3-18个碳原子的单价单环或多环饱和的烃基。环烷基基团可以是稠合的(例如，十氢萘基)或桥接的(例如，降冰片烷基)。环烷基基团的实例包括(但不限于)环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片烷基(norboranyl)、二环[2.2.2]辛基等。The term "cycloalkyl" or "carbocyclyl" means a monovalent monocyclic or polycyclic saturated hydrocarbon radical containing 3 to 18 carbon atoms. Cycloalkyl groups can be fused (eg, decahydronaphthyl) or bridged (eg, norbornyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norboranyl, bicyclo[2.2.2 ] Hinkie et al.
术语“环杂基”或“环杂烷基”或“杂环烷基”或“杂环基”意指成环原子含有C原子和至少一个选自B、O、N或S的杂原子的单价饱和的或部分饱和的单环或多环的基团，并且不具有芳香性。杂环基基团的实例包括(但不限于)氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、吡咯烷基、噁唑啉基、噁唑烷基、噻唑啉基、噻唑烷基、吡喃基、硫代吡喃基、四氢吡喃基、二噁啉基、哌啶基、吗啉基、硫代吗啉基、硫代吗啉基S-氧化物、硫代吗啉基S-二氧化物、哌嗪基、托烷基、噁唑烷酮基、1,4-二噁烷基、二氢呋喃基、1,3-二氧杂环戊烷基、咪唑烷基、咪唑啉基、1,3-二硫杂环戊烷基、高托烷基(homotropanyl)等。The term "cycloheteryl" or "cycloheteroalkyl" or "heterocycloalkyl" or "heterocyclyl" means a group whose ring atoms contain C atoms and at least one heteroatom selected from B, O, N or S A monovalent saturated or partially saturated monocyclic or polycyclic group that is not aromatic. Examples of heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, Thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S- Oxide, thiomorpholinyl S-dioxide, piperazinyl, tropyl, oxazolidinyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxane Pentyl group, imidazolidinyl group, imidazolinyl group, 1,3-dithiolanyl group, homotropanyl group (homotropanyl group) and the like.
术语“羟烷基”意指被一个或多个羟基基团取代的烷基基团。羟烷基基团的实例包括(但不限于)HO-CH2-、HO-CH2CH2-、CH2-CH(OH)-等。The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups. Examples of hydroxyalkyl groups include, but are not limited to, HO- CH2- , HO- CH2CH2- , CH2 -CH(OH)-, and the like.
术语“卤代烷基”意指被一个或多个卤素原子取代的烷基基团。卤代烷基基团的实例包括(但不限于)三氟甲基、二氟甲基、五氟乙基、三氯甲基等。The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.
术语“卤代烷氧基”意指被一个或多个卤素取代的烷氧基基团。卤代烷基基团的实例包括(但不限于)三氟甲氧基、二氟甲氧基、五氟乙氧基、三氯甲氧基等。The term "haloalkoxy" means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.
术语“氰基”意指-CN基团。The term "cyano" means a -CN group.
术语“氨基”意指-NH2基团。The term "amino" means a -NH2 group.
术语“烷基氨基”或“烷氨基”意指其中一个氢原子被烷基基团替代的氨基基团。烷基氨基基团的实例包括(但不限于)甲基氨基(-NH(CH3))、乙基氨基、丙基氨基、异丙基氨基、正丁基氨基、仲丁基氨基、叔丁基氨基等。The term "alkylamino" or "alkylamino" means an amino group in which one hydrogen atom is replaced by an alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino (-NH( CH3 )), ethylamino, propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino base amino, etc.
术语“二烷基氨基”或“二烷氨基”意指两个氢原子均被烷基基团替代的氨基基团，两个烷基基团可以是相同的或不同的。二烷基氨基基团的实例包括(但不限于)二甲基氨基(-N(CH3)2)、二乙基氨基、二丙基氨基、二异丙基氨基、二正丁基氨基、二仲丁基氨基、二叔丁基氨基、甲基(乙基)氨基、甲基(丁基)氨基等。The term "dialkylamino" or "dialkylamino" means an amino group in which both hydrogen atoms are replaced by an alkyl group, which may be the same or different. Examples of dialkylamino groups include, but are not limited to, dimethylamino (-N( CH3 ) 2 ), diethylamino, dipropylamino, diisopropylamino, di-n-butylamino, Di-sec-butylamino, di-tert-butylamino, methyl (ethyl) amino, methyl (butyl) amino, etc.
盐、前药和溶剂化物Salts, Prodrugs and Solvates
术语“前药”或“前药衍生物”意指母体化合物或活性药物物质的共价键合的衍生物或载体，其在展示其一种或多种药理学作用之前经历至少一些生物转化。一般而言，此类前药具有代谢 可裂解的基团，并在体内快速转化，以产生母体化合物。通常，以改善化学稳定性、改善个体的接受度和顺应性、改善生物利用度、延长作用时间、改善器官选择性、改善配制品(例如，增加的水溶性)和/或减少副作用(例如，毒性)为目标来配制前药。一般而言，前药本身具有弱的生物学活性或不具有生物学活性，并且在通常条件下是稳定的。采用本领域已知的方法可以容易地由母体化合物制备前药，例如描述于以下文献中的方法：A Textbook of Drug Design and Development[药物设计与开发教材]，Krogsgaard-Larsen和H.Bundgaard(编辑)，Gordon&Breach[戈登和布里奇出版社]，1991，特别是第5章：“Design and Applications of Prodrugs[前药的设计和应用]”；Design of Prodrugs[前药的设计]，H.Bundgaard(编辑)，Elsevier[爱思唯尔集团]，1985；Prodrugs:Topical and Ocular Drug Delivery[前药：局部和眼部药物递送]，K.B.Sloan(编辑)，Marcel Dekker马塞尔德克尔公司]，1998；Methods in Enzymology[酶学方法]，K.Widder等人(编辑)，第42卷，Academic Press[学术出版社]，1985，特别是309-396页；Burger's Medicinal Chemistry and Drug Discovery[伯格药物化学和药物发现]，第5版，M.Wolff(编辑)，John Wiley&Sons约翰威立父子出版公司]，1995，特别是第1卷和第172-178页以及第949-982页；Pro-Drugs as Novel Delivery Systems[前药作为新颖递送系统]，T.Higuchi和V.Stella(编辑)，Am.Chem.Soc.[美国化学会志]，1975；Bioreversible Carriers in Drug Design[药物设计中的生物可逆性载体]，E.B.Roche(编辑)，Elsevier[爱思唯尔集团]，1987，其各自通过引用全文的方式并入本文。The term "prodrug" or "prodrug derivative" means a covalently bonded derivative or carrier of a parent compound or active drug substance that undergoes at least some biotransformation before exhibiting one or more of its pharmacological effects. In general, such prodrugs have the ability to metabolize A cleavable group that is rapidly transformed in vivo to yield the parent compound. Typically, to improve chemical stability, improve individual acceptance and compliance, improve bioavailability, prolong duration of action, improve organ selectivity, improve formulation (e.g., increased water solubility), and/or reduce side effects (e.g., Toxicity) as the target to formulate prodrugs. In general, prodrugs themselves have weak or no biological activity and are stable under normal conditions. Prodrugs can be readily prepared from the parent compound using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds. ), Gordon & Breach [Gordon and Bridge Press], 1991, especially Chapter 5: "Design and Applications of Prodrugs [the design and application of prodrugs]"; Design of Prodrugs [the design of prodrugs], H.Bundgaard (Editor), Elsevier [Elsevier Group], 1985; Prodrugs: Topical and Ocular Drug Delivery [Prodrugs: Topical and Ocular Drug Delivery], KBSloan (editor), Marcel Dekker Marcel Dekker Company], 1998; Methods in Enzymology [Enzymology Methods], K. Widder et al. (editors), Vol. 42, Academic Press [Academic Press], 1985, especially pages 309-396; Burger's Medicinal Chemistry and Drug Discovery [Berg Medicinal Chemistry and Drug Discovery], 5th ed., M. Wolff (ed.), John Wiley & Sons], 1995, especially Vol. 1 and pp. 172-178 and pp. 949-982; Pro- Drugs as Novel Delivery Systems[prodrug as a novel delivery system], T.Higuchi and V.Stella (editors), Am.Chem.Soc.[American Chemical Society Journal], 1975; Bioreversible Carriers in Drug Design[drug design in Bioreversible Vectors], EB Roche (editor), Elsevier [Elsevier Group], 1987, each of which is herein incorporated by reference in its entirety.
术语“药学上可接受的前药”意指本发明的化合物的前药，其在合理的医学判断范围内，适合用于与人和低等动物的组织接触，而没有过度的毒性、刺激、过敏反应等，与合理的利益/风险比相称，并且在可能的情况下使其预期用途有效。The term "pharmaceutically acceptable prodrug" means a prodrug of a compound of the present invention which, within the scope of sound medical judgment, is suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, Anaphylaxis, etc., commensurate with a reasonable benefit/risk ratio and, where possible, valid for its intended use.
术语“盐”意指母体化合物的离子形式或母体化合物与合适的酸或碱反应后得到的母体化合物的酸式盐或碱式盐。本发明的化合物的盐可以通过传统化学方法从含有碱性或酸性部分的母体化合物合成。通常，通过使游离碱性或酸性母体化合物与化学计量的量或与过量的所希望的成盐无机或有机酸或碱在合适的溶剂或不同的溶剂组合中反应来制备盐。The term "salt" means the ionic form of the parent compound or the acid or base salt of the parent compound obtained by reacting the parent compound with a suitable acid or base. Salts of the compounds of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, salts are prepared by reacting the free basic or acidic parent compound with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or different combinations of solvents.
术语“药学上可接受的盐”意指本发明的化合物的盐，其在合理的医学判断范围内，适合用于与人和低等动物的组织接触，而没有过度的毒性、刺激、过敏反应等，与合理的利益/风险比相称，并且在可能的情况下使其预期用途有效。该术语包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。由于本发明的化合物在游离碱形式和盐形式两者中是有用的，实际上使用盐形式相当于使用碱形式。合适的盐的列表可以参见例如，S.M.Birge等人，J.Pharm.Sci.[药物科学杂志]，1977，66，第1-19页。The term "pharmaceutically acceptable salt" means a salt of a compound of the present invention which, within the scope of sound medical judgment, is suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction etc., commensurate with a reasonable benefit/risk ratio and, where possible, valid for their intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present invention are useful in both free base and salt forms, use of the salt form is practically equivalent to use of the base form. A list of suitable salts can be found, for example, in S.M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19.
术语“药学上可接受的酸加成盐”意指那些保留游离碱的生物学有效性和特性且并非是生物学或在其他方面不希望的盐，该盐可以是与无机酸(如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、硝酸、磷酸等)和有机酸(如乙酸、三氯乙酸、三氟乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、2-乙酰氧基苯甲酸、丁酸、樟脑酸、樟脑磺酸、肉桂酸、柠檬酸、二葡萄糖酸、乙磺酸、谷氨酸、乙醇酸、甘油磷酸、半硫酸、庚酸、己酸、甲酸、富马酸、2-羟基乙磺酸(羟乙基磺酸)、乳酸、马来酸、羟基马来酸、苹果酸、丙二酸、扁桃酸、均三甲苯磺酸、甲磺酸、萘磺酸、烟酸、2-萘磺酸、草酸、双羟萘酸、果胶酸、苯基乙酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、丙酮酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、对氨基苯磺酸、酒石酸、对甲苯磺酸、十一烷酸等)形成的。The term "pharmaceutically acceptable acid addition salt" means those salts which retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, which salts may be combined with inorganic acids such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, etc.) and organic acids (such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid Acid, Benzoic Acid, 2-Acetoxybenzoic Acid, Butyric Acid, Camphoric Acid, Camphorsulfonic Acid, Cinnamic Acid, Citric Acid, Digluconic Acid, Ethylsulfonic Acid, Glutamic Acid, Glycolic Acid, Glycerophosphoric Acid, Hemisulfuric Acid, Heptanoic acid, caproic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylene Sulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.).
术语“药学上可接受的碱加成盐”意指那些保留游离酸的生物学有效性和特性且并非是生物学或在其他方面不希望的盐，该盐是与无机碱(如氨或者氢氧化物、碳酸盐或碳酸氢盐)或金属阳离子(如钠、钾、锂、钙、镁、铁、锌、铜、锭、铝等)形成的。特别优选的是铵盐、钾盐、钠盐、钙盐和镁盐。衍生自药学上可接受的有机无毒碱的盐包括以下物质的盐：伯胺、仲胺和叔胺化合物，取代的胺(包括天然存在的取代的胺)，环胺和碱性离子交换树脂，如甲 胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、异丙胺、三丙胺、三丁胺、乙醇胺、二乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、海巴明(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲葡糖胺、可可碱、喋呤、哌嗪、哌啶、N-乙基哌啶、四甲基铵化合物、四乙基铵化合物、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、二苄胺、N,N-二苄基苯乙胺、1-二苯羟甲胺、N,N-二苄基乙烯二胺、多胺树脂等。特别优选的有机无毒碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱、咖啡因等。The term "pharmaceutically acceptable base addition salt" means those salts which retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable, which salts are formed with inorganic bases such as ammonia or hydrogen oxides, carbonates or bicarbonates) or metal cations (such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, ingot, aluminum, etc.). Particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amine compounds, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins , such as Jia Amine, Dimethylamine, Trimethylamine, Ethylamine, Diethylamine, Triethylamine, Isopropylamine, Tripropylamine, Tributylamine, Ethanolamine, Diethanolamine, 2-Dimethylaminoethanol, 2-Diethylaminoethanol , dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl glucosamine, theobromine, Pterin, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compound, tetraethylammonium compound, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methyl Morpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, N,N-dibenzylethylenediamine, polyamine resin, etc. Particularly preferred organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, caffeine, and the like.
术语“溶剂化物”意指由溶质(例如本发明的化合物)和溶剂(例如水、乙醇或乙酸)形成的可变化学计量的复合物。这种物理缔合可能涉及不同程度的离子键和共价键，还包括氢键。在某些情况下，溶剂化物能够分离(例如当一种或多种溶剂分子掺入结晶固体的晶格中时)。一般而言，本发明所选择的此类溶剂不会干扰溶质的生物学活性。代表性的溶剂化物包括水合物、乙醇化物、甲醇化物等。术语“水合物”意指溶剂是水的溶剂化物。The term "solvate" means a complex of variable stoichiometry formed from a solute (eg, a compound of the invention) and a solvent (eg, water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated (eg, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). In general, such solvents are selected for the present invention so as not to interfere with the biological activity of the solute. Representative solvates include hydrates, ethanolates, methanolates, and the like. The term "hydrate" means that the solvent is a solvate of water.
如下所讨论的本发明的化合物包括其游离碱或酸，及其盐、溶剂化物和前药，并且可以在其结构中包括适宜的衍生形式，例如氧化的硫原子或季铵化的氮原子(尽管没有明确说明或显示)，特别是其药学上可接受的形式。The compounds of the invention discussed below include their free bases or acids, as well as their salts, solvates and prodrugs, and may include in their structure suitably derivatized forms such as oxidized sulfur atoms or quaternized nitrogen atoms ( although not expressly stated or shown), especially in pharmaceutically acceptable forms thereof.
异构体isomer
术语“异构体”意指具有相同数量和种类的原子，并因此具有相同的分子量，但原子的空间排列方式或构型不同的化合物。该术语包括立体异构体和几何异构体。The term "isomer" means compounds that have the same number and kind of atoms, and thus the same molecular weight, but differ in the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.
术语“立体异构体”或“光学异构体”意指具有至少一个手性元素，例如手性原子或因旋转受限而导致具有垂直的不对称平面(例如，某些联苯、丙二烯和螺环化合物)，并且可以使平面偏振光发生旋转的稳定异构体。本发明的化合物(及其盐、溶剂化物或前药等衍生形式)包括不对称碳原子，因此可以作为单个立体异构体、外消旋体、以及对映异构体和非对映异构体的混合物存在。典型地，此类化合物将以外消旋混合物进行制备。然而，如果希望，此类化合物可以制备或分离成立体异构体，即作为单独的对映异构体或非对映异构体(或称“手性纯化合物”)，或作为富集立体异构体的混合物(或称“基本上手性纯化合物”)。如下文更详细讨论的，化合物的单独的立体异构体通过由含有所希望的手性中心的光学活性起始材料合成来制备，或者通过制备外消旋混合物后分离或拆分来制备。特定立体化学的起始化合物可以是商购的或者通过下文描述的方法制备并通过本领域熟知的技术拆分的。术语“对映异构体”或“对映体”意指彼此互为镜像而无法重叠的一对立体异构体。术语“非对映异构体”或“非对映体”意指彼此之间不构成镜像关系的一对立体异构体。术语“外消旋混合物”或“外消旋体”意指含有等份(通常为等摩尔)的一对对映异构体的混合物。术语“非外消旋混合物”意指含有不等份的一对对映异构体的混合物。The terms "stereoisomer" or "optical isomer" mean those having at least one chiral element, e.g. alkenes and spiro compounds) and are stable isomers that can rotate plane-polarized light. The compounds of the present invention (and derivative forms thereof such as salts, solvates, or prodrugs) include asymmetric carbon atoms and can therefore be obtained as individual stereoisomers, racemates, and enantiomers and diastereoisomers. A mixture of bodies exists. Typically, such compounds will be prepared as racemic mixtures. However, if desired, such compounds may be prepared or isolated as stereoisomers, either as individual enantiomers or diastereomers (or "chirally pure compounds"), or as stereoenriched A mixture of isomers (or "substantially chirally pure compound"). As discussed in more detail below, individual stereoisomers of compounds are prepared either synthetically from optically active starting materials containing the desired chiral centers, or by separation or resolution after preparation of racemic mixtures. Starting compounds of particular stereochemistry are either commercially available or prepared by the methods described below and resolved by techniques well known in the art. The term "enantiomer" or "enantiomer" means a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereoisomer" or "diastereomer" means a pair of stereoisomers that are not mirror images of each other. The term "racemic mixture" or "racemate" means a mixture containing equal parts (usually equimolar) of a pair of enantiomers. The term "nonracemic mixture" means a mixture containing unequal parts of a pair of enantiomers.
本领域熟知的是，化合物的生物学和药理学活性对化合物的立体化学敏感。因此，例如，对映异构体通常展示出显著不同的生物学活性，包括药代动力学特性的差异(包括代谢、蛋白结合等)和药理学特性(包括所展示的活性类型、活性程度、毒性等)。因此，本领域技术人员理解的是，当相对于其他对映异构体富集时或当与其他对映异构体分开时，其中一种对映异构体可以更具活性或可以展示出有益作用。因此，尽管可以使用药物的外消旋形式，但其通常不如施用等量的对映异构体纯的药物有效。实际上，在一些情况下，一种对映异构体可以是药理学上无活性的并且仅仅起简单的稀释剂作用。此外，一对对映异构体甚至可以具有明显不同的生物学活性。实际上，一些纯化的单一对映异构体相对于其外消旋体更具优势。因此，如果一种对映异构体在药理学上比其他对映异构体具有更高的活性、更低的毒性或者更优选的体内分布，则优选施用这种对映异构体在治疗上将是更有益的。通过这种方式，接受治疗的个体将暴露于更低总剂量的药物和更低剂量的可能具有毒性的对映异构体。It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including type of activity exhibited, degree of activity, toxicity, etc.). Thus, it is understood by those skilled in the art that one of the enantiomers may be more active or may exhibit Beneficial effect. Thus, while a racemic form of a drug can be used, it is generally not as effective as administering an equivalent amount of an enantiomerically pure drug. Indeed, in some cases one enantiomer may be pharmacologically inactive and act only as a simple diluent. Furthermore, a pair of enantiomers may even have distinctly different biological activities. Indeed, some purified single enantiomers are more dominant than their racemates. Therefore, if one enantiomer is pharmacologically more active, less toxic, or more preferred in vivo distribution than the other enantiomer, it is preferred to administer the enantiomer in the treatment of Admiral will be more helpful. In this way, the treated individual will be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer.
纯的对映异构体或者具有所希望的对映异构体过量(ee)或对映异构体纯度的混合物的制 备可以通过一种或多种本领域技术人员已知的用于(a)分离或拆分对映异构体或(b)选择性合成对映异构体的方法，或者这些方法的组合来完成。上述方法通常依赖于手性识别，例如使用手性固定相的色谱法、对映体选择性主体-客体络合、拆分或使用手性助剂合成、对映体选择性合成、酶促和非酶促动力学拆分、自发的对映体选择性结晶等。此类方法通常披露于以下文献：Chiral Separation Techniques:A Practical Approach[手性分离技术：一种实用的方法](第2版)，G.Subramanian(编辑)，Wiley-VCH[威利-VCH公司]，2000；T.E.Beesley和R.P.W.Scott，Chiral Chromatography[手性色谱法]，John Wiley&Sons[约翰威立父子出版公司]，1999；以及Satinder Ahuja，Chiral Separations by Chromatography[通过色谱法的手性分离]，Am.Chem.Soc.[美国化学会志]，2000。此外，用于定量对映异构体过量或纯度的方法(例如GC、HPLC、CE或NMR)和用于识别绝对构型和构象的方法(例如CD、ORD、X射线晶体学或NMR)同样是本领域熟知的。Preparation of pure enantiomers or mixtures with desired enantiomeric excess (ee) or enantiomeric purity The preparation can be obtained by one or more methods known to those skilled in the art for (a) separating or resolving enantiomers or (b) selectively synthesizing enantiomers, or a combination of these methods Finish. The above methods usually rely on chiral recognition, such as chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and Non-enzymatic kinetic resolution, spontaneous enantioselective crystallization, etc. Such methods are generally disclosed in the following literature: Chiral Separation Techniques: A Practical Approach [Chiral Separation Technique: A Practical Approach] (2nd Edition), G. Subramanian (Editor), Wiley-VCH [Wiley-VCH Company ], 2000; TEBeesley and RPWScott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem.Soc. [Journal of the American Chemical Society], 2000. In addition, methods for quantifying enantiomeric excess or purity (such as GC, HPLC, CE, or NMR) and methods for identifying absolute configuration and conformation (such as CD, ORD, X-ray crystallography, or NMR) are equally are well known in the art.
术语“几何异构体”意指由双键(例如，顺式-2-丁烯和反式-2-丁烯)或环结构(例如，顺式-1,3-二氯环丁烷和反式-1,3-二氯环丁烷)中的旋转自由度受限而产生的稳定异构体。使用顺式/反式惯例或使用E或Z系统表示异构体的具体构型，其中术语“E”或“E型”意指更高次序的取代基在双键的相对侧，术语“Z”或“Z型”意指更高次序的取代基在双键的同一侧。E型和Z型异构体的确定可以通过分析方法进行，如X射线晶体学、1H-NMR、和13C-NMR。The term "geometric isomer" means an isomer formed from a double bond (for example, cis-2-butene and trans-2-butene) or a ring structure (for example, cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane) is a stable isomer resulting from restricted rotational freedom. The specific configuration of an isomer is indicated using the cis/trans convention or using the E or Z system, where the term "E" or "E-type" means that the higher order substituents are on opposite sides of the double bond and the term "Z " or "Z type" means that the higher order substituents are on the same side of the double bond. Determination of E-form and Z-form isomers can be performed by analytical methods such as X-ray crystallography, 1 H-NMR, and 13 C-NMR.
术语“互变异构体”意指由化合物分子中某一原子在至少两个可连接位点上迅速迁移而产生的多个官能团异构体，但通常以其中一种比较稳定的异构体作为主要的存在形式，例如酮-烯醇(keto-enol)互变异构体、亚胺-烯胺(imine-enamine)互变异构体等。本发明的化合物能以多于一种的互变异构形式存在，因此本发明的化合物包括所有此类互变异构体。The term "tautomer" refers to multiple functional isomers produced by the rapid migration of an atom in a compound molecule at at least two attachable sites, but usually in the form of one of the more stable isomers. As main forms of existence, for example, keto-enol (keto-enol) tautomer, imine-enamine (imine-enamine) tautomer and the like. The compounds of the present invention can exist in more than one tautomeric form and thus the compounds of the present invention include all such tautomers.
一般而言，化合物的所有异构形式及其混合物，无论是单独的互变异构体、几何异构体或立体异构体，还是外消旋的或非外消旋的混合物，都是期望的，除非在该化合物的名称或结构中明确指出具体的异构形式。In general, all isomeric forms of compounds and mixtures thereof, whether individual tautomers, geometric isomers or stereoisomers, or racemic or nonracemic mixtures, are contemplated unless the specific isomeric form is clearly indicated in the name or structure of the compound.
药物组合物pharmaceutical composition
术语“药物组合物”意指呈适于口服施用或肠胃外施用的形式的本发明的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、立体异构体或互变异构体，以及至少一种药学上可接受的载体。术语“载体”意指涉及从一个组织、器官、系统或受试者的身体部分向另一个组织、器官、系统或受试者的身体部分携带或运输化合物或组合物的辅助性材料或媒介物，如液体或固体填充剂(或稀释剂)、赋形剂、溶剂、包封材料等。The term "pharmaceutical composition" means a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, in a form suitable for oral or parenteral administration Construct, and at least one pharmaceutically acceptable carrier. The term "vector" means an auxiliary material or vehicle involved in carrying or transporting a compound or composition from one tissue, organ, system or body part of a subject to another tissue, organ, system or body part of a subject , such as liquid or solid fillers (or diluents), excipients, solvents, encapsulating materials, etc.
药物施用、预防、改善和治疗Drug administration, prevention, amelioration and treatment
术语“个体”或“受试者”(例如“患者”)可以是哺乳动物，例如人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪或非人灵长类动物，如猴(如恒河猴)、黑猩猩、狒狒等。在某些实施方案中，受试者是灵长类动物。在某些其他的实施例中，受试者是人。如果受试者在施用药物(例如本发明的化合物或组合物)后将在生物学上、在医学上或在生活质量上获益，那么受试者对于这种预防、改善和/或治疗是有需要的。The term "individual" or "subject" (e.g., "patient") may be a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as Monkeys (such as rhesus monkeys), chimpanzees, baboons, etc. In certain embodiments, the subject is a primate. In certain other embodiments, the subject is a human. If the subject will benefit biologically, medically or in quality of life after administering the drug (such as a compound or composition of the present invention), then the subject is interested in such prevention, improvement and/or treatment needed.
当与化合物一起使用时，“有效量”或“预防、改善和/或治疗有效量”意指本发明的化合物的如下量，当向对其有需要的个体施用时，该量能够(i)治疗或预防特定疾病、病症或障碍，(ii)减轻或消除特定疾病、病症或障碍的一种或多种症状，或(iii)预防或延迟特定疾病、病症或障碍的一种或多种症状的发作。这样的量足以引起研究人员或临床医生所寻求的组织、器官、系统或个体的生物学或医学反应。构成有效量的本发明的化合物的具体用量将根据以下因素变化，例如，用于施用的化合物或组合物及其生物学性质(例如药代动力学性质)、施用时间和频次、施用周期、施用途径、所针对的疾病或障碍的类型及其严重程度、与本发明的化合物或组合物联用的药物，以及个体的年龄、性别、体重、一般健康和饮食等因素，可以由本领域技术人员据其掌握的专业知识和文献教示而确定。 "Effective amount" or "prophylactically, amelioratingly and/or therapeutically effective amount" when used with a compound means an amount of a compound of the invention which, when administered to an individual in need thereof, is capable of (i) Treating or preventing a particular disease, condition or disorder, (ii) alleviating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying one or more symptoms of a particular disease, condition or disorder onset. Such amounts are sufficient to elicit the biological or medical response in the tissue, organ, system or individual sought by the researcher or clinician. The specific amount of a compound of the invention that constitutes an effective amount will vary depending on factors such as the compound or composition used for administration and its biological properties (e.g., pharmacokinetic properties), time and frequency of administration, period of administration, administration The route, the type of disease or disorder targeted and its severity, the drugs used in combination with the compound or composition of the present invention, and factors such as the age, sex, weight, general health and diet of the individual can be determined by those skilled in the art. It is determined by its professional knowledge and literature teaching.
术语“抑制(inhibit、inhibiting或inhibition)”意指遏制特定疾病、病症或障碍。术语“预防(prevent、preventing或prevention)”意指特定疾病、病症或障碍的预防性治疗，或延迟疾病、病症或障碍的发作或进展。术语“改善(ameliorate、ameliorating或amelioration)”意指使特定疾病、病症或障碍向正常的生理学状态发展；或降低或减轻特定疾病、病症或障碍(或优化至少一种相关的生理学参数或生物标记物)。术语“治疗(treat、treating或treatment)”意指消除特定疾病、病症或障碍。The term "inhibit, inhibiting or inhibition" means to suppress a particular disease, condition or disorder. The terms "prevent, preventing or prevention" mean the prophylactic treatment of a particular disease, condition or disorder, or delaying the onset or progression of a disease, condition or disorder. The term "ameliorate, ameliorating or amelioration" means to progress a particular disease, condition or disorder towards a normal physiological state; or to reduce or alleviate a particular disease, condition or disorder (or to optimize at least one relevant physiological parameter or biomarker). ). The terms "treat, treating or treatment" mean the elimination of a particular disease, condition or disorder.
术语“药学上可接受的”意指物质(例如本发明的化合物或组合物，或其衍生形式)必须在化学和/或毒理学上与其他配伍成分和/或正在施用其的个体相容。The term "pharmaceutically acceptable" means that a substance (such as a compound or composition of the present invention, or a derivative thereof) must be chemically and/or toxicologically compatible with other compatible ingredients and/or the individual to whom it is administered.
术语“施用(administer、administering或administration)”意指将物质(例如本发明的化合物或组合物，或其衍生形式)递送至对其有需要的受试者，具体的递送方式可以是本领域技术人员熟知的，例如口服地、肠胃外地、皮下地、肌内地、通过管道或腔体地等。The term "administer, administering or administration" means delivering a substance (such as a compound or composition of the present invention, or a derivative thereof) to a subject in need thereof, and the specific delivery method may be a method skilled in the art Well-known, for example, orally, parenterally, subcutaneously, intramuscularly, through a catheter or a cavity, and the like.
术语“IKZF2依赖性疾病或障碍”意指任何直接地或间接地受IKZF2蛋白水平的调节影响的疾病或障碍。The term " IKZF2- dependent disease or disorder" means any disease or disorder that is directly or indirectly affected by the modulation of IKZF2 protein levels.
化合物compound
一方面，本发明提供了一类新颖的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，该类化合物具有如式(I)所示的结构：
In one aspect, the present invention provides a class of novel compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chirally pure compounds, stereoisomers or tautomers thereof, which have Structure as shown in formula (I):
其中：in:
X1、X2和X3各自独立地为CR8或N；X 1 , X 2 and X 3 are each independently CR 8 or N;
X4为CR9R10或C＝O，其中R9和R10各自独立地为氢或C1-C4烷基；X 4 is CR 9 R 10 or C=O, wherein R 9 and R 10 are each independently hydrogen or C 1 -C 4 alkyl;
R1、R2、R3和R8各自独立地为氢、羟基、巯基、卤素、叠氮基、氰基、取代或未取代的胺基、硝基、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C1-C6酯基、取代或未取代的C1-C6酰胺基、取代或未取代的C1-C6酰基、取代或未取代的C1-C6磺酰基、取代或未取代的C1-C6磺酰胺基、取代或未取代的C1-C6磺酸酯基、取代或未取代的C1-C6膦酰基、取代或未取代的C1-C6膦酰胺基或者取代或未取代的C1-C6膦酸酯基；R 1 , R 2 , R 3 and R 8 are each independently hydrogen, hydroxyl, mercapto, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight-membered ring heteroalkyl, substituted or unsubstituted C 1 -C 6 ester group, substituted or unsubstituted C 1 -C 6 amide group, substituted or Unsubstituted C 1 -C 6 acyl, substituted or unsubstituted C 1 -C 6 sulfonyl, substituted or unsubstituted C 1 -C 6 sulfonamide, substituted or unsubstituted C 1 -C 6 sulfonate substituted or unsubstituted C 1 -C 6 phosphono, substituted or unsubstituted C 1 -C 6 phosphonamido or substituted or unsubstituted C 1 -C 6 phosphonate;
或者，R1、R2和R3中的任意两个相互连接成取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基；Alternatively, any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl, a substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted five to ten membered heteroaryl;
R4、R5、R6和R7各自独立地为氢、羟基、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基；R 4 , R 5 , R 6 and R 7 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted Substituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight membered ring heteroalkyl, substituted or unsubstituted C 6 -C 10 aryl Or a substituted or unsubstituted five to ten membered heteroaryl group;
或者，R4和R5以及R6和R7各自独立地相互连接成取代或未取代的C3-C8环烷基或者取代或未取代的三至八元环杂烷基；Alternatively, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three- to eight-membered cycloheteroalkyl group;
为取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基或者取代或未取代的三至八元环杂烯基； is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl or a substituted or unsubstituted three to eight-membered cycloheteroalkenyl;
为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基； It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group;
为取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基； is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight membered heteroalkyl group, a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten Yuan Heteroaryl;
为取代或未取代的C6-C10芳基、取代或未取代的五至十元芳杂基、取代或未取代的C3-C8环烷基或者取代或未取代的三至八元环杂烷基； is a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted five to ten membered heteroaryl group, a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three to eight membered Cycloheteroalkyl;
所述烷杂基、环杂烷基和芳杂基中杂原子的个数各自独立地为1、2、3或4，每个所述杂原子各自独立地为B、N、O或S。The number of heteroatoms in the alkane group, cycloheteroalkyl group and aryl group is independently 1, 2, 3 or 4, and each of the heteroatoms is B, N, O or S independently.
在一些实施方案中，X1、X2和X3各自独立地为CR8，其中R8如式(I)中所定义。In some embodiments, each of X 1 , X 2 and X 3 is independently CR 8 , wherein R 8 is as defined in formula (I).
在一些优选的实施方案中，X1、X2和X3各自独立地为CR8，其中R8为氢、C1-C6卤代烷基或C1-C6卤代烷氧基。In some preferred embodiments, X 1 , X 2 and X 3 are each independently CR 8 , wherein R 8 is hydrogen, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy.
在一些更优选的实施方案中，X1、X2和X3各自独立地为C-H、C-CH2F、C-CHF2、C-CF3、C-OCH2F、C-OCHF2或C-OCF3。In some more preferred embodiments, X 1 , X 2 and X 3 are each independently CH, C-CH 2 F, C-CHF 2 , C-CF 3 , C-OCH 2 F, C-OCHF 2 or C-OCF 3 .
在一些进一步优选的实施方案中，X1、X2和X3均为C-H。In some further preferred embodiments, Xi , X2 and X3 are all CH.
在一些实施方案中，X4为CH2或C＝O。In some embodiments, X4 is CH2 or C=O.
在一些优选的实施方案中，X4为CH2。In some preferred embodiments, X4 is CH2 .
在一些实施方案中，R1、R2和R3各自独立地为氢、卤素、叠氮基、氰基、取代或未取代的胺基、硝基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的三至六元环杂烷基或者取代或未取代的C1-C4酰基。In some embodiments, R 1 , R 2 and R 3 are each independently hydrogen, halogen, azido, cyano, substituted or unsubstituted amine, nitro, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted three to six membered cycloheteroalkyl or substituted or unsubstituted C 1 -C 4 acyl.
在一些优选的实施方案中，R1、R2和R3各自独立地为氢、氟、氯、溴、碘、叠氮基、氰基、胺基、硝基、取代或未取代的甲基、取代或未取代的甲氧基、取代或未取代的吡咯烷基或者取代或未取代的乙酰基。In some preferred embodiments, R 1 , R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, azido, cyano, amine, nitro, substituted or unsubstituted methyl , substituted or unsubstituted methoxy, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted acetyl.
在一些更优选的实施方案中，R1、R2和R3各自独立地为氢、氟、氯、溴、氰基、胺基、硝基、三氟甲基、三氟甲氧基或乙酰基。In some more preferred embodiments, R 1 , R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, cyano, amine, nitro, trifluoromethyl, trifluoromethoxy or acetyl base.
在一些进一步优选的实施方案中，R1、R2和R3各自独立地为氟或氰基。In some further preferred embodiments, R 1 , R 2 and R 3 are each independently fluoro or cyano.
在另一些实施方案中，R1、R2和R3中的任意两个相互连接成取代或未取代的三至六元环杂烷基或者取代或未取代的五至六元芳杂基。In other embodiments, any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted three- to six-membered ring heteroalkyl group or a substituted or unsubstituted five- to six-membered heteroaryl group.
在另一些优选的实施方案中，R1、R2和R3中的任意两个相互连接成取代或未取代的三至六元含氧环杂烷基或者取代或未取代的五至六元含氮芳杂基。In other preferred embodiments, any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted three- to six-membered oxygen-containing cycloheteroalkyl group or a substituted or unsubstituted five- to six-membered Nitrogen-containing aryl group.
在另一些更优选的实施方案中，R1、R2和R3中的任意两个相互连接成取代或未取代的1,3-二氧环杂戊烷基、取代或未取代的1,2-氧硼环杂戊烷基或者取代或未取代的吡唑基。In other more preferred embodiments, any two of R 1 , R 2 and R 3 are connected to each other to form substituted or unsubstituted 1,3-dioxolane, substituted or unsubstituted 1, 2-Oxaborolyl or substituted or unsubstituted pyrazolyl.
在一些实施方案中，R4、R5、R6和R7各自独立地为氢或者取代或未取代的C1-C4烷基。In some embodiments, R 4 , R 5 , R 6 and R 7 are each independently hydrogen or substituted or unsubstituted C 1 -C 4 alkyl.
在一些优选的实施方案中，R4、R5、R6和R7各自独立地为氢或者取代或未取代的甲基。In some preferred embodiments, R 4 , R 5 , R 6 and R 7 are each independently hydrogen or substituted or unsubstituted methyl.
在一些更优选的实施方案中，R4、R5、R6和R7均为氢。In some more preferred embodiments, R4 , R5 , R6 and R7 are all hydrogen.
在另一些实施方案中，R4和R5以及R6和R7各自独立地相互连接成取代或未取代的C3-C6环烷基或者取代或未取代的三至六元环杂烷基。In other embodiments, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted three to six membered cycloheteroalkane base.
在另一些优选的实施方案中，R4和R5以及R6和R7各自独立地相互连接成取代或未取代的C3-C6环烷基。In other preferred embodiments, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 6 cycloalkyl group.
在另一些更优选的实施方案中，R4和R5以及R6和R7各自独立地相互连接成取代或未取 代的环丙基。In other more preferred embodiments, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to be substituted or unsubstituted Substituted cyclopropyl.
在一些实施方案中，为取代或未取代的三至六元环杂烷基或者取代或未取代的三至六元环杂烯基。In some embodiments, is a substituted or unsubstituted three- to six-membered cycloheteroalkyl group or a substituted or unsubstituted three- to six-membered cycloheteroalkenyl group.
在一些优选的实施方案中，为取代或未取代的哌啶基(例如， 等)或者取代或未取代的四氢吡啶基(例如， 等)。In some preferred embodiments, is substituted or unsubstituted piperidinyl (for example, etc.) or substituted or unsubstituted tetrahydropyridyl (for example, wait).
在一些更优选的实施方案中，为取代或未取代的或者取代或未取代的 In some more preferred embodiments, for substituted or unsubstituted either substituted or unsubstituted
在一些实施方案中，为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基。In some embodiments, It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group.
在一些优选的实施方案中，为取代或未取代的苯基(例如，等)、取代或未取代的吡啶基(例如，等)、取代或未取代的哒嗪基(例如，等)或者取代或未取代的嘧啶基(例如，等)。In some preferred embodiments, is substituted or unsubstituted phenyl (for example, etc.), substituted or unsubstituted pyridyl (for example, etc.), substituted or unsubstituted pyridazinyl (for example, etc.) or substituted or unsubstituted pyrimidinyl (for example, wait).
在一些更优选的实施方案中，为取代或未取代的 In some more preferred embodiments, for substituted or unsubstituted
在一些实施方案中，为取代或未取代的C3-C6环烷基(例如，等)或者取代或未取代的三至六元杂环烷基。In some embodiments, is a substituted or unsubstituted C 3 -C 6 cycloalkyl group (for example, etc.) or substituted or unsubstituted three to six membered heterocycloalkyl.
在一些优选的实施方案中，为取代或未取代的三至六元杂环烷基。 In some preferred embodiments, is a substituted or unsubstituted three to six membered heterocycloalkyl.
在一些更优选的实施方案中，为取代或未取代的哌嗪基(例如， 等)或者取代或未取代的哌啶基(例如，等)。In some more preferred embodiments, is substituted or unsubstituted piperazinyl (for example, etc.) or substituted or unsubstituted piperidinyl (for example, wait).
在一些进一步优选的实施方案中，为取代或未取代的 In some further preferred embodiments, for substituted or unsubstituted
在一些实施方案中，为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基。In some embodiments, It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group.
在一些优选的实施方案中，为取代或未取代的C6-C10芳基。In some preferred embodiments, is a substituted or unsubstituted C 6 -C 10 aryl group.
在一些更优选的实施方案中，为取代或未取代的苯基(例如，等)。In some more preferred embodiments, is substituted or unsubstituted phenyl (for example, wait).
在一些实施方案中，杂环烷基和杂芳基中杂原子的个数各自独立地为1、2或3，优选1或2，例如含有1个杂原子的吡咯烷基、四氢呋喃基、四氢噻吩基、吡咯基、呋喃基、噻吩基等，含有2个杂原子的咪唑烷基、噁唑烷基、噻唑烷基、咪唑基、噁唑基、噻唑基等，含有3个杂原子的1,2,4-三唑基、1,3,4-噁二唑基、1,3,4-噻二唑基等。In some embodiments, the number of heteroatoms in heterocycloalkyl and heteroaryl is independently 1, 2 or 3, preferably 1 or 2, such as pyrrolidinyl, tetrahydrofuryl, tetra Hydrothienyl, pyrrolyl, furyl, thienyl, etc., imidazolidinyl, oxazolidinyl, thiazolidinyl, imidazolyl, oxazolyl, thiazolyl, etc., containing 2 heteroatoms, containing 3 heteroatoms 1,2,4-triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, etc.
在一些实施方案中，杂环烷基和杂芳基各自独立地含有至少一个杂原子，每个杂原子各自独立地为B、N或O，优选N或O，例如含有2个氧原子的1,3-二氧杂环戊烷基含有1个氧原子和1个硼原子的2-羟基-1,2-氧杂环戊硼烷基含有2个氧原子和1个硼原子的2-苯基-1,3,2-二氧杂环戊硼烷基等。In some embodiments, heterocycloalkyl and heteroaryl each independently contain at least one heteroatom, each heteroatom is independently B, N or O, preferably N or O, for example 1 containing 2 oxygen atoms ,3-Dioxolanyl 2-Hydroxy-1,2-oxaborolyl containing 1 oxygen atom and 1 boron atom 2-Phenyl-1,3,2-dioxaborolyl containing 2 oxygen atoms and 1 boron atom wait.
在一些实施方案中，当基团被至少一个取代基取代时，每个取代基各自独立地为氰基、羟基、氟、氯、溴、碘、C1-C4烷基、C1-C4卤代烷基或C1-C4卤代烷氧基。In some embodiments, when a group is substituted with at least one substituent, each substituent is independently cyano, hydroxyl, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy.
在一些优选的实施方案中，每个取代基各自独立地为羟基、氟、氯、甲基或乙基。In some preferred embodiments, each substituent is independently hydroxy, fluoro, chloro, methyl or ethyl.
在一些更优选的实施方案中，每个取代基各自独立地为羟基、氟或甲基。In some more preferred embodiments, each substituent is independently hydroxy, fluoro, or methyl.
在一些具体的实施方案中，本发明的化合物具有如式(II)所示的结构，
In some specific embodiments, the compound of the present invention has a structure as shown in formula (II),
其中，X4、R1、R2、R3、如式(I)中所定义。Among them, X 4 , R 1 , R 2 , R 3 , as defined in formula (I).
在一些优选的实施方案中，式(II)中的X4为CH2；换言之，本发明的化合物具有如式(II’)所示的结构，
In some preferred embodiments, X 4 in formula (II) is CH 2 ; in other words, the compound of the present invention has the structure shown in formula (II'),
其中，R1、R2、R3、如式(I)中所定义。Among them, R 1 , R 2 , R 3 , as defined in formula (I).
在一些更具体的实施方案中，本发明的化合物具有如式(III)所示的结构，
In some more specific embodiments, the compound of the present invention has a structure as shown in formula (III),
其中，表示单键或双键；R1、R2、R3、如式(I)中所定义。in, Indicates a single or double bond; R 1 , R 2 , R 3 , as defined in formula (I).
在一些优选的实施方案中，式(III)中的表示单键；换言之，本发明的化合物具有如式(III’)所示的结构，
In some preferred embodiments, in formula (III) represents a single bond; in other words, the compound of the present invention has a structure as shown in formula (III'),
其中，R1、R2、R3、如式(I)中所定义。Among them, R 1 , R 2 , R 3 , as defined in formula (I).
在一些甚至更具体的实施方案中，本发明的化合物具有如式(IV)所示的结构，
In some even more specific embodiments, the compounds of the present invention have the structure shown in formula (IV),
其中，X5、X6、X7和X8各自独立地为CH或N；R1、R2、R3、如式(I)中所定义。Wherein, X 5 , X 6 , X 7 and X 8 are each independently CH or N; R 1 , R 2 , R 3 , as defined in formula (I).
在一些优选的实施方案中，式(IV)中的X5、X6、X7和X8各自独立地为CH或N，且至少一个为CH。In some preferred embodiments, X 5 , X 6 , X 7 and X 8 in formula (IV) are each independently CH or N, and at least one is CH.
在一些更优选的实施方案中，式(IV)中的X5、X6、X7和X8各自独立地为CH或N，且至少两个为CH。In some more preferred embodiments, X 5 , X 6 , X 7 and X 8 in formula (IV) are each independently CH or N, and at least two are CH.
在一些甚至更优选的实施方案中，式(IV)中的X5、X6、X7和X8各自独立地为CH或N，且至少三个为CH。In some even more preferred embodiments, X5 , X6 , X7 and X8 in formula (IV) are each independently CH or N, and at least three are CH.
在一些进一步优选的实施方案中，式(IV)中的X5、X6、X7和X8均为CH。In some further preferred embodiments, X 5 , X 6 , X 7 and X 8 in formula (IV) are all CH.
在一些进一步具体的实施方案中，本发明的化合物具有如式(V)所示的结构，
In some further specific embodiments, the compound of the present invention has a structure as shown in formula (V),
其中，X9和X10各自独立地为CH或N。Wherein, X 9 and X 10 are each independently CH or N.
在一些优选的实施方案中，式(V)中的X9和X10各自独立地为CH或N，且至少一个为N。In some preferred embodiments, X 9 and X 10 in formula (V) are each independently CH or N, and at least one is N.
在一些更优选的实施方案中，式(V)中的X9和X10均为N。In some more preferred embodiments, both X9 and X10 in formula (V) are N.
在一些更进一步具体的实施方案中，本发明的化合物具有如式(VI)所示的结构，
In some further specific embodiments, the compound of the present invention has a structure as shown in formula (VI),
其中，R1、R2和R3如式(I)中所定义。Wherein, R 1 , R 2 and R 3 are as defined in formula (I).
另一方面，本发明提供了以下具体的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体。

In another aspect, the present invention provides the following specific compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chiral pure compounds, stereoisomers or tautomers thereof.

化合物的制备Compound preparation
本发明的化合物可以使用下文所述的方法、合成有机化学领域中已知的合成方法或本领域技术人员所掌握的方法来制备，优选的方法包括(但不限于)下文所述的方法，其中起始材料是可商购的或者通过文献中披露的方法制备的。The compounds of the present invention can be prepared using the methods described below, synthetic methods known in the field of synthetic organic chemistry, or methods mastered by those skilled in the art. Preferred methods include (but are not limited to) the methods described below, wherein Starting materials were either commercially available or prepared by methods disclosed in the literature.
适于制备本发明的化合物的示例性方法包括以下步骤：
Exemplary methods suitable for preparing compounds of the invention include the following steps:
(1)在碱性条件下，作为起始原料的化合物I-1与化合物I-2在溶剂中反应，得到化合物I-3；(1) Under alkaline conditions, react compound I-1 and compound I-2 as starting materials in a solvent to obtain compound I-3;
(2)在钯催化剂参与下，化合物I-3与化合物I-4发生suzuki偶联反应，得到化合物I-5；(2) With the participation of a palladium catalyst, a Suzuki coupling reaction occurs between compound I-3 and compound I-4 to obtain compound I-5;
(3)在钯催化剂参与下，化合物I-5经催化氢化，得到化合物I-6；(3) With the participation of a palladium catalyst, compound I-5 is subjected to catalytic hydrogenation to obtain compound I-6;
(4)在酸性条件下，化合物I-6脱去Boc保护基，得到化合物I-7；和(4) Under acidic conditions, compound I-6 removes the Boc protecting group to obtain compound I-7; and
(5)在碱性条件下，化合物I-7与化合物I-8在溶剂中反应，得到化合物I-9，即本发明的式(VI)化合物；(5) Under alkaline conditions, compound I-7 and compound I-8 react in a solvent to obtain compound I-9, which is the compound of formula (VI) of the present invention;
其中：in:
适于制备化合物I-8的示例性方法包括以下步骤：
An exemplary method suitable for preparing compound 1-8 includes the following steps:
(a)在碱性条件下，化合物8a与哌嗪-1-羧酸叔丁酯在溶剂中反应，得到化合物8b；(a) under basic conditions, compound 8a reacts with piperazine-1-tert-butyl carboxylate in a solvent to obtain compound 8b;
(b)在酸性条件下，化合物8b脱去Boc保护基，得到化合物8c；和(b) under acidic conditions, compound 8b removes the Boc protecting group to obtain compound 8c; and
(c)在碱性条件下，化合物8c与1,4-二(氯甲基)苯在溶剂中反应，得到化合物I-8。(c) Under basic conditions, compound 8c reacts with 1,4-bis(chloromethyl)benzene in a solvent to obtain compound I-8.
以下结合具体实施例来进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件来进行。The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods without specific conditions indicated in the following examples are usually carried out according to conventional conditions or according to the conditions suggested by the manufacturer.
除非另有说明，否则本发明中的百分数、比率、比例或份数按重量计。Unless otherwise stated, percentages, ratios, proportions or parts herein are by weight.
除非另有说明，否则本发明中的核磁氢谱(1H-NMR)采集自Bruker 400MHz核磁共振仪，化学位移(δ)的单位是百万分之一(ppm)，内标是四甲基硅烷(TMS)，使用的缩略语的含义如下：s，单峰；d，二重峰；dd，双二重峰；ddd，双双二重峰；qd，四二重峰；t，三重峰；dt，双三重峰；q，四重峰；qu，五重峰；m，多重峰；br，宽峰。 Unless otherwise specified, the proton nuclear magnetic spectrum ( 1 H-NMR) among the present invention is collected from Bruker 400MHz nuclear magnetic resonance instrument, and the unit of chemical shift (δ) is one millionth (ppm), and internal standard is tetramethyl Silane (TMS), the abbreviations used have the following meanings: s, singlet; d, doublet; dd, double doublet; ddd, double doublet doublet; qd, quadruplet doublet; t, triplet; dt, doublet triplet; q, quartet; qu, quintet; m, multiplet; br, broad.
除非另有说明，否则本发明中的质谱(MS)采集自Quattro MicroTM API三重四极杆质谱仪。Unless otherwise stated, mass spectra (MS) in the present invention were collected on a Quattro Micro ™ API triple quadrupole mass spectrometer.
实施例1 4-(4-(4-((4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)-3-氟苯甲腈(化合物1)的制备Example 1 4-(4-(4-((4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-1-yl ) methyl) benzyl) piperazin-1-yl) preparation of -3-fluorobenzonitrile (compound 1)
S1：3-(5-溴-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S1: Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione
将4-溴-2-(溴甲基)苯甲酸甲酯(10g，32.5mmol)、3-氨基哌啶-2,6-二酮(5.9g，35.7mmol)溶于DMF(100mL)中，加入无水碳酸钾(13.5g，97.5mmol)，70℃下反应。4h后TLC显示反应完成。减压蒸去溶剂，加水打浆30min后过滤，滤饼用甲基叔丁基醚、乙酸乙酯洗涤，高真空干燥，得3-(5-溴-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮5.9g，收率为56％。Methyl 4-bromo-2-(bromomethyl)benzoate (10 g, 32.5 mmol), 3-aminopiperidine-2,6-dione (5.9 g, 35.7 mmol) were dissolved in DMF (100 mL), Add anhydrous potassium carbonate (13.5 g, 97.5 mmol) and react at 70°C. After 4 h TLC showed the reaction was complete. Evaporate the solvent under reduced pressure, add water to beat for 30 minutes, and then filter, wash the filter cake with methyl tert-butyl ether and ethyl acetate, and dry under high vacuum to obtain 3-(5-bromo-1-oxoisoindoline-2- Base) piperidine-2,6-dione 5.9g, the yield is 56%.
MS-ESI:m/z 324.2[M+H]+。MS-ESI: m/z 324.2 [M+H] + .
1H-NMR(400MHz,DMSO-d6):δ11.01(s,1H),7.89(s,1H),7.72(dd,J＝8.1,1.4Hz,1H),7.67(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.40(dd,J＝52.0,17.7Hz,2H),2.90(ddd,J＝18.8,13.2,5.4Hz,1H),2.64-2.55(m,1H),2.38(qd,J＝13.3,4.4Hz,1H),2.05-1.95(m,1H)。 1 H-NMR (400MHz, DMSO-d 6 ): δ11.01(s, 1H), 7.89(s, 1H), 7.72(dd, J=8.1, 1.4Hz, 1H), 7.67(d, J=8.1 Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.40(dd,J=52.0,17.7Hz,2H),2.90(ddd,J=18.8,13.2,5.4Hz,1H),2.64 -2.55 (m, 1H), 2.38 (qd, J=13.3, 4.4Hz, 1H), 2.05-1.95 (m, 1H).
S2：4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的制备
S2: 4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert Preparation of butyl ester
将4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(20.18g，62.58mmol)、3-(5-溴-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(16.6g，51mmol)溶于DMF(180mL)中，加入无水磷酸钾(13g，61.2mmol)、Pd(dppf)Cl2(1.86g，2.55mmol)，在氮气保护下于90℃反应。18h后TLC显示反应完成。乙酸乙酯、水打浆，过滤，高真空干燥，得粗产物21.6g，收率为99％。4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Tert-butyl ester (20.18g, 62.58mmol), 3-(5-bromo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (16.6g, 51mmol) were dissolved in DMF ( 180 mL), add anhydrous potassium phosphate (13 g, 61.2 mmol), Pd(dppf)Cl 2 (1.86 g, 2.55 mmol), and react at 90°C under nitrogen protection. After 18 h TLC showed the reaction was complete. Slurry with ethyl acetate and water, filter, and dry under high vacuum to obtain 21.6 g of crude product with a yield of 99%.
1H-NMR(400MHz,DMSO-d6):δ10.97(s,1H),7.73-7.63(m,2H),7.58(d,J＝7.9Hz,1H),6.30(s,1H),5.10(dd,J＝13.0,4.7Hz,1H),4.38(d,J＝33.2Hz,2H),4.03(s,2H),3.56(s,2H),2.98-2.81(m,1H),2.56(d,J＝14.8Hz,1H),2.38(dd,J＝21.6,9.2Hz,1H),2.12-1.89(m,1H),1.45(d,J＝19.6Hz,12H)。 1 H-NMR (400MHz, DMSO-d 6 ): δ10.97(s, 1H), 7.73-7.63(m, 2H), 7.58(d, J=7.9Hz, 1H), 6.30(s, 1H), 5.10(dd,J=13.0,4.7Hz,1H),4.38(d,J=33.2Hz,2H),4.03(s,2H),3.56(s,2H),2.98-2.81(m,1H),2.56 (d, J=14.8Hz, 1H), 2.38 (dd, J=21.6, 9.2Hz, 1H), 2.12-1.89 (m, 1H), 1.45 (d, J=19.6Hz, 12H).
S3：4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯的制备
S3: Preparation of tert-butyl 4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidine-1-carboxylate
将4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(21.6g，50.8mmol)溶于甲醇(600mL)，加入Pd/C(21.6g,50.8mmol)，在氢气氛下于70℃反应。48h后MS显示反应完成。过滤，收集滤液，减压下蒸去溶剂，残留物用快速柱层析法分离，得目标产物2.56g，收率为12％。4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl The ester (21.6g, 50.8mmol) was dissolved in methanol (600mL), added with Pd/C (21.6g, 50.8mmol), and reacted at 70°C under a hydrogen atmosphere. After 48h MS showed the reaction was complete. After filtration, the filtrate was collected, the solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography to obtain 2.56 g of the target product with a yield of 12%.
MS-ESI:m/z 372.2[M+H-56]+。MS-ESI: m/z 372.2 [M+H-56] + .
1H-NMR(400MHz,CDCl3):δ8.00(s,1H),7.83(d,J＝7.8Hz,1H),7.34(d,J＝7.9Hz,1H),5.23(dd,J＝13.2,5.1Hz,1H),4.40(dd,J＝60.2,15.9Hz,3H),2.93(d,J＝19.6Hz,1H),2.85-2.72(m,4H),2.47-2.29(m,2H),2.21(dd,J＝11.6,4.1Hz,1H),2.03-1.90(m,1H),1.84(d,J＝12.6Hz,3H),1.66(s,1H),1.49(s,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.00(s, 1H), 7.83(d, J=7.8Hz, 1H), 7.34(d, J=7.9Hz, 1H), 5.23(dd, J= 13.2,5.1Hz,1H),4.40(dd,J＝60.2,15.9Hz,3H),2.93(d,J＝19.6Hz,1H),2.85-2.72(m,4H),2.47-2.29(m,2H ),2.21(dd,J=11.6,4.1Hz,1H),2.03-1.90(m,1H),1.84(d,J=12.6Hz,3H),1.66(s,1H),1.49(s,12H) .
S4：3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的制备
S4: Preparation of 3-(1-oxo-5-(piperidin-4-yl)isoindoline-2-yl)piperidine-2,6-dione
将4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯(2.56g，6mmol)溶于二氯甲烷(15mL)、甲醇(3mL)中，加入HCl/1,4-二氧六环(4M，30mL)，室温下反应。2h后TLC显示反应完成。减压下蒸去溶剂，得残留物(2.265g)，其无需进一步纯化，直接用于下一步。Dissolve tert-butyl 4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (2.56 g, 6 mmol) in Add HCl/1,4-dioxane (4M, 30 mL) to dichloromethane (15 mL) and methanol (3 mL), and react at room temperature. After 2h TLC showed the reaction was complete. The solvent was evaporated under reduced pressure to give a residue (2.265 g), which was used in the next step without further purification.
MS-ESI:m/z 328.4[M+H]+。MS-ESI: m/z 328.4 [M+H] + .
S5：4-(4-氰基-2-氟苯基)哌嗪-1-羧酸叔丁酯的制备
S5: Preparation of tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate
向3,4-二氟苯甲腈(10g，71.9mmol)、哌嗪-1-羧酸叔丁酯(14.7g,79.1mmol)的二甲亚砜(60mL)溶液中，加入无水碳酸钾(14.9g，107.9mmol)，于100℃下反应。TLC显示反应完全。过滤，收集滤液，加入200mL水中，过滤，高真空干燥，得4-(4-氰基-2-氟苯基)哌嗪-1-羧酸叔丁酯16g，收率为73％。To a solution of 3,4-difluorobenzonitrile (10 g, 71.9 mmol), tert-butyl piperazine-1-carboxylate (14.7 g, 79.1 mmol) in dimethyl sulfoxide (60 mL) was added anhydrous potassium carbonate (14.9g, 107.9mmol), reacted at 100°C. TLC showed the reaction was complete. Filtrate, collect the filtrate, add 200 mL of water, filter, and dry under high vacuum to obtain 16 g of tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate with a yield of 73%.
1H-NMR(400MHz,CDCl3):δ7.39-7.34(m,1H),7.28(dd,J＝12.5,1.9Hz,1H),6.91(t,J＝8.5Hz,1H),3.62-3.55(m,4H),3.18-3.12(m,4H),1.48(s,9H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.39-7.34(m, 1H), 7.28(dd, J=12.5, 1.9Hz, 1H), 6.91(t, J=8.5Hz, 1H), 3.62- 3.55 (m, 4H), 3.18-3.12 (m, 4H), 1.48 (s, 9H).
S6：3-氟-4-(哌嗪-1-基)苯甲腈的制备
S6: Preparation of 3-fluoro-4-(piperazin-1-yl)benzonitrile
将4-(4-氰基-2-氟苯基)哌嗪-1-羧酸叔丁酯溶于二氯甲烷(60mL)中，加入三氟乙酸(32mL)，室温下反应。1h后TLC显示反应完全。减压蒸去溶剂，得3-氟-4-(哌嗪-1-基)苯甲腈的三氟乙酸盐(26.8g)。tert-butyl 4-(4-cyano-2-fluorophenyl)piperazine-1-carboxylate was dissolved in dichloromethane (60 mL), trifluoroacetic acid (32 mL) was added, and reacted at room temperature. After 1 h TLC showed the reaction was complete. The solvent was distilled off under reduced pressure to obtain trifluoroacetic acid salt of 3-fluoro-4-(piperazin-1-yl)benzonitrile (26.8 g).
MS-ESI:m/z 206.4[M+H]+。MS-ESI: m/z 206.4 [M+H] + .
S7：4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的制备
S7: Preparation of 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile
将3-氟-4-(哌嗪-1-基)苯甲腈的三氟乙酸盐(2g，3.6mmol)溶于DMF(10mL)，加入1,4-二(氯甲基)苯(640mg，3.6mmol)，DIPEA(3.2mL,18mmol)，60℃下反应。TLC显示反应完全。混合物加入50mL水中，乙酸乙酯提取，有机相减压蒸去溶剂，残留物用快速柱层析法分离，得目标产物660mg，收率为52％。The trifluoroacetate salt of 3-fluoro-4-(piperazin-1-yl)benzonitrile (2 g, 3.6 mmol) was dissolved in DMF (10 mL), and 1,4-bis(chloromethyl)benzene ( 640mg, 3.6mmol), DIPEA (3.2mL, 18mmol), react at 60°C. TLC showed the reaction was complete. The mixture was added to 50 mL of water, extracted with ethyl acetate, the organic phase was distilled off the solvent under reduced pressure, and the residue was separated by flash column chromatography to obtain 660 mg of the target product with a yield of 52%.
MS-ESI:m/z 344.8[M+H]+。MS-ESI: m/z 344.8 [M+H] + .
S8：4-(4-(4-((4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的制备
S8: 4-(4-(4-((4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-1-yl) Preparation of methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile
将4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈(101mg，0.29mmol)、3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮(107mg，0.29mmol)溶于DMF(4mL)中，加入DIPEA(0.2mL)，于100℃下反应。16h后TLC显示反应完成。乙酸乙酯提取，水洗、饱和食盐水洗，减压蒸去溶剂，残留物用快速柱层析分离，得目标产物64mg，收率为35％。4-(4-(4-(Chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (101 mg, 0.29 mmol), 3-(1-oxo-5-(piperazin Pyridine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (107mg, 0.29mmol) was dissolved in DMF (4mL), DIPEA (0.2mL) was added and reacted at 100°C . After 16 h TLC showed the reaction was complete. Extracted with ethyl acetate, washed with water and saturated brine, evaporated the solvent under reduced pressure, and separated the residue by flash column chromatography to obtain 64 mg of the target product with a yield of 35%.
MS-ESI:m/z 635.5[M+H]+。MS-ESI: m/z 635.5 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.02(s,1H),7.81(d,J＝8.2Hz,1H),7.35(d,J＝7.9Hz,7H),7.27(d,J＝1.7Hz,0H),7.24(d,J＝1.9Hz,1H),6.90(t,J＝8.5Hz,1H),5.21(dd,J＝13.3,5.1Hz,1H),4.48-4.28(m,2H),3.64(d,J＝6.9Hz,2H),3.57(s,2H),3.26-3.20(m,4H),3.11(dd,J＝21.9,14.4Hz,2H),2.96-2.88(m,1H),2.82(ddd,J＝22.3,13.7,7.2Hz,1H),2.71-2.55(m,5H),2.42-2.14(m,4H),2.01(dd,J＝11.7,6.4Hz,2H),1.86(d,J＝9.9Hz,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.02(s, 1H), 7.81(d, J=8.2Hz, 1H), 7.35(d, J=7.9Hz, 7H), 7.27(d, J= 1.7Hz, 0H), 7.24(d, J=1.9Hz, 1H), 6.90(t, J=8.5Hz, 1H), 5.21(dd, J=13.3, 5.1Hz, 1H), 4.48-4.28(m, 2H), 3.64(d, J=6.9Hz, 2H), 3.57(s, 2H), 3.26-3.20(m, 4H), 3.11(dd, J=21.9, 14.4Hz, 2H), 2.96-2.88(m ,1H),2.82(ddd,J=22.3,13.7,7.2Hz,1H),2.71-2.55(m,5H),2.42-2.14(m,4H),2.01(dd,J=11.7,6.4Hz,2H ), 1.86 (d, J=9.9Hz, 2H).
实施例2 4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)苄基)哌嗪-1-基)-3-氟苯甲腈(化合物2)的制备Example 2 4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-3,6-dihydro Preparation of pyridin-1(2H)-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (compound 2)
S1：3-(1-氧代-5-(1,2,3,6-四氢吡啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的制备
S1: Preparation of 3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindoline-2-yl)piperidine-2,6-dione
除了用4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯替换4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯外，3-(1-氧代-5-(1,2,3,6-四氢吡啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮与实施例1中3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的合成一致，收率为76％。In addition to using 4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert Butyl ester replaces tert-butyl 4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidine-1-carboxylate, 3-(1 -Oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindoline-2-yl)piperidine-2,6-dione and 3-(1 The synthesis of -oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione was consistent with a yield of 76%.
MS-ESI:m/z 326.4[M+H]+。MS-ESI: m/z 326.4 [M+H] + .
S2：4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的制备
S2: 4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-3,6-dihydropyridine Preparation of -1(2H)-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile
除了用3-(1-氧代-5-(1,2,3,6-四氢吡啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮替换3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮外，化合物2与实施例1中化合物1的合成一致，收率为74％。Except replacing 3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione for 3- Except for (1-oxo-5-(piperidin-4-yl)isoindoline-2-yl)piperidine-2,6-dione, the synthesis of compound 2 is consistent with that of compound 1 in Example 1. The rate is 74%.
MS-ESI:m/z 633.7[M+H]+。MS-ESI: m/z 633.7 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.97(s,1H),7.82(d,J＝8.0Hz,1H),7.50(d,J＝8.4Hz,1H),7.44(s,1H),7.36(dd,J＝11.1,8.9Hz,4H),7.28(dd,J＝1.9Hz,1H),6.90(t,J＝8.6Hz,1H),6.16(s,1H),5.22(dd,J＝13.3,5.1Hz,1H),4.40(dd,J＝62.1,15.9Hz,2H),3.80-3.63(m,3H),3.59(s,2H),3.24(s,5H),3.08(t,J＝7.1Hz,1H),2.93(d,J＝15.4Hz,1H),2.89-2.76(m,2H),2.64(s,5H),2.36(qd,J＝13.1,5.0Hz,1H),2.28-2.17(m,2H),2.01(dd,J＝11.9,6.3Hz,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.97(s, 1H), 7.82(d, J=8.0Hz, 1H), 7.50(d, J=8.4Hz, 1H), 7.44(s, 1H) ,7.36(dd,J=11.1,8.9Hz,4H),7.28(dd,J=1.9Hz,1H),6.90(t,J=8.6Hz,1H),6.16(s,1H),5.22(dd, J=13.3,5.1Hz,1H),4.40(dd,J=62.1,15.9Hz,2H),3.80-3.63(m,3H),3.59(s,2H),3.24(s,5H),3.08(t ,J=7.1Hz,1H),2.93(d,J=15.4Hz,1H),2.89-2.76(m,2H),2.64(s,5H),2.36(qd,J=13.1,5.0Hz,1H) , 2.28-2.17 (m, 2H), 2.01 (dd, J=11.9, 6.3Hz, 2H).
实施例3 4-(4-(4-(4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)苯甲腈(化合物3)的制备Example 3 4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-1-yl) Preparation of methyl)benzyl)piperazin-1-yl)benzonitrile (compound 3)
S1：4-(4-(4-(氯甲基)苄基)哌嗪-1-基)苯甲腈的制备
S1: Preparation of 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)benzonitrile
除了用4-(哌嗪-1-基)苯甲腈替换3-氟-4-(哌嗪-1-基)苯甲腈外，4-(4-(4-(氯甲基)苄基)哌嗪- 1-基)苯甲腈与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为60％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 4-(piperazin-1-yl)benzonitrile, 4-(4-(4-(chloromethyl)benzyl )Piperazine- 1-base) benzonitrile is consistent with the synthesis of 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile in Example 1, and the yield is 60 %.
1H-NMR(400MHz,CDCl3):δ8.01(s,2H),7.47(d,J＝9.0Hz,2H),7.34(d,J＝2.3Hz,4H),6.84(d,J＝9.0Hz,2H),4.59(s,2H),3.55(s,2H),3.35-3.29(m,4H),2.60-2.53(m,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.01(s, 2H), 7.47(d, J=9.0Hz, 2H), 7.34(d, J=2.3Hz, 4H), 6.84(d, J= 9.0Hz, 2H), 4.59(s, 2H), 3.55(s, 2H), 3.35-3.29(m, 4H), 2.60-2.53(m, 4H).
S2：4-(4-(4-(4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)苯甲腈的制备
S2: 4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidin-1-yl)methyl Base) benzyl) piperazin-1-yl) preparation of benzonitrile
除了用4-(4-(4-(氯甲基)苄基)哌嗪-1-基)苯甲腈替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物3与实施例1中化合物1的合成一致，收率为36％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)benzonitrile with 4-(4-(4-(chloromethyl)benzyl)piperazin-1- Except for base)-3-fluorobenzonitrile, the synthesis of compound 3 was consistent with that of compound 1 in Example 1, and the yield was 36%.
MS-ESI:m/z 617.4[M+H]+。MS-ESI: m/z 617.4 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.98(s,1H),7.81(d,J＝8.0Hz,1H),7.48(d,J＝9.0Hz,2H),7.35(d,J＝7.9Hz,5H),6.84(d,J＝9.0Hz,2H),5.21(dd,J＝13.3,5.1Hz,1H),4.39(dd,J＝57.1,16.0Hz,2H),3.82-3.61(m,2H),3.56(s,2H),3.39-3.28(m,4H),3.14(s,1H),3.08(dd,J＝14.5,7.1Hz,1H),2.92(dd,J＝10.2,7.7Hz,1H),2.84(dt,J＝17.9,8.9Hz,1H),2.67(s,1H),2.63-2.53(m,4H),2.35(s,2H),2.27-2.16(m,2H),2.06-1.94(m,1H),1.89(s,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.98(s, 1H), 7.81(d, J=8.0Hz, 1H), 7.48(d, J=9.0Hz, 2H), 7.35(d, J= 7.9Hz, 5H), 6.84(d, J=9.0Hz, 2H), 5.21(dd, J=13.3, 5.1Hz, 1H), 4.39(dd, J=57.1, 16.0Hz, 2H), 3.82-3.61( m,2H),3.56(s,2H),3.39-3.28(m,4H),3.14(s,1H),3.08(dd,J=14.5,7.1Hz,1H),2.92(dd,J=10.2, 7.7Hz, 1H), 2.84(dt, J＝17.9, 8.9Hz, 1H), 2.67(s, 1H), 2.63-2.53(m, 4H), 2.35(s, 2H), 2.27-2.16(m, 2H ), 2.06-1.94(m,1H), 1.89(s,2H).
实施例4 3-(1-氧代-5-(1-(4-((4-苯基哌嗪-1-基)甲基)苄基)哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮(化合物4)的制备Example 4 3-(1-oxo-5-(1-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)piperidin-4-yl)isoindoline- Preparation of 2-yl)piperidine-2,6-dione (compound 4)
S1：1-(4-(氯甲基)苄基)-4-苯基哌嗪的制备
S1: Preparation of 1-(4-(chloromethyl)benzyl)-4-phenylpiperazine
除了用1-苯基哌嗪替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(4-(氯甲基)苄基)-4-苯基哌嗪与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为61％。Except replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-phenylpiperazine, 1-(4-(chloromethyl)benzyl)-4-phenylpiperazine is the same as the implementation The synthesis of 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile in Example 1 was consistent, with a yield of 61%.
MS-ESI:m/z 301.2[M+H]+。MS-ESI: m/z 301.2 [M+H] + .
S2：3-(1-氧代-5-(1-(4-((4-苯基哌嗪-1-基)甲基)苄基)哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的制备
S2: 3-(1-oxo-5-(1-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)piperidin-4-yl)isoindoline-2 Preparation of -yl)piperidine-2,6-dione
除了用1-(4-(氯甲基)苄基)-4-苯基哌嗪替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物4与实施例1中化合物1的合成一致。收率为45％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluoro with 1-(4-(chloromethyl)benzyl)-4-phenylpiperazine Except for benzonitrile, the synthesis of compound 4 is consistent with that of compound 1 in Example 1. The yield is 45%.
MS-ESI:m/z 592.5[M+H]+。MS-ESI: m/z 592.5 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.96(s,1H),7.81(d,J＝7.9Hz,1H),7.38-7.29(m,6H),7.28-7.23(m,8H),6.92(d,J＝8.1Hz,2H),6.85(t,J＝7.3Hz,1H),5.22(dd,J＝13.3,5.1Hz,1H),4.39(dd,J＝60.3,15.9Hz,2H),3.57(s,4H),3.23-3.17(m,4H),3.05(d,J＝9.8Hz,2H),2.96-2.89(m,1H),2.88-2.76(m,1H),2.65-2.58(m,5H),2.42-2.28(m,1H),2.20(ddd,J＝33.2,19.1,16.6Hz,3H),1.84(s,3H),1.58-1.58(m,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.96(s, 1H), 7.81(d, J=7.9Hz, 1H), 7.38-7.29(m, 6H), 7.28-7.23(m, 8H), 6.92(d, J=8.1Hz, 2H), 6.85(t, J=7.3Hz, 1H), 5.22(dd, J=13.3, 5.1Hz, 1H), 4.39(dd, J=60.3, 15.9Hz, 2H ),3.57(s,4H),3.23-3.17(m,4H),3.05(d,J＝9.8Hz,2H),2.96-2.89(m,1H),2.88-2.76(m,1H),2.65- 2.58 (m, 5H), 2.42-2.28 (m, 1H), 2.20 (ddd, J=33.2, 19.1, 16.6Hz, 3H), 1.84 (s, 3H), 1.58-1.58 (m, 2H).
实施例5 3-(5-(1-(4-((4-(4-溴苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物5)的制备Example 5 3-(5-(1-(4-((4-(4-bromophenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxo Preparation of Isoindoline-2-yl)piperidine-2,6-dione (Compound 5)
S1：1-(4-溴苯基)-4-(4-(氯甲基)苄基)哌嗪的制备
S1: Preparation of 1-(4-bromophenyl)-4-(4-(chloromethyl)benzyl)piperazine
除了用1-(4-溴苯基)哌嗪替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(4-溴苯基)-4-(4-(氯甲基)苄基)哌嗪与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为33％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-(4-bromophenyl)piperazine, 1-(4-bromophenyl)-4-(4-(chloro Methyl) benzyl) piperazine is consistent with the synthesis of 4-(4-(4-(chloromethyl) benzyl) piperazin-1-yl)-3-fluorobenzonitrile in embodiment 1, yield is 33%.
MS-ESI:m/z 381.1[M+H]+。MS-ESI: m/z 381.1 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.35(s,2H),7.34-7.30(m,1H),6.78(d,J＝9.0Hz,1H),4.59(s,2H),3.56(s,2H),3.20-3.12(m,2H),2.60(d,J＝4.7Hz,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.35(s, 2H), 7.34-7.30(m, 1H), 6.78(d, J=9.0Hz, 1H), 4.59(s, 2H), 3.56( s, 2H), 3.20-3.12 (m, 2H), 2.60 (d, J=4.7Hz, 2H).
S2：3-(5-(1-(4-((4-(4-溴苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S2: 3-(5-(1-(4-((4-(4-bromophenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxoiso Preparation of Indoline-2-yl)piperidine-2,6-dione
除了用1-(4-溴苯基)-4-(4-(氯甲基)苄基)哌嗪替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物5与实施例1中化合物1的合成一致，收率为46％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl with 1-(4-bromophenyl)-4-(4-(chloromethyl)benzyl)piperazine )-3-fluorobenzonitrile, the synthesis of compound 5 was consistent with that of compound 1 in Example 1, and the yield was 46%.
MS-ESI:m/z 672.2[M+H]+。MS-ESI: m/z 672.2 [M+H] + .
1H-NMR(400MHz,DMSO-d6):δ10.98(s,1H),7.64(d,J＝7.8Hz,1H),7.49(s,1H),7.40(d,J＝8.4Hz,1H),7.32(d,J＝9.0Hz,2H),7.28(s,3H),6.87(d,J＝9.1Hz,2H),5.09(dd,J＝13.2,5.0Hz,1H),4.35(dd,J＝55.1,17.5Hz,2H),3.51-3.48(m,4H),3.14-3.09(m,4H),2.92(d,J＝9.0Hz,2H),2.68-2.60(m,2H),2.51(s,4H),2.41-2.35(m,1H),2.33(s,1H),2.02(dt,J＝14.2,8.2Hz,4H),1.79-1.68(m,3H)。 1 H-NMR (400MHz, DMSO-d 6 ): δ10.98(s, 1H), 7.64(d, J=7.8Hz, 1H), 7.49(s, 1H), 7.40(d, J=8.4Hz, 1H), 7.32(d, J=9.0Hz, 2H), 7.28(s, 3H), 6.87(d, J=9.1Hz, 2H), 5.09(dd, J=13.2, 5.0Hz, 1H), 4.35( dd,J=55.1,17.5Hz,2H),3.51-3.48(m,4H),3.14-3.09(m,4H),2.92(d,J=9.0Hz,2H),2.68-2.60(m,2H) , 2.51 (s, 4H), 2.41-2.35 (m, 1H), 2.33 (s, 1H), 2.02 (dt, J=14.2, 8.2Hz, 4H), 1.79-1.68 (m, 3H).
实施例6 3-(5-(1-(4-(3-甲氧基苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物6)的制备Example 6 3-(5-(1-(4-(3-methoxyphenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxoisoindol Preparation of Indoline-2-yl)piperidine-2,6-dione (Compound 6)
S1：1-(4-(氯甲基)苄基)-4-(3-甲氧基苯基)哌嗪的制备
S1: Preparation of 1-(4-(chloromethyl)benzyl)-4-(3-methoxyphenyl)piperazine
除了用1-(3-甲氧基苯基)哌嗪替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(4-(氯甲基)苄基)-4-(3-甲氧基苯基)哌嗪与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为58％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-(3-methoxyphenyl)piperazine, 1-(4-(chloromethyl)benzyl)-4 -(3-methoxyphenyl)piperazine is consistent with the synthesis of 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile in Example 1 , the yield was 58%.
MS-ESI:m/z 331.2[M+H]+。MS-ESI: m/z 331.2 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.02(s,1H),7.35(s,4H),7.16(t,J＝8.2Hz,1H),6.53(dd,J＝8.2,2.1Hz,1H),6.45(t,J＝2.3Hz,1H),6.41(dd,J＝8.1,2.1Hz,1H),4.59(s,2H),3.78(s,3H),3.56(s,2H),3.24-3.15(m,4H),2.63-2.54(m,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.02(s, 1H), 7.35(s, 4H), 7.16(t, J=8.2Hz, 1H), 6.53(dd, J=8.2, 2.1Hz, 1H), 6.45(t, J=2.3Hz, 1H), 6.41(dd, J=8.1, 2.1Hz, 1H), 4.59(s, 2H), 3.78(s, 3H), 3.56(s, 2H), 3.24-3.15 (m, 4H), 2.63-2.54 (m, 4H).
S2：3-(5-(1-(4-(3-甲氧基苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S2: 3-(5-(1-(4-(3-methoxyphenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxoisoindole Preparation of phen-2-yl)piperidine-2,6-dione
除了用1-(4-(氯甲基)苄基)-4-(3-甲氧基苯基)哌嗪替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物6与实施例1中化合物1的合成一致，收为率44％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazine-1 with 1-(4-(chloromethyl)benzyl)-4-(3-methoxyphenyl)piperazine Except for -yl)-3-fluorobenzonitrile, the synthesis of compound 6 was consistent with that of compound 1 in Example 1, with a yield of 44%.
MS-ESI:m/z 622.4[M+H]+。 MS-ESI: m/z 622.4 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.96(s,1H),7.81(d,J＝7.9Hz,1H),7.37-7.31(m,6H),7.16(t,J＝8.2Hz,1H),6.53(dd,J＝8.2,2.0Hz,1H),6.45(t,J＝2.3Hz,1H),6.41(dd,J＝8.1,2.0Hz,1H),5.22(dd,J＝13.3,5.1Hz,1H),4.39(dd,J＝60.1,15.9Hz,2H),3.78(s,3H),3.56(s,4H),3.24-3.16(m,5H),3.05(d,J＝11.4Hz,2H),2.98-2.88(m,1H),2.85(dd,J＝13.0,5.4Hz,1H),2.63-2.56(m,5H),2.42-2.07(m,4H),1.84(s,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.96(s, 1H), 7.81(d, J=7.9Hz, 1H), 7.37-7.31(m, 6H), 7.16(t, J=8.2Hz, 1H), 6.53(dd, J=8.2, 2.0Hz, 1H), 6.45(t, J=2.3Hz, 1H), 6.41(dd, J=8.1, 2.0Hz, 1H), 5.22(dd, J=13.3 ,5.1Hz,1H),4.39(dd,J=60.1,15.9Hz,2H),3.78(s,3H),3.56(s,4H),3.24-3.16(m,5H),3.05(d,J= 11.4Hz, 2H), 2.98-2.88(m, 1H), 2.85(dd, J=13.0, 5.4Hz, 1H), 2.63-2.56(m, 5H), 2.42-2.07(m, 4H), 1.84(s ,4H).
实施例7 3-(5-(1-(4-(4-硝基苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物7)的制备Example 7 3-(5-(1-(4-(4-nitrophenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxoisoindole Preparation of phen-2-yl)piperidine-2,6-dione (compound 7)
S1：1-(4-(氯甲基)苄基)-4-(4-硝基苯基)哌嗪的制备
S1: Preparation of 1-(4-(chloromethyl)benzyl)-4-(4-nitrophenyl)piperazine
除了用1-(4-硝基苯基)哌嗪替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(4-(氯甲基)苄基)-4-(4-硝基苯基)哌嗪与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为48％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-(4-nitrophenyl)piperazine, 1-(4-(chloromethyl)benzyl)-4- (4-nitrophenyl) piperazine is consistent with the synthesis of 4-(4-(4-(chloromethyl)benzyl) piperazin-1-yl)-3-fluorobenzonitrile in Example 1, and the obtained The rate is 48%.
MS-ESI:m/z 346.0[M+H]+。MS-ESI: m/z 346.0 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.12(d,J＝9.4Hz,2H),7.36(d,J＝3.0Hz,4H),6.81(d,J＝9.4Hz,2H),4.60(s,1H),3.56(s,1H),3.48-3.36(m,2H),2.67-2.52(m,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.12(d, J=9.4Hz, 2H), 7.36(d, J=3.0Hz, 4H), 6.81(d, J=9.4Hz, 2H), 4.60 (s,1H), 3.56(s,1H), 3.48-3.36(m,2H), 2.67-2.52(m,2H).
S2：3-(5-(1-(4-((4-(4-硝基苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S2: 3-(5-(1-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxo Preparation of isoindoline-2-yl)piperidine-2,6-dione
除了用1-(4-(氯甲基)苄基)-4-(4-硝基苯基)哌嗪替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物7与实施例1中化合物1的合成一致，收率为33％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazine-1- Except for base)-3-fluorobenzonitrile, the synthesis of compound 7 was consistent with that of compound 1 in Example 1, and the yield was 33%.
MS-ESI:m/z 655.4[M+H]+。MS-ESI: m/z 655.4 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.12(d,J＝9.3Hz,2H),7.97(s,1H),7.81(d,J＝7.9Hz,1H),7.40(dd,J＝40.7,32.2Hz,6H),6.81(d,J＝9.4Hz,2H),5.21(dd,J＝13.3,5.0Hz,1H),4.39(dd,J＝55.8,16.0Hz,2H),3.76-3.61(m,1H),3.57(s,2H),3.47-3.38(m,4H),3.09(d,J＝7.0Hz,1H),2.93(d,J＝18.0Hz,1H),2.84(dt,J＝17.7,8.9Hz,1H),2.77-2.64(m,1H),2.63-2.55(m,4H),2.37(dd,J＝13.1,5.0Hz,1H),2.26-2.17(m,1H),1.90(s,2H),1.57-1.51(m,3H),1.48-1.40(m,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.12(d, J=9.3Hz, 2H), 7.97(s, 1H), 7.81(d, J=7.9Hz, 1H), 7.40(dd, J= 40.7,32.2Hz,6H),6.81(d,J=9.4Hz,2H),5.21(dd,J=13.3,5.0Hz,1H),4.39(dd,J=55.8,16.0Hz,2H),3.76- 3.61(m,1H),3.57(s,2H),3.47-3.38(m,4H),3.09(d,J=7.0Hz,1H),2.93(d,J=18.0Hz,1H),2.84(dt ,J=17.7,8.9Hz,1H),2.77-2.64(m,1H),2.63-2.55(m,4H),2.37(dd,J=13.1,5.0Hz,1H),2.26-2.17(m,1H ), 1.90(s,2H), 1.57-1.51(m,3H), 1.48-1.40(m,2H).
实施例8 3-(5-(1-(4-(4-乙酰苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物8)的制备Example 8 3-(5-(1-(4-(4-acetylphenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxoisoindoline Preparation of -2-yl)piperidine-2,6-dione (Compound 8)
S1：1-(4-(4-(氯甲基)苄基)哌嗪-1-基)苯基)乙烷-1-酮的制备
S1: Preparation of 1-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)phenyl)ethan-1-one
除了用1-(4-(哌嗪-1-基)苯基)乙烷-1-酮替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(4-(4-(氯甲基)苄基)哌嗪-1-基)苯基)乙烷-1-酮与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为28％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-(4-(piperazin-1-yl)phenyl)ethan-1-one, 1-(4-( 4-(chloromethyl) benzyl) piperazin-1-yl) phenyl) ethane-1-one and 4-(4-(4-(chloromethyl) benzyl) piperazine- The synthesis of 1-yl)-3-fluorobenzonitrile was consistent with a yield of 28%.
MS-ESI:m/z 343.3[M+H]+。MS-ESI: m/z 343.3 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.87(d,J＝8.9Hz,2H),7.39-7.32(m,4H),6.85(d,J＝8.9Hz,2H),4.60(s,1H),3.56(s,1H),3.40-3.32(m,2H),2.63-2.55(m,2H),2.52(s,1H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.87(d, J=8.9Hz, 2H), 7.39-7.32(m, 4H), 6.85(d, J=8.9Hz, 2H), 4.60(s, 1H), 3.56(s,1H), 3.40-3.32(m,2H), 2.63-2.55(m,2H), 2.52(s,1H).
S2：3-(5-(1-(4-(4-乙酰苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶- 2,6-二酮的制备
S2: 3-(5-(1-(4-(4-acetylphenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1-oxoisoindoline- 2-yl)piperidine- Preparation of 2,6-diketones
除了用1-(4-(4-(氯甲基)苄基)哌嗪-1-基)苯基)乙烷-1-酮替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物8与实施例1中化合物1的合成一致，收率31％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)phenyl)ethan-1-one with 4-(4-(4-(chloromethyl)benzyl) ) piperazin-1-yl)-3-fluorobenzonitrile, compound 8 was synthesized in the same way as compound 1 in Example 1, and the yield was 31%.
MS-ESI:m/z 634.2[M+H]+。MS-ESI: m/z 634.2 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.02(s,1H),7.86(d,J＝9.0Hz,2H),7.80(d,J＝7.9Hz,1H),7.38(dd,J＝26.7,16.5Hz,6H),6.85(d,J＝9.0Hz,2H),5.20(dd,J＝13.3,5.1Hz,1H),4.38(dd,J＝55.0,16.1Hz,2H),3.65(dt,J＝13.3,6.5Hz,3H),3.57(s,2H),3.41-3.31(m,4H),3.08(q,J＝7.4Hz,3H),2.92(dd,J＝12.1,9.7Hz,1H),2.84(d,J＝13.1Hz,1H),2.7-2.64(m,1H),2.60(s,4H),2.51(s,3H),2.43-2.15(m,3H),1.91(s,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.02(s, 1H), 7.86(d, J=9.0Hz, 2H), 7.80(d, J=7.9Hz, 1H), 7.38(dd, J= 26.7,16.5Hz,6H),6.85(d,J=9.0Hz,2H),5.20(dd,J=13.3,5.1Hz,1H),4.38(dd,J=55.0,16.1Hz,2H),3.65( dt,J=13.3,6.5Hz,3H),3.57(s,2H),3.41-3.31(m,4H),3.08(q,J=7.4Hz,3H),2.92(dd,J=12.1,9.7Hz ,1H),2.84(d,J＝13.1Hz,1H),2.7-2.64(m,1H),2.60(s,4H),2.51(s,3H),2.43-2.15(m,3H),1.91( s, 2H).
实施例9 3-(5-(1-(4-((4-(2-氟-4-(三氟甲基)苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物9)的制备Example 9 3-(5-(1-(4-((4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)benzyl)piperidine- Preparation of 4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 9)
S1：1-(4-(氯甲基)苄基)-4-(2-氟-4-(三氟甲基)苯基)哌嗪的制备
S1: Preparation of 1-(4-(chloromethyl)benzyl)-4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine
除了用1-(2-氟-4-(三氟甲基)苯基)哌嗪替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(4-(氯甲基)苄基)-4-(2-氟-4-(三氟甲基)苯基)哌嗪与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为49％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine, 1-(4-(chloroform Base) benzyl)-4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine and 4-(4-(4-(chloromethyl)benzyl)piperazine in Example 1- The synthesis of 1-yl)-3-fluorobenzonitrile was consistent with a yield of 49%.
MS-ESI:m/z 387.2[M+H]+。MS-ESI: m/z 387.2 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.36(s,4H),7.34-7.29(m,1H),7.28-7.23(m,1H),6.96(t,J＝8.5Hz,1H),4.60(s,2H),3.57(s,2H),3.21-3.15(m,4H),2.66-2.59(m,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.36(s, 4H), 7.34-7.29(m, 1H), 7.28-7.23(m, 1H), 6.96(t, J=8.5Hz, 1H), 4.60 (s, 2H), 3.57 (s, 2H), 3.21-3.15 (m, 4H), 2.66-2.59 (m, 4H).
S2：3-(5-(1-(4-((4-(2-氟-4-(三氟甲基)苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S2: 3-(5-(1-(4-((4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)benzyl)piperidine-4 Preparation of -yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione
除了用1-(4-(氯甲基)苄基)-4-(2-氟-4-(三氟甲基)苯基)哌嗪替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物9与实施例1中化合物1的合成一致。收率为47％。Except replacing 4-(4-(4-(chloromethyl)) with 1-(4-(chloromethyl)benzyl)-4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine Except for benzyl)piperazin-1-yl)-3-fluorobenzonitrile, the synthesis of compound 9 is consistent with that of compound 1 in Example 1. The yield was 47%.
MS-ESI:m/z 678.4[M+H]+。MS-ESI: m/z 678.4 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.10(s,1H),7.80(d,J＝7.8Hz,1H),7.38-7.28(m,7H),7.23(s,1H),6.96(t,J＝8.4Hz,1H),5.22(dd,J＝13.3,5.1Hz,1H),4.38(dd,J＝60.4,15.9Hz,2H),3.57(s,4H),3.21-3.15(m,4H),3.05(d,J＝10.9Hz,2H),2.96-2.88(m,1H),2.83(ddd,J＝17.8,12.9,5.3Hz,1H),2.62(dd,J＝15.4,10.7Hz,5H),2.34(tt,J＝13.1,6.6Hz,1H),2.25-2.16(m,1H),2.12(s,2H),1.84(s,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.10(s, 1H), 7.80(d, J=7.8Hz, 1H), 7.38-7.28(m, 7H), 7.23(s, 1H), 6.96( t,J=8.4Hz,1H),5.22(dd,J=13.3,5.1Hz,1H),4.38(dd,J=60.4,15.9Hz,2H),3.57(s,4H),3.21-3.15(m ,4H),3.05(d,J=10.9Hz,2H),2.96-2.88(m,1H),2.83(ddd,J=17.8,12.9,5.3Hz,1H),2.62(dd,J=15.4,10.7 Hz, 5H), 2.34(tt, J=13.1, 6.6Hz, 1H), 2.25-2.16(m, 1H), 2.12(s, 2H), 1.84(s, 4H).
实施例10 3-(5-(1-(4-((4-(2,3-二氯苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物10)的制备Example 10 3-(5-(1-(4-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1 Preparation of -oxoisoindolin-2-yl)piperidine-2,6-dione (compound 10)
S1：1-(4-(氯甲基)苄基)-4-(2,3-二氯苯基)哌嗪的制备
S1: Preparation of 1-(4-(chloromethyl)benzyl)-4-(2,3-dichlorophenyl)piperazine
除了用1-(2,3-二氯苯基)哌嗪替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(4-(氯甲基)苄基)-4-(2,3-二氯苯基)哌嗪与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为38％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-(2,3-dichlorophenyl)piperazine, 1-(4-(chloromethyl)benzyl)- 4-(2,3-dichlorophenyl) piperazine and 4-(4-(4-(chloromethyl) benzyl) piperazin-1-yl)-3-fluorobenzonitrile in embodiment 1 The synthesis was consistent with a yield of 38%.
MS-ESI:m/z 371.1[M+H]+。MS-ESI: m/z 371.1 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.36(s,4H),7.15(s,1H),7.14(d,J＝3.5Hz,1H),6.95(dd,J＝6.5,3.1Hz,1H),4.59(s,2H),3.58(s,2H),3.06(s,4H),2.64(s,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.36(s, 4H), 7.15(s, 1H), 7.14(d, J=3.5Hz, 1H), 6.95(dd, J=6.5, 3.1Hz, 1H), 4.59(s, 2H), 3.58(s, 2H), 3.06(s, 4H), 2.64(s, 4H).
S2：3-(5-(1-(4-((4-(2,3-二氯苯基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S2: 3-(5-(1-(4-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)benzyl)piperidin-4-yl)-1- Preparation of oxoisoindolin-2-yl)piperidine-2,6-dione
除了用1-(4-(氯甲基)苄基)-4-(2,3-二氯苯基)哌嗪替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物10与实施例1中化合物1的合成一致，收率58％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazine with 1-(4-(chloromethyl)benzyl)-4-(2,3-dichlorophenyl)piperazine- Except for 1-yl)-3-fluorobenzonitrile, the synthesis of compound 10 was consistent with that of compound 1 in Example 1, with a yield of 58%.
MS-ESI:m/z 660.4[M+H]+。MS-ESI: m/z 660.4 [M+H] + .
1H-NMR(400MHz,DMSO-d6):δ10.98(s,1H),7.63(d,J＝7.9Hz,1H),7.49(s,1H),7.39(d,J＝8.1Hz,1H),7.33-7.24(m,6H),7.13(dd,J＝6.4,3.2Hz,1H),5.08(dd,J＝13.3,5.1Hz,1H),4.34(dd,J＝54.8,17.3Hz,2H),3.51(d,J＝11.7Hz,4H),2.98(s,4H),2.89(dd,J＝22.2,8.8Hz,3H),2.64(d,J＝22.1Hz,2H),2.53(s,4H),2.47–2.30(m,2H),2.00(dd,J＝21.9,16.5Hz,3H),1.81-1.64(m,4H)。 1 H-NMR (400MHz, DMSO-d6): δ10.98(s, 1H), 7.63(d, J=7.9Hz, 1H), 7.49(s, 1H), 7.39(d, J=8.1Hz, 1H ),7.33-7.24(m,6H),7.13(dd,J=6.4,3.2Hz,1H),5.08(dd,J=13.3,5.1Hz,1H),4.34(dd,J=54.8,17.3Hz, 2H), 3.51(d, J=11.7Hz, 4H), 2.98(s, 4H), 2.89(dd, J=22.2, 8.8Hz, 3H), 2.64(d, J=22.1Hz, 2H), 2.53( s, 4H), 2.47–2.30 (m, 2H), 2.00 (dd, J=21.9, 16.5Hz, 3H), 1.81–1.64 (m, 4H).
实施例11 3-(5-(1-(4-((4-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物11)的制备Example 11 3-(5-(1-(4-((4-(benzo[d][1,3]dioxolane-5-yl)piperazin-1-yl)methyl) Preparation of benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 11)
S1：4-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪-1-羧酸叔丁酯的制备
S1: Preparation of tert-butyl 4-(benzo[d][1,3]dioxolan-5-yl)piperazine-1-carboxylate
将5-溴苯并[d][1,3]二氧杂环戊烷(2.0g，9.95mmol)、哌嗪-1-羧酸叔丁酯(5.56g，29.85mmol)溶于甲苯(30mL)，加入ButONa(2.87g，29.85mmol)、(t-Bu)3PHBF4(145mg，0.5mmol)、Pd(OAc)2(56mg，0.25mmol)，在氮气保护下100℃反应过夜。TLC显示反应完全。过滤，滤饼用乙酸乙酯提取，减压下蒸去溶剂，残留物用快速柱层析法分离，得目标产物2.9g，收率为95％。5-Bromobenzo[d][1,3]dioxolane (2.0 g, 9.95 mmol), tert-butyl piperazine-1-carboxylate (5.56 g, 29.85 mmol) were dissolved in toluene (30 mL ), added But ONa (2.87g, 29.85mmol), (t-Bu) 3 PHBF 4 (145mg, 0.5mmol), Pd(OAc) 2 (56mg, 0.25mmol), and reacted overnight at 100°C under nitrogen protection. TLC showed the reaction was complete. After filtration, the filter cake was extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography to obtain 2.9 g of the target product with a yield of 95%.
MS-ESI:m/z 251.2[M+H-56]+。MS-ESI: m/z 251.2 [M+H-56] + .
1H-NMR(400MHz,CDCl3):δ6.72(d,J＝8.4Hz,1H),6.56(s,1H),6.38(s,1H),5.91(s,2H),3.57(s,4H),2.99(s,4H),1.47(d,J＝8.2Hz,9H)。 1 H-NMR (400MHz, CDCl 3 ): δ6.72(d, J=8.4Hz, 1H), 6.56(s, 1H), 6.38(s, 1H), 5.91(s, 2H), 3.57(s, 4H), 2.99 (s, 4H), 1.47 (d, J=8.2Hz, 9H).
S2：1-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪的制备
S2: Preparation of 1-(benzo[d][1,3]dioxolan-5-yl)piperazine
除了用4-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪-1-羧酸叔丁酯替换4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯外，1-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪与实施例1中3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的合成一致，收率为92％。Except replacing 4-(2,6-dioxopiperidine- 3-yl)-1-oxoisoindoline-5-yl)piperidine-1-carboxylate tert-butyl ester, 1-(benzo[d][1,3]dioxolane- 5-yl) piperazine is consistent with the synthesis of 3-(1-oxo-5-(piperidin-4-yl) isoindoline-2-yl) piperidine-2,6-dione in Example 1 , the yield was 92%.
MS-ESI:m/z 207.2[M+H]+。MS-ESI: m/z 207.2 [M+H] + .
S3：1-(苯并[d][1,3]二氧杂环戊烷-5-基)-4-(4-(氯甲基)苄基)哌嗪的制备
S3: Preparation of 1-(benzo[d][1,3]dioxolan-5-yl)-4-(4-(chloromethyl)benzyl)piperazine
除了用1-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪替换3-氟-4-(哌嗪-1-基)苯甲腈外，1-(苯并[d][1,3]二氧杂环戊烷-5-基)-4-(4-(氯甲基)苄基)哌嗪与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为66％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 1-(benzo[d][1,3]dioxolan-5-yl)piperazine, 1- (Benzo[d][1,3]dioxolan-5-yl)-4-(4-(chloromethyl)benzyl)piperazine and 4-(4-(4 The synthesis of -(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile was consistent with a yield of 66%.
MS-ESI:m/z 345.2[M+H]+。MS-ESI: m/z 345.2 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.35(s,4H),6.71(d,J＝8.4Hz,1H),6.55(d,J＝2.2Hz,1H),6.35(dd,J＝8.4,2.3Hz,1H),5.89(s,2H),4.59(s,2H),3.56(s,2H),3.13-3.03(m,4H),2.65-2.53(m,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.35(s, 4H), 6.71(d, J=8.4Hz, 1H), 6.55(d, J=2.2Hz, 1H), 6.35(dd, J= 8.4,2.3Hz,1H),5.89(s,2H),4.59(s,2H),3.56(s,2H),3.13-3.03(m,4H),2.65-2.53(m,4H).
S4：3-(5-(1-(4-((4-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S4: 3-(5-(1-(4-((4-(benzo[d][1,3]dioxolan-5-yl)piperazin-1-yl)methyl)benzyl Preparation of base) piperidin-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione
除了用1-(苯并[d][1,3]二氧杂环戊烷-5-基)-4-(4-(氯甲基)苄基)哌嗪替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物11与实施例1中化合物1的合成一致，收率为41％。Except replacing 4-(4-(4 Except for -(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, the synthesis of compound 11 was consistent with that of compound 1 in Example 1, and the yield was 41%.
MS-ESI:m/z 636.4[M+H]+。MS-ESI: m/z 636.4 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.96(s,1H),7.80(d,J＝7.9Hz,1H),7.34(dd,J＝10.8,8.1Hz,6H),6.71(d,J＝8.4Hz,1H),6.55(d,J＝2.3Hz,1H),6.35(dd,J＝8.5,2.4Hz,1H),5.89(s,2H),5.22(dd,J＝13.3,5.1Hz,1H),4.39(dd,J＝59.5,15.9Hz,2H),3.56(s,4H),3.12-3.00(m,6H),2.91(s,1H),2.88-2.73(m,1H),2.68–2.54(m,5H),2.35(qd,J＝13.1,5.2Hz,1H),2.22(s,3H),1.84(s,3H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.96(s, 1H), 7.80(d, J=7.9Hz, 1H), 7.34(dd, J=10.8, 8.1Hz, 6H), 6.71(d, J=8.4Hz, 1H), 6.55(d, J=2.3Hz, 1H), 6.35(dd, J=8.5, 2.4Hz, 1H), 5.89(s, 2H), 5.22(dd, J=13.3, 5.1 Hz,1H),4.39(dd,J＝59.5,15.9Hz,2H),3.56(s,4H),3.12-3.00(m,6H),2.91(s,1H),2.88-2.73(m,1H) , 2.68–2.54 (m, 5H), 2.35 (qd, J=13.1, 5.2Hz, 1H), 2.22 (s, 3H), 1.84 (s, 3H).
实施例12 3-(5-(1-(4-((4-(2-甲基-2H-吲唑-6-基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(化合物12)的制备Example 12 3-(5-(1-(4-((4-(2-methyl-2H-indazol-6-yl)piperazin-1-yl)methyl)benzyl)piperidine-4 Preparation of -yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (compound 12)
S1：4-(2-甲基-2H-吲唑-6-基)哌嗪-1-羧酸叔丁酯的制备
S1: Preparation of tert-butyl 4-(2-methyl-2H-indazol-6-yl)piperazine-1-carboxylate
除了用6-溴-2-甲基-2H-吲唑替换5-溴苯并[d][1,3]二氧杂环戊烷外，4-(2-甲基-2H-吲唑-6-基)哌嗪-1-羧酸叔丁酯与实施例11中4-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪-1-羧酸叔丁酯的合成一致，收率为99％。In addition to replacing 5-bromobenzo[d][1,3]dioxolane with 6-bromo-2-methyl-2H-indazole, 4-(2-methyl-2H-indazole- 6-yl) piperazine-1-carboxylic acid tert-butyl ester and 4-(benzo[d][1,3]dioxolane-5-yl)piperazine-1-carboxylic acid in Example 11 The synthesis of tert-butyl ester was consistent with a yield of 99%.
MS-ESI:m/z 261.2[M+H-56]+。MS-ESI: m/z 261.2 [M+H-56] + .
1H-NMR(400MHz,CDCl3):δ7.75(s,1H),7.52(d,J＝9.1Hz,1H),6.96(s,1H),6.92(d,J＝9.1Hz,1H),4.15(s,3H),3.65-3.57(m,4H),3.14(s,4H),1.49(s,9H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.75(s, 1H), 7.52(d, J=9.1Hz, 1H), 6.96(s, 1H), 6.92(d, J=9.1Hz, 1H) ,4.15(s,3H),3.65-3.57(m,4H),3.14(s,4H),1.49(s,9H).
S2：2-甲基-6-(哌嗪-1-基)-2H-吲唑的制备
S2: Preparation of 2-methyl-6-(piperazin-1-yl)-2H-indazole
除了用4-(2-甲基-2H-吲唑-6-基)哌嗪-1-羧酸叔丁酯替换4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯外，2-甲基-6-(哌嗪-1-基)-2H-吲唑与实施例1中3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的合成一致，收率为90％。Except that 4-(2,6-dioxopiperidin-3-yl)-1- Oxoisoindoline-5-yl) piperidine-1-carboxylic acid tert-butyl ester, 2-methyl-6-(piperazin-1-yl)-2H-indazole and 3- in Example 1 The synthesis of (1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione was consistent with a yield of 90%.
MS-ESI:m/z 217.2[M+H]+。MS-ESI: m/z 217.2 [M+H] + .
S3：6-(4-(氯甲基)苄基)哌嗪-1-基)-2-甲基-2H-吲唑的制备
S3: Preparation of 6-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-methyl-2H-indazole
除了用2-甲基-6-(哌嗪-1-基)-2H-吲唑替换3-氟-4-(哌嗪-1-基)苯甲腈外，6-(4-(氯甲基)苄基)哌嗪-1-基)-2-甲基-2H-吲唑与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为32％。Except for replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 2-methyl-6-(piperazin-1-yl)-2H-indazole, 6-(4-(chloroform Base) benzyl) piperazin-1-yl)-2-methyl-2H-indazole and 4-(4-(4-(chloromethyl)benzyl) piperazin-1-yl) in Example 1 The synthesis of -3-fluorobenzonitrile was consistent with a yield of 32%.
MS-ESI:m/z 355.2[M+H]+。MS-ESI: m/z 355.2 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.73(s,1H),7.49(d,J＝9.1Hz,1H),7.36(s,4H),6.95(s,1H),6.92(dd,J＝9.1,1.9Hz,1H),4.59(s,2H),4.13(s,3H),3.58(s,2H),3.25-3.18(m,4H),2.66-2.60(m,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.73(s, 1H), 7.49(d, J=9.1Hz, 1H), 7.36(s, 4H), 6.95(s, 1H), 6.92(dd, J=9.1, 1.9Hz, 1H), 4.59(s, 2H), 4.13(s, 3H), 3.58(s, 2H), 3.25-3.18(m, 4H), 2.66-2.60(m, 4H).
S4：3-(5-(1-(4-((4-(2-甲基-2H-吲唑-6-基)哌嗪-1-基)甲基)苄基)哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮的制备
S4: 3-(5-(1-(4-((4-(2-methyl-2H-indazol-6-yl)piperazin-1-yl)methyl)benzyl)piperidine-4- Preparation of -1-oxoisoindoline-2-yl)piperidine-2,6-dione
除了用6-(4-(氯甲基)苄基)哌嗪-1-基)-2-甲基-2H-吲唑替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物12与实施例1中化合物1的合成一致，收率为36％。Except replacing 4-(4-(4-(chloromethyl)benzyl)piperazine with 6-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-methyl-2H-indazole Except for azin-1-yl)-3-fluorobenzonitrile, the synthesis of compound 12 was consistent with that of compound 1 in Example 1, and the yield was 36%.
MS-ESI:m/z 646.3[M+H]+。MS-ESI: m/z 646.3 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.07(s,1H),7.80(d,J＝8.2Hz,1H),7.73(s,1H),7.49(d,J＝9.1Hz,1H),7.35(s,6H),6.95(s,1H),6.92(dd,J＝9.1,1.8Hz,1H),5.22(dd,J＝13.3,5.1Hz,1H),4.38(dd,J＝58.4,15.9Hz,2H),4.13(s,3H),3.63(s,2H),3.59(s,2H),3.22(d,J＝4.6Hz,4H),3.09(s,2H),2.99-2.88(m,1H),2.84(dt,J＝17.8,8.9Hz,1H),2.66(s,5H),2.43-2.28(m,1H),2.27-2.16(m,2H),2.01(dd,J＝15.2,9.2Hz,2H),1.86(s,2H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.07(s, 1H), 7.80(d, J=8.2Hz, 1H), 7.73(s, 1H), 7.49(d, J=9.1Hz, 1H) ,7.35(s,6H),6.95(s,1H),6.92(dd,J=9.1,1.8Hz,1H),5.22(dd,J=13.3,5.1Hz,1H),4.38(dd,J=58.4 ,15.9Hz,2H),4.13(s,3H),3.63(s,2H),3.59(s,2H),3.22(d,J＝4.6Hz,4H),3.09(s,2H),2.99-2.88 (m,1H),2.84(dt,J=17.8,8.9Hz,1H),2.66(s,5H),2.43-2.28(m,1H),2.27-2.16(m,2H),2.01(dd,J =15.2, 9.2Hz, 2H), 1.86(s, 2H).
实施例13 4-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)-3-(三氟甲基)苯甲腈(化合物13)的制备Example 13 4-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidine- Preparation of 1-yl)methyl)benzyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile (compound 13)
S1：4-(4-氰基-2-(三氟甲基)苯基)哌嗪-1-羧酸叔丁酯的制备
S1: Preparation of tert-butyl 4-(4-cyano-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate
除了用4-溴-3-(三氟甲基)苯甲腈替换5-溴苯并[d][1,3]二氧杂环戊烷外，4-(4-氰基-2-(三氟甲基)苯基)哌嗪-1-羧酸叔丁酯与实施例11中4-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪-1-羧酸叔丁酯的合成一致，收率为22％。In addition to replacing 5-bromobenzo[d][1,3]dioxolane with 4-bromo-3-(trifluoromethyl)benzonitrile, 4-(4-cyano-2-( Trifluoromethyl) phenyl) piperazine-1- tert-butyl carboxylate and 4-(benzo[d][1,3]dioxolane-5-yl) piperazine- The synthesis of tert-butyl 1-carboxylate was consistent with a yield of 22%.
MS-ESI:m/z 300.1[M+H-56]+。MS-ESI: m/z 300.1 [M+H-56] + .
1H-NMR(400MHz,CDCl3):δ7.92(d,J＝1.7Hz,1H),7.78(dd,J＝8.4,1.8Hz,1H),7.30(d,J＝8.5Hz,1H),3.71-3.48(m,4H),3.05-2.79(m,4H),1.48(s,9H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.92(d, J=1.7Hz, 1H), 7.78(dd, J=8.4, 1.8Hz, 1H), 7.30(d, J=8.5Hz, 1H) ,3.71-3.48(m,4H),3.05-2.79(m,4H),1.48(s,9H).
S2：4-(哌嗪-1-基)-3-(三氟甲基)苯甲腈的制备
S2: Preparation of 4-(piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
除了用4-(4-氰基-2-(三氟甲基)苯基)哌嗪-1-羧酸叔丁酯替换4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯外，4-(哌嗪-1-基)-3-(三氟甲基)苯甲腈与实施例1中3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的合成一致，收率为88％。Except replacing 4-(2,6-dioxopiperidin-3-yl)- 1-Oxoisoindoline-5-yl)piperidine-1-carboxylic acid tert-butyl ester, 4-(piperazin-1-yl)-3-(trifluoromethyl)benzonitrile and Examples The synthesis of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione in 1 was consistent and the yield was 88%.
MS-ESI:m/z 256.1[M+H]+。MS-ESI: m/z 256.1 [M+H] + .
S3：4-(4-(4-(氯甲基)苯基)哌嗪-1-基)-3-(三氟甲基)苯甲腈的制备
S3: Preparation of 4-(4-(4-(chloromethyl)phenyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
除了用4-(哌嗪-1-基)-3-(三氟甲基)苯甲腈替换3-氟-4-(哌嗪-1-基)苯甲腈外，4-(4-(4-(氯甲基)苯基)哌嗪-1-基)-3-(三氟甲基)苯甲腈与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率23％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 4-(piperazin-1-yl)-3-(trifluoromethyl)benzonitrile, 4-(4-( 4-(chloromethyl)phenyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile and 4-(4-(4-(chloromethyl)benzyl) in Example 1 The synthesis of piperazin-1-yl)-3-fluorobenzonitrile was consistent, and the yield was 23%.
MS-ESI:m/z 394.2[M+H]+。MS-ESI: m/z 394.2 [M+H] + .
1H-NMR(400MHz,CDCl3):δ7.88(d,J＝1.6Hz,1H),7.74(dd,J＝8.5,1.7Hz,1H),7.40-7.32(m,4H),7.29(d,J＝8.5Hz,1H),4.59(s,2H),3.57(s,2H),3.11-3.03(m,4H),2.60(s,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.88 (d, J=1.6Hz, 1H), 7.74 (dd, J=8.5, 1.7Hz, 1H), 7.40-7.32 (m, 4H), 7.29( d, J=8.5Hz, 1H), 4.59(s, 2H), 3.57(s, 2H), 3.11-3.03(m, 4H), 2.60(s, 4H).
S4：4-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)-3-(三氟甲基)苯甲腈的制备
S4: 4-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidine-1 Preparation of -yl)methyl)benzyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
除了用4-(4-(4-(氯甲基)苯基)哌嗪-1-基)-3-(三氟甲基)苯甲腈替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物13与实施例1中化合物1的合成一致，收率36％。Except replacing 4-(4-(4-(chloromethyl)phenyl)piperazin-1-yl)-3-(trifluoromethyl)benzonitrile with 4-(4-(4-(chloromethyl) )benzyl)piperazin-1-yl)-3-fluorobenzonitrile, the synthesis of compound 13 is consistent with that of compound 1 in Example 1, and the yield is 36%.
MS-ESI:m/z 685.4[M+H]+。MS-ESI: m/z 685.4 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.02(s,1H),7.88(d,J＝1.7Hz,1H),7.80(d,J＝7.8Hz,1H),7.73(dd,J＝8.5,1.8Hz,1H),7.37-7.27(m,7H),5.22(dd,J＝13.2,5.1Hz,1H),4.39(dd,J＝59.3,15.9Hz,2H),3.57(s,4H),3.14-3.02(m,6H),2.96-2.89(m,1H),2.88-2.76(m,1H),2.61(s,5H),2.43-2.06(m,4H),2.06-1.90(m,1H),1.85(s,3H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.02(s, 1H), 7.88(d, J=1.7Hz, 1H), 7.80(d, J=7.8Hz, 1H), 7.73(dd, J= 8.5,1.8Hz,1H),7.37-7.27(m,7H),5.22(dd,J＝13.2,5.1Hz,1H),4.39(dd,J＝59.3,15.9Hz,2H),3.57(s,4H ),3.14-3.02(m,6H),2.96-2.89(m,1H),2.88-2.76(m,1H),2.61(s,5H),2.43-2.06(m,4H),2.06-1.90(m ,1H), 1.85(s,3H).
实施例14 4-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)-3-(三氟甲氧基)苯甲腈(化合物14)的制备Example 14 4-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidine- Preparation of 1-yl)methyl)benzyl)piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile (compound 14)
S1：4-(4-氰基-2-(三氟甲氧基)苯基)哌嗪-1-羧酸叔丁酯的制备
S1: Preparation of tert-butyl 4-(4-cyano-2-(trifluoromethoxy)phenyl)piperazine-1-carboxylate
除了用4-溴-3-(三氟甲氧基)苯甲腈替换5-溴苯并[d][1,3]二氧杂环戊烷外，4-(4-氰基-2-(三氟甲氧基)苯基)哌嗪-1-羧酸叔丁酯与实施例11中4-(苯并[d][1,3]二氧杂环戊烷-5-基)哌嗪-1-羧酸叔丁酯的合成一致，收率为30％。In addition to replacing 5-bromobenzo[d][1,3]dioxolane with 4-bromo-3-(trifluoromethoxy)benzonitrile, 4-(4-cyano-2- (Trifluoromethoxy) phenyl) tert-butyl piperazine-1-carboxylate and 4-(benzo[d][1,3]dioxolane-5-yl)piperazine in Example 11 The synthesis of tert-butyl oxazine-1-carboxylate was consistent with a yield of 30%.
MS-ESI:m/z 318.8[M+H-56]+。MS-ESI: m/z 318.8 [M+H-56] + .
1H-NMR(400MHz,CDCl3):δ7.51(dd,J＝8.5,1.9Hz,1H),7.45(s,1H),6.99(d,J＝8.5Hz,1H),3.62-3.53(m,4H),3.17-3.10(m,4H),1.47(s,9H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.51(dd, J=8.5, 1.9Hz, 1H), 7.45(s, 1H), 6.99(d, J=8.5Hz, 1H), 3.62-3.53( m,4H), 3.17-3.10(m,4H), 1.47(s,9H).
S2：4-(哌嗪-1-基)-3-(三氟甲氧基)苯甲腈的制备
S2: Preparation of 4-(piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile
除了用4-(4-氰基-2-(三氟甲氧基)苯基)哌嗪-1-羧酸叔丁酯替换4-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-羧酸叔丁酯外，4-(哌嗪-1-基)-3-(三氟甲氧基)苯甲腈与实施例1中3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮的合成一致，收率为87％。Except replacing 4-(2,6-dioxopiperidin-3-yl) with tert-butyl 4-(4-cyano-2-(trifluoromethoxy)phenyl)piperazine-1-carboxylate -1-oxoisoindoline-5-yl)piperidine-1-carboxylic acid tert-butyl ester, 4-(piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile and The synthesis of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione in Example 1 was consistent, with a yield of 87%.
MS-ESI:m/z 274.8[M+H]+。MS-ESI: m/z 274.8 [M+H] + .
S3：4-(4-(4-(氯甲基)苯基)哌嗪-1-基)-3-(三氟甲氧基)苯甲腈的制备
S3: Preparation of 4-(4-(4-(chloromethyl)phenyl)piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile
除了用4-(哌嗪-1-基)-3-(三氟甲氧基)苯甲腈替换3-氟-4-(哌嗪-1-基)苯甲腈外，4-(4-(4-(氯甲基)苯基)哌嗪-1-基)-3-(三氟甲氧基)苯甲腈与实施例1中4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈的合成一致，收率为32％。In addition to replacing 3-fluoro-4-(piperazin-1-yl)benzonitrile with 4-(piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile, 4-(4- (4-(chloromethyl)phenyl)piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile and 4-(4-(4-(chloromethyl)benzyl) in Example 1 base) piperazin-1-yl)-3-fluorobenzonitrile was synthesized in the same way, and the yield was 32%.
MS-ESI:m/z 396.8[M+H]+。MS-ESI: m/z 396.8 [M+H] + .
S4：4-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)苄基)哌嗪-1-基)-3-(三氟甲氧基)苯甲腈的制备
S4: 4-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidine-1 Preparation of -yl)methyl)benzyl)piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile
除了用4-(4-(4-(氯甲基)苯基)哌嗪-1-基)-3-(三氟甲氧基)苯甲腈替换4-(4-(4-(氯甲基)苄基)哌嗪-1-基)-3-氟苯甲腈外，化合物14与实施例1中化合物1的合成一致，收率为37％。Except replacing 4-(4-(4-(chloromethyl)phenyl)piperazin-1-yl)-3-(trifluoromethoxy)benzonitrile with 4-(4-(4-(chloromethyl)phenyl) Except for benzyl)piperazin-1-yl)-3-fluorobenzonitrile, the synthesis of compound 14 was consistent with that of compound 1 in Example 1, with a yield of 37%.
MS-ESI:m/z 701.4[M+H]+。MS-ESI: m/z 701.4 [M+H] + .
1H-NMR(400MHz,CDCl3):δ8.09(s,1H),7.80(d,J＝8.0Hz,1H),7.48(dd,J＝8.5,1.7Hz,1H),7.42(s,1H),7.34(t,J＝6.3Hz,6H),6.97(d,J＝8.5Hz,1H),5.22(dd,J＝13.3,5.1Hz,1H),4.38(dd,J＝58.5,15.9Hz,2H),3.62(d,J＝9.5Hz,2H),3.56(s,2H),3.27-3.17(m,5H),3.08(s,2H),2.97-2.88(m,1H),2.85(dd,J＝13.0,5.3Hz,1H),2.60(s,6H),2.35(dd,J＝13.1,5.1Hz,1H),2.20(dd,J＝9.2,3.9Hz,3H),1.85(s,3H)。 1 H-NMR (400MHz, CDCl 3 ): δ8.09(s, 1H), 7.80(d, J=8.0Hz, 1H), 7.48(dd, J=8.5, 1.7Hz, 1H), 7.42(s, 1H), 7.34(t, J=6.3Hz, 6H), 6.97(d, J=8.5Hz, 1H), 5.22(dd, J=13.3, 5.1Hz, 1H), 4.38(dd, J=58.5, 15.9 Hz,2H),3.62(d,J=9.5Hz,2H),3.56(s,2H),3.27-3.17(m,5H),3.08(s,2H),2.97-2.88(m,1H),2.85 (dd, J=13.0,5.3Hz,1H),2.60(s,6H),2.35(dd,J=13.1,5.1Hz,1H),2.20(dd,J=9.2,3.9Hz,3H),1.85( s, 3H).
对比例1 3-(5-(1-苄基哌啶-4-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(WO2020/128972中的化合物I-57)的制备
Comparative Example 1 3-(5-(1-benzylpiperidin-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (compound in WO2020/128972 I-57) Preparation
将3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮(120mg，0.37mmol)、苯甲醛(98mg，0.92mmol)和醋酸钠(76mg，0.92mmol)溶于甲醇/二氯甲烷(10mL/10mL)中，室温下反应20min后，加入氰基硼氢化钠(46mg，0.73mmol)，于室温下反应过夜。TLC显示反应达到完全。混合物中加入饱和碳酸氢钠溶液洗涤，水洗涤。有机相用无水硫酸钠干燥，过滤，减压蒸去溶剂，残留物用快速柱层析法分离，得化合物I-57(40mg，0.1mmol)，收率为27％。3-(1-oxo-5-(piperidin-4-yl)isoindoline-2-yl)piperidine-2,6-dione (120mg, 0.37mmol), benzaldehyde (98mg, 0.92 mmol) and sodium acetate (76mg, 0.92mmol) were dissolved in methanol/dichloromethane (10mL/10mL), reacted at room temperature for 20min, added sodium cyanoborohydride (46mg, 0.73mmol), and reacted overnight at room temperature. TLC showed the reaction was complete. The mixture was washed with saturated sodium bicarbonate solution and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was separated by flash column chromatography to obtain compound I-57 (40 mg, 0.1 mmol) with a yield of 27%.
MS-ESI:m/z 418.5[M+H]+。MS-ESI: m/z 418.5 [M+H] + .
1H-NMR(400MHz,CDCl3):δ10.96(s,1H),7.63(d,J＝7.9Hz,1H),7.49(s,1H),7.40(d,J＝8.0Hz,1H),7.33(d,J＝4.4Hz,4H),7.25(dd,J＝8.7,4.3Hz,1H),5.09(dd,J＝13.2,5.1Hz,2H),4.35(dd,J＝53.3,17.1Hz,2H),3.51(s,2H),2.91(t,J＝14.2Hz,3H),2.62(dd,J＝25.2,14.2Hz,2H),2.38(dt,J＝17.6,12.7Hz,1H),2.03(dt,J＝14.5,9.0Hz,3H),1.72(dd,J＝14.1,11.1Hz,4H)。 1 H-NMR (400MHz, CDCl 3 ): δ10.96(s, 1H), 7.63(d, J=7.9Hz, 1H), 7.49(s, 1H), 7.40(d, J=8.0Hz, 1H) ,7.33(d,J=4.4Hz,4H),7.25(dd,J=8.7,4.3Hz,1H),5.09(dd,J=13.2,5.1Hz,2H),4.35(dd,J=53.3,17.1 Hz, 2H), 3.51(s, 2H), 2.91(t, J=14.2Hz, 3H), 2.62(dd, J=25.2, 14.2Hz, 2H), 2.38(dt, J=17.6, 12.7Hz, 1H ), 2.03 (dt, J = 14.5, 9.0 Hz, 3H), 1.72 (dd, J = 14.1, 11.1 Hz, 4H).
实验例1 Western Blot检测化合物处理后细胞中IKZF2蛋白的表达水平Experimental example 1 Western Blot detection of the expression level of IKZF 2 protein in cells after compound treatment
I.实验步骤：I. Experimental steps:
1.细胞复苏1. Cell recovery
准备完全培养基(1640+10％FBS+双抗)，37℃预热备用；从液氮罐取出Jurkat细胞，用镊子夹取冻存管盖子与瓶身交界线恰好下面位置，浸入37℃温水中，并不时摇动令其尽快融化；吸出细胞悬液，加到含10mL完全培养基的离心管中，混匀；室温下200g离心5min；弃去上清液，加入完全培养基，计数并调整细胞密度，接种至T25培养瓶中，37℃培养箱静置培养；次日更换培养液，期间根据细胞状态及密度进行传代。 Prepare complete medium (1640+10% FBS+double antibody), preheat at 37°C for standby; take out Jurkat cells from the liquid nitrogen tank, use tweezers to grasp the position just below the boundary line between the cap and the body of the cryopreservation tube, and immerse in warm water at 37°C , and shake it from time to time to melt it as soon as possible; suck out the cell suspension, add it to a centrifuge tube containing 10mL complete medium, and mix well; centrifuge at 200g for 5min at room temperature; discard the supernatant, add complete medium, count and adjust the cells Density, inoculated into T25 culture flasks, cultured in a 37°C incubator; the culture medium was replaced the next day, during which the cells were subcultured according to the state and density of the cells.
2.细胞铺板2. Cell Plating
细胞复苏并稳定一周后(细胞进入对数生长期)方可进行检测实验，实验前保证细胞活力大于90％。实验前完全培养基，预热至37℃备用。取出培养箱中对数生长期的细胞，当细胞密度达到80％以上，将细胞悬液移到离心管，200g离心5min。弃上清，加入5mL新鲜培养基重悬，计数后按照5×105/孔传代比例分入12孔板中。After the cells are recovered and stabilized for one week (the cells enter the logarithmic growth phase), the detection experiment can be carried out, and the cell viability must be greater than 90% before the experiment. Before the experiment, the complete medium was preheated to 37°C for use. Take out the cells in the logarithmic growth phase in the incubator, and when the cell density reaches above 80%, move the cell suspension to a centrifuge tube, and centrifuge at 200 g for 5 min. Discard the supernatant, add 5 mL of fresh medium to resuspend, count and divide into 12-well plates according to the passage ratio of 5×10 5 /well.
3.药物处理3. Drug handling
细胞铺板后，并按照要求加入不同终浓度的化合物(溶于DMSO)，空白对照组为DMSO，同时保证DMSO比例不超过0.1％，阳性对照组为I-57(参见专利申请WO2020/128972)，化合物浓度为1.0μM，药物处理24h后，收集细胞，200g离心5min。弃上清，细胞沉淀放入-80℃冰箱保存。After the cells were plated, compounds of different final concentrations (dissolved in DMSO) were added as required. The blank control group was DMSO, while ensuring that the DMSO ratio did not exceed 0.1%. The positive control group was I-57 (see patent application WO2020/128972), The concentration of the compound was 1.0 μM. After 24 hours of drug treatment, the cells were collected and centrifuged at 200 g for 5 minutes. The supernatant was discarded, and the cell pellet was stored in a -80°C refrigerator.
4.细胞蛋白提取4. Cell Protein Extraction
步骤1：从-80℃冰箱取出装在EP管中的细胞样品。Step 1: Take out the cell sample in the EP tube from the -80°C freezer.
步骤2：裂解：Step 2: Lysis:
A.各管加入0.045mL的1×工作浓度细胞裂解液(含Protease Inhibitor cocktail)，用枪头吹散细胞沉淀，使其充分裂解；A. Add 0.045mL of 1× working concentration cell lysate (containing Protease Inhibitor cocktail) to each tube, and blow off the cell pellet with the tip of the pipette to fully lyse it;
B.4℃裂解30min，置于冰水中超声破碎。B. Crack at 4°C for 30 minutes, then place in ice water for ultrasonication.
步骤3：离心(10000g；4℃；10min)，收集上清。Step 3: centrifuge (10000g; 4°C; 10min), and collect the supernatant.
5.使用BCA试剂盒测定蛋白浓度5. Determination of protein concentration using BCA kit
步骤1：在酶标板上加梯度浓度蛋白标准溶液，制蛋白标准曲线。Step 1: Add gradient concentration protein standard solution on the microtiter plate to make a protein standard curve.
步骤2：稀释待测样品10倍，使样品总体积为25μL。Step 2: Dilute the sample to be tested 10 times to make the total sample volume 25 μL.
步骤3：根据样品数，制备BCA工作液，按50体积试剂A加1体积试剂B，充分混匀。Step 3: Prepare BCA working solution according to the number of samples, add 50 volumes of reagent A to 1 volume of reagent B, and mix well.
步骤4：每孔中加入200μL的BCA工作液，震荡混匀，37℃放置30min，562nm下测定吸光值。以蛋白含量、吸光值为横、纵坐标，绘制标准曲线，再根据所测样品的吸光值，计算出对应样品的蛋白浓度(单位：μg/μL)。Step 4: Add 200 μL of BCA working solution to each well, shake and mix, place at 37°C for 30 minutes, and measure the absorbance at 562nm. Draw a standard curve with the protein content and absorbance value as the abscissa and ordinate, and then calculate the protein concentration (unit: μg/μL) of the corresponding sample according to the absorbance value of the measured sample.
6.Western Blot6. Western Blot
步骤1：根据蛋白浓度检测结果加入loading buffer(LDS sample buffer；sample reducing agent)调整上样量，30μg/孔上样，使用预制胶，按照标准规程操作电泳(200V；40min)。Step 1: According to the protein concentration test result, add loading buffer (LDS sample buffer; sample reducing agent) to adjust the sample volume, 30 μg/well sample, use precast gel, and operate electrophoresis according to standard procedures (200V; 40min).
步骤2：转膜：将蛋白转移至PVDF膜上，350mA，75min。Step 2: Membrane transfer: transfer protein to PVDF membrane, 350mA, 75min.
步骤3：封闭：使用封闭液(含5％脱脂奶粉的TBST)，室温封闭1h。Step 3: Blocking: use blocking solution (TBST containing 5% skimmed milk powder) at room temperature for 1 h.
步骤4：一抗孵育：使用Antibody dilution buffer按照1:1000的比例稀释Helios Antibody和GAPDH，4℃孵育过夜。用TBST洗涤3次，每次10min。Step 4: Primary antibody incubation: use Antibody dilution buffer to dilute Helios Antibody and GAPDH at a ratio of 1:1000, and incubate overnight at 4°C. Wash 3 times with TBST, 10 min each time.
步骤5：二抗孵育：使用Antibody dilution buffer按照1:2000的比例稀释HRP二抗，室温孵育1h。用TBST洗涤3次，每次10min。Step 5: Secondary antibody incubation: use Antibody dilution buffer to dilute the HRP secondary antibody at a ratio of 1:2000, and incubate at room temperature for 1 hour. Wash 3 times with TBST, 10 min each time.
步骤6：显影、定影：将等体积的Solution A和Solution B混合(Tanontm High-sig ECL Western Blotting Substrate)。去除洗过的印迹膜上多余的洗液，在膜上有蛋白的一面加上检测混合液。使用天能Tanon 4200全自动化学发光成像分析系统进行显色与成像。Step 6: Development and fixation: Mix equal volumes of Solution A and Solution B (Tanontm High-sig ECL Western Blotting Substrate). Remove the excess washing solution on the washed blot, and add the detection mixture to the protein side of the membrane. Use Tianneng Tanon 4200 automatic chemiluminescence imaging analysis system for color development and imaging.
II.实验结果：
II. Experimental results:
如上表所示，一方面，相较于现有技术(如专利申请WO2020/128972中的优选化合物I-57，按照对比例1中的方法制得)，本发明的化合物具有显著更优的IKZF2降解活性；另一方面，相较于IKZF1，本发明的化合物具有针对IKZF2的选择性降解活性。As shown in the above table, on the one hand, compared with the prior art (such as the preferred compound I-57 in the patent application WO2020/128972, prepared according to the method in Comparative Example 1), the compound of the present invention has significantly better IKZF 2 degradation activity; on the other hand, compared with IKZF 1 , the compound of the present invention has selective degradation activity against IKZF 2 .
以上实施例仅是本发明的优选实施方式，本发明的保护范围不仅局限于上述实施例，凡属于本发明思路下的技术方案均落入本发明的保护范围。若本领域技术人员进行的改动和变化不脱离本发明的精神和范围，则都应在本发明的保护范围之内。 The above embodiments are only preferred implementations of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions under the idea of the present invention fall within the protection scope of the present invention. If the changes and changes made by those skilled in the art do not depart from the spirit and scope of the present invention, they should all be within the protection scope of the present invention.

Claims (26)

  1. 如式(I)所示的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，
    A compound represented by formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer,
    其中，in,
    X1、X2和X3各自独立地为CR8或N；X 1 , X 2 and X 3 are each independently CR 8 or N;
    X4为CR9R10或C＝O，其中R9和R10各自独立地为氢或C1-C4烷基；X 4 is CR 9 R 10 or C=O, wherein R 9 and R 10 are each independently hydrogen or C 1 -C 4 alkyl;
    R1、R2、R3和R8各自独立地为氢、羟基、巯基、卤素、叠氮基、氰基、取代或未取代的胺基、硝基、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C1-C6酯基、取代或未取代的C1-C6酰胺基、取代或未取代的C1-C6酰基、取代或未取代的C1-C6磺酰基、取代或未取代的C1-C6磺酰胺基、取代或未取代的C1-C6磺酸酯基、取代或未取代的C1-C6膦酰基、取代或未取代的C1-C6膦酰胺基或者取代或未取代的C1-C6膦酸酯基；R 1 , R 2 , R 3 and R 8 are each independently hydrogen, hydroxyl, mercapto, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight-membered ring heteroalkyl, substituted or unsubstituted C 1 -C 6 ester group, substituted or unsubstituted C 1 -C 6 amide group, substituted or Unsubstituted C 1 -C 6 acyl, substituted or unsubstituted C 1 -C 6 sulfonyl, substituted or unsubstituted C 1 -C 6 sulfonamide, substituted or unsubstituted C 1 -C 6 sulfonate substituted or unsubstituted C 1 -C 6 phosphono, substituted or unsubstituted C 1 -C 6 phosphonamido or substituted or unsubstituted C 1 -C 6 phosphonate;
    或者，R1、R2和R3中的任意两个相互连接成取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基；Alternatively, any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl, a substituted or unsubstituted C 6 -C 10 aryl or substituted or unsubstituted five to ten membered heteroaryl;
    R4、R5、R6和R7各自独立地为氢、羟基、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基；R 4 , R 5 , R 6 and R 7 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted Substituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted three to eight membered ring heteroalkyl, substituted or unsubstituted C 6 -C 10 aryl Or a substituted or unsubstituted five to ten membered heteroaryl group;
    或者，R4和R5以及R6和R7各自独立地相互连接成取代或未取代的C3-C8环烷基或者取代或未取代的三至八元环杂烷基；Alternatively, R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three- to eight-membered cycloheteroalkyl group;
    为取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基或者取代或未取代的三至八元环杂烯基； is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight-membered cycloheteroalkyl or a substituted or unsubstituted three to eight-membered cycloheteroalkenyl;
    为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基； It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group;
    为取代或未取代的C3-C8环烷基、取代或未取代的三至八元环杂烷基、取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基； is a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted three to eight membered heteroalkyl group, a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten Yuan Heteroaryl;
    为取代或未取代的C6-C10芳基、取代或未取代的五至十元芳杂基、取代或未取代的C3-C8环烷基或者取代或未取代的三至八元环杂烷基； is a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted five to ten membered heteroaryl group, a substituted or unsubstituted C 3 -C 8 cycloalkyl group or a substituted or unsubstituted three to eight membered Cycloheteroalkyl;
    所述杂环烷基和杂芳基中杂原子的个数各自独立地为1、2、3或4，每个所述杂原子各自独立地为B、N、O或S。 The number of heteroatoms in the heterocycloalkyl and heteroaryl is 1, 2, 3 or 4 each independently, and each of the heteroatoms is B, N, O or S independently.
  2. 如权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound as claimed in claim 1 or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    X1、X2和X3各自独立地为CR8，其中R8如权利要求1中所定义，优选氢、C1-C6卤代烷基或C1-C6卤代烷氧基，更优选氢、C1-C6氟代烷基或C1-C6氟代烷氧基，进一步优选氢。X 1 , X 2 and X 3 are each independently CR 8 , wherein R 8 is as defined in claim 1, preferably hydrogen, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy, more preferably hydrogen, C 1 -C 6 fluoroalkyl or C 1 -C 6 fluoroalkoxy, more preferably hydrogen.
  3. 如权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    X4为CH2或C＝O，优选CH2。X 4 is CH 2 or C═O, preferably CH 2 .
  4. 如权利要求1至3中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    R1、R2和R3各自独立地为氢、卤素、叠氮基、氰基、取代或未取代的胺基、硝基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的三至六元环杂烷基或者取代或未取代的C1-C4酰基，优选氢、氟、氯、溴、碘、叠氮基、氰基、胺基、硝基、取代或未取代的甲基、取代或未取代的甲氧基、取代或未取代的吡咯烷基或者取代或未取代的乙酰基，更优选氢、氟、氯、溴、氰基、胺基、硝基、三氟甲基、三氟甲氧基或乙酰基，更优选氟或氰基；R 1 , R 2 and R 3 are each independently hydrogen, halogen, azido, cyano, substituted or unsubstituted amino, nitro, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted Substituted C 1 -C 4 alkoxy, substituted or unsubstituted three to six membered cycloheteroalkyl or substituted or unsubstituted C 1 -C 4 acyl, preferably hydrogen, fluorine, chlorine, bromine, iodine, azide group, cyano group, amino group, nitro group, substituted or unsubstituted methyl group, substituted or unsubstituted methoxy group, substituted or unsubstituted pyrrolidinyl group or substituted or unsubstituted acetyl group, more preferably hydrogen, fluorine , chlorine, bromine, cyano, amine, nitro, trifluoromethyl, trifluoromethoxy or acetyl, more preferably fluorine or cyano;
    或者，or,
    R1、R2和R3中的任意两个相互连接成取代或未取代的三至六元环杂烷基或者取代或未取代的五至六元芳杂基，优选取代或未取代的三至六元含氧环杂烷基或者取代或未取代的五至六元含氮芳杂基，更优选取代或未取代的1,3-二氧环杂戊基、取代或未取代的1,2-氧硼环杂戊基或者取代或未取代的吡唑基。Any two of R 1 , R 2 and R 3 are connected to each other to form a substituted or unsubstituted three- to six-membered cycloheteroalkyl group or a substituted or unsubstituted five- to six-membered heteroaryl group, preferably a substituted or unsubstituted three-membered to six-membered oxygen-containing cycloheteroalkyl group or substituted or unsubstituted five- to six-membered nitrogen-containing heteroaryl group, more preferably substituted or unsubstituted 1,3-dioxacyclopentyl, substituted or unsubstituted 1, 2-Oxaboropentyl or substituted or unsubstituted pyrazolyl.
  5. 如权利要求1至4中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer as described in any one of claims 1 to 4, wherein:
    R4、R5、R6和R7各自独立地为氢或者取代或未取代的C1-C4烷基，优选氢或者取代或未取代的甲基，更优选氢；R 4 , R 5 , R 6 and R 7 are each independently hydrogen or substituted or unsubstituted C 1 -C 4 alkyl, preferably hydrogen or substituted or unsubstituted methyl, more preferably hydrogen;
    或者，or,
    R4和R5以及R6和R7各自独立地相互连接成取代或未取代的C3-C6环烷基或者取代或未取代的三至六元环杂烷基，优选取代或未取代的C3-C6环烷基，更优选取代或未取代的环丙基。R 4 and R 5 and R 6 and R 7 are each independently connected to each other to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted three to six-membered cycloheteroalkyl, preferably substituted or unsubstituted C 3 -C 6 cycloalkyl, more preferably substituted or unsubstituted cyclopropyl.
  6. 如权利要求1至5中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    为取代或未取代的三至六元环杂烷基或者取代或未取代的三至六元环杂烯基，优选取代或未取代的哌啶基或者取代或未取代的四氢吡啶基。 is a substituted or unsubstituted three- to six-membered ring heteroalkyl group or a substituted or unsubstituted three- to six-membered ring heteroalkenyl group, preferably a substituted or unsubstituted piperidinyl group or a substituted or unsubstituted tetrahydropyridyl group.
  7. 如权利要求1至6中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基，优选取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的哒嗪基或者取代或未取代的嘧啶基， 更优选取代或未取代的苯基。 It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group, preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyridyl group Azinyl or substituted or unsubstituted pyrimidinyl, Substituted or unsubstituted phenyl is more preferred.
  8. 如权利要求1至7中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer as described in any one of claims 1 to 7, wherein:
    为取代或未取代的C3-C6环烷基或者取代或未取代的三至六元环杂烷基，优选取代或未取代的三至六元环杂烷基，更优选取代或未取代的哌嗪基或者取代或未取代的哌啶基，进一步优选取代或未取代的哌嗪基。 is a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted three to six-membered cycloheteroalkyl, preferably a substituted or unsubstituted three to six-membered cycloheteroalkyl, more preferably a substituted or unsubstituted Piperazinyl or substituted or unsubstituted piperidinyl, more preferably substituted or unsubstituted piperazinyl.
  9. 如权利要求1至8中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound or pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer as described in any one of claims 1 to 8, wherein:
    为取代或未取代的C6-C10芳基或者取代或未取代的五至十元芳杂基，优选取代或未取代的C6-C10芳基，更优选取代或未取代的苯基。 It is a substituted or unsubstituted C 6 -C 10 aryl group or a substituted or unsubstituted five to ten membered heteroaryl group, preferably a substituted or unsubstituted C 6 -C 10 aryl group, more preferably a substituted or unsubstituted phenyl group .
  10. 如权利要求1至9中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer as described in any one of claims 1 to 9, wherein:
    所述环杂烷基和芳杂基中杂原子的个数各自独立地为1、2或3，优选1或2；每个所述杂原子各自独立地为B、N或O，优选N或O。The number of heteroatoms in the cycloheteroalkyl and heteroaryl is independently 1, 2 or 3, preferably 1 or 2; each of the heteroatoms is independently B, N or O, preferably N or O.
  11. 如权利要求1至10中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    所述化合物为如式(II)所示的化合物，
    Described compound is the compound shown in formula (II),
    其中，in,
    X4、R1、R2、R3、如权利要求1中所定义。X 4 , R 1 , R 2 , R 3 , as defined in claim 1.
  12. 如权利要求1至11中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    所述化合物为如式(II’)所示的化合物，
    The compound is a compound shown in formula (II'),
    其中，in,
    R1、R2、R3、如权利要求1中所定义。R 1 , R 2 , R 3 , as defined in claim 1.
  13. 如权利要求1至12中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    所述化合物为如式(III)所示的化合物，
    The compound is a compound shown in formula (III),
    其中，in,
    表示单键或双键，优选单键； represents a single or double bond, preferably a single bond;
    R1、R2、R3、如权利要求1中所定义。R 1 , R 2 , R 3 , as defined in claim 1.
  14. 如权利要求1至13中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    所述化合物为如式(IV)所示的化合物，
    The compound is a compound shown in formula (IV),
    其中，in,
    X5、X6、X7和X8各自独立地为CH或N，优选X5、X6、X7和X8中的至少一个为CH，更优选X5、X6、X7和X8中的至少两个为CH，甚至更优选X5、X6、X7和X8中的至少三个为CH，进一步优选X5、X6、X7和X8均为CH；X 5 , X 6 , X 7 and X 8 are each independently CH or N, preferably at least one of X 5 , X 6 , X 7 and X 8 is CH, more preferably X 5 , X 6 , X 7 and X At least two of 8 are CH, even more preferably at least three of X 5 , X 6 , X 7 and X 8 are CH, further preferably X 5 , X 6 , X 7 and X 8 are all CH;
    R1、R2、R3、如权利要求1中所定义。 R 1 , R 2 , R 3 , as defined in claim 1.
  15. 如权利要求1至14中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    所述化合物为如式(V)所示的化合物，
    The compound is a compound shown in formula (V),
    其中，in,
    X9和X10各自独立地为CH或N，优选X9和X10中的至少一个为N，更优选X9和X10均为N；X 9 and X 10 are each independently CH or N, preferably at least one of X 9 and X 10 is N, more preferably X 9 and X 10 are both N;
    R1、R2、R3和如权利要求1中所定义。R 1 , R 2 , R 3 and as defined in claim 1.
  16. 如权利要求1至15中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，其中：The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer, wherein:
    所述化合物为如式(VI)所示的结构，
    Described compound is the structure shown in formula (VI),
    其中，R1、R2和R3如权利要求1中所定义。Wherein, R 1 , R 2 and R 3 are as defined in claim 1 .
  17. 下列化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体：


    The following compounds or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, chirally pure compounds, stereoisomers or tautomers:


  18. 一种药物组合物，其包含如权利要求1至17中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体，以及药学上可接受的载体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or Tautomers, and pharmaceutically acceptable carriers.
  19. 如权利要求18所述的药物组合物，其中：The pharmaceutical composition of claim 18, wherein:
    所述药物组合物进一步包含至少一种另外的药物活性成分。The pharmaceutical composition further comprises at least one additional pharmaceutically active ingredient.
  20. 如权利要求1至17中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者如权利要求18或19所述的药物组合物在制备IKZF2降解剂中的用途。The compound as claimed in any one of claims 1 to 17 or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or as claimed in Use of the pharmaceutical composition described in claim 18 or 19 in the preparation of an IKZF 2 degradation agent.
  21. 如权利要求1至17中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者如权利要求18或19所述的药物组合物在制备IKZF2蛋白水平调节剂，优选IKZF2蛋白水平降低剂中的用途。The compound as claimed in any one of claims 1 to 17 or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or as claimed in Use of the pharmaceutical composition described in claim 18 or 19 in the preparation of an IKZF 2 protein level regulator, preferably an IKZF 2 protein level lowering agent.
  22. 如权利要求1至17中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药、手性纯化合物、立体异构体或互变异构体或者如权利要求18或19所述的药物组合物在制备用于预防、改善和/或治疗IKZF2依赖性疾病或障碍的药物中的用途。The compound as claimed in any one of claims 1 to 17 or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, chiral pure compound, stereoisomer or tautomer or as claimed in Use of the pharmaceutical composition described in Claim 18 or 19 in the preparation of medicines for preventing, improving and/or treating IKZF 2 dependent diseases or disorders.
  23. 如权利要求22所述的用途，其中：The use as claimed in claim 22, wherein:
    所述IKZF2依赖性疾病或障碍受IKZF2蛋白水平升降的影响。 The IKZF2 - dependent disease or disorder is affected by the rise and fall of IKZF2 protein levels.
  24. 如权利要求22所述的用途，其中：The use as claimed in claim 22, wherein:
    所述IKZF2依赖性疾病或障碍为癌症。The IKZF2- dependent disease or disorder is cancer.
  25. 如权利要求24所述的用途，其中：The use according to claim 24, wherein:
    所述癌症为免疫应答缺陷的癌症或免疫原性癌症。The cancer is an immune response deficient cancer or an immunogenic cancer.
  26. 如权利要求24所述的用途，其中：The use according to claim 24, wherein:
    所述癌症选自肺癌(诸如非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC))、黑色素瘤(诸如脉络膜黑色素瘤)、乳腺癌(诸如三阴性乳腺癌(TNBC))、鼻咽癌(NPC)、微卫星稳定性结直肠癌(mssCRC)、微卫星不稳定性结直肠癌(msiCRC)、胸腺瘤、类癌、胃肠道间质瘤(GIST)、膀胱癌、胰腺癌、骨癌、神经胶质瘤、神经细胞瘤、食管癌、唇癌、喉癌、下咽癌、舌癌、腺癌、绒毛膜癌、泌尿癌、脑肿瘤(诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤)、支气管癌、骨髓瘤(诸如多发性骨髓瘤)、基底细胞瘤、畸胎瘤、精原细胞瘤、颅咽管瘤、骨肉瘤、乳头状瘤、芽状神经胶质瘤、肉瘤(诸如软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤)、血管瘤、瘢痕瘤、鳞状细胞癌、淋巴瘤(诸如霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、成人T细胞白血病/淋巴瘤(ATLL)、弥漫性大B细胞淋巴瘤(DLBCL)、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤(CTCL)以及中枢神经系统淋巴瘤)、支气管腺瘤、胸膜肺母细胞瘤、头颈癌(诸如头癌、颈癌、口咽癌以及口腔癌)、乳癌(诸如浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌)、消化道癌(诸如肛门癌、食道癌、胆囊癌、胃癌、小肠癌以及唾液腺癌)、甲状腺癌(诸如甲状腺髓样癌和乳头状甲状腺癌)、副甲状腺癌及其远距离转移灶、肝癌(诸如肝细胞癌、具有或不具有纤维板层形式的肝细胞癌、胆管细胞癌以及混合型肝细胞胆管细胞癌)、白血病(诸如急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓性白血病、慢性骨髓性白血病以及绒毛细胞白血病)、脑癌(诸如脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤)、生殖器官癌(诸如前列腺癌、睾丸癌、卵巢癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌以及子宫肉瘤)、尿道癌、眼癌(诸如眼内黑素瘤和成视网膜细胞瘤)、皮肤癌(诸如卡波西肉瘤、鳞状细胞瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌)、肾实质癌、肾癌(也称为肾细胞癌和肾腺癌)等相关癌症。 The cancer is selected from lung cancer (such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), melanoma (such as choroidal melanoma), breast cancer (such as triple negative breast cancer (TNBC)), nasopharyngeal carcinoma ( NPC), microsatellite stable colorectal cancer (mssCRC), microsatellite unstable colorectal cancer (msiCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), bladder cancer, pancreatic cancer, bone cancer , glioma, neurocytoma, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, adenocarcinoma, choriocarcinoma, urinary cancer, brain tumors (such as glioblastoma, astrocytoma , meningioma, medulloblastoma, and peripheral neuroectodermal tumors), bronchial carcinoma, myeloma (such as multiple myeloma), basal cell tumor, teratoma, seminoma, craniopharyngioma, osteosarcoma , papilloma, budding glioma, sarcomas (such as chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma, histiosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma ), hemangioma, keloid, squamous cell carcinoma, lymphoma (such as Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia/lymphoma (ATLL), diffuse large B-cell lymphoma (DLBCL), AIDS-related lymphoma, cutaneous T-cell lymphoma (CTCL), and central nervous system lymphoma), bronchial adenoma, pleuropulmonary blastoma, head and neck cancer (such as head cancer, neck cancer, oral pharynx and oral cavity), breast cancer (such as invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ and lobular carcinoma in situ), digestive tract cancer (such as anal, esophageal, gallbladder, stomach, small Salivary gland cancer), thyroid cancer (such as medullary thyroid carcinoma and papillary thyroid carcinoma), parathyroid carcinoma and its distant metastases, liver cancer (such as hepatocellular carcinoma, hepatocellular carcinoma with or without fibrolamellar form, cholangiocyte carcinoma and mixed hepatocellular cholangiocarcinoma), leukemia (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, and villous cell leukemia), brain cancer (such as brainstem and pituitary glia medulloblastoma, cerebellar and cerebral astrocytoma, etympanoma as well as neuroectodermal and pineal adenoma), reproductive organ cancers (such as prostate, testicular, ovarian, endometrial, cervical, vaginal, vulvar, and uterine sarcomas), urinary tract cancers, eye cancers (such as intraocular melanoma and retinoblastoma), skin cancers (such as Kaposi’s sarcoma, squamous cell tumors, Merkel cell Skin cancer and non-melanoma skin cancer), renal parenchymal cancer, kidney cancer (also known as renal cell carcinoma and renal adenocarcinoma) and related cancers.
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